Please help my friend, Kristina Brightbill

Last October was a nightmarishly dark time. My friend Seth had a catastrophic metabolic crisis a few days before his third birthday so severe that I honestly cannot believed that he survived. He was in the hospital in California trying to sort out effective and tolerated IV nutrition when he crashed. Seth is a mast cell kid with no safe foods. None.

As impossible as it sounds, Seth was not the only little boy at that hospital in California with no safe foods. There was another little boy there named Lucas, who also has mast cell disease. These little boys and their parents became very close friends, bonding over the absurdities and terror of having young children who can’t eat. Lucas’ mom, Kristina, was also a mast cell patient. When Seth was crashing, Kristina called me and we worried together.

At the time that Seth was having his metabolic crisis, Lucas was a year old and exclusively breastfed due to his frightening and prolific food reactions. Kristina had removed almost all foods from her diet in order to provide nutrition that could Lucas could tolerate. Eventually, she was only able to eat quinoa, organic cantaloupe and one brand of safe water. She herself was predictably experiencing physical issues from such a restricted diet. Her breast milk was Lucas’ only safe food and she sacrificed her health for his.

The week after we worried together on the phone about Seth, Kristina was preparing to take Lucas home to Florida after months admitted in California. On a Friday afternoon, she had anaphylaxis, and then she had a stroke. No one realized what was happening until it was too late. In a matter of hours, Kristina became a prisoner in her own body. The stroke was in her brainstem and she has locked-in syndrome.  She is 26 years old.

Kristina is completely aware and able to understand everything happening around her but cannot move or speak. She is able to communicate by blinking while someone points to letters and spelling words in this way. She continues to have ongoing health issues secondary to the stroke and mast cell disease. Her needs are very, very complex.

After months of inpatient care and stroke rehab, Kristina will be going home to be with her devoted husband, their son and her family and friends. Her home has required significant remodeling and she needs round the clock care to stay safe. Kristina also needs a vehicle that can transport her in her chair in order for her to be able to safely go home. As you can imagine, meeting all of these needs is a massively expensive and time consuming undertaking.

Parents of mast cell children often say that they would give anything to help their kids, that they would gladly lay down their lives to stop their children from suffering. Kristina literally gave everything she had to make her body a vessel capable of producing a food that her son could eat.

If you have ever been helped by this blog, or me, or anything I have written, please help my friend, Kristina.

Kristina’s family just found out about this contest to win a van that can transport her in her wheelchair. Please vote for her. Voting closes in two days but it is still worth a shot.  If the link doesn’t work, please cut and paste the following address into your browser:

http://www.mobilityawarenessmonth.com/entrant/kristina-brightbill-sarasota-fl/

If you are able and would like to donate there is an ongoing fundraiser for Kristina and Lucas, who will both need expensive lifelong care.  Please cut and paste the following address into your browser:

https://www.youcaring.com/kristina-brightbill-jedidiah-brightbill-lucas-brightbill-379577

Many thanks. Please keep this family in your thoughts/prayers/good intentions. There is always hope.

Patient questions: Everything you wanted to know about tryptase

I get a lot of questions about tryptase.

Tryptase is one of the most well characterized mast cell mediators and the first to be unique to mast cells. Serum tryptase is the most well known test for systemic mastocytosis and anaphylaxis. But mast cell patients sometimes test negative, complicating their lives and care.

There are a lot of reasons why mast cell patients test negative for tryptase. One reason is that a lot of the understanding of anaphylaxis hinged upon the ability of mediators to get quickly to the bloodstream to quickly spread to various organ systems. While this does happen, not all mediators move at the same speed. Tryptase is released from granules as large complexes with other mediators, like heparin. It takes time for it to dissociate enough to be active.

Tryptase also does a lot of things and breaks down lots of things. If there are things for it to break down in the immediate environment, it will still break them down whether or not you are having anaphylaxis. Eventually, the tryptase that wasn’t used up breaking things down gets to the bloodstream. This is why the ideal time to test for tryptase in blood is about 90-120 minutes after an allergic event/severe reaction/anaphylaxis. Following severe reaction/anaphylaxis, it can take about two weeks for tryptase to return to baseline.

The reason that most patients with systemic mastocytosis have high tryptase levels is because they have more mast cells and many mast cells secrete tryptase at rest. This means that even if they aren’t activated, they will still release tryptase regularly. The reason why baseline tryptase level is such an important marker for SM is because it distinguishes mastocytosis from anaphylaxis.

