CASE REPORT: Acute Hepatitis Induced by Bupropion

As an antidepressant, bupropion is considered to be a safe agent that usually causes infrequent and mild increase of serum liver enzymes. Asymptomatic elevation of serum transaminases was previously reported only in a single case. We describe a patient who developed typical acute hepatitis after receiving six weeks of bupropion for depression. His presentation was characterized with acute onset of symptoms associated with significantly elevated ALT, AST, and LDH and acute hepatic inflammation. The clinical course of our patient, including incubation period, pattern of liver enzyme elevation, and time of recovery, was similar to, but much more severe than, the case reported by Oslin and Duffy. Discontinuation of bupropion was followed by a rapid resolution of clinical symptoms and liver enzymes. The incidence of bupropion-induced hepatitis remains to be defined even though it appears to be relatively low. Since the clinical application of bupropion is broader, we must be aware of the clinical entity of bupropion-induced hepatitis.     

Icteric acute hepatitis E with no response of immunoglobulin M class anti‐hepatitis E virus antibody

A 68‐year‐old Japanese man developed icteric acute hepatitis during periodic care after undergoing gastrectomy due to early gastric cancer. The routine serological markers for hepatitis A, B and C viruses were all negative. Although the liver enzymes spontaneously recovered without any specific therapy, cholestasis was relatively prolonged and successfully treated with prednisolone. Determination of serum hepatitis E virus (HEV) RNA revealed the transient infection of HEV, and both immunoglobulin (Ig)A and IgG class anti‐HEV antibodies were detected after the disease onset, whereas those were negative when measured 3 weeks prior to the onset. In addition, the titer of serum IgA class antibody was associated with the clinical signs of hepatitis. In contrast, no IgM class antibody was detected throughout the course. This case suggests that screening only with IgM class antibody is not sufficient to detect acute HEV infection.     

Effect of ursodeoxycholic acid (UDCA) therapy for compensatory liver cirrhosis on liver function tests and serum bile acid metabolism]

Effect of ursodeoxycholic acid (600 mg/day 12 weeks) on liver function tests and bile acid metabolism were investigated in 6 patients with compensatory liver cirrhosis (CLC) and 6 with chronic active hepatitis (CAH). Serial determination of serum GOT, GPT and gamma-GTP after the initiation of UDCA revealed significant reduction in mean levels of these enzymes after 4 weeks, and further improvement was observed at the end of the 12-weeks treatment regimen (CLC: 79.3%, 81.1%, 51.5% of initial values, respectively, CAH: 61.2%, 59.3%, 42.8%). On the other hand, after UDCA administration, serum total bile acid increased and UDCA became the predominant bile acid in CLC and CAH patients. Other endogenous bile acids decreased in both groups, but reduction rate of serum chenodeoxycholic acid level in CLC was smaller than that in CAH group (CLC: 86.1% of initial values, respectively, CAH: 54.2%). During UDCA treatment, apparent side effect was not observed. We suggest that UDCA administration might constitute effective treatment for compensatory liver cirrhosis as well as chronic hepatitis.     

Acute hepatitis after riluzole administration

Riluzole is a new drug representing the first active treatment for amyotrophic lateral sclerosis. We report the cases of two patients who developed acute hepatitis after taking riluzole at the recommended dose (100 mg daily) for 7 and 4 weeks, respectively. In both cases, liver histology showed hepatocellular damage with inflammatory infiltration and microvesicular steatosis without fibrosis. Liver enzymes returned to normal 4 and 8 weeks, respectively, after riluzole withdrawal. In one case, the readministration of riluzole was followed by the relapse of hepatitis. These two observations strongly suggest that riluzole can induce acute hepatitis with associated hepatocellular damage and microvesicular steatosis. They also suggest that liver enzymes should be monitored during treatment with riluzole.     

Acute hepatitis A: combination of the relapsing and the cholestatic forms, two rare variants

Here we present an unusual case of a 23-year-old, otherwise healthy man who had a biphasic form of viral hepatitis A with a combination of two variants, the relapsing and cholestatic forms. One month after resolution of the first phase of acute hepatitis A, he was readmitted with jaundice and intense pruritus. During hospitalization, his serum bilirubin level increased to 50.2 mg/dL, with a slight increase in the other levels of liver enzymes. He was treated with ursodeoxycholic acid and later with corticosteroid therapy, resulting in resolution of symptoms and improvement of his liver function tests after 2 weeks. Medication therapy seems to be justified in markedly symptomatic patients with relapsing hepatitis.     

