The most dangerous and life-threatening manifestation of allergic diseases is anaphylaxis, a condition in which the cardiovascular system is responsible for the majority of clinical symptoms and for potentially fatal outcome. The heart is both a source and a target of chemical mediators released during allergic reactions. Mast cells are abundant in the human heart, where they are located predominantly around the adventitia of large coronary arteries and in close contact with the small intramural vessels. Cardiac mast cells can be activated by a
variety of stimuli including allergens, complement factors, general anesthetics, and muscle relaxants. Mediators released from immunologically activated human heart mast cells strongly influence ventricular function, cardiac rhythm, and coronary artery tone. The number and density of cardiac mast cells is increased in patients with ischemic heart disease and dilated cardiomyopathies. This observation may help explain why these conditions are major risk factors for fatal anaphylaxis. Although the skin (urticaria and angioedema) and the respiratory tract (laryngeal edema and bronchospasm) are the main organs involved in the early stages of anaphylaxis, dysfunction of the central and peripheral cardiovascular systems usually dictates the outcome of anaphylactic events.¹⁷

Gastrointestinal food allergies (an IgE immune response) do exist in both children and adults, but the majority of symptoms from ARF are due to either nonallergenic immune reactions to foods (IgG, IgA, or IgM mediated), or nonimmune reactions. Thus, although IgE immunoglobulin testing of food proteins is of clinical value in identifying an adverse reaction, exclusive use of such testing may be limiting.

Wheat allergy manifestations (an IgE-mediated response) affect the GI tract (vomiting, colic, diarrhea), skin (urticaria, eczema), respiratory tract (upper respiratory, asthma), or multiple systems (anaphylaxis). Sensitization is primarily through ingestion, but can be by inhalation or skin contact—even by wheat-containing cosmetics.¹⁸ Wheat, specifically its omega-5 gliadin fraction, is the most common allergen implicated in food-dependent, exercise-induced anaphylaxis (FDEIA), being positive in 53% of provocation tests. However the importance of more comprehensive testing parameters (including oral challenge) cannot be overemphasized. Skin testing demonstrated a 29% positive predictive value (PPV), and serum IgE a 9% PPV.¹⁹

The most allergenic foods (determined by IgE positivity) change according to the age group: egg being the most frequent in children under 5 years, and fresh fruits in children older than 5 years.

The most Common Clinical Manifestations of Food Allergy include:

The global population has more than doubled in the last 40 years supported by the “green revolution” in agriculture producing high-yield grain varieties, including semidwarf, high-yield, disease-resistant varieties of wheat, that are central to the modern diet.²¹ Awarding the Nobel Peace Prize in 1970 to Norman Ernest Borlaug recognized the value of dwarf wheat to humanity.

Arguably, one of the most researched conditions diagnosed from an ARF is celiac disease—an autoimmune reaction to wheat. Celiac disease has traditionally been clinically considered and then investigated with patients presenting with gastrointestinal (GI) symptoms. However, for every adverse reaction to wheat presenting with GI symptoms, there are eight presenting without GI symptoms.²² Thus, dependence on GI complaints as a prerequisite in considering an adverse reaction to wheat will allow a majority to escape diagnosis. This is a critical point of recognition for the clinician when considering an association of WRDs and cardiovascular health.

Celiac disease is an autoimmune inflammatory disease in response to exposure to the environmental antigen, wheat. It is characterized by autoantibody production (tissue transglutaminase and/or endomysium), autoimmune enteropathy, and autoimmune comorbidities up to 30 times more prevalent than in the general population.²³ This overly active immune reactivity is evident in untreated adults with CD being at increased risk of early atherosclerosis, as suggested by the presence of chronic inflammation, vascular impairment, unfavorable biochemical patterns, and relative lack of the classical risk factors. Certain cardiovascular maladies, including cardiomyopathy, myocarditis, arrhythmias, and premature atherosclerosis, are substantially more prevalent in individuals with CD as compared to individuals without the disease.²⁴,²⁵

There has been a dramatic increase in the number of articles on CD and cardiovascular function in the last 15 years with the largest number of documents published concerned CD in conjunction with cardiomyopathy (33 studies) (Figure 6.1), and there have also been substantial numbers of studies published on CD and thrombosis (27), cardiovascular risk (17), atherosclerosis (13), stroke (12), arterial function (11), and ischemic heart disease (11).²⁶