However, we have learned a lot about tryptase in the last several years, and it doesn’t seem like all mast cells secrete tryptase all the time. Mast cells are heavily influenced by their environment and the cells around them. Some mast cells make more tryptase than others and some release tryptase regularly and some don’t.

About 80-90% of SM patients have a baseline tryptase over 20 ng/ml. This means they tested over 20 ng/ml on two separate occasions when they had not recently had a severe event. But not all SM patients have elevated tryptase, but that doesn’t mean they don’t have more mast cells than usual. It is possible that their mast cells are concentrated in places in the body where tryptase will be used up before it gets to the bloodstream or that it will take too long to get there for the test to catch it. There is some evidence that tryptase testing is less reliable in overweight and obese women, and I’m sure that’s true. Some mast cells live in adipose tissue and that tissue is harder for large molecules to move through, like tryptase.

Our understanding of MCAS is that there is aberrant mast cell behavior without an abnormal number of mast cells. These patients generally have repeat negative biopsies and so the assumption is that they definitely don’t have SM. But tryptase is a crummy test and I think as a community we can’t really know if they have too many mast cells until we have more robust tests. I’m not saying MCAS patients have too many mast cells, but I’m saying I don’t really trust tryptase for detection of reaction/anaphylaxis in MCAS patients or, to be frank, in anyone.

So why do we still use tryptase if it’s a crummy test? It’s not a crummy test for everything. In particular, it is a very good indicator of disease progression (ISM to SSM to ASM) in patients who have a lot of mast cells. A steadily increasing tryptase level means that there is increased proliferation and can indicate moving to a state where organ damage is more likely. So it is helpful for those people. It’s not helpful for everyone else.

Tryptase testing is not affected in a meaningful way by any medications that I can think of. Mast cell stabilizers can decrease degranulation, but tryptase can also be released in other ways, and there has not been any demonstration that mast cell stabilizers are effective enough to affect this test. Antihistamines/other meds/steroids don’t affect tryptase level.

There was a consensus paper that came out several years ago in which it was posited that an increase in tryptase level of 2 ng/ml + 2% from baseline was indicative of mast cell activation and could be used in the diagnosis of MCAS. This is not widely agreed to in the US and the data supporting this has never been published so I personally understand the reluctance of providers to acknowledge this as a marker of mast cell activation.

The other big reason why mast cell patients may test normal for tryptase is that their reactions/anaphylaxis are not mediated by a pathway that triggers tryptase release like IgE does.  IgG activation and other pathways do not always demonstrate tryptase release.

I think I got everything. If you have more questions about tryptase, let me know.

Mood disorders and inflammation: High cortisol and low serotonin (Part 2 of 4)

There are multiple suspect pathways for causation of mood dysregulation in the setting of inflammation. One well described model hinges upon the ability of inflammatory mediators to impact the HPA axis, a system of hormone release that drives many physiologic functions in addition to the stress response.  Briefly, the central pathway of the HPA axis is that CRH causes production of ACTH, which causes production of cortisol, a stress hormone and a very potent anti-inflammatory under most circumstances.  Many molecules can affect the signaling of the HPA axis and contribute to inappropriate hormone regulation.

IL-1, IL-6, TNF and IFN-a are all inflammatory mediators released by mast cells and other cells. These mediators all activate the HPA axis, resulting in high production of CRH, ACTH and cortisol via a series of intertwined mechanisms. At the same time, inflammation also makes cortisol less effective.  There are several ways for this to occur. Inflammation can cause cells to make fewer receptors for cortisol, meaning that no matter how much cortisol is made, only a small fraction will be able to act on cells.  Persistently high cortisol levels decrease production of other anti-inflammatory molecules and molecules that mediate the anti-inflammatory action of cortisol.  High cortisol also tells the HPA axis that it doesn’t need to make more cortisol, so even though more may actually be necessary, your body doesn’t know that.

All of these factors coalesce to form a reality where cortisol may be elevated but with little anti-inflammatory effect because of the changes I mentioned above. High cortisol is associated with mood symptoms.

