Diabetes and the Metabolic Syndrome in Mental Health (I)

As I stated in my goodreads review, ‘If you’re a schizophrenic and/or you have a strong interest in e.g. the metabolic effects of various anti-psychotics, the book is a must-read’. If that’s not true, it’s a different matter. One reason why I didn’t give the book a higher rating is that many of the numbers in there are quite dated, which is a bit annoying because it means you might feel somewhat uncertain about how valid the estimates included still are at this point.

As pointed out in my coverage of the human drug metabolism text there are a lot of things that can influence the way that drugs are metabolized, and this text includes some details about a specific topic which may help to illustrate what I meant by stating in that post that people ‘self-experimenting’ may be taking on risks they may not be aware of. Now, diabetics who need insulin injections are taking a drug with a narrow therapeutic index, meaning that even small deviations from the optimal dose may have serious repercussions. A lot of things influence what is actually the optimal dose in a specific setting; food (“food is like a drug to a person with diabetes”, as pointed out in Matthew Neal’s endocrinology text, which is yet another text I, alas, have yet to cover here), sleep patterns, exercise (sometimes there may be an impact even days after you’ve exercised), stress, etc. all play a role, and even well-educated diabetics may not know all the details.

A lot of drugs also affect glucose metabolism and insulin sensitivity, one of the best known drug types of this nature probably being the corticosteroids because of their widespread use in a variety of disorders, including autoimmune disorders which tend to be more common in autoimmune forms of diabetes (mainly type 1). However many other types of drugs can also influence blood glucose, and on the topic of antidepressants and antipsychotics we actually know some stuff about these things and about how various medications influence glucose levels; it’s not a big coincidence that people have looked at this, they’ve done that because it has become clear that “[m]any medications, in particular psychotropics, including antidepressants, antipsychotics, and mood stabilizers, are associated with elevations in blood pressure, weight gain, dyslipidemias, and/or impaired glucose homeostasis.” (p. 49). Which may translate into an increased risk of type 2 diabetes, and impaired glucose control in diabetics. Incidentally the authors of this text observes in the text that: “Our research group was among the first in the field to identify a possible link between the development of obesity, diabetes, and other metabolic derangements (e.g., lipid abnormalities) and the use of newer, second-generation antipsychotic medications.” Did the people who took these drugs before this research was done/completed know that their medications might increase their risk of developing diabetes? No, because the people prescribing it didn’t know, nor did the people who developed the drugs. Some probably still don’t know, including some of the medical people prescribing these medications. But the knowledge is out there now, and the effect size is in the case of some drugs argued to be large enough to be clinically relevant. In the context of a ‘self-experimentation’-angle the example is also interesting because the negative effect in question here is significantly delayed; type 2 diabetes takes time to develop, and this is an undesirable outcome which you’re not going to spot the way you might link a headache the next day to a specific drug you just started out with (another example of a delayed adverse event is incidentally cancer). You’re not going to spot dyslipidemia unless you keep track of your lipid levels on your own or e.g. develop xanthomas as a consequence of it, leading you to consult a physician. It helps a lot if you have proper research protocols and large n studies with sufficient power when you want to discover things like this, and when you want to determine whether an association like this is ‘just an association’ or if the link is actually causal (and then clarifying what we actually mean by that, and whether the causal link is also clinically relevant and/or for whom it might be clinically relevant). Presumably many people taking all kinds of medical drugs these days are taking on risks which might in a similar manner be ‘hidden from view’ as was the risk of diabetes in people taking second-generation antipsychotics in the near-past; over time epidemiological studies may pick up on some of these risks, but many will probably remain hidden from view on account of the amount of complexity involved. Even if a drug ‘works’ as intended in the context of the target variable in question, you can get into a lot of trouble if you only focus on the target variable (“if a drug has no side effects, then it is unlikely to work“). People working in drug development know this.

The book has a lot of blog-worthy stuff so I decided to include some quotes in the coverage below. The quotes are from the first half of the book, and this part of the coverage actually doesn’t talk much about the effects of drugs; it mainly deals with epidemiology and cost estimates. I thus decided to save the ‘drug coverage’ to a later post. It should perhaps be noted that some of the things I’d hoped to learn from Ru-Band Lu et al.’s book (blog coverage here) was actually included in this one, which was nice.

“Those with mental illness are at higher risk and are more likely to suffer the severe consequences of comorbid medical illness. Adherence to treatment is often more difficult, and other factors such as psychoneuroendocrine interactions may complicate already problematic treatments. Additionally, psychiatric medications themselves often have severe side effects and can interact with other medications, rendering treatment of the mental illness more complicated. Diabetes is one example of a comorbid medical illness that is seen at a higher rate in people with mental illness.”

“Depression rates have been studied and are increased in type 1 and type 2 diabetes. In a meta-analysis, Barnard et al. reviewed 14 trials in which patients with type 1 diabetes were surveyed for rates of depression.16 […] subjects with type 1 diabetes had a 12.0% rate of depression compared with a rate of 3.4% in those without diabetes. In noncontrolled trials, they found an even higher rate of depression in patients with type 1 diabetes (13.4%). However, despite these overall findings, in trials that were considered of an adequate design, and with a substantially rigorous depression screening method (i.e., use of structured clinical interview rather than patient reported surveys), the rates were not statistically significantly increased (odds ratio [OR] 2.36, 95% confidence interval [CI] 0.69–5.4) but had such substantial variation that it was not sufficient to draw a conclusion regarding type 1 diabetes. […] When it comes to rates of depression, type 2 diabetes has been studied more extensively than type 1 diabetes. Anderson et al. compiled a large metaanalysis, looking at 42 studies involving more than 21,000 subjects to assess rates of depression among patients with type 1 versus type 2 diabetes mellitus.18 Regardless of how depression was measured, type 1 diabetes was associated with lower rates of depression than type 2 diabetes. […] Depression was significantly increased in both type 1 and type 2 diabetes, with increased ORs for subjects with type 1 (OR = 2.9, 95% CI 1.6 –5.5, […] p=0.0003) and type 2 disease (OR = 2.9, 95% CI 2.3–3.7, […] p = 0.0001) compared with controls. Overall, with multiple factors controlled for, the risk of depression in people with diabetes was approximately twofold. In another large meta-analysis, Ali et al. looked at more than 51,000 subjects in ten different studies to assess rates of depression in type 2 diabetes mellitus. […] the OR for comorbid depression among the diabetic patients studied was higher for men than for women, indicating that although women with diabetes have an overall increased prevalence of depression (23.8 vs. 12.8%, p = 0.0001), men with diabetes have an increased risk of developing depression (men: OR = 1.9, 95% CI = 1.7–2.1 vs. women: OR = 1.3, 95% CI = 1.2–1.4). […] Research has shown that youths 12–17 years of age with type 1 diabetes had double the risk of depression compared with a teenage population without diabetes.21 This amounted to nearly 15% of children meeting the criteria for depression.

As many as two-thirds of patients with diabetes and major depression have been ill with depression for more than 2 years.44 […] Depression has been linked to decreased adherence to self-care regimens (exercise, diet, and cessation of smoking) in patients with diabetes, as well as to the use of diabetes control medications […] Patients with diabetes and depression are twice as likely to have three or more cardiac risk factors such as smoking, obesity, sedentary lifestyle, or A1c > 8.0% compared with patients with diabetes alone.47 […] The costs for individuals with both major depression and diabetes are 4.5 times greater than for those with diabetes alone.53

“A 2004 cross-sectional and longitudinal study of data from the Health and Retirement Study demonstrated that the cumulative risk of incident disability over an 8-year period was 21.3% for individuals with diabetes versus 9.3% for those without diabetes. This study examined a cohort of adults ranging in age from 51 to 61 years from 1992 through 2000.”

Although people with diabetes comprise just slightly more than 4% of the U.S. population,3 19% of every dollar spent on health care (including hospitalizations, outpatient and physician visits, ambulance services, nursing home care, home health care, hospice, and medication/glucose control agents) is incurred by individuals with diabetes” (As I noted in the margin, these are old numbers, and prevalence in particular is definitely higher today than it was when that chapter was written, so diabetics’ proportion of the total cost is likely even higher today than it was when that chapter was written. As observed multiple times previously on this blog, most of these costs are unrelated to the costs of insulin treatment and oral anti-diabetics like metformin, and indirect costs make out a quite substantial proportion of the total costs).

In 1997, only 8% of the population with a medical claim of diabetes was treated for diabetes alone. Other conditions influenced health care spending, with 13.8% of the population with one other condition, 11.2% with two comorbidities, and 67% with three or more related conditions.6 Patients with diabetes who suffer from comorbid conditions related to diabetes have a greater impact on health services compared with those patients who do not have comorbid conditions. […] Overall, comorbid conditions and complications are responsible for 75% of total medical expenditures for diabetes.” (Again, these are old numbers)

“Heart disease and stroke are the largest contributors to mortality for individuals with diabetes; these two conditions are responsible for 65% of deaths. Death rates from heart disease in adults with diabetes are two to four times higher than in adults without diabetes. […] Adults with diabetes are more than twice as likely to have multiple diagnoses related to macrovascular disease compared to patients without diabetes […] Although the prevalence of cardiovascular disease increases with age for both diabetics and nondiabetics, adults with diabetes have a significantly higher rate of disease. […] The management of macrovascular disease, such as heart attacks and strokes, represents the largest factor driving medical service use and related costs, accounting for 52% of costs to treat diabetes over a lifetime. The average costs of treating macrovascular disease are $24,330 of a total of $47,240 per person (in year 2000 dollars) over the course of a lifetime.17 Moreover, macrovascular disease is an important determinant of cost at an earlier time than other complications, accounting for 85% of the cumulative costs during the first 5 years following diagnosis and 77% over the initial decade. [Be careful here: This is completely driven by type 2 diabetics; a 10-year old newly diagnosed type 1 diabetic does not develop heart disease in the first decade of disease – type 1s are also at high risk of cardiovascular disease, but the time profile here is completely different] […] Cardiovascular disease in the presence of diabetes affects not only cost but also the allocation of health care resources. Average annual individual costs attributed to the treatment of diabetes with cardiovascular disease were $10,172. Almost 51% of costs were for inpatient hospitalizations, 28% were for outpatient care, and 21% were for pharmaceuticals and related supplies. In comparison, the average annual costs for adults with diabetes and without cardiovascular disease were $4,402 for management and treatment of diabetes. Only 31.2% of costs were for inpatient hospitalizations, 40.3% were for outpatient care, and 28.6% were for pharmaceuticals.16

Of individuals with diabetes, 2% to 3% develop a foot ulcer during any given year. The lifetime incidence rate of lower extremity ulcers is 15% in the diabetic population.20 […] The rate of amputation in individuals with diabetes is ten times higher than in those without diabetes.5 Diabetic lower-extremity ulcers are responsible for 92,000 amputations each year,21 accounting for more than 60% of all nontraumatic amputations.5 The 10-year cumulative incidence of lower-extremity amputation is 7% in adults older than 30 years of age who are diagnosed with diabetes.22 […] Following amputation, the 5-year survival rate is 27%.23 […] The majority of annual costs associated with treating diabetic peripheral neuropathy are associated with treatment of ulcers […] Overall, inpatient hospitalization is a major driver of cost, accounting for 77% of expenditures associated with individual episodes of lower-extremity ulcers.24

By 2003, diabetes accounted for 37% of individuals being treated for renal disease in the United States. […] Diabetes is the leading cause of kidney failure, accounting for 44% of all newly diagnosed cases. […] The amount of direct medical costs for ESRD attributed to diabetes is substantial. The total adjusted costs in a 24-month period were 76% higher among ESRD patients with diabetes compared with those without diabetes. […] Nearly one half of the costs of ESRD are due to diabetes.27” [How much did these numbers change since the book was written? I’m not sure, but these estimates do provide some sort of a starting point, which is why I decided to include the numbers even though I assume some of them may have changed since the publication of the book]

Every percentage point decrease in A1c levels reduces the risk of microvascular complications such as retinopathy, neuropathy, and nephropathy by 40%.5 However, the trend is for A1c to drift upward at an average of 0.15% per year, increasing the risk of complications and costs.17 […] A1c levels also affect the cost of specific complications associated with diabetes. Increasing levels affect overall cost and escalate more dramatically when comorbidities are present. A1c along with cardiovascular disease, hypertension, and depression are significant independent predictors of health care
costs in adults with diabetes.”

August 10, 2016 Posted by | Books, Cardiology, Diabetes, Economics, Epidemiology, Medicine, Nephrology, Pharmacology, Psychiatry | Leave a comment

Eating disorders… (I)

“Dermatologists have an important role in the early diagnosis of eating disorders since skin signs are, at times, the only easily detectable symptoms of hidden anorexia and bulimia nervosa. Forty cutaneous signs have been recognized”

The full title of the book is Eating Disorders and the Skin, but there’s a lot of stuff about eating disorders in general in this book as well, and I figured I’d mostly focus on the ‘general stuff’ in this post. Here’s my goodreads review of the book, which I gave 3 stars.

Here are the DSM-IV-TR diagnostic criteria for anorexia nervosa:

“1. Refusal to maintain body weight at or above a minimally normal weight for age and height (e.g., weight loss leading to maintenance of body weight less than 85% of that expected, or failure to make expected weight gain during period of growth, leading to body weight less than 85% of that expected).

2. Intense fear of gaining weight or becoming fat even though underweight.

3. Disturbance in the way in which one’s body weight or shape is experienced, undue influence of body weight or shape on self-evaluation, or denial of the seriousness of the current low body weight.

4.4. In postmenarcheal females, amenorrhea, i.e., the absence of at least three consecutive menstrual cycles.”

Interestingly, aside from anorexia [-AN] and bulimia [-BN] (diagnostic criteria here), there’s also a big category called ED-NOS – Eating Disorder Not Otherwise Specified. That’s for cases that don’t really fit into the standard criteria for specific eating disorders; they note than an example of this type could be a female fitting all diagnostic criteria for AN except that she has regular menses. It is perhaps worth mentioning here that surprisingly enough (…to me), menstrual irregularities are not limited to cases of AN, thus: “In almost 50% of bulimic patients, menstrual irregularities, such as oligomenorrhea or amenorrhea, take place”. They note in the book that there’s been some concern about the validity of the ED-NOS category, which makes up almost 60% of patients with an eating disorder. Eating disorders are much more common in females than in males (“Males are generally reported to account for 5–10% of anorectics and 10–15% of bulimics identified in the general population”), and particular subgroups mentioned to be at high risk are athletes, models and dancers. It’s noted in the book that most epidemiological studies are conducted in high-risk settings, whereas epidemiological studies assessing risk in the general population are somewhat rarer. One problem complicating matters a little in terms of estimating risk is that an eating disorder cannot be diagnosed through a self-report questionnaire; you need a structured or semi-structured interview to make a diagnosis, which makes things more expensive. As in other contexts one way to get around this issue, at least to some extent, is to employ multi-step screening protocols – in this case a two-step procedure in which individuals at high risk are identified at the first step through inexpensive means, and these individuals are then later assessed more carefully in the second step, employing more accurate (and expensive) methods.

They note that in Western countries, point prevalence of AN in female adolescent (the highest risk sub-group) is estimated at 0.2-1% of the population, whereas the prevalence studies on bulimia nervosa indicates that this eating disorder is somewhat more common, with the majority of studies finding prevalences of 1.5-5%; do recall again that most studies as already mentioned look at high-risk subgroups, so total population prevalence is likely to be lower than this. They observe in the book that general-practice studies find that the incidence of anorexia nervosa is less than one in ten-thousand per year (8 per 100,000 per year); so full-blown AN certainly is likely quite rare in low-risk populations.

On lifetime risk, the book notes that:

“Most of the epidemiological studies on ED [eating disorders] have evaluated the prevalence of full syndromes of both AN [anorexia nervosa] and BN [bulimia nervosa]. The few studies that have evaluated partial or subclinical manifestations of EDs in young females, however, found lifetime prevalence rates of 5–12% for atypical AN and 1–4.8% for atypical BN and up to 14.6% in adolescent samples”.

A review of epidemiological studies concluded that there’s no evidence of either a secular increase in AN or BN over time; to the extent that the number of people with diagnosed BN has increased over time, changes in diagnostic and referral practices likely account for this. On a related topic it is noted in the book that “It is a common idea among clinicians that early-onset cases of anorexia nervosa (AN) are increasing, but few data in the literature are available to demonstrate this trend.”

AN most commonly present among females at the age of 15-19, whereas BN presents a little later, most commonly at the age of 20-24. But eating disorders are not limited to teenagers and young adults: “Even if anorexia nervosa and bulimia nervosa occur characteristically in females during adolescence and young adulthood, there have been case reports of illness beginning after the age of 25 and even after the menopause, and some authors suggest that the rates of eating disorders in older patients may be increasing [2]. Clinical impression suggests that the late-onset cases present with more depressive features than the adolescent counterpart. […] dieting is considered one of the most salient precipitating factors.”

Self-report metrics can only help you so much when you’re trying to assess risk; a major problem in this context is that denial of illness is a very common feature in these patient populations (so you certainly can’t just ask people if their relationship with food/exercise etc. might be unhealthy…): “typically, [the] course [of an eating disorder] is characterized by a high fluidity between the diagnostic classes; furthermore, the patient often denies even to himself the psychiatric nature of the disease” (recall also that “denial of the seriousness of the current low body weight” is included in the diagnostic criteria). The book covers a lot of symptoms which relate to low body weight – like cold intolerance, bradycardia (slow heart rate), acrocyanosis (bluish discoloration of the hands and feet, caused by slow circulation), systemic hypotension (low blood pressure), lots of skin signs (I haven’t decided yet how much detail I’ll go into, so let’s leave it at that now) – or e.g. to purging behaviours (throat and tooth pain due to vomiting and enamel erosion), but it would go much too far to discuss all these in detail here. One to me interesting aspect of the coverage was that whereas BMI is a useful sign, it’s not itself a diagnostic criterion; the authors note that a BMI below 18.5 is considered pathological, but when listing main signs of anorexia nervosa the most important diagnostic sign (or at least the first one listed) is a BMI below 17.5; I assume part of the discussion surrounding the validity of the ED-NOS category probably relate to individuals who’re in this ‘border area’; they likely have some symptoms due to low body mass (like e.g. cold intolerance), but they don’t have full-blown AN (there are a lot of things that can go wrong when you have low body mass – there are a lot of symptoms described in this book!). It’s also important to note that very different symptom patterns can be present at similar levels of BMI, as the severity of symptoms also relate to how fast body mass decreases – the body is actually capable of adjusting quite well to lower energy intake states (in the short run at least), and so “if weight loss is gradual, it is possible to maintain, even for a long time, an apparent metabolic equilibrium.”

Anorexics have high mortality rates: “From a meta-analysis of 119 studies involving 5,590 patients, Steinhausen reported a crude mortality rate of 5% which exceeded 9% in a followup of 10 years.” Remember when thinking about those estimates that most of the people in these studies were likely young women – these numbers are high, and the authors note that anorexia nervosa “represents the major cause of death of young women in the age between 12 and 25 years.”

Most deaths are due to ventricular arrhythmia; the book goes into some detail about how anorexia affects the cardiovascular system, but I won’t discuss this in detail. An important observation is that: “Cardiac findings tend to disappear with weight recovery.” I assume this comment relates mostly to findings like QTc prolongation, QTc dispersion, and mitral valve prolapse, all of which are found in anorexics, whereas I’d be surprised if cardiac abnormalities related to direct damage to the heart muscle resolve themselves after weight gain, but the book does not go into details on this topic, except in the sense that it is noted that heart failure is uncommon in anorexics. Among those who survive their illness, osteoporosis is a major irreversible long-term problem. People with higher body mass tend to have a higher bone mineral density and thus a lower risk of osteoporosis (unless they get type 2 diabetes, in which case the situation is, well, complicated), so perhaps it’s not really surprising that women with AN and very low body mass index tend to develop osteoporosis. They certainly do:

“Osteopenia and osteoporosis represent one of the most relevant and potentially not reversible complications of eating disorders. This complication is particularly severe when eating disorders have an early onset […] Bone loss is an early effect of the disease, already present after 6–12 months […] In untreated patients, bone loss ranges from 4% up to 10% per year […]. In case of recovery, the progressive loss of BMD [bone mineral density] stops, but in most cases, a normal bone mass is not restored [64].”

It’s noted that bone loss is due to both hormonal and metabolic factors; estrogen plays a role, and “BMD loss in AN is more rapid and severe than in other hypoestrogenic conditions”. Despite this observation weight gain is considered the primary treatment modality of osteoporosis in this context (i.e., not estrogen therapy), and research using estrogen therapy to try to boost bone mineral density in anorexics who did not also gain weight has not been successful.

A to me interesting aspect of the coverage which I could not help but discuss here is how eating disorders relate to diabetes; the book has a few remarks on this topic:

“The concurrence of an eating disorder with insulin-dependent diabetes has been outlined by several researchers: especially bulimia nervosa and disorder not otherwise specified (EDNOS) are reported to be significantly higher in females with type 1 diabetes […] In case of comorbidity, ED onset followed the diagnosis of IDDM in 70% of the patients [10]. Specific aspects of diabetes and its management could, in fact, potentially increase a particular susceptibility to the development of an eating disorder: weight gain, associated with initiation of insulin treatment and dietary restraint, might, in fact, trigger body dissatisfaction and the drive for thinness with consequent weight control behaviors ranging from healthy to very unhealthy behaviors […] insulin omission [is] a common weight loss behavior in girls with IDDM and eating disorder […] APA Guidelines 2006 suggest that insulin omission should be considered a specific type of purging behavior in the next DSM revision”.

I don’t know if this suggested change has been implemented at this point, but it would make a lot of sense. To people who don’t know what this ‘insulin omission’ they talk about is all about, the short version is that if you’re a type 1 diabetic in need of regular insulin injections, if you don’t take enough insulin you lose weight and you can eat pretty much whatever you like without gaining weight; which is of course an unfortunate though likely very attractive option for young women to have. The downside of engaging in systematic insulin omission behaviour of that kind is that you’ll likely go blind from your diabetes and/or die of kidney failure or DKA if you do that for an extended period of time.

January 2, 2016 Posted by | Books, Diabetes, Epidemiology, Medicine, Psychology | 4 Comments

Diabetic Bone Disease

This is an excellent book. I decided to include in this post the entire book description included on goodreads, even if it’s somewhat long, because I thought the description gave a good overview of the topics covered in this book:

“Providing the most up-to-date research and current clinical knowledge of diabetic bone disease and the challenges still facing the research and clinical care communities, this book unites insights from endocrinology and orthopedics to create a truly unique text. The first part covers clinical and pre-clinical applications and research. The first two chapters present the clinical and epidemiological data about diabetic bone disease, evaluated and reviewed for type 1 and type 2, respectively. This is followed by discussions of how the propensity to fracture in diabetic bone disease can impact fracture risk assessments and how it can be adjusted for using current clinically relevant fracture risk models. A comprehensive overview of orthopedic complications observed in diabetes is next, as well as a focus on the consequences of diabetes on periodontal disease. Other topics include the utility of skeletal biomarkers in assessing diabetic bone disease, how drugs used to treat diabetes may also have skeletal consequences, and the possibility that diabetes may fundamentally impact early progenitor cells of various bone lineages and thus globally impact bone. The second part covers biomechanics and bone quality in diabetes: how diabetes ultimately may impact the architecture, integrity, and quality of bone. Utilizing the expertise of top researcher and clinicians in diabetic bone disease in one comprehensive text, this volume will be a useful and thought-provoking resource for endocrinologists and orthopedic surgeons alike.”

I would note that the book is also a useful and thought-provoking resource if you’re just a random diabetic who happens to know enough about medicine and related topics to make sense of a book like this one – i.e. if you’re someone like me. A few related observations from the book’s preface:

“Historically, most attention has been focused on four major complications known to afflict many individuals with T1DM and T2DM: retinopathy, neuropathy, nephropathy, and cardiovascular disease. However, epidemiological data now show that other tissues and organs may be significantly impacted by the diabetic state—and the skeletal system is now emerging as a primary target of diabetes-mediated damage (i.e., diabetic bone disease).
Studies have demonstrated that osteopenia and osteoporosis may be frequent complications of T1D, both in children and adults, and that T1D is associated with decreased bone density and increased fracture risk. In contrast to T1D, T2D has typically not been associated with osteopenia or osteoporosis and, in fact, has been more often associated with increased BMD [bone mineral density]. However, newer data show that bone quality and bone microarchitecture may be compromised in both conditions, suggesting that underlying mechanisms related to increased risk to fracture may be contributory to both forms of diabetes.
In this volume, we provide the reader with up-to-date information about what is currently known about diabetic bone disease and what are the challenges still facing the research and clinical care communities.”

This was a topic about which I knew next to nothing, and one of emotional responses I had early on to some of the coverage in the book was to think along the lines of: ‘Ah, type 1 diabetes, the gift that keeps on giving…’ or perhaps: ‘How was I not told this???’ It reminded me a bit of how I felt back when I realized some years ago that my diabetes was probably also messing with my lungs, without me knowing about it and despite nobody having told me anything about that (for details on that topic, see e.g. this paper). As far as I can remember, bone health has never come up during conversations I have had over the years in the past with endocrinologists or diabetes nurses, nor has it ever been discussed in detail in publications I’ve read on diabetes-related topics; the closest I’ve got has probably been remarks about individuals developing diabetics during childhood being slightly shorter than non-diabetics on average, due to (non-specific) disease-related adverse effects on growth during childhood. Relevant mechanisms have not been discussed in any detail, and actually what I had read on the topic of diabetes and growth had basically lead me to believe that a slight growth disadvantage was really all there was to this topic, as a potential interaction between diabetes status and osteoporosis risk was never touched upon in these publications. To give a great illustrative example, Sperling et al.‘s comprehensive textbook (~600 pages) about type 1 diabetes includes exactly 3 hits for osteoporosis in the text, all of which relate to very specific subtopics and none of which even remotely relate to the highly increased risk of fractures which type 1 diabetes in particular confers – the authors of that text clearly had no idea that type 1 diabetes dramatically increases the risk of fractures and poor bone health; there are zero indications to the contrary. It’s probably not uncommon to see important information in textbooks which people forget about in clinical practice (perhaps because the people working in clinical practice read different textbooks, in which this information was not included…), but it’s certainly less common to see important information not included in textbooks because the textbook authors simply don’t know about them. It seems highly likely to me that a lot of health care providers involved in diabetes care currently do not know anything about the topics discussed in this publication; I hope this state of affairs will change in the future.

As also noted in the comments above, the relationship between diabetes and bone health is complicated and interacts with type; type 1 seems to be much worse for the bones than is type 2, and the relationship between in particular type 2 diabetes and bone health is not at all simple. Type 2 diabetics tend to have both some elevated non-diabetes-related risk factors for fractures (in one chapter the authors thus list in that category obesity, reduced muscle quality, poor balance, and falls – e.g. but not only hypoglycemia-related) and some diabetes-specific risk factors ((/very) poor glycemic control probably increases risk (but see also below), duration of disease increases risk, medications – e.g. the thiazolidinedione drug class used to treat type 2 diabetes), but these don’t fully account for the increased risk.

Most of the standard metrics used to assess fracture risk, such as FRAX, do not take diabetes status into account, which is a problem – “studies indicate that FRAX systematically underestimates fracture risk in patients with T2DM” (this problem is not just related to FRAX, thus elsewhere in the publication it is noted more generally that: “fracture prediction tools underestimate fracture risk in diabetes”). The only one of the widely used risk assessment tools which does take diabetes status into account is the QFracture tool, but this tool “has not been specifically evaluated with regard to calibration in individuals with diabetes”; so there is a lot of uncertainty here. This state of affairs is of course hardly ideal, especially not considering how the number of type 2 diabetics is projected to increase over time in the years to come. It is worth keeping in mind that the total population prevalence of type 2 can be deceiving people here into thinking this is less of a problem than it really is, as most people at increased risk of fractures are old people, and type 2 incidence/prevalence increases with age: “Type 2 diabetes affects over 25 % of older adults in the United States, including diagnosed and undiagnosed cases [11].” The hip fracture estimates included in Vestergaard’s meta-review discussed below indicate a relative risk of hip-fracture of ~1.4 in the type 2 diabetic sub-population, and if you multiply that number by the 25% prevalence among elderly people in the US, that’s more than a third of all fractures in older adults. That’s a lot of people, and a lot of risk not well accounted for.

