Never bet against occam, p.21
Never Bet Against Occam, page 21
Fiona had a long medication list, most of it irrelevant to the discussion here, but she noted that since beginning twice-daily cetirizine and ranitidine in September 2012, her rash and diarrhea had markedly reduced. Allergies include vomiting with clarithromycin, sulfa, and the sulfa-based celecoxib, headaches upon exposure to “blue dyes,” hives upon exposure to norfloxacin, imaging contrast dye, oxycodone, methylsulfonylmethane, codeine, or hydrocodone, and unspecified reaction to metoclopramide. A reaction in July 2012 to CT contrast was quelled with prednisone and diphenhydramine, and she also found the prednisone helped her GI issues.
My exam of Fiona was notable for her pulse of 93 (technically in the normal range, but in truth higher than it should have been for a thin 52 year old at rest), diffuse slight clamminess to her skin, sparse scattering of small irregularly contoured patches of macular red rash, cherry angiomata where she thought she had a petechial rash, poor dentition (including several missing teeth), clear lungs (albeit with a single dry cough at one point on deep inspiration), mild mid-abdominal tenderness on deep palpation, and mild distal paresthesias. On a light scratch test on the upper back, moderately bright dermatographism quickly emerged and was fully sustained when last checked 10 minutes later.
With regard to her prior laboratory testing, suffice to say that she had been very thoroughly evaluated, but nothing diagnostic had ever been found, including a normal tryptase level. An abdominal CT in August 2009 showed thickening and distention of the second and third portions of the duodenum. An abdominopelvic CT in December 2011 showed hepatic cysts and a single renal cyst. Her only known GI biopsies on file were from April 2005, including a proximal transverse colon biopsy provocatively showing “mild non-specific active colitis with eosinophilia” and an ascending colon biopsy also provocatively showing “mild non-specific active colitis.”
My initial assessment was thus: “As I initially noted, [Fiona] has suffered an extraordinarily complex, obviously multisystem array of polymorbidity, much of it of an inflammatory theme. Although I can envision many diagnoses that can account for assorted subsets of her problems, I know of very few illnesses that might possibly account for the entire range of these findings. Given the old maxim about common things occurring commonly – and we have been learning rapidly these past few years that mast cell disease is far more common than historically appreciated – I think it’s far more likely that she has been suffering a mast cell activation syndrome (MCAS) her entire life, and far less likely that she has been suffering any of the variety of rare inborn autoinflammatory syndromes which virtually always cause such severe pediatric morbidity as to be diagnosed by pediatricians or geneticists relatively early in life. With regard to her EDS diagnosis, I note that EDS Type III is the only type of EDS which to date has defied all efforts to identify a root mutational defect, and given that I have a number of MCAS patients previously diagnosed with EDS Type III (among a number of other comorbidities, of course), what I suspect is going on here is chronic aberrant elaboration of a particular set of mediators (drawn from amongst the mast cell’s repertoire of more than 200 such molecular signals) not only influencing virtually every other system and organ in the body but also influencing connective tissue development to yield the “hyperextensible” phenotype long associated with EDS Type III.”
I asked her to submit to testing for MCAS, but as she didn’t have a diagnosis yet, I didn’t feel I could responsibly recommend any treatment beyond the antihistamines she was already using.
A few weeks later we had an answer in her elevated plasma prostaglandin D2 level (123 pg/ml, normal 35-115), elevated plasma histamine level (9 nmol/L, normal 0-8), elevated serum chromogranin A (155 ng/ml, normal 0-95), elevated plasma free norepinephrine (1449 pg/ml, normal 80-520), and Factor VIII (205%, normal 50-150%).
I made recommendations to her local physician to begin trying MCAS-directed medications one at a time. The patient e-mailed me several months later:
Hmmm. So UTIs that don’t behave like UTIs might indeed not be UTIs and instead might be IC – and IC might be a sign of something more fundamental than just a GU issue.
