Influence of polymorphic N-acetyltransferase phenotype on the inhibition and induction of acetaminophen bioactivation with long-term isoniazid.

OBJECTIVE: To determine in patients receiving isoniazid prophylaxis whether an increase in the CYP2E1 dependent formation clearance of acetaminophen (paracetamol) to N-acetyl-p-benzoquinone imine (NAPQI) occurs during a normal 24-hour isoniazid dose interval and whether the interaction is dependent on acetylation status. METHODS: Acetaminophen elimination kinetics were determined on four different occasions. Ten subjects were assigned to receive acetaminophen either simultaneously with the 8 am dose of isoniazid or 12 hours after the isoniazid dose. One week later, on the last day of isoniazid therapy, subjects received acetaminophen at the alternate time of day. The control phase acetaminophen administrations were repeated 1 and 2 weeks later, following the initial randomization. Isoniazid acetylation (NAT2) genotype was determined by analysis of genomic DNA obtained from peripheral blood leukocytes. RESULTS: The mean NAPQI formation clearance was inhibited 57% when acetaminophen and isoniazid were coadministered but was unchanged compared with time-matched control when acetaminophen was given 12 hours after the isoniazid dose. However, when data from subjects was segregated according to isoniazid (INH) acetylation phenotype, the mean ratio of NAPQI formation clearances (+INH/-INH) with 8 PM acetaminophen was significantly higher for fast acetylators compared with slow acetylators (1.36 versus 0.68; p = 0.006). CONCLUSIONS: Fast metabolizers of isoniazid appeared to clear the inducer or inhibitor from the active site of CYP2E1 more rapidly, which resulted in an increased formation of NAPQI 12 hours after the isoniazid dose. In contrast, formation of NAPQI for slow isoniazid metabolizers remained inhibited.

Hepatitis C and renal failure.

Chronic hepatitis C virus (HCV) infection is common among patients with chronic renal failure. This chronic viral infection can result in significant morbidity and mortality. Liver failure from chronic hepatitis C is one of the leading causes of death among long-term survivors of renal transplantation. HCV infection also can be a cause of glomerulonephritis and nephrotic syndrome. Recognition of these conditions is important to optimize the management of these patients.

Renal disease in hepatitis C-positive liver transplant recipients.

Glomerular abnormalities are frequent in patients undergoing liver transplantation; however, renal dysfunction following transplantation is mainly attributed to cyclosporine toxicity. Membranoproliferative glomerulonephritis (MPGN) is seen in patients infected with hepatitis C virus (HCV), the virus responsible for 30% of the end-stage liver disease leading to liver transplantation. To determine the incidence of renal abnormalities in liver transplant recipients and the association with HCV, we undertook a longitudinal study in HCV-positive (n=91) and HCV-negative (n=106) liver transplant recipients. Mean creatinine clearance before transplantation was 94 ml/min/1.73 m2 in HCV+ patients and 88 ml/min/1.73 m2 in HCV- patients. By 3 months after transplantation, the mean creatinine clearance decreased by approximately one third in both groups. A greater proportion of HCV+ patients excreted >2 g protein/day after transplantation (P=0.05) and had renal biopsies showing MPGN than did HCV- recipients (4/10 HCV+ patients vs. 0/7 HCV- patients; P=0.1). In the HCV+ group, proteinuria was not associated with recurrent HCV hepatitis, DQ matching, posttransplant diabetes, or hypertension. Treatment of HCV-related MPGN with interferon-alpha2b appeared to stabilize proteinuria and renal function but did not reverse renal dysfunction nor cause liver allograft rejection. After transplantation, HCV+ patients had similar renal function over 3 years after transplantation, compared with HCV- patients, but they had an increased risk of proteinuria and occurrence of MPGN that was only partially responsive to interferon.

Cholestasis and alcoholic liver disease.

Histologic cholestasis and clinical jaundice may be seen in all stages of alcoholic liver disease. In rare cases, isolated cholestasis without significant steatosis, hepatitis, or cirrhosis is identified in an alcoholic patient. The mechanisms of ethanol-induced cholestasis are not well studied but may involve compression of intrahepatic biliary radicals or interference with basolateral uptake and intracellular transport of bile acids. In the evaluation of the jaundiced alcoholic patient, clinical, biochemical, and radiologic data are usually sufficient to distinguish alcohol-induced liver disease from extrahepatic biliary obstruction. In cases where the diagnosis is not readily apparent, more invasive studies such as liver biopsy or ERCP may be necessary. The risk of these invasive studies is directly related to the degree of underlying hepatic dysfunction.