Addison's disease as a rare cause of chronically elevated liver enzymes

Common causes of chronically elevated serum liver enzymes include fatty liver disease, chronic viral hepatitis, autoimmune hepatitis, or hereditary metabolic disorders. Adrenocortical insufficiency can also cause elevated liver enzymes. Since 1990 only 11 cases have been reported. We here report a 52-year-old man with elevated liver enzymes (1.5 x upper limit of normal) over the past 10 years. Furthermore, hyponatremia and hyperkalemia were noted. He complained of fatigue and low blood pressure over the past few years. At physical examination a dark complexion was noted. After ruling out chronic viral hepatitis, autoimmune disease, metabolic or hereditary disorders, rare causes of elevated liver enzymes were considered. The endocrinological work-up revealed Addison's disease as cause of serum electrolyte disturbance and elevated liver enzymes. The patient was successfully treated with hydrocortisol and fludrocortisol. After one week, liver enzymes, serum electrolytes and arterial blood pressure had normalized. In conclusion, for patients with constantly elevated liver enzymes also rare, extrahepatic diseases have to be considered. Addison's disease is a rare but fully reversible cause for elevated liver enzymes.     

New perspectives in occult hepatitis C virus infection

Occult hepatitis C virus (HCV) infection, defined as the presence of HCV RNA in liver and in peripheral blood mononuclear cells (PBMCs) in the absence of detectable viral RNA in serum by standard assays, can be found in anti-HCV positive patients with normal serum levels of liver enzymes and in anti-HCV negative patients with persistently elevated liver enzymes of unknown etiology. Occult HCV infection is distributed worldwide and all HCV genotypes seem to be involved in this infection. Occult hepatitis C has been found not only in anti-HCV positive subjects with normal values of liver enzymes or in chronic hepatitis of unknown origin but also in several groups at risk for HCV infection such as hemodialysis patients or family members of patients with occult HCV. This occult infection has been reported also in healthy populations without evidence of liver disease. Occult HCV infection seems to be less aggressive than chronic hepatitis C although patients affected by occult HCV may develop liver cirrhosis and even hepatocellular carcinoma. Thus, anti-HCV negative patients with occult HCV may benefit from antiviral therapy with pegylated-interferon plus ribavirin. The persistence of very low levels of HCV RNA in serum and in PBMCs, along with the maintenance of specific T-cell responses against HCV-antigens observed during a long-term follow-up of patients with occult hepatitis C, indicate that occult HCV is a persistent infection that is not spontaneously eradicated. This is an updated report on diagnosis, epidemiology and clinical implications of occult HCV with special emphasis on anti-HCV negative cases.     

Changes of hepatitis B virus DNA in liver and serum caused by recombinant leukocyte interferon treatment: analysis of intrahepatic replicative hepatitis B virus DNA

Twenty patients with HBeAg-positive chronic liver disease were given large doses of recombinant leukocyte interferon for 4 weeks. Changes of hepatitis B virus DNA in livers and sera were analyzed by the molecular hybridization technique in paired biopsies obtained before and 2 weeks after treatment. Serum hepatitis B virus DNA was examined before, during and after the treatment until 4 weeks post-interferon. Analysis of hepatic hepatitis B virus DNA revealed species that appeared to represent various forms of replicative hepatitis B virus DNA, i.e., relaxed circular, linear, supercoiled and single-stranded hepatitis B virus DNA, respectively. No evidence of integration of hepatitis B virus DNA in genomic DNA was obtained. Of 15 cases which were positive for hepatic hepatitis B virus DNA before treatment and in which paired biopsies were obtained, hepatic hepatitis B virus DNA became negative in 4, decreased in 5 and unchanged in 6. Among several types of replicative viral DNA in liver tissue, supercoiled hepatitis B virus DNA tended to remain after other forms were reduced. A close correlation between hepatic and serum hepatitis B virus DNA was found in 37 liver biopsy samples and corresponding sera. These results indicate that interferon treatment reduces serum hepatitis B virus levels by inhibiting viral replication in the liver and that persistence or reappearance of hepatitis B virus in serum after interferon is associated with replication.     

Hepatitis E infection with a benign course during vedolizumab treatment for Crohn's disease: A case report

We present a 49 year old female patient with Crohn's disease (CD) in remission on vedolizumab therapy who experienced a symptomatic, though benign, course of acute hepatitis E. Routine blood tests showed substantial elevation of liver enzymes and polymerase chain reaction (PCR) testing confirmed hepatitis E virus (HEV) infection. Vedolizumab therapy was paused, liver enzymes improved three weeks after infection and normalized after six months. The patient recovered completely from mild symptoms. This case shows that hepatitis E is a potential cause of acute hepatitis during vedolizumab therapy, and in this case the infection has run a benign course.     

