A guide to the management of hepatitis E infection during pregnancy

Introduction: Hepatitis E virus (HEV) infection has distinct features, depending upon the genotype and geographical area. HEV genotypes 1 and 2 are endemic to various developing countries causing epidemics of acute viral hepatitis with human to human transmission. On the other hand, HEV genotypes 3 and 4 prevalent in developed countries commonly lead to subclinical infection and are transmitted zoonotically. HEV infection typically causes acute self-limiting illness associated with low morbidity and mortality. Infection with HEV genotype 1 or 2 in pregnancy, especially in the third trimester may lead to severe illness and fulminant liver failure. Poor maternal and fetal outcomes have been reported.

Areas covered: This review highlights the various aspects of HEV infection in pregnancy including diagnosis, management, and prevention.

Expert commentary: Treatment is mainly supportive with diligent monitoring and intensive care. Therapeutic termination of pregnancy cannot be recommended based to the available literature. Early liver transplantation (LT) should be considered in these patients although the indications and timing of LT are still controversial. Prevention of HEV infection or illness by improved sanitation and active/passive immunization needs further research.     

Risk factors for vertical transmission of hepatitis E virus infection

Hepatitis E virus (HEV) infection can be vertically transmitted, but the factors that transmit the disease to foetuses are still unclear. We studied a total of 144 pregnant women with HEV infection. Cord blood and newborn samples were taken for analysis. Nutritional factors were evaluated on the basis of anthropometric parameters and biochemical factors, and HEV viral load was quantified by real‐time PCR. Sequencing of HEV‐positive samples was performed. Approximately 14.63% (6/41) of pregnant patients with acute liver failure (ALF) died before delivery. Vertical transmission was observed in 46.09% (59/128) of HEV‐IgM‐positive mothers. Approximately 23.80% (10/42) of newborns in the acute viral hepatitis group and 29.41% (5/17) in the ALF group were positive for HEV‐RNA. No significant difference was observed in the occurrence of vertical transmission in HEV groups. Viral load was found to be a significant predictor for vertical transmission of HEV infection adjusted with haemoglobin and folate in derivation cohort group. Incorporating these variables, a new score predicting vertical transmission of HEV was derived. Using these significant predictors, the probability for vertical transmission of HEV was well stratified in the validation group (P>.05). In conclusion, viral load was associated with vertical transmission of HEV infection. A valid prediction score model was generated that was verified in a validation cohort group.     

Aetiology,clinical course and outcome of sporadic acute viral hepatitis in pregnancy

Hepatitis E causes large-scale epidemics in endemic areas. The disease, during epidemics, has increased incidence and severity in pregnant women. Sporadic acute viral hepatitis (AVH) is common in endemic areas. The relationship of sporadic AVH and pregnancy has not been well studied. Over a 3-year period we prospectively studied 76 pregnant women and 337 non-pregnant women of childbearing age with sporadic acute viral hepatitis for aetiology, clinical course and outcome of disease. The aetiology in sporadic AVH was hepatitis A virus (HAV) in six (1.5%), hepatitis B virus (HBV) in 62 (15%), hepatitis C virus (HCV) in seven (1.7%), hepatitis D virus (HDV) co-infection in six (1.5%), hepatitis E virus (HEV) in 205 (49.6%), and hepatitis non-A-to-E (HNAE) in 127 (30.7%). Sixty-five (85.5%) pregnant women and 140 (41.5%) nonpregnant women had hepatitis E. The proportion of pregnant women was 31.7% in HEV group and 5.3% in non-HEV group [P < 0.001; OR=8.3 (95%C1 4.2-16.3)]. The prevalence of HEV in pregnant women in first trimester (76.9%), second trimester (88.9%), third trimester (83.8%) and puerperium (100%) did not differ significantly (P=0.09). Forty-seven (61.8%) of the 76 pregnant women developed fulminant hepatic failure (FHF), 69.2% in HEV group and 10% in non-HEV group (P < 0.001). Thirty-four (10.1%) nonpregnant women developed fulminant hepatic failure, 10% in HEV group and 9.7% in non-HEV group (P=0.86). FHF had occurred in four (40%) of 10 patients with HE in first trimester as against 41 (74.5%) of 55 patients in second trimester and beyond (P=0.015). Amongst the major complications of fulminant hepatic failure, cerebral oedema (53.2%) and disseminated intravascular coagulation (21.3%) occurred more often in pregnant women than in nonpregnant women (29.4% and 2.8%; P=0.03 and 0.016, respectively) while infections occurred more often in nonpregnant women (36.1%) than in pregnant women (10.6%; P=0.003). Fifty (61.7%) patients with FHF died [25 (53.2%) pregnant women and 25 (69.5%) nonpregnant women (P=0.06)]. Cerebral oedema and HEV aetiology were independent variables of survival in patients with FHF. Patients with cerebral oedema had worse prognosis and patients with HEV aetiology had best chances of survival. Hence HEV was the most common cause of sporadic AVH in this endemic area. High proportion of pregnant women and increased severity of disease in pregnancy were limited to patients with hepatitis E. Sporadic AVH caused by agents other than HEV did not show any special predilection to or increased severity in pregnancy. FHF in pregnant women caused by HEV was an explosive disease with short pre- encephalopathy period, rapid development of cerebral oedema and high occurrence of disseminated intravascular coagulation and may represent a severe manifestation of a Schwartzmann-like phenomenon.     

