Never bet against occam, p.17
Never Bet Against Occam, page 17
Testing showed moderate elevations in serum and urinary prostaglandin D2 as well as the less specific mast cell mediators Factor VIII and norepinephrine. I cautioned him that we had no way to predict which mast-cell-targeted medications would most effectively control his dysfunctional mast cells and that it would require a patient, persistent, methodical approach to trying the available interventions one by one. And indeed, it did take patience, persistence, and a methodical approach, and as of this writing we still haven’t found any single hugely effective (“home run”) drug, but in two years of trying (and discarding several medications along the way), he found that a regimen of antihistamines, ketotifen, celecoxib, lorazepam, montelukast, and low-dose hydroxyurea controlled his symptoms well enough that he now has significantly more good days than bad (whereas before virtually every day was a bad day) and he is sufficiently comfortable that, for the time being, he is not interested in trying any other medications.
The respiratory tract issues with MCAS include issues related to inflammation and edema all up and down the tract. Symptoms include sinonasal congestion, internal (post-nasal) and external nose drip, hoarseness and laryngitis, cough (much more commonly dry than productive), shortness of breath (medically called dyspnea). Wheezing (often diagnosed as asthma) appears to be less common than dyspnea.
The dyspnea is of a curious form, as most patients deny feeling “short of breath” and instead most commonly report, “I just can’t catch a deep breath,” but testing usually can’t find anything wrong and physicians begin to wonder if the complaint is psychosomatic. It’s obviously a real symptom, though, and my suspicion is that short-lived, migratory flares of edema, inflammation, and/or bronchoconstriction cause this symptom. Of course, flares of such an ephemeral nature almost certainly won’t be present when the patient presents for scheduled pulmonary function testing, but even if they are present, they usually aren’t severe enough, or affecting a wide enough extent of the respiratory tree, to cause abnormalities in pulmonary function testing. On X-ray and CT scanning, inflammation appears as “patchy ground-glass infiltrates,” but most physicians interpret such a reading as indicative of pneumonia (i.e., infection) and give little thought to the possibility of sterile inflammation even if no fever is present.
Mast cells may even play critical roles in the development of chronic obstructive pulmonary disease (COPD) and interstitial pulmonary fibrosis, which usually lead eventually to death.
Chapter 14: Cardiovascular Findings in MCAS
Getting to the Heart of the Matter
A wide range of cardiovascular issues can afflict – and can seem to afflict – MCAS patients. Let’s start with a typical “fake-out” case that also illustrates the extremes to which such patients sometimes need to go to get the treatments they know will help them. I’ll follow that with another couple of cases that demonstrate real cardiovascular issues from MCAS, and then we’ll wrap up the chapter with a general discussion of the cardiovascular issues in MCAS.
“Gladys,” a 54-year old nurse, was referred by her allergist in October 2012 for further evaluation of suspected mast cell disease. Like most such patients, she reported an extraordinarily complicated, essentially lifelong history of unwellness. She had been a “preemie twin” (her twin sister unfortunately died around the time of birth) and dated her history with illness back to her days as a toddler, observing she was “always” a “sickly” child suffering frequent attacks of asthma and frequent respiratory “infections” often requiring hospitalization. She also noted she had always found it “easy to get colds and respiratory and GI viruses” since childhood. The worst of the respiratory issues seemed to spontaneously resolve around age 4, though she had continued the rest of her life suffering occasional acute onset of dyspnea (especially when exposed to smoke). She also noted frequent ear infections throughout childhood and adolescence but otherwise was well until problems with frequent “urinary tract infections” began around age 21 and had continued to the present – though she said only about 50% of these “infections” had actually shown positive cultures, even when she had substantial urinary-tract-infection-like (UTI-like) symptoms including bleeding, pain, malaise, and right kidney pain. She suffered bacterial meningitis at age 24 with her first pregnancy (conceived with the help of fertility drugs), but her daughter was born fine and had been healthy since. During her second pregnancy at age 26, she suffered a number of traumas including falling (for unclear reasons), death of her husband by electrocution, and then victimized by a motor vehicle accident that caused bleeding throughout the last month of pregnancy, but her son was born fine and had been healthy since. Soon after remarrying, her third pregnancy, at age 28, led to problems with toxemia and “heart issues” throughout (including episodes of her distal extremities and face turning blue, acute dyspnea, and palpitations), but no diagnosis was made, no treatment was given, and another son was born healthy except for supraventricular tachycardia requiring ablation at age 16. All pregnancies were delivered by C-sections.
