This week the curriculum moves into hematology.
Correction: During the malaria discussion, I mis-spoke and said that JBS Haldane was the originator of the p=.05 convention that is widely used in research. This was actually Sir Ronald Fisher, who along with Haldane, is considered a founder of population genetics. Here is a link to Statistical Methods for Research Workers (see: page 45), where Fisher first wrote of the idea. Because I’ll likely not find a reasonable place to talk about Haldane again during the podcast, I’m including a short excerpt from a fantastic book (A Short History of Nearly Everything) by Bill Bryson that touches on JBS Haldane and his father:
A great deal of what we know about surviving at extremes is owed to the extraordinary father-and-son team of John Scott and J. B. S. Haldane. Even by the demanding standards of British intellectuals, the Haldanes were outstandingly eccentric. The senior Haldane was born in 1860 to an aristocratic Scottish family (his brother was Viscount Haldane) but spent most of his career in comparative modesty as a professor of physiology at Oxford. He was famously absent-minded. Once after his wife had sent him upstairs to change for a dinner party he failed to return and was discovered asleep in bed in his pajamas. When roused, Haldane explained that he had found himself disrobing and assumed it was bedtime. His idea of a vacation was to travel to Cornwall to study hookworm in miners. Aldous Huxley, the novelist grandson of T. H. Huxley, who lived with the Haldanes for a time, parodied him, a touch mercilessly, as the scientist Edward Tantamount in the novel Point Counter Point .
Haldane’s gift to diving was to work out the rest intervals necessary to manage an ascent from the depths without getting the bends, but his interests ranged across the whole of physiology, from studying altitude sickness in climbers to the problems of heatstroke in desert regions. He had a particular interest in the effects of toxic gases on the human body. To understand more exactly how carbon monoxide leaks killed miners, he methodically poisoned himself, carefully taking and measuring his own blood samples the while. He quit only when he was on the verge of losing all muscle control and his blood saturation level had reached 56 percent—a level, as Trevor Norton notes in his entertaining history of diving, Stars Beneath the Sea, only fractionally removed from nearly certain lethality.
Haldane’s son Jack, known to posterity as J.B.S., was a remarkable prodigy who took an interest in his father’s work almost from infancy. At the age of three he was overheard demanding peevishly of his father, “But is it oxyhaemoglobin or carboxyhaemoglobin?” Throughout his youth, the young Haldane helped his father with experiments. By the time he was a teenager, the two often tested gases and gas masks together, taking turns to see how long it took them to pass out.
Though J. B. S. Haldane never took a degree in science (he studied classics at Oxford), he became a brilliant scientist in his own right, mostly in Cambridge. The biologist [and Nobel laureate] Peter Medawar, who spent his life around mental Olympians, called him “the cleverest man I ever knew.” Huxley likewise parodied the younger Haldane in his novel Antic Hay, but also used his ideas on genetic manipulation of humans as the basis for the plot of Brave New World. Among many other achievements, Haldane played a central role in marrying Darwinian principles of evolution to the genetic work of Gregor Mendel to produce what is known to geneticists as the Modern Synthesis.
Whereas his father’s principal interests concerned miners and poisoning, the younger Haldane became obsessed with saving submariners and divers from the unpleasant consequences of their work. With Admiralty funding he acquired a decompression chamber that he called the “pressure pot.” This was a metal cylinder into which three people at a time could be sealed and subjected to tests of various types, all painful and nearly all dangerous. Volunteers might be required to sit in ice water while breathing “aberrant atmosphere” or subjected to rapid changes of pressurization. In one experiment, Haldane simulated a dangerously hasty ascent to see what would happen. What happened was that the dental fillings in his teeth exploded. “Almost every experiment,” Norton writes, “ended with someone having a seizure, bleeding, or vomiting.” The chamber was virtually soundproof, so the only way for occupants to signal unhappiness or distress was to tap insistently on the chamber wall or to hold up notes to a small window.
On another occasion, while poisoning himself with elevated levels of oxygen, Haldane had a fit so severe that he crushed several vertebrae. Collapsed lungs were a routine hazard. Perforated eardrums were quite common, but, as Haldane reassuringly noted in one of his essays, “the drum generally heals up; and if a hole remains in it, although one is somewhat deaf, one can blow tobacco smoke out of the ear in question, which is a social accomplishment.”