Factors affecting the mortality of pediatric fulminant hepatic failure in relation to hepatitis B virus infection

AIM: To investigate the factors affecting the outcome of fulminant hepatic failure (FHF) in children in relation to hepatitis B virus (HBV) infection. METHODS: Retrospective review of a total of 94 cases (61 males and 33 females, aged from 1 month to 15 years) recruited from nine tertiary referral centers in Taiwan from 1985 to 1999. RESULTS: The overall mortality rate was 75%. Patients in the mortality group were of an older age, had higher peak total bilirubin levels, a longer prothrombin time, and a lower percentage of HBV positivity (P < 0.001, P = 0.003, P = 0.0027 and P = 0.042, respectively). Mortality was 65% in the HBV positive (n = 42) and 83% in the HBV negative (n = 52) group (P = 0.05). In the HBV positive group, the prothrombin time was noted to be the single factor affecting outcome (P = 0.036). In the HBV negative group, older age and higher peak value of total serum bilirubin were suggestive of poor survival rate (P < 0.001 and P = 0.006, respectively). Multivariate analysis revealed that total bilirubin was the single factor affecting outcome in the HBV-negative group. The mortality rate of HBV positive children in three consecutive time periods without liver transplantation (1985-1989, 1990-1994, 1995-1999) decreased gradually (91, 67 and 38%, respectively, with P = 0.027). This change was not observed in HBV-negative cases. CONCLUSIONS: Hepatitis B virus positive FHF had a lower mortality rate than HBV negative FHF, with each group having different factors affecting mortality.     

Comparison of clinical features of acute hepatitis caused by hepatitis E virus (HEV) genotypes 3 and 4 in Sapporo, Japan

In Japan, indigenous acute hepatitis E is not a rare disease, and is mainly caused by hepatitis E virus (HEV) genotypes 3 and 4. Whether there is a difference in clinical features between the two genotypes remains unclear. This study compares the clinical features of patients infected with the two. From January, 1994, to December, 2003, 9 infected with HEV genotype 3 and 27 patients with genotype 4 were enrolled. Patients with genotype 4 had significantly higher peak alanine aminotransferase levels (median 3430IU/L, interquartile range 1747-4763 versus 1052IU/L, 845-2707; p=0.01). The lowest prothrombin time was lower in the genotype 4 group (61%, 42-77 versus 84%, 70-96; p=0.05). In our series, patients with genotype 4 had longer median duration of hospital stay (26.5 days, 18-31 versus 18 days, 12-23.5; p=0.06). The patients with genotype 4 infection tended to have more severe clinical manifestations than those with genotype 3 infection.     

Acute hepatitis E virus infection causing acute liver failure requiring living‐donor liver transplantation in a non‐pregnant immunocompetent woman

We report a rare case of acute liver failure from acute hepatitis E virus (HEV) in a non‐pregnant woman without comorbidities who survived after liver transplantation. The source was likely consumption of partially cooked pig liver. HEV genotype 3 is the second most common genotype causing acute hepatitis E in developed countries. Fulminant hepatitis E rarely occurs without a risk factor, as in our patient. Vigilant monitoring for chronic hepatitis E in post‐transplant immunocompromised patients is needed.     

Fulminant hepatitis and the new G/GBV-C flavivirus

A new virus within the family Flaviviridae, 'hepatitis' G/GBV-C, has been incriminated by several authors as a causative factor of idiopathic or cryptogenic fulminant hepatitis, a syndrome of presumed viral aetiology. Review of worldwide data from 22 studies on 364 cases indicates that G/GBV-C infection is present in approximately 20% of idiopathic cases but a similar or even higher prevalence is detected in fulminant hepatitis of viral B, D or C aetiology, reflecting a high rate of parenteral viral exposure rather than a specific aetiology of fulminant hepatic failure. An aetiopathogenic role of G/GBV-C in fulminant hepatitis seems to be further refuted by the analysis of other data in the literature. The presence of G/GBV-C infection in fulminant hepatic failure is largely a result of secondary infection or coinfection. The aetiopathogenetic mystery of cryptogenic or idiopathic fulminant hepatitis remains unsolved.     