Decrease of serotonin activity is also seen in mood disorders. Tryptophan is a precursor to serotonin, a hormone and neurotransmitter that heavily regulates mood.  Cortisol increases the activity of a molecule called tryptophan 2,3-dioxygenase (TDO), which removes the amino acid tryptophan from the pool of molecules to break down. Inflammatory molecules like interferon increase activity of the enzyme IDO, which decreases serotonin production.  IDO breaks down tryptophan to molecules that cannot be made into serotonin, such as kynerenin and quinolonic acid.  These metabolites have been observed as elevated in models of depression and anxiety.

Another way that inflammatory mediators affect the action of serotonin is to hasten its degradation. Both TNF and IL-6 increase the breakdown of serotonin to 5-HIAA.

References:

Furtado M, Katzman MA. Examining the role of neuroinflammation in major depression. Psychiatry Research 2015: 229, 27-36.

Rosenblat JD, et al. Inflamed moods: a review of the interactions between inflammation and mood disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2014; 53, 23-34.

Interplay between mast cells and hormones: Part 1 of 8

Hormone Location released Major functions Interaction with mast cells Reference
Activin Ovaries Promotes FSH production and secretion 

Enhances activity of LH

 

Promotes wound healing

 

Stimulates mast cell maturation 

Activin causes mast cells to increase expression of a gene (TAP) that in turn promotes more activin activity

Funaba M, et al. Identified of tocopherol-associated protein as an activing/TGFb inducible gene in mast cells. Biochimica et Biophysica Acta – Molecular Cell Research 2006: 1768 (8), 900-906.
Adiponectin Adipose tissue, placenta Increase insulin sensitivity and transfer of glucose to cells from blood 

Protect against metabolic syndrome, diabetes mellitus and NASH

 

Suppress production of glucose

Mast cells regulate formation of adipose tissue 

PGD2 drives differentiation of fibroblasts into adipocytes

 

Adiponectin may be associated with asthma in obese patients

Nigro E, et al. Role of adiponectin in sphingosine-1-phosphate induced airway hyperresponsiveness and inflammation. Pharmacological Research 2016: 103, 114-122. 

Reena*, et al. Mast cell stabilizers obviate high fat diet-induced renal dysfunction in rats. European Journal of Pharmacology 2016: 777, 96-103.

Adrenocorticotropic hormone (ACTH)/ corticotropin Pituitary Stimulates corticosteroid and androgen synthesis and release in response to physical or emotional stress Binding at pituitary histamine H4 receptors induces release of ACTH 

Anaphylaxis and reactions trigger release of CRH, increasing release of ACTH

Meng J, et al. Histamine H4 receptors regulate ACTH in AtT-20 cells. European Journal of Pharmacology 2008, 587: 335-336. 

Theoharides TC, et al. Mast cells and inflammation. Biochimica et Biophysica Acta 2012: 1822, 21-33.

Aldosterone and other mineralocorticoids Adrenal gland (cortex) Increases sodium and water reabsorption in kidney, increasing blood volume and blood pressure 

Promotes excretion of potassium and hydrogen ions from the kidney

Aldosterone release is controlled by renin-angiotensin system 

Mast cell mediators such as chymase and renin participate in the renin-angiotensin system, driving up blood pressure.

 

Excessive release of serotonin by mast cells can also increase aldosterone production.

Lalli E, et al. Local control of aldosterone production and primary aldosteronism. Trends in Endocrinology & Metabolism 2016: 27 (3): 123-131. 

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 2013: 138, 53-65.

Amylin Pancreas Suppresses hunger reflex 

Slows gastric emptying

Dysregulation of amylin contributes to lack of appetite and bloating in gastroparesis. 

Histamine binding at H1 receptor encourages release of amylin, causing appetite suppression.

Potes CS, Lutz TA. Brainstem mechanisms of amylin-induced anorexia. Physiology & Behavior 2010: 100, 511-518. 

Kedar A, et al. Dysregulation of hormones insulin and amylin is associated with the symptoms of bloating and anorexia in diabetic gastroparesis. AGA Abstracts, Mo1583.

Angiotensin Liver Release of aldosterone 

Vasoconstriction

 

Increase of blood pressure

Angiotensin participates in the angiotensin-renin system, which regulates blood pressure.Many mast cell mediators, such as chymase, carboxypeptidase  A and renin, participate in this system. Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016: x, 1-10. 

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 2013: 138, 53-65.

