Autoimmune Gastrointestinal Dysmotility (AGID) Evaluation
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Published: April 2012Print Record of Viewing
Identification of autoimmune gastrointestinal dysmotility (AGID) can result in early diagnosis of an associated cancer and reversibility of symptoms with immunotherapy. Dr. Andrew McKeon will review the diagnostic testing algorithm for autoimmune gastrointestinal dysmotility, define the clinical utility of an AGID evaluation, and describe interpretation of laboratory testing.
Presenter: Andrew McKeon, MB, BCh, MD
- Consultant in the Neuroimmunology Laboratory in the Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology at Mayo Clinic in Rochester, Minnesota
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Our presenter for this program is Andrew McKeon, MB BCh (N-AI), consultant in the Neuroimmunology Laboratory in the Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology at Mayo Clinic in Rochester, Minnesota. Dr. McKeon will review the diagnostic testing algorithm for autoimmune gastrointestinal dysmotility (AGID), define the clinical utility of an Autoimmune Gastrointestinal Dysmotility Evaluation, and describe interpretation of laboratory testing. Thank you, Dr. McKeon.
Thank you, Sharon, for that introduction. Hello, my name is Dr. Andrew McKeon. I am going to talk to you today about a new evaluation to aid the evaluation of patients with a suspected autoimmune gastrointestinal dysmotility disorder.
This new profile is called the autoimmune gastrointestinal dysmotility profile or AGID profile.
So what is autoimmune gastrointestinal dysmotility? This is a limited form of dysautonomia with prominent gastrointestinal symptoms. In this disorder the enteric nervous system is targeted by the immune system. These disorders are mediated by neural specific IgG antibodies or by effector T cells. These disorders may occur on an idiopathic basis or in some cases may occur associated with a systemic cancer, which is also known as a paraneoplastic disorder.
The symptoms of these autoimmune gastrointestinal disorders include early satiety, anorexia, nausea, vomiting, weight loss, constipation, or diarrhea. The onset of these disorders may occur either subacutely or insidiously. Other components of the autonomic nervous system may also be affected to a greater or lesser degree. Other symptoms may include orthostatic dizziness, also known as orthostatic hypotension, bladder dysfunction, dry eyes, and dry mouth.
Diagnostic clues from the history could include a personal or family history of autoimmunity or cancer. Oncological associations have been seen in a paraneoplastic context in patients with autoimmune gastrointestinal dysmotility and these include carcinomas (usually of the lung), breast, endometrium or GI system, and sometimes thymoma.
The importance of an early diagnosis of autoimmune gastrointestinal dysmotility lies in less morbidity with early treatment. Many of these patients have a favorable response to pyridostigmine which can improve synaptic transmission by inhibiting acetylcholinesterase. Many of these patients will improve with immunotherapies such as intravenous immunoglobulin or intravenous steroids, particularly if started early. Longer term therapy with immunosuppressants may be required if objective benefit is noted with the initial trial of therapy. Depending on the antibody or profile of antibodies detected, a search for cancer may be initiated on this basis. Sometimes particular antibodies detected or a profile of antibodies detected can help identify the histological type of cancer present, and thus guide, oncological investigations.
AGID: Laboratory Findings
So, how are patients with AGID, or autoimmune gastrointestinal dysmotility, identified and evaluated? Since many of the symptoms that I mentioned above are quite nonspecific, when the history is suggestive of a gastrointestinal dysmotility disorder, abnormalities can be objectively documented with further testing. Abnormalities may include slow emptying on a gastric small intestinal or colonic nuclear transit study. Also there may be abnormalities detected on esophageal gastroduodenal or colonic manometry. Also abnormalities may be found on anorectal manometry with balloon expulsion.
AGID: Antibody Evaluation
In that context, the autoimmune gastrointestinal dysmotility antibody evaluation can aid the diagnosis of both idiopathic autoimmune and paraneoplastic disorders and, as mentioned, multiple antibodies are commonly found coexisting together and the specific neoplasm may be predictable by the antibody profile. For example, ANNA-1 antibody with an N-type calcium channel antibody is predictive of small cell carcinoma.