A problem related to the above observations in the context of type 2 diabetes (and most of the research that has been done in this area has been done on type 2 diabetes, for reasons which should be obvious (“type 1 diabetes mellitus (T1D) accounts for dual-energy X-ray absorptiometry (DXA), a standard way to measure bone mineral density also used to diagnose osteoporosis, does not ‘pick up on’ the excess risk associated with T2DM; in type 2 individuals risk is elevated even when taking DXA measurements into account (this fact may actually be one argument why the QFracture tool may not be bad at all to apply to people in this patient subgroup; QFracture does not include DXA numbers, and if a substantial proportion of the risk is unrelated to the DXA estimates in type 2 anyway then maybe they’re not that important to include). The arguably poor performance of DXA in the context of fracture risk in type 2 diabetes have lead to the development of other tools which might be better at assessing risk in this patient population, and the authors of some of the later chapters of the book talk in some detail about these tools and the results derived from related studies using these tools. It should perhaps be noted in the context of DXA and bone mineral density numbers that one of the clear differences between type 1 and type 2 here is that bone mineral density tends to be decreased in type 1 diabetes, whereas it’s usually if anything increased in type 2 (but the increased, or at least not lowered, bone mineral density in type 2 does not translate into a lower risk of fracture; risk is still elevated, which is what is surprising and not easy to fully account for).

An interesting aspect of the coverage was that the relationship between glycemic control and bone health seems to not be completely clear; to me the coverage of this topic throughout the various chapters (many chapters cover closely related topics and there’s some coverage overlap, but I didn’t mind this at all) reminded much more of the typical coverage you see in publications discussing how the risk of macrovascular complications relate to glycemic control (…’it’s complicated’) than it reminded me of how the risk of microvascular complications relate to glycemic control (…’hyperglycemia increases risk and there’s a dose-response relationship between complication risk and the level of hyperglycemia’). One problem is that low Hba1c may increase the fall risk because of an increased risk of hypoglycemic episodes, increasing risk at the lower end of the spectrum.

The book has a lot of stuff about the specifics of what might be going on at the cellular level and so on, but I won’t talk much about that here even if I found it interesting (it would take a lot of time to go over the details here); one key point to take take away from that part of the coverage should however be mentioned here, and that is that that stuff thoroughly convinced me that there’s no way the increased fracture risks observed in the various epidemiological studies presented at the beginning of the publication are flukes. There are good reasons to think that diabetes may be bad for the bones, quite aside from the reason that they seem to break their bones more often than other people do.

I have included some data and key observations from the book below. As the post is rather long I decided to highlight/bold a few of the most important observations (they’re not bolded in the book).

In patients with T1D, an increased incidence of osteopenia and osteoporosis has been recognized for over three decades [10–14], occurring not only in adults, but in children as well [15–17]. Many more recent studies have since validated these early findings, demonstrating a reduced bone mineral density (BMD) in T1D [18–22]. Clinical factors associated with lower bone density include: male gender […]; longer duration of disease […]; younger age at diagnosis […]; lower endogenous insulin or C-peptide levels [27]; low body mass index (BMI) […]; and possibly the presence of chronic diabetes comorbidities or associated autoimmunity [29]. Some studies also suggest that greater longitudinal decrements in BMD occur over time in males [24]. […] In most studies, poor glycemic control does not seem to be strongly associated with a reduced BMD [18–20, 22, 23, 30, 31] […] T1D is […] associated with an increased risk for fracture, higher than the risk in type 2 diabetes (T2D)”

among risk factors for hip fracture in >33,000 middle-aged adults in Sweden (~25–60 years), the strongest risk factor for both women […] and men […] was diabetes [49], suggesting that the presence of diabetes was a major risk determinant for this age group. Similar findings had been reported years before in middle-aged Norwegian women and men […] Together, [studies conducted during the last 15 years on type 1 diabetics] demonstrate an unequivocally increased fracture risk at the hip [compared to non-diabetic controls], with most demonstrating a six to ninefold increase in relative risk. […] type I DM patients have hip fractures at a younger age on average, with a mean of 43 for women and 41 for men in one study. Almost 7 % of people with type I DM can be expected to have sustained a hip fracture by age 65 [7] […] Patients with DM and hip fracture are at a higher risk of mortality than patients without DM, with 1-year rates as high as 32 % vs. 13 % of nondiabetic patients […] Though only a very few studies have examined fracture risk at other skeletal sites [51, 54], an increased risk for vertebral fracture is also a consistent finding in studies that have quantified this. […] in one study, an approximate threefold increase in risk for all non-vertebral fractures was reported in men with T1D”.

“studies […] suggest that cumulative changes in bone architecture are beginning early in childhood, particularly in those diagnosed with T1D at very young ages [73]. Compared with nondiabetic children, reductions in BMD [68, 74–78] and bone size, specifically total cross-sectional area (CSA) [73, 79] and cortical area [15, 80], are relatively consistent findings. […] As a whole, […] studies suggest that systemic markers of bone formation in T1D are generally indicative of a condition in which bone formation is reduced. […] Taken together, it would appear that T1D is characterized best as a state of inappropriately lowered bone turnover which exists in conjunction with relative osteoblast dysfunction [90] and, hence, low bone formation […] serum AGE concentrations are clearly elevated in T1D during childhood [138], even during preschool and prepubertal years […] skin AGEs […] are increased in children with both T1D and T2D, to the extent that “approximately 4–6 years of diabetes exposure in some children may be sufficient to increase skin AGEs to levels that would naturally accumulate only after ~25 years of chronological aging””.

“diabetic bone has a greater propensity for fracture than is predicted by BMD […] A role for the skeletal accumulation of advanced glycation end products […], chronic hyperglycemia [30], oxidative stress [63], and microarchitectural bone defects [64] have all been proposed, and it is expected that the pathological mechanisms leading to bone fragility in T1D are multifactorial […] Beyond fragility fractures, other skeletal complications also occur disproportionately in persons with T1D, including fracture-healing complications (nonunion, malunion) [66], Charcot osteoarthropathy [67], osteomyelitis, and diabetic foot syndrome.”

“In orthopaedics, patients with diabetes have a number of associated disorders, and these present a challenge as many have an increased hospital stay, higher risk of infection, and higher risk of complications after orthopaedic treatment. The orthopaedic-related problems in diabetes are varied, and the true causal links between diabetes and the disorders are largely unknown. […] The incidence of trigger finger [/stenosing tenosynovitis] is 7–20 % of patients with diabetes comparing to only about 1–2 % in nondiabetic patients […] The prevalence of [carpal tunnel syndrome, CTS] in patients with diabetes has been estimated at 11–30 % [130, 133, 153, 156], and is dependent on the duration of diabetes. […] Type I DM patients have a high prevalence of CTS with increasing duration of disease, up to 85 % after 54 years of DM. However the prevalence does not seem to be associated with glycemic control”

“Diabetes increases the severity and risk of periodontitis, the most common lytic disease of bone and a frequent complication of diabetes […] The risk of periodontitis is increased approximately 2–4 times in diabetic versus nondiabetic subjects [4, 47]. In one study, periodontitis was found in 60 % of T1DM patients compared to 15 % without diabetes [48]. Patients with diabetes are at higher risk of severe periodontitis compared with nondiabetic subjects […] There is a direct link between persistent hyperglycemia, an exaggerated inflammatory response to periodontal pathogens and periodontal bone loss”.

Because diabetic bone disease in type 1 diabetes represents a deficit in osteoblast function and bone formation, antiresorptive therapies for osteoporosis (e.g., bisphosphonates, denosumab) may be ineffective in this form of secondary osteoporosis […] Calcium and vitamin D supplementation […] is considered standard-of-care for osteoporosis treatment [162]. Nonetheless, 1 year of calcitriol supplementation in young adults with recent-onset T1D did not significantly change circulating markers of bone turnover […] very little information from comparative effectiveness studies is available on the treatment of osteoporosis in T1D.”

Type 2 does not increase risk nearly as much as does type 1:

“In 2007 Vestergaard published a meta-analysis of hip fracture results that included eight studies and reported an age-adjusted summary relative risk for hip fracture of 1.38 (1.25–1.53), comparing those with and without T2D [14]. This increase in fracture risk with T2D occurred in spite of higher bone density in those with T2D. […] Most [15–21], but not all [22, 23], subsequent studies have reported increased rates of hip fracture with T2D in age-adjusted models. […] Evidence that more frequent falls do not fully account for increased fracture risk with T2D […], combined with evidence from rodent models [55], has led to the conclusion that diabetic bone is more fragile for a given BMD. Understanding the aspects of bone that are affected by diabetes and that result in fragile bone has been an important focus of research on diabetes and skeletal health.”

The effect of glycemic control on fracture risk, BMD, and falls remains poorly understood and controversial.

“Diabetic patients with multiple complications appear to be at higher risk of fracture, but results are mixed for the association between specific complications and fracture.”

“Our current understanding of the pathogenesis of skeletal fragility in [type 2] diabetes suggests a working model […], whereby poor glucose control in patients with T2DM leads to increases in AGEs that have negative effects on osteoblasts, which in turn causes a reduction in bone formation. This defect in bone formation subsequently results in low bone turnover in T2DM patients, which prolongs the lifespan of type I collagen in bone, thereby leaving it particularly vulnerable to damage from increased AGEs. Ultimately, this creates a “vicious cycle” that may contribute to reduced bone quality and increased fracture risk in patients with T2DM.”

As for an overall assessment of the book, I gave the book five stars on goodreads, because it’s basically to a significant extent written the way I’d like Springer publications like this one to be written. The language in one chapter (out of 11) was slightly sub-optimal, but aside from that chapter every single chapter was in my opinion well written, some of them very well written. Frequent discussions of the results of meta-analyses were included in the book. The authors seemed in general to be aware of potential problems with specific interpretations and to me seemed cautious about drawing strong conclusions from the data they had at hand; in terms of the analytical level of the coverage the publication for example included comments about problems with confounding by indication in cross section analyses. There were a couple of places in one of the later chapters where it was slightly difficult for me to figure out ‘what was going on’, but the coverage included in the next chapter of the book clarified these issues; I was not willing to subtract a star because of that.

December 3, 2015 Posted by | Books, Diabetes, Epidemiology, Medicine | Leave a comment

Effects of Antidepressants

I gave the book two stars on goodreads. The contributors to this volume are from Brazil, Spain, Mexico, Japan, Turkey, Denmark, and the Czech Republic; the editor is from Taiwan. In most chapters you can tell that the first language of these authors is not English; the language is occasionally quite bad, although you can usually tell what the authors are trying to say.

The book is open access and you can read it here. I have included some quotes from the book below:

“It is estimated that men and women with depression are 20.9 and 27 times, respectively, more likely to commit suicide than those without depression (Briley & Lépine, 2011).” [Well, that’s one way to communicate risk… See also this comment].

“depression is on average twice as common in women as in men (Bromet et al., 2011). […] sex differences have been observed in the prevalence of mental disorders as well as in responses to treatment […] When this [sexual] dimorphism is present [in rats, a common animal model], the drug effect is generally stronger in males than in females.”

“Several reports indicate that follicular stimulating and luteinizing hormones and estradiol oscillations are correlated with the onset or worsening of depression symptoms during early perimenopause […], when major depressive disorder incidence is 3-5 times higher than the male matched population of the same [age] […]. Several longitudinal studies that followed women across the menopausal transition indicate that the risk for significant depressive symptoms increases during the menopausal transition and then decreases in […] early postmenopause […] the impact of hormone oscillations during perimenopause transition may affect the serotonergic system function and increase vulnerability to develop depression.”

“The use of antidepressant drugs for treating patients with depression began in the late 1950s. Since then, many drugs with potential antidepressants have been made available and significant advances have been made in understanding their possible mechanisms of action […]. Only two classes of antidepressants were known until the 80’s: tricyclic antidepressants and monoamine oxidase inhibitors. Both, although effective, were nonspecific and caused numerous side effects […]. Over the past 20 years, new classes of antidepressants have been discovered: selective serotonin reuptake inhibitors, selective serotonin/norepinephrine reuptake inhibitors, serotonin reuptake inhibitors and alpha-2 antagonists, serotonin reuptake stimulants, selective norepinephrine reuptake inhibitors, selective dopamine reuptake inhibitors and alpha-2 adrenoceptor antagonists […] Neither the biological basis of depression […] nor the precise mechanism of antidepressant efficacy are completely understood […]. Indeed, antidepressants are widely prescribed for anxiety and disorders other than depression.”

“Taken together the TCAs and the MAO-Is can be considered to be non-selective or multidimensional drugs, comparable to a more or less rational polypharmacy at the receptor level. This is even when used as monotherapy in the acute therapy of major depression. The new generation of selective antidepressants (the selective serotonin reuptake inhibitors (SSRIs)), or the selective noradrenaline and serotonin reuptake inhibitors (SNRIs) have a selective mechanism of action, thus avoiding polypharmacy. However, the new generation antidepressants such as the SSRIs or SNRIs are less effective than the TCAs. […] The most selective second generation antidepressants have not proved in monotherapy to be more effective on the core symptoms of depression than the first generation TCAs or MAOIs. It is by their safety profiles, either in overdose or in terms of long term side effects, that the second generation antidepressants have outperformed the first generation.”

“Suicide is a serious global public health problem. Nearly 1 million individuals commit suicide every year. […] Suicide […] ranks among the top 10 causes of death in every country, and is one of the three leading causes of death in 15 to 35-year olds.”

“Considering patients that commit suicide, about half of them, at some point, had contact with psychiatric services, yet only a quarter had current or recent contact (Andersen et al., 2000; Lee et al., 2008). A study conducted by Gunnell & Frankel (1994) revealed that 20-25% of those committing suicide had contact with a health care professional in the week before death and 40% had such contact one month before death” (I’m assuming ‘things have changed’ during the last couple of decades, but it would be interesting to know how much they’ve changed).

“In cases of suicide by drug overdose, TCAs have the highest fatal toxicity, followed by serotonin and noradrenalin reuptake inhibitors (SNRIs), specific serotonergic antidepressants (NaSSA) and SSRIs […] SSRIs are considered to be less toxic than TCAs and MAOIs because they have an extended therapeutic window. The ingestion of up to 30 times its recommended daily dose produces little or no symptoms. The intake of 50 to 70 times the recommended daily dose can cause vomiting, mild depression of the CNS or tremors. Death rarely occurs, even at very high doses […] When we talk about suicide and suicide attempt with antidepressants overdose, we are referring mainly to women in their twenties – thirties who are suicide repeaters.”

“Physical pain is one of the most common somatic symptoms in patients that suffer depression and conversely, patients suffering from chronic pain of diverse origins are often depressed. […] While […] data strongly suggest that depression is linked to altered pain perception, pain management has received little attention to date in the field of psychiatric research […] The monoaminergic system influences both mood and pain […], and since many antidepressants modify properties of monoamines, these compounds may be effective in managing chronic pain of diverse origins in non-depressed patients and to alleviate pain in depressed patients. There are abundant evidences in support of the analgesic properties of tricyclic antidepressants (TCAs), particularly amitriptyline, and another TCA, duloxetine, has been approved as an analgesic for diabetic neuropathic pain. By contrast, there is only limited data regarding the analgesic properties of selective serotonin reuptake inhibitors (SSRIs) […]. In general, compounds with noradrenergic and serotonergic modes of action are more effective analgesics […], although the underlying mechanisms of action remain poorly understood […] While the utility of many antidepressant drugs in pain treatment is well established, it remains unclear whether antidepressants alleviate pain by acting on mood (emotional pain) or nociceptive transmission (sensorial pain). Indeed, in many cases, no correlation exists between the level of pain experienced by the patient and the effect of antidepressants on mood. […] Currently, TCAs (amitriptyline, nortriptiline, imipramine and clomipramine) are the most common antidepressants used in the treatment of neuropathic pain processes associated with diabetes, cancer, viral infections and nerve compression. […] TCAs appear to provide effective pain relief at lower doses than those required for their antidepressant effects, while medium to high doses of SNRIs are necessary to produce analgesia”. Do keep in mind here that in a neuropathy setting one should not expect to get anywhere near complete pain relief with these drugs – see also this post.

“Prevalence of a more or less severe depression is approximately double in patients with diabetes compared to a general population [for more on related topics, see incidentally this previous post of mine]. […] Diabetes as a primary disease is typically superimposed by depression as a reactive state. Depression is usually a result of exposure to psycho-social factors that are related to hardship caused by chronic disease. […] Several studies concerning comorbidity of type 1 diabetes and depression identified risk factors of depression development; chronic somatic comorbidity and polypharmacy, female gender, higher age, solitary life, lower than secondary education, lower financial status, cigarette smoking, obesity, diabetes complications and a higher glycosylated hemoglobin [Engum, 2005; Bell, 2005; Hermanns, 2005; Katon, 2004]”

November 11, 2015 Posted by | Books, Diabetes, Epidemiology, Medicine, Pharmacology, Psychiatry, Psychology | Leave a comment

Oxford Handbook of Clinical Medicine (II)

Here’s my first post about the book. I’ve read roughly 75% of the book at this point (~650 pages). The chapters I’ve read so far have dealt with the topics of: ‘thinking about medicine’ (an introductory chapter), ‘history and examination’, cardiovascular medicine, chest medicine, endocrinology, gastroenterology, renal medicine, haematology, infectious diseases, neurology, oncology and palliative care, rheumatology, and surgery (this last one is a long chapter – ~100 pages – which I have not yet finished). In my first post I (…mostly? I can’t recall if I included one or two observations made later in the coverage as well…) talked about observations included in the first 140 pages of the book, which relate only to the first three topics mentioned above; the chapter about chest medicine starts at page 154. In this post I’ll move on and discuss stuff covered in the chapters about cardiovascular medicine, chest medicine, and endocrinology.

In the previous post I talked a little bit about heart failure, acute coronary syndromes and a few related topics, but there’s a lot more stuff in the chapter about cardiovascular medicine and I figured I should add a few more observations – so let’s talk about aortic stenosis. The most common cause is ‘senile calcification’. The authors state that one should think of aortic stenosis in any elderly person with problems of chest pain, shortness of breath during exercise (exertional dyspnoea), and fainting episodes (syncope). Symptomatic aortic stenosis tends to be bad news; “If symptomatic, prognosis is poor without surgery: 2–3yr survival if angina/syncope; 1–2yr if cardiac failure. If moderate-to-severe and treated medically, mortality can be as high as 50% at 2yrs”. Surgery can improve the prognosis quite substantially; they note elsewhere in the coverage that a xenograft (e.g. from a pig) aortic valve replacement can last (“may require replacement at…”) 8-10 years, whereas a mechanical valve lasts even longer than that. Though it should also be noted in that context that the latter type requires life-long anticoagulation, whereas the former only requires this if there is atrial fibrilation.

Next: Infective endocarditis. Half of all cases of endocarditis occur on normal heart valves; the presentation in that case is one of acute heart failure. So this is one of those cases where your heart can be fine one day, and not many days later it’s toast and you’ll die unless you get treatment (often you’ll die even if you do get treatment as mortality is quite high: “Mortality: 5–50% (related to age and embolic events)”; mortality relates to which organism we’re dealing with: “30% with staphs [S. Aureus]; 14% if bowel organisms; 6% if sensitive streptococci.”). Multiple risk factors are known, but some of those are not easily preventable (renal failure, dermatitis, organ transplantation…); don’t be an IV drug (ab)user, and try to avoid getting (type 2) diabetes.. The authors note that: “There is no proven association between having an interventional procedure (dental or non-dental) and the development of IE”, and: “Antibiotic prophylaxis solely to prevent IE is not recommended”.

Speaking of terrible things that can go wrong with your heart for no good reason, hypertrophic cardiomyopathy (-HCM) is the leading cause of sudden cardiac death in young people, with an estimated prevalence of 1 in 500. “Sudden death may be the first manifestation of HCM in many patients”. Yeah…

The next chapter in the book as mentioned covers chest medicine. At the beginning of the chapter there’s some stuff about what the lungs look like and some stuff about how to figure out whether they’re working or not, or why they’re not working – I won’t talk about that here, but I would note that lung problems can relate to stuff besides ‘just’ lack of oxygen; they can also for example be related to retention of carbon dioxide and associated acidosis. In general I won’t talk much about this chapter’s coverage as I’m aware that I have covered many of the topics included in the book before here on the blog in other posts. It should perhaps be noted that whereas the chapter has two pages about lung tumours and two pages about COPD, it has 6 pages about pneumonia; this is still a very important disease and a major killer. Approximately one in five (the number 21% is included in the book) patients with pneumonia in a hospital setting die. Though it should perhaps also be observed that maybe one reason why more stuff is not included about lung cancer in that chapter is that this disease is just depressing and doctors can’t really do all that much. Carcinoma of the bronchus make up ~19% of all cancers and 27% of cancer deaths in the UK. In terms of prognosis, non-small cell lung cancer has a 50% 2-year mortality in cases where the cancer was not spread at presentation and a 90% 2-year mortality in cases with spread. That’s ‘the one you would prefer’: Small cell lung cancer is worse as small cell tumours “are nearly always disseminated at presentation” – here the untreated median survival is 3 months, increasing to 1-1,5 years if treated. The authors note that only 5% (of all cases, including both types) are ‘cured’ (they presumably use those citation marks for a reason). Malignant mesothelioma, a cancer strongly linked to asbestos exposure most often developing in the pleura, incidentally also has a terrible prognosis (”

5-8% of people in the UK have asthma; I was surprised the number was that high. Most people who get it during childhood either grow out of it or suffer much less as adults, but on the other hand there are also many people who develop chronic asthma late in life. In 2009 approximately 1000 people in the UK died of asthma – unless this number is a big underestimate, it would seem to me that asthma at least in terms of mortality is a relatively mild disease (if 5% of the UK population has asthma, that’s 3 million people – and 1000 deaths among 3 million people is not a lot, especially not considering that half of those deaths were in people above the age of 65). COPD is incidentally another respiratory disease which is more common than I had thought; they note that the estimated prevalence in people above the age of 40 in the UK is 10-20%.

The endocrinology chapter has 10 pages about diabetes, and I won’t talk much about that coverage here as I’ve talked about many of these things before on the blog – however a few observations are worth including and discussing here. The authors note that 4% of all pregnancies are complicated by diabetes, with the large majority of cases (3.5%) being new-onset gestational diabetes. In a way the 0,5% could be considered ‘good news’ because they reflect the fact that outcomes have improved so much that a female diabetic can actually carry a child to term without risking her own life or running a major risk that the fetus dies (“As late as 1980, physicians were still counseling diabetic women to avoid pregnancy” – link). But the 3,5%? That’s not good: “All forms [of diabetes] carry an increased risk to mother and foetus: miscarriage, pre-term labour, pre-eclampsia, congenital malformations, macrosomia, and a worsening of diabetic complications”. I’m not fully convinced this statement is actually completely correct, but there’s no doubt that diabetes during pregnancy is not particularly desirable. As to which part of the statement I’m uncertain about, I think gestational diabetes ‘ought to’ have somewhat different effects than type 1 especially in the context of congenial malformations. Based on my understanding of these things, gestational diabetes should be less likely to cause congenital malformations than type 1 diabetes in the mother; diabetes-related congenital malformations tend to happen/develop very early in pregnancy (for details, see the link above) and gestational pregnancy is closely related to hormonal changes and changing metabolic demands which happen over time during pregnancy. Hormonal changes which occur during pregnancy play a key role in the pathogenesis of gestational diabetes, as the hormonal changes in general increase insulin resistance significantly, which is what causes some non-diabetic women to become diabetic during pregnancy; these same processes incidentally also causes the insulin demands of diabetic pregnant women to increase a lot during pregnancy. You’d expect the inherently diabetogenic hormonal and metabolic processes which happen in pregnancy to play a much smaller role in the beginning of the pregnancy than they do later on, especially as women who develop gestational diabetes during their pregnancy would be likely to be able to compensate early in pregnancy, where the increased metabolic demands are much less severe than they are later on. So I’d expect the risk contribution from ‘classic gestational diabetes’ to be larger in the case of macrosomia than in the case of neural tube defects, where type 1s should probably be expected to dominate – a sort of ‘gestational diabetics don’t develop diabetes early enough in pregnancy for the diabetes to be very likely to have much impact on organogenesis’-argument. This is admittedly not a literature I’m intimately familiar with and maybe I’m wrong, but from my reading of their diabetes-related coverage I sort of feel like the authors shouldn’t be expected to be intimately familiar with the literature either, and I’m definitely not taking their views on these sorts of topics to be correct ‘by default’ at this point. This NHS site/page incidentally seems to support my take on this, as it’s clear that the first occasion for even testing for gestational diabetes is at week 8-12, which is actually after a substantial proportion of diabetes-related organ damage would already be expected to have occurred in the type 1 diabetes context (“There is an increased prevalence of congenital anomalies and spontaneous abortions in diabetic women who are in poor glycemic control during the period of fetal organogenesis, which is nearly complete by 7 wk postconception.” – Sperling et al., see again the link provided above. Note that that entire textbook is almost exclusively about type 1 diabetes, so ‘diabetes’ in the context of that quote equals T1DM), and a glucose tolerance test/screen does not in this setting take place until weeks 24-28.

The two main modifiable risk factors in the context of gestational diabetes are weight and age of pregnancy; the risk of developing gestational diabetes  increases with weight and is higher in women above the age of 25. One other sex/gender-related observation to make in the context of diabetes is incidentally that female diabetics are at much higher risk of cardiovascular disease than are non-diabetic females: “DM [diabetes mellitus] removes the vascular advantage conferred by the female sex”. Relatedly, “MI is 4-fold commoner in DM and is more likely to be ‘silent’. Stroke is twice as common.” On a different topic in which I’ve been interested they provided an observation which did not help much: “The role of aspirin prophylaxis […] is uncertain in DM with hypertension.”

They argue in the section about thyroid function tests (p. 209) that people with diabetes mellitus should be screened for abnormalities in thyroid function on the annual review; I’m not actually sure this is done in Denmark and I think it’s not – the DDD annual reports I’ve read have not included this variable, and if it is done I know for a fact that doctors do not report the results to the patient. I’m almost certain they neglected to include a ‘type 1’ in that recommendation, because it makes close to zero sense to screen type 2 diabetics for comorbid autoimmune conditions, and I’d say I’m probably also a little skeptical, though much less skeptical, about annual screenings of all type 1s being potentially cost-effective. Given that autoimmune comorbidities (e.g. Graves’ disease and Hashimoto’s) are much more common in women than in men and that they often present in middle-aged individuals (and given that they’re more common in people who develop diabetes relatively late, unlike me – see Sperling) I would assume I’m relatively low risk and that it would probably not make sense to screen someone like me annually from a cost-benefit/cost-effectiveness perspective; but it might make sense to ask the endocrinologist at my next review about how this stuff is actually being done in Denmark, if only to satisfy my own curiosity. Annual screening of *female*, *type 1* diabetics *above (e.g.) the age of 30* might be a great idea and perhaps less restrictive criteria than that can also be justified relatively easily, but this is an altogether very different recommendation from the suggestion that you should screen all diabetics annually for thyroid problems, which is what they recommend in the book – I guess you can add this one to the list of problems I have with the authors’ coverage of diabetes-related topics (see also my comments in the previous post). The sex- and age-distinction is likely much less important than the ‘type’ restriction and maybe you can justify screening all type 1 diabetics (For example: “Hypothyroid or hyperthyroid AITD [autoimmune thyroid disease] has been observed in 10–24% of patients with type 1 diabetes” – Sperling. Base rates are important here: Type 1 diabetes is rare, and Graves’ disease is rare, but if the same HLA mutation causes both in many cases then the population prevalence is not informative about the risk an individual with diabetes and an HLA mutation has of developing Graves’) – but most diabetics are not type 1 diabetics, and it doesn’t make sense to screen a large number of people without autoimmune disease for autoimmune comorbidities they’re unlikely to have (autoimmunity in diabetes is complicated – see the last part of this comment for a few observations of interest on that topic – but it’s not that complicated; most type 2 diabetics are not sick because of autoimmunity-related disease processes, and type 2 diabetics make up the great majority of people with diabetes mellitus in all patient populations around the world). All this being said, it is worth keeping in mind that despite overt thyroid disease being relatively rare in general, subclinical hypothyroidism is common in middle-aged and elderly individuals (“~10% of those >55yrs”); and the authors recommend treating people in this category who also have DM because they are more likely to develop overt disease (…again it probably makes sense to add a ‘T1’ in front of that DM).

Smoking is sexy, right? (Or at least it used to be…). And alcohol makes other people look sexy, right? In a way I find it a little amusing that alcohol and smoking are nevertheless two of the three big organic causes of erectile dysfunction (the third is diabetes).

How much better does it feel to have sex, compared to how it feels to masturbate? No, they don’t ask that question in the book (leave that to me…) but they do provide part of the answer because actually there are ways to quantify this, sort of: “The prolactin increase ( and ) after coitus is ~400% greater than after masturbation; post-orgasmic prolactin is part of a feedback loop decreasing arousal by inhibiting central dopaminergic processes. The size of post-orgasmic prolactin increase is a neurohormonal index of sexual satisfaction.”