Hepatitis B and transplantation.

Hepatitis B infection can add significantly to the morbidity and mortality of transplantation. Patients with hepatitis B can have severe recurrent disease following liver transplantation. Reactivation of occult disease can occur during chemotherapy or immunosuppression. Hepatitis B also can be acquired at the time of transplantation. Intensive study of transplant patients with hepatitis B has led to a new understanding of the immunobiology of hepatitis B virus.

Quantitative studies of the hepatitis B viral pre-S proteins: lack of correlation with the HBeAg status.

Radioimmunoassays for the determination of the relative amounts of hepatitus B viral pre-S proteins present in serum samples have been developed which utilize antibodies against synthetic peptides corresponding to the amino termini of these proteins. The assays were shown to be sensitive and specific. These assays have been used to examine hepatitis B surface antigen positive human plasma samples for the presence and relative amounts of pre-S proteins. Contrary to previously published data, it was found that there is no correlation between the presence of the pre-S proteins and the HBeAg status of the plasma, but that the ability to detect the pre-S proteins is only a function of the hepatitis surface antigen titre of the plasma. It is concluded that the pre-S proteins would not serve as a useful marker for active viral replication.

Clinical trial: interferon alpha-2b continuous long-term therapy vs. repeated 24-week cycles for re-treating chronic hepatitis C.

BACKGROUND: Treatment options are limited for patients with hepatitis C virus who do not experience sustained viral eradication with pegylated interferon and ribavirin therapy. AIM: To compare, in an open-label, randomized study, long-term continuous interferon alpha-2b treatment with repeated 24-week courses in patients with chronic hepatitis C virus that relapsed after prior interferon monotherapy. METHODS: A total of 499 patients received 24 weeks of interferon alpha-2b, 3 MIU administered 3 TIW. Responders (normal alanine aminotransferase and negative hepatitis C virus -RNA, n = 244) were then randomized to continuous interferon therapy (1, 2 or 3 MIU TIW depending on response) or cyclical therapy (3 MIU TIW for 24 weeks per relapse). Mean Knodell inflammation (I + II + III) and necrosis (IV) scores at baseline vs. year 2 were compared. RESULTS: Patients receiving continuous low-dose therapy vs. cycled therapy had larger reductions in inflammation (-3.9 vs. -3.1) and fibrosis (-0.49 vs. -0.24). Among both groups, the mean change was -3.4 for inflammation and -0.36 for fibrosis. Overall, 73% (95% CI: 67-79) of patients experienced reduced inflammation and 28% (95% CI: 22-34) had reduced fibrosis. CONCLUSIONS: Our results suggest hepatitis C virus patients experiencing viral suppression during long-term maintenance therapy with interferon demonstrate histological improvement. Further prospective trials testing this hypothesis are in progress.

Liver transplantation. American Association for the Study of Liver Diseases.

Liver transplantation has revolutionized the care of patients with end-stage liver disease. Liver transplantation is indicated for acute or chronic liver failure from any cause. Because there are no randomized controlled trials of liver transplantation versus no therapy, the efficacy of this surgery is best assessed by carefully comparing postoperative survival with the known natural history of the disease in question. The best examples of this are in primary biliary cirrhosis and primary sclerosing cholangitis, for which well-validated disease-specific models of natural history are available. There are currently relatively few absolute contraindications to liver transplantation. These include severe cardiopulmonary disease, uncontrolled systemic infection, extrahepatic malignancy, severe psychiatric or neurological disorders, and absence of a viable splanchnic venous inflow system. One of the most frequently encountered contraindications to transplantation is ongoing destructive behavior caused by drug and alcohol addiction. The timing of the surgery can have a profound impact on the mortality and morbidity of patients undergoing liver transplantation. Because of the long waiting lists for donor organs, the need to project far in advance when transplantation might be required has proven to be one of the greatest challenges to those treating patients with end-stage liver disease. Three important questions must be addressed in a patient being considered for liver transplantation: (1) when should the patient be referred for possible transplantation? (2) when should the patient be listed for transplantation? and (3) when is the patient too sick to have a reasonable chance of surviving the perioperative period?

Recurrent hepatitis C after liver transplantation.

