Pathophysiology of disease (IV)
“Stimulation of α1-adrenergic receptors results in an increase in intracellular calcium concentrations. Several mechanisms are involved. First, there is activation of phospholipase C by the guanine nucleotide binding (G) protein, [G8]. Phospholipase C hydrolyzes the membrane-bound phospholipid, phosphatidylinositol-4,5-biphosphate, to generate two second messengers: diacylglycerol and inositol 1,4,5-trisphosphate. Diaglycerol in turn activates protein kinase C, which phosphorylates various cellular substrates, and inositol-1,4,5-trisphosphate stimulates release of intracellular calcium, which then initiates various cellular responses. Activation of α2-adrenergic receptors results in a decrease in intracellular cAMP. The mechanism involves receptor interaction with an inhibitory G protein, Gi , leading to inhibition of adenylyl cyclase. The fall in cAMP level leads to a decrease in activity of the cAMP-dependent protein kinase A […]
Hypercalcemia may occur, related to excessive production of PTHrP in cases of malignancy or PTH itself in cases associated with hyperparathyroidism. Occasionally, ectopic production of ACTH by the pheochromocytoma may lead to a severe hypokalemic metabolic acidosis.”
The quote above is from chapter 12 of the book, which is about Disorders of the Adrenal Medulla. I was reminded of this. As I pointed out in my latest post about the book: “It’s a great book – it’s well written, I’m learning a lot. But on the flip-side the book is, and was, hard work to read”. I’m now getting to stuff which I don’t know much about, and there are places now where I’m basically completely lost; not many, but they’re there. I added some remarks about chapters 7-9 in the last post and back then I considered covering chapter 10 later; I’ve now finished chapter 11 and also read chapters 12-14. These chapters cover heart disease, vascular disease, disorders of the adrenal medulla (as mentioned), gastrointestinal disease and liver disease. I think I’ve talked a lot about cardiovascular disorders here on the blog before – at least I’ve read a lot – and I’ve seen quite a few lectures about the topic before, so I won’t talk much about that stuff here. There was some new and interesting stuff in those chapters, but I’d need to cover a lot of ground before I could get to that stuff if I wanted readers unfamiliar with this topic to also get something out of my coverage, and I can’t justify putting in that much work given how many people are likely to even read this post. I should perhaps note before moving on that the reason why I’m lost is because I’m lazy, not because the book is badly written. I’m sure I could look up all the relevant terms and mechanisms and make sense of most of this stuff; I’m just not going to do it because it would be too much work. Less will have to do.
Anyway, chapter 12 is a short yet interesting chapter which covers a topic I’d sort of been annoyed about not understanding very well in some of the previous chapters of the book. Not all of it is equally easy to understand (…), but I now believe that I understand the role catecholamines (norepinephrine, epinephrine, dopamine) play better than I did before. The pathophysiology part of that chapter only deals with pheochromocytoma in any amount of detail. Go have a look at those two links (and perhaps some of the links in those articles) if you want to know what kind of stuff is covered in this chapter. I should point out that even if few details are added about other stuff besides pheochromocytoma in that latter part of the chapter, one of the unrelated observations actually relates to a mechanism with which I was familiar, but had never really understood in detail (..I still don’t, really, but that’s not the point – see below..). Here’s the relevant quote:
“Sympathetic neural failure, caused by deficient production of norepinephrine, presents clinically as orthostatic (postural) hypotension. Adrenomedullary failure, caused by deficient production of epinephrine, usually causes little or no disability. However, in some patients with insulin-dependent diabetes mellitus, adrenomedullary failure is associated with glucagon deficiency […] This combined deficiency was originally described in patients with advanced diabetic autonomic neuropathy. More recently, the combined deficiency has been found in a subset of patients who fail to develop hypoglycemia-related symptoms. In such patients, the central nervous system fails to recognize hypoglycemia and to mount defenses against it. The failure of the central nervous system to recognize hypoglycemia results both from strict antecedent glucose control and from one or more recent hypoglycemic episodes (hypoglycemia-associated autonomic failure). Obviously, this failure predisposes to recurrent episodes of hypoglycemia in a vicious circle.”
