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Chapter: Medical Immunology: Organ-Specific Autoimmune Diseases

Autoimmune Diseases of the Gastrointestinal Tract and Liver

Pernicious or megaloblastic anemia is a severe form of anemia secondary to a special type of chronic atrophic gastritis associated with lack of absorption of vitamin B12.



A. Pernicious Anemia

Pernicious or megaloblastic anemia is a severe form of anemia secondary to a special type of chronic atrophic gastritis associated with lack of absorption of vitamin B12. Pathologi-cally the disease is associated with chronic atrophic gastritis and with defective production and/or function of intrinsic factor, which is required for the absorption of vitamin B12. Three types of autoantibodies have been described in patients with this disease:

·              Type I (blocking) antibodies, present in 75% of patients, bind to intrinsic factor (IF) and prevent its binding to vitamin B12.

·              Type II (binding) antibodies react with the IF–vitamin B12 complex and inhibit IF ac-tion. The type II antibody is found in 50% of patients, and it does not occur in the absence of type I antibody.

·              Type III (parietal canalicular) antibodies, present in the microvilli of the canalicular system of the gastric mucosa, are detected in 85–90% of patients and react with the parietal cell, inhibiting the secretion of IF.

In 10–15% of patients with pernicious anemia, no antibody can be detected with cur-rently available techniques. Other autoimmune diseases such as thyroiditis and Addison’s disease are diagnosed with abnormally high frequency in patients with pernicious anemia.

Severe neuropathy and megaloblastic anemia dominate the clinical picture in patients with vitamin B12 deficiency. The development of neuropathy is a consequence of the fact that vitamin B12 is an essential coenzyme for the metabolism of homocysteine, the metabolic precursor of methionine and choline. Choline is required for the synthesis of choline-containing phospholipids, and methionine is also needed for the methylation of ba-sic myelin. The synthesis of fatty acids is also abnormal, and those abnormal fatty acids are incorporated into neural tissues. Therefore, the metabolism of myelin is abnormal in pa-tients with vitamin B12 deficiency resulting in demyelination and nerve tissue damage. The symptoms include weakness and numbing of the extremities, secondary to loss of myelin on the dorsal and lateral spinal tracts. Signs consist of loss of vibratory sense, ataxia, inco-ordination, and impaired mentation.

The hematopoietic abnormalities are a consequence of the fact that vitamin B12 is re-quired for the normal cellular metabolism of tetrahydrofolate; if tetrahydrofolate is not properly synthesized, folate will not be properly conjugated, and a tissue folate deficiency will ensue. In turn, purine metabolism is impaired, DNA metabolism is abnormal, and hematopoiesis cannot proceed normally. This affects the bone marrow because the hemopoietic precursors are rapidly dividing cells. Red cells, granulocytes, as well as platelets are affected. The term megaloblastic anemia refers to the finding of abnormal red cells in the peripheral blood and hypercellularity with numerous megaloblasts on the bone marrow (from which the term megaloblastic anemia derives). Neutopenia, hypersegmented neutrophils, and mild to moderate thrombocytopenia are often present in these patients. Parenteral administration of vitamin B12 is followed by a marked increase in reticulocyte count, which is considered diagnostic.

Abnormalities of the digestive tract include atrophic glossitis and gastritis, which probably result from impaired epithelial regeneration. A histamine stimulation test of the gastric cells will show achlorhydria.

Treatment involves intramuscular injection of vitamin B12 that will correct both hematological and neurological manifestations.

B. Primary Biliary Cirrhosis

Primary biliary cirrhosis (autoimmune cholangitis) is a chronic granulomatous inflamma-tory liver disease that results in destruction of the intrahepatic biliary tree, specifically af-fecting the epithelium of the small intrahepatic bile ducts. This disease is often associated with other autoimmune diseases such as Sjogrën’s syndrome and sclerodema.

Although the true pathogenic process is not known, several immunological abnor-malities can be demonstrated, such as antimitochondrial antibodies, detected in over 99% of patients, circulating serum immune complexes, increased levels of serum immunoglob-ulins, and abnormal counts and function of CD+ and CD8+ T lymphocytes.

The disease is mainly a disease of middle-aged women. The onset is insidious and is heralded by pruritus and symptoms of cholestasis. Jaundice is a late sign. Patients have a large, nontender liver. The most significant findings from the diagnostic point of view in-clude detection of antimitochondrial antibodies and increase in serum alkaline phosphatase with normal transaminases and bilirubin.