The 8:1 ratio of extraintestinal versus intestinal symptoms is not limited to celiac disease. In a prospective 1-year study of suspected nonceliac gluten sensitivity (NCGS)-related disorders from 38 Italian centers (27 centers of adult
gastroenterology, 5 of internal medicine, 4 of pediatrics, and 2 of allergy)—all recognized as referral centers of excellence and included in the register of the Italian Health Ministry for the diagnosis of gluten-related disorders), 53% of patients presented with nonabdominal complaints. The most frequent extraintestinal manifestations were fatigue and lack of well-being, reported by 64% and 68%, respectively, of the enrolled subjects. In addition, a high prevalence of neuropsychiatric symptoms including headache (54%), anxiety (39%), “foggy mind” (38%), and arm/leg numbness (32%) were recorded. Other extraintestinal manifestations emerging from the analysis of the survey responses were joint/muscle pain often misdiagnosed as fibromyalgia (31%), weight loss (25%), anemia (22%), due both to iron deficiency and low folic acid, depression (18%), dermatitis (18%), and skin rash (29%).²⁷ With its global impact in the body and lack of isolated tissue vulnerability, a high degree of suspicion is required for a clinician to investigate a presenting patient for a WRD.

A gluten-free diet (GFD), the mainstay of treatment for CD, is increasingly being adopted by people without a diagnosis of celiac disease. Gluten-free (GF) eating patterns have become a mainstream phenomenon during recent years, and nearly one-third of Americans report having attempted to eliminate or reduce the amount of dietary gluten they consume.²⁸

Birthweight has been directly associated with later-in-life cardiovascular disease. Ascertained deaths from stroke and coronary heart disease in 13,249 men revealed standardized mortality ratios (SMRs) for stroke fell by 12% (95% Cl 1-22) and for coronary heart disease by 10% (6-14) between each of five groupings of increasing birthweight (<or = 5.5 lb, 5.6-6.5 lb, 6.6-7.5 lb, 7.6-8.5 lb, and > 8.5 lb).²⁹ In an observational study, those who had had low birthweights had relatively high death rates from coronary heart disease in adult life.³⁰ It has been demonstrated that people who were small at birth as a result of growth retardation, rather than those born prematurely, were at increased risk of mortality from CVD.³¹ Similarly, a systematic review of 34 studies examining the relation between birthweight and blood pressure in different populations around the world found strong support for an association between low birthweight and high blood pressure in prepubertal children and adults.³²

Although the fetal genome determines growth potential in utero, the weight of evidence suggests that it plays a subordinate role in determining the growth that is actually achieved. Rather, it seems that the dominant determinant of fetal growth is the environmental milieu (nutrition, hormonal, microbial) in which the fetus develops, and in particular, the microbiome, nutrient and oxygen supply.³³,³⁴

One in every 70 pregnant women admitted to a major city hospital in Italy suffered from untreated celiac disease; 70% had a poor outcome of pregnancy, and 8/9 women had a second healthy baby after 1 year on a GFD.³⁵ An unfavorable neonatal outcome was not only associated with maternal celiac disease but also with paternal celiac disease. Infants of celiac mothers weighed 222 g less than the population average, and infants of celiac fathers weighed 266 g less than the population average. The risk of a low birthweight baby to celiac fathers was fivefold higher than that in the general population (11% versus 2.5%).³⁶

Intrauterine growth retardation (IUGR) is defined as a poorly growing fetus whose weight is less than the tenth percentile for its gestational age based on a standard curve for the general population. In addition to common causes such as smoking and alcohol abuse, numerous studies have linked celiac disease and IUGR. Rates for IUGR are significantly higher (threefold) in celiac patients, 6.3% versus 2.1%.³⁷ In a study of 211 infants and 127 mothers with celiac disease and 1260 control deliveries, there was a 3.4-fold increased risk of IUGR in infants whose mothers had untreated celiac disease.³⁸ This study also found that women with celiac disease gave birth to infants with a mean birthweight that was 238 g lower than observed in the control deliveries. However, the women with celiac disease who were on GFDs gave birth to babies 67 g heavier than the controls. Investigating the correlation from a reverse perspective, patients with both repeated spontaneous abortions (RSA) and IUGR showed a statistically significant higher frequency of celiac disease when tested serologically than did the controls (with no RSA or IUGR). Specifically, 8 % of RSA patients and 15% of IUGR patients were positive for celiac antibodies, whereas all controls were negative.³⁹