Ganglionic Acetylcholine Receptor (AChR) Autoantibod
I will now go into a little more detail about the ganglionic alpha-3 acetylcholine receptor autoantibody since this is the most commonly encountered antibody marker of autoimmune gastrointestinal dysmotility. When this antibody is found in a patient with autoimmune gastrointestinal dysmotility this may be accompanied by other signs of dysautonomia outside of the gastrointestinal system. The antibody level often reflects the severity of dysautonomia.
Ganglionic AChR Autoantibody
Values greater than 1.00 nanomole per liter are usually accompanied by other signs of dysautonomia in addition to gastrointestinal problems. Values between 0.03 and 0.99 nanomoles per liter reflect an autoimmune gastrointestinal dysmotility that may be isolated or signs outside of the gastrointestinal system may be mild. Overall cancer is detected in 30% of seropositive patients. A variety of cancers have been associated with this antibody and these include adenocarcinoma, small cell carcinoma, thymoma, and lymphoma.
AGID Antibody Profile
On the next slide I am going to go through the profile and the different antibodies that are tested for. Before I do that, I am just going to briefly mention that there are 3 different types of antibodies tested for. First of all, the neuronal nuclear antibody such as ANNA-1 or antineuronal nuclear antibody type-1 which in the literature is also known as anti-Hu antibody. As mentioned earlier, this is associated with small cell carcinoma. Then another group of antibodies which have specificity for antigens in cytoplasm of neuronal cells or muscle cells. These include CRMP-5, IgG, GAD-65 antibody and striational antibody. Finally, another group of antibodies known as the cation-channel antibodies, include the mentioned ganglionic acetylcholine receptor autoantibody but also antibody targeting muscle acetylcholine receptors, N-type calcium channel antibody and the voltage-gated potassium channel antibody.
So now to look at this in the format of the testing algorithm. This is just an overall view of it and then I'll go on to show this in more detail, focusing in on various aspects of the algorithm.
There are some antibodies tests that are always tested for and these are in the box just below "always performed." These are tested using a variety of assays including immunofluorescence, ELISA and immunoprecipitation assays.
There are 4 situations in which additional testing may be done. I’m going to discuss these from left to right. The first is the immunofluorescence pattern is indeterminate. In this situation there may be an antibody staining pattern suspicious for ANNA-1, but not all of the characteristic features are present. In that setting we will additionally do a paraneoplastic Western blot to look for the characteristic pattern associated with this antibody. The second setting and the third setting would occur where an antibody pattern suggestive of amphiphysin or CRMP-5 IgG were detected. Then we would confirm the presence of either of these antibodies with recombinant Western blots for the appropriate antibody, either amphiphysin or CRMP-5 IgG.
The final setting in which additional testing may be done would be where the acetylcholine receptor binding antibody or striational antibody were detected. For this, the possibility of an antibody profile supportive of thymoma would come to mind. This could be further explored by doing testing for the acetylcholine receptor modulating antibody and CRMP-5 IgG by Western blot.
Clinical Utility of AGID Evaluation
So what are the appropriate clinical circumstances to do the autoimmune gastrointestinal dysmotility serological evaluation? There are 5 specific uses for this testing. Firstly, this could be used for investigating acquired idiopathic gastrointestinal dysmotility to see if an idiopathic autoimmune or paraneoplastic basis can be established for this. This can then help direct treatment. If 1 or more of the antibodies described were detected, this may increase the clinician’s confidence that a trial of immunosuppression is warranted. Thirdly, the antibody profile detected can help predict the cancer type. Fourthly, this testing can be used to investigate gastrointestinal dysmotility occurring during cancer therapy that was not explainable by recurrent cancer or metastasis.
This then can help distinguish autoimmune gastrointestinal dysmotility from chemotherapy side effects. Finally, a rising antibody titer in a previously seropositive patient can suggest cancer recurrence.
In summary, the autoimmune gastrointestinal dysmotility serological evaluation aids the investigation of new onset idiopathic gastrointestinal dysmotility. Detection of 1 or more of this profile of autoantibodies may lead to detection of unsuspected cancer and seropositivity will indicate a potentially immunotherapy responsive disorder.
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