Clinical Information

Autoimmune gastrointestinal dysmotility (AGID) is a limited form of dysautonomia (also known as autoimmune autonomic ganglionopathy or neuropathy) that is sometimes a paraneoplastic disorder. Neoplasms most frequently found are lung cancer, thymoma, and miscellaneous adenocarcinomas. Diagnosis is confirmed by objective abnormalities on gastrointestinal (GI) motility studies (eg, gastric, small intestinal, or colonic nuclear transit studies; esophageal, gastroduodenal, or colonic manometry or anorectal manometry with balloon expulsion). These disorders target autonomic postganglionic synaptic membranes and, in some cases, ganglionic neurons and autonomic nerve fibers, and may be accompanied by sensory small fiber neuropathy. Onset may be subacute or insidious. There may be additional manifestations of dysautonomia (eg, impaired pupillary light reflex, anhidrosis, orthostatic hypotension, sicca manifestations, and bladder dysfunction) or signs of other neurologic impairment. Autonomic reflex testing and a thermoregulatory sweat test are valuable aids in the documentation of objective abnormalities.

The serological profile of AGID may include autoantibodies specific for onconeural proteins found in the nucleus, cytoplasm, or plasma membrane of neurons or muscle. Some of these autoantibodies are highly predictive of an underlying cancer. A commonly encountered autoantibody marker of AGID is the ganglionic neuronal alpha-3-acetylcholine receptor (alpha-3-AChR) autoantibody. The pathogenicity of this autoantibody was demonstrated in rabbits immunized with a recombinant extracellular fragment of the alpha-3-AChR subunit and in mice injected with IgG from high-titered alpha-3-AChR autoantibody-positive rabbit or human sera. A direct relationship between antibody titer and severity of dysautonomia occurs in both experimental animals and patients. Patients with high alpha-3-AChR autoantibody values (>1.0 nmol/L) generally present with profound pandysautonomia, and those with lower alpha-3-AChR autoantibody values may have limited autoimmune dysautonomia or other neurological signs and symptoms.

Importantly, cancer is detected in 30% of patients with alpha-3-AChR autoantibody. Cancer risk factors include the patient's previous or family history of cancer, history of smoking, or social and environmental exposure to carcinogens. Early diagnosis and treatment of the neoplasm favor less morbidity from the GI dysmotility disorder. The cancers recognized most frequently with alpha-3-AChR autoantibody include lymphoma and adenocarcinomas of breast, lung, prostate, and GI tract. A specific neoplasm is often predictable when a patient's autoantibody profile includes other autoantibodies to onconeural proteins shared by neurons, glia, or muscle. Small-cell lung carcinoma is found in 80% of patients who are antineuronal nuclear antibody-type 1 (ANNA-1, also known as anti-Hu) positive, and 23% of patients who are ANNA-1 positive have GI dysmotility. The most common GI manifestation is gastroparesis but the most dramatic is pseudoobstruction.