Drug-Induced Liver Injury

Drug hepatoxicity can be nonidiosyncratic (predictable), as in the case of acetaminophen, or idiosyncratic (unpredictable). This review article focuses primarily on idiosyncratic drug-induced liver injury (DILI). New epidemiologic data suggest that approximately 20 new cases of DILI per 100,000 persons occur each year. Idiosyncratic DILI accounts for 11% of the cases of acute liver failure in the United States. Risk factors for DILI include medication dose, drug lipophilicity, and extent of hepatic metabolism. There is mixed evidence to support the role of host factors such as age, sex, and chronic liver disease in the development of DILI. For specific drugs, a genetic predisposition appears to be a risk factor for DILI. Suspected cases of idiosyncratic DILI should be categorized as hepatitic, cholestatic, or mixed on the basis of the degree/ratio of abnormalities in the alanine aminotransferase and alkaline phosphatase. A careful evaluation for other causes of liver disease should be performed, though a liver biopsy is rarely needed. There is evidence that some patients with DILI may actually have hepatitis E and this diagnosis should be considered. Amoxicillin/clavulanate isoniazid, and nonsteroidal anti-inflammatory drugs are among the most common causes of DILI. Drug discontinuation or dechallenge should lead to an improvement in liver biochemistries in most patients, though a bilirubin value of more than 3 g/dL is associated with mortality of at least 10%. New biomarkers for DILI using proteomics and micro RNA appear promising but require further study. New studies on drugs with potential for causing DILI are reviewed herein, including tumor necrosis factor-alpha antagonists, fluoroquinolones, tyrosine kinase inhibitors, statins, and supplements. PubMed was used with search terms of drug induced liver injury OR DILI with filter settings of “English language” and “humans” and custom date range of “January 1, 2000.” The authors also manually searched bibliographies from key references and included seminal references before the year 2000.     

Cross‐genotype‐specific T‐cell responses in acute hepatitis E virus (HEV) infection

Hepatitis E is an inflammatory liver disease caused by infection with the hepatitis E virus (HEV). In tropical regions, HEV is highly endemic and predominantly mediated by HEV genotypes 1 and 2 with >3 million symptomatic cases per year and around 70 000 deaths. In Europe and America, the zoonotic HEV genotypes 3 and 4 have been reported with continues increasing new infections per year. So far, little is known about T‐cell responses during acute HEV genotype 3 infection. Therefore, we did a comprehensive study investigating HEV‐specific T‐cell responses using genotypes 3‐ and 1‐specific overlapping peptides. Additional cytokines and chemokines were measured in the plasma. In four patients, longitudinal studies were performed. Broad functional HEV‐specific CD4⁺ and CD8⁺ T‐cell responses were detectable in patients acutely infected with HEV genotype 3. Elevated of pro‐ and anti‐inflammatory cytokine levels during acute HEV infection correlated with ALT levels. Memory HEV‐specific T‐cell responses were detectable up to >1.5 years upon infection. Importantly, cross‐genotype HEV‐specific T‐cell responses (between genotypes 1 and 3) were measurable in all investigated patients. In conclusion, we could show for the first time HEV‐specific T‐cell responses during and after acute HEV genotype 3 infection. Our data of cross‐genotype HEV‐specific T‐cell responses might suggest a potential role in cross‐genotype‐specific protection between HEV genotypes 1 and 3.     

Time course of hepatitis E‐specific antibodies in adults

Hepatitis E virus (HEV) is highly endemic in industrialized countries, but there is a lack of knowledge on individual and overall antibody concentration dynamics. The aim of this study was to characterize longitudinal concentration changes of anti‐HEV immunoglobulin G (anti‐HEV IgG) by enzyme immunoassay (EIA). In total, 199 serum samples collected from 45 subjects over 18 years were analysed. A wide range of anti‐HEV IgG levels was found. Overall, anti‐HEV IgG significantly decreased after an observation period of at least 5 years. One negative seroconversion was observed. Four individual profiles suggested single and even multiple HEV reinfections despite pre‐existing HEV antibodies.     

Localization of a new enteric non-A,non-B [HEV] virus in target organ liver

ThirteenMacaca mulatta monkeys were used for transmission of enteric non-A, non-B hepatitis virus (HEV) by the portal vein (PV) route. All these animals developed changes which are found in selflimiting acute viral hepatitis e.g. rise in liver enzymes, the presence of HEV specific viral particles in the stool and histological changes in the liver from 21 to 45 days after HEV inoculation. All the animals recovered completely as reflected by normalization of liver enzymes, and regenerative changes in the liver. The present report highlights the ultrastructural changes in the livers of these experimental monkeys. The histopathological changes included infiltration of lymphocytes and polymorphonucleocytes around the necrotic area, swelling of mitochondria, dilation of smooth endoplasmic reticulum (ER), and presence of 27–34 nm virus particles during the acute phase of the disease. In comparison, 9 control monkeys did not show any such histological changes.     

