Never bet against occam, p.18
Never Bet Against Occam, page 18
Gladys returned several weeks later reporting the switch from diclofenac to celecoxib was very positive, as all of the anaphylactoid and GI side effects (abdominal pain, cramps, diarrhea) and anxiety the diclofenac used to cause had completely resolved, while the one positive effect she had been gaining from the diclofenac – control of her otherwise “crippling” joint pain – had been controlled very well by celecoxib at just 100 mg twice daily. She noted ongoing occasional reactions to environmental provocations such as a new type of perfume she had opened recently, but she had learned to aggressively take diphenhydramine for these reactions, and this strategy was working very reliably for her, usually settling down her reactions within minutes to a few hours. She even reported having recently had a reaction recently which at first she was certain was going to require a trip to the ER (based on her past experiences) but this time settled down quickly with self-treatment at home. She was quite pleased with how she was doing.
Unfortunately, at her next appointment two months later, Gladys reported she had suffered a break-in at her home, causing anxiety and then chest discomfort. She thought that lorazepam likely would significantly contribute to settling her flare, but she could not access the drug via phone calls to her other doctors, and I was out of town, so she went to the ER with her complaint of chest pain. She requested lorazepam, but this was not given. She was recommended to undergo cardiac catheterization and accepted this because the premedication regimen would include lorazepam. She says that her flare symptoms dramatically settled upon receiving the premedication regimen, and the catheterization then was performed and – surprise! – reported to her as negative. She said she had been steadily improving since then and, except for some minor residual URI-type symptoms, she was almost back to her prior baseline. She additionally noted she had been instructed to double her atenolol to help better control her blood pressure, but this seemed to be causing new edema in the lower legs and feet at the end of the day and didn’t seem to have helped her blood pressure. She requested a prescription for lorazepam to have on hand to assist with control of her flares. I provided this but reminded her of the importance of getting new symptoms promptly evaluated rather than assuming they’re directly due to flares of mast cell activation.
Gladys is typical of MCAS patients who have chest pain that (appropriately) worries physicians about the possibility of angina or an actual heart attack (or, as it’s medically called, a myocardial infarction or MI, resulting from obstruction of blood flow through the coronary arteries to the heart muscle) and yet has no obstructions in her coronary arteries. It’s not known yet whether the chest discomfort in these sorts of situations is a result of a flare of inflammation or spasm of the chest wall or esophagus or lung or some other thoracic structure, but it’s not likely being caused by damage to muscle (chest, heart, or esophageal) since our blood testing has gotten pretty good for detecting muscle damage, and yet such patients usually don’t show any signs of muscle damage.
To contrast, here’s a case of how significantly – and yet oddly – MCAS can affect the cardiovascular system.
“John,” a 48-year old former welder retired since age 30 when his first heart attack occurred, was referred to me in September 2008 regarding his apparent problems with excessive blood clotting, or what we medically call a hypercoagulable syndrome. He reported a principal problem of having had 9 heart attacks (in med-speak, “myocardial infarctions,” or “MIs”), 10 coronary artery stent placements, a one-vessel coronary artery bypass about 4-5 years earlier (though the grafted vessel clotted off about a month later), and 5 strokes, 1 of which was so large that it was read on MRI as a tumor, prompting a neurosurgeon to explore that area of his brain, finding to his surprise it was a scar from the stroke. John’s chronic problems included residual left hand numbness and minimal residual dysarthria (difficulty speaking) from his strokes, alleged near- deafness bilaterally (which he thought was due to auditory trauma from when he used to work in noisy environments, though he never seemed to have any difficulty hearing me), “arthritis” and “3 herniated discs” in his neck, chronic mild scattered bruising ever since being placed on the anti-platelet drug clopidogrel to try to keep him from clotting, a decade of chronic diffuse aches and pains in all of his joints along with numbness in his feet and hands, and problems with low blood sugars (in contrast to his siblings, who all had problems with high blood sugars).