Porphyrias & Anemias
We talked about lead poisoning and basophilic stippling, as well as how to differentiate lead poisoning from major thalassemia (in the context of basophilic stippling) based on serum iron (which is more likely to be normal in thalassemia). We also discussed functional asplenia in sickle cell disease — here’s a 1969 paper from the NEJM. Addie mentioned thinking Goljan had said that HbSS kiddos were functionally asplenic by age 2; here’s a reference that says it’s “usually complete by 5 years of age.” For one more reference → Robbins (2016, 9e) says on page 636-7, “In early childhood, the spleen is enlarged up to 500 gm by red pulp congestion, which is caused by the trapping of sickled red cells in the cords and sinuses. With time, however, the chronic erythrostasis leads to splenic infarction, fibrosis, and progressive shrinkage, so that by adolescence or early adulthood only a small nubbin of fibrous splenic tissue is left; this process is called autosplenectomy.”
Porphyrias involve a couple of different enzymes, and we also discussed one drug (a p450 inducer) that is important to never give to someone who has porphyria. Goodman & Gilman, 12e, p472 says that because, “barbiturates enhance porphyrin synthesis, they are absolutely contraindicated in patients with acute intermittent porphyria or porphyria variegata.” Note that there was some confusion in our discussion about whether this applies just to phenobarbital or to all barbiturates — phenobarbital may be the high yield test answer, but this makes it pretty clear that it applies to all.
Addie mentioned Howell-Jolly Bodies and listening to Goljan. Malaria also came up, particularly with regard to sickle cell and evolutionary adaptations. Here’s a really interesting mathematical paper on vector disease modeling. And here’s a paper from Nature Genetics that talks about 20x blood density of oocytes in HbSS persons with plasmodium infection, as well as 2-4x likelihood of transmission. Finally, here are three different papers talking about the ~90% protection for cerebral malaria. A genome wide analysis of Plasmodium falciparum intraerythrocytic development cycle genes found that genes for host invasion and early blood stage replication,
“contained a significant excess of nonsynonymous polymorphisms in P. falciparum relative to fixed differences [and these data] are consistent with the model of an ‘evolutionary arms race’ between the mammalian immune system and the exposed proteins of Plasmodium parasites”
Guttae → ‘gtt’ → IV drip
We talked about VWF and the variance in individual VWF levels as a function of blood group, with type-O having the lowest VWF (on average) and AB having the highest. To quote the linked paper: “Orstavik and colleagues found that 66 percent of the total variation in plasma VWF levels was genetically determined and that 30 percent of this genetic component was explained by ABO blood group.” Perhaps an even more interesting quote is this one:
“…the influence of ABO blood groups on plasma VWF levels can make difficult the diagnosis of type 1 VWD since the normal range for VWF:Ag in group O individuals extends below 50 IU/dL, which is commonly accepted as the lower normal limit.”
Which leads to our EBM topic for this episode: understanding how “normal” lab value ranges are set. In short, a reference range covers 95% of the population of interest. The key point being that some people with ‘abnormal’ values do not actually have a pathological process at work, but are simply folks who fall outside some interval we have subjectively decided to call ‘normal.’ Lab values are just one part of the bigger picture. This discussion took place in the context of talking about normal sodium values, and the crazy high serum Na seen in a patient who drank a quart of soy sauce and somehow lived. Kim asked about the safe speed at which one can correct hyponatremia, and although the generally accepted answer is 10-12 mEq per 24h, a 2015 paper in NEJM says:
“If the plasma sodium concentration is less than 120 mmol per liter, or if there are risk factors for osmotic demyelination, correction of the plasma sodium concentration by more than 8 mmol per liter per day should be meticulously avoided…”
— Episode credits —
Hosted by Addie, Kim, and Alex. Audio production and editing by Addie. Theme music compositions (Too Cool, and Laserpack) by Kevin MacLeod of incompetech.com, licensed under Creative Commons: By Attribution 3.0 License.