INFO: 1993 ls of Internal Medicine - Non-A, Non-B Post-Transfusion Hepatitis

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ARTICLE Non-A, Non-B Post-Transfusion Hepatitis Looking Back in the

Second Decade L. Koretz; Abbey; ; and Gitnick 15 July 1993 | Volume 119 Issue 2 | Pages 110-115 Objective: To determine the long-term course of non-A, non-B post-transfusion hepatitis. Design: Follow-up in 1989 to 1992 of patients prospectively identified as having contracted non-A, non-B post-transfusion hepatitis between 1972 and

1980. Setting: A university hospital. Patients: Patients who were prospectively followed from receipt of blood products and in whom otherwise unexplained abnormalities in their serum alanine aminotransferase levels developed without serologic evidence of exposure to hepatitis A or B. Measurements: The presence or absence of clinical evidence of liver failure or symptoms of chronic hepatitis. Results: Of 90 patients identified in the 1970s, 80 were recontacted and evaluated between 1989 and 1992. Based on the current status of these 80 patients and on the last known status of the remaining patients, the following observations were made: 1) Although about 40% had some symptoms during the early phase of the disease, none subsequently

experienced significant clinical problems related to hepatic inflammation; 2) eight patients (seven with chronic hepatitis) developed hepatic failure; and 3) life-Table analysisshowed that the probabilities of developing clinical evidence of cirrhosis after 16 years of disease in the entire cohort, in the subgroup who developed chronic hepatitis, in the patients who had hepatitis C, and in those with chronic hepatitis C were 18%, 21%, 17%, and 20%, respectively. Conclusions: For most of the study patients, non-A, non-B post-transfusion hepatitis was a biochemical and histologic disease that had not yet caused hepatic symptoms. If hepatic failure does occur, it is usually seen only after 10 or more years of disease. Before that time, many infected persons die due to other disease processes. Non-A, non-B post-transfusion hepatitis is a sequela commonly associated with the receipt of blood products. In most prospective series conducted before the introduction of surrogate and acquired immunodeficiency syndrome (AIDS) screening, otherwise unexplained abnormalities in serum alanine aminotransferase (ALT) levels developed in about 10% of transfused patients during the 6 months after transfusion [1,2,3]. Usually, no concomitant serologic evidence of exposure to hepatitis A or B virus could be identified, suggesting that one or more non-A, non-B agents were responsible

[4]. The abnormal ALT values persisted for more than 6 months in about 50% of patients [5,6]. The magnitude of this disease was not appreciated before these prospective studies because of the difficulty in recognizing these patients on the basis of symptoms. During the early phase of the illness, only a minority of patients experience severe fatigue, nausea, and vomiting, and even fewer manifest full-blown clinical symptoms including jaundice [1].

Those who have mild fatigue often blame it, perhaps correctly, on the disease for which they received the transfusion. Very few in whom prolonged abnormalities in serum aminotransferase levels develop complain of any symptoms, although some describe varying degrees of fatigue [7]. Rapidly progressive liver disease and acute symptomatic exacerbations are both uncommon in this form of chronic hepatitis, although the aminotransferase levels may remain abnormal or fluctuate for years. Several diagnostic tools, such as blood tests or biopsies, can detect signs of disease. These signs may exist in the absence of symptoms and may become the focus of attention or of therapy [8]. Disease is perceived by patients, however, if they have symptoms. Signs such as an abnormal ALT level or histologic evidence of inflammation do not themselves interfere with the quality of a person's life. As long as liver function is compensated, a person may remain unaware of the presence of cirrhosis. Thus, the important concern for the patient with non-A,non-B post-transfusion hepatitis is the development of liver failure (or liver cancer) secondary to cirrhosis. Between 1972 and 1980, we identified patients with non-A,non-B post-transfusion hepatitis. We recently evaluated this cohort, focusing on the presence or absence of clinical evidence of liver

failure. Methods TopMethodsResultsDiscussionAuthor & Article InfoReferencesBetween 1972 and 1980, two prospective studies of post-transfusion hepatitis were conducted at the University of California at Los Angeles (UCLA). These studies have been previously described [9]. All patients had normal ALT levels before transfusion and were prospectively identified as having developed non-A, non-B post-transfusion hepatitis when they met the following criteria: 1) the development of at least two consecutive abnormal ALT levels, at least one being twice the upper limit of normal or greater (five times the upper limit of normal or greater in the first