November 1, 2015 Posted by | Books, Cancer/oncology, Cardiology, Diabetes, Epidemiology, Immunology, Medicine | Leave a comment

Oxford Handbook of Clinical Medicine (I)

“We wrote this book not because we know so much, but because we know we remember so little…the problem is not simply the quantity of information, but the diversity of places from which it is dispensed. Trailing eagerly behind the surgeon, the student is admonished never to forget alcohol withdrawal as a cause of post-operative confusion. The scrap of paper on which this is written spends a month in the pocket before being lost for ever in the laundry. At different times, and in inconvenient places, a number of other causes may be presented to the student. Not only are these causes and aphorisms never brought together, but when, as a surgical house officer, the former student faces a confused patient, none is to hand.”

‘But now you don’t need to look for those scraps of paper anymore because we’ve collected all that information right here, in this book,’ the authors would argue. Or at least some of the important information is included here (despite this being a 900+ page textbook, many books on subtopics covered in the book are much longer than that; for example the Holmes et al. textbook dealing only with sexually transmitted diseases is more than twice as long as this one. Of course a book with that kind of page count will only ever be a ‘handbook’ to someone with acromegaly…).

Anyway, I’m currently reading this book and I figured I should probably talk about a few of the observations made in the book here, to make them easier to remember later on. The book is intended to be used as a reference work for doctors so in a way trying to remember stuff written in it is a strange thing to do – the point of the book is after all that you don’t need to remember all that stuff – but I would prefer to remember some of the things written in this book and this’ll be easier to do if I write about them here on the blog, instead of just ‘keeping them hidden in the book’, so to speak.

I’m assuming nobody reading along here are planning on reading this book so I wasn’t sure how much sense it would make to add impressions about the way it’s written etc. here, but I decided to note down a few things on these topics anyway. I have noted along the way that the authors sometimes include comments about a condition which they only cover later in the same chapter, and this has bothered me a few times; on the other hand I’m well aware that when you’re trying to write a book where it’s supposed to be easy to look things up quickly you need to make some key decisions here and there which will be likely to impact the reading experience of people who read the book from cover to cover the way I am negatively. Most chapters are structured a bit the same way the ‘[Topic X] At a glance…’ textbooks I’ve read in the past were (Medical Statistics at a Glance, Nutrition at a Glance, The Endocrine System at a Glance); the chapters vary in length (for example there are roughly 70 pages about cardiovascular medicine, 40 pages about endocrinology, 50 pages about gastroenterology, and 30 pages about renal medicine) but they generally seem to be structured in much the same way; the chapters are segmented – many chapter segments are two-page segments, which were also predominant in the At a glance texts – and each segment deals with a specific topic in some detail, with details about many aspects of the disease/condition in question, such as information about e.g. incidence/prevalence, risk factors, some notes on pathophysiology, presentation/symptoms/signs, diagnostics (tests to perform, key symptoms to keep in mind, etc.), treatment options (drugs/surgery/etc.?, dosage, indications/contraindications, side effects, drug interactions, etc.), potential complications, and prognostic information. Not all chapters are structured in the ‘two-page-segments’ way even though this seems to be the baseline structure in many contexts; it’s clear that they’ve given some thought as to how best to present the information included in the coverage. I recall from the At a glance texts that I occasionally thought that the structure felt unnatural, and that they seemed to have committed to a suboptimal coverage format in the specific context – I have not thought along such lines while reading this book, which to me is a sign that they’ve handled these things well. Deviation from the default format occurs e.g. in the chapter on cardiovascular medicine, which has quite a few successive pages on which various types of ECG abnormalities are illustrated (I looked at that stuff and I like to think that I understand this stuff better than I used to now, but I must admit that this was one of the sections of this book into which I did not put a lot of effort, as it in some sense felt like ‘irrelevant knowledge’ – so don’t expect me to be able to tell a right bundle branch block from an acute anterior myocardial infarction on an EEG without having access to this book…). It’s perhaps important to point out that despite the condensed structure of the book the coverage is reasonably detailed; this is not a book with two pages about ‘heart disease’, it’s a book with two pages about rheumatic fever, two pages about right heart valve disease, two pages about infective endocarditis, two pages about broad complex tachycardia, etc. And many of the pages include a lot of information. I have read textbooks dealing with many of the topics they cover and this is also not my first general ‘clinical medicine’ text (that was McPhee et al.), but I’m learning new stuff from the book even about topics with which I’m familiar, which is really nice. It’s a pretty good book so far, even if it’s not perfect; I’m probably at a four star rating at the moment.

In the parts to follow I’ll talk about some of the observations included in the book which I figured might be worth repeating here.

The first observation: They note in the book that 80% of people above the age of 85 years (in Britain) live at home and that 70% of those people can manage stairs; they argue in the same context that any deterioration in an elderly patient should be considered to be from treatable disease until proven otherwise (i.e., the default should not be to say that ‘that’s probably just ageing’).

“Unintentional weight loss should always ring alarm bells”.

A diabetic is probably well-advised to be aware of some of the signs of peripheral arterial disease. These include loss of hair, pallor, shiny skin, cyanosis (bluish discoloration of the skin), dry skin, scaling, deformed toenails, and lowered skin temperature.

“Normally 400-1300mL of gas is expelled PR in 8-20 discrete (or indiscrete) episodes per day. […] most patients with ‘flatulence’ have no GI disease. Air swallowing (aerophagy) is the main cause of flatus; here N2 is the chief gas. If flatus is mostly methane, N2 and CO2, then fermentation by bowel bacteria is the cause,[42] and reducing carbohydrate intake (eg less lactose and wheat) may help.[43]”

If there are red blood cells in the urine, this is due to cancer or glomerulonephritis (let’s not go into details here – we’ll just call this one ‘kidney disease’ for now) until proven otherwise. Painless visual haematuria (blood in the urine) usually equals bladder cancer – it’s definitely a symptom one should have a talk with a doctor about. The book does not mention this, but it’s important to keep in mind however that red/brownish urine is not always due to blood in the urine; it can also be caused by drugs and vegetable dyes (link). I was very surprised about this one in the context of ways to prevent UTIs: “There is no evidence that post-coital voiding, or pre-voiding, or advice on wiping patterns in females is of benefit.[6]” Drinking more water and drinking cranberry or lingo berry juice daily works/lowers risk.

Kidney function is often impaired in people who are hospitalized, with acute kidney injury (-AKI) occurring in up to 18% of hospital patients. It’s an important risk factor for mortality. Mortality can be very high in people with AKI, for example people admitted with burns who develop AKI have an 80% mortality rate, and with trauma/surgery it’s 60%. Up to 30 % of cases are preventable, and preventable causes include medications (continuing medications as usual e.g. after surgery can be catastrophic, and some of the drugs that can cause kidney problems are drugs people take regularly for chronic conditions such as high blood pressure or diabetes (metformin in particular)) and contrast material used in CT scans and procedures. Kidney function is incidentally often also (chronically) impaired in old people, most of which have no symptoms; “many elderly people fall into CKD [chronic kidney disease] stage 3 but have little or no progression over many years.” Symptoms of chronic kidney disease will usually not present until stage four is reached, but if onset of kidney failure is slow even people in the later stages may remain asymptomatic. The authors question whether it makes sense to label the old people in stage 3 with an illness; I’m not sure I completely agree (lowered kidney function increases cardiovascular risk, and some of those people may want to address this, if possible), but I’d certainly agree with the position that there’s a risk of overdiagnosis here.

A few more observations about kidneys. The chief cause of death from renal failure is cardiovascular disease, and in the first two stages of chronic kidney disease, the risk of dying from cardiovascular disease is higher than the risk of ever reaching stage 5, end-stage-renal-failure. Blood pressure control is very important in kidney disease as the authors argue that even a small drop in blood pressure may save significant kidney function. The causal link between BP and kidney disease goes both ways: “Hypertension often causes renal problems […] and most renal diseases can cause hypertension”. Once people require renal replacement therapy (RRT) such as haemodialysis mortality is high: Annual mortality is ~20%, mainly due to cardiovascular disease. The authors talk a little bit about diabetes and kidney disease in the book and among other things include the following observations:

“Diabetes is best viewed as a vascular disease with the kidney as one of its chief targets for end-organ damage. The single most important intervention in the long-term care of DM is the control of BP, to protect the heart, the brain, and the kidney. Renal damage may be preventable with good BP and glycaemic control.
In type 1 DM nephropathy is rare in the first 5yrs, after 10yrs annual incidence rises to a peak at 15yrs, then falls again. Those who have not developed nephropathy at 35yrs are unlikely to do so. In type 2 DM around 10% have nephropathy at diagnosis and up to half will go on to develop it over the next 20yrs. 20% of people with type 2 DM will develop ESRF.”

I was surprised by the observation above that “Those who have not developed nephropathy at 35yrs are unlikely to do so”, and I’m not sure I’d agree with the authors about that. The incidence of diabetes-related nephropathy peaks after a diabetes duration of 10-20 years and declines thereafter, but it doesn’t go to zero: “The risk for the development of diabetic nephropathy is low in a normoalbuminuric patient with diabetes’ duration of greater than 30 years. Patients who have no proteinuria after 20-25 years have a risk of developing overt renal disease of only approximately 1% per year.” (link). I’d note that a risk of 1% per year translates to a roughly 25% risk of developing overt renal disease over a 30 year time-frame, and that diabetics with the disease might not agree that a risk of that magnitude means that they are ‘unlikely’ to develop nephropathy, even if the annual risk is not high. Even if the annual risk were only half of that, 0,5%, the cumulative risk over a 30 year period would still be 14%, or roughly one in seven – are people with risks of that magnitude really ‘unlikely’ to develop nephropathy? This is certainly arguable. Many type 1 diabetics are diagnosed in childhood (peak incidence is in the early teenage years) and they can expect to live significantly longer than 20-25 years with the disease – if you disregard the ‘tail risk’ here, you seem in my opinion to be likely to neglect a substantial proportion of the total risk. This is incidentally not the only part of the book where I take issue with their coverage of topics related to diabetes, elsewhere in the book they note that:

“People who improve and maintain their fitness live longer […] Avoiding obesity helps too, but weight loss per se is only useful in reducing cardiovascular risk and the risk of developing diabetes when combined with regular exercise.”

Whereas in the case of nephropathy you can sort of argue about the language being imprecise and/or words meaning different things to different people, here things are a bit more clear because this is just plain WRONG. See e.g. Rana et al. (“Obesity and physical inactivity independently contribute to the development of type 2 diabetes; however, the magnitude of risk contributed by obesity is much greater than that imparted by lack of physical activity”). This is in my opinion the sort of error you should not find in a medical textbook.

Moving on to other parts of the coverage, let’s talk about angina. There are two types of angina – stable and unstable angina. Stable angina is induced by effort and relieved by rest. Unstable angina is angina of increasing severity or frequency, and it occurs at rest or minimal exertion. Unstable angina requires hospital admission and urgent treatment as it dramatically increases the risk of myocardial infarction. Some more stuff on related topics from the book:

“ACS [acute coronary syndrome] includes unstable angina and evolving MI [myocardial infarction], which share a common underlying pathology—plaque rupture, thrombosis, and inflammation”. Symptoms are: “Acute central chest pain, lasting >20min, often associated with nausea, sweatiness, dyspnoea [shortness of breath], palpitations [awareness of your heart beat]. May present without chest pain (‘silent’ infarct), eg in the elderly or diabetics. In such patients, presentations may include: syncope [fainting], pulmonary oedema, epigastric pain and vomiting, […] acute confusional state, stroke, and diabetic hyperglycaemic states.”

The two key questions to ask in the context of ACS are whether troponin (a cardiac enzyme) levels are elevated and whether there is ST-segment elevation. If there’s no ST-segment elevation and symptoms settle without a rise in troponin levels -> no myocardial damage (that’s the best case scenario – the alternatives are not as great..). In ACS, many deaths occur very soon after symptoms present; 50 % of deaths occur within two hours of symptom onset. “Up to 7% die before discharge.” Some MI complications have very high associated mortalities, for example a ventricular septal defect following an MI implies a 50% mortality rate during the first week alone.

Heart failure is a state in which the cardiac output is inadequate for the requirements of the body. It’s actually not that uncommon; the prevalence is 1-3% of the general population, increasing to roughly 10% “among elderly patients”. 25-50% die within 5 years of diagnosis, and if admission is needed the five year mortality rises to 75%.

Hypertension is a major risk factor for stroke and MI and according to the authors causes ~50% of all vascular deaths. Aside from malignant hypertension, which is relatively rare, hypertension is usually asymptomatic; the authors note specifically that “Headache is no more common than in the general population.” Isolated systolic hypertension, the most common form of hypertension, affects more than half of all people above the age of 60. “It is not benign: doubles risk of MI, triples risk of CVA [cerebrovascular accident, i.e. stroke].” The authors argue that: “Almost any adult over 50 would benefit from [antihypertensives], whatever their starting BP.” I think that’s downplaying the potential side effects of treatment, but it’s obvious that many people might benefit from treatment. Steps you can take to lower your BP without using medications according to the authors include: Reducing alcohol and salt intake, increasing exercise, reducing weight if obese, stop smoking, low-fat diet. They talk quite a bit about the different medications used to treat hypertension – I won’t cover that stuff in much detail, but I thought it was worth including the observation that ACE-inhibitors may be the 1st choice option in diabetics (especially if there’s renal involvement). On a related note, beta-blockers and thiazides may both increase the risk of new-onset diabetes.

October 22, 2015 Posted by | Books, Cardiology, Diabetes, Medicine, Nephrology, Pharmacology | Leave a comment

Peripheral Neuropathy & Neuropathic Pain: Into the light (II)

Here’s my first post about the book. As I mentioned in that post, I figured I should limit detailed coverage to the parts of the book dealing with stuff related to diabetic/metabolic neuropathies. There’s a chapter specifically about ‘diabetic and uraemic neuropathies’ in the book and most of the coverage below relates to content covered in that chapter, but I have also included some related observations from other parts of the book as they seemed relevant.

It is noted in the book’s coverage that diabetes is the commonest cause of neuropathy in industrialized countries. There are many ways in which diabetes can affect the nervous system, and not all diabetes-related neuropathies affect peripheral nerves. Apart from distal symmetric polyneuropathy, which can probably in this context be thought of as ‘classic diabetic neuropathy’, focal or multifocal involvement of the peripheral nervous system is also common, and so is autonomic neuropathy. Diabetics are also at increased risk of inflammatory neuropathies such as CIDP – chronic inflammatory demyelinating polyneuropathy (about which the book also has a chapter). Late stage complications of diabetes usually relate to some extent to vessel wall abnormalities and their effects, and the blood vessels supplying the peripheral nerves can be affected just like all other blood vessels; in that context it is of interest to note that the author mentions elsewhere in the book that “tissue ischaemia is more likely to be symptomatic in nerves than in most other organs”. According to the author there isn’t really a great way to classify all the various manifestations of diabetic neuropathy, but most of them fall into one of three groups – distal symmetrical sensorimotor (length-dependent) polyneuropathy (DSSP); autonomic neuropathy; and focal- and multifocal neuropathy. The first one of these is by far the most common, and it is predominantly a sensory neuropathy (‘can you feel this?’ ‘does this hurt?’ ‘Is this water hot or cold?’ – as opposed to motor neuropathy: ‘can you move your arm?’) with no motor deficit.

Neuropathies in diabetics are common – how common? The author notes that the prevalence in several population-based surveys has been found to be around 30% “in studies using restrictive definitions”. The author does not mention this, but given that diabetic neuropathy usually has an insidious onset and given that diabetes-related sensory neuropathy “can be totally asymptomatic”, survey-based measures are if anything likely to underestimate prevalence. Risk increases with age and duration of diabetes; the prevalence of diabetic peripheral neuropathy is more than 50% in type 1 diabetics above the age of 60.

DSSP may lead to numbness, burning feet, a pins and needles sensation and piercing/stabbing pain in affected limbs. The ‘symmetric’ part of the abbreviation means that it usually affects both sides of the body, instead of e.g. just one foot or hand. The length-dependence mentioned in the parenthesis earlier relates in a way to the pathophysiological process. The axons of the peripheral nervous system lack ribosomes, and this means that essential proteins and enzymes needed in distal regions of the nervous system need to be transported great distances through the axons – which again means that neurons with long axons are particularly vulnerable to toxic or metabolic disturbances (introducing a length-dependence aspect in terms of which nerves are affected) which may lead to so-called dying-back axonal degeneration. The sensory loss can be restricted to the toes, extend over the feet, or it can migrate even further up the limbs – when sensory loss extends above the knee, signs and symptoms of nerve damage will usually also be observed in the fingers/hands/forearms. In generalized neuropathies a distinction can be made in terms of which type of nerve fibres are predominantly involved. When small fibres are most affected, sensory effects relating to pain- and temperature perception predominate, whereas light touch, position and vibratory senses are relatively preserved; on the other hand abnormalities of proprioception and sensitivity to light touch, often accompanied by motor deficits, will predominate if larger myelinated fibres are involved. DSSP is a small fibre neuropathy.

One of the ‘problems’ in diabetic neuropathy is actually that whereas sensation is affected, motor function often is not. This might be considered much better than the alternative, but unimpaired motor function actually relates closely to how damage often occurs. Wounds/ulcers developing on the soles of the feet (plantar ulcers) are very common in conditions in which there is sensation loss but no motor involvement/loss of strength; people with absent pain sensation will not know when their feet get hurt, e.g. because of a stone in the shoe or other forms of micro-trauma, but they’re still able to walk around relatively unimpaired and the absence of protective sensation in the limbs can thus lead to overuse of joints and accidental self-injury. A substantial proportion of diabetics with peripheral neuropathy also have lower limb ischaemia from peripheral artery disease, which further increases risk, but even in the absence of ischaemia things can go very wrong (for more details, see Edmonds, Foster, and Sanders – I should perhaps warn that the picture in that link is not a great appetite-stimulant). Of course one related problem here is that you can’t just stop moving around in order to avoid these problems once you’re aware that you have peripheral sensory neuropathy; inactivity will lead to muscle atrophy and ischaemia, and that’s not good for your feet either. The neuropathy may not ‘just’ lead to ulcers, but may also lead to the foot becoming deformed – the incidence of neuroarthropathy is approximately 2%/year in diabetics with peripheral neuropathy. Foot deformity is sometimes of acute onset and may be completely painless, despite leading to (painless) fractures and disorganization of joints. In the context of ulcers it is important that foot ulcers often take a *very* long time to heal, and so they provide excellent entry points for bacteria which among other things can cause chronic osteomyelitis (infection and inflammation of the bone and bone marrow). Pronounced motor involvement is as mentioned often absent in DSSP, but it does sometimes occur, usually at a late stage.

The author notes repeatedly in the text that peripheral neuropathy is sometimes the presenting symptom in type 2 diabetes, and I thought I should include that observation here as well. The high blood glucose may not be what leads the patient to see a doctor – sometimes the fact that he can no longer feel his toes is. At that point the nerve damage which has already occurred will of course usually be irreversible.

When the autonomic nervous system is affected (this is called Diabetic Autonomic Neuropathy, -DAN), this can lead to a variety of different symptoms. Effects of orthostatic hypotension (-OH) are frequent complaints; blackouts, faintness and dizziness or visual obscuration on standing are not always due to side effects of blood pressure medications. The author notes that OH can be aggravated by tricyclic antidepressants which are often used for treating chronic neuropathic pain (diabetics with autonomous nervous system disorder will often have, sometimes painful, peripheral neuropathy as well). Neurogenic male impotence seems to be “extremely common”; this leads to the absence of an erection at any time under any circumstances. The bladder may also be involved, which can lead to increased intervals between voiding and residual urine in the bladder after voiding, which can lead to UTIs. It is noted that retrograde ejaculation is frequent in people with bladder atony. The gastrointestinal system can be affected; this is often asymptomatic, but may lead to diarrhea and constipation causing weight loss and malnutrition. Associated diarrhea may be accompanied by fecal incontinence. DAN can lead to hypoglycemia unawareness, making glycemic control more difficult to accomplish. Sweating disorders are common in the feet. When a limb is affected by neuropathy the limb may lose its ability to sweat, and this may lead to other parts of the body (e.g. the head or upper trunk) engaging in ‘compensatory sweating’ to maintain temperature control. Abnormal pupil responses, e.g. in the form of reduced light reflexes and constricted pupils (miosis), are common in diabetics.

Focal (one nerve) and occasionally also multi-focal (more than one nerve) neuropathic syndromes also occur in the diabetic setting. The book spends quite a bit of time talking about what different nerves do and what happens when they stop working, so it’s hard to paint a broad picture of how these types of problems may present – it all depends on which nerve(s) is (are) affected. Usually in the setting of these disorders the long-term prognosis is good, or at least better than in the setting of DSSP; nerve damage is often not permanent. It seems that in terms of cranial nerve involvement, oculomotor nerve palsies are the most common, but still quite rare, affecting 1-2% of diabetics. Symptoms are rapid onset pain followed by double vision, and “spontaneous and complete recovery invariably occurs within 2-3 months” – I would like to note that as far as diabetes complications go, this is probably about as good as it gets… In so-called proximal diabetic neuropathy (-PDN), another type of mononeuropathy/focal neuropathy, the thighs are involved, with numbness or pain, often of a burning character which is worse at night, as well as muscle wasting. That syndrome progresses over weeks or months, after which the condition usually stabilizes and the pain improves, though residual muscle weakness seems to be common. Unlike in the case of DSSP, deficits in PDN are usually asymmetric, and both motor involvement and gradual recovery is common – it’s important to note in this context that DSSP virtually never improves spontaneously and often has a progressive course. Multi-focal neuropathies affect only a small proportion of diabetics, and in terms of outcome patterns they might be said to lie somewhere in between mononeuropathies and DSSP; outcomes are better than in the case of DSSP, but long-term sequelae are common.

Diabetics are at increased risk of developing pressure palsies in general. According to the author carpal tunnel syndrome occurs in 12% of diabetic patients, and “the incidence of ulnar neuropathy due to microlesions at the elbow level is high”.

In diabetics with renal failure caused by diabetic nephropathy (or presumably for that matter renal failure caused by other things as well, but most diabetics with kidney failure will have diabetic nephropathy) neuropathy is common and often severe. Renal failure impairs nerve function and is responsible for sometimes severe motor deficits in these patients. “Recovery from motor deficits is usually good after kidney transplant”. Carpal tunnel syndrome is very common in patients on long-term dialysis; 20 to 50 % of patients dialysed for 10 years or more are reported to have carpal tunnel syndrome. The presence of neuropathy in renal patients is closely related to renal function; the lower renal function, the more likely neurological symptoms become.

As you’ll learn from this book, a lot of things can cause peripheral neuropathies – and so the author notes that “In focal neuropathy occurring in diabetic patients, a neuropathy of another origin must always be excluded.” It’s not always diabetes, and sometimes missing the true cause can be a really bad thing; for example cancer-associated paraneoplastic syndromes are often associated with neuropathy (“paraneoplastic syndromes affect the PNS [Peripheral Nervous System] in up to one third of patients with solid tumors”), and so missing ‘the true cause’ in the case of a focal neuropathy may mean missing a growing tumour.

In terms of treatment options, “There is no specific treatment for distal symmetric polyneuropathy.” Complications can be treated/ideally prevented, but we have no drugs the primary effects of which are to specifically stop the nerves from dying. Treatment of autonomic neuropathy mostly relates to treating symptoms, in particular symptomatic OH. Treatment of proximal diabetic neuropathy, which is often very painful, relates only to pain management. Multifocal diabetic neuropathy can be treated with corticosteroids, minimizing inflammation.

Due to how common diabetic neuropathy is, most controlled studies on treatment options for neuropathic pain have involved patients with distal diabetic polyneuropathy. Various treatment options exist in the context of peripheral neuropathies, including antidepressants, antiepileptic drugs and opioids, as well as topical patches. In general pharmacological treatments will not cause anywhere near complete pain relief: “For patients receiving pharmacological treatment, the average pain reduction is about 20-30%, and only 20-35% of patients will achieve at least a 50% pain reduction with available drugs. […] often only partial pain relief from neuropathic pain can be expected, and […] sensory deficits are unlikely to respond to treatment.” Treatment of neuropathic pain is often a trial-and-error process.

October 17, 2015 Posted by | Books, Cancer/oncology, Diabetes, Epidemiology, Medicine, Neurology, Pharmacology | Leave a comment

Peripheral Neuropathy & Neuropathic Pain: Into the light (I)

“Peripheral neuropathy is a common medical condition, the diagnosis of which is often protracted or delayed. It is not always easy to relate a neuropathy to a specific cause. Many people do not receive a full diagnosis, their neuropathy often being described as ‘idiopathic’ or ‘cryptogenic’. It is said that in Europe, one of the most common causes is diabetes mellitus but there are also many other known potential causes. The difficulty of diagnosis, the limited number of treatment options, a perceived lack of knowledge of the subject — except in specialised clinics, the number of which are limited — all add to the difficulties which many neuropathy patients have to face. Another additional problem for many patients is that once having received a full, or even a partial diagnosis, they are then often discharged back to their primary healthcare team who, in many instances, know little about this condition and how it may impact upon their patients’ lives. In order to help bridge this gap in medical knowledge and to give healthcare providers a better understanding of this often distressing condition, The Neuropathy Trust has commissioned a new book on this complex topic.

As well as covering the anatomy of the nervous system and the basic pathological processes that may affect the peripheral nerves, the book covers a whole range of neuropathic conditions. These include, for example, Guillain Barre syndrome, chronic inflammatory demyelinating polyneuropathy, vasculitic neuropathies, infectious neuropathies, diabetic and other metabolic neuropathies, hereditary neuropathies and neuropathies in patients with cancer.”

The stuff above is the part of the amazon book description I decided to include when I added the book to goodreads.

The book is dense. There are a lot of terms defined in the book and a lot of topics covered. Despite being a quite shortish book only a couple hundred pages long (compare for example with related books like this one), it’s still the sort of book which many people might consider using as a reference work (I certainly consider doing that). The author really knows his stuff. According to the website of the European Neurological Society, “The ENS has now become the most prominent society of neurologists on the European Continent with a total of 2300 (including all categories) members from 60 countires [sic] worldwide.” I mention this because five years ago Gérard Said, the author, became the President of the ENS. He’s done/accomplished a lot of stuff besides that, the link has more details about him and what’s he’s done but what it boils down to is that this guy as already mentioned really knows his stuff. I disliked the comment on the front cover of the book that it was Written by one of the world’s leading experts and I at first considered it a decent argument against reading the book, but actually it’s probably both a fair and accurate statement; it seems like this guy really is one of the top guys in his field (I have no clue why someone like this does not have a wikipedia page whereas [random celebrity whose name I don’t know] does – well, I do have a clue, but…).

I don’t find the book particularly hard to read, but I’m frequently looking stuff up and I’ve read textbooks dealing with similar topics before (see e.g. here and here) – maybe I’m underestimating how difficult the book might be to read and understand for someone without much medical knowledge, but I think you should be perfectly able to get through the book without already having a detailed understanding of the neurological system; in my opinion the book is potentially useful for patients as well as medical practitioners, at least if the patient is willing to put in some work. An extensive glossary is included at the beginning of the book, defining most of the terms with which people might be unfamiliar. If you were wondering why I looked up so many words and concepts on wikipedia and other online sources (see below) in spite of the glossary, I should note that this is how I generally read books like this one; wiki or google will often provide additional details compared to the information included in standard glossaries, and often it’s even faster to look up such stuff online than it might be to locate the definition in the book. Another big reason for looking up key terms online was that I decided early on that a link collection like the one included below might be the best way to illustrate here on the blog which kind of content is covered in the book. Regardless of how you decide to look up stuff along the way, you should definitely not skip the definitions included in the glossary before reading the book proper – many of the terms you won’t be able to remember just on account of having read the words and definitions once or twice, but it’s definitely a good idea to have a look even so before moving on; this is probably the first book I’ve read in which the glossary was located at the front of the book instead of somewhere in the back, and it’s not a coincidence that the author decided to organize the book this way.

As a small aside, I thought this might be a reasonable place to add a ‘meta’ comment related to my book posts more generally. I’ve been considering writing slightly shorter posts about the non-fiction books I’m reading/have read; ‘classical posts’ of the kind I’ve written a lot of in the past can easily end up taking four-five hours for me to write and edit, and this means that if I don’t write short posts about the books I may easily end up not blogging them at all. This is an undesirable outcome for me. What I’ve been doing instead lately is to review more books on goodreads than I used to do; the idea being that if I end up not blogging the book, I’ll at least have reviewed it on goodreads. This incidentally means that if you want to keep track of my reading these days and would like to know what I think about the books I’m reading, the front page of this blog is no longer enough; you may need to also pay attention to my activities on goodreads or keep track of my reading via this link (I update that book list very often, usually every time I’ve finished a book). I don’t like to ‘branch out’ like that, but I also don’t like the idea of cross-posting goodreads reviews on the blog, and recently I’ve found it hard to know how to do these things optimally – this is where I’ve ended up. These days I’ll usually add a goodreads review of a non-fiction book quite shortly after I’ve finished the book, especially if I’m not sure if I’ll blog the book later.