Here’s another example:
“Barbara” was a 35-year old accountant when she was referred to me in March 2012. She, too, dated her chronic unwellness literally back to her earliest memories in childhood, noting she had never been without chronic malaise, fatigue, an assortment of “GI issues” (e.g., abdominal pain and alternating diarrhea and constipation), difficulty standing for extended periods, then onset around the time of menarche of chronic problems with severe headaches. She lived overseas from age 8 to age 11, but she is certain her symptoms began well before she moved there. Repeated testing for mononucleosis was negative until she tested positive for this during a “flare” of her assortment of symptoms while a senior in high school, though she cannot remember whether she had any adenopathy at the time. (Substantial adenopathy, especially about the neck, is a virtually inescapable accompaniment to the Epstein Barr virus infection of mononucleosis when it occurs at this age.)
In Barbara’s late teens, problems with spontaneous vomiting (preceded by onset of significant headache just seconds earlier) and chronic nausea emerged, and she had been on 19 different PPIs since age 19. Though initially she never had “heartburn,” now she noted that reflux reliably developed whenever she tried to taper off or stop her PPI du jour. Age 19 is also when she suffered a bout of Clostridium difficile colitis, and though this was treated, it soon relapsed and required re-treatment, and this is around the time when her chronic problems with diffusely migratory soft tissue and joint pains began.
At age 21 Barbara suffered a bout of severe diarrhea leading to hospitalization and colonoscopy with a diagnosis of severe colitis; no definitive cause was found, though she says some of her physicians attributed this to her oral contraceptives which had been started at age 15 to try to help (and which did help) her abdominal cramps. Even after she recovered from the colitis, alternating diarrhea and constipation continued, nausea and vomiting decreased but did not resolve, and headache and fatigue problems continued.
By her late 20s Barbara began having difficulty attending adequately to her work as an accountant. Postural orthostatic tachycardia syndrome (POTS) was diagnosed in 2007 using a tilt table test; she was started on various medications which she was still taking, but overall she thought that avoidance of her “triggers” of heat, cold, sun, stress, and exertion helped her control her symptoms more than her medications did. Such avoidance helped her feel somewhat better in that she was “not as completely exhausted” but still felt easily overtaxed and frequently experienced flushing.
Barbara’s medical history also included a sweat gland problem of unknown cause called hydradenitis suppurativa, a spontaneously detached retina in 2010, alleged history of iron-deficiency anemia of uncertain cause, frequent urinary tract “infections” occurring both spontaneously and with any sexual activity but virtually always with negative urine cultures and a negative thorough urologic work-up to date (except for finding renal papillary necrosis), club feet at birth, and scoliosis.
Although she denied any irritation or sores of the nose or mouth, dental problems, edema (except in response to spicy foods and alcohol), enlarged or tender lymph nodes, or syncope, Barbara endorsed subjective fevers, chills, feeling cold much of the time, frequent headaches, diffusely migratory achiness, diffusely migratory pruritus, dry eyes, intermittent difficulties focusing her vision, frequent coryza and sneezing (antihistamine nasal spray helped quell this), easy bruising, chronic throat discomfort/irritation, subtle dyspnea intermittently at rest and more so on exertion, occasional proximal dysphagia, frequent non-anginal chest discomfort, frequent palpitations, reflux issues as above, chronic nausea and vomiting, chronic diarrhea alternating with constipation, polyuria, frequent urinary tract “infections,” reactivity to alcohol and spicy food (both causing a rash of patches of dry scaly skin and facial edema and flushing which can last for up to 2 weeks), occasional insomnia, diffusely migratory tingling/numbness paresthesias (mostly in the distal extremities), episodic cognitive dysfunction, and presyncopal episodes several times daily.
Her father allegedly had both polycythemia vera and Hodgkin’s disease (which he survived) in his 60s; he eventually died of heart disease. Her mother’s side of the family was rife with rheumatologic issues. There was lung cancer and relatively early onset leukemia on her father’s side of the family, though those who got lung cancer were smokers. There was no personal history of tobacco or illegal substance use, let alone alcohol abuse.
