Never bet against occam, p.27
Never Bet Against Occam, page 27
The last time (as of this writing) that I saw Paul, several months later, he was doing well on his medications, his rotator cuff had been repaired, and repeat bone densitometry showed major improvement in bone density.
Meanwhile, Jacquelyn helps us (in medicine, anyway) re-learn that not all excess ferritin is from iron overload…
Jacquelyn had sickle cell anemia, and if ever there were a disease that illustrates the old saw that the more we know, the more we know we don’t know, it’s sickle cell anemia (SCA). I’ll tell Jacquelyn’s interesting story in just a moment, but I think it would help for you to first have a bit of background in SCA.
SCA, as many know, was the first human disease to be traced (back in 1956) to a specific genetic mutation. (I won’t even call it a genetic defect because the mutation actually helps people who have it survive infection, which can be lethal, by the parasite that causes malaria. The mutation, however, is nothing but bad news in people who live in places – such as the U.S. – where malaria is rare.) In people with SCA, in their DNA code (i.e., their genes) for the part of hemoglobin known as beta globin, a change (i.e., a mutation) in a single letter in the code results in a slightly different beta globin protein, and thus a slightly different hemoglobin protein into which the beta globin gets incorporated. The different hemoglobin is designated hemoglobin S (HbS), as distinguished from normal hemoglobin A (HbA). The function of hemoglobin, as many also know, is to convey oxygen from the lungs to the tissues and to convey carbon dioxide from the tissues to the lungs. HbS performs this function just as well as HbA when there’s enough oxygen around, but when there’s less oxygen around, the HbS protein does something that the HbA protein doesn’t: it sticks to other copies of itself. When they form, these aggregates, or polymers, of HbS quickly turn the red blood cell (RBC) from its normal self as a highly flexible bag stuffed full of independent, free-floating HbS protein molecules into an inflexible bag – shaped like a sickle, actually – stuffed full of rigid aggregates of HbS protein molecules.
This change in flexibility has critical consequences because many of the smallest blood vessels – the capillaries – that RBCs need to travel through are actually smaller in diameter than the RBCs themselves, so it’s only because the normal RBC is flexible and squeezable that it can get through such tight passages. RBCs full of polymerized HbS, though, aren’t flexible and can’t be squeezed, so they create the proverbial logjam at the point where the capillary gets too small. The medical term for this is vaso-occlusion, or occlusion of a blood vessel, and the consequences are exactly what you’d think would happen if oxygen in the RBCs, and other nutrients in the blood, can’t get through to the tissues that need them: these tissues start dying. And, unsurprisingly, it hurts. This is a sickle cell vaso-occlusive crisis, or pain crisis, in action, and it can be quite severe and disabling both in the short term and, if the patient suffers crises often enough, the long term, too.
It’s been more than a half-century since the discovery of the disease’s ultimate cause, though, and we still can do little more to treat the acute crisis than provide the suffering patient with IV fluids (to try to help dilate the blood vessels a little bit and break up the logjams) and pain medications (such as narcotics). Even giving extra oxygen doesn’t seem to help SCA patients suffering a “routine” vaso-occlusive crisis. And as far as preventing crises goes, we’ve learned a couple of tricks – a daily oral medication called hydroxyurea can help, regular (typically monthly) transfusions of normal RBCs can help – but it’s the uncommon patient in whom such tricks eliminate sickle crises. There even is a small portion of the SCA population in whom we can perform a stem cell transplant that will cure the disease, but this comes at the risk of causing substantial other medical complications, not to mention a great financial cost (though that cost overall is far less than a lifetime of care for sickle cell crises).
One of the most curious aspects of SCA, though, stems from the observation that most people with SCA have relatively infrequent and less severe crises, while a relatively small minority (roughly 5-15%) have frequent and more severe crises. This is a curious distinction because if the disease is caused in every patient by exactly the same mutation, why would different patients suffer such greatly different consequences?