Human genomics of acute liver failure due to hepatitis B virus infection: An exome sequencing study in liver transplant recipients

Acute liver failure (ALF) or fulminant hepatitis is a rare, yet severe outcome of infection with hepatitis B virus (HBV) that carries a high mortality rate. The occurrence of a life‐threatening condition upon infection with a prevalent virus in individuals without known risk factors is suggestive of pathogen‐specific immune dysregulation. In the absence of established differences in HBV virulence, we hypothesized that ALF upon primary infection with HBV could be due to rare deleterious variants in the human genome. To search for such variants, we performed exome sequencing in 21 previously healthy adults who required liver transplantation upon fulminant HBV infection and 172 controls that were positive for anti‐HBc and anti‐HBs but had no clinical history of jaundice or liver disease. After a series of hypothesis‐driven filtering steps, we searched for putatively pathogenic variants that were significantly associated with case‐control status. We did not find any causal variant or gene, a result that does not support the hypothesis of a shared monogenic basis for human susceptibility to HBV‐related ALF in adults. This study represents a first attempt at deciphering the human genetic contribution to the most severe clinical presentation of acute HBV infection in previously healthy individuals.     

Variability of hepatitis E serologic assays in a pediatric liver transplant recipient: challenges to diagnosing hepatitis E virus infection in the United States

Hepatitis E virus (HEV) is an emerging cause of viral hepatitis among immunocompromised individuals in developed countries. Yet the diagnosis of HEV infection in the United States remains challenging, because of the variable sensitivity and specificity of currently available tests, and the lack of a US Food and Drug Administration‐approved test. We report a case of multiple discordant HEV serology results in a pediatric liver transplant recipient with idiopathic hepatitis, and review the challenges to diagnosis of HEV infection in the United States.     

Immunohistochemistry for the diagnosis of hepatitis E virus infection

Hepatitis E virus (HEV) is an emerging pathogen and the most common cause of acute viral hepatitis all over the world. We describe here an immunohistochemical method for the detection of HEV antigens (pORF2 and pORF3) in formalin-fixed, paraffin-embedded liver tissues using monoclonal antibodies raised against two of the virus proteins (pORF2 and pORF3). We analysed their specificity and sensitivity in comparison with serology and nucleic acid detection in cases of acute liver failure (ALF). We used this test on 30 liver biopsies collected post-mortem from the patients of ALF caused by HEV infection. These cases were selected on the basis of positive results for enzyme immunoassay (IgM anti-HEV). Of the 30 cases taken from the archives of the Department of Pathology, the antibodies successfully stained all. However, only 25 serum samples (83.3%) of these were positive for HEV RNA. Fifteen controls used (Five noninfected liver tissues, five HBV- and five hepatitis C virus-infected liver tissues) were all negative. The immunohistochemical assay described here may prove a valuable tool for the detection of HEV infection in biopsy, autopsy and explant liver tissues and can serve as a link along with other available tests to delineate the extent of HEV-associated problem worldwide.     

Shift of hepatitis E virus RNA from hepatocytes to biliary epithelial cells during acute infection of rhesus monkey

Hepatitis E virus (HEV) has been considered to be the major cause of enterically transmitted non-A, non-B hepatitis in developing countries. However, little is known about viral replication and localization in the liver. The aim of this study was to examine the distribution of HEV-infected cells in experimentally infected animals. Seven captured wild rhesus monkeys were inoculated intravenously with faecal extract derived from a Myanmar strain of HEV. Animals were killed at different time-points of clinical illness: during early infection, during prehepatitis with viral-like particles in bile, during acute hepatitis and during convalescence. Intrahepatic localization of HEV was analysed using non-isotopic thymine dimer in situ hybridization (NITDISH). Both plus and minus strands of HEV RNA were found in hepatocytes during the early infection period. Staining in the submembranous cytoplasmic region of hepatocytes was observed. In the prehepatitis period, both plus and minus strand HEV RNAs appeared in the canalicular side of isolated bile epithelial cells. Subsequently, HEV RNA became universally distributed in the cytoplasm of medium-size bile epithelial cells. After recovery, HEV RNA disappeared.     