The pathogenesis of aggressive liver injury in patients with severe disease requiring retransplantation is not well understood, although genotype and type and degree of immunosuppression and rejection episodes may be important. Nevertheless, our understanding of recurrent hepatitis C after transplantation is rapidly evolving, and effective treatment with interferon and ribavirin may be available in the near future. In this sense, the situation is reminiscent of transplantation for hepatitis B 10 years ago. A number of retransplants were performed for severe recurrent disease before it was appreciated how futile this was. It was not until HBIG was shown to be effective in preventing severe recurrent disease that a major impact on this serious problem was achieved. Further advances in the care of patients undergoing transplantation for hepatitis C will result from enhanced understanding of hepatitis C, more cautious treatment of these patients with immunosuppression, and effective treatment for severe recurrent hepatitis C after liver transplantation. It will not come from retransplantation in these unfortunate individuals.

Viral hepatitis: prevention and prophylaxis.

Hepatitis A is spread by fecal-oral transmission and accounts for 25% of the cases of sporadic hepatitis in this country; fatal cases have been documented but are unusual, and chronic hepatitis A has not been documented. Hepatitis B is spread by varied routes of transmission, fecal-oral being the least important, and accounts for half the cases of sporadic hepatitis in this country; fatal cases are well documented and chronic hepatitis B is common. The only documented route of transmission of non-A, non-B hepatitis is parenteral; fatal and chronic cases have been documented, and a quarter of the cases of sporadic hepatitis are non-A, non-B. Diagnosis of the etiology of viral hepatitis cannot be determined on clinical grounds but must be made through serologic tests.

Therapy of hepatitis C: meta-analysis of interferon alfa-2b trials.

We performed an independent meta-analysis of all available randomized clinical trials of interferon alfa-2b in patients with chronic hepatitis C. Articles published between 1986 and 1996 had to include previously untreated patients who were randomly allocated to therapy with at least 2 million units (MU) of interferon alfa-2b three times weekly for 24 weeks. A total of 32 trials met the inclusion criteria. Of these, 20 compared interferon-treated patients to placebo recipients or untreated patients and were used in the primary meta-analysis that compared rates of end-of-treatment and 6-month post-treatment sustained biochemical (normal alanine aminotransferase [ALT] levels) responses, end-of-treatment and 6-month sustained virological responses (absence of hepatitis C virus [HCV] RNA), and end-of-treatment histological responses in patients with paired biopsies. An additional 12 trials compared different doses, duration, or strategies of treatment. In comparison with no treatment, interferon alfa-2b therapy was associated with significant improvement in all end points measured. End-of-treatment biochemical responses were seen in 47% of treated patients compared with 4% of controls (odds ratio, 25.1; P < .0001). The biochemical responses were sustained for at least 6 months in 23% of treated patients compared with 2% of controls (odds ratio, 17.8; P < .0001). End-of-treatment virologic responses were observed in 29% of treated patients compared with 5% of controls (odds ratio, 9.4; P < .001) and 6-month sustained virologic responses were documented in 8% of treated patients compared with 1% of controls (odds ratio, 8.6; P < .001). Histological responses were recorded in 73% of treated patients compared with 38% of controls (odds ratio, 4.8; P < .0001). Extended therapy for 12 to 24 months resulted in significant improvement in 6-month sustained responses: 27% versus 14% (odds ratio, 2.9; P < .001). Higher dose therapy also resulted in modest increases in end-of-treatment (61% vs. 52%; odds ratio, 1.8; P < .02) and 6-month sustained responses (28% vs. 19%; odds ratio, 2.2; P < .01).

Hepatitis C in clinical practice.

Hepatitis C virus infection is now one of the most important causes of chronic liver disease. Primary care physicians play an important role in the diagnosis and initial work-up of patients infected with this virus. Understanding which patients may be at risk is the first step. By understanding the correct use of hepatitis C virus diagnostic testing and the risk and benefits of antiviral therapy, providers will be better equipped to screen and counsel their patients.

Health assessment for chronic HCV infection: results of quality of life.

