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Plasmapheresis as a Therapy for Chronic Intestinal Pseudo-Obstruction
© William Alford 1996
Chronic Intestinal Pseudo-Obstruction (CIP) is a neuromuscular disease of the intestinal tract affecting gut motility, the pathogenesis of which is unclear. With nonspecific symptoms, multiple possible mechanisms of dysfunction (neural, humoral, or myogenic), non-uniformity of classification, and a paucity of therapeutic modalities, it is overwhelming to the growing population of patients. Symptoms including nausea, vomiting, bloating, gaseousness, and abdominal pain, along with the frequent concurrent complications such as cognitive deficits and dysautonomia (including orthostatic hypotension), leave patients with a very low quality of life. While CIP is not well known to most physicians and symptoms are frequently designated as functional due to negative clinical testing, newly developed technology has shown it to be a very real organic disease. Many researchers feel that the low numbers of confirmed cases of CIP are due to this lack of recognition by diagnosticians.
The immune system normally works to protect the body by mobilizing defenses to infections caused by bacteria, fungi, parasites, and viruses, as well as suppressing cancer. During this defense, protein molecules called immunoglobulin (antibodies) combine with substances called antigens that are foreign to the body and present on the surface of the invading pathogens.
When viruses infect a cell and begin to replicate, the cell chops some of the viral proteins into fragments (the antigens) and displays them on the surface of the cell to signal the immune system into activity. Once the immune system is activated, a complex process begins to produce the antibodies to that specific antigen. These antibodies not only destroy the antigens, but remain in the body to protect against future infections of that same pathogen. The antibodies are intended to protect against foreign antigens, but sometimes the system goes awry and antibodies are produced that attack and injure the body's own tissues. When this happens, it is called an autoimmune disease and the antibodies are then called autoantibodies. The autoantibodies may attack any organ system of the body and manifest as different diseases depending on the systems affected.
Some CIP researchers have performed full thickness biopsies of the small intestine and discovered an infiltration of lymphocytes in the tissues of some persons with pseudo-obstruction (PWP) that may suggest an autoimmune disease. Complicated staining procedures of these same biopsies allow the neurons of the enteric nervous system (ENS) to be counted and PWP often have less than the average normal count, although there is some disagreement about the accuracy of such averages. A loss of neurons may indicate an autoimmune attack on the ENS.
An analysis of the sera of PWP with the Western Blot test which separates proteins by bands of peptides of molecular weight has sometimes shown numerous but non-specific auto-antibodies that may indicate an autoimmune process as well (Abell, 1994). These autoantibodies sometimes clear from the sera with treatments of leuprolide acetate (Smalley, 1995).
A number of neuropathies (loss of nerve function), including Guillain-Barre syndrome, diabetic neuropathy, and the neuropathy of Lupus and AIDS, are thought to be the result of autoimmune disease. Insulin-dependent diabetes (IDDM) is an autoimmune disease in which the immune system destroys the insulin producing beta cells in the pancreas, with neuropathy being a common complication of the disease (50% or more of diabetics). In recent studies, when nerve cells were cultured in a dish and exposed to sera from IDDM patients with neuropathy, they were inhibited or killed, but not when exposed to the sera from controls, leading to the hypothesis that antibodies associated with IDDM may contribute to the development of neuropathy in some IDDM patients (Pettinger, 1995).
Whole blood is made up of three main components; plasma, platelets, and red blood cells, and each component can be separated. Apheresis refers to the process that allows a donor to give just one component of blood. In this case, plasmapheresis (PP) allows a recipient to accept just plasma—the yellow liquid in which the blood cells are suspended. It has dissolved in it salts, fats, carbohydrates, vitamins, minerals, and other plasma proteins. Burn victims benefit from plasma donations because the plasma transfusion adds liquid volume and protein to the patient's blood supply.
However, when plasmapheresis is used to treat autoimmune diseases, the patient's entire plasma volume is replaced with that of a donor. The platelets and red blood cells of the recipient are separated from their own plasma and returned to them with the donor's plasma. As with any other blood transfusion, there is always the danger of infection both from the infusion site and from donated plasma, as well as the danger of blood clots. However since only plasma is replaced, the risk of acquiring viral illness from the donors is less than with whole blood transfusions since three times the amount of plasma than whole blood can be obtained from one donor, thus lessening the number of donors the recipient is exposed to.