The frequency of vascular thrombotic events associated with CD are increased,⁴⁰ can be recurrent,⁴¹ and may be present at multiple locations.⁴² Endothelial dysfunction is the earliest sign of atherosclerosis and associated with cardiovascular events.⁴³,⁴⁴ The detection of endothelial dysfunction in healthy subjects may indicate an increased risk for cardiovascular events (heart failure, stroke, erectile dysfunction, peripheral artery disease) and can be used as a predictor of clinical prognosis (morbidity/mortality) in patients with coronary artery disease. In the first functional challenge study of the brachial artery in individuals with CD, response to a hyperemic challenge revealed a significant reduced response of celiac patients versus controls.

Endothelial dysfunction at the macrovascular level was found in celiac patients and is one of the earliest signs of atherosclerosis.⁴⁵ Areas with improved markers on a GFD include the common carotid arteries for intima-media thickness and the humeral artery for endothelium-dependent dilatation.⁴⁶

In an age- and sex-matched control study of 65 patients with CD (mean age 6.74 ± 4.6 years) and 51 controls, serum levels of vascular adhesion molecule-1, intercellular adhesion molecule-1, endothelial selectin, vascular endothelial cadherin, high-sensitivity C-reactive protein, and homocysteine levels were measured. The average soluble vascular adhesion molecule-1 (CD versus control group: 1320 ± 308 versus 1120 ± 406 ng/mL, P = .006), soluble intercellular adhesion molecule-1 (336 ± 99 versus 263 ± 67 ng/mL, P = .025), and soluble endothelial selectin (113.9 ± 70 versus 76.9 ± 32 ng/mL, P = .007) levels were significantly higher in cases of newly diagnosed CD than in the control group. Soluble vascular adhesion molecule-1 (1050 ± 190 ng/mL) and soluble endothelial selectin (68.7 ± 45 ng/mL) levels in patients with CD, who were fully compliant with a GFD, were significantly lower than that in those newly diagnosed as having CD (P = .003 and P = .0012, respectively). These results show that serum adhesion molecule levels are higher in patients with CD and may explain some of the risks associated with endothelial dysfunction seen in CD.⁴⁷

CD youth have also been associated with increased risk of developing early atherosclerosis. They are also more likely to have greater mean low-density lipoprotein (LDL) cholesterol and have thicker carotid intima-media as compared with controls, and their endothelium-dependent dilatation is decreased, all of which negatively affect vascular function.⁴⁸,⁴⁹

A relationship with increased carotid intima-media thickness (CIMT) and decreased flow-mediated dilatation (FMD) in addition to elevated CRP and homocysteine levels in recently diagnosed young CD patients has been identified. The GFD improved CIMT, FMD, and CRP levels.⁵⁰ These findings support the theory that chronic inflammation in CD patients increases the risk of premature atherosclerosis. CIMT values are significantly higher in patients with coexisting diabetes and CD as compared to those patients with diabetes or CD alone.⁵¹

In adult CD patients lacking cardiovascular risk factors, abnormal homocysteine, erythrocyte sedimentation rate, C-reactive protein, and insulin levels, along with inflammation, may be contributing to arterial stiffening.⁵² Correlation has been shown between restoration of the small intestinal villous atrophy and normalization of vascular parameters in gluten-abstinent CD patients.⁵³,⁵⁴

