Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B

BACKGROUND: Nucleoside analogues such as lamivudine for chronic hepatitis B have an excellent safety profile while patients are on therapy but reactivation flares occur in 19-50% of patients after stopping therapy, some of whom develop liver decompensation. AIMS: To describe and report three cases who developed fatal hepatitis B reactivation after stopping nucleoside analogue therapy. SUBJECTS AND RESULTS: Three patients are described who developed hepatitis B reactivation and liver decompensation after stopping therapy. One of the three patients was participating in a famciclovir trial and the other two were receiving lamivudine therapy for active hepatitis B infection. All three patients had documented hepatitis B flares, and all had hepatitis B virus DNA detected at that time. All patients developed decompensated liver disease despite one patient having had a prior liver biopsy showing absence of cirrhosis. Reintroduction of lamivudine therapy failed to halt progression of liver decompensation even after hepatitis B virus DNA had been demonstrated to be absent. Sequencing for lamivudine resistant mutants in two cases where serum was available failed to show evidence of mutations associated with lamivudine resistance. CONCLUSION: Hepatitis B virus reactivation, leading to decompensation and death, are possible complications of treatment withdrawal and patients should be monitored closely if therapy is ceased.     

Acute liver failure and the Molecular Adsorbents Recirculating System: early experience in a tertiary care hospital in Mexico City

Acute liver failure is a clinical condition associated with high mortality despite recent technological advances. Supportive devices such as the Molecular Adsorbents Recirculating System (MARS) provide therapeutic strategies to add time to find an organ for orthotopic liver transplantation or to allow the native liver to recover sufficiently to make transplantation unnecessary. In this series of cases, we discuss our initial experiences with three patients with acute liver failure. One patient had high bilirubin levels caused by Epstein-Barr virus infection and responded well after three MARS sessions. In a second patient, MARS therapy was used to treat acute-on-chronic liver failure caused by chronic hepatitis B virus infection that had not been treated previously; because of severe hemodynamic compromise, only one MARS session was performed. The third patient had an initial diagnosis of acute liver failure and cryptogenic hepatitis, and was treated with five MARS sessions as a supportive measure until the definitive diagnosis (metastatic disease) was performed. In all patients, MARS therapy was well tolerated and induced only mild hypokalemia. In conclusion, although MARS therapy was an effective strategy for these cases of liver failure and greatly improved the biochemical variables, its impact on the mortality rate has not yet been determined.     

Left-sided heart failure presenting as hepatitis

Overt liver disease caused by left-sided heart failure is seldom recognized unless there is obvious hypotension. We now report 4 patients whose initial diagnosis was hepatitis but who were later shown to have central hepatic necrosis associated with left ventricular failure. Signs of right-sided heart failure were absent. Hepatitis was initially suspected in 3 patients because of striking transaminase elevations and in 1 patient because of jaundice and symptoms compatible with hepatitis. Liver biopsies performed on all patients revealed central hepatic necrosis without evidence of acute or chronic hepatitis. Left ventricular failure was documented in all 4 patients. One patient had coronary artery disease, and the other three patients had valvular heart disease. Liver function tests became normal or improved in all cases as the underlying heart disease was treated. We believe that liver dysfunction secondary to left ventricular failure is not uncommon and can be seen in the absence of right-sided heart failure or hypotension.     

Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis

BACKGROUND: There is little information about the effect of infliximab on the clinical course of liver disease in Crohn's disease patients with concomitant hepatitis B virus (HBV) infection. Theoretically, immunosuppression induced by infliximab will facilitate viral replication which could be followed by a flare or exacerbation of disease when therapy is discontinued. There are no specific recommendations on surveillance and treatment of HBV before infliximab infusion. Two cases of severe hepatic failure related to infliximab infusions have been described in patients with rheumatic diseases. PATIENTS AND METHODS: Hepatitis markers (C and B) and liver function tests were prospectively determined to 80 Crohn's disease patients requiring infliximab infusion in three hospitals in Spain. RESULTS: Three Crohn's disease patients with chronic HBV infection were identified. Two of the three patients with chronic HBV infection suffered severe reactivation of chronic hepatitis B after withdrawal of infliximab therapy and one died. A third patient, who was treated with lamivudine at the time of infliximab therapy, had no clinical or biochemical worsening of liver disease during or after therapy. From the remaining 80 patients, six received the hepatitis B vaccine. Three patients had antibodies to both hepatitis B surface antigen (anti-HBs) and hepatitis B core protein (anti-HBc) with normal aminotransferase levels, and one patient had positive anti-hepatitis C virus (HCV) antibodies, negative HCV RNA, and normal aminotransferase levels. Except for the patients with chronic HBV infection, no significant changes in hepatic function were detected. CONCLUSIONS: Patients with Crohn's disease who are candidates for infliximab therapy should be tested for hepatitis B serological markers before treatment and considered for prophylaxis of reactivation using antiviral therapy if positive.     

Idiopathic granulomatous hepatitis with a prolonged course: effect of corticosteroid therapy.

The effect of corticosteroid (or ACTH) therapy on 4 patients with idiopathic granulomatous hepatitis is described. All patients presented with spiking fever and chills and none had jaundice. Only 1 patient had an enlarged tender liver and 3 had splenomegaly. The erythrocyte sedimentation rate was increased in all cases while the white blood cell count was typically normal. Impairment in liver function was insignificant and consisted of a mild elevation of SGOT and alkaline phosphatase activities and prolonged prothrombin time. All patients presented a diagnostic challenge. The diagnosis was established by routine liver biopsies in 3 cases and by laparotomy in the 4th. The etiology could not be established. All patients reacted dramatically to prednisone (or ACTH) after failure of other therapeutic regimens. The disease has, however, been present for 5 years in 1 patient and 10 years in another, Relapses occur after cessation of therapy.     

慢性乙型肝炎伴凝血因子Ⅶ缺乏1例并文献复习

目的复习慢性乙型肝炎合并遗传性凝血因子Ⅶ缺乏的特点。方法分析1例慢性乙型肝炎伴遗传性凝血因子Ⅶ缺乏症患者的临床资料,并复习相关文献。结果该患者PT明显延长,FⅦ活性降低,而APTT及其他凝血因子活性均正常,HBV标记物阳性,而肝功能指标正常。结论遗传性凝血因子Ⅶ缺乏症是临床上一种非常少见的出血性疾病,多伴有基因缺陷,目前尚无根治的方法。对于慢性乙型肝炎患者PT明显延长而肝功能正常时,应积极查找肝病以外的原因。     

Liver histology in hepatitis C infection: a comparison between patients with persistently normal or abnormal transaminases.

Forty two cases of confirmed hepatitis C virus (HCV) infection with available liver histology were studied. Most patients, 23 of 42 (55%) had abnormal liver function tests but 19 of 42 (45%) had persistently normal liver transaminases (mean aspartate transaminase (AST) 24.1 IU/l, mean follow up 10 months). Histological examinations in the group with normal AST activities were normal in two of 19 (11%), showed non-specific reactive hepatitis in eight of 19 (42%), chronic persistent hepatitis in six of 19 (31%), and chronic active hepatitis in three of 19 (16%). Twenty three of 42 (55%) had either persistently or temporary raised liver transaminases (mean AST 96.2 IU/l, mean follow up 16 months). Histological examinations in this second group with abnormal liver biochemistry showed reactive hepatitis in five of 23 (22%), chronic persistent hepatitis in six of 23 (26%), chronic active hepatitis in 10 of 23 (43%), and cirrhosis in two (9%). Average alcohol intake was significantly higher in the group within abnormal liver function (17.8 v 6.4 units, p = 0.01). Although serious pathology was more frequent in the abnormal transaminase group, significant liver pathology (chronic persistent hepatitis or chronic active hepatitis) was found in nine of 19 (47%) of cases with repeatedly normal transaminases. Liver biopsy is advised in all cases of chronic hepatitis C infection to accurately assess both the degree of fibrosis and the current activity of the disease.     