Clearly, there must be other factors at work in SCA patients that modulate the severity of the disease, and over time we have been learning about some of those factors. Some patients, for example, have additional mutations (either in beta globin or the other major component of hemoglobin, alpha globin) that interact with the sickle mutation. Most such additional mutations seem to have an ultimate clinical impact of lessening the severity of the disease. On the other hand, inflammation clearly worsens not only the vaso-occlusive crises themselves but also the risk for development of such crises, and it’s clear that some SCA patients are chronically more inflamed than others and thus have chronically worse courses of the disease – patients I will call “the poor-phenotype sicklers.” Inflammation is an awfully complex phenomenon, though, and we remain just as far from a complete understanding of why some SCA patients are chronically inflamed as we do for non-SCA patients. Regardless of why they are more inflamed, though, poor-phenotype sicklers on average clearly suffer not only more frequent and severe crises but also incur more frequently and severely the complications of SCA beyond vaso-occlusive crises, a few examples of which are strokes and other blood clots, a type of respiratory failure called acute chest syndrome, and kidney failure.
As mentioned earlier in this book, soon after I began recognizing MCAS in many of my chronically ill patients whose known diagnoses didn’t account for many of their symptoms, I began seeing much the same pattern in most of the poor-phenotype sicklers already under my care. Wondering if MCAS might be one significant source of inflammation in them which might be controllable to the point of turning them into good-phenotype sicklers, I began looking for MCAS in them, and the more I looked for it, the more I found it, and the more I found it, the more I treated it, and the more I treated it, the better they got. I reported my findings in 32 such patients in an article, which the American Journal of the Medical Sciences was kind enough to publish in 2014.
Jacquelyn was one of those patients and certainly a “poster child” not only for the devastation that MCAS could cause in an SCA patient but also for the improvement that could be wrought upon recognition and successful treatment of her MCAS – but her case is instructive, too, with regard to one of the metabolic effects of MCAS (or, truthfully, almost any inflammatory process), namely, elevation in the serum ferritin level. We physicians are taught relatively early in medical school that the ferritin level in the blood goes up when there is too much iron in the body, and it sometimes (often, but not always) goes up when there is inflammation in the body. You can probably easily imagine, though, that when a patient has a condition requiring frequent blood transfusions – as is the case for many poor-phenotype sicklers – it becomes easy to think that most or all of the elevation in ferritin levels seen in such patients is attributable to the iron overload that inescapably accompanies such transfusions, and to forget, or at least disregard or discount, how much of the elevation might be coming from inflammation. In fact, many such patients are chronically administered chelation medications to try to leech the excess iron out of their bodies (via the urine) to avoid the substantial toxicities of long-term iron overload, and yet many of these patients never see any significant reduction in their massively elevated ferritin levels – but it’s almost always the case that such elevations are blamed exclusively on iron overload, with no consideration for how much a problem of uncontrolled inflammation might be contributing.
You can also probably easily imagine that when the patient has a definitively established diagnosis of a genetically based disease, everything that happens to the patient that has ever been reported as being seen in patients with that disease – such as a flare of diffuse, migratory pain – is going to be attributed almost reflexively to that disease, with little to no consideration of alternative diagnostic possibilities. Little wonder, then, that MCAS, whose range of symptoms and morbidities overlaps a good bit with what’s found in SCA, would virtually always be missed in SCA patients even if physicians were aware of MCAS and no matter how prevalent MCAS might be in the SCA population.
So with all of that as context, let’s get back to Jacquelyn’s story, or, as I like to summarize it, the epitome of the classic “Take two aspirin and call me in the morning” doctor’s tale.