Gladys then moved a few states away and soon started suffering severe malaise, dyspnea, and palpitations for which she was hospitalized and diagnosed with ventricular ectopy. She then soon suffered a left leg deep venous thrombosis and pulmonary embolus requiring anticoagulation with warfarin for a year. Her ectopy proved refractory to multiple medication trials but eventually “settled down” with flecainide.
Next, waxing/waning aching in the distal extremities (especially the legs) developed and was diagnosed (without biopsy) as “fibrous myositis.” Endometriosis was also diagnosed. She underwent hysterectomy at age 30. Fibroid tumors were found throughout the peritoneum, and she was determined to need right ovarian torsion surgery, but the left ovary was accidentally resected first, and then a month later she had the right ovary resected. She subsequently had yet another procedure for lysis of adhesions (for ongoing abdominal pain), and then an appendectomy, but abdominal pain and constipation nevertheless persisted (at least until around 2009).
Since her 30s Gladys had also noticed “irritable bowel” symptoms and frequent attacks of sneezing (up to 18 sneezes in a row) while eating. She also had begun suffering spontaneous ligament and tendon tears.
After six years in her new home, Gladys moved back to the town she had come from and soon (after walking into a glass door) needed surgery for a herniated C5-6 disc whose primary pathology she dated back to age 22, when she was kicked in the neck by a psychiatric patient. At age 34 she underwent a right partial mastectomy for a suspicious lesion, which proved to be benign.
At age 38 she again moved several states away and did well except for continued “UTIs” and “colds” and “respiratory and abdominal stuff.” At age 42 she again moved a few states away and continued suffering “UTIs.” She continued using diclofenac for “arthritis” and “fibrous myositis” in her hips and hands and legs, as if she failed to take it, her pain prevented her from even getting out of bed.
At age 45 she moved once again and soon underwent cholecystectomy for her ongoing attacks of abdominal pain. After the surgery, she noted the attacks continued, “just not as bad” – but her irritable bowel symptoms in general actually seemed to worsen. A C4-5 spine fusion was needed (unclear cause), and she also incurred a stress fracture in the right foot simply upon stepping off a curb. She also tore a right foot tendon.
At age 52, during a visit in May 2010 to her primary physician, Gladys was prescribed a combination pill of simvastatin and extended-release niacin for hypercholesterolemia, took a single dose, developed a rash, then took another dose about 1-2 days later and immediately developed a sensation of “bee stings” about her skin and severe diarrhea and malaise and dyspnea, palpitations, diffusely erythematous rash (“I looked like a lobster”), and diffuse tremor. Evaluation in the emergency room (ER) led to treatment with epinephrine, famotidine, diphenhydramine, and methylprednisolone, which “turned it around,” but she was admitted anyway (for three days) for continued wheezing and was discharged still feeling unwell. She had required frequent ER visits ever since for similar reactions from assorted foods (such as shrimp at a Japanese restaurant) or medications (such as naproxen or an epidural injection for a ruptured disc). It was questioned whether she was reacting to lidocaine, so she was switched to bupivacaine (with premedications) for subsequent injections and appeared to tolerate it OK. She also suffered an episode of Salmonella urosepsis (severe urinary tract infection) requiring home IV antibiotics for two weeks via a peripherally inserted central catheter (PICC), and she thought the otherwise unidentified premedications she got with PICC placement helped her feel the best she had been in a long time.