Atrial natriuretic peptide (ANP) Heart Reduce systemic vascular resistance and water, sodium and fat in blood, decreasing blood pressure 

Decrease cardiac output

 

Vasodilator

 

 

ANP directly activates mast cells, resulting in release of histamine, serotonin and TNF in a dose dependent fashion. 

ANP is associated with mast cell driven inflammation and swelling.

Chai, OK. The role of mast cells in atrial natriuretic peptide-induced cutaneous inflammation. Regulatory Peptides 2011: 167, 79-85.

Mood disorders and inflammation: Mediators (Part 1 of 4)

Mood disorders are the leading cause of disability in many countries around the world. Depression alone affects a staggering number of people, currently thought to be about 350 million people worldwide.  Its prevalence and diagnosis is increasing to such an extent that the WHO expects it to be the primary cause of global disease burden in less than 15 years.

Mood disorders are commonly found in patients diagnosed with inflammatory conditions.  Cardiovascular disease, diabetes, metabolic syndrome, asthma, allergies and many autoimmune diseases co-occur with these psychiatric conditions.  While providers are often tempted to attribute depression, anxiety and maladaptive behaviors to the stress of having chronic health issues, a significant body of evidence firmly supports the idea that mood disorders are themselves inflammatory conditions and therefore biologically ordained. Furthermore, having a mood disorder can affect prognosis in some diseases.

A number of inflammatory molecules participate in immune response, including histamine, prostaglandins, bradykinin, leukotrienes, CRP, interferon, cortisol and cytokines.  These substances are released in response to physical stresses such as infection, trauma or disease process.  Psychological stress also triggers inflammatory response with increases of molecules such as IL-6, IL-1b, TNF and CRP.

Several studies have definitively found that mood symptoms are associated with increased levels of inflammatory markers.  PGE2, CRP, TNF, IL-1b, IL-2 and IL-6 were all elevated in both peripheral blood and cerebrospinal fluid in patients with major depressive disorder.  A massive 25-80% of hepatitis C patients experience depressive symptoms when they begin treatment with interferon, a potent inflammatory molecule. Elevated interferon and IL-2 levels have been observed early in the depressive event.

In human patients, studies have simulated an inflammatory response by inoculation with toxins, proteins associated with infectious organisms, or interferon. In one study, an inflammatory response was provoked by inoculation with Salmonella endotoxin.  While they suffered no physical symptoms, anxiety, depressed mood and decreased memory function was observed along with elevated TNF, IL-6 and cortisol levels.  Another study found that inoculation with LPS (a substance found in bacterial cell membranes) triggered a dose dependent increase in IL-6, IL-10, TNF, cortisol and norepinephrine, which in turn triggered a dose dependent increase in anxiety, “poor mind” and decreased long term memory functions.

References:

Furtado M, Katzman MA. Examining the role of neuroinflammation in major depression. Psychiatry Research 2015: 229, 27-36.

Rosenblat JD, et al. Inflamed moods: a review of the interactions between inflammation and mood disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2014; 53, 23-34.

 

Kounis Syndrome: Stress (Part 4 of 4)

The phenomenon we now called Kounis Syndrome has previously been called by names like morphologic cardiac reactions, acute carditis and lesions with basic characteristics of rheumatic carditis. It is sometimes still referred to as allergic angina or allergic myocardial infarction/heart attack depending upon the presentation. Allergic angina, which affected patients as microvascular angina, was first noted to progress to allergic heart attack in 1991.

In a small study done at a hospital, 31 patients with anaphylaxis or non-anaphylactic severe allergic reactions had higher serum troponin I than healthy control patients.  Among those 31 patients, those that experienced anaphylaxis had the highest troponin I overall.  This report, and similar findings, indicates that cardiovascular damage may be a frequent component of anaphylaxis, well beyond what is reported.

Mast cell patients often struggle to identify which is the chicken and which is the egg in the many instances of comorbid conditions. There is no such confusion here – mast cell activation causes Kounis Syndrome.  Tryptase increases in peripheral blood during a spontaneous heart attack.  However, when coronary spasm is induced with medications, there is no such increase in tryptase.  In instances where Kounis Syndrome was caused by disruption of an atherosclerotic plaque, mast cells entered the lesion and released mediators prior to the initiation of the coronary event.

