Pathophysiology of Disease: An Introduction to Clinical Medicine (2nd edition) (II)

My first post about the book can be found here. In this post I’ll talk a little bit the chapters 4-5, which deal with infectious diseases and neoplasia.

When reading chapter 4 – on infectious diseases – it was a great help to have read chapter 3 first – that chapter had a lot of stuff on how the body defends itself against the kind of stuff they talk about in chapter 4, and even though they recap a bit of that stuff in chapter 4 it’s probably smart to read those two chapters in the order they appear in the book. I did not find chapter 4 particularly hard to read, in part probably because this stuff is closely related to the microbiology stuff I read in the past, which dealt in much more detail with the microorganisms causing these diseases. There’s a lot of important concepts covered: transmission mechanisms; factors impacting disease susceptibility; the normal microbial flora and how it relates to this topic at hand; constitutive defences the body (‘defence mechanisms which do not require prior contact with the microorganism – such as physical and chemical barriers to colonization, inflammatory response, the complement system, and phagocytosis); disease progression (to cause disease all microorganisms must go through four stages: they must encounter the host, gain entry, multiply and spread, and cause host tissue injury. The course of an infection may vary from asymptomatic to life threatening; an important distinction is between acute (and sub-acute) and chronic infections). Chronic infection is not the only outcome of a long-term colonization; an individual may also enter a carrier state, or the infection may become latent until reactivation.).

After the ‘general stuff’ has been covered in chapter 4, they deal with the pathophysiology of some examples of infectious diseases; infective endocarditis (bacterial or fungal infection of the interior of the heart), meningitis, pneumonia, infectious diarrhea, and sepsis/sepsis syndrome/septic shock. I’ll not go into much detail about these diseases, but I should probably note here that the names we use to describe infectious diseases like these may cause people to misunderstand how they work: To be clear, there isn’t just one ‘endocarditis bacterium’ or a specific ‘meningitis bacterium’. When specific sites/organ systems are invaded by microorganisms which spread and cause tissue damage (damage which can be caused both by the toxins released by the invading microorganisms and by the host response to the invasion), we have a name for that – but many different microorganisms may cause symptoms by invading the specific site or organ system in question, though some are more likely to affect specific sites than others. Sometimes the names of the microorganisms may even add to this confusion; for example one of the most common causes of bacterial meningitis (infection of the meninges) in children aged 2 months to 15 years is H Influenzae (which kind of sounds like, well…).

Chapter 5 deals with neoplasia. If you dont’ feel like reading this stuff, at least read Mukherjee. The chapter deals briefly with colon carcinoma as an example of an epithelial neoplasia; this stuff from Khan Academy is another great resource on this subject – it also deals a bit with cancer development more generally, and it’s a lot more accessible than is this chapter.

Anyway, the chapter… It starts out with a bit of a downer: “The recognition of overt malignancy by physical examination or imaging requires the presence in the body of about 1 billion malignant cells.” It goes on to note that: “A preclinical phase may sometimes be recognized” but even so, “More commonly, the preclinical phase goes undetected until invasive cancer, occasionally with regional or distant metastases, is already present.” That’s the way it is. The chapter then goes on to talk about many of the same things Mukherjee covers in the latter half of his book, like the role of tumor suppressor genes and oncogenes, the role of environmental triggers (carcinogens), inheritance, … In the field of oncology there seems to be a big focus on the role of genetic changes taking place in the cell(s), and: “A paradigm for sequential genetic alterations has been proposed as a necessary set of events leading to tumorigenesis.” Mukherjee also has more on this, if you’re interested. There are a lot of oncogenes and tumor suppressor genes that play a role in human cancers. In terms of the phenotypic changes they cause, this table is relevant (click to view full size):

A good related quote from the first part of the chapter:

“Molecular and cellular changes in tumor cells are, in a sense, a modification of normal physiology that benefits their growth and spread. The initial alterations may be “preprogrammed” in rare inherited malignancies, or they may be acquired as a consequence of mutations brought about by environmental exposure or occuring by chance during normal cell division. In a process akin to evolution, albeit in a fast time frame, additional genetic changes occur that favor further growth, invasion, and spread. Evasion of the host’s immune system, enhanced proliferative and invasive potential, and resistance to therapy are examples of early, middle, and late changes in the progression of neoplasia.”