Chronic graft-versus-host disease complicated by acute hepatitis B

We observed a 45-year-old man with acute hepatitis B while receiving treatment of chronic graft-versus-host disease (GVHD) of the liver. When he developed a sudden elevation of serum aminotransferases 17 months after bone marrow transplantation, he was under immunosuppressive therapy consisting of cyclosporin A against chronic GVHD of the liver. Serologic tests for hepatitis B virus (HBV) showed no reactivation but de novo acute infection. The serum levels of aminotransferases after elevation of biliary tract enzymes increased mildly. However, icterus was not observed in his sequential course. A liver biopsy specimen revealed mild acute liver injury accompanied by slight degeneration of bile ducts. It is presumed that owing to immunosuppressive therapy, his liver dysfunction was relatively mild, and the hepatitis became quiescent without becoming serious. On the other hand, the serum of the patient remained hepatitis B surface antigen positive for more than 1 year after the onset of the hepatitis, which suggested chronicity of HBV infection.     

Determination of HBeAg by radioimmunoassay: prognostic implications in hepatitis B.

A radioimmunoassay was used to determine the presence of the hepatitis B e antigen (HBeAg) and anti-HBe in the serum of 12 hepatitis B patients, who were follofed from an early phase of the illness into convalescence. The duration of detectable HBeAg in serum from these patients, in all ow whom the disease ran a normal course, was compared with the persistence of HBeAg in serum of nine patients with a protracted course and persistence of HBsAg in serum for more than 1 year. None of the hepatitis B patients with a normal course of the disease had HBeAg demonstrable for more than 9 weeks after the onset of illness (mean 5.4 weeks), whereas all patients developing chronic hepatitis had HBeAg in serum for more than 1 year after the onset of illness. These findings indicate that the detection of HBeAg in serum by radioimmunoassay for 10 weeks or more after the onset of illness implies a great risk of progression of the hepatitis B infection to chronic liver disease.     

Adrenal rest tumor of the liver causing Cushing's syndrome: treatment with ketoconazole preceding an apparent surgical cure

Ketoconazole, an imidazole derivative known to inhibit cytochrome P450-dependent adrenal enzymes was given to a patient with a functioning adrenal rest tumor of the liver in preparation for surgery. The drug was administered in a stepwise manner for 42 days starting with 400 mg and reaching 1 g the last 4 weeks of the trial. Clear clinical improvement was evident early in the trial and was associated with evidence of amelioration of her hypercortisolism and striking changes in serum and urinary levels of steroid hormones and metabolites. Sex steroids in serum and urine fell dramatically from the first day to the end of the trial. Urinary 17-ketosteroid excretion fell from a basal average of 139 mg/24 h to near normal levels within a week of therapy; serum testosterone fell from a basal level of 2.4 to 0.18 ng/ml; serum 17 beta-estradiol fell likewise from 1096 to 150 pg/ml. In contrast, cortisol levels in serum and urine increased in the first 2 weeks of the trial and subsequently fell to values below the basal levels. Similarly, serum 17 alpha-OH-progesterone levels increased 63% above the basal levels by day 6 of the trial and declined afterwards. Nine months after successful tumor resection the patient is apparently cured as judged by steroid hormone levels and physical appearance. We conclude that ketoconazole was effective in blocking tumoral steroidogenesis which resulted in clinical benefit.     

Studies of GB hepatitis agent in tamarins

Three tamarins (Saguinus labiatus), two of which had previously been infected with hepatitis A virus and parenteral non-A, non-B hepatitis, were inoculated intravenously with the agent of GB hepatitis. All three animals developed alanine aminotransferase abnormalities 2 weeks after inoculation. Peak alanine aminotransferase levels were recorded 4 weeks postinoculation. These declined thereafter but continued to fluctuate at abnormal levels for 32 weeks. Liver biopsies showed liver cell swelling and inflammation with focal necrosis. Portal tracts and areas around central veins were heavily infiltrated with mononuclear cells. A fourth animal (no previous exposure to hepatitis viruses) inoculated with GB was killed on Day 15 postinoculation. Serum and extracts of liver and feces from this day were used as inocula for three other animals. Only the serum and liver extract transmitted GB hepatitis. The fecal specimen did not transmit and a fecal extract taken at a later date from another animal was also noninfectious. GB hepatitis virus is distinct from the viruses causing Type A and blood-borne non-A, non-B-hepatitis. Although the virus is present in serum and has previously been transmitted per os, it is not shed in feces.     

