Nutritional Markers Of Histamine Intolerance in Ehlers-Danlos Syndromes
Introduction: Ehlers-Danlos syndromes (EDS) are a group of hereditary disorders of connective tissue involving collagen synthesis and regulation. Many people with hypermobile EDS suffer from gastrointestinal (GI) dysmotility and gastroesophageal reflux disease (GERD). Recommended agents for these GI co-morbidities, such as proton pump inhibitors, interfere with the absorption of key micronutrients. Thus, patients with EDS are at significant risk for nutritional imbalance.matologic, neuropsychiatric, and gastrointestinal complications of MCAD are partly attributable to histamine. Not only produced by mast cells but also basophils and neurons, histamine plays an important role in homeostasis, including neurotransmission, cell cycling, hematopoiesis, wound healing, and immunoregulation. Following binding of Immunoglobulin receptors or activation of the complement system, preformed histamine is released into the local connective tissue, through extrusion of cytoplasmic granules, called degranulation.
Hypersensitivity disorders, including mast cell activation disease (MCAD), are emerging as a recognized comorbidity with the hypermobile type of EDS. Many dermatologic, neuropsychiatric, and gastrointestinal complications of MCAD are partly attributable to histamine. Not only produced by mast cells but also basophils and neurons, histamine plays an important role in homeostasis, including neurotransmission, cell cycling, hematopoiesis, wound healing, and immunoregulation. Following binding of Immunoglobulin receptors or activation of the complement system, preformed histamine is released into the local connective tissue, through extrusion of cytoplasmic granules, called degranulation.
Histamine is synthesized from histidine via the vitamin B6-dependent enzyme histadine decarboxylase. Extracellular and intracellular catabolism of histamine is reliant on several enzymes, inclusive of both diamine oxidase (DAO) in both pathways and monoamine oxidase (MAO) in the intracellular pathway. Both enzymes require riboflavin-derived flavin adenine dinucleotide (FAD) as their co-factor. Single nucleotide polymorphisms to DAO (rs2070586 (A>G), rs2111902 (A>C,T) and rs3741774 (G>A,T,C)) may cause histamine intolerance. However, elevated histamine inhibits DAO, mast cell degranulation in the setting of EDS may also cause of histamine intolerance. This pilot study examines nutritional markers for histamine intolerance in individuals with EDS.
Methods: We conducted a retrospective analysis of Metabolomix+ (Genova Diagnostics) nutritional test results of 60 consecutive patients (14 male/46 female) with EDS, seen in a private clinic, from December 2021 to January 2022. This noninvasive urine collection test assesses organic acids and amino acids and provides levels with regard to age/gender specific reference ranges and magnitude of deficiency or excess, indicating a need for tailored support.
We computed the proportion of patients with elevated xanthurenic acid, kynurenic acid and/or increased essential amino acids. These markers indicate a need for vitamin B6 to address biochemical dysfunction. Both xanthurenic acid and kynurenic acid are metabolites synthesized in the kynurenin pathway that forms niacin from tryptophan in a B6-dependent reaction. Elevation of essential amino acids indicates need for vitamin B6 as synthesis of non-essential amino acids via transamination is also B6-dependent. This correlates to higher production of histamine. Glutaric acid at very high levels is associated with glutaric aciduria type 1, an autosomal-recessive disorder resulting from a deficiency of mitochondrial glutaryl-CoA dehydrogenase necessary for the metabolism of lysine, hydroxylysine, and tryptophan. Milder elevations can be indicative of riboflavin deficiency unrelated to inborn error of metabolism. Moreover, increased glutaric acid correlates with histamine intolerance.
Results: The median age was 37 years (range: 6-73). The proportion of patients with abnormal results were as follows: histidine (22%), isoleucine (12%), leucine (12%), lysine (34%), methionine (32%), phenylalanine (7%), taurine (64%), threonine (25%), tryptophan (32%), and valine (10%). Only 4 of 59 patients had normal results for all essential amino acids examined; 35 patients had at least one high abnormal result and an additional 20 patients had moderate abnormal results, indicating B6 insufficiency. Also, 57% had high abnormal values in glutaric acid, a finding that is also associated with histamine intolerance. This is particularly noteworthy since many of these patients would have been taking riboflavin-5-phosphate supplements already. 22% of the patients had abnormal (high) xanthurenic acid and 13% abnormal high kynurenic acid.
Conclusion: Nutritional testing is a promising approach to understanding and treating the neurologic, immunologic, hematologic, and psychiatric manifestations and comorbidities of EDS.