Okay, back to the book: I think I’ll limit semi-detailed discussion of the book’s contents to the stuff included about diabetic/metabolic neuropathies, and although I’ve already encountered some relevant content and useful observations on that topic at this point, I have not yet read the chapter devoted to this topic. So you should expect me to post another post about this book some time in the future. I’ve read roughly half the book at this point and as mentioned in an earlier update on goodreads I’m seriously considering giving this book a five star rating. The book has way too much stuff to talk about all of it in detail, so what I’ll do below is to add some links to topics/terms/etc. discussed in the coverage so far which I looked up along the way, to give you a few more details than did the quote at the beginning:

Peripheral neuropathy.
Spinal nerves.
Anterior grey column.
Motor neuron.
Afferent nerve fiber.
Nodes of Ranvier.
Charcot–Marie–Tooth neuropathy.
Guillain–Barré syndrome.
Acute motor axonal neuropathy.
POEMS syndrome.
Monoclonal gammopathy of undetermined significance.
Vasa nervorum.
Vasculitic neuropathy.
Granulomatosis with polyangiitis.
Churg-Strauss syndrome.
Mononeuritis Multiplex.

October 12, 2015 Posted by | Books, Diabetes, Medicine, meta, Neurology | Leave a comment

A few lectures

This one was mostly review for me, but there was also some new stuff and it was a ‘sort of okay’ lecture even if I was highly skeptical about a few points covered. I was debating whether to even post the lecture on account of those points of contention, but I figured that by adding a few remarks below I could justify doing it. So below a few skeptical comments relating to content covered in the lecture:

a) 28-29 minutes in he mentions that the cutoff for hypertension in diabetics is a systolic pressure above 130. Here opinions definitely differ, and opinions about treatment cutoffs differ; in the annual report from the Danish Diabetes Database they follow up on whether hospitals and other medical decision-making units are following guidelines (I’ve talked about the data on the blog, e.g. here), and the BP goal of involved decision-making units evaluated is currently whether diabetics with systolic BP above 140 receive antihypertensive treatment. This recent Cochrane review concluded that: “At the present time, evidence from randomized trials does not support blood pressure targets lower than the standard targets in people with elevated blood pressure and diabetes” and noted that: “The effect of SBP targets on mortality was compatible with both a reduction and increase in risk […] Trying to achieve the ‘lower’ SBP target was associated with a significant increase in the number of other serious adverse events”.

b) Whether retinopathy screenings should be conducted yearly or biennially is also contested, and opinions differ – this is not mentioned in the lecture, but I sort of figure maybe it should have been. There’s some evidence that annual screening is better (see e.g. this recent review), but the evidence base is not great and clinical outcomes do not seem to differ much in general; as noted in the review, “Observational and economic modelling studies in low-risk patients show little difference in clinical outcomes between screening intervals of 1 year or 2 years”. To stratify based on risk seems desirable from a cost-effectiveness standpoint, but how to stratify optimally seems to not be completely clear at the present point in time.

c) The Somogyi phenomenon is highly contested, and I was very surprised about his coverage of this topic – ‘he’s a doctor lecturing on this topic, he should know better’. As the wiki notes: “Although this theory is well known among clinicians and individuals with diabetes, there is little scientific evidence to support it.” I’m highly skeptical, and I seriously question the advice of lowering insulin in the context of morning hyperglycemia. As observed in Cryer’s text: “there is now considerable evidence against the Somogyi hypothesis (Guillod et al. 2007); morning hyperglycemia is the result of insulin lack, not post-hypoglycemic insulin resistance (Havlin and Cryer 1987; Tordjman et al. 1987; Hirsch et al. 1990). There is a dawn phenomenon—a growth hormone–mediated increase in the nighttime to morning plasma glucose concentration (Campbell et al. 1985)—but its magnitude is small (Periello et al. 1991).”

I decided not to embed this lecture in the post mainly because the resolution is unsatisfactorily low so that a substantial proportion of the visual content is frankly unintelligible; I figured this would bother others more than it did me and that a semi-satisfactory compromise solution in terms of coverage would be to link to the lecture, but not embed it here. You can hear what the lecturer is saying, which was enough for me, but you can’t make out stuff like effect differences, p-values, or many of the details in the graphic illustrations included. Despite the title of the lecture on youtube, the lecture actually mainly consists of a brief overview of pharmacological treatment options for diabetes.

If you want to skip the introduction, the first talk/lecture starts around 5 minutes and 30 seconds into the video. Note that despite the long running time of this video the lectures themselves only take about 50 minutes in total; the rest of it is post-lecture Q&A and discussion.

October 3, 2015 Posted by | Diabetes, Lectures, Mathematics, Medicine, Nephrology, Pharmacology | Leave a comment

Cost-effectiveness analysis in health care (II)

Here’s my first post about the book.

Like in the first post I cannot promise I have not already covered the topics I’m about to cover in this post before on the blog. In this post I’ll include and discuss material from two chapters of the book: the chapters on how to measure, value, and analyze health outcomes, and the chapter on how to define, measure, and value costs. In the last part of the post I’ll also talk a little bit about some research related to the coverage which I’ve recently looked at in a different context.

In terms of how to measure health outcomes the first thing to note is that there are lots and lots of different measures (‘thousands’) that are used to measure aspects of health. The symptoms causing problems for an elderly man with an enlarged prostate are not the same symptoms as the ones which are bothering a young child with asthma, and so it can be very difficult to ‘standardize’ across measures (more on this below).

A general distinction in this area is that between non-preference-based measures and preference-based measures. Many researchers working with health data are mostly interested in measuring symptoms, and metrics which do (‘only’) this would be examples of non-preference-based measures. Non-preference based measures can again be subdivided into disease- and symptom-specific measures, and non-disease-specific/generic measures; an example of the latter would be the SF-36, ‘the most widely used and best-known example of a generic or non-disease-specific measure of general health’.

Economists will often want to put a value on symptoms or quality-of-life states, and in order to do this you need to work with preference-based measures – there are a lot of limitations one confronts when dealing with non-preference-based measures. Non-preference based measures tend for example to be very different in design and purpose (because asthma is not the same thing as, say, bulimia), which means that there is often a lack of comparability across measures. It is also difficult to know how to properly trade off various dimensions included when using such metrics (for example pain relief can be the result of a drug which also increases nausea, and it’s not perfectly clear when you use such measures whether such a change is to be considered desirable or not); similar problems occur when taking the time dimension into account, where problems with aggregation over time and how to deal with this pop up. Various problems related to weighting are recurring problems; for example a question can be asked when using such measures which symptoms/dimensions included are more important? Are they all equally important? This goes for both the weighting of various different domains included in the metric, and for how to weigh individual questions within a given domain. Many non-preference-based measures contain an implicit equal-interval assumption, so that a move from (e.g.) level one to level two on the metric (e.g. from ‘no pain at all’ to ‘a little’) is considered the same as a move from (e.g.) level three to level four (e.g. ‘quite a bit’ to ‘very much’), and it’s not actually clear that the people who supply the information that goes into these metrics would consider such an approach to be a correct reflection of how they perceive these things. Conceptually related to the aggregation problem mentioned above is the problem that people may have different attitudes toward short-term and long-term health effects/outcomes, but non-preference-based measures usually give equal weight to a health state regardless of the timing of the health state. The issue of some patients dying is not addressed at all when using these measures, as they do not contain information about mortality; which may be an important variable. For all these reasons the authors argue in the text that:

“In summary, non-preference-based health status measures, whether disease specific or generic, are not suitable as outcome measures in economic evaluation. Instead, economists require a measure that combines quality and quantity of life, and that also incorporates the valuations that individuals place on particular states of health.
The outcome metric that is currently favoured as meeting these requirements and facilitating the widest possible comparison between alternative uses of health resources is the quality-adjusted life year“.

Non-preference-based tools may be useful, but you will usually need to go ‘further’ than those to be able to handle the problems economists will tend to care the most about. Some more observations from the chapter below:

“the most important challenge [when valuing health states] is to find a reliable way of quantifying the quality of life associated with any particular health state. There are two elements to this: describing the health state, which […] could be either a disease-specific description or a generic description intended to cover many different diseases, and placing a valuation on the health state. […] these weights or valuations are related to utility theory and are frequently referred to as utilities or utility values.
Obtaining utility values almost invariably involves some process by which individuals are given descriptions of a number of health states and then directly or indirectly express their preferences for these states. It is relatively simple to measure ordinal preferences by asking respondents to rank-order different health states. However, these give no information on strength of preference and a simple ranking suffers from the equal interval assumption […]; as a result they are not suitable for economic evaluation. Instead, analysts make use of cardinal preference measurement. Three main methods have been used to obtain cardinal measures of health state preferences: the rating scale, the time trade-off, and the standard gamble. […] The large differences typically observed between RS [rating scale] and TTO [time trade-off] or SG [standard gamble] valuations, and the fact that the TTO and SG methods are choice based and therefore have stronger foundations in decision theory, have led most standard texts and guidelines for technology appraisal to recommend choice-based valuation methods [The methods are briefly described here, where the ‘VAS’ corresponds to the rating scale method mentioned – the book covers the methods in much more detail, but I won’t go into those details here].”

“Controversies over health state valuation are not confined to the valuation method; there are also several strands of opinion concerning who should provide valuations. In principle, valuations could be provided by patients who have had first-hand experience of the health state in question, or by experts such as clinicians with relevant scientific or clinical expertise, or by members of the public. […] there is good evidence that the valuations made by population samples and patients frequently vary quite substantially [and] the direction of difference is not always consistent. […] current practice has moved towards the use of valuations obtained from the general public […], an approach endorsed by recent guidelines in the UK and USA explicitly recommend that population valuations are used”.

Given the very large number of studies which have been based on non-preference based instruments, it would be desirable for economists working in this field to somehow ‘translate’ the information contained in those studies so that this information can also be used for cost-effectiveness evaluations. As a result of this an increasing number of so-called ‘mapping studies’ have been conducted over the years, the desired goal of which is to translate the non-preference based measures into health state utilities, allowing outcomes and effects derived from the studies to be expressed in terms of QALYs. There’s more than one way to try to get from a non-preference based metric to a preference-based metric and the authors describe three approaches in some detail, though I’ll not discuss those approaches or details here. They make this concluding assessment of mapping studies in the text:

“Mapping studies are continuing to proliferate, and the literature on new mapping algorithms and methods, and comparisons between approaches, is expanding rapidly. In general, mapping methods seem to have reasonable ability to predict group mean utility scores and to differentiate between groups with or without known existing illness. However, they all seem to predict increasingly poorly as health states become more serious. […] all forms of mapping are ‘second best’, and the existence of a range of techniques should not be taken as an argument for relying on mapping instead of obtaining direct preference-based measurements in prospectively designed studies.”

I won’t talk too much about the chapter on how to define, measure and value costs, but I felt that a few observations from the chapter should be included in the coverage:

“When asking patients to complete resource/time questionnaires (or answer interview questions), a particularly important issue is deciding on the optimum recall period. Two types of recall error can be distinguished: simply forgetting an entire episode, or incorrectly recalling when it occurred. […] there is a trade-off between recall bias and complete sampling information. […] the longer the period of recall the greater is the likelihood of recall error, but the shorter the recall period the greater is the problem of missing information.”

“The range of patient-related costs included in economic valuations can vary considerably. Some studies include only the costs incurred by patients in travelling to a hospital or clinic for treatment; others may include a wider range of costs including over-the-counter purchases of medications or equipment. However, in some studies a much broader approach is taken, in which attempts are made to capture both the costs associated with treatments and the consequences of illness in terms of absence from or cessation of work.”

An important note here which I thought I should add is that whereas many people unfamiliar with this field may translate ‘medical costs of illness’ with ‘the money that is paid to the doctor(s)’, direct medical costs will in many cases drastically underestimate the ‘true costs’ of disease. To give an example, Ferber et al. (2006) when looking at the costs of diabetes included two indirect cost components in their analysis – inability to work, and early retirement – and concluded that these two cost components made up approximately half of the total costs of diabetes. I think there are reasons to be skeptical of the specific estimate on account of the way it is made (for example if diabetics are less productive/earn less than the population in general, which seems likely if the disease is severe enough to cause many people to withdraw prematurely from the labour market, the cost estimate may be argued to be an overestimate), but on the other hand there are multiple other potentially important indirect cost components they do not include in the calculation, such as e.g. disease-related lower productivity while at work (for details on this, see e.g. this paper – that cost component may also be substantial in some contexts) and things like spousal employment spill-over effects (it is known from related research – for an example, see this PhD dissertation – that disease may impact on the retirement decisions of the spouse of the individual who is sick, not just the individual itself, but effects here are likely to be highly context-dependent and to vary across countries). Another potentially important variable in an indirect cost context is informal care provision. Here’s what they authors say about that one:

“Informal care is often provided by family members, friends, and volunteers. Devoting time and resources to collecting this information may not be worthwhile for interventions where informal care costs are likely to form a very small part of the total costs. However, in other studies non-health-service costs could represent a substantial part of the total costs. For instance, dementia is a disease where the burden of care is likely to fall upon other care agencies and family members rather than entirely on the health and social care services, in which case considering such costs would be important.
To date [however], most economic evaluations have not considered informal care costs.”

August 23, 2015 Posted by | Books, Diabetes, Economics, Medicine | Leave a comment

Random stuff

It’s been a while since I posted anything here so I figured I should at least post something…

i. A few Khan Academy videos I watched a while back:

(No comments)

(Bookmark remark: (‘Not completely devoid of slight inaccuracies as usual – e.g. in meningitis, neck stiffness is not as much as symptom as it is a clinical sign (see Chamberlain’s symptoms and signs…))’

(Bookmark remark: ‘Very simplified, but not terrible’)

(No comments)

ii. I previously read the wiki on strategic bombing during WW2, but the article did not really satisfy my curiosity and it turns out that the wiki also has a great (featured) article about Air raids on Japan (a topic not covered in a great amount of detail in the aforementioned wiki article). A few random observations from the article:

“Overall, the attacks in May destroyed 94 square miles (240 km2) of buildings, which was equivalent to one seventh of Japan’s total urban area.”

“In Tokyo, Osaka, Nagoya, Yokohama, Kobe, and Kawasaki, “over 126,762 people were killed … and a million and a half dwellings and over 105 square miles (270 km2) of urban space were destroyed.”[136] In Tokyo, Osaka and Nagoya, “the areas leveled (almost 100 square miles (260 km2)) exceeded the areas destroyed in all German cities by both the American and English air forces (approximately 79 square miles (200 km2)).”[136]

“In financial terms, the Allied air campaign and attacks on merchant ships destroyed between one third and a quarter of Japan’s wealth.[289]

“Approximately 40 percent of the urban area of the 66 cities subjected to area attacks were destroyed.[290] This included the loss of about 2.5 million housing units, which rendered 8.5 million people homeless.”

iii. A few longer lectures I’ve watched recently but did not think were particularly good: The Fortress (GM Akobian, Chess), Safety in the Nuclear Industry (Philip Thomas, Gresham College), War, Health and Medicine: The medical lessons of World War I (Mark Harrison, Gresham College – topic had potential, somehow did not like ‘the delivery’; others may find it worth watching).

iv. I play a lot of (too much) chess these days, so I guess it makes sense to post a little on this topic as well. Here’s a list of some of my recent opponents on the ICC: GM Zurab Azmaiparashvili, IM Jerzy Slaby, IM Petar Gojkovic, GM Goran Kosanovic, IM Jeroen Bosch, WGM Alla Grinfeld. I recall encountering a few titled players when I started out on the ICC and my rating was still adjusting and stabilizing, but now I’ve sort of fixed at a level around 1700-1800 in both the 1, 3 and 5 minute pools – sometimes a bit higher, sometimes a bit lower (and I’ve played relatively few 5 minute games so far)). This is a level where at least in bullet some of the semi-regular opponents I’ll meet in the rating pool are guys like these. I was quite dissatisfied with my play when I started out on the ICC because I hadn’t realized how tough it is to maintain a high rating there; having a closer look at which sort of opponents I was actually facing gradually made me realize I was probably doing quite well, all things considered. Lately I’ve been thinking that I have probably even been doing quite a bit better than I’d thought I had. See also this and this link. I’ve gradually concluded that I’m probably never ‘going back’ now that I’ve familiarized myself with the ICC server.

And yes, I do occasionally win against opposition like that, also on position – below an example from a recent game against a player not on the list above (there are quite a few anonymous title-holders as well on the server):

Click to view full size – the list to the lower left is a list of other players online on the server at that point in time, ordered by rating; as should be clear, lots of title-holders have relatively low ratings (I’m not completely sure which rating pool was displayed in the sidebar at that time, but the defaults on display for me are 5- or 3-minutes, so for example the international master ‘softrain’ thus had either a 3 or 5 minute rating of 1799 at that time. Do note that ICC requires proof for titles to display on the server; random non-titled players do not display as titleholders on the ICC (actually the formally approved titled accounts obviously do not account for all accounts held by title-holders as some titled players on the server use accounts which do not give away the fact that they have a title).

Here’s another very nice illustration of how tough the X-minute pools are (/how strong the players playing on the ICC are):

Wang Hao
Again, click to view in full size. This is Chinese Grandmaster Wang Hao‘s ICC account. Wang Hao is currently #39 on the FIDE list of active chess players in the world, with a FIDE rating above 2700. Even his 5-minute rating on the ICC, based on more than a thousand games, is below 2300, and his current 3 minute rating is barely above 2000. With numbers like those, I currently feel quite satisfied with my 1700-1800 ratings (although I know I should be spending less time on chess than I currently do).

v. A few words I’ve recently encountered on Anaphora, usufruct, mimesis, amanuensis, peculate, elide, ataraxia, myrmidon, velleity.

vi. A few other wiki links: Fritz Haber, Great Stink (featured), Edward Low (a really nice guy, it seems – “A story describes Low burning a French cook alive, saying he was a “greasy fellow who would fry well”, and another tells he once killed 53 Spanish captives with his cutlass.[6]“), 1940 Soviet ultimatum to Lithuania (‘good article’).

vii. A really cute paper from the 2013 Christmas edition of the British Medical Journal: Were James Bond’s drinks shaken because of alcohol induced tremor? Here’s the abstract:

Objective To quantify James Bond’s consumption of alcohol as detailed in the series of novels by Ian Fleming.

Design Retrospective literature review.

Setting The study authors’ homes, in a comfy chair.

Participants Commander James Bond, 007; Mr Ian Lancaster Fleming.

Main outcome measures Weekly alcohol consumption by Commander Bond.

Methods All 14 James Bond books were read by two of the authors. Contemporaneous notes were taken detailing every alcoholic drink taken. Predefined alcohol unit levels were used to calculate consumption. Days when Bond was unable to consume alcohol (such as through incarceration) were noted.

Results After exclusion of days when Bond was unable to drink, his weekly alcohol consumption was 92 units a week, over four times the recommended amount. His maximum daily consumption was 49.8 units. He had only 12.5 alcohol free days out of 87.5 days on which he was able to drink.

Conclusions James Bond’s level of alcohol intake puts him at high risk of multiple alcohol related diseases and an early death. The level of functioning as displayed in the books is inconsistent with the physical, mental, and indeed sexual functioning expected from someone drinking this much alcohol. We advise an immediate referral for further assessment and treatment, a reduction in alcohol consumption to safe levels, and suspect that the famous catchphrase “shaken, not stirred” could be because of alcohol induced tremor affecting his hands.”

viii. A couple of other non-serious links which I found hilarious:
1) The Prof(essor) or Hobo quiz (via SSC).
2) Today’s SMBC. I’ll try to remember the words in the votey in the highly unlikely case I’ll ever have use for them – in my opinion it would be a real tragedy if one were to miss an opportunity to make a statement like that, given that it was at all suitable to the situation at hand..

July 6, 2015 Posted by | Chess, Diabetes, Epidemiology, History, Immunology, Infectious disease, Khan Academy, Lectures, Medicine, Personal | Leave a comment


Sorry for the infrequent updates. I realized blogging Wodehouse books takes more time than I’d imagined, so posting this sort of stuff is probably a better idea.

i. Dunkirk evacuation (wikipedia ‘good article’). Fascinating article, as are a few of the related ones which I’ve also been reading (e.g. Operation Ariel).

“On the first day of the evacuation, only 7,669 men were evacuated, but by the end of the eighth day, a total of 338,226 soldiers had been rescued by a hastily assembled fleet of over 800 boats. Many of the troops were able to embark from the harbour’s protective mole onto 39 British destroyers and other large ships, while others had to wade out from the beaches, waiting for hours in the shoulder-deep water. Some were ferried from the beaches to the larger ships by the famous little ships of Dunkirk, a flotilla of hundreds of merchant marine boats, fishing boats, pleasure craft, and lifeboats called into service for the emergency. The BEF lost 68,000 soldiers during the French campaign and had to abandon nearly all of their tanks, vehicles, and other equipment.”

One way to make sense of the scale of the operations here is to compare them with the naval activities on D-day four years later. The British evacuated more people from France during three consecutive days in 1940 (30th and 31st of May, and 1st of June) than the Allies (Americans and British combined) landed on D-day four years later, and the British evacuated roughly as many people on the 31st of May (68,014) as they landed by sea on D-day (75,215). Here’s a part of the story I did not know:

“Three British divisions and a host of logistic and labour troops were cut off to the south of the Somme by the German “race to the sea”. At the end of May, a further two divisions began moving to France with the hope of establishing a Second BEF. The majority of the 51st (Highland) Division was forced to surrender on 12 June, but almost 192,000 Allied personnel, 144,000 of them British, were evacuated through various French ports from 15–25 June under the codename Operation Ariel.[104] […] More than 100,000 evacuated French troops were quickly and efficiently shuttled to camps in various parts of southwestern England, where they were temporarily lodged before being repatriated.[106] British ships ferried French troops to Brest, Cherbourg, and other ports in Normandy and Brittany, although only about half of the repatriated troops were deployed against the Germans before the surrender of France. For many French soldiers, the Dunkirk evacuation represented only a few weeks’ delay before being killed or captured by the German army after their return to France.[107]

ii. A pretty awesome display by the current world chess champion:

If you feel the same way I do about Maurice Ashley, you’ll probably want to skip the first few minutes of this video. Don’t miss the games, though – this is great stuff. Do keep in mind when watching this video that the clock is a really important part of this event; other players in the past have played a lot more people at the same time while blindfolded than Carlsen does here – “Although not a full-time chess professional [Najdorf] was one of the world’s leading chess players in the 1950s and 1960s and he excelled in playing blindfold chess: he broke the world record twice, by playing blindfold 40 games in Rosario, 1943,[8] and 45 in São Paulo, 1947, becoming the world blindfold chess champion” (link) – but a game clock changes things a lot. A few comments and discussion here.
In very slightly related news, I recently got in my first win against a grandmaster in a bullet game on the ICC.

iii. Gastric-brooding frog.


“The genus was unique because it contained the only two known frog species that incubated the prejuvenile stages of their offspring in the stomach of the mother.[3] […] What makes these frogs unique among all frog species is their form of parental care. Following external fertilization by the male, the female would take the eggs or embryos into her mouth and swallow them.[19] […] Eggs found in females measured up to 5.1 mm in diameter and had large yolk supplies. These large supplies are common among species that live entirely off yolk during their development. Most female frogs had around 40 ripe eggs, almost double that of the number of juveniles ever found in the stomach (21–26). This means one of two things, that the female fails to swallow all the eggs or the first few eggs to be swallowed are digested. […] During the period that the offspring were present in the stomach the frog would not eat. […] The birth process was widely spaced and may have occurred over a period of as long as a week. However, if disturbed the female may regurgitate all the young frogs in a single act of propulsive vomiting.”

Fascinating creatures.. Unfortunately they’re no longer around (they’re classified as extinct).

iv. I’m sort of conflicted about what to think about this:

“Epidemiological studies show that patients with type-2-diabetes (T2DM) and individuals with a diabetes-independent elevation in blood glucose have an increased risk for developing dementia, specifically dementia due to Alzheimer’s disease (AD). These observations suggest that abnormal glucose metabolism likely plays a role in some aspects of AD pathogenesis, leading us to investigate the link between aberrant glucose metabolism, T2DM, and AD in murine models. […] Recent epidemiological studies demonstrate that individuals with type-2 diabetes (T2DM) are 2–4 times more likely to develop AD (35), individuals with elevated blood glucose levels are at an increased risk to develop dementia (5), and those with elevated blood glucose levels have a more rapid conversion from mild cognitive impairment (MCI) to AD (6), suggesting that disrupted glucose homeostasis could play a […] causal role in AD pathogenesis. Although several prominent features of T2DM, including increased insulin resistance and decreased insulin production, are at the forefront of AD research (710), questions regarding the effects of elevated blood glucose independent of insulin resistance on AD pathology remain largely unexplored. In order to investigate the potential role of glucose metabolism in AD, we combined glucose clamps and in vivo microdialysis as a method to measure changes in brain metabolites in awake, freely moving mice during a hyperglycemic challenge. Our findings suggest that acute hyperglycemia raises interstitial fluid (ISF) Aβ levels by altering neuronal activity, which increases Aβ production. […] Since extracellular Aβ, and subsequently tau, aggregate in a concentration-dependent manner during the preclinical period of AD while individuals are cognitively normal (27), our findings suggest that repeated episodes of transient hyperglycemia, such as those found in T2DM, could both initiate and accelerate plaque accumulation. Thus, the correlation between hyperglycemia and increased ISF Aβ provides one potential explanation for the increased risk of AD and dementia in T2DM patients or individuals with elevated blood glucose levels. In addition, our work suggests that KATP channels within the hippocampus act as metabolic sensors and couple alterations in glucose concentrations with changes in electrical activity and extracellular Aβ levels. Not only does this offer one mechanistic explanation for the epidemiological link between T2DM and AD, but it also provides a potential therapeutic target for AD. Given that FDA-approved drugs already exist for the modulation of KATP channels and previous work demonstrates the benefits of sulfonylureas for treating animal models of AD (26), the identification of these channels as a link between hyperglycemia and AD pathology creates an avenue for translational research in AD.”

Why am I conflicted? Well, on the one hand it’s nice to know that they’re making progress in terms of figuring out why people get Alzheimer’s and potential therapeutic targets are being identified. On the other hand this – “our findings suggest that repeated episodes of transient hyperglycemia […] could both initiate and accelerate plaque accumulation” – is bad news if you’re a type 1 diabetic (I’d much rather have them identify risk factors to which I’m not exposed).

v. I recently noticed that Khan Academy has put up some videos about diabetes. From the few ones I’ve had a look at they don’t seem to contain much stuff I don’t already know so I’m not sure I’ll explore this playlist in any more detail, but I figured I might as well share a few of the videos here; the first one is about the pathophysiology of type 1 diabetes and the second one’s about diabetic nephropathy (kidney disease):

vi. On Being the Right Size, by J. B. S. Haldane. A neat little text. A few quotes:

“To the mouse and any smaller animal [gravity] presents practically no dangers. You can drop a mouse down a thousand-yard mine shaft; and, on arriving at the bottom, it gets a slight shock and walks away, provided that the ground is fairly soft. A rat is killed, a man is broken, a horse splashes. For the resistance presented to movement by the air is proportional to the surface of the moving object. Divide an animal’s length, breadth, and height each by ten; its weight is reduced to a thousandth, but its surface only to a hundredth. So the resistance to falling in the case of the small animal is relatively ten times greater than the driving force.

An insect, therefore, is not afraid of gravity; it can fall without danger, and can cling to the ceiling with remarkably little trouble. It can go in for elegant and fantastic forms of support like that of the daddy-longlegs. But there is a force which is as formidable to an insect as gravitation to a mammal. This is surface tension. A man coming out of a bath carries with him a film of water of about one-fiftieth of an inch in thickness. This weighs roughly a pound. A wet mouse has to carry about its own weight of water. A wet fly has to lift many times its own weight and, as everyone knows, a fly once wetted by water or any other liquid is in a very serious position indeed. An insect going for a drink is in as great danger as a man leaning out over a precipice in search of food. If it once falls into the grip of the surface tension of the water—that is to say, gets wet—it is likely to remain so until it drowns. A few insects, such as water-beetles, contrive to be unwettable; the majority keep well away from their drink by means of a long proboscis. […]

It is an elementary principle of aeronautics that the minimum speed needed to keep an aeroplane of a given shape in the air varies as the square root of its length. If its linear dimensions are increased four times, it must fly twice as fast. Now the power needed for the minimum speed increases more rapidly than the weight of the machine. So the larger aeroplane, which weighs sixty-four times as much as the smaller, needs one hundred and twenty-eight times its horsepower to keep up. Applying the same principle to the birds, we find that the limit to their size is soon reached. An angel whose muscles developed no more power weight for weight than those of an eagle or a pigeon would require a breast projecting for about four feet to house the muscles engaged in working its wings, while to economize in weight, its legs would have to be reduced to mere stilts. Actually a large bird such as an eagle or kite does not keep in the air mainly by moving its wings. It is generally to be seen soaring, that is to say balanced on a rising column of air. And even soaring becomes more and more difficult with increasing size. Were this not the case eagles might be as large as tigers and as formidable to man as hostile aeroplanes.