At ages 3 and 8, Jacquelyn had suffered strokes which together had left her with chronic right-sided weakness (hemiparesis) and difficulty speaking (dysarthria), and between these problems and her chronic fatigue and malaise, there was no question she was fully disabled. She also had a history of acute chest syndrome and a blood clot related to a long-term IV catheter she used to have. She was “always” in the ER or the hospital for sickle cell pain crises, which often were complicated by pneumonia and sinusitis. Interestingly, she was the daughter of a Jehovah’s Witness (though not one herself), and as a result she had long refused transfusion therapy, but during a prolonged crisis hospitalization at age 31, she began accepting transfusions; however, no sustained clinical improvement was seen. There were some other oddities to her course, too. For one, she had suffered occasional periods, lasting from a few months to two years, of significantly worsened anemia attributed to a particular type of virus called parvovirus B19 which indeed can be an acute cause of severe anemia – except no evidence of this virus, not even on the most sensitive molecular testing available, was ever found in her. For another, on occasional CT scanning over more than a decade, she was found to have months-long periods of liver enlargement (hepatomegaly) that would mysteriously come on and then just as mysteriously go away all by itself. Plus, there was another remarkable oddity: although one of the supposedly inescapable consequences of SCA is destruction (and resulting gross shrinkage) of the spleen by early childhood, her CT scans found her spleen to be persistently of normal adult size. It also showed mild enlargement of a few scattered lymph nodes deep in her abdomen and pelvis, which never changed much, and the cause of this adenopathy was never apparent.
Around the time of that prolonged crisis hospitalization at age 31, new migraine headaches and frequent severe whole back pain emerged, occasioning even more frequent ER visits and hospitalizations in which these symptoms were attributed to her SCA. Jacquelyn was referred to my care at that time.
In general across multiple physical examinations, she was a thin woman appearing her stated age with right hemiparesis and a stuttering-type dysarthria from her old strokes, wearing leg braces, and frequently in moderate to severe diffuse pain. Despite her strokes, she was usually alert and oriented. Vital signs were usually unremarkable. The abdomen was usually unremarkable. She often reported pain in her extremities, chest, or along the length of her spine, but my palpation at those sites usually did not appear to provoke more pain.
I knew from the outset of her relationship with me that there was something odd about her SCA for it to be making her so much sicker than the average SCA patient, but it wasn’t until a few months after she first came under my care that I finally had a chance to take a long, careful look at her record to try to begin ferreting out clues as to what might be causing her so much difficulty. Sure, there were the zillion and one pain crises and other events in her record – all attributed to her SCA, of course – but what really stood out were long-term modest abnormalities in some of her labs. (Fortunately, the electronic medical record system my institution was using at the time had lab results dating back to 1993, and it was trivial to look at the long-term trend in each lab test. I have to admit to being disappointed when the institution switched to a new system in 2012 that made it much more difficult to look at long-term trends, plus only the most recent five years’ worth of data was migrated to the new system.) Her coagulation screening tests were often mildly abnormal, something you typically see only with use of anticoagulants except that most of the times at which she had abnormalities in these tests were times at which she was not using anticoagulants. Serum ferritin records dating back to age 16 showed longstanding, highly variable hyperferritinemia (898-11,424 ng/ml, normal 10-300) even before she began accepting transfusion therapy. There were also chronic mild elevations in her white blood cell count (leukocytosis) and chronic mild intermittent elevations in her platelet counts and percentages of monocytes, eosinophils, and basophils. The inflammation inherent in severely painful SCA crises might – emphasis on “might,” not “necessarily did” – account for some portion of the elevations in her ferritin level, coagulation tests, white blood cell count, and monocyte percentage, but it was highly unlikely that it would account for the elevations in the eosinophil and basophil percentages. Therefore, something else – also likely an inflammatory factor of some sort – was more likely responsible for at least the eosinophil and basophil elevations, and if there indeed was another inflammatory factor present, maybe it was also responsible for at least some portions of the elevations in the ferritin levels, coagulations tests, white blood cell counts, platelet counts, and monocyte percentages.