Barbara’s current medications included the proton pump inhibitor esomeprazole plus a number of medications for her POTS including fludrocortisone, propranolol, midodrine, and L-methylfolate. She knew of no frank medication allergies; there were just the allergies to spicy foods and alcohol.
My exam found Barbara to be a somewhat pale, vaguely unhappy/tired/chronically ill-appearing woman with slight left upper quadrant tenderness to even modest palpation and, on a light scratch test on the upper back, bright dermatographism (erythroderma only, no hives) immediately emerged and was fully sustained when I last checked it again 20 minutes later.
The history reeked of MCAS, so I sent off “the usual” blood and urine testing and also asked the pathologist to retrieve and re-examine her 2007 GI tract biopsies with CD117 staining and an eye toward mast cell disease. Her 24-hour urinary prostaglandin D2 level was about 50% above the upper limit of normal, and her chromogranin level A was elevated both on and off her PPI. Her old duodenal biopsy, too, showed a mild increase in mast cells.
Antihistamines quickly helped some of her symptoms (including her GU symptoms), but she still was in need of significant further improvement. She just as quickly proved unable to tolerate even low-dose aspirin (skin boils, bleeding, GERD, and nasal burning). A trial of lorazepam caused intolerable depression at the low dose of just 0.5 mg twice daily, and a trial of doxepin also proved intolerable (grogginess) after just 10 days at a very low dose. However, in September 2012 she began a trial of oral cromolyn and soon found that one vial (200 mg) four times daily worked best for her, relieving virtually all of the symptoms not already addressed by the antihistamines.
And, lest you think that the GU issues in MCAS are only found in women, here’s a final story for this chapter demonstrating men to have “equal opportunity” for MCAS-driven GU issues.
“Mickey” was a 52-year old white male disabled airline pilot when he was referred to me in June 2009 by his primary physician for further evaluation of chronic painful mild splenomegaly. He started by telling me that in 2005, shortly after a bout of “food poisoning,” he developed acute left-sided abdominal pain, which was initially diagnosed as a kidney stone. This pain slowly improved over the next several weeks, except that it never fully resolved and indeed had persisted ever since in a waxing/waning fashion. A CT scan performed early in the work-up of this problem found mild splenomegaly which immediately led to his being grounded from flight duty and being placed on disability; he has been told he had to be pain-free for at least six months before he could requalify for flight duty, but the longest he had been able to go without pain was about two months. When the splenomegaly was found, he was immediately referred to a local hematologist/oncologist who ran many tests (including a repeat CT in February 2009 showing stable to slightly reduced splenomegaly) but could find no explanation for his pain and splenomegaly.
On further history, many other complaints emerged, all of them new since the “food poisoning” episode in 2005. Mickey told me he had always been quite healthy previously and denied any prior chronic medical problems or major medical events. The left upper abdominal quadrant pain waxed and waned and was sometimes accompanied by nausea – and sometimes even non-bloody vomiting. The worst episodes of pain occurred roughly every 2-4 weeks; the pain was 8 on a 0-to-10 scale and left him curled on the floor in a fetal position. His family always wanted to take him to the ER when this happened, but he knew the pang would resolve after 5-10 minutes, and it always did just that. He endorsed early satiety and a 25 lb. weight gain since all of this began. He said his temperature often felt as if it were in flux, sometimes making him feel hot but more often making him feel cold, sometimes even with mild rigors. He endorsed near daily night sweats. He also noted episodic migratory edema, most often in the feet and/or hands. He noted an itchy red rash about his lower neck that had plagued him since his illness began and which, he said, had defied diagnostic and therapeutic efforts by multiple dermatologists.
Mickey had been chronically fatigued since the illness began, sometimes feeling as if he couldn’t even get out of bed in the morning. He had acute-onset “spells,” every few days to every few weeks, of lightheadedness accompanied by a flushed appearance. His eyes were chronically irritated, as if they were dry (he thought it might be from his contacts, but moisturizing solutions such as saline didn’t seem to help at all). He said he has bad gastroesophageal reflux disease and had “learned the hard way” he could not do without ranitidine. He also had a “bad back” and “arthritis in all my joints.”