John told me all of his problems dated back to the appearance at age 15 of enlarged lymph nodes through his neck and underarm areas (medically speaking, the axillae), accompanied by fevers, chills, profuse sweats, diffuse aches and pains, and anemia. A trial of the chemotherapy drug methotrexate did not help, and he underwent removal of his painfully enlarged spleen at that time, and though there was some debate as to whether the underlying diagnosis was Hodgkin’s vs. non-Hodgkin’s lymphoma, ultimately a precise diagnosis could not be made and he did not receive further treatment. He says his enlarged lymph nodes (which had not responded to the brief trial of methotrexate) went away on their own after the splenectomy and had never returned. Although he wasn’t having any fevers, sweats, or weight loss that might have signaled return of lymphoma (which sometimes can trigger clotting), he said he had had irritable bowel syndrome for 20 years, consistently producing diarrhea 10-15 times daily in all that time; he said his last colonoscopy and EGD in early 2008 showed only a few benign polyps. He had been evaluated for Buerger’s disease, which causes arterial obstruction, but that had turned out to be negative. He has complained of headaches at various times in the past. He also had been diagnosed with emphysema and said he got pneumonia very easily. He had undergone extensive evaluation in the past for his hypercoagulable syndrome by two hematologists I know and respect very much, but no diagnosis had ever been established.
John had smoked one pack of cigarettes per day since age 13. There was no history of alcohol abuse or illegal substance use. He said his job as a nuclear submarine welder had routinely involved exposure to radiation as well as asbestos. His father had hypertension and asbestosis, and heart disease was rampant throughout his mother’s side of the family; his mother died at age 52, allegedly due to diabetes-related coronary artery disease (CAD). Four sisters had diabetes; one had autoimmune hyperthyroidism called Graves’ disease. His maternal grandfather died at age 42 of a “massive stroke.” His maternal great-great grandfather died of “large lymph nodes all over.”
Exam found an outwardly healthy appearing man except for his smoker’s voice, mild bruising scattered about the extremities, and minimal residual neurologic deficits in the left hand.
I reviewed every one of John’s 15 years’ worth of lab results on file. He indeed had undergone very extensive evaluations of his clotting system, but no hypercoagulable syndrome had ever been found, either inborn or acquired. Curiously, though, his prothrombin time (PT) and/or partial thromboplastin time (PTT) (two very common screening tests of coagulation system function) had been modestly abnormal (elevated) on some occasions which didn’t correlate with acute presentations in which he would have been anticoagulated (different anticoagulants normally elevate the PT or PTT). Other subtle oddities abounded, too. His mean corpuscular volume (MCV, or average red blood cell size) was consistently modestly elevated through 2006. He has been consistently mildly anemic throughout 1997 and then again ever since 2002. He had had a fairly consistent mild elevation in his white blood cell count since at least 1993, but perhaps that was just due to his splenectomy. His red cell distribution widths (RDWs, measures of the variability in red blood cell size) had been consistently mildly elevated since 2004. The total amount of the IgM type of antibody had always been low in him, roughly half to two-thirds normal. Extensive blood studies looking for molecular traces of B- and T-cell lymphomas had been negative. Eosinophils were occasionally slightly elevated, but he also had frequently shown a moderate percentage of “reactive lymphocytes” on many of his blood counts. CT imaging in 1995 and 2005 showed persistent mild adenopathy at many places about his body. H. pylori gastritis had been found in 1993 and again in 1995. EGD and colonoscopic biopsies in the 1990s had found mild chronic inflammation in the small and large bowel and benign colonic polyps. Skin biopsy of a cyanotic right great toe in 1995 and again in 1996 found microvascular thrombosis both times. A skin biopsy in 1998 of an itchy back lesion found an “atypical lymphoreticular infiltrate.”