study), occurring within 6 months of transfusion; 2) the absence of serologic evidence for recent hepatitis A (negative IgM-specific antibody to hepatitis A) or hepatitis B (negative hepatitis B surface antigen (HBsAg) and negative IgM-specific antibody to hepatitis B core antigen (anti-HBc)); and 3) the absence of any explanation for the abnormalities in the ALT levels other than the presence of presumed viral infection. Patients who developed post-transfusion hepatitis were asked to continue in the prospective evaluation. Those whose ALT values became normal within 6 months of disease onset were considered to have had acute hepatitis and no additional follow-up was sought at that time. Those whose ALT values remained abnormal for longer than 6 months were considered to have developed chronic

hepatitis and were asked to continue in an open-ended follow-up. Over the years, many study patients in whom chronic hepatitis developed were lost to follow-up for various reasons (death, move from the area, loss of interest, or lack of desire for continued blood tests). In the fall of 1988, a formal attempt was begun to locate all study patients in whom non-A, non-B post-transfusion hepatitis developed and to evaluate each for the presence or absence of symptoms or signs of hepatitis and evidence of clinical hepatic failure. Symptomatic hepatitis was defined as the presence of one or more of the following: jaundice, loss of appetite, weight loss, or fatigue. (For fatigue to be considered to be significant, it had to interfere with the patient's daily lifestyle.) No symptom could

be reasonably attributed to a coexistent disease process. Clinical hepatic failure was considered to exist if one or more of the following was found or had occurred: 1) Gastrointestinal bleeding of variceal origin; 2) ascites (not due to noncirrhotic causes); 3) hepatic encephalopathy; 4) hepatic coagulopathy (abnormal prothrombin time not correctable by the parenteral administration of vitamin K); 5) hypersplenism (leukopenia or thrombocytopenia not due to noncirrhotic causes; or 6) hypoalbuminemia (a serum albumin level less than the normal range not due to noncirrhotic causes). A telephone interview was conducted to assess current and past health status of all surviving patients who could be located. Questions were designed to identify problems related to hepatic failure.

Where pertinent, requests were made to obtain outside medical records. Patients were also asked to submit to a formal history and physical examination and to have blood obtained for the following tests: complete blood count, serum chemistry panel, prothrombin time, and partial thromboplastin time (PT). If the patient agreed to come to UCLA, the examination was conducted by one of the investigators. In a few circumstances, the investigator went to the patient's home. If the patient did not agree to these arrangements, medical records or examinations were sought from his or her personal physician. To be considered evaluable between 1989 and 1992, patients had to have completed at least the telephone interview and the laboratory tests. If a patient was dead, a telephone interview was conducted with a family

member (or some other knowledgeable contact) to ascertain the state of the patient's previous health and the cause of death. In addition, requests were made to obtain pertinent medical records (for example, death certificates or records of terminal hospitalization). Because of the variability in the duration of follow-up, the probability of clinical hepatic failure developing was calculated using life-Table analysisRF 10 *. The end point was the appearance of clinical hepatic failure. The time at risk began with the onset of post-transfusion hepatitis and extended until the end point was achieved, until the last medical evaluation, or until death without evidence of clinical hepatic failure. Other statistical comparisons were made by the chi-square test with the Yates correction or by the Student t-test

[11]. Between 1972 and 1980, 95 patients with non-A, non-B post-transfusion hepatitis were identified, including the 69 patients previously described [7]. In addition, 20 patients originally classified as having had hepatitis B have since been reclassified. Eighteen had evidence of anti-HBc in the early post-transfusion serum. None of these 18 patients tested positive for IgM-anti-HBc, and the anti-HBc disappeared shortly afterward in all cases. It was presumed that this finding represented passive transfusion of anti-HBc, and the patients were reclassified as having

had non-A, non-B disease. Two patients had had post-transfusion increases in the titer of antibody to HBsAg (anti-HBs); the increases in both cases were low-grade and may have represented passive administration of anti-HBs. In retrospect, these patients were also not thought to have had hepatitis B viral infection, and they were also reclassified as having had non-A, non-B-induced disease. Finally, six patients were identified from the last part of the second prospective study; these patients have not been previously described. Of these 95 patients, 5 were excluded from this analysis. In one case, the abnormal ALT level did not reach the biochemical criterion of twice the upper limit of normal until after 6 months of disease. The other four patients had concomitant liver diseases (sclerosing

cholangitis (one patient), biopsy-proven cirrhosis before transfusion (one patient), and other potential causes of chronic hepatitis (two patients)), which made it difficult to determine the natural history of the transfusion-associated disease. We therefore evaluated the remaining 90 patients. Serologic tests for antibodies against hepatitis C (anti-HCV) have become available [12]. The stored sera of these patients were tested by a commercial assay that detects antibody to the C-100 HCV antigen (Ortho HCV Enzyme-Linked Immunosorbent Assay (ELISA) Test System, Ortho Diagnostic Systems, Raritan, New Jersey), and those patients who failed to show seroconversion by this assay were tested by a