Detection of hepatitis E virus RNA and genotype in Bangladesh

Background/Aims:  Hepatitis E virus (HEV) in Bangladesh has not been adequately documented. We report HEV RNA and genotype detection in Bangladesh.
Methods:  In total, 82 samples were used; 36 sporadic acute hepatitis (AH), 12 fulminant hepatitis (FH), 14 chronic liver disease (CLD) and 20 from an apparently healthy population (HP) positive for both immunoglobulin (Ig) M and IgG specific anti-HEV antibodies (anti-HEV). The male/female ratio was 61/21, ages 12–67 (mean 30.4) years. RNA was extracted, transcribed to cDNA and amplified in nt 6345–6490 (ORF2) of HEV. Nucleic and amino acid sequences were determined. Homology comparison between Bangladesh clones and other representative HEV clones and phylogenetic tree analyses were done. Relations between HEV RNA-positivity and clinical factors were analyzed.
Results:  HEV RNA was positive in 9/36 (25.0%) of AH cases, 4/12 (33.3%) FH, 3/14 (21.4%) CLD and 0/20 (0%) HP samples; total 16/82 (19.5%). Four factors correlated significantly with HEV RNA-positivity (Mann-Whitney U test); alanine aminotransferase (ALT) ( P  = 0.0229), aspartate aminotransferase (AST) ( P  = 0.0448), and titers of IgG ( P  = 0.0208) and IgM ( P  = 0.0095) specific anti-HEV. The 16 HEV clones were divided mainly into two groups, A and B, including six different cDNA sub-groups.
Conclusion:  HEV RNA was found in sporadic AH and FH and sub-clinical CLD cases, but not in HP. HEV RNA-positivity was significantly related to values of ALT and AST and titers of IgG and IgM specific anti-HEV, with IgM specific anti-HEV showing the most significant relationship. All clones were genotype I, which is prevalent in South Asia.     

Immunogenicity and safety of a two-dose regimen with hepatitis E virus vaccine in healthy adults in rural Bangladesh: A randomized,double-blind,controlled, phase 2/pilot trial

BackgroundHepatitis E virus (HEV) is a major cause of acute viral hepatitis worldwide and it contributes to considerable maternal and neonatal mortality and morbidity in many low-income countries like Bangladesh. A three-dose regimen of a vaccine against HEV (HEV 239) has shown promising results in China. The effects and safety of this vaccine in other populations and with different dosing regimens remains uncertain.ObjectivesInvestigate the immune response and safety of a two-dose regimen with the HEV 239 vaccine among healthy adults. Examine the feasibility of conducting a larger HEV 239 vaccine trial in rural Bangladesh.MethodsOne-hundred healthy men and non-pregnant women 16–39 years old were randomized in a 1:1 ratio to receive two doses of either the study (HEV) or control (Hepatitis B virus, HBV) vaccine (at 0, 1 month). Blood samples were collected at day 0, day 60 and 2 years after vaccination. The primary endpoints were the proportion and severity of adverse events up to 2 months after dose one and the longitudinal shift in anti-HEV IgG levels from day 0 to day 60 and 2 years after vaccination.ResultsAdverse events to HEV 239 were comparable to the control vaccine, mild in severity and resolved within one to nine days. All participants in the study group seroconverted and achieved high levels of HEV IgG antibodies that remained positive for two years in all but one. A T-cell response was detected one month after HEV 239 vaccination.ConclusionOur results show that two doses of the HEV 239 vaccine produces broad and likely functional immune responses against HEV that remain for at least two years. The safety profile was acceptable and a phase four study of HEV 239 in rural Bangladesh is feasible.ClinicalTrials.gov Identifier: NCT02759991.     

Prevalence of HEV RNA in Croatian blood donors

ObjectivesHEV infection is asymptomatic for immunocompetent blood donors (BD). Transfused HEV-infected blood products may cause potentially hazardous HEV infection in immunocompromised patients. Evaluation of the need for routine BD HEV RNA screening primarily demands the establishment of HEV infection prevalence in Croatian BD.Materials and methodsWe tested BD samples in ID-NAT with the Procleix UltrioPlex E screening test for simultaneous detection of HBV DNA, HCV RNA, HIV-1,2 RNA, and HEV RNA (Grifols, Spain). HEV infection was confirmed with HEV RNA quantitative test (Altona Diagnostics, Germany) and HEV IgM and HEV IgG antibody test (DIA.PRO Diagnostic Bioprobes, Italy). We analysed the HEV RNA sequence and performed a phylogenetic analysis. We recorded BD’s anamnestic data and dietary habits. BDs gave follow-up samples after two months and did not donate blood for six months.ResultsBetween December 2021 and March 2022, we tested 8,631 donations and found four HEV RNA-positive donations, which equals to one in 2,158 donations (0.046 %, 95 % confidence interval, 0.018 %-0.119 %). Confirmatory HEV RNA testing gave results from negative to 4.73E + 3 IU/ml HEV RNA. Three donations were in the serological window period. We have genotyped HEV RNA of two infected BD as genotype HEV-3c. Blood donors didn’t report any health problems and their diet included pork. Testing on follow-up samples presented seroconversion and no HEV RNA could be detected.ConclusionThe incidence of HEV RNA infection in BD in Croatia corresponds with other European data. The decision on implementation of HEV NAT screening in Croatia needs an expert team evaluation of the possible risk of TT-HEV infection.