It is thought that abnormal proteins may remain in the plasma after a viral illness has run its course and continue to stimulate the antibody response. Cytomegalovirus (CMV) is present in a large part of the population and has been implicated in some CIP cases. Recent studies have shown almost half of CMV positive patients to have autoantibody abnormalities (Rao, 1996). A normal human protein, CD13, is emanated from CMV-infected cells and could become immunogenic if presented to the immune system with the CMV and indeed the presence of CD13-specific antibodies has been detected in the majority of bone marrow transplant patients with CMV and none in controls, including patients with various autoimmune diseases (Soderberg 1996). Environmental toxins can also attach to proteins in the plasma and cause the immune system to then see these normal proteins as foreign (an example of this is the clustering of MS in workers in industries using zinc chloride, which has an affinity for myelin). Other naturally occurring protein fragments are sequestered in the brain and separated from the immune system by the blood-brain barrier; if these proteins escape into the bloodstream, the immune system may not recognize them as “self” since it has no prior exposure to them. Removing these abnormal antibodies with PP and reducing the burden of denatured proteins may stop the autoimmune response.
The Guillain-Barre syndrome is a disease of the peripheral nerves resulting in weakness, vague numbness, urinary incontinence, and unsteady gait. Its onset frequently follows viral infection and clinical evaluation often reveals an elevated titer to cytomegalovirus IgM, anti rubella antibody, or other viral agent antibodies. Severe symptoms can result from demyelinating motor-sensory neuropathy if the antibodies begin to attack the myelin sheaths surrounding the nerves. After plasma exchange symptoms can resolve and the patient dramatically recover (Saito M, 1994; Kuller JA, 1995).
Multiple sclerosis patients have benefited from PP combined with interferon treatments since an interferon inhibitor factor which has only recently been isolated and characterized is removed, resulting in marked increases of interferon in the sera (Medenica 1994).
A case has been reported of protracted diarrhea due to autoimmune enteropathy (disease of the small intestine) resistant to both immuno-suppressive agents and an exclusion diet, leading to a severe systemic vasculitic illness. When treated with intensive plasmapheresis there was a complete resolution of the vasculitic process. When the patient unfortunately died from septicemia, post mortem investigation revealed such a complete clearing of the autoimmune disease in the gut that the surgeons were “stunned” by the dramatic physical changes of the gut (Jenkins HR, 1994).
These indications that some factor in the sera may be involved with neuron loss or inhibition, the link of ENS neuron loss and CIP, and the successful results obtained with PP with other diseases related to neuropathies is the rationale for this proposal. A paper dealing with recovery from Guillain-Barre Syndrome due to CMV states: “Plasmapheresis has theoretical benefit for any disease associated with an abnormal plasma factor such as a toxin, antibody, or immune complex.”
There are significant numbers of enteric neurons that have neither excitatory nor inhibitory action, whose function is unclear, and which could be considered “sleeping neurons” that could potentially “awaken” once disease causing factors were removed. There is also some evidence that there may be precursor cells in the enteric nervous system that may regenerate or become active under certain conditions.
Plasmapheresis may have promise as a therapy for CIP and consideration seems warranted.
References
Abell T, Duncan U, Kuns J, Waters B, Voeller G, Dean P, Smalley D, Serum Autoimmune Antibodies Levels as Predictors of Morphologic Abnormalities of Nerve and Gut, Gastroenterology 106(2): A491, 1994.
Dong L, Pittenger G, Vinik A, Mechanisms of Nerve Cell Death in People with Insulin-Dependent Diabetes, The Diabetes Institues, Eastern Virginia Medical School, Norfolk, VA.
Jenkins HR, Jewkes F, Vujanic GM, Systemic Vasculitis Complicating Infantile Autoimmune Enteropathy, Archives of Disease in Childhood 71(6):534-5, Dec 1994.
Kuller JA, Katz VL, McCoy MC, Hansen WF, Pregnancy Complicated by Guillain-Barre Syndrome, Southern Medical Journal 88(9):987-9, Sept 1995.
Mathias J, Women's Hospital , personal communication.
Medenica RD, Mukerjee S, Alonso K, Lazovic G, Huschart T, Plasmapheresis combined with Interferon: An effective therapy for Multiple Sclerosis, Journal of Clinical Apheresis, 9(4):222-7, 1994.
Rao R, Medical Tribune: Obstetrician & Gynecologist Edition 3(17): 1996.
Saito M, Hozumi I, Dawakami A, Tsuji S, A Case of Post-Rubella Buillain-Barre Syndorme Associated with Ulcerative Colitis (Japanese), Clinical Neurology 34(11):1121-4, Nov 1994.
Soderberg C, Sumitran-Karuppan S, Ljungman P, Moller E, CD13-specific Autoimmunity in Cytomegalovirus-infected Immunocompromised Patients, Transplantation, 61(4):594-600, Feb 1996.
Pittenger G, Eastern Virginia Medical School, personal communication.
Smalley D, University of Tennessee Pathology, personal communication.
Yuki N, Successful Plasmaplheresis in Bickerstaff's Brain Stem Enceopalitis Associated with Anti-GQ1b Antibody, Journal of the Neurological Sciences 131(1):108-10, Jul 1995.
William Alford copyright ©1996. Permission is granted to copy and reproduce in any not-for-profit information arena.
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