Drug-induced autoimmune liver disease: A diagnostic dilemma of an increasingly reported disease.

The aetiology of autoimmune hepatitis (AIH) is uncertain but the disease can be triggered in susceptible patients by external factors such as viruses or drugs. AIH usually develops in individuals with a genetic background mainly consisting of some risk alleles of the major histocompatibility complex (HLA). Many drugs have been linked to AIH phenotypes, which sometimes persist after drug discontinuation, suggesting that they awaken latent autoimmunity. At least three clinical scenarios have been proposed that refers to drug- induced autoimmune liver disease (DIAILD): AIH with drug-induced liver injury (DILI); drug induced-AIH (DI-AIH); and immune mediated DILI (IM-DILI). In addition, there are instances showing mixed features of DI-AIH and IM-DILI, as well as DILI cases with positive autoantibodies. Histologically distinguishing DILI from AIH remains a challenge. Even more challenging is the differentiation of AIH from DI-AIH mainly relying in histological features; however, a detailed standardised histologic evaluation of large cohorts of AIH and DI-AIH patients would probably render more subtle features that could be of help in the differential diagnosis between both entities. Growing information on the relationship of drugs and AIH is being available, being drugs like statins and biologic agents more frequently involved in cases of DIAILD. In addition, there is some evidence on the fact that patients diagnosed with DIAILD may have had a previous episode of hepatotoxicity. Further collaborative studies in DIAILD will strengthen the knowledge and understanding of this intriguing and complex disorder which might represent different phenotypes across the spectrum of disease.

Drug-induced acute liver injury mimicking autoimmune hepatitis after intake of dietary supplements containing glucosamine and chondroitin sulfate

INTRODUCTION Herbal and dietary supplements are widely used as measures to improve and preserve health and well-being. Among the bestselling preparations are dietary supplement containing glucosamine and chondroitine sulfate taken to improve symptoms of osteoarthritis. METHODS AND RESULTS We here present a case of a male patient with biopsy-proven acute and severe autoimmune hepatitis subsequent to intake of a preparation containing glucosamine and chondroitine sulfate. Response to steroids was favorable and resulted in complete remission of the patient. Diagnostic work-up of the case revealed no other possible cause of liver injury, and causality assessment using the Roussel Uclaf Causality Assessment Method (RUCAM) resulted in a possible causal relationship between intake of glucosamine and chondroitine sulfate and the adverse hepatic reaction. CONCLUSION The present case recalls that products containing glucosamine and chondroitine sulfate can occasionally cause acute liver injury mimicking autoimmune hepatitis, and reminds of the potential dangers of compounds with poor efficacy and ill-defined safety records.

Coxiella burnetii as a possible cause of autoimmune liver disease: a case report.

INTRODUCTION: Q fever is a zoonotic infection that may cause severe hepatitis. Q-fever hepatitis has not yet been associated with autoimmune hepatitis and/or primary biliary cirrhosis. CASE PRESENTATION: We describe a 39-year-old man of Sri Lankan origin with chronic Q-fever hepatitis who developed autoantibodies compatible with autoimmune hepatitis/primary biliary cirrhosis overlap syndrome. Ursodeoxycholic acid in addition to antibiotic therapy markedly improved hepatic enzyme levels suggesting that autoimmunity, potentially triggered by the underlying infection, was involved in the pathogenesis of liver damage. CONCLUSION: We suggest that Coxiella burnetii might trigger autoimmune liver disease. Patients with Q-fever hepatitis who respond poorly to antibiotics should be investigated for serological evidence of autoimmune hepatitis, primary biliary cirrhosis or overlap syndrome, as these patients could benefit from adjunctive therapy with ursodeoxycholic acid. Conversely, C. burnetii serology might be necessary in patients with autoimmune liver disease in order to exclude underlying Coxiella infection.

The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury.