The simple way to think about cancer is this: Cancer cells outcompete the surrounding cells because they’re better at growing and spreading, and they cause disease because the reason why they’re better at growing and spreading is that they’re no longer doing what they’re supposed to be doing, and because they’re taking up space and nutrients from the cells that still do their jobs.

The chapter also has some stuff on breast cancer and talks a bit about the BRCA mutations. After that they talk about mesenchymal, neuroendocrine and germ cell neoplasias, which are types of neoplasias the pathophysiology of which “can be described in terms of the embryonic tissue of origin.” The examples they include are carcinoid tumors, testicular cancer, and sarcomas. Again the naming of these diseases may be a bit confusing – tissue will often migrate during development and you can actually end up with, say, a testicular neoplasm which is not located anywhere near your testes (for example, the testicular tissue may have migrated to your chest..). Then they cover hematologic neoplasms (blood, bone marrow, or lymph nodes), and here they’ve included some stuff on lymphomas (“uncontrolled proliferation and potential dissemination of lymphocytes“) and AML, a type of leukemia (Mukherjee has a lot more stuff on that). I found it surprising that they did not spend more time on the last part, the systemic effects of neoplasia – basically they only spend one page on that stuff, though they do also include a few tables to illustrate these aspects of the diseases. I’ve included one of the figures below (click to view in a higher resolution):

Indirect systemic effects of cancer which are not caused by the local presence of cancer cells are what’s called pareneoplastic syndromes.

The Emperor of All Maladies

By Siddhartha Mukherjee. It is another one of the books I received in the mail Tuesday. I didn’t plan on reading it before this weekend, but ‘things didn’t go as planned.’ I started out with a few pages Tuesday evening and basically I just couldn’t stop reading. Now I’ve finished the book.

It’s gotten a lot of attention around the web, which was part of why I decided to have a go at it. The attention it has received is not undeserved. I’d have liked more data but then again I always want more data. Here are a few interesting observations from the book:

“In 1870, the per capita consumption in America was less than one cigarette per year. A mere thirty years later, Americans were consuming 3.5 billion cigarettes and 6 billion cigars every year. By 1953, the average annual consumption of cigarettes had reached thirty-five hundred per person. On average, an adult American smoked ten cigarettes every day, an average Englishman twelve, and a Scotsman nearly twenty. [...] between 1940 and 1944, the fraction of female smokers in the United States more than doubled, from 15 to 36 percent.”

If you assume they wouldn’t have started in case there hadn’t been a World War, you can probably add another few million people to the list of war casualties right there. How about later on? “By 1994, the per capita consumption of cigarettes in America had dropped for nearly twenty straight years (from 4,141 in 1974 to 2,500 in 1994), representing the most dramatic downturn in smoking rates in history.” But before that point the results of the changed smoking habits were not hard to observe in the data:

“Between 1970 and 1994, lung cancer deaths among women over the age of fifty-five had increased by 400 percent, more than the rise in the rates of breast and colon cancer combined. This exponential upswing in mortality had effaced nearly all gains in survival not just for lung cancer, but for all other types of cancer. [...] Lung cancer was still the single biggest killer among cancers, responsible for nearly one-fourth of all cancer deaths.”

A few other interesting bits:

“Prostate cancer represents a full third of all cancer incidence in men — sixfold that of leukemia and lymphoma. In autopsies of men over sixty years old, nearly one in every three specimens will bear some evidence of prostatic malignancy.” (but you already knew that first part, right?)

“Cisplatin was unforgettable in more than one sense. The drug provoked an unremitting nausea, a queasiness of such penetrating force and quality that had rarely been encountered in the history of medicine: on average, patients treated with the drug vomited twelve times a day.”