second-generation test (Ortho HCV 2.0 ELISA Test System) [13]. Patients who were anti-HCV negative before transfusion (or, in some cases, before the onset of disease) and who developed anti-HCV in the first year after the hepatitis began were considered to have hepatitis C. (These seroconversions were not considered to be a consequence of passive transfusion of antibody, because the anti-HCV was shown to persist for more than 6 months or because the titer, as reflected by the optical density, increased over time.) In addition, patients who no longer had pretransfusion or predisease sera available were defined as having hepatitis C if anti-HCV was present for at least 6 months in their postdisease sera.

The study was conducted in accordance with guidelines established by the Human Subject Protection Committee at UCLA. All potential study participants received an oral explanation of the study as well as an informed consent document approved by that committee; all those who participated signed the consent form voluntarily. Results TopMethodsResultsDiscussionAuthor & Article InfoReferencesSuccessful follow-up was achieved in 80 (89%) of the 90 patients. In addition, three other patients were contacted by phone and found to have no historical evidence or current symptoms of hepatitis or liver failure. Because laboratory tests were not done in these patients, their status was only considered as of their last study evaluation. The remaining seven patients are still lost to

follow-up; four were not seen after participating in the study for less than a year, and the remaining three had follow-up information available for 16, 19, and 136 months, respectively. The characteristics of the 90 patients are shown in Table 1. Acute hepatitis occurred in 31 patients; 55 developed chronic disease. The remaining four patients had abnormal ALT levels when last seen, but they stopped participation within the first 6 months of their illness, and it could not be determined if or when the abnormality resolved. When the patients were separated into groups according to the duration of their initial disease, no obvious differences were noted in demographic and clinical

characteristics. View this table:[in this window][in a new window] Table 1. Characteristics of Study

Patients Based on anti-HCV testing, 64 patients could be classified as having hepatitis C; 59 of these patients had documented seroconversions. Thirteen other patients for whom comparable (in time) sera specimens were available remained negative for anti-HCV when tested by the ELISA assay. Of the remaining 13 patients, 8 had inadequate amounts of sera available to determine whether anti-HCV seroconversion had occurred, 4 had ongoing transfusion requirements that confused the serologic results, and 1 had anti-HCV in her pretransfusion serum specimen. Only about 40% of these 90 patients had symptoms in the early phase of illness; approximately 15% had jaundice. None of those in whom chronic

hepatitis developed continued to have significant symptoms. Hepatitis was not responsible for any debility after the first 2 months. To date, evidence of clinical hepatic disease developed in eight patients. The features of these eight patients (patients A through H) are summarized in Table 2. Only one (patient H) has been known to have liver failure in the absence of chronic hepatitis, and his disease may have been due to alcohol abuse, not to a viral infection. View this table:[in this window][in a new window] Table 2. Features of Patients in whom Clinical Hepatic Failure Developed Two other patients known to have cirrhosis based on earlier liver biopsies did not develop evidence of clinical hepatic

failure. They, like patients A and B, were previously described [7]. One died of metastatic cancer; the other was completely well when seen at his home in 1989, more than 11 years after cirrhosis was histologically diagnosed. Other patients may also have pathologic evidence of cirrhosis; however, liver biopsies were not routinely obtained for most of the 90 patients. The probability of liver failure occurring over time is shown in Figure 1. It took at least 6 years for liver failure to become clinically apparent in any of the patients, and, in six of the eight, this

event was only observed in the second decade. After 16 years, the probability of demonstrable liver failure was 18%. View larger version (18K):[in this window][in a new window] Figure 1. Cumulative probability of clinical liver failure ((bullet)) or death from nonhepatic causes (X) over time since the onset of post-transfusion hepatitis In contrast, at least 33 of the original 90 patients died without evidence of liver failure. The probability of death from nonhepatic causes (14%) is also shown in Figure