But it is time that we pass to some of the advantages of size. One of the most obvious is that it enables one to keep warm. All warmblooded animals at rest lose the same amount of heat from a unit area of skin, for which purpose they need a food-supply proportional to their surface and not to their weight. Five thousand mice weigh as much as a man. Their combined surface and food or oxygen consumption are about seventeen times a man’s. In fact a mouse eats about one quarter its own weight of food every day, which is mainly used in keeping it warm. For the same reason small animals cannot live in cold countries. In the arctic regions there are no reptiles or amphibians, and no small mammals. The smallest mammal in Spitzbergen is the fox. The small birds fly away in winter, while the insects die, though their eggs can survive six months or more of frost. The most successful mammals are bears, seals, and walruses.” [I think he’s a bit too categorical in his statements here and this topic is more contested today than it probably was when he wrote his text – see wikipedia’s coverage of Bergmann’s rule].

May 26, 2015 Posted by | Biology, Chess, Diabetes, Epidemiology, History, Khan Academy, Lectures, Medicine, Nephrology, Neurology, Wikipedia, Zoology | Leave a comment

Data on Danish diabetics (Dansk Diabetes Database – National årsrapport 2013-2014)

[Warning: Long post].

I’ve blogged data related to the data covered in this post before here on the blog, but when I did that I only provided coverage in Danish. Part of my motivation for providing some coverage in English here (which is a slightly awkward and time consuming thing to do as all the source material is in Danish) is that this is the sort of data you probably won’t ever get to know about if you don’t understand Danish, and it seems like some of it might be worth knowing about also for people who do not live in Denmark. Another reason for posting stuff in English is of course that I dislike writing a blog post which I know beforehand that some of my regular readers will not understand. I should perhaps note that some of the data is at least peripherally related to my academic work at the moment.

The report which I’m covering in this post (here’s a link to it) deals primarily with various metrics collected in order to evaluate whether treatment goals which have been set centrally are being met by the Danish regions, one of the primary political responsibilities of which is to deal with health care service delivery. To take an example from the report, a goal has been set that at least 95 % of patients with known diabetes in the Danish regions should have their Hba1c (an important variable in the treatment context) measured at least once per year. The report of course doesn’t just contain a list of goals etc. – it also presents a lot of data which has been collected throughout the country in order to figure out to which extent the various goals have been met at the local levels. Hba1c is just an example; there are also goals set in relation to the variables hypertension, regular eye screenings, regular kidney function tests, regular foot examinations, and regular tests for hyperlipidemia, among others.

Testing is just one aspect of what’s being measured; other goals relate to treatment delivery. There’s for example a goal that the proportion of (known) type 2 diabetics with an Hba1c above 7.0% who are not receiving anti-diabetic treatment should be at most 5% within regions. A thought that occurred to me while reading the report was that it seemed to me that some interesting incentive problems might pop up here if these numbers were more important than I assume they are in the current decision-making context, because adding this specific variable without also adding a goal for ‘finding diabetics who do not know they are sick’ – and no such goal is included in the report, as far as I’ve been able to ascertain – might lead to problems; in theory a region that would do well in terms of identifying undiagnosed type 2 patients, of which there are many, might get punished for this if their higher patient population in treatment as a result of better identification might lead to binding capacity constraints at various treatment levels; capacity constraints which would not affect regions which are worse at identifying (non-)patients at risk because of the existence of a tradeoff between resources devoted to search/identification and resources devoted to treatment. Without a goal for identifying undiagnosed type 2 diabetics, it seems to me that to the extent that there’s a tradeoff between devoting resources to identifying new cases and devoting resources to the treatment of known cases, the current structure of evaluation, to the extent that it informs decision-making at the regional level, favours treatment over identification – which might or might not be problematic from a cost-benefit point of view. I find it somewhat puzzling that no goals relate to case-finding/diagnostics because a lot of the goals only really make sense if the people who are sick actually get diagnosed so that they can receive treatment in the first place; that, say, 95% of diabetics with a diagnosis receives treatment option X is much less impressive if, say, a third of all people with the disease do not have a diagnosis. Considering the relatively low amount of variation in some of the metrics included you’d expect a variable of this sort to be included here, at least I did.

The report has an appendix with some interesting information about the sex ratios, age distributions, how long people have had diabetes, whether they smoke, what their BMIs and blood pressures are like, how well they’re regulated (in terms of Hba1c), what they’re treated with (insulin, antihypertensive drugs, etc.), their cholesterol levels and triglyceride levels, etc. I’ll talk about these numbers towards the end of the post – if you want to get straight to this coverage and don’t care about the ‘main coverage’, you can just scroll down until you reach the ‘…’ point below.

The report has 182 pages with a lot of data, so I’m not going to talk about all of it. It is based on very large data sets which include more than 37.000 Danish diabetes patients from specialized diabetes units (diabetesambulatorier) (these are usually located in hospitals and provide ambulatory care only) as well as 34.000 diabetics treated by their local GPs – the aim is to eventually include all Danish diabetics in the database, and more are added each year, but even as it is a very big proportion of all patients are ‘accounted for’ in the data. Other sources also provide additional details, for example there’s a database on children and young diabetics collected separately. Most of the diabetics which are not included here are patients treated by their local GPs, and there’s still a substantial amount of uncertainty related to this group; approximately 90% of all patients connected to the diabetes units are assumed at this point to be included in the database, but the report also notes that approximately 80 % of diabetics are assumed to be treated in general practice. Coverage of this patient population is currently improving rapidly and it seems that most diabetics in Denmark will likely be included in the database within the next few years. They speculate in the report that the inclusion of more patients treated in general practice may be part of the explanation why goal achievement seems to have decreased slightly over time; this seems to me like a likely explanation considering the data they present as the diabetes units in general are better at achieving the goals set than are the GPs. The data is up to date – as some of you might have inferred from the presumably partly unintelligible words in the parenthesis in the title, the report deals with data from the time period 2013-2014. I decided early on not to copy tables into this post directly as it’s highly annoying to have to translate terms in such tables; instead I’ve tried to give you the highlights. I may or may not have succeeded in doing that, but you should be aware, especially if you understand Danish, that the report has a lot of details, e.g. in terms of intraregional variation etc., which are excluded from this coverage. Although I far from cover all the data, I do cover most of the main topics dealt with in the publication in at least a little bit of detail.

The report concludes in the introduction that for most treatment indicators no clinically significant differences in the quality of the treatment provided to diabetics are apparent when you compare the different Danish regions – so if you’re looking at the big picture, if you’re a Danish diabetic it doesn’t matter all that much if you live in Jutland or in Copenhagen. However some significant intra-regional differences do exist. In the following I’ll talk in a bit more detail about some of data included in the report.

When looking at the Hba1c goal (95% should be tested at least once per year), they evaluate the groups treated in the diabetes units and the groups treated in general practice separately; so you have one metric for patients treated in diabetes units living in the north of Jutland (North Denmark Region) and you have another group of patients treated in general practice living in the north of Jutland – this breakdown of the data makes it possible to not only compare people across regions but also to investigate whether there are important differences between the care provided by diabetes units and the care provided by general practitioners. When dealing with patients receiving ambulatory care from the diabetes units all regions meet the goal, but in Copenhagen (Capital Region of Denmark, (-CRD)) only 94% of patients treated in general practice had their Hba1c measured within the last year – this was the only region which did not meet the goal for the patient population treated in general practice. I would have thought beforehand that all diabetes units would have 100% coverage here, but that’s actually only the case in the region in which I live (Central Denmark Region) – on the other hand in most other regions, aside from Copenhagen again, the number is 99%, which seems reasonable as I’m assuming a substantial proportion of the remainder is explained by patient noncompliance, which is difficult to avoid completely. I speculate that patient compliance differences between patient populations treated at diabetes units and patient populations treated by their GP might also be part of the explanation for the lower goal achievement of the general practice population; as far as I’m aware diabetes units can deny care in the case of non-compliance whereas GPs cannot, so you’d sort of expect the most ‘difficult’ patients to end up in general practice; this is speculation to some extent and I’m not sure it’s a big effect, but it’s worth keeping in mind when analyzing this data that not all differences you observe necessarily relate to service delivery inputs (whether or not a doctor reminds a patient it’s time to get his eyes checked, for example); the two main groups analyzed are likely to also be different due to patient population compositions. Differences in patient population composition may of course also drive some of the intraregional variation observed. They mention in their discussion of the results for the Hba1c variable that they’re planning on changing the standard here to one which relate to the distributional results of the Hba1c, not just whether the test was done, which seems like a good idea. As it is, the great majority of Danish diabetics have their Hba1c measured at least annually, which is good news because of the importance of this variable in the treatment context.

In the context of hypertension, there’s a goal that at least 95% of diabetics should have their blood pressure measured at least once per year. In the context of patients treated in the diabetes units, all regions achieve the goal and the national average for this patient population is 97% (once again the region in which I live is the only one that achieved 100 % coverage), but in the context of patients treated in general practice only one region (North Denmark Region) managed to get to 95% and the national average is 90%. In most regions, one in ten diabetics treated in general practice do not have their blood pressure measured once per year, and again Copenhagen (CRD) is doing worst with a coverage of only 87%. As mentioned in the general comments above some of the intraregional variation is actually quite substantial, and this may be a good example because not all hospitals are doing great on this variable. Sygehus Sønderjylland, Aabenraa (in southern Jutland), one of the diabetes units, had a coverage of only 67%, and the percentage of patients treated at Hillerød Hospital in Copenhagen (CRD), another diabetes unit, was likewise quite low, with 83% of patients having had their blood pressure measured within the last year. These hospitals are however the exceptions to the rule. Evaluating whether it has been tested if patients do or do not have hypertension is different from evaluating whether hypertension is actually treated after it has been discovered, and here the numbers are less impressive; for the type 1 patients treated in the diabetes units, roughly one third (31%) of patients with a blood pressure higher than 140/90 are not receiving treatment for hypertension (the goal was at most 20%). The picture was much better for type 2 patients (11% at the national level) and patients treated in general practice (13%). They note that the picture has not improved over the last years for the type 1 patients and that this is not in their opinion a satisfactory state of affairs. A note of caution is that the variable only includes patients who have had a blood pressure measured within the last year which was higher than 140/90 and that you can’t use this variable as an indication of how many patients with high blood pressure are not being treated; some patients who are in treatment for high blood pressure have blood pressures lower than 140/90 (achieving this would in many cases be the point of treatment…). Such an estimate will however be added to later versions of the report. In terms of the public health consequences of undertreatment, the two patient populations are of course far from equally important. As noted later in the coverage, the proportion of type 2 patients on antihypertensive agents is much higher than the proportion of type 1 diabetics receiving treatment like this, and despite this difference the blood pressure distributions of the two patient populations are reasonably similar (more on this below).

Screening for albuminuria: The goal here is that at least 95 % of adult diabetics are screened within a two-year period (There are slightly different goals for children and young adults, but I won’t go into those). In the context of patients treated in the diabetes units, the northern Jutland Region and Copenhagen/RH failed to achieve the goal with a coverage slightly below 95% – the other regions achieved the goal, although not much more than that; the national average for this patient population is 96%. In the context of patients treated in general practice none of the regions achieve the goal and the national average for this patient population is 88%. Region Zealand was doing worst with 84%, whereas the region in which I live, Region Midtjylland, was doing best with a 92% coverage. Of the diabetes units, Rigshospitalet, “one of the largest hospitals in Denmark and the most highly specialised hospital in Copenhagen”, seems to also be the worst performing hospital in Denmark in this respect, with only 84 % of patients being screened – which to me seems exceptionally bad considering that for example not a single hospital in the region in which I live is below 95%. Nationally roughly 20% of patients with micro- or macroalbuminuria are not on ACE-inhibitors/Angiotensin II receptor antagonists.

Eye examination: The main process goal here is at least one eye examination every second year for at least 90% of the patients, and a requirement that the treating physician knows the result of the eye examination. This latter requirement is important in the context of the interpretation of the results (see below). For patients treated in diabetes units, four out of five regions achieved the goal, but there were also what to me seemed like large differences across regions. In Southern Denmark, the goal was not met and only 88 % had had an eye examination within the last two years, whereas the number was 98% in Region Zealand. Region Zealand was a clear outlier here and the national average for this patient population was 91%. For patients treated in general practice no regions achieved the goal, and this variable provides a completely different picture from the previous variables in terms of the differences between patients treated in diabetes units and patients treated in general practice: In most regions, the coverage here for patients in general practice is in the single digits and the national average for this patient population is just 5 %. They note in the report that this number has decreased over the years through which this variable has been analyzed, and they don’t know why (but they’re investigating it). It seems to be a big problem that doctors are not told about the results of these examinations, which presumably makes coordination of care difficult.

The report also has numbers on how many patients have had their eyes checked within the last 4 years, rather than within the last two, and this variable makes it clear that more infrequent screening is not explaining anything in terms of the differences between the patient populations; for patients treated in general practice the numbers are still here in the single digits. They mention that data security requirements imposed on health care providers are likely the reason why the numbers are low in general practice as it seems common that the GP is not informed of the results of screenings taking place, so that the only people who gets to know about the results are the ophthalmologists doing them. A new variable recently included in the report is whether newly-diagnosed type 2 diabetics are screened for eye-damage within 12 months of receiving their diagnosis – here they have received the numbers directly from the ophthalmologists so uncertainty about information sharing doesn’t enter the picture (well, it does, but the variable doesn’t care; it just measures whether an eye screen has been performed or not) – and although the standard set is 95% (at most one in twenty should not have their eyes checked within a year of diagnosis) at the national level only half of patients actually do get an eye screen within the first year (95% CI: 46-53%) – uncertainty about the date of diagnosis makes it slightly difficult to interpret some of the specific results, but the chosen standard is not achieved anywhere and this once again underlines how diabetic eye care is one of the areas where things are not going as well as the people setting the goals would like them to. The rationale for screening people within the first year of diagnosis is of course that many type 2 patients have complications at diagnosis – “30–50 per cent of patients with newly diagnosed T2DM will already have tissue complications at diagnosis due to the prolonged period of antecedent moderate and asymptomatic hyperglycaemia.” (link).

The report does include estimates of the number of diabetics who receive eye screenings regardless of whether the treating physician knows the results or not; at the national level, according to this estimate 65% of patients have their eyes screened at least once every second year, leaving more than a third of patients in a situation where they are not screened as often as is desirable. They mention that they have had difficulties with the transfer of data and many of the specific estimates are uncertain, including two of the regional estimates, but the general level – 65% or something like that – is based on close to 10.000 patients and is assumed to be representative. Approximately 1% of Danish diabetics are blind, according to the report.

Foot examinations: Just like most of the other variables: At least 95 % of patients, at least once every second year. For diabetics treated in diabetes units, the national average is here 96% and the goal was not achieved in Copenhagen (CRD) (94%) and northern Jutland (91%). There are again remarkable differences within regions; at Helsingør Hospital only 77% were screened (95% CI: 73-82%) (a drop from 94% the year before), and at Hillerød Hospital the number was even lower, 73% (95% CI: 70-75), again a drop from the previous year where the coverage was 87%. Both these numbers are worse than the regional averages for all patients treated in general practice, even though none of the regions meet the goal. Actually I thought the year-to-year changes in the context of these two hospitals were almost as interesting as the intraregional differences because I have a hard time explaining those; how do you even set up a screening programme such that a coverage drop of more than 10 % from one year to the next is possible? To those who don’t know, diabetic feet are very expensive and do not seem to get the research attention one might from a cost-benefit perspective assume they would (link, point iii). Going back to the patients in general practice on average 81 % of these patients have a foot examination at least once every second year. The regions here vary from 79% to 84%. The worst covered patients are patients treated in general practice in the Vordingborg sygehus catchment area in the Zealand Region, where only roughly two out of three (69%, 95% CI: 62-75%) patients have regularly foot examinations.

Aside from all the specific indicators they’ve collected and reported on, the authors have also constructed a combined indicator, an ‘all-or-none’ indicator, in which they measure the proportion of patients who have not failed to get their Hba1c measured, their feet checked, their blood pressure measured, kidney function tests, etc. … They do not include in this metric the eye screening variable because of the problems associated with this variable, but this is the only process variable not included, and the variable is sort of an indicator of how many of the patients are actually getting all of the care that they’re supposed to get. As patients treated in general practice are generally less well covered than patients treated in the diabetes units at the hospitals I was interested to know how much these differences ‘added up to’ in the end. For the diabetes units, 11 % of patients failed on at least one metric (i.e. did not have their feet checked/Hba1c measured/blood pressure measured/etc.), whereas this was the case for a third of patients in general practice (67%). Summed up like that it seems to me that if you’re a Danish diabetes patient and you want to avoid having some variable neglected in your care, it matters whether you’re treated by your local GP or by the local diabetes unit and that you’re probably going to be better off receiving care from the diabetes unit.

Some descriptive statistics from the appendix (p. 95 ->):

Sex ratio: In the case of this variable, they have multiple reports on the same variable based on data derived from different databases. In the first database, including 16.442 people, 56% are male and 44% are female. In the next database (n=20635), including only type 2 diabetics, the sex ratio is more skewed; 60% are males and 40% are females. In a database including only patients in general practice (n=34359), like in the first database 56% of the diabetics are males and 44% are females. For the patient population of children and young adults included (n=2624), the sex ratio is almost equal (51% males and 49% females). The last database, Diabase, based on evaluation of eye screening and including only adults (n=32842), have 55% males and 45% females. It seems to me based on these results that the sex ratio is slightly skewed in most patient populations, with slightly more males than females having diabetes – and it seems not improbable that this is to due to a higher male prevalence of type 2 diabetes (the children/young adult database and type 2 database seem to both point in this direction – the children/young adult group mainly consists of type 1 patients as 98% of this sample is type 1. The fact that the prevalence of autoimmune disorders is in general higher in females than in males also seems to support this interpretation; to the extent that the sex ratio is skewed in favour of males you’d expect lifestyle factors to be behind this.

Next, age distribution. In the first database (n=16.442), the average and the median age is 50, the standard deviation is 16, the youngest individual is 16 and the oldest is 95. It is worth remembering in this part of the reporting that the oldest individual in the sample is not a good estimate of ‘how long a diabetic can expect to live’ – for all we know the 95 year old in the database got diagnosed at the age of 80. You need diabetes duration before you can begin to speculate about that variable. Anyway, in the next database, of type 2 patients (n=20635), the average age is 64 (median=65), the standard deviation is 12 and the oldest individual is 98. In the context of both of the databases mentioned so far some regions do better than others in terms of the oldest individual, but it also seems to me that this may just be a function of the sample size and ‘random stuff’ (95+ year olds are rare events); Northern Jutland doesn’t have a lot of patients so the oldest patient in that group is not as old as the oldest patient from Copenhagen – this is probably but what you’d expect. In the general practice database (n=34359), the average age is 68 (median=69) and the standard deviation is 11; the oldest individual there is 102. In the Diabase database (n=32842), the average age is 62 (median=64), the standard deviation is 15 and the oldest individual is 98. It’s clear from these databases that most diabetics in Denmark are type 2 diabetics (this is no surprise) and that a substantial proportion of them are at or close to retirement age.

The appendix has a bit of data on diabetes type, but I think the main thing to take away from the tables that break this variable down is that type 1 is overrepresented in the databases compared to the true prevalence – in the Diabase database for example almost half of patients are type 1 (46%), despite the fact that type 1 diabetics are estimated to make up only 10% of the total in Denmark (see e.g. this (Danish source)). I’m sure this is to a significant extent due to lack of coverage of type 2 diabetics treated in general practice.

Diabetes duration: In the first data-set including 16.442 individuals the patients have a median diabetes duration of 21,2 years. The 10% cutoff is 5,4 years, the 25% cutoff is 11,3 years, the 75% cutoff is 33,5 years, and the 90% cutoff is 44,2 years. High diabetes durations are more likely to be observed in type 1 patients as they’re in general diagnosed earlier; in the next database involving only type 2 patients (n=20635), the median duration is 12.9 years and the corresponding cutoffs are 3,8 years (10%); 7,4 years (25%); 18,6 years (75%); and 24,7 years (90%). In the database involving patients treated in general practice, the median duration is 6,8 years and the cutoffs reported for the various percentiles are 2,5 years (10%), 4,0 (25%), 11,2 (75%) and 15,6 (90%). One note not directly related to the data but which I thought might be worth adding here is that of one were to try to use these data for the purposes of estimating the risk of complications as a function of diabetes duration, it would be important to have in mind that there’s probably often a substantial amount of uncertainty associated with the diabetes duration variable because many type 2 diabetics are diagnosed after a substantial amount of time with sub-optimal glycemic control; i.e. although diabetes duration is lower in type 2 populations than in type 1 populations, I’d assume that the type 2 estimates of duration are still biased downwards compared to type 1 estimates causing some potential issues in terms of how to interpret associations found here.

Next, smoking. In the first database (n=16.442), 22% of diabetics smoke daily and another 22% are ex-smokers who have not smoked within the last 6 months. According to the resource to which you’re directed when you’re looking for data on that kind of stuff on Statistics Denmark, the percentage of daily smokers was 17% in 2013 in the general population (based on n=158.870 – this is a direct link to the data), which seems to indicate that the trend (this is a graph of the percentage of Danes smoking daily as a function of time, going back to the 70es) I commented upon (Danish link) a few years back has not reversed or slowed down much. If we go back to the appendix and look at the next source, dealing with type 2 diabetics, 19% of them are smoking daily and 35% of them are ex-smokers (again, 6 months). In the general practice database (n=34.359) 17% of patients smoke daily and 37% are ex-smokers.

BMI. Here’s one variable where type 1 and type 2 look very different. The first source deals with type 1 diabetics (n=15.967) and here the median BMI is 25.0, which is comparable to the population median (if anything it’s probably lower than the population median) – see e.g. page 63 here. Relevant percentile cutoffs are 20,8 (10%), 22,7 (25%), 28,1 (75%), and 31,3 (90%). Numbers are quite similar across regions. For the type 2 data, the first source (n=20.035) has a median BMI of 30,7 (almost equal to the 1 in 10 cutoff for type 1 diabetics), with relevant cutoffs of 24,4 (10%), 27,2 (25%), 34,9 (75%), and 39,4 (90%). According to this source, one in four type 2 diabetics in Denmark are ‘severely obese‘ and more diabetics are obese than are not. It’s worth remembering that using these numbers to implicitly estimate the risk of type 2 diabetes associated with overweight is problematic as especially some of the people in the lower end of the distribution are quite likely to have experienced weight loss post-diagnosis. For type 2 patients treated in general practice (n=15.736), the median BMI is 29,3 and cutoffs are 23,7 (10%), 26,1 (25%), 33,1 (75%), and 37,4 (90%).

Distribution of Hba1c. The descriptive statistics included also have data on the distribution of Hba1c values among some of the patients who have had this variable measured. I won’t go into the details here except to note that the differences between type 1 and type 2 patients in terms of the Hba1c values achieved are smaller than I’d perhaps expected; the median Hba1c among type 1s was estimated at 62, based on 16.442 individuals, whereas the corresponding number for type 2s was 59, based on 20.635 individuals. Curiously, a second data source finds a median Hba1c of only 48 for type 2 patients treated in general practice; the difference between this one and the type 1 median is definitely high enough to matter in terms of the risk of complications (it’s more questionable how big the effect of a jump from 59 to 62 is, especially considering measurement error and the fact that the type 1 distribution seems denser than the type 2 distribution so that there aren’t that many more exceptionally high values in the type 1 dataset), but I wonder if this actually quite impressive level of metabolic control in general practice may not be due to biased reporting, with GPs doing well in terms of diabetes management being also more likely to report to the databases; it’s worth remembering that most patients treated in general practice are still not accounted for in these data-sets.

Oral antidiabetics and insulin. In one sample of 20.635 type 2 patients, 69% took oral antidiabetics, and in another sample of 34.359 type 2 patients treated in general practice the number was 75%. 3% of type 1 diabetics in a sample of 16.442 individuals also took oral antidiabetics, which surprised me. In the first-mentioned sample of type 2 patients 69% (but not the same amount of individuals – this was not a reporting error) also took insulin, so there seems to be a substantial number of patients on both treatments. In the general practice sample included the number of patients on insulin was much lower, as only 14% of type 2 patients were on insulin – again concerns about reporting bias may play a role here, but even taking this number at face value and extrapolating out of sample you reach the conclusion that the majority of patients on insulin are probably type 2 diabetics, as only roughly one patient in 10 is type 1.

Antihypertensive treatment and treatment for hyperlipidemia: Although there as mentioned above seems to be less focus on hypertension in type 1 patients than on hypertension in type 2 patients, it’s still the case that roughly half (48%) of all patients in the type 1 sample (n=16.442) was on antihypertensive treatment. In the first type 2 sample (n=20635), 82% of patients were receiving treatment against hypertension, and this number was similar in the general practice sample (81%). The proportions of patients in treatment for hyperlipidemia are roughly similar (46% of type 1, and 79% and 73% in the two type 2 samples, respectively).

Blood pressure. The median level of systolic blood pressure among type 1 diabetics (n=16442) was 130, with the 75% cutoff intersecting the hypertension level (140) and 10% of patients having a systolic blood pressure above 151. These numbers are almost identical to the sample of type 2 patients treated in general practice, however as earlier mentioned this blood pressure level is achieved with a lower proportion of patients in treatment for hypertension. In the second sample of type 2 patients (n=20635), the numbers were slightly higher (median: 133, 75% cutoff: 144, 90% cutoff: 158). The median diastolic blood pressure was 77 in the type 1 sample, with 75 and 90% cutoffs of 82 and 89; the data in the type 2 samples are almost identical.

April 24, 2015 Posted by | Data, Diabetes, Epidemiology, Medicine | Leave a comment

An Introduction to Medical Diagnosis (4)

Here’s a previous post in the series covering this book. There’s a lot of stuff in these chapters, so the stuff below’s just some of the things I thought were interesting and worth being aware of. I’ve covered three chapters in this post: One about skin, nails and hair, one about the eye, and one about infectious and tropical diseases. I may post one more post about the book later on, but I’m not sure if I’ll do that or not at this point so this may be the last post in the series.

Okay, on to the book – skin, nails and hair (my coverage mostly deals with the skin):

“The skin is a highly specialized organ that covers the entire external surface of the body. Its various roles include protecting the body from trauma, infection and ultraviolet radiation. It provides waterproofing and is important for fluid and temperature regulation. It is essential for the detection of some sensory stimuli. […] Skin problems are extremely common and are responsible for 10–15 per cent of all consultations in general practice. […] Given that there are around 2000 dermatological conditions described, only common and important conditions, including some that might be especially relevant in the examination setting, can be covered here.”

Urticaria is characterized by the development of red dermal swellings known as weals […]. Scaling is not seen and the lesions are typically very itchy. The lesions result from the release of histamine from mast cells. An important clue to the diagnosis is that individual lesions come and go within 24 hours, although new lesions may be appearing at other sites. Another associated feature is dermographism: a firm scratch of the skin with an orange stick will produce a linear weal within a few minutes. Urticaria is common, estimated to affect up to 20 per cent of the population at some point in their lives.”

“Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are thought to be two ends of a spectrum of the same condition. They are usually attributable to drug hypersensitivity, though a precipitant is not always identified. The latent period following initiation of the drug tends to be longer than seen with a classical maculopapular drug eruption. The disease is termed:
*SJS when 10 per cent or less of the body surface area epidermis detaches
*TEN when greater than 30 per cent detachment occurs.
Anything in between is designated SJS/TEN overlap. Following a prodrome of fever, an erythematous eruption develops. Macules, papules, or plaques may be seen. Some or all of the affected areas become vesicular or bullous, followed by sloughing off of the dead epidermis. This leads to potentially widespread denudation of skin. […] The affected skin is typically painful rather than itchy. […] The risk of death relates to the extent of epidermal loss and can exceed 30 per cent. […] A widespread ‘drug rash’ that is very painful should ring alarm bells.”