“The incidence of CML remains unchanged from the past: only a few thousand patients are diagnosed with this form of leukemia every year. But the prevalence of CML—the number of patients presently alive with the disease—has dramatically changed with the introduction of Gleevec [a new treatment option - there's much more about it in the book and the wikipedia article also covers this]. As of 2009, CML patients treated with Gleevec are expected to survive an average of thirty years after their diagnosis. Based on that survival figure, Hagop Kantarjian estimates that within the next decade, 250,000 people will be living with CML in America, all of them on targeted therapy. Druker’s drug will alter the national physiognomy of cancer, converting a once-rare disease [people just died of it in the past] into a relatively common one”

He doesn’t cover the economics of cancer and cancer treatment in much detail and present problems and developments in this area are not covered at all. Included in the postscript is however an interview dealing with some of the stuff not covered in the book, and after reading that part I’m in a way glad he didn’t write about this stuff – when dealing with the question of the high costs of relatively recently discovered targeted therapies, he does not even mention FDA’s role in driving up costs when answering that question, which is telling me that this is a subject he simply doesn’t know enough about to cover, at least at the present point in time. If you want to know more the FDA’s role in driving up costs of new medical treatments, including new cancer treatments, Megan McArdle has written about that stuff often though I don’t have a specific link at hand; google is your friend.

The book is very USA-centric, but I didn’t consider that a big issue. It’s also ‘popular science’. That was initially a strong argument for not buying the book, but on the other hand the popular science aspect also means that the book is easy to read and won’t take you very long to get through even though the page count is significant.

It’s a wonderful read.

Screening for breast cancer

“Main results

Eight eligible trials were identified.We excluded a biased trial and included 600,000 women in the analyses. Three trials with adequate randomisation did not show a significant reduction in breast cancer mortality at 13 years (relative risk (RR) 0.90, 95% confidence interval (CI) 0.79 to 1.02); four trials with suboptimal randomisation showed a significant reduction in breast cancer mortality with an RR of 0.75 (95% CI 0.67 to 0.83). The RR for all seven trials combined was 0.81 (95% CI 0.74 to 0.87).

We found that breast cancer mortality was an unreliable outcome that was biased in favour of screening, mainly because of differential misclassification of cause of death. The trials with adequate randomisation did not find an effect of screening on cancer mortality, including breast cancer, after 10 years (RR 1.02, 95% CI 0.95 to 1.10) or on all-cause mortality after 13 years (RR 0.99, 95% CI 0.95 to 1.03).

Numbers of lumpectomies and mastectomies were significantly larger in the screened groups (RR 1.31, 95% CI 1.22 to 1.42) for the two adequately randomised trials that measured this outcome; the use of radiotherapy was similarly increased.

Authors’ conclusions
Screening is likely to reduce breast cancer mortality. As the effect was lowest in the adequately randomised trials, a reasonable estimate is a 15% reduction corresponding to an absolute risk reduction of 0.05%. Screening led to 30% overdiagnosis and overtreatment, or an absolute risk increase of 0.5%. This means that for every 2000 women invited for screening throughout 10 years, one will have her life prolonged and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress for many months because of false positive findings. It is thus not clear whether screening does more good than harm.”

…

From this review by Gøtzsche and Nielsen from The Nordic Cochrane Centre. Here’s a relatively recent press release from Cochrane (in Danish). Here’s a related article published a few days ago. By now, it seems that Gøtzsche thinks it is quite clear whether screening does more good than harm:

“I believe the time has come to realise that breast cancer screening programmes can no longer be justified,” Gøtzsche said.”

Maybe there’s a way to modify the current screening programmes somewhat so that they include mainly/only relatively high-risk subpopulations – but identifying just who the high-risk individuals are is never easy, which is part of why screening programmes like these are undertaken in the first place. Either way, if the results reported above are ‘in the right ballpark’ a serious cost/benefit analysis should in my mind lead to a rejection of the current programme(s).

Superfreakonomics (1,5?)

Have read the first 100 pages now, a few interesting passages from the book:

1) “In the early 1910s, the Department of Justice conducted a census of 310 cities in 26 states to tally the number of prostitutes in the United States: “We arrive at the conservative figure of approximately 200,000 women in the regular army of vice.”
At the time, the American population included 22 million women between the ages of fifteen and forty-four. If the DOJ numbers are to be believed, 1 og every 110 women in that age range was a prostitute. But most prostitutes, about 85 percent, were in their twenties. In that age range, 1 of every 50 American women was a prostitute.
The market was particularly strong in Chicago, which had more than 1000 known brothels.”