Rapid-onset primary biliary cirrhosis resembling drug-induced liver injury

A 54-year-old woman was admitted to our hospital because of acute liver injury. Since she had a history of having used a diet product, drug-induced liver injury (DILI) was initially considered. However, the patient was subsequently diagnosed as suffering from primary biliary cirrhosis (PBC) based on the findings of liver histology and serum anti-mitochondrial antibody positivity. Overlap syndrome between PBC and autoimmune hepatitis (AIH) was also suspected, however, serum levels of aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase became normal three months later, after treatment with combination therapy comprising ursodeoxycholic acid plus bezafibrate. We therefore concluded that the liver disease in this patient was actually PBC, but that it resembled overlap syndrome or DILI. In cases of PBC, a rapid onset, as frequently seen in the case of DILI, viral hepatitis or AIH, is not common. We herein report a rare case of PBC which resembled DILI.     

Aplastic anemia and severe pancytopenia during treatment with peg-interferon,ribavirin and telaprevir for chronic hepatitis C

Telaprevir and Boceprevir are the first direct acting antivirals approved for chronic hepatitis C in combination with peg-interferon alfa and ribavirin.Pancytopenia due to myelotoxicity caused by these drugs may occur,but severe hematological abnormalities or aplastic anemia(AA) have not been described.We collected all cases of severe pancytopenia observed during triple therapy with telaprevir in four Spanish centers since approval of the drug in 2011.Among 142 cirrhotic patients receiving treatment,7 cases of severe pancytopenia(5%) were identified and three were consistent with the diagnosis of AA.Mean age was 59 years,five patients had compensated cirrhosis and two patients had severe hepatitis C recurrence after liver transplantation.Severe pancytopenia was diagnosed a median of 10 wk after the initiation of therapy.Three patients had pre-treatment hematological abnormalities related to splenomegaly.In six patients,antiviral treatment was interrupted at the onset of hematological abnormalities.Two patients died due to septic complications and one patient due to acute alveolar hemorrhage.The remaining patients recovered.Severe pancytopenia and especially AA,are not rare during triple therapy with telaprevir in patients with advanced liver disease.Close monitoring is imperative in this setting to promptly detect serious hematological disorders and to prevent further complications.     

Severe liver injury after treatment with the leukotriene receptor antagonist zafirlukast

BACKGROUND: In registration trials, zafirlukast, an asthma medication, caused asymptomatic elevated aminotransferase levels in up to 5% of participants. Until now, however, no cases of severe hepatitis attributed to zafirlukast have been reported. OBJECTIVE: To report the clinical characteristics of three patients with severe hepatitis due to zafirlukast. DESIGN: Case report. SETTING: One community hospital and two university hospitals. PATIENTS: Three middle-aged women taking zafirlukast, 20 mg twice per day. INTERVENTION: Discontinuation of zafirlukast therapy in three patients, steroid therapy in two patients, and orthotopic liver transplantation in one patient. MEASUREMENTS: Serum aminotransferase and bilirubin levels, standard blood tests for causes of hepatitis other than drug toxicity, and liver biopsy in two patients. RESULTS: Patient 1 recovered spontaneously, had a severe relapse after inadvertent rechallenge with the medication, and ultimately made a complete recovery. Patient 2 developed subfulminant hepatic failure and required liver transplantation. Patient 3 developed severe hepatitis that improved after treatment with corticosteroids. Liver tissue was available from two patients and showed histologic changes commonly associated with drug reactions. CONCLUSION: Patients receiving zafirlukast may develop severe liver injury and should be observed for signs and symptoms of hepatitis.     