Distinguishing drug-induced liver injury (DILI) from idiopathic autoimmune hepatitis (AIH) can be challenging. We performed a standardized histologic evaluation to explore potential hallmarks to differentiate AIH versus DILI. Biopsies from patients with clinically well-characterized DILI [n = 35, including 19 hepatocellular injury (HC) and 16 cholestatic/mixed injury (CS)] and AIH (n = 28) were evaluated for Ishak scores, prominent inflammatory cell types in portal and intra-acinar areas, the presence or absence of emperipolesis, rosette formation, and cholestasis in a blinded fashion by four experienced hepatopathologists. Histologic diagnosis was concordant with clinical diagnosis in 65% of cases; but agreement on final diagnosis among the four pathologists was complete in only 46% of cases. Interface hepatitis, focal necrosis, and portal inflammation were present in all evaluated cases, but were more severe in AIH (P < 0.05) than DILI (HC). Portal and intra-acinar plasma cells, rosette formation, and emperiopolesis were features that favored AIH (P < 0.02). A model combining portal inflammation, portal plasma cells, intra-acinar lymphocytes and eosinophils, rosette formation, and canalicular cholestasis yielded an area under the receiver operating characteristic curve (AUROC) of 0.90 in predicting DILI (HC) versus AIH. All Ishak inflammation scores were more severe in AIH than DILI (CS) (P ≤ 0.05). The four AIH-favoring features listed above were consistently more prevalent in AIH, whereas portal neutrophils and intracellular (hepatocellular) cholestasis were more prevalent in DILI (CS) (P < 0.02). The combination of portal inflammation, fibrosis, portal neutrophils and plasma cells, and intracellular (hepatocellular) cholestasis yielded an AUC of 0.91 in predicting DILI (CS) versus AIH. Conclusion: Although an overlap of histologic findings exists for AIH and DILI, sufficient differences exist so that pathologists can use the pattern of injury to suggest the correct diagnosis.

Non-alcoholic fatty liver disease associated with hypobetalipoproteinemia: report of three cases and a novel mutation in APOB gene

Background: Non-alcoholic fatty liver disease, the leading cause of chronic liver disease in children, is defined by hepatic fat infiltration >5% of hepatocytes, in the absence of excessive alcohol intake, evidence of viral, autoimmune or drug-induced liver disease. Conditions like rare genetic disorders must be considered in the differential diagnosis. Case Report: Two male brothers, and a non-related girl, all overweight, had liver steatosis. One of the brothers and the girl had elevated transaminases; all three presented with low total cholesterol, low density lipoproteins and very low density lipoproteins cholesterol levels, hypotriglyceridemia and low apolipoprotein B. A liver biopsy performed in the brother with citolysis confirmed steatohepatitis and the molecular study of apolipoprotein B gene showed a novel homozygous mutation (c.9353dup p.Asn3118Lysfs17). Patients with cytolysis lost weight, however liver steatosis persists. Conclusion: Fatty liver disease might be a consequence of hypobetalipoproteinemia. Evidence is scarce due to low number of reported cases.

Assessment of drug-induced hepatotoxicity in clinical practice: a challenge for gastroenterologists.

Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and post-commercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug's hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be fine-tuned as further information is collected.

Genetic variations in drug-induced liver injury (DILI): resolving the puzzle.

Despite stringent requirements for drug development imposed by regulatory agencies, drug-induced liver injury (DILI) is an increasing health problem and a significant cause for failure to approve drugs, market withdrawal of commercialized medications, and adoption of regulatory measures. The pathogenesis is yet undefined, though the rare occurrence of idiosyncratic DILI (1/100,000–1/10,000) and the fact that hepatotoxicity often recurs after re-exposure to the culprit drug under different environmental conditions strongly points toward a major role for genetic variations in the underlying mechanism and susceptibility. Pharmacogenetic studies in DILI have to a large extent focused on genes involved in drug metabolism, as polymorphisms in these genes may generate increased plasma drug concentrations as well as lower clearance rates when treated with standard medication doses. A range of studies have identified a number of genetic variants in drug metabolism Phase I, II, and III genes, including cytochrome P450 (CYP) 2E1, N-acetyltransferase 2, UDP-glucuronosyltransferase 2B7, glutathione S-transferase M1/T1, ABCB11, and ABCC2, that enhance DILI susceptibility (Andrade et al., 2009; Agundez et al., 2011). Several metabolic gene variants, such as CYP2E1c1 and NAT2 slow, have been associated with DILI induced by specific drugs based on individual drug metabolism information. Others, such as GSTM1 and T1 null alleles have been associated with enhanced risk of DILI development induced by a large range of drugs. Hence, these variants appear to have a more general role in DILI susceptibility due to their role in reducing the cell's antioxidative capacity (Lucena et al., 2008). Mitochondrial superoxide dismutase (SOD2) and glutathione peroxidase 1 (GPX1) are two additional enzymes involved in combating oxidative stress, with specific genetic variants shown to enhance the risk of developing DILI

Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury.