“Various skin problems arise in patients with diabetes mellitus. Bacterial and fungal infections are more common, due to impaired immunity. Vascular disease and neuropathy lead to ulceration on the feet, which can sometimes be very deep and there may be underlying osteomyelitis. Granuloma annulare […] and necrobiosis lipoidica have also been associated with diabetes, though many cases are seen in non-diabetic patients. The former produces smooth papules in an annular configuration, often coalescing into a ring. The latter usually occurs over the shins giving rise to yellow-brown discoloration, with marked atrophy and prominent telangiectasia. There is often an annular appearance, with a red or brown border. Acanthosis nigricans, velvety thickening of the flexural skin […], is seen with insulin resistance, with or without frank diabetes. […] Diabetic bullae are also occasionally seen and diabetic dermopathy produces hyperpigmented, atrophic plaques on the legs. The aetiology of these is unknown.”

“Malignant melanoma is one of the commonest cancers in young adults [and it] is responsible for almost three-quarters of skin cancer deaths, despite only accounting for around 4 per cent of skin cancers. Malignant melanoma can arise de novo or from a pre-existing naevus. Most are pigmented, but some are amelanotic. The most important prognostic factor for melanoma is the depth of the tumour when it is excised – Breslow’s thickness. As most malignant melanomas undergo a relatively prolonged radial (horizontal) growth phase prior to invading vertically, there is a window of opportunity for early detection and management, while the prognosis remains favourable. […] ‘Red flag’ findings […] in pigmented lesions are increasing size, darkening colour, irregular pigmentation, multiple colours within the same lesion, and itching or bleeding for no reason. […] In general, be suspicious if a lesion is rapidly changing.”

The eye:

“Most ocular surface diseases […] are bilateral, whereas most serious pathology (usually involving deeper structures) is unilateral […] Any significant reduction of vision suggests serious pathology [and] [s]udden visual loss always requires urgent investigation and referral to an ophthalmologist. […] Sudden loss of vision is commonly due to a vascular event. These may be vessel occlusions giving rise to ischaemia of vision-serving structures such as the retina, optic nerve or brain. Alternatively there may be vessel rupture and consequent bleeding which may either block transmission of light as in traumatic hyphaema (haemorrhage into the anterior chamber) and vitreous haemorrhage, or may distort the retina as in ‘wet’ age-related macular degeneration (AMD). […] Gradual loss of vision is commonly associated with degenerations or depositions. […] Transient loss of vision is commonly due to temporary or subcritical vascular insufficiency […] Persistent loss of vision suggests structural changes […] or irreversible damage”.

There are a lot of questions one might ask here, and I actually found it interesting to know how much can be learned simply by asking some questions which might help narrow things down – the above are just examples of variables to consider, and there are others as well, e.g. whether or not there is pain (“Painful blurring of vision is most commonly associated with diseases at the front of the eye”, whereas “Painless loss of vision usually arises from problems in the posterior part of the eye”), whether there’s discharge, just how the vision is affected (a blind spot, peripheral field loss, floaters, double vision, …), etc.

“Ptosis (i.e. drooping lid) and a dilated pupil suggest an ipsilateral cranial nerve III palsy. This is a neuro-ophthalmic emergency since it may represent an aneurysm of the posterior communicating artery. […] In such cases the palsy may be the only warning of impending aneurysmal rupture with subsequent subarachnoid haemorrhage. One helpful feature that warns that a cranial nerve III palsy may be compressive is pupil involvement (i.e. a dilated pupil).”

“Although some degree of cataract (loss of transparency of the lens) is almost universal in those >65 years of age, it is only a problem when it is restricting the patient’s activity. It is most commonly due to ageing, but it may be associated with ocular disease (e.g. uveitis), systemic disease (e.g. diabetes), drugs (e.g. systemic corticosteroids) or it may be inherited. It is the commonest cause of treatable blindness worldwide. […] Glaucoma describes a group of eye conditions characterized by a progressive optic neuropathy and visual field loss, in which the intraocular pressure is sufficiently raised to impair normal optic nerve function. Glaucoma may present insidiously or acutely. In the more common primary open angle glaucoma, there is an asymptomatic sustained elevation in intraocular pressure which may cause gradual unnoticed loss of visual field over years, and is a significant cause of blindness worldwide. […] Primary open angle glaucoma is asymptomatic until sufficiently advanced for field loss to be noticeable to the patient. […] Acute angle closure glaucoma is an ophthalmic emergency in which closure of the drainage angle causes a sudden symptomatic elevation of intraocular pressure which may rapidly damage the optic nerve.”

“Age-related macular degeneration is the commonest cause of blindness in the older population (>65 years) in the Western world. Since it is primarily the macula […] that is affected, patients retain their peripheral vision and with it a variable level of independence. There are two forms: ‘dry’ AMD accounts for 90 per cent of cases and the more dramatic ‘wet’ (also known as neovascular) AMD accounts for 10 per cent. […] Treatments for dry AMD do not alter the course of the disease but revolve around optimizing the patient’s remaining vision, such as using magnifiers. […] Treatments for wet AMD seek to reverse the neovascular process”.

“Diabetes is the commonest cause of blindness in the younger population (<65 years) in the Western world. Diabetic retinopathy is a microvascular disease of the retinal circulation. In both type 1 and type 2 diabetes glycaemic control and blood pressure should be optimized to reduce progression. Progression of retinopathy to the proliferative stage is most commonly seen in type 1 diabetes, whereas maculopathy is more commonly a feature of type 2 diabetes. […] Symptoms
*Bilateral. *Usually asymptomatic until either maculopathy or vitreous haemorrhage. [This is part of why screening programs for diabetic eye disease are so common – the first sign of eye disease may well be catastrophic and irreversible vision loss, despite the fact that the disease process may take years or decades to develop to that point] *Gradual loss of vision – suggests diabetic maculopathy (especially if distortion) or cataract. *Sudden loss of vision – most commonly vitreous haemorrhage secondary to proliferative diabetic retinopathy.”

Recap of some key points made in the chapter:
“*For uncomfortable/red eyes, grittiness, itchiness or a foreign body sensation usually indicate ocular surface problems such as conjunctivitis.
*Severe ‘aching’ eye pain suggests serious eye pathology such as acute angle closure glaucoma or scleritis.  *Photophobia is most commonly seen with acute anterior uveitis or corneal disease (ulcers or trauma). [it’s also common in migraine]
*Sudden loss of vision is usually due to a vascular event (e.g. retinal vessel occlusions, anterior ischaemic optic neuropathy, ‘wet’ AMD).
*Gradual loss of vision is common in the ageing population. It is frequently due to cataract […], primary open angle glaucoma (peripheral field loss) or ‘dry’ AMD (central field loss).
*Recent-onset flashes and floaters should be presumed to be retinal tear/detachment.
*Double vision may be monocular (both images from the same eye) or binocular (different images from each eye). Binocular double vision is serious, commonly arising from a cranial nerve III, IV or VI palsy. […]
the following presentations are sufficiently serious to warrant urgent referral to an ophthalmologist: sudden loss of vision, severe ‘aching’ eye pain, new-onset flashes and floaters, [and] new-onset binocular diplopia.”

Infectious and tropical diseases:

“Patients with infection (and inflammatory conditions or, less commonly, malignancy) usually report fever […] Whatever the cause, body temperature generally rises in the evening and falls during the night […] Fever is often lower or absent in the morning […]. A sensation of ‘feeling hot’ or ‘feeling cold’ is unreliable – healthy individuals often feel these sensations, as may those with menopausal flushing, thyrotoxicosis, stress, panic, or migraine. The height and duration of fever are important. Rigors (chills or shivering, often uncontrollable and lasting for 20–30 minutes) are highly significant, and so is a documented temperature over 37.5 °C taken with a reliable oral thermometer. Drenching sweats are also highly significant. Rigors generally indicate serious bacterial infections […] or malaria. An oral temperature >39 °C has the same significance as rigors. Rigors generally do not occur in mild viral infections […] malignancy, connective tissue diseases, tuberculosis and other chronic infections. […] Anyone with fever lasting longer than a week should have lost weight – if a patient reports a prolonged fever but no weight loss, the ‘fever’ usually turns out to be of no consequence. […] untouched meals indicate ongoing illness; return of appetite is a reliable sign of recovery.”

“Bacterial infections are the most common cause of sepsis, but other serious infections (e.g. falciparum malaria) or inflammatory states (e.g. pancreatitis, pre-eclamptic toxaemia, burns) can cause the same features. Below are listed the indicators of sepsis – the more abnormal the result, the more severe is the patient’s condition.
*Check if it is above 38 °C or below 36 °C.
*Simple viral infections seldom exceed 39 °C.
*Temperatures (from any cause) are generally higher in the evening than in the early morning.
*As noted above, rigors (uncontrollable shivering) are important indicators of severe bacterial infection or malaria. […] A heart rate greater than 90 beats/min is abnormal, and in severe sepsis a pulse of 140/min is not unusual. […] Peripheries (fingers, toes, nose) are often markedly cooler than central skin (trunk, forehead) with prolonged capillary refill time […] Blood pressure (BP) is low in the supine position (systolic BP <90 mmHg) and falls further when the patient is repositioned upright. In septic shock sometimes the BP is unrecordable on standing, and the patient may faint when they are helped to stand up […] The first sign [of respiratory disturbance] is a respiratory rate greater than 20 breaths/min. This is often a combination of two abnormalities: hypoxia caused by intrapulmonary shunts, and lactic acidosis. […] in hypoxia, the respiratory pattern is normal but rapid. Acidotic breathing has a deep, sighing character (also known as Kussmaul’s respiration). […] Also called toxic encephalopathy or delirium, confusion or drowsiness is often present in sepsis. […] Sepsis is always severe when it is accompanied by organ dysfunction. Septic shock is defined as severe sepsis with hypotension despite adequate fluid replacement.”

“Involuntary neck stiffness (‘nuchal rigidity’) is a characteristic sign of meningitis […] Patients with meningitis or subarachnoid haemorrhage characteristically lie still and do not move the head voluntarily. Patients who complain about a stiff neck are often worried about meningitis; patients with meningitis generally complain of a sore head, not a sore neck – thus neck stiffness is a sign, not a symptom, of meningitis.”

“General practitioners are generally correct when they say an infection is ‘a virus’, but the doctor needs to make an accurate assessment to be sure of not missing a serious bacterial infection masquerading as ‘flu’. […]
*Influenza is highly infectious, so friends, family, or colleagues should also be affected at the same time – the incubation period is short (1–3 days). If there are no other cases, question the diagnosis.
*The onset of viraemic symptoms is abrupt and often quite severe, with chills, headache, and myalgia. There may be mild rigors on the first day, but these are not sustained.
*As the next few days pass, the fever improves each day, and by day 3 the fever is settling or absent. A fever that continues for more than 3 days is not uncomplicated ’flu, and nor is an illness with rigors after the first day.
*As the viraemia subsides, so the upper respiratory symptoms become prominent […] The patient experiences a combination of: rasping sore throat, dry cough, hoarseness, coryza, red eyes, congested sinuses. These persist for a long time (10 days is not unusual) and the patient feels ‘miserable’ but the fever is no longer prominent.”

“Several infections cause a similar picture to ‘glandular fever’. The commonest is EBV [Epstein–Barr Virus], with cytomegalovirus (CMV) a close second; HIV seroconversion may look clinically identical, and acute toxoplasmosis similar (except for the lack of sore throat). Glandular fever in the USA is called ‘infectious mononucleosis’ […] The illness starts with viraemic symptoms of fever (without marked rigors), myalgia, lassitude, and anorexia. A sore throat is characteristic, and the urine often darkens (indicating liver involvement). […] Be very alert for any sign of stridor, or if the tonsils meet in the middle or are threatening to obstruct (a clue is that the patient is unable to swallow their saliva and is drooling or spitting it out). If there are any of these signs of upper airway obstruction, give steroids, intravenous fluids, and call the ENT surgeons urgently – fatal obstruction occasionally occurs in the middle of the night. […] Be very alert for a painful or tender spleen, or any signs of peritonism. In glandular fever the spleen may rupture spontaneously; it is rare, but tragic. It usually begins as a subcapsular haematoma, with pain and tenderness in the left upper quadrant. A secondary rupture through the capsule then occurs at a later date, and this is often rapidly fatal.”

April 7, 2015 Posted by | Books, Cancer/oncology, Diabetes, Infectious disease, Medicine, Neurology | Leave a comment

A Systematic Review… (II)

Yesterday I gave some of the reasons I had for disliking the book; in this post I’ll provide some of the reasons why I kept reading. The book had a lot of interesting data. I know I’ve covered some of these topics and numbers before (e.g. here), but I don’t mind repeating myself every now and then; some things are worth saying more than once, and as for the those that are not I must admit I don’t really care enough about not repeating myself here to spend time perusing the archives in order to make sure I don’t repeat myself here. Anyway, here are some number from the coverage:

“Twenty-two high-burden countries account for over 80 % of the world’s TB cases […] data referring to 2011 revealed 8.7 million new cases of TB [worldwide] (13 % coinfected with HIV) and 1.4 million people deaths due to such disease […] Around 80 % of TB cases among people living with HIV were located in Africa. In 2011, in the WHO European Region, 6 % of TB patients were coinfected with HIV […] In 2011, the global prevalence of HIV accounted for 34 million people; 69 % of them lived in Sub-Saharan Africa. Around five million people are living with HIV in South, South-East and East Asia combined. Other high-prevalence regions include the Caribbean, Eastern Europe and Central Asia [11]. Worldwide, HIV incidence is in downturn. In 2011, 2.5 million people acquired HIV infection; this number was 20 % lower than in 2001. […] Sub-Saharan Africa still accounts for 70 % of all AIDS-related deaths […] Worldwide, an estimated 499 million new cases of curable STIs (as gonorrhoea, chlamydia and syphilis) occurred in 2008; these findings suggested no improvement compared to the 448 million cases occurring in 2005. However, wide variations in the incidence of STIs are reported among different regions; the burden of STIs mainly occurs in low-income countries”.

“It is estimated that in 2010 alone, malaria caused 216 million clinical episodes and 655,000 deaths. An estimated 91 % of deaths in 2010 were in the African Region […]. A total of 3.3 billion people (half the world’s population) live in areas at risk of malaria transmission in 106 countries and territories”.

“Diarrhoeal diseases amount to an estimated 4.1 % of the total disability-adjusted life years (DALY) global burden of disease, and are responsible for 1.8 million deaths every year. An estimated 88 % of that burden is attributable to unsafe supply of water, sanitation and hygiene […] It is estimated that diarrhoeal diseases account for one in nine child deaths worldwide, making diarrhoea the second leading cause of death among children under the age of 5 after pneumonia”

“NCDs [Non-Communicable Diseases] are the leading global cause of death worldwide, being responsible for more
deaths than all other causes combined. […] more than 60 % of all deaths worldwide currently stem from NCDs [3].
In 2008, the leading causes of all NCD deaths (36 million) were:
• CVD [cardiovascular disease] (17 million, or 48 % of NCD deaths) [nearly 30 % of all deaths];
• Cancer (7.6 million, or 21 % of NCD deaths) [about 13 % of all deaths]
• Respiratory diseases (4.2 million, or 12 % of NCD deaths) [7 % of all deaths]
• Diabetes (1.3 million, 4 % of NCD deaths) [4].” [Elsewhere in the publication they report that: “In 2010, diabetes was responsible for 3.4 million deaths globally and 3.6 % of DALYs” – obviously there’s a lot of uncertainty here. How to avoid ‘double-counting’ is one of the major issues, because we have a pretty good idea what they die of: “CVD is by far the most frequent cause of death in both men and women with diabetes, accounting for about 60 % of all mortality”].

“Behavioural risk factors such as physical inactivity, tobacco use and unhealthy diet explain nearly 80 % of the CVD burden”

“nearly 80 % of NCD deaths occur in low- and middle-income countries [4], up sharply from just under 40 % in 1990 […] Low- and lower-middle-income countries have the highest proportion of deaths from NCDs under 60 years. Premature deaths under 60 years for high-income countries were 13 and 25 % for upper-middle-income countries. […] In low-income countries, the proportion of premature NCD deaths under 60 years is 41 %, three times the proportion in high-income countries [7]. […] Overall, NCDs account for more than 50 % of DALYs [disability-adjusted life years] in most counties. This percentage rises to over 80 % in Australia, Japan and the richest countries of Western Europe and North America […] In Europe, CVD causes over four million deaths per year (52 % of deaths in women and 42 % of deaths in men), and they are the main cause of death in women in all European countries.”

“Overall, age-adjusted CVD death rates are higher in most low- and middle-income countries than in developed countries […]. CHD [coronary heart disease] and stroke together are the first and third leading causes of death in developed and developing countries, respectively. […] excluding deaths from cancer, these two conditions were responsible for more deaths in 2008 than all remaining causes among the ten leading causes of death combined (including chronic diseases of the lungs, accidents, diabetes, influenza, and pneumonia)”.

“The global prevalence of diabetes was estimated to be 10 % in adults aged 25 + years […] more than half of all nontraumatic lower limb amputations are due to diabetes [and] diabetes is one of the leading causes of visual impairment and blindness in developed countries [14].”

“Almost six million people die from tobacco each year […] Smoking is estimated to cause nearly 10 % of CVD […] Approximately 2.3 million die each year from the harmful use of alcohol. […] Alcohol abuse is responsible for 3.8 % of all deaths (half of which are due to CVD, cancer, and liver cirrhosis) and 4.5 % of the global burden of disease […] Heavy alcohol consumption (i.e. ≥ 4 drinks/day) is significantly associated with an about fivefold increased risk of oral and pharyngeal cancer and oesophageal squamous cell carcinoma (SqCC), 2.5-fold for laryngeal cancer, 50 % for colorectal and breast cancers and 30 % for pancreatic cancer [37]. These estimates are based on a large number of epidemiological studies, and are generally consistent across strata of several covariates. […] The global burden of cancer attributable to alcohol drinking has been estimated at 3.6 and 3.5 % of cancer deaths [39], although this figure is higher in high-income countries (e.g. the figure of 6 % has been proposed for UK [9] and 9 % in Central and Eastern Europe).”

“At least two million cancer cases per year (18 % of the global cancer burden) are attributable to chronic infections by human papillomavirus, hepatitis B virus, hepatitis C virus and Helicobacter pylori. These infections are largely preventable or treatable […] The estimate of the attributable fraction is higher in low- and middle-income countries than in high-income countries (22.9 % of total cancer vs. 7.4 %).”

“Information on the magnitude of CVD in high-income countries is available from three large longitudinal studies that collect multidisciplinary data from a representative sample of European and American individuals aged 50 and older […] according to the Health Retirement Survey (HRS) in the USA, almost one in three adults have one or more types of CVD [11, 12]. By contrast, the data of Survey of Health, Ageing and Retirement in Europe (SHARE), obtained from 11 European countries, and English Longitudinal Study of Aging (ELSA) show that disease rates (specifically heart disease, diabetes, and stroke) across these populations are lower (almost one in five)”

“In 1990, the major fraction of morbidity worldwide was due to communicable, maternal, neonatal, and nutritional disorders (47 %), while 43 % of disability adjusted life years (DALYs) lost were attributable to NCDs. Within two decades, these estimates had undergone a drastic change, shifting to 35 % and 54 %, respectively”

“Estimates of the direct health care and nonhealth care costs attributable to CVD in many countries, especially in low- and middle-income countries, are unclear and fragmentary. In high-income countries (e.g., USA and Europe), CVD is the most costly disease both in terms of economic costs and human costs. Over half (54 %) of the total cost is due to direct health care costs, while one fourth (24 %) is attributable to productivity losses and 22 % to the informal care of people with CVD. Overall, CVD is estimated to cost the EU economy, in terms of health care, almost €196 billion per year, i.e., 9 % of the total health care expenditure across the EU”

“In the WHO European Region, the Eastern Mediterranean Region, and the Region of the Americas, over 50 % of women are overweight. The highest prevalence of overweight among infants and young children is in upper-to-middle-income populations, while the fastest rise in overweight is in the lower-to-middle-income group [19]. Globally, in 2008, 9.8 % of men and 13.8 % of women were obese compared to 4.8 % of men and 7.9 % of women in 1980 [27].”

“In low-income countries, around 25 % of adults have raised total cholesterol, while in high-income countries, over 50 % of adults have raised total cholesterol […]. Overall, one third of CHD disease is attributable to high cholesterol levels” (These numbers seem very high to me, but I’m reporting them anyway).

“interventions based on tobacco taxation have a proportionally greater effect on smokers of lower SES and younger smokers, who might otherwise be difficult to influence. Several studies suggest that the application of a 10 % rise in price could lead to as much as a 2.5–10 % decline in smoking [20, 45, 50, 56].”

“The decision to allocate resources for implementing a particular health intervention depends not only on the strength of the evidence (effectiveness of intervention) but also on the cost of achieving the expected health gain. Cost-effectiveness analysis is the primary tool for evaluating health interventions on the basis of the magnitude of their incremental net benefits in comparison with others, which allows the economic attractiveness of one program over another to be determined [More about this kind of stuff here]. If an intervention is both more effective and less costly than the existing one, there are compelling reasons to implement it. However, the majority of health interventions do not meet these criteria, being either more effective but more costly, or less costly but less effective, than the existing interventions [see also this]. Therefore, in most cases, there is no “best” or absolute level of cost-effectiveness, and this level varies mainly on the basis of health care system expenditure and needs [102].”

“The number of new cases of cancer worldwide in 2008 has been estimated at about 12,700,000 [3]. Of these, 6,600,000 occurred in men and 6,000,000 in women. About 5,600,000 cases occurred in high-resource countries […] and 7,100,000 in low- and middle-income countries. Among men, lung, stomach, colorectal, prostate and liver cancers are the most common […], while breast, colorectal, cervical, lung and stomach are the most common neoplasms among women […]. The number of deaths from cancer was estimated at about 7,600,000 in 2008 […] No global estimates of survival from cancer are available: Data from selected cancer registries suggest wide disparities between high- and low-income countries for neoplasms with effective but expensive treatment, such as leukaemia, while the gap is narrow for neoplasms without an effective therapy, such as lung cancer […]. The overall 5-year survival of cases diagnosed during 1995– 1999 in 23 European countries was 49.6 % […] Tobacco smoking is the main single cause of human cancer worldwide […] In high-income countries, tobacco smoking causes approximately 30 % of all human cancers [9].”

“Systematic reviews have concluded that nutritional factors may be responsible for about one fourth of human cancers in high-income countries, although, because of the limitations of the current understanding of the precise role of diet in human cancer, the proportion of cancers known to be avoidable in practicable ways is much smaller [9]. The only justified dietary recommendation for cancer prevention is to reduce the total caloric intake, which would contribute to a decrease in overweight and obesity, an established risk factor for human cancer. […] The magnitude of the excess risk [associated with obesity] is not very high (for most cancers, the relative risk (RR) ranges between 1.5 and 2 for body weight higher than 35 % above the ideal weight). Estimates of the proportion of cancers attributable to overweight and obesity in Europe range from 2 % [9] to 5 % [34]. However, this figure is likely to be larger in North America, where the prevalence of overweight and obesity is higher.”

“Estimates of the global burden of cancer attributable to occupation in high-income countries result in the order of 1–5 % [9, 42]. In the past, almost 50 % of these were due to asbestos alone […] The available evidence suggests, in most populations, a small role of air, water and soil pollutants. Global estimates are in the order of 1 % or less of total cancers [9, 42]. This is in striking contrast with public perception, which often identifies pollution as a major cause of human cancer.”

“Avoidance of sun exposure, in particular during the middle of the day, is the primary preventive measure to reduce the incidence of skin cancer. There is no adequate evidence of a protective effect of sunscreens, possibly because use of sunscreens is associated with increased exposure to the sun. The possible benefit in reducing skin cancer risk by reduction of sun exposure, however, should be balanced against possible favourable effects of UV radiation in promoting vitamin D metabolism.”

March 30, 2015 Posted by | alcohol, Books, Cancer/oncology, Cardiology, Data, Diabetes, Epidemiology, Infectious disease, Medicine | Leave a comment

An Introduction to Medical Diagnosis (3)

Despite not actually having reading all that many books this year I’m way behind on blogging the books I’ve read, so I thought I might as well try to catch up a bit. You can find my previous coverage of the book here and here.

In this post I’ll cover the chapters about the musculoskeletal system, the endocrine system, and the breast.

“Disorders of the musculoskeletal system make up 20–25 per cent of a general practitioner’s workload and account for significant disability in the general population. […] The chief symptoms to identify in the musculoskeletal assessment are: *pain *stiffness *swelling *impaired function *constitutional [regarding constitutional symptoms, “Patients with arthritis may describe symptoms of fatigue, fever, sweating and weight loss”]. […] As a rule mechanical disorders (e.g. OA [Osteoarthritis], spondylosis, and tendinopathies) are worsened by activity and relieved by rest. In severe degenerative disease the pain may, however, be present at rest and disturb sleep. Inflammatory disorders tend to be painful both at rest and during activity and are associated with worsened stiffness after periods of prolonged rest. The patient may note that stiffness is relieved somewhat by movement. Both mechanical and inflammatory disorders may be worsened by excessive movement.”

“The lifetime incidence of lower back pain is about 60 per cent and the greatest prevalence is between ages 45 and 65 years. Over 90 per cent of low back pain is mechanical and self-limiting. […] Indicators of serious pathology in lumbar pain: ‘red flags’ of serious pathology that requires further investigation […] are: *presenting under age 20 and over age 55 years *prolonged stiffness (>6 weeks) *sudden onset of severe pain *pain that disturbs sleep (>6 weeks) *thoracic pain *nerve root symptoms – including spinal claudication (pain on walking resolved by rest), saddle numbness, and loss of bladder or bowel control *chronic persistent pain (>12 weeks) *weight loss *history of carcinoma.”

“Osteoarthritis is a chronic degenerative and mechanical disorder characterized by cartilage loss. It is the most common form of arthritis, estimated to affect 15 per cent of the population of the UK over the age of 55 years. It is second only to cardiovascular disease as a cause of disability. Weight-bearing joints are chiefly involved (e.g. facets in the spine, hip and knee). […] There is little evidence to link OA with repetitive injury from occupation, except perhaps knee bending in men. Dockers and miners have a higher incidence of knee OA.”

“Rheumatoid arthritis […] is the most common ARD [Autoimmune Rheumatic Diseases] and is characterized by the presence of a symmetrical destructive polyarthritis with a predisposition for the small joints of the hands, wrists and feet. It is more common in women than men and may present at any age though most often in the third to fourth decade. […] Onset is typically insidious and progressive pain, stiffness and symmetrical swelling of small joints occurs. Up to a third of patients may have a subacute onset with symptoms of fatigue, malaise, weight loss, myalgia, morning stiffness and joint pain without overt signs of swelling. A mono- or bilateral arthropathy of the shoulder or wrist may account for up to 30–40 per cent of initial presentations”

“[Osteoporosis] remains a significant cause of morbidity and mortality. Peak bone mass is usually achieved in the third decade and is determined by both genetic and environmental factors. After the age of 35 the amount of bone laid down is less than that reabsorbed during each remodelling cycle. The net effect is age-related loss of bone mass. Up to 15 per cent of bone mass can also be lost over the 5-year period immediately post menopause. Symptomless reduction in bone mass and strength results in an increased risk of fracture; it is the resulting fractures that lead to pain and morbidity. Major risk factors to be considered in osteoporosis are: *race (white or Asian > African Caribbean) *age *gender *family history of maternal hip fracture *previous low trauma fracture (low trauma defined as no greater than falling from standing height) *long-term use of corticosteroids *malabsorption disorders *endocrinopathies […] *inflammatory arthritis […] Other risk factors include: *low body mass index […] *late menarche and early menopause *nulliparity *reduced physical activity *low intake of calcium (below 240 mg daily) *excess alcohol intake *smoking *malignancy (multiple myeloma).”

“Infection may give rise to systemic inflammatory arthritis or vasculitis. The condition ‘reactive arthritis’ is also recognized. […] It is usually triggered by sexually transmitted infection such as with Chlamydia trachomatis. The acute inflammatory reaction is treated with NSAIDs and corticosteroids and often ‘burns out’ after 6–18 months [Had to read that one twice: 18 months…]. It may leave lasting joint damage. […] Septic arthritis constitutes an acute emergency. The presentation is usually one of a rapid onset of severe pain in a hot swollen joint, the pain so severe that the patient cannot bear for it to be touched or moved.”

“Focal pain, swelling, or a low trauma fracture in the spine or long bones should alert suspicion [of neoplasia]. Primary tumours of bone include the benign (but often very painful) osteoid-osteoma, chondromas, and malignant osteosarcoma. Metastatic carcinoma may be secondary to a primary lesion in the lung, breast, prostate, kidney or thyroid. Haematological malignancies including lymphomas and leukaemias may also lead to diffuse bone involvement.”