Histological evolution of chronic hepatitis C. Factors related to progression

We have evaluated the histological progression of liver disease in 29 untreated patients with chronic hepatitis C. All patients were positive to antibodies to hepatitis C virus by ELISA2 and RIBA2. Two liver biopsies were carried out for each patient, with an interval ranging between 12 and 126 months (mean 50.2±30.7). In all cases the usual histological classification was applied and the histological activity index scoring system according to Knodell et al. was determined. Fifteen cases worsened (51.7%), 12 cases showed no histological changes (41.4%) and two patients improved (6.9%). Cirrhosis was found in five patients (18.5%) in the second liver biopsy. Epidemiological, clinical, biochemical and histological parameters were compared between the group without histological progression and the group with impairment in liver histology. Factors related to histological worsening were: more advanced age (p=0.002), high levels of aspartate aminotransferase (p=0.04), high global histological activity index (p=0.03) and piecemeal necrosis and bridging necrosis scores (p=0.02) at first biopsy. The histological activity index can be applied to assess the natural history of chronic viral hepatitis, and is a good tool to evaluate the prognosis. Thus chronic hepatitis C virus infection is a histologically progressive disease in at least half the cases.     

Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis

There is evidence to suggest that rifampicin is an effective second line therapy for controlling pruritus in patients with chronic cholestatic liver disease. It is most widely used as an antipruritic agent in the autoimmune cholestatic liver disease, primary biliary cirrhosis (PBC). Rifampicin has been reported as causing hepatitis in patients being treated for tuberculosis. Most reports of this have been confounded however by the concurrent use of other hepatotoxic antitubercular therapy. Here we report a single centre experience of the use of rifampicin in PBC, and describe three cases of significant hepatitis associated with rifampicin therapy. Two of these patients had significant impairment of liver synthetic function (necessitating liver transplantation in one case). These are the first reports of impaired hepatic synthetic function due to rifampicin monotherapy. Rifampicin caused significant hepatitis in 7.3% (95% confidence interval 2.5-19.4%) of patients treated for cholestatic liver disease in our centre.     

Acarbose-induced acute hepatitis. Report of two events in the same patient

A 57-year-old woman with non-insulin-dependent diabetes mellitus and inadequate glycemic control was prescribed acarbose (100 mg 3 times daily). Two months later she presented with acute hepatitis (ALT 2,300 IU/l). Other causes of liver damage were excluded. Three months after acarbose had been discontinued, all results of laboratory tests returned to normal values. Three years later the patient was given acarbose again. Acarbose (100 mg three times daily) had been added to glibenclamide (15 mg daily) 2 weeks before she presented with acute hepatitis (ALT 2,778 IU/l). Acarbose was stopped and the results of liver tests returned to normal within 2 months. Of the eight cases of acarbose-associated hepatotoxicity previously reported, five (as well as the two presented herein) were Spanish. The latency period, from the start of drug therapy to the onset of liver injury, was relatively long (> 2 months). We suggest that acarbose be included in the list of drugs which may induce acute hepatitis.     

Clinicopathological features of hepatocellular carcinoma--comparison of hepatitis B seropositive and seronegative patients

Clinicopathological features were studied in 113 non-alcoholic patients with histology-proven hepatocellular carcinoma, of whom 35 were positive for hepatis B virus surface antigen (HBsAg), 23 were negative for all seromarkers for hepatitis B virus, and 55 were negative for HBsAg, but positive for anti-HBs and/or anti-core antibody (anti-HBc) with low titers. It was found that the age of the patient at the time of diagnosis was significantly lower in HBsAg cases than in the other two groups. Serum alpha-fetoprotein levels were often normal or below 100 ng/ml in the seronegative cases, and its measurement less frequently served as a diagnostic clue. Otherwise, clinically there was no difference between the three groups except for more frequent liver disease within the second degree of kinship in the HBsAg patients. Histopathological study of the livers showed that there were more expanding type hepatocellular carcinomas in the seronegative cases as compared with the HBsAg positive cases. There was no autoimmune chronic liver disease in these patients. These observations and data seem to indicate that there are certain differences between HBsAg positive and seronegative hepatocellular carcinomas. Since most patients had progressive liver disease, it is likely that many of these seronegative cases had chronic non-A, non-B viral disease, which is very common in Japan. It may be inferred further that non-A, non-B hepatitis virus is less carcinogenic as compared with hepatitis B virus.     