No, we’re not done yet with Gladys’ story – not even close. She had suffered “constant” back pain since 2009 due to ruptured and bulging discs. In 2011 she suffered two episodes of acute onset of edema, chest discomfort, and dyspnea upon sun exposure for which she took antihistamines and felt better within 48 hours. She was empirically started on standing H1/H2 antihistamines after her third ER visit for anaphylaxis and felt that after a year of this treatment her daily diarrhea has decreased and she had had “only” 2-3 hospitalizations for malaise and hypokalemia (low potassium). She always felt “hyper” throughout her body with diffuse sensations of “crawling,” “bee stings,” and palpitations and dyspnea. Hydroxyzine had helped insomnia. Oral cromolyn caused “bad edema” and dyspnea. Niacin was found to be a trigger, too. She complained about diffusely migratory waxing/waning bone pain without any clear trigger. In September 2012 she suffered spontaneous onset of a “bad” diffuse pruritic (itchy) erythematous (red) folliculitic (pimply) rash; her dermatologist thought it was due to mast cell disease and recommended nightly hydroxyzine, which helped the pruritus and rash, but when she noticed symptoms were relapsing in the mid-afternoon, she started taking a second dose in the late afternoon and noticed this helped even more. She repeatedly said, “I now have a life” with these medications, but she was not always well and was looking to achieve further improvement.
On review of systems, although she denied fevers, feeling cold much of the time, irritation of the mouth, vomiting, enlargement or tenderness in the nodal areas, or syncope, Gladys endorsed chills, feeling hot much of the time, soaking sweats, diffusely migratory pruritus, headaches (worse since 2009), chronic fatigue, diffusely migratory muscle/bone/joint pain, irritation of the eyes (her optometrist told her she had the driest eyes she had ever seen, along with corneal and scleral ulcers, and she now was regularly using eye drops to help with these problems, but evaluation for Sjögren syndrome had been negative, and besides, Sjögren syndrome couldn’t possibly explain all that had gone on in her), episodic difficulty focusing her vision, irritation of the nose, coryza, light epistaxis, easy bruising, occasional “hemorrhoidal” rectal bleeding, irritation of the throat with constant throat clearing and frequent dry cough (“it drives my husband crazy”), dyspnea, chest discomfort/pain, palpitations, slight proximal dysphagia, GERD, unprovoked nausea, diarrhea alternating with constipation (though much less constipation since 2009), diffusely migratory rash, diffusely migratory edema, episodic diffusely migratory tingling/numbness and burning paresthesias and fasciculations and tremors, restless legs, insomnia, waxing/waning alopecia, onychodystrophy, new dental cavities since 2009 despite a lifetime of good dental hygiene, cognitive dysfunction, virtually daily episodes of presyncope (not always postural), and a 50 lb. weight gain since 2009 possibly due to decreased exercise since her dyspnea impedes exercise.
There were no known hematologic issues in the family history. Her mother, now deceased, had osteoarthritis and survived some sort of a rare type of cancer in her duodenum in her 50s. There have been no issues with tobacco, alcohol, or illegal substances.
Her current medications included atenolol, butalbital/acetaminophen/caffeine (Fioricet), cetirizine in the morning, cyclobenzaprine, diclofenac, epinephrine autoinjector (but had never used it), esomeprazole, conjugated estrogen, fexofenadine, flecainide, hydroxyzine (afternoon and evening), potassium, ranitidine, tramadol, and triamterene/hydrochlorothiazide (Maxzide). She anaphylaxed to lidocaine, naproxen, niacin-simvastatin, and azithromycin, and she noted codeine caused her nausea and morphine caused her pruritus. The last time she had IV contrast (without premedication), she felt hot and noted some dyspnea but didn’t anaphylax. Nevertheless, this had been listed on her chart as causing anaphylaxis and she had been cautioned to henceforth always get premedicated before taking IV contrast.
Exam found a slightly plump but otherwise outwardly healthy appearing woman. Vitals signs were notable for a blood pressure of 163/83 (her highest in about a year). Key findings included her comfortable general appearance, some dental fillings, slight diaphoresis (sweating), mild scattered bruising, resolving diffuse sparsely scattered rash of small (< 1 cm) ulcerative skin lesions, and just the slightest trace of distal bilateral lower extremity edema. On a light scratch test on the upper back, mild dermatographism immediately emerged and remained fully sustained when last checked 10 minutes later.