Hepatitis δ virus infection in India

Serological markers of hepatitis δ virus (HDV) and hepatitis B virus (HBV) infection were studied in 87 HBsAg positive patients, comprised of 18 patients with uncomplicated acute viral hepatitis (AVH), 34 patients with fulminant hepatic failure (FHF), 18 patients with subacute hepatic failure (SAHF) and 17 patients with chronic active hepatitis (CAH). The prevalence of HDV infection was found to be 27.8%, 20.6%, 16.7% and 11.8%, respectively in these four groups. Co-infection of HDV and HBV was common amongst patients with AVH but superinfection by HDV in chronic HBV carriers was the predominant form of infection in patients with FHF, SAHF and CAH. HDV superinfection in these groups did not significantly alter the common tests of liver function or the DNA-polymerase positivity.     

The long-term efficacy of plasma-derived hepatitis B vaccine in babies born to carrier mothers

summary.  The long-term efficacy of a childhood hepatitis B vaccination programme was evaluated. A total of 112 newborn babies of hepatitis B carrier mothers were given hepatitis B immune globulin (HBIG) and a 10-μg three-dose regimen of plasma-derived vaccine administered at a conventional (0, 1, 6 months), delayed (2, 3, 8 months) or accelerated (0, 1, 2 months) schedule. The vaccinees were followed up to determine their anti-HBs status over a 16-year period. Upon completion of the vaccination schedules, 92.6% developed antibody against surface antigen (anti-HBs) seroconverion, the rate of which fell to 33.3% at year 16. The three schedules were equally effective in preventing chronic infection, with a protective efficacy of 88.9% from hepatitis B surface antigen (HBsAg) carriage, compared with historical control. Vaccinees on the delayed schedule had a slightly higher seroconversion rate over years, and were better able to maintain an anti-HBs level of ≥ 100 iu/L. Overall, a quarter demonstrated evidence of exposure to the virus, being positive for antibody against core antigen or HBsAg, or mounting a rise in anti-HBs during the follow-up period. We conclude that a three-dose hepatitis B vaccination regimen is generally effective in protecting newborns of hepatitis B carrier mothers from infection and chronic carriage. Booster is not needed even after 16 years of monitoring.     

Clinical features and determinants of chronicity in hepatitis E virus infection

Hepatitis E virus (HEV) has traditionally been associated with an acute, self‐limiting hepatitis and is not known to have any chronic sequelae. HEV genotypes 1 and 2, which are human pathogens, have been associated with this self‐limiting presentation, in both sporadic and epidemic settings. HEV genotype 3, which is zoonotically transmitted, is increasingly being reported as a cause of chronic infection in immunocompromised patients. These include patients with solid organ transplants, patients receiving chemotherapy for haematologic malignancies and patients infected with HIV. Chronic infection is associated with rapidly progressing liver disease and extrahepatic manifestations including neurologic disorders. We review the clinical manifestations of chronic HEV infection and discuss factors determining persistence and chronicity of HEV.     

Coexistence of IgM antihepatitis A virus and IgM antihepatitis E virus in acute viral hepatitis: a prospective, multicentre study in Korea

This study investigated the clinical, serological and molecular characteristics of coexistence of both immunoglobulin M (IgM) antihepatitis A virus (HAV) and IgM antihepatitis E virus (HEV) in acute viral hepatitis using a prospective, multicentre design. Among a total of 771 symptomatic cases with acute viral hepatitis enrolled in a Korean city from September 2006 to August 2008, coexistence of IgM anti-HAV and IgM anti-HEV was found in 43 patients (A+E group; 6%), while the existence of IgM anti-HAV alone was found in 595 patients (A group; 77%) and that of IgM anti-HEV alone in 14 patients (E group; 2%). Clinical data analysis and measurement of IgM and IgG anti-HEV were performed using two different commercial kits, and HAV RNA and HEV RNA were detected in available serum or stool samples. The clinical features of the A+E group were similar to those of the A group. HAV RNA detection rates in the A+E and A group were similar, while HEV RNA was detected only in the stool samples of the E group, not in the A+E group. Comparative testing of anti-HEV using two different ELISA kits showed markedly discordant results for IgM anti-HEV positivity and consistently low positivity for IgG anti-HEV in the A+E group. Coexistence of IgM anti-HEV measured by the Genelabs ELISA kit in the setting of hepatitis A appears to yield false-positive results in nonendemic areas of HEV infection. Diagnosis of hepatitis E using IgM anti-HEV should be made with caution.