“Diabetes mellitus is becoming a major public health problem. This is particularly true for type 2 diabetes, the prevalence of which is increasing rapidly due to the association with obesity and physical inactivity. Much of the morbidity, and cost, of diabetes care is due to the associated complications, rather than directly to hyperglycaemia and its management. Thyroid disease and polycystic ovarian syndrome are also prevalent [endocrine] conditions. Most other endocrine disorders are uncommon”

“The classic triad of symptoms associated with diabetes mellitus consists of: *thirst *polyuria (often nocturia) *weight loss.
Many patients will also experience pruritus or balanitis, fatigue and blurred vision. Some people, particularly those with newly presenting type 1 diabetes diabetes mellitus (T1DM) or with marked hyperglycaemia in type 2 diabetes mellitus (T2DM), may have a ‘full house’ of symptoms, in which case it is generally not difficult to suspect the diagnosis. However, other patients, particularly those with only modestly elevated blood glucose concentrations in T2DM, will have fewer, milder symptoms, and some may be entirely asymptomatic. […] symptoms potentially suggestive of diabetes may have alternative causes, particularly in elderly people, for example, frequency and nocturia in an older man may be due to bladder outflow obstruction, and many medical disorders are associated with weight loss. The symptom complex of thirst, polydipsia and polyuria most commonly suggests a diagnosis of uncontrolled diabetes mellitus but can occur in other settings. Some patients taking diuretics will experience similar symptoms. A dry mouth, perhaps associated with drug usage (e.g. tricyclic antidepressants) or certain medical conditions (e.g. Sjögren’s syndrome), may lead to increased fluid intake in an attempt at symptom relief.”

“The blood glucose concentration at diagnosis is not useful as a guide to whether an individual patient has T1DM or T2DM. Patients with T1DM can be in severe ketoacidosis with a blood glucose less than 20 mmol/L, and even below 10 mmol/L on occasions, whereas T2DM can present with a hyperosmolar state with blood glucose levels over 50 mmol/L.”

“30–50 per cent of patients with newly diagnosed T2DM will already have tissue complications at diagnosis due to the prolonged period of antecedent moderate and asymptomatic hyperglycaemia. […] Diabetes mellitus is much more than a disorder of glucose metabolism. The complications of diabetes can affect many of the organ systems leading to associated cardiac, vascular, renal, retinal, neurological and other disorders.”

“Pain is one of the commonest presenting disorders in the female breast, occurring in both pre-and postmenopausal women. […] In most women, there is no obvious or serious underlying breast pathology present […] In males, pain is not uncommon in gynaecomastia (swelling of male breast). […] A discrete lump, nodularity or thickening is the next most common mode of presentation. Size may vary (frequently ‘pea-sized’), but can be large. Onset may be acute (several days) or longstanding (several months). Fluctuation with the menstrual cycle is common in young women. Pain and tenderness are features of cysts, less common with fibroadenomas (unless rapidly growing or phylloides tumours), uncommon with cancer, except with rapidly expanding, aggressive (grade 3) and inflammatory tumours. The commonest lump in women below 30 years is a fibroadenoma; in women 30–45 years, a cyst and those over 45 years, cancer. […] Careful assessment of a lump can indicate whether the breast lesion is benign or malignant: *if it is rounded, smooth, mobile, tense and tender it is most likely to be a cyst (30 to 45 years of age) *if it is rounded, smooth, mobile, firm and non-tender it is most likely to be a fibroadenoma (under 30 years of age) *malignant lumps are rare in women under 30 years and uncommon under 40 years (4 per cent of breast cancers). Cancers are usually irregular, firm or hard, with variable involvement of overlying skin or deeper structures.”

“Retraction (intermittent, partial or chronic) is often a concern to women. It can be idiopathic or associated with malignancy in the retroareolar region, but usually is seen in the postmenopausal breast and is secondary to glandular atrophy and replacement by fibrosis and major duct ectasia. Congenital absence is very rare, whereas accessory nipples are seen in 2 per cent of women.” [Again, I had to read that one twice. 2 %! Who knew! Also, this condition seems to be even more common in males (see the link above).]

“Five to 10 per cent of women will, at some stage, present with a macrocyst. Microcysts are more common but tend to be occult. Breast cysts are commonest between the ages of 35 and 50, but can occur outside this age range, particularly in women who have been taking HRT. […] Patients present with a palpable lump or nodularity. When acute and large, the lump can be tender and the patient complains of pain. Typically cysts are well-circumscribed, smooth, mobile and, on occasion, tender lumps.”

“Nipple discharge in premenopausal women is likely to be associated with, or be due to, benign disease. It is the predominant clinical feature in up to 10 per cent of women presenting with breast cancer. […] *Purulent and coloured discharges are usually indicative of benign disease (infection and fibrocystic disease, respectively). *Spontaneous bilateral milky discharge (multiple ducts) most commonly occurs in women of reproductive age and is called galactorrhoea. […] *Clear, serous or bloodstained discharges are not infrequently associated with neoplastic disease”

“Carcinoma of the breast is one of the most common cancers (23 per cent of all female malignancies in the developed world) […]. One in 10 women develops breast cancer during her lifetime. […] Breast cancer is very rare in women under the age of 25. About 4 per cent occur under the age of 40. There is a plateau in incidence between the ages of 45 and 55, and beyond 55 years it continues to increase steadily into the 80s. […] The most common (70 per cent) presentation is a palpable lump, nodularity or thickening in the breast, usually detected by the patient. Typically the lump is firm or hard, well defined, with an irregular surface. […] About 25 per cent of women in the UK present with large primary tumours […], or locally advanced breast cancers […]. In some cases, particularly elderly patients, the tumour may have been present for some time, but hidden by the patient from her relatives due to fear and anxiety […]. Occasionally patients may even deny the presence of a tumour as a psychological coping strategy. […] Breast cancer is the most common malignant condition occurring during pregnancy. The incidence is approximately 1 in 2500 pregnancies, and poses many medical and psychological problems, both for the woman and her relatives.”

March 24, 2015 Posted by | Books, Cancer/oncology, Diabetes, Epidemiology, Medicine | Leave a comment

The Psychology of Lifestyle (I)

“Improving lifestyles is thought to be one of the most effective means of reducing mortality and morbidity in the developed world. However, despite decades of health promotion, there has been no significant difference to lifestyles and instead there are rising levels of inactivity and obesity. The Psychology of Lifestyle addresses the role psychology can play in reversing the trend of deleterious lifestyle choices. It considers the common characteristics of lifestyle behaviours and reflects on how we can inform and improve interventions to promote healthy lifestyles. […] The chapters cover key lifestyle behaviours that impact on health – eating, physical activity, drinking, smoking, sex and drug use – as well as combinations of behaviours.”

I gave the book two stars on goodreads. There are multiple reasons why it did not get a higher rating despite containing quite a lot of material which I consider to be worth blogging.  One reason is that the book is really UK-centric; it’s written by British authors for a British audience. Which is fine if you’re from Britain, but it does mean that some of the details included (such as drinking pattern breakdowns for England, Scotland, and Wales) may not be super interesting to the non-British readership. Another reason is that some of the numbers included in the publication are frankly not trustworthy, and the inclusion of those numbers without critical comments on part of the authors occasionally made me question their judgment. To give an example, it is at one point during the coverage noted that: “Women aged 16–19 were least likely to be using contraception despite almost two-thirds of teenagers having had intercourse by age 13 (CDC 2007b).” The problem I have with this quote is that they don’t comment anywhere in the publication upon the fact that this estimate is, if applied to the general population, frankly unbelievable, taking into account other estimates from the literature, including other estimates from US samples (see e.g. this previous post of mine). It’s clear that it’s an estimate derived from a specific sample, but it’s not made clear that the characteristics of the sample were probably very different from the characteristics of the population about which the reader is using the quote to make inferences. To illustrate just how difficult it is to believe that the estimate has much, if any, external validity, according to the estimates reported in fig. 6.2 in the link in the parenthesis above, you don’t get to the point where two-thirds have had sexual intercourse before the age of 19. The estimate they include in the book is not just weird and strange, it’s so weird and strange that anybody who knows anything about that literature would know the estimate is weird and strange, and would at least comment upon why it is perhaps not to be trusted (my guess would be that this estimate is derived from a sample displaying a substantial amount of selection bias due to opportunistic sampling from a very high-risk group). Yet they don’t comment on these things at all, apparently not only taking it to some extent at face value, but also asking the reader to do the same. This was almost an unforgivable error on part of the authors and I was strongly considering not reading on when I got to this point – I don’t really think you can not comment on this kind of thing if you decide to include numbers like those in your coverage in the first place.

Another problem is that there’s also occasionally some sloppy reporting which makes it hard to understand what the research they’re reporting on is actually saying; one example is that they note in the publication (p.185) that: “Young people aged over 15 accounted for 40 per cent of new HIV infections in 2006” – which immediately makes me start wondering whether e.g. a 25-year old would be considered ‘young’, according to this estimate? What about a 30-year old? The publication is silent on the issue of where the right-hand side cut-off is located, making the estimate much less useful than it otherwise would be.

A fourth(?) issue is that a lot of this stuff is correlational research, and there are a lot of cross-section studies and pretty much no longitudinal studies. At a few points do the authors caution against drawing strong conclusions from this kind of research and are frank about the problems which are present, but at other points in the coverage they then to me seem to later on just draw some of those semi-strong conclusions anyway, disregarding the methodological concerns (which are huge).

A fifth issue is that there are some hidden assumptions hidden in the coverage, assumptions which some people might categorize as ‘political’ or something along those lines; these didn’t much bother me because politics and that kind of thing isn’t something I care very much about, as mentioned many times before (though do also see my comments below..), but I’m sure some readers will take issue with what in some sense might be described as ‘the tone’ of the coverage. To be fair they do briefly touch upon e.g. the ethics of smoking bans, but you’re never in doubt where they stand on these issues (bans are fine, most interventions aimed at making the population healthier seem to be fine with the authors), and readers who find government interventions less desirable/justifiable than the authors do may take issue with specific recommendations and implicit assumptions in the coverage. The coverage in the last chapter is sort of a counter-weight to much of the rest of the coverage in the sense that ‘the case against bans and regulation’ gets reasonable coverage here, but I’d say the rest of the book is not really written in a manner which would lead most readers to believe it’s not a good idea to regulate *a lot*.

A sixth personal issue I have with the book is that the book is written in a manner I personally consider to be somewhat disagreeable. It’s a really classic textbook with stuff like a section in the beginning of the chapter outlining ‘what you’ll learn from this chapter’. These kinds of things perhaps wouldn’t be as much of an issue to me if I actually agreed with the authors about what you might be argued to be learning, or not learning, from the coverage in a given chapter. To take an example of what I’m talking about, at the beginning of chapter 7 you learn that: “At the end of this chapter you will: […] understand the nature of sexually transmitted diseases and their health consequences, along with their extent nationwide”. This is just one of 6 learning goals presented. Having read roughly the first third of Holmes et al., I can safely say that reading that book instead would be a lot more helpful than reading the chapter in this book in terms of achieving the learning goal presented, and I might add that if an author of a textbook thinks that you’ll ‘understand the nature of sexually transmitted diseases and their health consequences’ after having read a chapter in a textbook like this one, maybe that author shouldn’t be writing textbooks. This isn’t really fair because the chapter has a lot of useful stuff (and because I have a nagging suspicion that such silly learning goals may well be (politically?) mandated, and that this is probably part of the explanation for why they’re included in books like this one in the first place), but I hate interacting with clueless people with delusions of competence/knowledge, and if people are writing textbooks this way you’ll end up with a lot of people like that coming out the other end.

Despite the above-mentioned problems (and a few others) there’s also a lot of nice stuff in the book, and I’ll share some of that stuff below and in future posts about the book.

“One of the problems with attempting to arrive at a conclusion about what constitutes a lifestyle disease is the myriad of definitions under which diseases are categorised. […] Interestingly, few authors would include sexually transmitted diseases under the lifestyle umbrella, although they could be argued to be entirely under behavioural control, with none of the genetic component that plays a part in aetiology of the six major lifestyle diseases as identified by Doyle (2001). […] In between an ‘imprudent lifestyle’ (Doyle 2001) and the development of a chronic life-threatening or life-foreshortening condition lie a number of precursors of disease. High cholesterol, high blood pressure and obesity are risk factors for the development of a number of the aforementioned lifestyle diseases. The distinction between these precursors, the diseases they predict and the behaviours that are associated with them is often blurred. They are often presented as diseases per se”.

Even though there’s some disagreement about whether or not risk factors are actually Diseases or not, I would caution against the idea that they’re somehow ‘less severe’ than ‘an actual Disease’, unless they actually are; high blood pressure increases the risk of e.g. stroke substantially, so in some ways it’s actually quite a bit worse than some ‘agreed-upon Diseases’ which have less significant health impacts and may not actually kill anybody. I was reminded of this stuff (the blurring of diseases and risk factors) and some related problems very recently during a conversation with a friend, and I’ll allow myself to digress a bit to talk about this stuff in a little more detail here even though it’s only marginally related to the book coverage. Anyway, it seems to me that a lot of people who’d prefer a more ‘fair’ health care resource allocation (‘less money for people who caused their own health problems and more for the others’), a goal towards which I feel sympathetically inclined, are not really aware of how complicated these things are and how difficult it may be to make anything even resembling ‘fair’ distinctions between conditions which are/may be caused by behaviour and conditions which are not, to take but one of many issues. I can usually easily see the impetus for ‘changing things in the direction suggested’, but new problems pop up at every junction and it seems perfectly obvious to me that you’re not going to get rid of unfairness by not giving fat people any money to pay for their insulin. Some of the politically feasible solutions may conceivably make matters worse, e.g. because restricting access to (some types of) medical care may just shift expenditures and perhaps lead to higher expenditures on other treatments to which coverage is maintained (and you’d expect coverage to be maintained to some degree – alternatives are not politically viable). I’m aware that the role of preventative care is from a ‘pure cost standpoint’ probably somewhat overblown (usually preventative care does not save money in the long run, as they tend to cost more money than they save – see e.g. Glied and Smith’s coverage), but this stuff is complicated for many reasons. Some of the current disease treatment modalities in widespread use might well be conceived of as preventative medicine as well, and it’d probably make sense to think of them that way in the case of major changes to insurance coverage profiles. Let’s for example try to compare two models. In the first one insulin for type 2 diabetes is covered, and acute hospitalizations as a result of hypo- and hyperglycemia (DKA, HHS) are also covered. Assume now that the coverage for insulin is removed, but acute hospitalizations would still be covered. It would be quite easy for this change to result in an increase in the total costs incurred by the insurance provider, because hospitalizations are a lot more expensive than insulin, and it’s easy to see why excluding coverage of insulin might lead to more acute hospitalizations among type 2 diabetics (I’m too lazy to look up the numbers, but to people who have no idea about the magnitudes involved here one number which I seem to recall and which should illustrate the issues quite nicely is that in terms of the costs involved, one diabetes-related hospitalization corresponds to something like 8 months of treatment – not insulin, all treatment, including doctor’s visits, blood tests, etc., etc.). Evaluating efficiency in such a context would be really difficult because the conclusion drawn would also depend upon how a third factor, long-term complications, are managed. On the margin, a lot of patients face a tradeoff between the risk of hospitalization from hypoglycemia and the risk of developing chronic health complications such as kidney disease (many patients could decrease their risk of e.g. diabetic retinopathy, -neuropathy or -nephropathy by lowering their Hba1c, but this could easily lead to an increased risk of hypoglycemic episodes – which is part of why patients don’t), and if insurance companies are only expected to care about short-term complications/acute stuff then that may lead to some interesting dynamics, e.g. insurers offering cheaper contracts to diabetics with poor (and known to be sub-optimal, from a health standpoint) glycemic control. Another problem/complication is that even if preventative care-interventions tend to cost more money than they save by decreasing the need for other interventions long-term, they may easily cost less money (sometimes substantially less) per unit of health than a lot of other stuff we’re willing to have cost-sharing mechanisms, whether public or private, pay for – which means that if you’re very strongly in favour of ‘not subsidizing the unhealthy’, you may end up rejecting cost-sharing mechanisms  promoting interventions which could potentially add a lot of health on the cheap and might be considered no-brainers in any other context. One could also talk about genes and how the impact of life-style is probably highly heterogeneous, so that some people have a lot more leeway in terms of living unhealthily than do others, making a ‘nobody gets insurance coverage if it might be their own fault’ perhaps just as unfair as the converse position where everybody gets covered. I don’t know, I haven’t added it all together and done the math, but I’m willing to bet that neither have the people who may suggest that sort of thing, and I’d be skeptical about assuming you even can ‘do the math’ given the amount of knowledge required to make sense of all the complications. I’m reasonably certain the system most people would evaluate as optimal through a Rawlsian veil of ignorance would not be at either end of the extremes of what might be termed ‘the responsibility axis’ (‘if there’s any chance it might be your own fault, you don’t get any money from us’ being at one end, and ‘it doesn’t matter how you’ve behaved during your life – of course we’ll cover all your treatment costs related to those five chronic, very expensive, and completely preventable diseases you seem to have contracted’-being at the other end), even assuming the proposed model would be the only one available (thus sidestepping the problem that both models would certainly be outcompeted by alternatives in an actual insurance market where different options might be available to health care consumers). Tradeoffs are everywhere, and they’re not going away. I could probably add another related rant here about how many of the issues private insurance market decision-makers have to deal with are identical to the ones confronting public sector decisions-makers, but I think I’ll stop here as the post is quite long enough as it is – back to the book coverage:

“The behaviours that are usually cited as being involved in the aetiology of lifestyle diseases are poor diet, lack of physical activity, cigarette smoking […] and, increasingly, excess drinking […] The taking of illegal drugs is also lifestyle behaviour with health consequences […] Sexual practices are also often described as health and/or lifestyle behaviours by public health professionals […] Major lifestyle diseases are coronary heart disease, stroke, lung cancer, colon cancer, diabetes and chronic obstructive pulmonary disease. […] health-related lifestyles can be defined as behavioural choices made by individuals about eating, physical activity, drinking alcohol, smoking tobacco, taking drugs and sexual practices. […] lifestyle behaviours are all chronic rather than acute behaviours. Usually individuals will practise regular patterns of these behaviours and their future behaviour will be best predicted by the choices they have made in the past. […] lifestyle behaviours have the majority of their positive consequences in the present and the majority of their negative outcomes in the future. Any lifestyle behavioural change intervention consequently requires individuals to be future orientated.”

“Measuring any type of behaviour creates a number of challenges for psychologists. Instruments need to be valid, reliable, practical, non-reactive (that is to say they should not alter the behaviour they seek to measure) and have the appropriate degree of specificity […]. Few methods of measurement meet all these requirements. For none of the lifestyle behaviours identified by this text is there a single accepted ‘gold standard’ measurement tool. Methods of behavioural assessment can be categorised as observational, self report or physiological. Observational and self-report methods are often not validated effectively, whereas physiological methods are often valid but impractical or unacceptable to the study population. […] The variation in methods available to measure lifestyle behaviours creates problems in interpreting research and survey data. First, researchers differ in what they choose to measure and second, even if they choose to measure the same aspect of behaviour, they can differ widely in the method they choose to collect their data and the way they choose to present their findings. Throughout the research literature on lifestyle behaviours, different methods of measurement confuse and hinder direct comparisons.”

“Since the late 1970s regular travel by foot or by bicycle has declined by 26 per cent (Department of Health, Physical Activity, Health Improvement and Prevention 2004).”

“emotional reactions to risky situations can often diverge from cognitive assessments of the same situation. If division occurs emotional reactions usually override cognitive reactions and drive behaviour. One reason for the domination of emotional responses over cognitive assessment is that emotional responses are rapid and rational analyses usually take time […] Many researchers investigating the role of emotion in risk perception conceptualise it as inferior to analytical responses. Indeed it is often dismissed as a source of lay error […] The emotion most usually associated with risk is anxiety (Joffe 2003). Dismissing anxiety as a biasing factor in ‘accurate’ risk perception is problematic. Anxiety is the intermediate goal of many risk communications, particularly public health communications. The primary goal is preventative behaviour but anxiety is considered an essential initiating motivation. Many health promotions are based on this fear drive hypothesis […]. The fear-drive model is generally considered outdated in academic health psychology […] but it is worth considering as it remains a central, if unacknowledged, tenet of many health promotion campaigns. […] The fear-drive model principally proposes that fear is an unpleasant emotion and people are motivated to try to reduce their state of fear. Health promotion has taken this notion and applied it to communication. If a communication evokes fear or anxiety then the fear drive model suggests that the recipient will be motivated to reduce this unpleasant emotive state. If the communication also contains behavioural advice, either implicitly or explicitly, then individuals may follow this advice […] Fear is intuitively appealing as a means of promoting behavioural change but the role it plays in initiating behavioural change is not clear cut or consistent […]. However, this has been effectively denied […] by health professionals for over half a century.”

“Self-efficacy is the belief that one can carry out specific behaviours in specified situations […]. Self-efficacy has been extensively studied [and] has been argued to be enhanced by personal accomplishment or mastery, vicarious experience or verbal persuasion […]. Self-efficacy is not unrealistic optimism as it is based on experience […]. Self-efficacy is similar to the broader construct of self-esteem but can be distinguished by three aspects: self-efficacy implies a personal attribution; it is prospective, referring to future behaviours and finally it is an operative construct in that the cognition is proximal to the behaviour […]. Self-efficacy is one of the best predictors of behavioural change whereas self-esteem has been found to be a poor predictor of behavioural change […]. Ajzen (1988, 1998) has consistently argued that behaviour-specific constructs fare better than generalised dispositions in predicting behaviour. The success of self-efficacy and the failure of self-esteem in predicting a range of behaviours adds considerable weight to this principle of compatibility [I remember an analogous argument being made in Leary et al.]. […] Perceived self-efficacy has been found to be the major instigating force in both intentions to change lifestyle behaviours and actual behavioural change […] Outcome expectancies, goals and perceived impediments have also been found to be predictive in some studies”

“Stage theories have become increasing popular in recent years […]. Many theorists have argued that different cognitions may be important at different stages in promoting health behaviour […] According to all stage theories a person can move through a series of stages in the process of behavioural change […] Different factors are important at different stages, although the theory allows for some overlap. […] interpreting whether the data supports a stage theory of behaviour is fraught with difficulties. […] Regardless of the method of analysis there appears [however] to be little empirical evidence for the existent of discrete stages that could not equally well be explained as categorisation of a continuum […].”

“There are differences in the level of obesity between the different UK countries. In Northern Ireland, some 64 per cent of men and 53 per cent of women are overweight or obese (NISRA 2006). Similarly, in Scotland 64 per cent of men and 57 per cent of women are so classified (Scottish Executive 2005) […] In England, 65.2 per cent of men and 57 per cent of women were reported as being at least overweight. The results from the Health Survey for England show that the proportion of adults with a desirable BMI decreased between 1993 and 2005, from 41.0 per cent to 32.2 per cent among men and from 49.5 per cent to 40.7 per cent among women. There was no significant change in the proportion of adults who were overweight. The proportion who were categorised as obese (BMI 30+) increased from 13.2 per cent of men in 1993 to 23.1 per cent in 2005 and from 16.4 per cent to 24.8 per cent of women (Information Centre 2006).”

“The National Diet and Nutrition Survey (DoH/FSA 2002) reported on a range of socio-demographic factors related to diet and obesity. For example, those in the low working-class group consumed more calories, considerably more fat, more salt and non-milk extrinsic sugars than those in the middle and upper classes. Furthermore those on low income eat a less varied diet compared to those in the upper classes. […] people living on state benefits and reduced income eat less fruit and vegetables, less fish and less high-fibre foods […] children of semi-skilled and unskilled manual workers are more likely to eat fatty food, less fruit and vegetables, and more sweets than those children of professionals and managers. […] research suggests that nearly 20 per cent of those aged between 4 and 18 years eat no fruit at all during a typical week […] Rayner and Scarborough (2005) estimated that food related ill-health is responsible for about 10 per cent of morbidity and mortality in the UK. […] They estimated that food accounts for costs of £6 billion a year (9 per cent of the NHS budget).”

“the amount of sedentary time spent watching TV by children in the UK has doubled since the 1960s (Reilly and Dorosty 1999)”

March 18, 2015 Posted by | Books, Diabetes, Epidemiology, Medicine, Psychology | Leave a comment

Diabetes: The Biography

“When I retired from clinical practice in 1998, my intention was (and still is) to write a definitive, exhaustively referenced, history of diabetes, which would be of interest primarily to doctors. However, I jumped at the suggestion of the editors of this series at Oxford University Press that I should write a biography of diabetes that would be about a tenth of the length of a full history with a minimum of references, for a wide general readership.”

This book is the result. As I pointed out on goodreads, this book is really great. The book is not particularly technical compared to other books about diabetes which I’ve read in the past, however this semi-critical review does make the point that the coverage is occasionally implicitly ‘asking too much’ even from diabetic readers (“There were parts of all this that lost my interest or that I lacked the background to appreciate”). Whereas the reviewer was apparently to some extent getting lost in the details, so was I – but in a completely different way; I was simply amazed at the amount of small details and interesting observations included in the book that I did not know, and I loved every single chapter of the book. The author of the other review incidentally also states that: “I don’t recommend that anyone read this who is not already familiar with diabetes, either by having it or knowing someone with it.” I’d note that I’m not sure I agree with this recommendation, to the extent that it’s even ‘relevant’ – these days such people who don’t even know anyone with diabetes might well be a bit hard to find, on account of the fact that diabetes has become a quite common illness. Presumably a significant proportion of the people who assume they don’t know anyone with the disease might well do so anyway, because a very large number of people have type 2 diabetes without knowing it. I think a reader would get more out of the book if he or she has diabetes or knows someone with diabetes, but a lot of people who do not would also benefit from knowing the stuff in this book. Not only in a ‘and now you know how bad type 2 is and why you should get checked out if you think you’re at risk’-sense (there’s incidentally also a lot of stuff about type 1), but also in the ‘the history of diabetes is really quite fascinating’-sense. I do think it is.

Have a look at this image. The book included a similar picture (not exactly the same one, but it’s of the same patient and the ‘before’ picture is obviously taken at the same time this one was), which is of Billy Leroy, a type 1 diabetic, before and after he started insulin. He was one of the first patients treated with insulin (the first human treated with insulin was Leonard Thompson, in 1922). Billy Leroy’s weight in the first picture, where he was 3 years old, was 6.8 kg (the 5 % (underweight) CDC body weight cutoff at the age of 3 is 12 kg) – during the three months after he started on insulin, his weight doubled. The author argues in the beginning of the book that: “When people are asked to rank diseases in order of seriousness, diabetes is usually at the mild end of the spectrum.” This may or may not be true, but the picture to which I link above certainly adds a detail which is important to keep in mind but easy to forget when evaluating ‘the severity’ of the disease today – type 1 diabetes in particular is not much fun if you don’t have access to insulin, and until the early 1920s people with this disease simply died, most of them quite fast. (They all still do – like all other humans – but they live a lot longer before they die…)

The author knows his stuff and the book has a lot of content, making it hard to know what to pick out and mention in particular in a review like this – however below I have added a few quotes from the book and some observations made along the way. The content covering the late nineteenth century and the first couple of decades of the twentieth century, before it was discovered that insulin could save the lives of a lot of sick children, would in my opinion on its own be a strong reason for reading the book; but the chapters covering the periods that came after are wonderful as well. When insulin was discovered a religiously inclined mind might well be tempted to think of the effects on young type 1 diabetic children as almost miraculous; but gradually doctors treating diabetics came to realize (the patients never knew, because they were not told – it is pointed out in the book that the fact that it might make a lot of sense to give patients with a disease like diabetes some discretion in terms of how to treat their illness is a in a historical context very new idea; active patient involvement in medical decision-making is one of the cornerstones of current treatment regimes, for good reason, and I found it really surprising and frustrating to learn how this disease was treated in the past) that things might be more complicated than they had initially been assumed to be. Type 2 diabetics had suffered from late stage complications like blindness and kidney failure for centuries, but such complications had never before been observed in type type 1 diabetics before insulin, because diabetes presenting in children were pre-insulin universally fatal. It turned out that many of the children who were initially ‘saved’ by insulin in the early 1920s ended up suffering from severe complications just a couple of decades later, and many of them died early from these complications:

“After the Second World War it became clear that [diabetic] kidney disease could also affect the young, and there were increasingly frequent reports of diabetics who had been saved by insulin as children only to succumb to kidney failure in their 20s and 30s. Fifty of Joslin’s child patients who had started insulin before 1929 were followed up in 1949, when a third had died at an average age of 25, after having had diabetes for an average of 17.6 years. One half had died of kidney failure and the other half of tuberculosis and other infections. […] In the experience of the Joslin group, only 2 per cent of deaths of young diabetic patients before 1937 were due to kidney disease, but, of those who died between 1944 and 1950, more than half had advanced kidney disease. Results in Europe were equally bad. In 1955 all of eighty-seven Swiss children had signs of kidney disease after sixteen years of diabetes, and after twenty-one years all had died. Most young people with diabetic kidney disease also had severe retinopathy and many became blind—by the mid 1950s diabetes was the commonest cause of new blindness in people under the age of 50. […] Such devastating cases were being increasingly reported in the medical literature in the late 1940s and early 1950s, but they were not publicized in the lay press, presumably to avoid spreading despair and despondency and puncturing the myth that insulin had solved the problem of diabetes […] The British Diabetic Association (founded in 1935) produced a quarterly Diabetic Journal for its lay members, but no issue from 1940 to 1960 mentions complications”.