Non-alcoholic fatty liver disease in HIV-positive patients predisposes for acute-on-chronic liver failure: two cases

Non-alcoholic fatty liver disease is a prominent feature in HIV-positive patients. We present two patients with long-lasting HIV-infection who suffered from this disease, as induced by highly active anti-retroviral therapy (HAART). The patients developed acute-on-chronic (AOC) liver failure after either (case 1) acute infection with hepatitis A virus (HAV) or (case 2) methamphetamine abuse ('Ecstasy'). Approximately 1 week after visiting an area endemic for HAV, case 1, a male patient, presented with icterus, elevated liver transaminases and HAV IgM. Previous examinations had demonstrated normal liver transaminase activities while hepatic steatosis had been suspected. He developed complications associated with liver failure including renal failure as well as pleural and pericardial effusions. Case 2, a second male patient, developed both liver failure and lactic acidosis 24 h after methamphetamine abuse. Both patients suffered from fatty liver in the pre-acute stage as indicated by ultrasound examination. After developing symptoms of liver failure, HAART was discontinued in both patients. Follow-up visits demonstrated that the patients recovered clinically with almost normalized laboratory parameters. In HIV infection, HAART-induced hepatopathological alterations may exist despite the absence of relevant laboratory parameters. These patients are likely to develop AOC liver failure when subjected to acute risk factors such as hepatitis viruses and narcotics or other drugs. In patients treated with HAART, we thus highly recommend hepatitis A and B virus vaccinations, and close monitoring of liver parameters.     

Liver enzyme elevation induced by hyperemesis gravidarum: aetiology,diagnosis and treatment

Three primigravidae were admitted during the first trimester of pregnancy with nausea, vomiting, ketonuria and liver enzyme elevation of varying severity. A 29-year-old woman had elevated aminotransferase values, at levels described in the literature (ASAT 112 U/l, ALAT 214 U/l). The second patient, a woman aged 26 years, had undergone in vitro fertilisation and showed higher liver enzyme elevation, including the total bilirubin level (ASAT 250 U/l, ALAT 474 U/l, total bilirubin 59.8 micromol/l). A 30-year-old woman had extremely high aminotransferase values (ASAT 705 U/l, ALAT 1674 U/l) and she is the first reported patient with ALAT values exceeding 1,000 U/l in connection with hyperemesis gravidarum. Gallstone disease, viral and drug-induced hepatitis were excluded in all of these patients. Treatment was symptomatic and the abnormal liver tests returned to normal promptly when the vomiting resolved, independent of the severity of liver enzyme elevation. The pregnancies proceeded normally and all three patients delivered healthy babies.     

Acute hepatic lesion caused by Giardia lamblia

A study was made of 20 rats infested by Giardia muris in which a histologic study was made of the liver, as well as of 25 patients with giardiasis and elevated alanine-aminotransferase levels. Patients with positive A or B hepatitis markers, cholelithiasis or history of drug or alcohol use were excluded. Tests of liver function and liver biopsy were performed and antiparasite therapy was given during three months of follow-up, after which the liver biopsy was repeated. Humoral alterations were compared to those of 30 patients with acute viral hepatitis (15 type A and 15 type B) over the same periods of time. In 20% of the rats, nonspecific liver lesions were found. In the patients liver enzymes and the thymol test normalized a month after treatment and serum bile acids became normal in the third month. The liver biopsy demonstrated hepatic damage in 94% of the patients (in 20 cases cell lesions and in 12 cases inflammatory lesions) which regressed in the third month, the follow-up biopsy being normal after eradication of the parasite was confirmed. The comparative study with viral hepatitis showed highly significant differences in all the variables studied during the follow-up stage. Emphasis is placed on the importance of this lesion and its differential diagnosis to prevent its progression to chronic liver disease.     