BACKGROUND & AIMS Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy's Law and to develop a model for predicting ALF in patients with DILI. METHODS We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL). RESULTS Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL greater than 2-fold the upper limit of normal (×ULN) and either ALT level greater than 3 × ULN, a ratio (R) value (ALT × ULN/alkaline phosphatase × ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest ×ULN/ alkaline phosphatase × ULN value) of 5 or greater. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, the level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels greater than 2 × ULN. An algorithm based on AST level greater than 17.3 × ULN, TBL greater than 6.6 × ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity. CONCLUSIONS When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF.

Significance of serum adiponectin levels in patients with chronic liver disease.

Adiponectin, which plays a pivotal role in metabolic liver diseases, is reduced in concentration in patients with NASH (non-alcoholic steatohepatitis). The aim of the present study was to determine adiponectin concentrations in patients with different forms and stages of chronic liver diseases. Serum adiponectin concentrations were measured in 232 fasting patients with chronic liver disease: 64 with NAFLD (non-alcoholic fatty liver disease), 123 with other chronic liver disease (e.g. viral hepatitis, n=71; autoimmune disease, n=18; alcohol-induced liver disease, n=3; or elevated liver enzymes of unknown origin, n=31) and 45 with cirrhosis. Circulating adiponectin levels were significantly lower in patients with NAFLD in comparison with patients with other chronic liver disease (4.8+/-3.5 compared with 10.4+/-6.3 microg/ml respectively; P<0.0001). Circulating adiponectin levels were significantly higher in patients with cirrhosis in comparison with patients without cirrhosis (18.6+/-14.5 compared with 8.4+/-6.1 microg/ml respectively; P<0.0001). Adiponectin concentrations correlated negatively with body weight (P<0.001), serum triacylglycerols (triglycerides) (P<0.001) and, in women, with BMI (body mass index) (P<0.001). Adiponectin concentrations correlated positively with serum bile acids (P<0.001), serum hyaluronic acid (P<0.001) and elastography values (P<0.001). Adiponectin levels were decreased in patients with NAFLD. In conclusion, adiponectin levels correlate positively with surrogate markers of hepatic fibrosis (transient elastography, fasting serum bile acids and hyaluronate) and are significantly elevated in cases of cirrhosis.

Major Histocompatibility Class II Pathway Is Not Required for the Development of Nonalcoholic Fatty Liver Disease in Mice.

Single-nucleotide polymorphisms within major histocompatibility class II (MHC II) genes have been associated with an increased risk of drug-induced liver injury. However, it has never been addressed whether the MHC II pathway plays an important role in the development of nonalcoholic fatty liver disease, the most common form of liver disease. We used a mouse model that has a complete knockdown of genes in the MHC II pathway (MHCII(Δ/Δ)). Firstly we studied the effect of high-fat diet-induced hepatic inflammation in these mice. Secondly we studied the development of carbon-tetra-chloride- (CCl4-) induced hepatic cirrhosis. After the high-fat diet, both groups developed obesity and hepatic steatosis with a similar degree of hepatic inflammation, suggesting no impact of the knockdown of MHC II on high-fat diet-induced inflammation in mice. In the second study, we confirmed that the CCl4 injection significantly upregulated the MHC II genes in wild-type mice. The CCl4 treatment significantly induced genes related to the fibrosis formation in wild-type mice, whereas this was lower in MHCII(Δ/Δ) mice. The liver histology, however, showed no detectable difference between groups, suggesting that the MHC II pathway is not required for the development of hepatic fibrosis induced by CCl4.

Lymphocyte populations in liver biopsy specimens from patients with chronic liver disease

The characterisation of lymphocytes from liver biopsies indicates that 'activated' T lymphocytes are present in the liver in alcohol induced hepatitis, chronic active hepatitis (HBS+ve and -ve), and in primary biliary cirrhosis but not in inactive cirrhosis, chronic persistent hepatitis, extrahepatic and drug induced cholestasis. A greater percentage of lymphocytes bear Fc-receptors in chronic active hepatitis than in alcohol induced hepatitis or cholestatic liver disease. The concentration of 'activated' T cells in the peripheral blood in all groups studied was within the normal range, suggesting that the 'activated' T cells found in the liver were reacting to either native or foreign antigens within the liver. The data on Fc-receptor bearing cells are consistent with the involvement of antibody assisted K cell mediated cytotoxicity in chronic active hepatitis.