Stress is well known to induce mast cell degranulation.  It has been documented in dozens of papers from various disciplines in the last twenty years. Corticotropin releasing hormone (CRH) is a stress hormone that can bind to the CRHR-1 receptor on mast cells, inducing the manufacture of VEGF. At the same time as CRH is released, neurotensin can also be released.  Experimental work has shown that stress induced mast cell degranulation can be compromised if the neurotensin receptor is blocked.

Reactive oxygen species can activate mast cells and induce sensory nerves to release substance P.  Substance P is a potent mast cell degranulator, inducing secretion of histamine and release of VEGF and other inflammatory mediators. These multiple activation pathways triggered by stress result in mast cell mediator release, which can induce coronary hypersensitivity syndromes such as Kounis Syndrome.

References:

Kounis NG, et al. Kounis Syndrome (allergic angina and allergic myocardial infarction). In: Angina Pectoris: Etiology, Pathogenesis and Treatment 2008.

Lippi G, et al. Cardiac troponin I is increased in patients admitted to the emergency department with severe allergic reactions. A case-control study. International Journal of Cardiology 2015, 194: 68-69.

Kounis NG, et al. The heart and coronary arteries as primary target in severe allergic reactions: Cardiac troponins and the Kounis hypersensitivity-associated acute coronary syndrome. International Journal of Cardiology 2015, 198: 83-84.

Fassio F, et al. Kounis syndrome: a concise review with focus on management. European Journal of Internal Medicine 2016; 30:7-10.

Kounis Syndrome: Aspects on pathophysiology and management. European Journal of Internal Medicine 2016.

Kounis NG. Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med 2016

Kounis NG. Coronary hypersensitivity disorder: the Kounis Syndrome. Clinical Therapeutics 2013, 35 (5): 563-571.

Alevizos M, et al. Stress triggers coronary mast cells leading to cardiac events. Ann Allergy Asthma Immunol 2014; 112 (4): 309-315.

Kounis Syndrome: Treatment (Part 3 of 4)

Kounis Syndrome treatment requires amelioration of both allergic and cardiovascular symptoms.

  • Type I KS patients may only need treatment for allergic aspects without ever progressing to heart attack.
  • Type II and III KS patients are recommended to follow acute coronary event protocol recommended by ACS.
Treatment of allergic aspects of Kounis Syndrome
Drug class Medication Dosage Notes
H1 inverse agonist Diphenhydramine 1-2 mg/kg

50mg IV is a frequent dosage used for mast cell patients experiencing anaphylaxis symptoms

Can cause hypotension and decrease blood flow through coronary artery if given bolus; should be given slowly
H2 antagonist Ranitidine 1 mg/kg
Famotidine 40mg IV is a frequent dosage used for mast cell patients experiencing anaphylaxis symptoms
Corticosteroid Methylprednisolone or other Methylprednisolone 120 mg IV is a frequent dosage used for mast cell patients experiencing anaphylaxis symptoms Corticosteroids are not used for immediate effect, but to prevent biphasic reactions.Corticosteroid treatment in active heart attack patients has not been found to be harmful.Corticosteroids were recommended as early as 2008 by Kounis for several reasons: inhibition of eicosanoid synthesis, decreasing amount of prostaglandins, leukotrienes and thromboxanes that can be made; reduction of inflammation by increasing death receptor CD95 on some cells; synthesis of annexins, proteins that modulate inflammatory cells and their actions

 

 

Fluid support IV fluids Crystalloid normal saline; avoid colloid solution Use with caution to avoid pulmonary edema
Epinephrine Epinephrine IM dose: 0.2-0.5mg every 5-15 minutes Can contribute to myocardial ischemiaCan prolong the QTc interval

Can cause coronary vasospasm and arrhythmias, especially if given IV

Glucagon is an alternative in patients for whom epinephrine is inappropriate

 

 