I pretty thoroughly re-evaluated John for virtually every inborn or acquired hypercoagulable syndrome that hadn’t already been checked out, but all the tests came back negative – around the time when I was figuring out my first few MCAS patients. I hadn’t yet seen MCAS-induced clotting (not that I was aware of, anyway), but I was rapidly learning that MCAS can affect many other systems in the body depending on which mediators the given patient’s dysfunctional mast cells would produce, so given that some of these mediators clearly had interactions with the clotting system, why wouldn’t the clotting system, too, be involved in the clinical presentation in at least some MCAS patients?
And, indeed, subsequent testing for MCAS showed a significantly elevated chromogranin A level (178 ng/ml, normal 0-50), a significantly elevated urinary prostaglandin D2 level (399 pg/ml, normal 100-280), and an elevated plasma free norepinephrine (591 pg/ml, normal 10-520). I asked the pathologist to re-examine John’s old GI tract biopsies for evidence of mast cell disease, but that additional testing was negative.
I set about reviewing John’s old MI and stroke records in detail, and the story that emerged was not what I had expected. John had actually never been found to have any obstructions in any of his own arteries. In fact, his first few MI presentations really puzzled his cardiologists precisely because repeated catheterizations never showed any CAD. Finally, somewhere around the fourth MI, his cardiologists felt compelled to place a stent in the artery that the tests said should have been the occluded artery, and since that time he had undergone numerous stent placements – and had always soon developed obstructions located exclusively in the stents. As noted above, he also underwent a coronary artery bypass, and soon after the operation an obstruction developed in the grafted vessel.
Unfortunately, although H1 and H2 histamine receptor blockers and inhaled and oral cromolyn helped John a little bit with a range of his symptoms, I never found a “home run” drug for him before he died in early 2011 from another MI.
In retrospect, I suspect his MCAS not only drove his baseline hypercoagulability but also led to abnormal reactions to his stents (ironically, most of them of the variety suffused with one immunosuppressive drug or another to try to prevent immune reactions) that provoked the intra-stent clotting.
So MCAS can affect thoracic structures to mimic a heart attack, and it can affect blood vessels to cause an actual heart attack, but what about the heart itself?
“Regina” was a 50-year old jewelry designer when I was initially asked to see her in the hospital in May 2011 while she was recovering from a strange case of heart failure, but her history of lifelong unwellness stretched back literally a lifetime. As far back as she could remember, she had been allergic to grass and shellfish and “could never play outside” and to the present could not “touch a Christmas tree.” She had had waxing/waning diffusely migratory pruritus since childhood. She had always been “sensitive” to most medications. She had reportedly suffered a seizure at age 2. She had suffered seemingly unprovoked episodes of what sounded like hives about her fingers since childhood. She said she had suffered asthma as a child, but this resolved by adolescence. She had been dealing with irritation of both of her eyes as well as “constant” coryza and a “constant lump in my throat” “my whole life.”
Regina also noted she had suffered frequent unprovoked palpitations “my whole life.” At age 16 she was in a bad motor vehicle accident causing extensive orthopedic trauma including bilateral femur fractures. She was in the hospital for 8-1/2 months and had great trouble healing from surgeries including Staph infections “that would not heal.” She had been markedly fatigued, waxing/waning, ever since that accident and also had carried a diagnosis of post-traumatic stress disorder (PTSD) ever since that accident.
As if all of that history wasn’t bad enough, she then suffered a second severe motor vehicle accident at age 37. Her right leg was again crushed, requiring implantation of several plates, and she had very limited flexion remaining in the right knee. She also accumulated multiple vertebral disc problems with this second accident.
Then, believe it or not, in 2008 (at age 47) she suffered a third car accident. Regina told me none of these accidents was her fault (i.e., she didn’t lose control of her car). She said she had been in constant back pain for many years; “I don’t know what it’s like to have a day and not be in pain,” she told me. She had long sought care at a spine care center for her back problems and even underwent a rhizotomy (selective spinal cord nerve root destruction) there in 2008 to try to control the pain (after which surgery, curiously, she gained another 35 lbs.), but then, because it was becoming too difficult to travel to their facilities, she began seeing a new pain management physician locally in December 2010.