The concentration of sFasL, ICE and IL-1beta in the serum and the liver tissue of chronic HCV infected patients

BACKGROUND/AIMS: In HCV infected patients HCV, apoptosis is as important as cytotoxicity. The aim of the present study was to estimate the activity of apoptosis in patients infected with hepatitis C before and during antiviral treatment. METHODOLOGY: 23 patients with hepatitis C were treated with Rebetron for 12 months. The concentration of IL-1beta, ICE and sFasL in the serum and liver tissue was analyzed before treatment was begun. The concentrations of IL-1beta, ICE and sFasL after 2 and 12 weeks of treatment were also analyzed. The concentrations of IL-1beta, ICE and sFasL in the liver tissue of patients with hepatitis C were compared with the concentrations in liver tissue of patients with alcohol related liver damage, but not HBV or HCV infected. RESULTS: Only 35% of the patients eliminated HCV-RNA from the blood six months after treatment had ended. The concentration of ICE and IL-1beta in the liver tissue of patients with hepatitis C was compared to concentrations in the liver tissue of patients with alcohol related liver damage. The concentration of sFasL in the liver tissue was twice as high among patients with alcohol related liver damage in comparison to the patients with infected hepatitis C. In the control group sFasL and ICE were not confirmed in the serum. After antiviral therapy the number of patients with sFas ligand in the blood increased (before beginning treatment 1 patient, after 12 weeks 8 patients). The high concentrations of ICE and IL-1beta in the serum showed a tendency to decrease during 12 weeks of therapy in the successfully treated patients. CONCLUSIONS: The HCV seems to be a mild stimulator of apoptosis. There was only a slight correlation between the morphology changes in the liver tissue and apoptosis in patients with HCV. There was no correlation between the success of the therapy and the apoptosis activity.     

Maintenance therapy with ribavirin in patients with chronic hepatitis C who fail to respond to combination therapy with interferon alfa and ribavirin

To assess the efficacy and safety of maintenance therapy with ribavirin alone in chronic hepatitis C, 108 patients were treated with the combination of interferon alfa and ribavirin for 24 weeks; those who failed to have a virologic response were offered enrollment in a randomized, double-blind, controlled trial of ribavirin (1,000-1,200 mg daily) versus placebo for the subsequent 48 weeks. Patients were monitored at regular intervals with symptom questionnaires, serum aminotransferase levels, hepatitis C virus (HCV) RNA levels, and complete blood counts and underwent liver biopsy at the completion of therapy. Among 108 patients, 50 were still HCV RNA positive after 24 weeks of treatment, of whom 34 agreed to be randomized to continue either ribavirin monotherapy or placebo. Among 17 patients who received placebo, there was no overall improvement in symptoms, serum alanine aminotransferase (ALT) levels, HCV RNA levels, or hepatic histology. Among the 17 patients who received ribavirin, serum ALT levels and necroinflammatory features of liver histology were improved, whereas symptoms, HCV RNA levels, and hepatic fibrosis scores were not changed significantly from baseline. Responses to ribavirin seemed to be categorical, such that 8 patients (47%) had definite improvement in liver histology. Patients with improved histology had improvements in serum ALT levels both on combination therapy and after switching to ribavirin monotherapy. In conclusion, continuation of ribavirin monotherapy may maintain serum biochemical improvements that occur during interferon-ribavirin combination therapy in some patients and that these improvements are often associated with decreases in necroinflammatory changes in the liver. Whether these improvements will ultimately result in prevention of progression of hepatitis C requires further study.     

Serial change in serum concentration of type III procollagen N-terminal peptide after TAE in hepatocellular carcinoma, and analysis of gel filtration pattern of the peptide

In the present study, we have measured the serum concentration of PIIIP in patients with various liver diseases, and studied serial changes in serum PIIIP after TAE and its gel filtration pattern in 10 cases of hepatocellular carcinoma undergone TAE. The following results were obtained. 1) Serum concentration of PIIIP was 12.3 +/- 6.1 ng/ml in normal controls and elevated significantly in liver cirrhosis, liver cirrhosis with hepatocellular carcinoma, chronic active hepatitis, and acute hepatitis. 2) There was no significant difference in the serum concentrations of PIIIP between liver cirrhosis and liver cirrhosis with hepatocellular carcinoma. The result suggested that serum PIIIP cannot be a specific marker of hepatocellular carcinoma. However, the serum PIIIP concentration was decreased 2 or 4 weeks after TAE in effective cases, whereas increased in ineffective cases. Thus, the measurement of serial change in the serum PIIIP after TAE was considered to be useful for evaluating the effectiveness of TAE. 3) In analysing the elution patterns of serum PIIIP by gel chromatography, the peak of 125I-PIIIP antigen decreased 4 weeks after TAE in effective cases, whereas, no change was observed in the elution profile by gel chromatography 4 weeks after TAE in ineffective cases. These results seem to be caused by necrosis of hepatocellular carcinoma by TAE, and suggest the possibility that PIIIP is produced in hepatocellular carcinoma tissue.     

