Autoimmune Gastrointestinal Dysmotility Evaluation, Serum
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
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 found most commonly 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 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-AChR (acetylcholine receptor) 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 symptoms and signs.
Importantly, cancer is detected in 30% of patients with alpha-3-AChR autoantibody. Cancer risk factors include the patient's past or family History of cancer, history of smoking, or social/environmental exposure to carcinogens. Early diagnosis and treatment of the neoplasm favors less morbidity from the GI dysmotility disorder. The cancers recognized most commonly with alpha-3-AChR autoantibody Include adenocarcinomas of breast, lung, prostate, and GI tract, or lymphoma. 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 antineuronal nuclear antibody-type 1 (ANNA-1) (anti-Hu)-positive patients and 23% of ANNA-1-positive patients have GI dysmotility. The most common GI manifestation is gastroparesis, but the most dramatic is pseudo-obstruction.
Investigating unexplained weight loss, early satiety, anorexia, nausea, vomiting, constipation or diarrhea in a patient with past or family history of cancer or autoimmunity
Directing a focused search for cancer
Investigating gastrointestinal symptoms that appear in the course or wake of cancer therapy, not explainable by recurrent cancer, metastasis or therapy. Detection of autoantibodies on this profile helps differentiate autoimmune gastrointestinal dysmotility from the effects of chemotherapy.
Detecting early evidence of cancer recurrence in previously seropositive patients who have a rising titer of 1 or more autoantibodies
Antibodies directed at onconeural proteins shared by neurons, muscle and certain cancers are valuable serological markers of a patient's immune response to cancer. They are not found in healthy subjects, and are usually accompanied by subacute symptoms and signs. It is not uncommon for more than 1 antibody to be detected. Three classes of antibodies are recognized (the individual antibodies from each class included in the profile are denoted in parentheses):
-Antineuronal nuclear autoantibody-type 1
-Neuronal and muscle cytoplasmic (CRMP-5, glutamic acid decarboxylase, and striational)
-Plasma membrane cation channel (neuronal ganglionic [alpha-3-AChR (acetylcholine receptor)] and muscle AChR, neuronal voltage-gated N-type calcium channel, neuronal voltage-gated potassium channel antibodies). All of these autoantibodies are potential effectors of autoimmune gastrointestinal dysmotility.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Negative results do not exclude autoimmune gastrointestinal dysmotility or cancer.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
ANTINEURONAL NUCLEAR ANTIBODY-TYPE 1 (ANNA-1)
Neuron-restricted patterns of IgG staining that do not fulfill criteria for ANNA-1 may be reported as unclassified antineuronal IgG. Complex patterns that include non-neuronal elements may be reported as uninterpretable.
STRIATIONAL (STRIATED MUSCLE) ANTIBODIES
GLUTAMIC ACID DECARBOXYLASE (GAD65) ANTIBODY ASSAY
< or =0.02 nmol/L
GANGLIONIC ACETYLCHOLINE RECEPTOR (ALPHA3) AUTOANTIBODY
< or =0.02 nmol/L
NEURONAL VOLTAGE-GATED POTASSIUM CHANNEL (VGKC) AUTOANTIBODY
< or =0.02 nmol/L
N-TYPE CALCIUM CHANNEL ANTIBODY
< or =0.03 nmol/L
ACETYLCHOLINE RECEPTOR (MUSCLE AChR) BINDING ANTIBODY
< or =0.02 nmol/L
NEUROMYELITIS OPTICA (NMO)/AQUAPORIN-4-IGG CELL-BINDING ASSAY
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Lennon VA, Sas DF, Busk MF, et al: Enteric neuronal autoantibodies in pseudo-obstruction with small cell lung carcinoma. Gastroenterology 1991;100:137-142
2. Lucchinetti CF, Kimmel DW, Lennon VA: Paraneoplastic and oncological profiles of patients seropositive for type 1 anti-neuronal nuclear autoantibodies. Neurology 1998;50:652-657
3. Vernino S, Adamski J, Kryzer TJ, et al: Neuronal nicotinic ACh receptor antibody in subacute autonomic neuropathy and cancer-related syndromes. Neurology 1998;50:1806-1813
4. Vernino S, Low PA, Fealey RD, et al: Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000;343:847-855
5. Pittock SJ, Kryzer TJ, Lennon VA: Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol 2004;56:715-719
6. Dhamija R, Tan KM, Pittock SJ, et al: Serological profiles aiding the diagnosis of autoimmune gastrointestinal dysmotility. Clin Gastroenterol Hepatol 2008;6:988-992
7. McKeon A, Lennon VA, Lachance DH, et al: The ganglionic acetylcholine receptor autoantibody: oncological, neurological and serological accompaniments. Arch Neurol 2009;66(6):735-741
8. Kraichely RE, Farrugia G, Castell DO, et al: Neural autoantibody profile of primary achalasia. Dig Dis Sci 2010 Feb;55(2):307-311