1. Although this mortality rate may seem inordinately high, it should be remembered that most of these patients were middle-aged when they were transfused and that they all had underlying disease processes necessitating transfusion. Could any of these "nonhepatic deaths" actually have been due to liver disease? Medical records were available for 26 of these patients; 12 deaths were due to malignancies, 8 to atherosclerosis, and 1 each to congenital heart disease, chronic pulmonary disease, chronic renal failure, bowel obstruction, sepsis, and AIDS. No case showed any indication of hepatic decompensation. In two other instances, death certificates indicated deaths due to cancer and stroke, respectively. According to the families, four of the five patients for

whom no documentation was available died of atherosclerosis, cancer, or respiratory failure. In only one case was the cause of death unknown; the family was not aware of any liver problems in this patient. For the purposes of the analysis, these five patients were assumed to have died of nonhepatic causes. This assumption was made because the family histories had proved reliable in the other cases. Nine of the documented 28 deaths were known to us in the course of the original follow-ups; in the other 19, the information provided by the families was confirmed by records received subsequently. Post-transfusion hepatitis-related liver failure may only occur in the subset of patients who develop chronic hepatitis; only one patient with acute disease did so in this series, and he probably had cirrhosis

due to chronic alcohol abuse. The 16-year probability of liver failure developing in the 55 patients with chronic hepatitis was 21%. Six of the seven patients who manifested liver failure years after developing chronic hepatitis were known to have serologic evidence of HCV exposure (see Table 2. The 16-year probabilities of liver failure for the subgroups of the 64 patients who had documented hepatitis C exposure and the 50 who developed chronic hepatitis C were 17% and 20%, respectively. Discussion TopMethodsResultsDiscussionAuthor & Article InfoReferencesFor many years, the frequent occurrence of non-A, non-B

post-transfusion hepatitis and its progression to a chronic biochemical and histologic process have been recognized. Several groups, including our own, have expressed concern over the potential disasters that may be in the making. From the physician's perspective, this disease is a source of worry. A patient, on the other hand, might view the process differently. Except perhaps for the first few weeks or months of disease (when recovering from the illness that originally necessitated the transfusion), these patients appear to go about their daily lives unencumbered. In fact, the principal source of their symptoms may not be liver disease but rather the anxiety associated with seeing their physicians, the knowledge that their blood test results are abnormal, and the number of additional needles thrust

into their veins (or into their livers). A few of these patients do develop manifestations of liver failure at some time. For them, liver disease truly exists. Our experience, however, is that, at least for the first 16 years, this occurrence is less common. Most of our patients have continued to do well with regard to their livers, although they have not escaped the ravages of other processes. This is not to say that, in the next few years, these potential time bombs will not begin to explode more often. This phenomenon has been seen in young children with inherited coagulopathies and in patients with chronic renal disease. These persons are exposed to hepatitis viruses and, if they live long enough, develop cirrhosis [14,15]. Most patients with non-A, non-B post-transfusion hepatitis, however, are middle-aged before they are exposed to the virus; our patients were, on average, in their sixth decade of life when transfused. If more than 15 years are needed for cirrhosis to become a clinical problem, many of these patients will die as a result of other disease processes first. Hepatitis C virus is the predominant cause of post-transfusion hepatitis, and an ongoing infection by this agent is probably an important pathophysiologic step in the development of end-stage liver disease. Six of the eight patients (patients B through G) who developed clinical hepatic failure had serologic evidence of HCV infection, and a

seventh (patient A) had inadequate sera available to make this determination. Only patient H, whose disease may not have even been due to a viral infection, failed to exhibit anti-HCV. A potential problem in this study is that not every patient was seen for the full duration of the follow-up. This limitation has implications for those who died and for those who survived. At least 33 patients appeared to have died without liver failure after leaving the study. When outside medical records were available, the causes of death reported to us by family and friends were substantiated. These records, however, were not available in all cases. A liver-related cause of death may not have been known by a patient's family or recorded on his or her death certificate. One patient (with documented chronic hepatitis

C) in this series died without a specific cause being known to her family; if she actually died of a complication of cirrhosis, the 16-year likelihood of liver failure would have been 19% (all patients), 23% (chronic hepatitis patients only), 18% (all documented hepatitis C), and 22% (chronic hepatitis C), respectively. Forty-three patients were located and available for follow-up (including patients C, D, E, and F). Although 19 patients (including patients C and D) were examined by the investigators, the remaining 24 (including patients E and F) had their clinical evaluations done by outside physicians who may have been less familiar with some subtleties of early liver failure. The laboratory data obtained in these patients, however, showed no evidence of liver failure, and the earliest manifestation of the

hepatic disease in most of these patients was hypersplenism. It is unlikely that early liver failure was missed in these 22 patients. With one exception (patient H, in whom alcohol may have actually been a more important etiologic consideration), clinical hepatic failure was only observed in patients in whom the disease failed to resolve biochemically within 6 months. A wide variety of preceding abnormal enzyme patterns were seen in these seven patients. Clinical hepatic failure has occurred in a patient with chronic low-grade elevations (patient , in two with widely fluctuating abnormalities that did (patient E) or did not (patient A) become normal intermittently, in one in whom the intermittently abnormal values were only low grade (patient F), and in one who appeared to have a prolonged resolution of his