The perception that chronic hepatitis C is an asymptomatic disease contrasts with many studies that show a strong association between chronic hepatitis C, hepatocellular cancer, and fatal liver disease. In order to resolve these issues, it is logical to directly evaluate the quality of life in patients with chronic hepatitis C and to compare this to the normal population as well as cohorts of patients with other chronic diseases. The Sickness Impact Profile was used to evaluate the impact of disease and interferon therapy on health-related quality of life in patients with chronic hepatitis C. Using this tool, patients with chronic hepatitis C had a total Sickness Impact Profile score of 9.0, compared with a score of 3.6 among the general population (P < 0.05). Patients with chronic hepatitis C also had significantly worse scores in almost every category of the Sickness Impact Profile that could be compared. However, statistically significant differences were observed only at the 24-week evaluation for work and at the end-point evaluation for the sleep and rest and recreation and pastimes categories. A more sophisticated instrument, based on the Medical Outcomes Study 36-item short-form health survey, found that patients with chronic hepatitis C scored significantly lower (P < 0.01) than the general population on each of the subscales in this survey. In addition, they scored significantly lower than patients with hypertension in seven of the subscales and two additional generic scales. Patients with chronic hepatitis C were most comparable to those with type II diabetes. A larger, more comprehensive study is underway to further evaluate these relationships.

Hepatitis C virus in renal disease.

Hepatitis C virus (HCV) is the most frequent cause of liver disease in dialysis and renal transplant recipients. Approximately 20% to 30% of the dialysis population is infected with HCV. HCV is also recognized as a cause of membranoproliferative and membranous glomerulonephritis. Enzyme immunoassay or recombinant immunoblot assay identify antibodies to multiple HCV antigens and are useful in the diagnosis of HCV infection, including infections in dialysis patients. However, after transplantation, HCV RNA identification by polymerase chain reaction is often required to detect the infection. The natural history of HCV infection using the new viral markers remains to be defined in patients treated for end-stage renal disease.

Diagnostic testing for hepatitis C.

Diagnostic tests for hepatitis C virus have improved dramatically over the past decade. Highly accurate tests are now available for screening patients for possible hepatitis C infections and confirming the presence of active viral infection. HCV RNA levels and genotype are very useful in assessing the likelihood of response to antiviral therapy and in guiding the optimum duration of treatment. Absence of detectable HCV RNA using PCR methodology has become the gold standard of successful treatment of patients with chronic hepatitis C. The various tests for hepatitis C are expensive and have their limitations. However, selective use of these assays has greatly improved the care of patients with chronic hepatitis C.

Thyroid function tests in patients with acute and resolved hepatitis B virus infection.

Serum thyroid hormones and thyroid hormone binding were sequentially measured in 20 patients with acute hepatitis B infection. Criteria to select patients consisted of a positive test for hepatitis B surface antigen, aspartate aminotransferase (AsAT) concentration greater than 400 U/L during the acute illness, and available serum specimens after recovery. The mean serum thyroxine (T4) concentration (+/- SE) was 12.5 +/- 0.6 microgram/dL during acute infection and 7.4 +/- 0.3 microgram/dL after recovery (p less than 0.001), whereas mean free T4 index values did not significantly differ. The mean serum thyroxine-binding globulin (TBG) concentration was significantly increased (p less than 0.001) during acute illness and accounted for the reversible of serum and the increased serum T4 concentrations. The rise in serum TBG correlated with the rise in AsAT during the acute illness (p less than 0.04) suggesting nonspecific release of these proteins from injured hepatocytes. The mean free triiodothyronine (T3) index was decreased during acute hepatitis (p less than 0.001) and returned to normal after recovery, indicating that acute hepatitis B infection, like other nonthyroidal illnesses, is associated with decreased T4 to T3 conversion in peripheral tissues.

Assessment of hepatitis C virus quasispecies heterogeneity by gel shift analysis: correlation with response to interferon therapy.

Hepatitis C virus (HCV) quasispecies heterogeneity was assessed in pretreatment sera of 22 patients treated with interferon (IFN). Quasispecies heterogeneity was quantitated by analysis of 490 hypervariable region 1 (HVR1) clones using gel shift analysis (GSA), which allowed determination of two components of HCV quasispecies heterogeneity: genetic complexity (number of variants) and genetic diversity (mean genetic distance between variants). HCV genotype and pretreatment RNA titer were similar between responders (n = 12) and nonresponders (n = 10). GSA correlated well with nucleotide sequencing for estimating HCV genetic diversity (R = .952; P < .001). A positive correlation of .666 (P < .001) was observed between genetic diversity and complexity, suggesting that these components of quasispecies heterogeneity were related. However, while there were no significant differences in pretreatment complexity or genetic diversity among response groups, higher pretreatment genetic diversity was predictive of response failure (P = .041). Assessment of HVR1 heterogeneity by GSA revealed important relationships between quasispecies genetic diversity, complexity, and response to IFN therapy and suggested a need for analysis of other HCV genes.