Now, a diabetic gets sick because of problems with the beta-cells in the pancreas. Yet here’s a chapter about how the adrenal medulla works, and diabetes just sort of pops up. It also pops up in the chapter after this, the one about gastrointestinal disease, where diabetic autonomic neuropathy can cause various problems e.g. related to peristalsis. Naturally there are a lot of other places it pops up, the main point is just that biological systems are actually really complicated and subsystems you might have assumed – for one reason or another – to be relatively independent of each other may sometimes surprise you and turn out to be in fact quite closely interconnected. I’m having quite a few realizations of this kind along the way while reading this book (most of them incidentally not in any way related to diabetes).
Chapter 13 deals with gastrointestinal disease. It starts out by giving a brief ‘big-picture’ overview of what the gastrointestinal system looks like, which functions it has to perform (motility, secretion, digestion, absorption), how it’s controlled. After that it goes into more details about each subsystem (oropharynx and esophagus, stomach, gallbladder, small intestine, colon), and covers briefly an overview of how things might go wrong on a functional level (disorders of motility, disorders of secretion, disorders of digestion and absorption). After this, it covers some specific disorders in more detail in the pathophysiology part of the chapter; these disorders include esophageal achalasia, reflex esophagitis (heartburn), various forms of acid-peptic disease (e.g. peptic ulcer), gastroparesis (here diabetes as mentioned pops up again!), gallstones, Crohn’s disease and ulcerative colitis, and diverticulosis.
A few remarks related to that chapter. The first remark relates to neural control of this biological system. I’ll quote from the book:
“Gastrointestinal tract functions are controlled by both the central nervous system, working through autonomic components of the peripheral nervous system, and by the enteric nervous system. The size and complexity of the enteric nervous system is remarkable: It contains more neurons than the spinal cord and receives sensory input from neurons specialized to detect chemical, osmotic, thermal and other changes in the lumen, or mechanical activity involving the gut wall. This information is integrated with and modified by input from the central nervous system via the sympathetic and parasympathetic neurons, which synapse with intramural neurons and provide the program for motor neurons. In this way, otherwise random and uncontrolled phasic motor and secretory activity of the gut becomes purposeful and coordinated, as manifested by characteristic gut programs such as peristalsis and sphincter control.”
As the wikipedia article also points out: “More than 90% of the body’s serotonin lies in the gut, as well as about 50% of the body’s dopamine”. Most people probably don’t think much about how their guts work when they think about how their neural wiring is set up, but this stuff’s a really important part of the big picture.
The second thing I’ll comment on from this chapter is probably a somewhat more familiar topic; I assume that today most people have heard about Helicobacter pylori (-Hp) and know that it plays a role in peptic-ulcer disease. An interesting thing that the book points out which I did not know is that roughly half the world’s population is infected with Hp, with higher rates in poor countries. “As many as 90% of infected individuals show signs of inflammation (gastritis or duodenitis) on endoscopy, though typically many of these individuals are clinically asymptomatic.” Given that far less than half the world’s population actually develop ulcers, there’s a lot of other stuff besides Hp playing a role in disease progression; “only about 15% of infected individuals ever develop a clinically significant ulcer.” However Hp is still an important pathogen with clinical relevance, because “of patients who do develop acid-peptic disease, almost all have H pylori infection. Furthermore, treatment that does not eradicate H pylori is associated with rapid recurrence of acid-peptic disease in most patients.”
Chapter 14 is about liver disease. I won’t have time to write about that stuff today, but I figured I really ought to post something today (sorry for the infrequent updates!) and this was as far as I got – posts like this one take quite a bit of time to write. I’ll probably get back to that chapter later, it’s quite interesting (for instance, did you know that the liver receives roughly 25% of the total cardiac output, corresponding to roughly 1,5 litres of blood each minute?)…
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