The book makes it clear that patients were for many years basically to some extent kept in the dark about the severity of their condition, but in all fairness for a long time the doctors treating them frankly didn’t know enough to give them good information on a lot of topics anyway. The book has some really interesting observations included about how medical men of the times thought about various aspects of the illness and treatment, and how many of the things we know today, some of which ‘seem obvious’, really were not to people at the time. Many attempts have been made over time to explain why people got diabetes, and especially type 1 was really quite hard to pin down – type 2 was somewhat easier because the lifestyle component was hard to miss; however it was natural to explain the disease in terms of the symptoms it caused, and some of those symptoms in type 2 diabetics were complications which are best considered secondary to the ‘true’ disease process. For example because many type 2 diabetics suffered from disorders of the nervous system, neuropathy, the nervous system was for a while assumed to be implicated in causing diabetes – but although disorders of the nervous system can and often do present in long-standing diabetes, they are not why type 2 diabetics get sick. Kidney problems were thought to be “part and parcel of diabetes in the 19th century.” Oskar Minkowsky made it clear in 1889 that removal of the pancreas caused severe (‘type 1-like’) diabetes in dogs – but despite this discovery it still took a long time for people to figure out how it worked. This wasn’t because people at the time were stupid. One problem faced at the time was that the pancreas actually looked quite normal in people who died from diabetes – the islet cells which are implicated in the disease weigh around 1-1.5 grams altogether, and make up only a very small proportion of the pancreas (1% or so). Many doctors found it hard to imagine that the islets cells could be reponsible for controlling carbohydrate metabolism (and other aspects of metabolism as well – “It is important to realize that diabetes is not just a glucose disease. There are also abnormalities of fat metabolism”). The pancreas wasn’t the only organ that looked normal – despite the excessive urination the kidneys did as well, and so did other organs, to the naked eye. All major features of diabetic retinopathy (diabetic eye disease) had been described by the year 1890 with the aid of the ophthalmoscope, so people knew the eyes of people with long-standing diabetes looked different; how to interpret these findings was however not clear at the time – some argued the eye damage found in diabetics was not different from eye damage caused by hypertension, and treatment options were non-existent anyway.

Many of the treatment options discussed among medical men before insulin were diets, and although dietary considerations are important in the treatment context today, it’s probably fair to say that not all of the supposed dietary remedies of the past were equally sensible: “One diet that had a short vogue in the 1850s was sugar feeding, brainchild of the well-known but eccentric French physician Pierre Piorry (1794–1879). He thought that diabetics lost weight and felt so weak because of the amount of sugar they lost in the urine and that replacing it should restore their strength”. (Aargh!). For the curious (or desperate) man, though, there were alternatives to diets: “A US government publication in 1894 listed no less than forty-two anti-diabetic remedies including bromides, uranium nitrate, and arsenic.” Relatedly, “in England until 1925, any drug could be advertised and marketed as a cure for any disease, even if it was completely ineffective”. Whether or not diets ‘worked’ depended in part on what those proposed diets included (see above..), whether people followed them, and whether people who presented were thin or fat. In the book Tattersall mentions that already from the middle of the nineteenth century many physicians thought that there were two different types of diabetes (there are more than two, but…). The thin young people presenting with symptoms were by many for decades considered hopeless cases (that they were hopeless cases was even noted in medical textbooks at the time), because they had this annoying habit of dying no matter what you did.

It should be noted that the book indirectly provides some insights into the general state of medical research and medical treatment options over time; for an example of the former it is mentioned that the first clinical trial (with really poor randomization/selection mechanisms, it seems from the description in the book) dealing with diabetes was undertaken in the 1960es: “the FDA demanded randomized controlled trials for the first time in 1962, and [the University Group Diabetes Program (UGDP)] was the first in diabetes. Before 1962 the evidence in support of therapeutic efficacy put to the FDA was often just ‘testimonials’ from physicians who casually tested experimental drugs on their patients and were paid for doing so.” See also this link. An example of the latter would be the observation made in the book that: “until the 1970s treatment for a heart attack was bed rest for five or six weeks, while nature took its course.” Diabetics were not the only sick people who had a tough time in the past.

One interesting question related to what people didn’t know in the beginning after the introduction of insulin was how the treatment might work long-term. The author notes that newspapers in the early years made people believe that insulin would be a cure; it was thought that insulin might nurse the islet cells back to health, so that they’d start producing insulin on their own again – which was actually not a completely stupid idea, as e.g. kidneys had the ability to recover after acute glomerulonephritis. The fact that diabetics often started on high doses which could then be lowered a month or two later even lent support to this idea; however it was discovered quite fast that regeneration was not taking place. Remarkably, insulin was explored as a treatment option for other diseases in the 1920s, and was actually used to stimulate appetite in tuberculosis patients and ‘in the insane refusing food’, an idea which came about because one of its most obvious effects was weight gain. This effect was also part of the reason why insulin was for a long time not considered an attractive option for type 2 diabetics, who instead were treated only with diet unless this treatment failed to reduce blood sugar levels sufficiently (these were the only two treatment options until the 1950s); most of them were already overweight and insulin caused weight gain, and besides insulin didn’t work nearly as well in them as it did in young and lean people with type 1 because of insulin resistance, which lead to the requirement of high doses of the drug.

Throughout much of the history of diabetes, diabetics did not measure their blood glucose regularly – what they did instead was measuring their urine, figuring out if it contained glucose or not (glucose in the urine indicates that the blood glucose is quite high). This meant that the only metric they had available to them to monitor their disease on a day to day basis was one which was unable to measure low blood glucose, and which could only (badly) distinguish between much too high blood glucose values and not-much-too-high values. Any type of treatment regime like the one I’m currently on would be completely impossible without regular blood tests on a daily basis, and I was very surprised about how late the idea of self-monitoring of blood glucose appeared; like the measurement of Hba1c, this innovation did not appear until the late 1970s. Few years after that, the first insulin pen revolutionized treatment regimes and made treatment regimes using multiple rejections each day much more common than they had been in the past, facilitating much better metabolic control.

The book has a lot of stuff about specific complications and the history of treatment advances – both the ones that worked and some of the ones that didn’t. If you’re a diabetic today, you tend to take a lot of stuff for granted – and reading a book like this will really make you appreciate how many ideas had to be explored, how many false starts there were, how much work by so many different people actually went into giving you the options you have today, keeping you alive, and perhaps even relatively well. One example of the type of treatment options which were considered in the past but turned out not to work was curative pancreas transplants, which were explored in the 60es and 70es: “Pancreas transplantation offered a potential cure of type 1 diabetes. The first was done in 1966 […] Worldwide in the next eleven years, fifty-seven transplants were done, but only two worked for more than a year”. Recent attempts to stop people at risk of developing type 1 diabetes from becoming sick are also discussed in the last part of the book, and in this context he makes a point I was familiar with: “[Repeated] failures [in this area] are particularly frustrating, because, in the best animal model of type 1 diabetes, the NOD mouse, over 100 different interventions can prevent diabetes.” This is one of the reasons why I tend to be skeptical about results from animal studies. Although he spends many pages on complications – which in a book like this makes a lot of sense given how common these complications were (and to some extent still are), and how important a role they have played in the lives of people suffering from diabetes throughout the ages – I have talked about many of these things before, just as I have talked about the results of various large-scale trials like the DCCT trial and the UKPDS (see e.g. this and this), so I will not discuss such topics in detail here. I do however want to briefly remind people of what kind of a disease badly managed type 2 diabetes (the by far most common of the two) is, especially if it is true as the author argues in the introduction that many people perceive of it as a relatively mild disease – so I’ll end the post with a few quotes from the book:

“I took over the diabetic clinic in Nottingham in 1975 and three years later met Lilian, an overweight 60-year-old woman who was on tablets for diabetes. She had had sugar in her urine during her last pregnancy in 1957 but was well until 1963, when genital itching (pruritus vulvae) led to a diagnosis of diabetes. She attended the clinic for two years but was then sent back to her GP with a letter that read: ‘I am discharging this lady with mild maturity onset diabetes back to your care.’ She continued to collect her tablets but had no other supervision. When I met her after she had had diabetes for eighteen years she was blind, had had a heart attack, and had had one leg amputated below the knee. The reason for the referral to me was an ulcer on her remaining foot, which would not heal. […] Someone whose course is not dissimilar to that of Lilian is Sue Townsend (b. 1946), author of the Adrian Mole books. She developed diabetes at the age of 38 and after only fifteen years was blind from retinopathy and wheelchair bound because of a Charcot foot, a condition in which the ankle disintegrates as a result of nerve damage. Neuropathy has also destroyed the nerve endings in her fingers, so that, like most other blind diabetics, she cannot read Braille. She blames her complications on the fact that she cavalierly disregarded the disease and kept her blood sugars high to avoid the inconvenience of hypoglycaemic (low-blood-sugar) attacks.”

January 25, 2015 Posted by | Books, Diabetes, Medicine, Nephrology | Leave a comment

A brief note on diabetes cures

I friend pointed me to a Danish article talking about this. I pointed out a few problems and reasons to be skeptical to my friend, and I figured I might as well share a few thoughts on these matters here as well. I do not have access to my library at the present point in time, so this post will be less well sourced than most posts I’ve written on related topics in the past.

i. I’ve had diabetes for over 25 years. A cure for type 1 diabetes has been just around the corner for decades. This is not a great argument for assuming that a cure will not be developed in a few years’ time, but you do at some point become a bit skeptical.

ii. The type of ‘mouse diabetes’ people use when they’re doing research on animal models such as e.g. NOD mice, from which many such ‘breakthroughs’ are derived, is different from ‘human diabetes’. As pointed out in the reddit thread, “Doug’s group alone has cured diabetes in mice nearly a dozen times”. This may or may not be true, but I’m pretty sure that at the present point in time my probability of being cured of diabetes would be significantly higher if I happened to be one of those lab mice.

iii. A major related point often overlooked in contexts like these is that type 1 diabetes is not one disease – it is a group of different disorders all sharing the feature that the disease process involved leads to destruction of the pancreatic beta-cells. At least this is not a bad way to think about it. This potentially important neglected heterogeneity is worth mentioning when we’re talking about cures. To talk about ‘type 1 diabetes’ as if it’s just one disease is a gross simplification, as multiple different, if similar, disease processes are at work in different patients; some people with ‘the disease’ get sick in days or weeks, in others it takes years to get to the point where symptoms develop. Multiple different gene complexes are involved. Prognosis – both regarding the risk of diabetes-related organ damage and the risk of developing ‘other’ autoimmune conditions (‘other’ because it may be the same disease process causing the ‘other’ diseases as well), such as Hashimoto’s thyroiditis – depends to some extent on the mutations involved. This stuff relates also to the question of what we mean by the word ‘cure’ – more on this below. You might argue that although diabetics are different from each other and vary in a lot of ways, the same thing could be said about the sufferers of all kinds of other diseases, such as, say, prostate cancer. So maybe heterogeneity within this particular patient population is not that important. But the point remains that we don’t treat all prostate cancer patients the same way, and that some are much easier to cure than others.

iv. The distinction between types (type 1, type 2) makes it easy to overlook the fact that there are significant within-group heterogeneities, as mentioned above. But the complexity of the processes involved are perhaps even better illustrated by pointing out that even between-group distinctions can also sometimes be quite complicated. The distinction between type 1 and type 2 diabetes is a case in point; usually people say only type 1 is auto-immune, but it was made clear in Sperling et al.’s textbook that that’s not really true; in a minority of type 2 diabetics autoimmune processes are also clearly involved – and this is actually highly relevant as these subgroups of patients have a much worse prognosis than the type 2 diabetics without autoantibody markers, as they’ll on average progress to insulin-dependent disease (uncontrollable by e.g. insulin-sensitizers) much faster than people without an auto-immune disease process. In my experience most people who talk about diabetes online, also well-informed people e.g. in reddit/askscience threads, are not (even?) aware of this. I mention it because it’s one obvious example of how within-group hidden heterogeneities can have huge relevance for which treatment modalities are desirable or useful. You’d expect type 2’s with auto-immune processes involved would need a different sort of ‘cure’ than ‘ordinary type 2’s’. For a little more on different ‘varieties’ of diabetes, see also this and this.

There are as already mentioned also big differences in outcomes between subgroups within the type 1 group; some people with type 1 diabetes will end up with three or four ‘different'(?) auto-immune diseases, whereas others will get lucky and ‘only’ ever get type 1 diabetes. Not only that, we also know that glycemic control differences between those groups do not account for all the variation in between-group differences in outcomes in terms of diabetes-related complications; type 1 diabetics hit by ‘other’ auto-immune processes (e.g. Graves’ disease) tend to be more likely to develop complications to their diabetes than the rest, regardless of glycemic control. Would successful beta-cell transplants, assuming these at some point become feasible, and achieved euglycemia in that patient population still prevent thyroid failure later on? Would the people more severely affected, e.g. people with multiple autoimmune conditions, still develop some of the diabetes-related complications, such as cardiovascular complications, even if they had functional beta cells and were to achieve euglycemia, because those problems may be caused by disease aspects like accelerated atherosclerosis to some extent perhaps unrelated to glycemic control? These are things we really don’t know. It’s very important in that context to note that most diabetics, both type 1 and type 2, die from cardiovascular disease, and that the link between glycemic control and cardiovascular outcomes is much weaker than the one between glycemic control and microvascular complications (e.g., eye disease, kidney disease). There may be reasons why we do not yet have a good picture of just how important euglycemia really is, e.g. because glucose variability and not just average glucose levels may be important in terms of outcomes (I recall seeing this emphasized recently in a paper, but I’m not going to look for a source) – and Hba1c only account for the latter. So maybe it does all come back to glycemic control, it’s just that we don’t have the full picture yet. Maybe. But to the extent that e.g. cardiovascular outcomes – or other complications in diabetics – are unrelated to glycemic control, beta-cell transplants may not improve cardiovascular outcomes at all. One potential cure might be one where diabetics get beta-cell transplants, achieve euglycemia and are able to drop the insulin injections – yet they still die too soon from heart disease because other aspects of the disease process has not been addressed by the ‘cure’. I don’t think at the current point in time that we really know enough about these diseases to really judge if a hypothetical diabetic with functional transplanted beta-cells may not still to some extent be ‘sick’.

v. If your cure requires active suppression of the immune system, not much will really be gained. A to some people perhaps surprising fact is that we already know how to do ‘curative’ pancreas transplants in diabetics, and these are sometimes done in diabetic patients with kidney failure (“In most cases, pancreas transplantation is performed on individuals with type 1 diabetes with end-stage renal disease, brittle diabetes [poor glycemic control, US] and hypoglycaemia unawareness. The majority of pancreas transplantation (>90%) are simultaneous pancreas-kidney transplantation.” – link) – these people would usually be dead without a kidney transplant and as they already have to suffer through all the negative transplant-related effects of immune suppression and so on, the idea is that you might as well switch both defective organs now you’re at it, if they’re both available. But immune suppression sucks and these patients do not have great prognoses so this is not a good way to deal with diabetes in a ‘healthy diabetic’; if rejection problems are not addressed in a much better manner than the ones currently available in whole-organ-transplant cases, the attractiveness of any such type of intervention/’cure’ goes down a lot. In the study they tried to engineer their way around this issue, but whether they’ve been successful in any meaningful way is subject to discussion – I share ‘SirT6”s skepticism at the original reddit link. I’d have to see something like this working in humans for some years before I get too optimistic.

vi. One final aspect is perhaps noting. Even a Complete and Ideal Cure involving beta-cell transplants in a setting where it turns out that everything that goes wrong with all diabetics is really blood-glucose related, is not going to repair the damage that’s already been done. Such aspects will of course matter much more to some people than to others.

October 12, 2014 Posted by | Diabetes, Nephrology | Leave a comment

100 Cases in Clinical Pathology

This book is another publication from the 100 Cases … series which I’ve talked about before – I refer to these posts for some general comments about what this series is like and some talk about the other books in the series which I’ve read. The book is much like the others, though of course the specific topics covered are different in the various publications. I liked this book and gave it 3 stars on goodreads. The book has three sections: a section dealing with ‘chemical pathology, immunology and genetics’; a section dealing with ‘histopathology’; and a section dealing with ‘haematology’. As usual I knew a lot more about some of the topics covered than I did about some of the others. Some cases were quite easy, others were not. Some of the stuff covered in Greenstein & Wood’s endocrinology text came in handy along the way and enabled me for example to easily identify a case of Cushing’s syndrome and a case of Graves’ disease. I don’t think I’ll spoil anything by noting that two of the cases in this book involved these disorders, but if you plan on reading it later on you may want to skip the coverage below, as I have included some general comments from the answer sections of the book in this post.

As someone who’s not working in the medical field and who will almost certainly never need to know how to interpret a water deprivation test (also covered in detail in Greenstein and Wood, incidentally), there are some parts of books like this one which are not particularly ‘relevant’ to me; however I’d argue that far from all the stuff included in a book like this one is ‘stuff you don’t need to know’, as there are also for example a lot of neat observations included about how specific symptoms (and symptom complexes) are linked to specific disorders, some related ideas about which other medical conditions might cause similar health problems, and which risk factors are potentially important to have in mind in specific contexts. If you’ve had occasional fevers, night sweats and experienced weight loss over the last few months, you should probably have seen a doctor a while ago – knowledge included in books like this one may make the reader perhaps a bit less likely to overlook an important and potentially treatable health problem, and/or increase awareness of potential modifiable risk factors in specific contexts. A problem is however that the book will be hard to read if you have not read any medical textbooks before, and in that case I would probably advise you against reading it as it’s almost certainly not worth the effort.

I have added a few observations from the book below.

“After a bone marrow transplant (and any associated chemotherapy), the main risks are infection (from low white cell counts and the use of immunosuppressants, such as cyclosporin), bleeding (from low platelet counts) and graft versus host disease (GVHD). […] An erythematous rash that develops on the palms or soles of the feet of a patient 10–30 days after a bone marrow transplant is characteristic of GVHD. […] GVHD is a potentially life-threatening problem that can occur in up to 80% of successful allogeneic bone marrow transplants. […] Clinically, GVHD manifests like an autoimmune disease with a macular-papular rash, jaundice and hepatosplenomegaly and ultimately organ fibrosis. It classically involves the skin, gastrointestinal tract and the liver. […] Depending on severity, treatment of acute GVHD may involve topical and intravenous steroid therapy, immunosuppression (e.g. cyclosporine), or biologic therapies targeting TNF-α […], a key inflammatory cytokine. […] Prognosis is related to response to treatment. The mortality of patients who completely respond can still be around 20%, and the mortality in those who do not respond is as high as 75%.”

“The leading indication for a liver transplant is alcoholic cirrhosis in adults and biliary atresia in children. […] The overall one-year survival of a liver transplant is over 90%, with 10-year survival of around 70%. […] Transplant rejection can be classified by time course, which relates to the underlying immune mechanism: • Hyperacute organ rejection occurs within minutes of the graft perfusion in the operating theatre. […] The treatment for hyperacute rejection is immediate removal of the graft. • Acute organ rejection take place a number of weeks after the transplant […] The treatment for acute rejection includes high dose steroids. • Chronic organ rejection can take place months to years after the transplant. […] As it is irreversible, treatment for chronic rejection is difficult, and may include re-transplantation.”

“Chronic kidney disease (CKD) is characterized by a reduction in GFR over a period of 3 or more months (normal GFR is >90–120 mL/min). It arises from a progressive impairment of renal function with a decrease in the number of functioning nephrons; generally, patients remain asymptomatic until GFR reduces to below 15 mL/min (stage V CKD). Common causes of CKD are (1) diabetes mellitus, (2) hypertension, (3) glomerulonephritis, (4) renovascular disease, (5) chronic obstruction or interstitial nephritis, and (6) hereditary or cystic renal disease”

“The definition of an aneurysm is an abnormal permanent focal dilatation of all the layers of a blood vessel. An AAA [abdominal aortic aneurysm] is defined when the aortic diameter, as measured below the level of the renal arteries, is one and a half times normal. Women have smaller aortas, but for convenience, more than 3 cm qualifies as aneurysmal. The main risk factors for aneurysm formation are male gender, smoking, hypertension, Caucasian/European descent and atherosclerosis. Although atherosclerosis is a risk factor and both diseases share common predisposing factors, there are also differences. Atherosclerosis is primarily a disease of the intima, the innermost layer of the vessel wall, whereas in aneurysms there is degeneration of the media, the middle layer. […] The annual risk of rupture equals and begins to outstrip the risk of dying from surgery when the aneurysm exceeds 5.5 cm. This is the size above which surgical repair is recommended, comorbidities permitting. […] Catastrophic rupture, as in this case, presents with hypovolaemic shock and carries a dismal prognosis.” [The patient in the case history died soon after having arrived at the hospital]

“Stroke refers to an acquired focal neurological deficit caused by an acute vascular event. The neurological deficit persists beyond 24 hours, in contrast to a transient ischaemic attack (TIA) where symptoms resolve within 24 hours, although the distinction is now blurred with the advent of thrombolysis. […] Strokes are broadly categorized into ischaemic and haemorrhagic types, the majority being ischaemic. The pathophysiology in a haemorrhagic stroke is rupture of a blood vessel causing extravasation of blood into the brain substance with tissue damage and disruption of neuronal connections. The resulting haematoma also compresses surrounding normal tissue. In most ischaemic strokes, there is thromboembolic occlusion of vessels due to underlying atherosclerosis of the aortic arch and carotid arteries. In 15–20% of cases, there is atherosclerotic disease of smaller intrinsic blood vessels within the brain[…]. A further 15–20% are due to emboli from the heart. […] The territory and the extent of the infarct influences the prognosis; [for example] expressive dysphasia and right hemiparesis are attributable to infarcts in Broca’s area and the motor cortex, both frontal lobe territories supplied by the left middle cerebral artery.”

“The stereotypical profile of a gallstone patient is summed up by the 4Fs: female, fat, fertile and forty. However, while gallstones are twice as common in females, increasing age is a more important risk factor. Above the age of 60, 10–20% of the Western population have gallstones. […] Most people with cholelithiasis are asymptomatic, but there is a 1–4% annual risk of developing symptoms or complications. […] Complications depend on the size of the stones. Smaller stones may escape into the common bile duct, but may lodge at the narrowing of the hepatopancreatic sphincter (sphincter of Oddi), obstructing the common bile duct and pancreatic duct, leading to obstructive jaundice and pancreatitis respectively. […] In most series, alcohol and gallstones each account for 30–35% of cases [of acute pancreatitis]. […] Once symptomatic, the definitive treatment of gallstone disease is generally surgical via a cholecystectomy.”

“Breast cancer affects 1 in 8 women (lifetime risk) in the UK. […] Between 10 and 40% of women who are found to have a mass by mammography will have breast cancer. […] The presence of lymphovascular invasion indicates the likelihood of spread of tumour cells beyond the breast, thereby conferring a poorer outlook. Without lymph node involvement, the 10-year disease-free survival is close to 70–80% but falls progressively with the number of involved nodes.”

“Melanoma is a cancer of melanocytes, the pigmented cells in the skin, and is caused by injury to lightly pigmented skin by excessive exposure to ultraviolet (UV) radiation […] The change in colour of a pre-existing pigmented lesion with itching and bleeding and irregular margins on examination are indicators of transformation to melanoma. Melanomas progress through a radial growth phase to a vertical growth phase. In the radial growth phase, the lesion expands horizontally within the epidermis and superficial dermis often for a long period of time. Progression to the vertical phase is characterized by downward growth of the lesion into the deeper dermis and with absence of maturation of cells at the advancing front. During this phase, the lesion acquires the potential to metastasize through lymphovascular channels. The probability of this happening increases with increasing depth of invasion (Breslow thickness) by the melanoma cells. […] The ABCDE mnemonic aids in the diagnosis of melanoma: Asymmetry – melanomas are likely to be irregular or asymmetrical. Border – melanomas are more likely to have an irregular border with jagged edges. Colour – melanomas tend to be variegated in colour […]. Diameter – melanomas are usually more than 7 mm in diameter. Evolution – look for changes in the size, shape or colour of a mole.”

“CLL [chronic lymphocytic leukaemia] is the most common leukaemia in the Western world. Typically, it is picked up via an incidental lymphocytosis in an asymptomatic individual. […] The disease is staged according to the Binet classification. Typically, patients with Binet stage A disease require no immediate treatment. Symptomatic stage B and all stage C patients receive chemotherapy. […] cure is rare and the aim is to achieve periods of remission and symptom control. […] The median survival in CLL is between four and six years, though some patients survive a decade or more. […] There is […] a tendency of CLL to transform into a more aggressive leukaemia, typically a prolymphocytic transformation (in 15–30% of patients) or, less commonly (<10% of cases), transformation into a diffuse large B-cell lymphoma (a so-called Richter transformation). Appearance of transformative disease is an ominous sign, with few patients surviving for more than a year with such disease.”

“Pain, swelling, warmth, tenderness and immobility are the five cardinal signs of acute inflammation.”

“Osteomyelitis is an infection of bone that is characterized by progressive inflammatory destruction with the formation of sequestra (dead pieces of bone within living bone), which if not treated leads to new bone formation occurring on top of the dead and infected bone. It can affect any bone, although it occurs most commonly in long bones. […] Bone phagocytes engulf the bacteria and release osteolytic enzymes and toxic oxygen free radicals, which lyse the surrounding bone. Pus raises intraosseus pressure and impairs blood flow, resulting in thrombosis of the blood vessels. Ischaemia results in bone necrosis and devitalized segments of bone (known as sequestra). These sequestra are important in the pathogenesis of non-resolving infection, acting as an ongoing focus of infection if not removed. Osteomyelitis is one of the most difficult infections to treat. Treatment may require surgery in addition to antibiotics, especially in chronic osteomyelitis where sequestra are present. […] Poorly controlled diabetics are at increased risk of infections, and having an infection leads to poor control of diabetes via altered physiology occurring during infection. Diabetics are prone to developing foot ulcers, which in turn are prone to becoming infected, which then act as a source of bacteria for infecting the contiguous bones of the feet. This process is exacerbated in patients with peripheral neuropathy, poor diabetic control and peripheral vascular disease, as these all increase the risk of development of skin breakdown and subsequent osteomyelitis.” [The patient was of course a diabetic…]

“Recent onset fever and back pain suggest an upper UTI [urinary tract infection]. UTIs are classified by anatomy into lower and upper UTIs. Lower UTIs refer to infections at or below the level of the bladder, and include cystitis, urethritis, prostatitis, and epididymitis (the latter three being more often sexually transmitted). Upper UTIs refer to infection above the bladder, and include the ureters and kidneys. Infection of the urinary tract above the bladder is known as pyelonephritis [which] may be life threatening or lead to permanent kidney damage if not promptly treated. UTIs are also classified as complicated or uncomplicated. UTIs in men, the elderly, pregnant women, those who have an indwelling catheter, and anatomic or functional abnormality of the urinary tract are considered to be complicated. A complicated UTI will often receive longer courses of broader spectrum antibiotics. Importantly, the clinical history alone of dysuria and frequency (without vaginal discharge) is associated with more than 90% probability of a UTI in healthy women. […] In women, a UTI develops when urinary pathogens from the bowel or vagina colonize the urethral mucosa, and ascend via the urethra into the bladder. During an uncomplicated symptomatic UTI in women, it is rare for infection to ascend via the ureter into the kidney to cause pyelonephritis. […] Up to 40% of uncomplicated lower UTIs in women will resolve spontaneously without antimicrobial therapy. The use of antibiotics in this cohort is controversial when taking into account the side effects of antibiotics and their effect on normal flora. If prescribed, antibiotics for uncomplicated lower UTIs should be narrow-spectrum […] Most healthcare-associated UTIs are associated with the use of urinary catheters. Each day the catheter remains in situ, the risk of UTI rises by around 5%. Thus inserting catheters only when absolutely needed, and ensuring they are removed as soon as possible, can prevent these.”

September 24, 2014 Posted by | alcohol, Books, Cancer/oncology, Cardiology, Diabetes, Immunology, Medicine, Microbiology, Nephrology, Neurology | Leave a comment