Labs on file were notable for moderate hypercholesterolemia (223-532 mg/dl, upper normal 200) and moderately severe hypertriglyceridemia (244-1759 mg/dl, upper normal 150), minimal transaminitis, mild hypoproteinemia and hypoalbuminemia, three normal tryptases in 2011-2012, mildly elevated chromogranin A (105 ng/ml, normal 0-50), and negative extensive evaluations for pheochromocytoma, carcinoid, and a variety of other autoimmune diseases and neuroendocrine cancers except for an elevated plasma free norepinephrine at 889 pg/ml (normal 80-520). IgG, IgA, and IgM antibody levels were normal. Only about 25% of the many urine cultures on file showed unequivocal infection. CT scanning had shown marked hepatic steatosis (fatty infiltration of the liver). Cardiac function was normal on echocardiogram. Bone densitometry in 2005 was normal.
My assessment at the time was that “this is about as classic a presentation of mast cell activation syndrome as one can see. Every single thing that has ever happened to her is potentially attributable to mast cell disease (even including the hyperlipidemia – she’s not the first MCAS patient I’ve seen with severe hypertriglyceridemia which virtually normalizes on effective MCAS treatment – and the elevated chromogranin and norepinephrine, which are known mast cell mediators (though obviously not completely specific for the mast cell)). Tryptase is almost always normal (to perhaps slightly elevated) in MCAS, as this is not systemic mastocytosis, a disease of mast cell proliferation which almost always drives elevations in tryptase.”
I pursued additional testing for levels of mediators more specific to mast cell production than chromogranin and norepinephrine, and the first round of testing found elevated plasma histamine (13 nmol/L, normal 0-8), but the prostaglandin D2 testing at that point was compromised by her use of diclofenac, an NSAID. She did a second round of testing after having abstained from NSAID use for a week, and this time not only was the plasma histamine again elevated (same level as before) but also the serum, and spot and 24-hour urinary, prostaglandin D2 tests were all about 50-150% above their upper limits of normal. While enduring this testing and waiting for results, though, she had continued having “bad days” just as often as “good days,” with problems including a flu-like syndrome (despite getting the seasonal flu vaccine 7-8 weeks earlier), a “regular” cold, a true urinary tract infection, bilateral middle ear inflammation that was treated as if it was due to an infection, and an Achilles tendinitis. Meanwhile, she remained grateful that standing H1/H2 blocking therapy seemed to still be helping her stay out of the ER.
I noted that Gladys needed to move on to additional maneuvers to try to get better control over her disease, and NSAIDs and benzodiazepines often are inexpensive maneuvers to be tried next. (NSAIDs help by blocking the cyclo-oxygenase 1 and 2 (COX1 and COX2) enzymes that are necessary for prostaglandin production, and benzodiazepines not only engage inhibitory mast-cell-surface benzodiazepine receptors but also neural receptors that can help decrease stress that can result in CNS release of mediators (such as corticotropin releasing hormone) that can trigger mast cell activation.) However, she had anaphylaxed to naproxen and suffered the same effects, though to a lesser degree, with diclofenac and tolerated those effects on an ongoing basis because she knew that going without the diclofenac led to rapid relapse of “crippling” joint pain. Thus, I decided that before we necessarily resorted to adding a whole new class of drug (benzodiazepines) to her regimen, she should try tweaking her NSAID regimen by changing diclofenac to celecoxib since I had seen the COX2-only-blocking celecoxib be better tolerable in some MCAS patients who react to classic COX1-and-COX2-blocking NSAIDs. She did not have any (known) sulfa allergy that would predict allergy to celecoxib. Some insurers require evidence of having “failed” at least two classic NSAIDs before going on to celecoxib, and she certainly couldn’t tolerate naproxen, and clearly diclofenac was suboptimally effective for her disease and also caused symptoms, and she had been told by her allergist to never take aspirin, so I thought it reasonable to declare that she had failed 2+ NSAIDs and ought to be approved for celecoxib. We briefly discussed the slight cardiac risks with celecoxib and I wrote the prescription.