…

2) “Teaching has traditionally been dominated by women. A hundred years ago, it was one of the few jobs available to women that didn’t involve cooking, cleaning, or other menial labor. (Nursing was another such profession, but teaching was far more prominent, with six teachers for every nurse.) At the time, nearly 6 percent of the female work-force were teachers, trailing only laborers (19 percent), servants (16 percent), and laundresses (6,5 percent). [...] As of 1940, an astonishing 55 percent of all college-educated female workers in their thirties were employed as teachers.”

Yes, the teacher numbers are interesting, but damn, so are the others – a 100 years ago, appr. 1 in 6 women employed were servants! Here’s a bit more:

“In 1960, about 40 percent of female teachers scored in the top quintile of IQ and other aptitude tests, with only 8 percent in the buttom. Twenty years later, fewer than half as many were in the top quintile, with more than twice as many in the buttom.”

Combine this fact and the development since then with the Flynn effect and you get at least part of the explanation why teachers were more respected in the past. They, and especially the females, were much smarter on average.

…

3) “Alan Krueger combed through a Hezbollah newsletter called Al-Ahd (The Oath) and compiled biographical details on 129 dead shahids (martyrs). He then compared them with men from the same age bracket in the general populace of Lebanon. The terrorists, he found, were less likely to come from a poor family (28 percent versus 33 percent) and more likely to have at least a high-school education (47 percent versus 38 percent).
A similar analysis of Palestinian suicide bombers by Claude Berrebi found that only 16 percent came from impoverished families, versus more than 30 percent of male Palestinians overall. More than 60 percent of the bombers, meanwhile, had gone beyond high school, versus 15 percent of the populace.
In general, Krueger found, “terrorists tend to be drawn from well-educated, middle-class or high-income families”.”

…

4) “The beauty of terrorism – if you’re a terrorist – is that you can succeed even by failing. [...] Let’s say it takes an average of one minute to reomve and replace your shoes in the airport security line. In the United States alone, this procedure happens roughly 560 million times per year. Five hundred and sixty million minutes equals more than 1,065 years – which, divided by 77.8 years (the average U.S. life expectancy at birth), yields a total of nearly 14 person-lives. So even though Richard Reid [the failed shoe bomber] failed to kill a single person, he levied a tax that is the time equivalent of 14 lives per year.”

…

5) “Until the 1960s, hospitals simply weren’t designed to treat emergencies. “If you brought someone to a hospital at night,” Feied [Craig Feied, according to the book 'an emergency-medicine specialist'] says, “the doors would be locked. You’d ring the bell, a nurse would come down to see what you wanted. She might let you in, then she’d call the doctor at home, and he might or might not come in.” Ambulances were often run by the local mortuary. It is hard to think of a better example of misaligned incentives: a funeral director who is put in charge of helping a patient not die!”

[...]

“In a given year, an excellent ER doctor’s patients will have a twelve-month death rate that is nearly 10 percent lower than the average. This may not sound like much, but in a busy ER with tens of thousands of patients, an excellent doctor might save six or seven lives a year relative to the worst doctor.”

‘No, it doesn’t sound like much and that really isn’t a big difference’ I’d say, unless you’re one of those six or seven marginal people of course. But the difference between the best and an average ER doctor seems to be quite small – it’s probably much bigger in other specialties. A Dane at the age of 30 can expect to live 8,5 years more if he’s never smoked than if he’s a heavy smoker, so a GP who’s good at making people stop smoking will save dozens of lives every year on that count alone.

…

6) “More than $40 billion is spent worldwide each year on cancer drugs.”

(I’d have thought the number was bigger than that)

“cancer patients make up 20 percent of Medicare cases but consume 40 percent of the Medicare drug budget.”

“A typical chemotherapy regime for non-small-cell lung cancer costs more than $40,000 but helps extend a patient’s life by an average of just two months.”

…

I like the book so far.