There is no satisfactory treatment for this disease. Penicillamine, a heavy metal–chelating agent, has been used with some success. By unknown mechanisms, this drug is known to reduce the ratio of helper to suppressor cells, which is reflected into a de-pression of humoral immune responses in both experimental animals and humans. How-ever, penicillamine is nephrotoxic, and its use may be associated with severe side effects.

C. Chronic Active Hepatitis

Chronic active hepatitis (CAH) is a disease characterized by persistent hepatic inflamma-tion, necrosis, and fibrosis, which often lead to hepatic insufficiency and cirrhosis. It can be subclassified by its etiology as virus-induced, drug-induced, or chemically induced, au-toimmune, and cryptogenic (cases that do not fit into any of the other groups).

Viral chronic active hepatitis can be caused by a variety of hepatotropic viruses, namely hepatitis B, C, and D viruses. The liver disease is often accompanied by extrahep-atic manifestations suggestive of immune complex disease, such as arthralgias, arthritis, skin rash, vasculitis, and glomerulonephritis. These manifestations are believed to result from chronic viral antigen release, eliciting an antibody response and consequent immune complex formation and deposition in different tissues and organs.

Autoimmune chronic active hepatitis is characterized by the presence of autoantibod-ies and by lack of evidence of viral infection. Based on the pattern of autoantibodies detected in different patients, CAH can be subclassified into four types. The best characterized is the classic autoimmune chronic hepatitis (also known as “lupoid hepatitis”), defined by the de-tection of antinuclear antibodies. The term “lupoid” is used to stress the common feature (i.e., antinuclear antibodies) of this type of CAH and systemic lupus erythematosus. The antinu-clear antibodies in autoimmune CAH are heterogeneous and are not directed against any spe-cific nuclear antigen. In addition, autoantibodies to liver membrane antigens and to smooth muscle are also detected in patients with this type of CAH. The other types of autoimmune chronic active hepatitis are characterized by different patterns of detection of autoantibodies to smooth muscle, liver-kidney microsomal antigens, and soluble liver antigens.

The autoimmune form of CAH affects predominantly young or postmenopausal women. A genetic predisposition is suggested by the strong association with certain MHC antigens, particularly HLA-B1, B8, DRw3, and DRw4, which are also found in association with other autoimmune disorders. In addition, relatives may suffer from a variety of “au-toimmune” diseases, such as thyroiditis, diabetes mellitus, autoimmune hemolytic anemia, and Sjogrën’s syndrome. Evidence suggesting a dysregulation of the immune system in these patients includes marked hypergammaglobulinemia and detection of multiple au-toantibodies.

Liver damage in all forms of CAH is believed to be the result of a cell-mediated im-mune response against altered hepatocyte membrane antigens. Both circulating and liver-derived lymphocytes from these patients have been shown to be cytotoxic for liver cells in vitro. Antibody-dependent cell-mediated cytotoxicity has also been suggested as playing a pathogenic role.

In the case of viral infections, the expression of viral proteins in the cell membrane of infected cells could be the initiating stimulus for the response. The trigger of most au-toimmune forms of CAH remains unknown. In some cases, drugs, particularly α-methyl-dopa, may play the initiating role. -Methyldopa is believed to modify membrane proteins of a variety of cells and induce immune responses that cross-react with native membrane proteins and perpetuate the damage, even after the drug has been removed.

The pathogenesis of cryptogenic CAH, in which there is no evidence of viral infec-tion, exposure to drugs known to be associated with CAH, or autoimmune responses, re-mains unknown. It is possible that most of these cases are caused by an undetected viral in-fection or by exposure to an unsuspected drug or chemical agent.

The diagnosis of CAH is usually established by liver biopsy. Typically, the biopsy will reveal a picture of “piecemeal necrosis,” characterized by marked mononuclear cell infiltration of the periportal spaces and/or paraseptal mesenchymal-parenchymal junc-tions, often expanding into the lobules. Plasma cells are often prominent in the infiltrate. There is also evidence of hepatocyte necrosis at the periphery of the lobules, with evi-dence of regeneration and fibrosis. It is believed that this picture reflects an immune at-tack of the infiltrating lymphocytes directed against the periportal and paraseptal lym-phocytes. In one quarter to one half of the patients (depending on the study), evidence of postnecrotic cirrhosis is detected, and in some patients the evolution towards cirrhosis is progressive.

Treatment involves administration of glucocorticoids in the autoimmune forms and antiviral agents in cases associated with viral infection. α-Interferon administration seems beneficial for patients with viral CAH, who can complete several months of therapy with-out severe side effects. In some cases interferon administration is associated with the emer-gence of antinuclear antibodies, which usually disappear after therapy is discontinued, but rarely may evolve towards a complete picture of autoimmune CAH requiring glucocorti-coid therapy.

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