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When one is preparing to treat a patient with hepatitis C, it is imperative to be exact and thorough when taking the patient history and performing a physical examination to minimize the potential for an autoimmune disorder.INFECTIOUS DISEASENoncaseating Granulomas and Other ‘Surprises’ During the Treatment of Hepatitis CBy Steven J. Bergstrom, BS, PA-CHepatitis C by itself, as a disease entity, is difficult and sometimes perplexing to treat. As the treatment progresses, the side effects may manifest themselves in different forms and in varying intensities and frequencies of occurrence. Certain autoimmune diseases are quiescent and may be actuated by interferon alfa-2b treatment. There is always the possibility of unmasking hidden diseases that may become relative contraindications for the treatment of the original disease. This situation at times may require the collaboration of other specialists and detours from the original treatment plan. This article presents two cases, one of autoimmune disease–sarcoidosis–and one of infectious disease–tuberculosis–that manifested during treatment with interferon alfa-2b. HCV Background Chronic infection with the hepatitis C virus (HCV) is one of the most common bloodborne infections in the United States. Moreover, the complications from this infection are the most frequent indications for liver transplantation in this country. Estimates by the Centers for Disease Control and Prevention indicate that 1.8% of the U.S. population (approximately 4 million Americans) is currently infected with HCV. Most infected individuals are asymptomatic and therefore are unaware of their infections. HCV infection is usually discovered on routine blood exams performed during annual physical examinations and wellness checkups. If the routine exams such as chemistry panels show elevated liver tests, with positive HCV-RNA testing accomplished, hepatitis C is confirmed. Hepatitis C causes an estimated 8,000 to 10,000 deaths annually in the United States.1 The current standard of therapy for hepatitis C is a combination of ribavirin and interferon alfa-2b.2 The medicines have a number of side effects. These side effects may range from mild to severe and include systemic influenza-like symptoms, bone marrow suppression, emotional lability (irritability and depression), autoimmune reactions (especially autoimmune thyroiditis) and miscellaneous side effects, such as overwhelming fatigue and energy loss, alopecia, rashes, diarrhea and numbness and tingling of the extremities. With the exception of autoimmune thyroiditis, these side effects are reversible upon dose lowering or cessation of therapy.3 Given the usual six- to 12-month course of treatment, patients with chronic hepatitis C may develop new medical problems during therapy, such as diabetes mellitus, thyroid disorders or autoimmune illnesses or infections. Alternatively, an underlying disease may be unmasked during the course of treatment. When either of these problems occurs, the strategy involved in the treatment of the patient may be altered. With management recommendations from other specialists, the hepatologist is able to determine the appropriate dose and interval of treatment in order to obtain optimal results. Here are two cases are presented involving the onset of granulomatous diseases that occurred during therapy for chronic hepatitis C. Case 1 Case 1 is a 51-year-old man who tested positive for HCV antibodies in 1997 while undergoing a series of routine laboratory tests. He had acute hepatitis B in 1981 with complete resolution and seroconversion to a positive surface antibody. His risk factors for hepatitis C included prior intravenous drug use in the late 1960s and several tattoos. There was no history of other gastrointestinal diseases or autoimmune disorders. He exercised regularly and was in good physical condition. There was no known history of tuberculosis or other mycobacterial diseases. His medications included a bronchodilator for mild asthma and thyroid hormone replacement therapy. The patient did have a long history of international travel dating back almost 30 years. The physical examination was unremarkable for a healthy-appearing man with normal vital signs. His general examination was normal. The liver was palpable at the right costal margin. The spleen tip was not palpable. He was noted to have some palmar erythema but no other stigmata of chronic liver disease. Screening laboratory results showed: Alanine transaminase (ALT): 243 U/L Aspartate transaminase (AST): 138 U/L Albumin: 4.4 g/dL Globulin: 3.0 g/dL Bilirubin: 1.1 mg/dL White blood cell (WBC) count: 3.6 x 106/L Platelet count: 132 x 109/L. Ultrasound of the gallbladder showed a 1.5 cm gallstone. The hepatic parenchyma was unremarkable. No masses were present. No splenomegaly was noted. A liver biopsy revealed stage II fibrosis and grade 1 inflammation (Scheuer scale). The HCV RNA level was 480,000 copies/mL. The patient received 5 MU of interferon alfa-2b daily for four weeks. He then was switched to 5 MU of interferon alfa-2b three times per week and was started on ribavirin therapy at a dose of 800 mg daily. After combination therapy was initiated, a series of events occurred that required a change in the treatment plan. After four months of treatment, the patient started to notice increased side effects. He developed moodiness, late-evening fatigue and intermittent headaches. He lost 10 pounds during this period. His attitude remained positive and he desired to continue with the treatment. After a total of eight months of therapy, his treatment was discontinued because of neutropenia and severe anemia. The patient was admitted to the hospital and required transfusion with packed red blood cells because his hemoglobin level dropped to 5.8 g/dL. He underwent a bone marrow biopsy, which revealed noncaseating granulomas. Special stains and cultures were negative for bacteria and mycobacteria. He was also found to have acute renal failure with a serum creatinine of 6.7 mg/dL. A skin test performed for tuberculosis was negative with positive controls. His renal failure was thought to be due to the intake of large doses of over-the-counter ibuprofen. His anemia was thought to be due to multiple causes: hemolysis associated with the interferon alfa-2b/ribavirin therapy, acute renal failure and the granulomatous process in the bone marrow. He was also found to have elevated serum calcium of 11.2 mg/dL. A chest X-ray was normal. Measurement of serum angiotensin-converting enzyme (ACE) level was normal. Because of his history of international travel, he was started empirically on antituberculosis therapy. He was also referred to an endocrinologist for the hypercalcemia. The calcium normalized within a month and he did not again show symptoms for hypercalcemia. No specific therapy was prescribed for the hypercalcemia. The patient also developed symptomatic gallstones and required cholecystectomy and postoperative endoscopic retrograde cholangiopancreatography (ERCP) plus endoscopic sphincterotomy for choledocholithiasis. A liver biopsy performed at the time of his cholecystectomy revealed the presence of noncaseating granulomas. The patient has now finished a nine-month course of antituberculosis therapy and is asymptomatic. His anemia has completely resolved. His serum calcium level is normal. His renal dysfunction resolved within a few months of stopping ibuprofen. His liver tests are normal. His hepatitis C viral count was undetectable six months after the end of antiviral therapy. Case 2 Case 2 is a 42-year-old man who self-referred for evaluation of hepatitis C previously diagnosed in 1998. He had a history of abnormal liver tests for the past seven years. He admitted to experimentation with intranasal and intravenous drugs in the mid-1980s. He abstained from drugs for 11 years. He had a history of drinking one to two bottles of beer per day up until February 1997, but then quit completely when he learned that he had hepatitis C. His history was remarkable only for a sleep disorder. The surgical history of the patient, who worked as a commercial diver, included the extraction of a sea-urchin tentacle from his right foot. His history was negative for any other chronic infections or autoimmune conditions. He denied any pulmonary symptoms. The physical examination was unremarkable. The liver was palpable at right costal margin with a smooth edge. The spleen tip was not palpable. There were no findings consistent with chronic liver disease. The extremities were without lesions. Laboratory results showed:
Ultrasound of the gallbladder was unremarkable. The liver biopsy revealed stage III fibrosis with severe inflammation. The HCV RNA level was 610,000 copies/mL. The patient began treatment with interferon alfa-2b, 3 MU six days per week, and ribavirin 1,000 mg daily. The course of treatment progressed with the usual mild and manageable side effects. Nine months into the course of treatment, the patient developed a cough and wheezing. A chest X-ray was normal. He was treated for reactive airway disease with an inhaler. Sinusitis and weight loss ensued. The patient also developed some "woody" subcutaneous nodules on both legs. They were biopsied and shown to contain noncaseating granulomas. Special stains