Folic acid and vitamin B₁₂, along with vitamin B₆ and riboflavin, are needed for the metabolism of homocysteine, which is widely considered to be a risk factor for heart disease and stroke. Higher levels of homocysteine have been found in untreated patients with CD compared with healthy controls, with normalization after recovery from villous atrophy. The B-complex of vitamins are principally absorbed in the proximal part of the small intestine, which is the primary site of the inflammatory cascade in CD and NCWS (nonceliac wheat sensitivity). With associated deficiencies of the B-complex and protein S from malabsorption, a thrombophilia may result from hyperhomocysteinemia.⁵⁵,⁵⁶,⁵⁷ The thrombotic events in CD may also result from dehydration due to diarrhea.⁵⁸ Cerebral venous sinus thrombosis can occur in CD patients⁵⁵,⁵⁹,⁶⁰,⁶¹ even in absence of gastrointestinal symptoms,⁶⁰ but can resolve with symptomatic treatment.⁵⁵ Venous thrombosis can be a sequela of undetected CD⁵⁷,⁶²,⁶³,⁶⁴,⁶⁵,⁶⁶,⁶⁷,⁶⁸,⁶⁹ and may result in thromboembolic events.⁶³,⁷⁰ CD may be accompanied by portal vein thrombosis,⁷¹,⁷² and mesenteric⁷³ or splenic⁷⁴ vein thrombosis may present in occult or subclinical celiac disease.⁷³ There is an increased risk of developing venous thromboembolism from chronic inflammation and vitamin deficiency in CD.⁵⁹,⁷⁵,⁷⁶

Patients with CD have been found to be at an increased risk for stroke, and recurrent stroke, which can persist after onset of the GFD.⁷⁷,⁷⁸,⁷⁹ CD should be considered as a possible etiology for stroke cases of unknown cause, particularly in youth, whether gastrointestinal manifestations are evident or not.⁸⁰ The pathogenesis of stroke in CD youth may involve vitamin B₁₂ deficiency⁸¹ and possibly hyperhomocysteinemia, which may be secondary to folic acid deficiency,⁸² cerebral arterial vasculopathy, and antiphospholipid syndrome, a secondary autoimmune disorder which also carries a higher prevalence in celiac disease.⁸³,⁸⁴,⁸⁵ Because CD is a potentially treatable cause of cerebral vasculopathy and stroke,⁸⁶ serology, specifically TG2 antibodies, should be included in the evaluation for cryptogenic stroke in childhood, even in the absence of typical gastrointestinal symptoms.⁸⁵,⁸⁷

Dramatically reduced cholecystokinin secretion, a common finding in CD,⁸⁸ is responsible for the reduced absorptive mechanism of fat-soluble vitamins, thus may result in coagulopathy attributable to vitamin K deficiency.⁸⁹,⁹⁰

In untreated CD, continual systemic inflammation can deteriorate aortic function, and this deterioration is predictive of subclinical atherosclerosis and future cardiovascular events.⁹¹ Aortic strain and distensibility tend to be significantly lower, and the aortic stiffness index significantly higher, in untreated CD patients versus controls.⁹² Owing to the continual systemic inflammation seen in CD (and NCWS), patients are at increased risk for coronary artery disease.⁵²

The symptoms of malabsorption are alleviated with GFD. However, given the poor compliance to a recommended GFD (see below), vitamin B₆, B₁₂, and folate deficiencies might still be observed in patients with malabsorption. This may cause hyperhomocysteinemia, which may increase the risk of vascular diseases. Hyperhomocysteinemia may cause endothelial dysfunction including arterial vasospasm, activation of tissue-type plasminogen activator and factor V, increased platelet aggregation, and inhibition of protein C, all of which can result in plaque rupture, vascular damage, and vasoconstriction.⁹³ Elevated homocysteine levels are associated with spontaneous coronary artery dissection.⁹⁴

Diastolic dysfunction is an important early finding in children with CD and postulated to be the earliest cardiac complication of pediatric CD. Examining cardiac function in pediatric controls, recently diagnosed pediatric CD (Group 1) and CD children 10+ months on a GFD (Group 2) revealed significantly shorter deceleration time (DT) and left ventricle (LV) isovolumetric relaxation time (IVRT) in Group 1 compared to Group 2 and the control group (P = .002, P = .015).⁹⁵ Suggested theories explaining cardiac dysfunction include nutritional deficiency triggered by intestinal malabsorption and an autoimmune inflammatory response in myocardial tissue via molecular mimicry caused by immune system activation from increased macromolecular absorption of numerous antigens following increased intestinal permeability.⁹⁶,⁹⁷