Drug-induced linear IgA bullous dermatosis probably induced by furosemide.

Linear IgA bullous dermatosis (LABD) is an autoimmune disease, characterized by linear deposition of IgA along the basement membrane zone. Drug-induced LABD is rare but increasing in frequency. A new case of drug-induced LABD associated with the administration of furosemide is described.

Changes in biomarkers of liver disease during successful combination antiretroviral therapy in HIV-HCV-coinfected individuals.

BACKGROUND: We investigated changes in biomarkers of liver disease in HIV-HCV-coinfected individuals during successful combination antiretroviral therapy (cART) compared to changes in biomarker levels during untreated HIV infection and to HIV-monoinfected individuals. METHODS: Non-invasive biomarkers of liver disease (hyaluronic acid [HYA], aspartate aminotransferase-to-platelet ratio index [APRI], Fibrosis-4 [FIB-4] index and cytokeratin-18 [CK-18]) were correlated with liver histology in 49 HIV-HCV-coinfected patients. Changes in biomarkers over time were then assessed longitudinally in HIV-HCV-coinfected patients during successful cART (n=58), during untreated HIV-infection (n=59), and in HIV-monoinfected individuals (n=17). The median follow-up time was 3.4 years on cART. All analyses were conducted before starting HCV treatment. RESULTS: Non-invasive biomarkers of liver disease correlated significantly with the histological METAVIR stage (P<0.002 for all comparisons). The mean ±sd area under the receiver operating characteristic (AUROC) curve values for advanced fibrosis (≥F3 METAVIR) for HYA, APRI, FIB-4 and CK-18 were 0.86 ±0.05, 0.84 ±0.08, 0.80 ±0.09 and 0.81 ±0.07, respectively. HYA, APRI and CK-18 levels were higher in HIV-HCV-coinfected compared to HIV-monoinfected patients (P<0.01). In the first year on cART, APRI and FIB-4 scores decreased (-35% and -33%, respectively; P=0.1), mainly due to the reversion of HIV-induced thrombocytopaenia, whereas HYA and CK-18 levels remained unchanged. During long-term cART, there were only small changes (<5%) in median biomarker levels. Median biomarker levels changed <3% during untreated HIV-infection. Overall, 3 patients died from end-stage liver disease, and 10 from other causes. CONCLUSIONS: Biomarkers of liver disease highly correlated with fibrosis in HIV-HCV-coinfected individuals and did not change significantly during successful cART. These findings suggest a slower than expected liver disease progression in many HIV-HCV-coinfected individuals, at least during successful cART.

Plasma hydroxy-metronidazole/ metronidazole ratio in hepatitis C virus-induced liver disease

It has been suggested that the measurement of metronidazole clearance is a sensitive method for evaluating liver function. The aim of this study was to evaluate the usefulness of plasma hydroxy-metronidazole/metronidazole ratios as indicators of dynamic liver function to detect changes resulting from the various forms of chronic hepatitis C virus (HCV) infection. A total of 139 individuals were studied: 14 healthy volunteers, 22 healthy, asymptomatic, consecutive anti-HCV-positive HCV-RNA negative subjects, 81 patients with chronic hepatitis C (49 with moderate/severe chronic hepatitis and 34 with mild hepatitis), and 20 patients with cirrhosis of the liver. HCV status was determined by the polymerase chain reaction. Plasma concentrations of metronidazole and its hydroxy-metabolite were measured by reverse-phase high-performance liquid chromatography with ultraviolet detection in a blood sample collected 10 min after the end of a metronidazole infusion. Anti-HCV-positive HCV-RNA-negative individuals demonstrated a significantly reduced capacity to metabolize intravenously infused metronidazole compared to healthy individuals (0.0478 ± 0.0044 vs 0.0742 ± 0.0232). Liver cirrhosis patients also had a reduced plasma hydroxy-metronidazole/metronidazole ratio when compared to the other groups of anti-HCV-positive individuals (0.0300 ± 0.0032 vs 0.0438 ± 0.0027 (moderate/severe chronic hepatitis) vs 0.0455 ± 0.0026 (mild chronic hepatitis) and vs 0.0478 ± 0.0044 (anti-HCV-positive, HCV-RNA-negative individuals)). These results suggest an impairment of the metronidazole metabolizing system induced by HCV infection that lasts after viral clearance. In those patients with chronic hepatitis C, this impairment is paralleled by progression of the disease to liver cirrhosis.