for organisms were negative. Cultures were also negative. He was responding well to antiviral therapy with a normal serum ALT and a nondetectable HCV RNA level. The decision was made to stop his interferon alfa-2b/ribavirin combination therapy. He went on to develop hypercalcemia. The peak serum level of calcium was 15 mg/dL. His ACE level was elevated. The patient was diagnosed with nonpulmonary sarcoidosis. It was thought that most likely the interferon therapy had helped to unmask this preexisting autoimmune condition. The patient was treated briefly with prednisone for the hypercalcemia, which did become symptomatic. His leg lesions resolved. His calcium normalized, and the sinus and pulmonary complaints both resolved. His liver enzymes once again became elevated and the HCV RNA became detectable. The patient requested repeat interferon alfa-2b therapy for his hepatitis C. The decision was made to initiate interferon alfa-2b monotherapy at a dose of 3 MU three times per week. His liver enzymes once again normalized. We are awaiting the determination of the virologic response. Discussion Tuberculosis is caused by the bacteria Mycobacterium tuberculosis. The disease, now uncommon in the United States, usually affects the lungs, although in up to one-third of cases other organs are involved. Tuberculosis is usually classified as pulmonary or extrapulmonary. If properly treated, tuberculosis caused by drug-susceptible strains is manageable in virtually all cases. If untreated, the disease may be fatal within five years in more than half of cases.4 The risk that latent M. tuberculosis infection will proceed to active disease is directly related to the patient’s degree of immunosuppression.4 Sarcoidosis is a chronic, multisystem disorder that can affect all parts of the body. Its cause is unknown. In affected organs, characteristics of sarcoidosis include accumulation of T lymphocytes and mononuclear phagocytes, noncaseating epithelioid granulomas and derangement of the normal tissue architecture. Generally, skin anergy and depressed cellular immune processes in the blood occur, but sarcoidosis is characterized at the sites of disease by exaggerated T-helper lymphocyte immune processes. The organ most frequently affected is the lung, followed by involvement of the skin, eyes and lymph nodes. The disease can be acute or subacute and self-limiting, or chronic. Various infectious and noninfectious agents have been associated with this disease, but no specific agent has been proven to cause it. However, data consistently show that sarcoidosis is caused by an exaggerated cellular immune response (acquired, inherited or both) to a limited class of persistent antigens or self-antigens.5 Sarcoidosis is seen in less than 1% of the U.S. population, and hepatitis C is seen in about 18% of the population. Together, they are considered to be uncommon. During the course of treatment, both cases had certain similarities. Both patients developed granulomas and hypercalcemia. Treatment had to be reduced or stopped until secondary problems were resolved. Once the granulomas resolved, patients continued treatment. Both patients had a good biochemical response. In case 1, the patient had a travel history with no evidence of sarcoidosis but was treated presumptively for extrapulmonary tuberculosis with noncaseating granulomas. As treatment progressed, all signs and symptoms–weight loss, increased serum calcium, severe anemia, neutropenia and the granulomas–resolved. In case 2, the patient had no prior history of sarcoidosis; however, as the treatment progressed, evidence revealed sarcoidosis with noncaseating granulomas. Both cases required the collaboration of other specialists who helped guide the patient back to the main path of therapy, combat hepatitis C and move the patient toward the end goal of being virus-free. When one is preparing to treat a patient with hepatitis C, it is imperative to be exact and thorough when taking the patient history and performing a physical examination to minimize the potential for an autoimmune disorder to present during treatment. Sarcoidosis is exacerbated by and is a contraindication for interferon treatment. Autoimmune diseases, such as lupus erythematosus, scleroderma, Sjögren’s syndrome and rheumatoid arthritis, are often preexisting. Taking this approach, combined with acquiring sufficient laboratory data, will minimize the possibility of encountering diseases of autoimmune origin that may manifest during the course of treatment. v Steven J. Bergstrom is a physician assistant and a Hepatology Fellow in Ventura, Calif. References
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