Speculations on the connection of α-Gal allergy to Coronary
Artery Disease.
Pitsios Constantinos1,2, Dimitriou
Anastasia2, Vassilopoulou Emilia3.
1. Medical School, University of Cyprus, Nicosia, Cyprus
2. Allergy Private Practice Network, Athens, Greece
3. International Hellenic University, Department of Nutritional Sciences
and Dietetics, Thessaloniki, Greece
Authors have no conflict of interest to declare
Corresponding author :
Constantinos Pitsios
Medical School, University of Cyprus
Panepistimiou 1, 2109 Aglantzia
Nicosia, Cyprus
Tel; +30 6974348638
Email; pitsios.constantinos@ucy.ac.cy
Statement:
Authors have no conflict of interest
Pitsios C, was the main author and clinical supervisor.
Dimitriou A;
drdimiana@gmail.com , was
the clinician of the cases reported and reviewed the paper.
Vassilopoulou E;
vassilopoulouemilia@gmail.com
, has contributed as author to the diet suggestions and as reviewer.
Text word count; 866
To the Editor,
In 2009, we reported a case-report of generalized allergic reaction
during the performance of allergy tests to red meat products [1]. It
was the case of a 59-year-old male, with a 10-year-long anamnesis of
several anaphylactic episodes (urticaria-angioedema and asthma attacks)
2 hours after the consumption of mammalian meats. He was tolerating
dairies and avian meat. His medical history was including seborrheic
dermatitis, gastric ulcer, coronary artery disease (CAD) and symptoms of
exercise-induced bronchospasm [1]. Since all reactions were reported
to happen after the ingestion of well-cooked meat we concluded that the
culprit allergen was heat-stabile, without being able to specify it.
Two more cases of allergy to red meat, males, 68-year-old (yo) and 52yo
respectively, were referred to us last year, both confirmed with skin
prick tests. The 68yo patient reported tolerating small quantities of
cold cuts. They both had anamnesis of CAD. At that time, CAD had been
recently described as comorbidity to mammalian meat allergy and α-Gal
allergen was inculpated [2]. Patients’ sensitization to α-Gal was
later confirmed with specific IgE test (sIgE) against this allergen. We
tried to contact the first case of meat allergy in order to prescribe
the same test, but unfortunately we were informed that he had passed
away due to myocardial infarction.
In the 2010s, tick bites were recognized as the main “sensitizer” to
α-Gal, causing cross-allergic reactions to mammalian meat [3]. Our
patients are located in the rural area of the island of Euboea, Greece,
engaged in outdoor activities and tick bites seem the most reasonable
explanation of their sensitization. Three genera of IxodidaeFamily are the main ticks parasitizing humans in Greece;Rhipicephalus , Ixodes and Hyalomma [4].
Although not all tick bites cause IgE-sensitization to α-Gal, the above
mentioned do [3, 5].
Alpha-Gal has been recognized as the culprit allergen for severe and
fatal anaphylaxis to the mAb cetuximab, while case-reports have been
published also for drugs like heparin, vaccines and anti-venom [3].
Although parenteral administration can cause immediate allergy, food
allergy due to α-Gal is commonly expressed with a delay in symptom onset
and is dose-unrelated, features also noticed in our cases [6]. The
pathophysiological mechanism differs when α-Gal is administeredvia the parenteral route than intake via the
gastrointestinal system. α-Gal parenteral administration (i.g injection
of cetuximab) triggers an acute IgE-mediated reaction, while a delayed
allergy is observed when it enters through the digestive system.
The pathophysiological background of the ‘digestive’ delay has been
elucidated by an in vitro study, analyzing the transport of α-Gal
through the intestinal epithelium [7]. It was found that only the
lipid-bound α-Gal is able to cross the intestinal epithelium, while
protein-bound α-Gal was not detected in the basolateral media of
enterocytes [7]. Alpha-Gal contained in glycolipids is digested,
absorbed and enters the blood stream by the thoracic duct after hours,
explaining the late-onset of allergic symptoms [3, 7]. Furthermore
in α-Gal allergic patients, dairies may cause delayed onset of
gastrointestinal symptoms over 2 hours [8].
There is a strong epidemiological connection between CAD and “α-Gal
syndrome”, a term used to describe different clinical allergies due to
this allergen [9]. This relationship has been confirmed by a study
using intravascular ultrasound imaging in subjects undergoing cardiac
catheterization [2]. A mechanistic model has been proposed to
clarify this connection, describing the delivery of α-Gal epitopes
-connected to lipid particles- to mast cells within atherosclerotic
plaques [9].
Due to the intraindividual tolerability to the culprit allergen,
patients with α-Gal allergy exclude or reduce mammalian meat from their
diet, but often consume tolerable quantities of products containing
α-Gal. This can induce local mast cell degranulation leading to chronic
mast cell activation and pro-inflammatory events contributing to the
chronic inflammatory procedures of CAD pathogenesis [9]. Our
objection is that if mast cells play a pivotal role to this
inflammation, red meat ingestion would cause a massive mast cell
degranulation in atherosclerotic plaques so angina would be a common
symptom of the delayed-type allergic reactions to red meat, resembling
to Kounis Syndrome.
The hypothesis that small tolerable quantities cause the ongoing
coronary inflammation via local mast cell degranulation is an
emerging concern for us. Based on the knowledge that participation of
chylomicrons and inflammation are common parameters of CAD and α-Gal
sensitization, their exact immunological connection remains to be
clarified. Can α-Gal molecules generate the inflammation, as plaque’s
component, maybe through a process of immune-complexes? Are they
inducing transdifferentiation of vascular smooth muscle cells to
macrophages or local proliferation of monocytes and formation of foam
cells?
Immunological pathophysiology of CAD is still unclear, while on the
other hand epidemiological data seem definite and alarming. In order to
avoid worsening of CAD by accumulation of lipoproteins containing α-Gal,
we recommend the strict avoidance of all α-gal containing food,
regardless the tolerance-level of each patient. Thus, dairies, gelatin
and mammalian meat products should be avoided.
Should a patient with CAD be tested for α-Gal? Screening in vivoand in vitro tests have been established as prevention in the
field of Cardiology. The impact of α-Gal should further be investigated
and compared between areas with high prevalence of sensitization due to
tick bites and tick bites free. Metabolomic profiling of such patients
will clarify the future of α-Gal allergy.