biochemical disease after a year (patient D). Interferon has been proposed enthusiastically as a treatment for chronic non-A, non-B hepatitis [16,17]. Six-month courses of this drug have been shown to decrease, and even normalize, increased ALT values as well as associated histologic inflammation, although these abnormalities frequently recur when the interferon is stopped. The major question that these trials do not answer is whether interferon will prevent the progression of the disease to clinically important liver failure [8]. Because patients with chronic

non-A, non-B post-transfusion hepatitis are relatively asymptomatic, such treatment will not make them feel much better in the short term. A long-term study, using clinical hepatic failure as the end point, is required to establish clinically meaningful efficacy. In conclusion, non-A, non-B post-transfusion hepatitis is a biochemical and histologic, but not symptomatic, disease for most patients. As the years and decades pass, some patients will develop clinical hepatic failure. Among those who survive for 15 years from the onset of hepatitis, the probability of such liver failure within that period appears to be about 20%. Acknowledgments: The authors thank Sally Memmott and Sylvia Anguiano for assistance in revising the manuscript and Deborah Lott for editorial assistance.

Author and Article Information TopMethodsResultsDiscussionAuthor & Article InfoReferencesFrom the Center for Health Sciences, University of California, Los Angeles, California.Requests for Reprints: L. Koretz, MD, Department of Medicine, Olive View Medical Center, 14445 Olive View Drive, Sylmar, CA 91342. References TopMethodsResultsDiscussionAuthor & Article InfoReferences 1. Aach RD, Kahn RA. Post-transfusion hepatitis: current perspectives. Ann Intern Med. 1980;92:539-46.[Medline] 2. Seeff LB, Zimmerman HJ, EC, Finkelstein JD, -Point P, Greenlee HB, et al. A randomized, double blind controlled trial of the efficacy of immune serum globulin for the prevention of post-transfusion hepatitis. A Veterans Administration cooperative study. Gastroenterology. 1977;72:111-21.[Medline] 3. Feinman SV, Berris B, Bojarski S. Posttransfusion hepatitis in Toronto, Canada. Gastroenterology. 1988;95:464-9.[Medline] 4. Knodell RG, Conrad ME, Dienstag JL, Bell CJ. Etiological spectrum of post-transfusion hepatitis. Gastroenterology. 1975;69:1278-85.[Medline] 5. Koretz RL, Suffin SC, Gitnick GL. Post-transfusion chronic liver disease. Gastroenterology. 1976;71:797-803.[Medline] 6. Berman M, Alter HJ, Ishak KG, Purcell RH, EA. The chronic sequelae of non-A, non-B hepatitis. Ann Intern Med. 1979;91:1-6.[Medline] 7. Koretz RL, Stone O, Mousa M, Gitnick GL. Non-A, non-B posttransfusion hepatitis--a decade later. Gastroenterology. 1985;88: 1251-4.[Medline] 8. Koretz RL. Interferon and chronic non-A, non-B hepatitis: whom are we treating? Hepatology. 1990;12:613-5. 9. Koretz RL, Stone O, Gitnick GL. The long-term course of non-A, non-B post-transfusion hepatitis. Gastroenterology. 1980;79:893-8.[Medline] 10. Greenstein AJ, Sachar DB, Pasternack BS, Janowitz HD. Reoperation and recurrence in Crohn's colitis and ileocolitis. Crude and cumulative rates. N Engl J Med. 1975;293:685-90.[Abstract] 11. Hill AB. A Short Textbook of Medical Statistics. Tenth edition. London: Hodder and Stoughton; 1977. 12. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989;244:359-62.[Medline] 13. Van der Poel CL, Cuypers HTM, Reesink HW, Weiner AJ, Quan S, DiNello R, et al. Confirmation of hepatitis C virus infection by new four-antigen recombinant immunoblot assay. Lancet. 1991;337: 317-9.[Medline] 14. Editorial. Chronic liver disease and haemophilia. Lancet. 1988;2: 1465-6. 15. Parfrey PS, Farge D, Forbes RD, Dandavino R, Kenick S, Guttman RD. Chronic hepatitis in end-stage renal disease: comparison of HBsAg-negative and HBsAg-positive patients. Kidney Int. 1985;28: 959-67.[Medline] 16. GL, Balart LA, Schiff ER, K, Bodenheimer HC Jr, Perrillo RP, et al. Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. N Engl J Med. 1989;321:1501-6.[Abstract] 17. Di Bisceglie AM, P, Kassianides C, Lisker-Melman M, Murray L, Waggoner J, et al. Recombinant interferon alfa therapy for chronic hepatitis C. A randomized, double-blind,

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