Adult patients with CD and diabetes demonstrate the microvascular complications in both conditions. At diagnosis of CD, adult type 1 diabetic patients had worse glycemic control (8.2 versus 7.5%, P = .05), lower total cholesterol (4.1 versus 4.9, P = .014), lower HDL cholesterol (1.1 versus 1.6, P = .017), and significantly higher prevalence of retinopathy (58.3% versus 25%, P = .02), nephropathy (41.6% versus 4.2%, P = .009), and peripheral neuropathy (41.6% versus 16.6%, P = .11) than adult type 1 diabetic patients without CD. After 1 year on a GFD, only the lipid profile improved overall, but in adherent individuals HbA1c and markers for nephropathy improved.⁹⁸ The potential role of altered apolipoprotein A-I (Apo A-I) secretion in newly diagnosed CD patients offers an explanation for the different results observed between diabetic nephropathy (DN) and diabetic retinopathy (DR). Apo A-I is the major HDL structural protein, essential for reverse transport of cholesterol from peripheral tissue to the liver. It is also characterized by antioxidant and anti-inflammatory effects. Apo A-I has been reported as being synthesized by the liver and the intestine and, more recently, by the vitreous fluid and retinal pigment epithelium. Serum levels of HDL and Apo A-I are decreased in individuals with CD, and subsequent restoration of blood lipid profile is observed after GFD.⁹⁹ The reduced intestinal secretion of Apo A-I in individuals with type 1 diabetes affected by CD could contribute to the increased prevalence of DN in these subjects compared with individuals with type 1 diabetes alone and would also be of relevance in the assessment of macrovascular complications in these patients. Also, the restoration of Apo A-I and HDL levels due to the normalization of the intestinal villi after GFD could be responsible, at least partially, for the improvement of DN.¹⁰⁰

Ischemic heart disease (IHD, defined as death or incident disease in myocardial infarction or angina pectoris) is one of the main causes of death. The underlying pathology in IHD is atherosclerosis, and it seems that chronic inflammation plays an important role in the development of atherosclerosis. A population-based study of 28,190 unique individuals diagnosed with Marsh 3 CD, and 12,598 unique individuals diagnosed with inflammation without villous atrophy (Marsh 1-2), found a 19% increased risk of IHD in individuals with CD. This study also found a 28% increased risk of IHD in individuals with small intestinal inflammation but no villous atrophy and a 14% increase in individuals with normal mucosa but positive CD serology (latent CD).¹⁰¹ The discovery of a suspected WRD demonstrating significant increased mortality independent of small intestinal histopathology is of critical importance to clinicians and reinforces the necessity of an understanding of WRD outside of total villous atrophy CD. These risks were found to persist for years after
commencing the GFD.¹⁰² Persistent inflammation maintaining increased intestinal permeability even in the presence of villous regeneration is suspect.

Autoimmune diseases tend to have long, asymptomatic prodromal periods and the initiating events leading to loss of self-tolerance occurring long before the disease becomes clinically manifest. Several different pathological processes have the potential to break tolerance and contribute to the development of autoimmune disease. The mechanism of molecular mimicry (antigenic similarity between pathogenic organisms or foreign proteins and self-proteins) is one of them.

Primary mechanisms involved in food protein-induced autoimmunity are antibody molecular mimicry, cross-reactivity, and covalent binding of food and human tissue proteins creating neoepitopes. Shared amino acid homology between multiple peptides of wheat and human tissues as well as dairy proteins and human tissues has been illustrated.¹⁰³,¹⁰⁴,¹⁰⁵

The molecular mimicry or cross-reactivity hypothesis proposes that an exogenous substance, mostly produced or possessed by infectious agents or foods, may trigger an immune response against self-antigens. Susceptible individuals consume a food or have a bacterial exposure, and initiate an inflammatory immune response that has antigenic similarity to self-antigens. As the result, these food or pathogen-specific antibodies bind to the host structures possessing cross-reactive self-antigens and cause tissue damage and disease. The most familiar of these mechanisms occur in celiac disease with the antigen gluten. As an example, arguably, the most recognized preventive measure in health care to this mimicry mechanism is the use of antibiotics prior to dental visits. In rheumatic fever carditis, for example, the basic pathogenic process involves production of antibodies against Streptococcus which express high levels of M protein antigens, a molecule that shares structural similarities with those found in the heart valves and endocardial membrane. With standard dental care, perforation of the epithelial lining of the gums occurs creating potentially pathogenic gum permeability, allowing macromolecules of oral bacteria to migrate through the normally restrictive membrane barrier. The use of antibiotics in dental care is designed to mitigate the initial immune protective response against the invading pathogen (streptococcus), thus reducing the risk of a cross-reactivity to cardiac tissue.