Diagnoses and Disorders Mistaken for IBS

Qasim Aziz, PhD, from Barts and the London School of Medicine and Dentistry, started the session with a presentation of the GI manifestations in patients with Ehler Danlos Syndrome (EDS). He described EDS as a spectrum of symptoms from simple joint hypermobility and no other symptoms to severe hypermobile EDS that presents with fatigue syndrome, chronic pain, anxiety and postural orthostatic tachycardia syndrome (POTS). Patients with EDS have very high healthcare utilization and a very low quality of life. 

Patients with EDS have a range of comorbidities, and many are disorders of gut-brain interaction (DGBI). Patients who present with hypermobility can be stratified by DGBI into three clusters: foregut disorders, IBS, and no IBS. The first group presents with higher anxiety and worse quality of life, and often have functional dyspepsia and reflux that contribute to nutritional symptoms and eating disorders. Providing both nutritional and psychological support is important for these individuals.

Some preclinical data has suggested a mechanistic link between EDS and DGBI, including tenascin X (TNX) deficiency that slows calretinin-mediated colonic motility and accelerates gastric emptying. In addition, loss of soft tissue at the esophageal hiatus may disrupt vagal nerve signaling. ECM fragmentation in plasma also suggest deficiencies in connective tissue.
 
Matthew J. Hamilton, MD, from Brigham and Women’s Hospital, described GI manifestations of mast cell activation syndrome (MCAS), which also presents along a spectrum and is largely idiopathic. Mast cells line surfaces of the body that interact with the environment, including the skin, airway, and GI tract. In the intestine, mast cells are involved in permeability of the epithelial barrier, interact with other immune cells including eosinophils in the mucosa, interact with muscle, and are involved in gut-brain axis. IBS pathophysiology mirrors mast cell intestinal pathologic functions. Mast cells release mediators directly on the nerve cell surface to activate the TrkA receptor, which is involved in peripheral pain sensation. Activation of mast cells can be triggered by alcohol, medications, scents or odors, certain foods, temperature extremes, stress, and menses, and stimulate episodic and often severe symptoms across body systems.

The consensus diagnostic criteria for MCAS are: (1) presence of typical signs and symptoms in two or more organs; (2) laboratory evidence of mast cell activation (serum tryptase elevation and/or urine mast cell mediators such as N-methylhistamine, prostaglandins, and leukotriene E4); (3) treatment response to medications that block mast cell mediators; and (4) the absence of other diagnoses that can explain the symptoms. Blood tryptase levels must be measured within 6 hours after a symptomatic event, which can be challenging; spot urine samples can be collected by patients up to 12 hours after an event. Endoscopy and biopsy will appear normal except for elevated mast cell numbers in the colon, though no diagnostic threshold has been defined.

Treatment is multipronged and includes targeting mast cells with antihistamines type 1 and 2, mast cell stabilizers, leukotriene antagonists like monolukast, and other advanced therapies; treating symptoms; dietary intervention; mind/body support; and social support. Other comorbid conditions of MCAS include depression and anxiety, a history of trauma, ARFID, symptom hypervigilance, and lack of resilience and coping skills.

Linda Ahn Bui Nguyen, MD, from Stanford University, described GI manifestations of postural orthostatic tachycardia syndrome (POTS). The autonomic nervous system is the basis for fight (sympathetic, controls motor and sensory signals to the GI tract) or flight (parasympathetic, “rest and digest”). POTS is an autonomic disorder in which heart rate increases by 30 bpm or up to 120 bpm for at least 10 minutes after standing, in the absence of hypotension. Symptoms also include dizziness and migraine, as well as GI symptoms such as nausea, bloating, and abdominal pain. Small bowel motility is dysregulated in those with POTS, with evidence of small fiber neuropathy that is associated with more severe symptoms. Patients may have extraintestinal and immune comorbidities. 

Diagnosis is step-wise and starts with screening for DGBIs. If the patient is young and has multiple DGBIs, then EDS is a possibility. If there is also flushing and hives, then MACS might be present. Patients with DGBI with or without EDS are candidates for POTS assessment. Treatment of POTS focuses on lifestyle modifications, volume expansion with fluids and salt, compression, heart rate-lowering medications, and vagal nerve stimulation, which can also improve gastric emptying. Treatment should prioritize the use of therapies that can address more than one comorbid condition.