So what might this other inflammatory factor be? None of the other things I know of that can cause elevations in both eosinophils and basophils seemed to be present, but I had learned by this point that mast cell disease could do it. And so when she returned in October 2009 with ongoing severe back pain not helped one bit by a recent significant increase in narcotics by one of her other doctors, I decided to pursue the evaluation for MCAS. I sent her off to the lab to have blood and urine taken for levels of serum tryptase and chromogranin A, serum prostaglandin D2 (PGD2), plasma histamine, and urinary PGD2 and N-methylhistamine (NMH), and because pain was her major issue, I asked her to start aspirin 650 mg twice a day since it helps some patients with mast cell disease and she said she had previously tolerated it well in occasional use, so I didn’t have to worry much about her being one those mast cell disease patients in whom aspirin would trigger an even greater flare of symptoms.
She returned two months later reporting reduction in average pain from 9/10 to 6/10 and modest improvement in ability to perform activities of daily living. ER visits had been virtually eliminated, and she hadn’t had another hospitalization. Migraine headaches had resolved. The previously ordered blood tests were normal except for serum chromogranin A which was double the upper limit of normal; plasma histamine was at the upper limit of normal. It turned out she hadn’t provided the requested 24-hour urine sample previously, but she provided it at this visit – even though the urinary PGD2 result likely would be substantially compromised by her ongoing aspirin use. Fascinatingly, her serum ferritin, which had long been markedly elevated, including long before she started getting regular transfusions, had completely normalized. Because her pain was still at 6/10 on average, I asked her to further increase aspirin to 650 mg every eight hours (though I’ll note that I no longer push aspirin dosing beyond 650 mg twice daily, as I have seen a couple of GI bleeds at higher doses, and since it’s obviously my desire to make my patients better, not worse, I don’t think the potential benefits at higher doses are worth the risk).
She returned six weeks later reporting her pain had reduced to an average of 0-4/10. Fatigue and malaise were much better. The frequency of her crises dramatically decreased. She previously had been bed-bound most of each day but now was fully active, participating in household chores and going on outings with friends including shopping trips and even a fishing trip! The patient and her family were very happy with her improvement. The urine sample turned in at the last visit had yielded an N-methylhistamine level of 155 ng/ml (normal 30-200), and the PGD2 level was just barely still within the normal range at 273 pg/ml (normal 100-280), making me wonder how high it would have been if she hadn’t been on aspirin while collecting the urine sample. Nevertheless, she was doing so much better, and everything was so consistent with MCAS at that point, that I didn’t feel it right to ask her to stop the aspirin in order to collect another urine sample for another PGD2 determination. Oh, and her ferritin was still normal, too.
Because of the likelihood that she would remain on aspirin for the long term, I added twice-daily loratadine and famotidine and daily omeprazole to her regimen. She eventually found she was able to sustain her improvement with just twice-daily aspirin dosing, and she also eventually learned that her “sickle crises” usually could be aborted if she temporarily increased her aspirin and antihistamines to more frequent dosing sufficiently soon after onset of symptoms.
Now 36 years old, she still requires very occasional ER visits and hospitalizations for crises. Interestingly, her serum ferritin briefly escalates to the 600-800 ng/dl range during such events – surely a sign of an acute spike in inflammation, not iron overload – and then soon returns to normal once the crisis is over.
Ferritin levels that don’t signify what they’re assumed to signify. Ridiculously weak bones at ridiculously young ages. Horrible hypertriglyceridemia controlled by imatinib. Severe magnesium deficits cured by antihistamines. These, of course, are just a few examples of the huge range of endocrinologic and metabolic abnormalities I have seen in MCAS patients. There also have been the cases of severe, “brittle” diabetes as well as cases of marked drop in blood sugar following each flare of symptoms. Humongous weight gain. Inexplicable, severe thyroid function abnormalities which thyroid medication could never stabilize. Otherwise inexplicable pituitary hormone abnormalities, otherwise inexplicable adrenal hormone abnormalities, otherwise inexplicable pancreatic hormone abnormalities, otherwise inexplicable sex hormone abnormalities, and so on and so forth – all with MCAS eventually identified, and all improving upon identification of MCAS-targeted therapy effective for the individual patient.