Treatment of coronary syndrome in Kounis Syndrome
Drug class Medication Dosage Notes
Nitroglycerin Nitroglycerin Sublingual: 0.3-0.4 mg every five minutesIV: 5-10mcg/min, increased by 10 mcg/min every 5 minutes Causes dilation of coronary vesselsIncreases bloodflow to counteract myocardial ischemia
Calcium channel blocker Diltiazem, verapamil Example  ER dosing for verapamil: 80mg orally every eight hours, immediate release Vasodilators
NSAID Aspirin 160-325 mg Prevent clot formation
P2Y12 receptor inhibitor Clopidogrel 75mg daily Taken with aspirin to prevent clot formation; some medical bodies recommend P2Y12 inhibitors with aspirin, while others recommend aspirin alone
Glycosaminoglycan Heparin IV: 5000 IU bolus, followed by infusion of heparin until PTT 1.5-2.5 above normal Type III patientsHeparin may cause allergic reaction, especially in bolus
Opioid Fentanyl 1-2 mcg/kg Drug of choice for pain management, causes small amount of mast cell degranulation, other opiates risk large scale degranulationDoes not affect cardiac output
N/A Stent placement if vessel narrowed by atherosclerosis N/A

 

Notes:

Beta blockers are contraindicated in Kounis Syndrome for the same reason they are contraindicated in mast cell patients – they block the action of epinephrine, which complicates treatment of anaphylaxis.

IV acetaminophen is generally well tolerated by mast cell patients but is not appropriate for Kounis Syndrome. Acetaminophen reduces cardiac output and systemic vascular resistance which can cause severe low blood pressure and aggravate cardiogenic shock.

References:

Kounis NG, et al. Kounis Syndrome (allergic angina and allergic myocardial infarction). In: Angina Pectoris: Etiology, Pathogenesis and Treatment 2008.

Lippi G, et al. Cardiac troponin I is increased in patients admitted to the emergency department with severe allergic reactions. A case-control study. International Journal of Cardiology 2015, 194: 68-69.

Kounis NG, et al. The heart and coronary arteries as primary target in severe allergic reactions: Cardiac troponins and the Kounis hypersensitivity-associated acute coronary syndrome. International Journal of Cardiology 2015, 198: 83-84.

Fassio F, et al. Kounis syndrome: a concise review with focus on management. European Journal of Internal Medicine 2016; 30:7-10.

Kounis Syndrome: Aspects on pathophysiology and management. European Journal of Internal Medicine 2016.

Kounis NG. Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med 2016

Kounis NG. Coronary hypersensitivity disorder: the Kounis Syndrome. Clinical Therapeutics 2013, 35 (5): 563-571.

Kounis Syndrome: Diagnosis (Part 2 of 4)

Separating the symptoms of the coronary syndrome from those caused by the coincident allergic reaction is difficult.  Acute chest pain is the hallmark symptom of Kounis Syndrome. While other symptoms may be present, such as nausea, fainting, and shortness of breath, they can also be attributed to the allergic reaction.  Likewise, many of the clinical markers for KS may also appear during anaphylaxis, including cold extremities, very fast or very low heart rate, low blood pressure, palpitations, and sweating. Given the significant overlap in presentation with allergic symptoms, KS is not often diagnosed, though it likely affects a larger population than represented in literature.

Troponins and cardiac enzymes like creatinine kinase are important markers for coronary syndrome, but they are not always elevated in KS. Measurement of mast cell mediators like histamine or tryptase is not always accurate due to the short lifetime of these molecules in the body.  Released histamine is only present in blood for about eight minutes, while tryptase has a half-life of about ninety minutes.

An electrocardiogram (EKG) should be performed as part of the diagnostic process.  A number of signs have been seen in KS patients, including atrial or ventricular fibrillation, bigeminal rhythm, heart block, nodal rhythm, sinus bradycardia or tachycardia, ST segment depression or elevation, T-wave flattening or inversion, QRS or QT prolongation, and ventricular ectopics.  Beyond EKG, there are additional markers that may be present with Kounis Syndrome.  A chest x-ray may show an enlarged heart.  Echocardiogram may show dilated cardiac chambers. Angiography of the coronary artery can reveal spasm or thrombosis. In coronary biopsies, infiltration by mast cells and eosinophils may be found.  Elevation of eosinophils in the blood may also be present.

Having no history of coronary artery disease can make diagnosis more complicated for KS Type I patients, who also may have normal troponins and EKG. Dynamic cardiac MRI with gadolinium can show a subendocardial lesion in patients with KS Type I. Newer imaging techniques such as SPECT have been able to identify myocardial ischemia in KS Type I where coronary angiography had showed no irregularities.

References:

Kounis NG, et al. Kounis Syndrome (allergic angina and allergic myocardial infarction). In: Angina Pectoris: Etiology, Pathogenesis and Treatment 2008.