Treatment strategies for recurrent hepatitis C after liver transplantation

Chronic hepatitis C is a common indication for liver transplantation, accounting for 25% to 50% of all transplantation candidates in most transplant centers. Despite uncertainties regarding rates of disease progression after transplantation, a consensus is emerging that recurrent HCV infection results in liver failure in a significant although currently unmeasured proportion of patients, and that the period over which this progression occurs is shorter than in the immunocompetent population. As the disease process moves into its second decade after transplantation it can be anticipated that future morbidity and liver-related mortality will increase. Whether disease progression is accelerated by definable factors is not yet fully established, but HCV RNA levels before or soon after transplantation and aggressive immunosuppressive measures appear to influence the post-transplantation outcome. Strategies to prevent or to reduce the effect of HCV infection after liver transplantation are therefore essential. The ability to intervene in this disease is currently limited. The main obstacles are the difficulty in predicting the outcome in the individual patient and the lack of effective therapy. In contrast with hepatitis B, in which hepatitis B immune globulin has improved survival, there are no therapeutic strategies to prevent recurrent HCV infection. Neither IFN nor ribavirin, when administered as a single agent, results in sustained viral clearance. However, administration of both drugs in combination, either to prevent disease or to treat recurrence, appears promising. The inability of currently available antiviral therapy to eliminate HCV in the setting of liver transplantation suggests that indefinite treatment designed to suppress viral replication will be necessary. The feasibility of such an approach will depend on the development of drugs that reduce the histologic activity of hepatitis, improve graft and patient survival, and have side effect profiles that are acceptable to patients.     

Post-transfusional vs. sporadic non-A, non-B chronic hepatitis. A clinico-pathological and evolutive study

The clinical, morphological and evolutive features of 60 patients with chronic hepatitis, presumably caused by non-A, non-B virus infection, have been retrospectively analyzed. In all the cases the disease began as an acute episode of viral hepatitis that was followed by persistently abnormal liver function tests. No patient had evidence of current or past hepatitis B virus infection and other known causes of chronic liver disease were excluded. Thirty patients had received blood transfusions in the recent past, five were drug addicts and the source of the infection was not identified in the remaining 25, in whom the disease was considered to be sporadic. Clinical or biochemical differences between patients with post-transfusional and sporadic non-A, non-B chronic hepatitis were not observed, but liver histology showed a higher proportion of patients with chronic persistent hepatitis in the sporadic (72%) than in the transfusional group (53%). On follow-up, sustained normalization of liver function tests was observed in 46% of the cases with sporadic hepatitis but only in 13% of the cases with post-transfusion hepatitis. These observations suggest that non-A, non-B chronic hepatitis is more severe in patients with transfusion-related infection than in sporadic cases.     

Clinical study of IgA antibody against hepatitis C virus core antigen in patients with type C chronic liver disease

Immunoglobulin A class antibody to hepatitis C virus core antigen (IgA anti-HCc) was measured in the serum of 128 patients with type C chronic liver disease. Fifty-eight patients (45.3%) were seropositive. IgA anti-HCc was detected in only one of 20 patients with chronic persistent hepatitis; however, 52.3% (46/88) of patients with chronic active hepatitis and 55% (11/20) of patients with liver cirrhosis were seropositive. Histological examination revealed that 22 (71.0%) of 31 patients with severe disease activity were seropositive compared to 35 (44.9%) of 78 patients with moderate (P<0.05) and one (5.3%) of 19 patients with mild (P<0.01) histological changes. IgA anti-HCc was measured sequentially in 65 patients who underwent interferon therapy. There was a significant difference between responders and other patients in the mean ratio of IgA anti-HCc titers one month after therapy. Three months after therapy, IgA anti-HCc was detectable in only two of 15 responders who were IgA anti-HCc seropositive at the start of therapy. In contrast, IgA anti-HCc reappeared three months after therapy despite a temporary decrease to undetectable levels in all nonresponders. We conclude that IgA anti-HCc is a useful marker to identify the presence of active type C liver disease and that the disappearance of IgA anti-HCc three months after interferon therapy predicts a good response in treated patients.