Two-step progression of varenicline-induced autoimmune hepatitis

We describe a rare case of drug-induced hepatitis due to the smoking cessation agent varenicline in a 46-year-old Asian woman. The liver injury progressed in two steps. First, the liver injury started in the absence of viral/autoimmune responses, and withdrawal of varenicline lowered the increase in the levels of liver enzymes immediately. Such findings suggested varenicline-induced liver injury. Second, hepatitis recurred in association with conversion of antinuclear antibody from negative to positive about 8 weeks after the initial episode. Histology upon recurrence of liver injury revealed interface hepatitis with lymphocytic and lymphoplasmacytic portal inflammatory infiltrates extending into lobules. Such findings suggested autoimmune hepatitis. Corticosteroid treatment was effective for recurrent hepatitis. The clinical course suggests that varenicline caused drug-induced liver injury and subsequent autoimmune hepatitis. Some autoimmune changes were probably involved in the mechanism of varenicline-induced liver injury.     

Prevalence of hepatitis in early syphilis among an HIV cohort

To investigate the prevalence of syphilitic hepatitis among a group of HIV-infected patients we performed a cross-sectional observational study of consecutive HIV-infected patients with early syphilis attending University Hospital Birmingham between 1 January 2005 and 31 August 2008. The AIDS Clinical Trials Group grading for abnormal liver enzymes was used to identify hepatitis. A total of 62 HIV-infected patients were diagnosed with early syphilis during the study period. Twelve (19.3%) of them demonstrated abnormal liver enzymes consistent with syphilitic hepatitis involving raised levels of alanine aminotransferase, aspartate transaminase, alkaline phosphatase or gamma-glutamyl transferase (GGT). Grade 3 hepatotoxicity was observed among five patients. None of the patients with syphilitic hepatitis had grade IV hepatitis or abnormal bilirubin levels. Liver biopsy was not carried out in any of the patients, and following completion of treatment of syphilis all abnormal liver enzymes returned to normal levels after a median of 16 weeks. Exclusion of syphilis must be considered when investigating hepatic disease in HIV-infected patients.     

Anicteric liver damage during nitrofurantoin medication.

Four patients are described in whom anicteric hepatitis appeared to be related to the use of nitrofurantoin. All the patients had increased serum transaminase levels, hypergammaglobulinaemia, and liver biopsies suggestive of chronic active hepatitis. Three patients showed cirrhotic features in the biopsy and two had circulating albumin-IgG-complexes ('tailing-albumin'). The serum transaminases became normal within weeks after withdrawal of the drug whereas the hypergammaglobulinaemia and the liver biopsy findings persisted essentially unchanged during two to six months of observation. One patient was re-challenged with nitrofurantoin, which resulted in recurrence of elevated serum transaminases after nine weeks medication.     

Pancreatic involvement in chronic viral hepatitis

AIM:To elucidate the frequency and characteristics of pancreatic disorders in the course of chronic viral hepatitis. METHODS:We prospectively assessed the serum pancreatic enzyme levels and imaging findings in patients with chronic viral hepatitis and healthy control subjects. RESULTS: Serum amylase (t-Amy), salivary amylase (s-Amy), pancreatic amylase (p-Amy) and serum lipase levels were higher in hepatitis patients in comparison to control subjects. However, in asymptomatic viral carriers, only the serum t-Amy levels were higher than those of the controls. The levels of each enzyme rose with the progression of liver disease in patients with hepatitis B or C; whereas the levels of each enzyme within the same clinical stage of the disease did not differ between patients diagnosed with either hepatitis B or hepatitis C virus. Imaging findings demonstrated chronic pancreatitis in only 1 out of 202 patients (0.5%). CONCLUSION: Our data suggest that serum levels of pancreatic enzymes increase with the progression of liver disease in patients diagnosed with viral hepatitis. Pancreatic disease, asymptomatic in most cases, may represent an extrahepatic manifestation of chronic viral hepatitis.