Lippi G, et al. Cardiac troponin I is increased in patients admitted to the emergency department with severe allergic reactions. A case-control study. International Journal of Cardiology 2015, 194: 68-69.

Kounis NG, et al. The heart and coronary arteries as primary target in severe allergic reactions: Cardiac troponins and the Kounis hypersensitivity-associated acute coronary syndrome. International Journal of Cardiology 2015, 198: 83-84.

Fassio F, et al. Kounis syndrome: a concise review with focus on management. European Journal of Internal Medicine 2016; 30:7-10.

Kounis Syndrome: Aspects on pathophysiology and management. European Journal of Internal Medicine 2016.

Kounis NG. Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med 2016

Kounis NG. Coronary hypersensitivity disorder: the Kounis Syndrome. Clinical Therapeutics 2013, 35 (5): 563-571.

Kounis Syndrome: Subtypes and effects of mast cell mediators (Part 1 of 4)

Kounis Syndrome (KS) is an acute coronary syndrome that arises as a direct result of mast cell degranulation during an allergic or anaphylactic reaction.

KS usually presents as chest pain during an acute allergic or anaphylactic reaction. There are three recognized variants:

Type I: Patient has no predisposing coronary artery disease.

There are two possible outcomes:

  • Coronary artery spasm with no appreciable increase in cardiac enzymes or troponins
  • Coronary artery spasm that evolves to acute myocardiac infarction (heart attack) with accompanying increase in cardiac enzymes or troponins

Type II: Patient has history of coronary artery disease. There are two possible outcomes:

  • Coronary artery spasm with no appreciable increase in cardiac enzymes or troponins
  • Plaque erosion or rupture that evolves to acute myocardiac infarction (heart attack) with accompanying increase in cardiac enzymes or troponins

Type III: Patient has history of coronary artery disease and a drug eluting coronary stent. There are two possible outcomes:

  • Coronary artery spasm with no appreciable increase in cardiac enzymes or troponins
  • Thrombosis that evolves to acute myocardiac infarction (heart attack) with accompanying increase in cardiac enzymes or troponins

A number of mast cell mediators have effects that can cause coronary spasm or thrombosis.  Beyond their direct effects, they also perpetuate an inflammatory cycle that results in activation and infiltration by inflammatory cells

Mediator Effect
Histamine Coronary vasoconstriction, activation of platelets, increase expression of tissue factor
Chymase Activation of interstitial collagenase, gelatinase, stromelysin resulting in plaque rupture, generation of angiotensin II, a powerful vasoconstrictor
Cathepsin D Generation of angiotensin II, a powerful vasoconstrictor
Leukotrienes (LTC4, LTD4, LTE4) Powerful vasoconstrictor, levels increased during acute unstable angina
Tryptase Activation of interstitial collagenase, gelatinase, stromelysin resulting in plaque rupture
Thromboxane Platelet aggregation, vasoconstriction
PAF Vasoconstriction, aggregation of platelets
Platelets Vasoconstriction, thrombosis

 

References:

Kounis Syndrome (allergic angina and allergic myocardial infarction). Kounis NG, et al. In: Angina Pectoris: Etiology, Pathogenesis and Treatment 2008.

Lippi G, et al. Cardiac troponin I is increased in patients admitted to the emergency department with severe allergic reactions. A case-control study. International Journal of Cardiology 2015, 194: 68-69.

Kounis NG, et al. The heart and coronary arteries as primary target in severe allergic reactions: Cardiac troponins and the Kounis hypersensitivity-associated acute coronary syndrome. International Journal of Cardiology 2015, 198: 83-84.

Fassio F, et al. Kounis syndrome: a concise review with focus on management. European Journal of Internal Medicine 2016; 30:7-10.

Kounis Syndrome: Aspects on pathophysiology and management. European Journal of Internal Medicine 2016.

Motion carries

For questions that have generic answers, I will remove identifying information and then answer them in a post.  For questions that involve consideration of significant history, I will respond privately in email as soon as I am able.  These posts will be marked “Q&A” and will be indexed in a dropdown menu.

I am taking a break this week from MastAttack (site, FB and email) to relax and get some rest.  I have set up auto posts for this week, including a series on Kounis Syndrome that discusses pathology, diagnosis and treatment.

Hope everyone has a great week!

xoxo

Lisa