His worst stiffness was in the morning; a “very hot” shower helped him loosen up. He was occasionally constipated but had not noticed any diarrhea. He had occasionally briefly had bloody urine these past few years with episodes of his “kidney stones,” which were always on the left; except for those rare instances of bloody urine, his urine has never appeared an abnormal color, even when left standing. He said that at one point porphyria was suspected and testing was run and indeed hinted at the disease, but he says when his case was reviewed by a porphyria expert, the expert thought it was not likely he had porphyria.
Mickey had had much more difficulty recovering from minor infections, or healing from minor trauma, since the illness began. He also had noted occasional tingling/numbness in his toes, soles, and fingertips. He denied any respiratory issues, including no problems with wheezing. He said his family had noted to him that his mood had chronically changed since he got sick and that he was now often quite irritable, though he thought it was due to the chronic pain.
Mickey also told me he had had one summer, around age 11 or 12, when he spent much of the summer ill with central (not left upper quadrant) abdominal pain which was never diagnosed and which, at the end of the summer, spontaneously resolved and never returned.
His father survived a bout with prostate cancer; his mother lost a bout with breast cancer; a maternal aunt, too, may have had breast cancer. He had two healthy sons. He worked part-time as a retail store clerk, a job he took because he was getting “bored crazy” at home. There was no history of use or abuse of tobacco, alcohol, or illegal substances.
Exam was notable solely for tenderness to palpation across the upper abdomen, worst in the middle of this area (the epigastrium), together with a modest, red, mildly blanching rash about the full circumference of his neckline, but he never scratched at it. I also noted mild dermatographism.
My assessment at that initial visit was that “Chronic leukemias and lymphomas of any sort really don’t fit the full picture here, nor do metabolic diseases leading to splenic infiltration. I can’t imagine a solid tumor that could explain all of these findings. Porphyria doesn’t fit very well, either; I suspect what was seen on his porphyria screening was a mildly elevated coproporphyrin or uroporphyrin fraction, which can be seen in virtually any stressful situation. And I can’t think of a single chronic infection that would produce this particular clinical picture. Instead, this whole situation sounds fairly classic for mast cell disease of some sort, though I can’t presently tell whether it’s a qualitative/dysfunctional mast cell issue, i.e., idiopathic mast cell activation disorder, vs. the frankly proliferative classic systemic mastocytosis.” (You can see from this how the terminology has evolved over time. Today, “mast cell activation disorder [or disease]” is the top-level term, encompassing not only mastocytosis but also the MCAS that I meant at the time in my use of the term “mast cell activation disorder.”) To start, I recommended blood and urine testing for mast cell disease.
He was a hard one to diagnose, as three rounds of testing were negative, though there were doubts along the way as to whether the specimens were being handled correctly, and the first couple of tests were done when he was feeling relatively well. I kept thinking along the way about other potential diagnoses, and I did order some additional tests in other directions, but they were all negative and the overall picture kept fitting mast cell disease better than anything else. After three negative rounds of testing, I not only asked him to wait for a “particularly bad day” and then pursue a fourth round of testing, but I also referred him to the gastroenterologist for upper and lower endoscopy with blind biopsies. And indeed, on a bad day his urinary prostaglandin D2 was found to be elevated, and though every single one of his GI tract biopsies was reported as benign on routine staining, almost all of them showed mildly increased mast cells on special staining. We finally had a diagnosis of MCAS.
He’s had a complex therapeutic history since, but after about three years finally found a combination of antihistamines, low-dose dasatinib, and vitamin C got him feeling well again. He eventually re-applied for flight privileges, passed his flight physical, finished retraining, and is now back in the cockpit. For purposes of this chapter, I want to focus on one of the symptoms that had been plaguing him the worst, a waxing/waning, occasionally spasmodic deep pelvic discomfort that would sometimes progress up into the abdomen, usually on the left side, sometimes convincing him he must have a kidney stone, except that repeated evaluations for such were always negative. His urologist repeatedly found his prostate to be in a “state of spasm” but was never able to find a cause for it.