Regina told me she got a series of “16 steroid shots” in her back from that physician over the course of several weeks that resulted in marked abdominal bloating, hoarseness, facial edema, and dermatologic changes such that her “skin didn't feel right.” Then, in February 2011, she joined her family at a restaurant and ate a roast beef sandwich, and though the rest of her family was fine, a few hours later she developed severe non-bloody vomiting and diarrhea that quickly led to an ER visit and hospitalization for dehydration, during which 5-day stay she also was newly diagnosed with diabetes mellitus type 2 and diverticulitis. She again got out of the hospital for five days but then had to be readmitted for nine days, this time for a new diagnosis of congestive heart failure. She was out of the hospital again for 2-1/2 weeks, then acutely developed an odd type of chest pain (brief (2-10 minute) episodes of severe “grabbing” central chest pain) and returned to the ER, was hospitalized, and was soon transferred to the cardiology service at my hospital, where she stayed for a week and was diagnosed with severe systolic heart failure of uncertain cause (on assorted testing, both atria and ventricles were enlarged and left ventricular ejection fraction was 8% (normal is 50% or higher), but no scar or infiltrative process was found; cardiac catheterization was not done, but cardiac MRI suggested no arterial or venous disease of any sort). Since discharge, she had been suffering “severe” fatigue (“sleeping all the time” but also staying up most of every night), and felt overwhelmed, depressed, and as if she couldn’t feel anything. She also felt more like an “it” than a woman; “my femininity is gone.”
Past medical history also included endometriosis for which she underwent surgery not too long before her first pregnancy at age 30 (presented breach, delivered a daughter by C-section). She then underwent another pregnancy two years later, delivering a son. She was diagnosed with obstructive sleep apnea in 2008 and, though CPAP initially was helpful, she soon became intolerant of it and had largely given it up.
On review of systems she denied problems with fevers, queasiness/nausea/vomiting, rash, or neuropathy (except her left leg as described above), but she endorsed a wide range of other problems including feeling cold (“freezing”) virtually all the time for the past several months (following, oddly, a very long prior history of feeling hot virtually all the time), chills, unprovoked (often at nighttime) soaking sweats since 2009, relatively new problems with frequent headaches, waxing/waning visual acuity over the last year or so, development of sores in her mouth whenever she was nervous, onset of malaise whenever she had to wear pink-colored clothing, seasonal allergies, proximal dysphagia, “grabbing” chest pain (for which she had used furosemide and sublingual nitroglycerin three times since she was discharged), relatively new GERD, weight loss since discharge, intermittent right hearing loss for 2-30 minutes, frequent crying, “constant” urethral burning since a urinary catheter was placed during one of her recent hospitalizations, newly constipated since discharge (which she attributed to her medication regimen), diffusely migratory waxing/waning aching ever since her first accident at age 16, fairly frequent, unprovoked episodic cognitive dysfunction and panic attacks since her car accident in 1997, and frequent episodes of “vertigo” for many years now (always seem to be orthostatic in nature). She denied frank syncope. She noted that very tiny macular hyperpigmented areas had been newly appearing scattered all about her skin over the last several months. She had “always” had a problem with “rotting teeth” in spite of what she felt was good attention to dental hygiene since childhood. She said her periods had recently abruptly stopped.
Regina’s father had been ill for the last 10 years of his life with diabetes, heart disease (requiring a four-vessel coronary artery bypass), and a Staph infection requiring revision of the sternal incision for his coronary artery bypass; already a double-amputee from gangrene, he eventually died a day before a planned hand amputation for gangrene. Her mother had never been ill, but a maternal uncle (a smoker) died of metastatic lung cancer. This uncle’s son had been afflicted lifelong by eczema, and this uncle’s daughter had just delivered a baby “covered” in eczema. A maternal aunt had diabetes. Her maternal grandmother had suffered two episodes of septicemia, one in labor in her first pregnancy, which led to loss of the baby, the other a fatal episode allegedly related to diabetes. Her daughter was healthy, but her son had an enlarged heart.
