Harshad Devarbhavi

Drug‐Induced liver injury with hypersensitivity features has a better outcome: A single‐center experience of 39 children and adolescents

Drug‐induced liver injury (DILI) is rare in children and adolescents, and, consequently, data are remarkably limited. We analyzed the causes, clinical and biochemical features, natural history, and outcomes of children with DILI. Consecutive children with DILI from 1997 to 2004 (retrospective) and 2005 to 2010 (prospective) were studied based on standard criteria for DILI. Thirty‐nine children constituted 8.7% of 450 cases of DILI. There were 22 boys and 17 girls. Median age was 16 years (range, 2.6‐17). Combination antituberculous drugs were the most common cause (n = 22), followed by the anticonvulsants, phenytoin (n = 10) and carbamazepine (n = 6). All of the 16 children (41%) who developed hypersensitivity features, such as skin rashes, fever, lymphadenopathy, and/or eosinophilia, including the 3 with Stevens‐Johnson syndrome, survived. Those with hypersensitivity presented earlier (24.5 versus 35 days; P = 0.24) had less severe disease (MELD, 16 versus 29; P = 0.01) and had no mortality (0/16 versus 12/23; P < 0.001), compared to those without hypersensitivity. The 12 fatalities were largely the result of antituberculous DILI (n = 11). The presence of encephalopathy and ascites were associated with mortality, along with hyperbilirubinemia, high international normalized ratio, and serum creatinine. According to the Roussel Uclaf Causality Assessment Method, 18 were highly probable, 14 probable, and 7 possible. Thirty‐two children were hospitalized. Conclusion: DILI is not uncommon in children and accounts for 8.7% of all patients with DILI. Antituberculous drugs and anticonvulsants are the leading causes of DILI in India. Overall mortality is high (30.7%), largely accounted by antituberculous drugs. Children with DILI and hypersensitivity features present early, have less severe disease, and, consequently, a better prognosis, compared to those without, and are often associated with anticonvulsants or sulfonamides. (HEPATOLOGY 2011;)

An Update on Drug-induced Liver Injury.

Idiosyncratic drug-induced liver injury (DILI) is an important cause of morbidity and mortality following drugs taken in therapeutic doses. Hepatotoxicity is a leading cause of attrition in drug development, or withdrawal or restricted use after marketing. No age is exempt although adults and the elderly are at increased risk. DILI spans the entire spectrum ranging from asymptomatic elevation in transaminases to severe disease such as acute hepatitis leading to acute liver failure. The liver specific Roussel Uclaf Causality Assessment Method is the most validated and extensively used for determining the likelihood that an implicated drug caused DILI. Asymptomatic elevation in liver tests must be differentiated from adaptation. Drugs producing DILI have a signature pattern although no single pattern is characteristic. Antimicrobial and central nervous system agents including antiepileptic drugs are the leading causes of DILI worldwide. In the absence of a diagnostic test or a biomarker, the diagnosis rests on the evidence of absence of competing causes such as acute viral hepatitis, autoimmune hepatitis and others. Recent studies show that antituberculosis drugs given for active or latent disease are still a major cause of drug-induced liver injury in India and the West respectively. Presence of jaundice signifies a severe disease and entails a worse outcome. The pathogenesis is unclear and is due to a mix of host, drug metabolite and environmental factors. Research has evolved from incriminating candidate genes to genome wide analysis studies. Immediate cessation of the drug is key to prevent or minimize progressive damage. Treatment is largely supportive. N-acetylcysteine is the antidote for paracetamol toxicity. Carnitine has been tried in valproate injury whereas steroids and ursodeoxycholic acid may be used in DILI associated with hypersensitivity or cholestatic features respectively. This article provides an overview of the epidemiology, the patterns of hepatotoxicity, the pathogenesis and associated risk factors besides its clinical management.

Outcome and determinants of mortality in 269 patients with combination anti-tuberculosis drug-induced liver injury

Worldwide anti‐tuberculosis (TB) drug‐induced liver disease (DILI) is an important cause of hepatotoxicity, and drug‐induced acute liver failure (ALF). Reported series on anti‐TB DILI are limited by a mix of cases with mild transaminase elevation or adaptation. Our aim was to analyze the clinical features, laboratory characteristics, outcome, and determine predictors of 90‐day mortality.

Severe Falciparum Malaria Simulating Fulminant Hepatic Failure

OBJECTIVE To identify clinical and laboratory features of patients with malarial hepatitis simulating fulminant hepatic failure (MHsFHF) and distinguish it from viral FHF. PATIENTS AND METHODS At a tertiary care unit in Bangalore, India, we compared clinical and laboratory characteristics of 25 patients with MHsFHF with those of 25 patients with viral FHF from November 1996 to January 2000. RESULTS No statistically significant differences were seen in duration of jaundice, altered consciousness, and the interval between onset of jaundice and altered consciousness between the 2 groups. Hepatomegaly and splenomegaly were present in 72% and 48% of patients with MHsFHF and in 12% and 0% of patients with viral FHF (P<.001), respectively. The MHsFHF group had a significantly lower hemoglobin level (9.3 g/dL vs 12.9 g/dL), total leukocyte count (9.1 x 10(9)/L vs 18 x 10(9)/L), platelet count (44.8 x 10(9)/L vs 218.6 x 10(9)/L), and transaminases (alanine aminotransferase, 86.2 U/L vs 1230.0 U/L; aspartate aminotransferase, 131.9 U/L vs 720.0 U/L) (P<.001). Thrombocytopenia and elevated serum urea nitrogen were universal in patients with MHsFHF. Prothrombin time was abnormal in all patients with viral FHF and in only 1 patient with MHsFHF. Of patients with MHsFHF, 24% died; of patients with viral FHF, 76% died (P=.02). CONCLUSIONS In endemic areas, severe malaria should be considered in the differential diagnosis of FHF. Hepatomegaly and normal prothrombin time in the setting of FHF are suggestive of malaria, and a peripheral blood smear should be obtained for diagnostic confirmation.

Drug-induced liver injury associated with stevens-Johnson syndrome/toxic epidermal necrolysis: Patient characteristics, causes, and outcome in 36 cases.

The liver and skin are the organs most commonly involved in serious adverse drug reactions. Rarely a drug reaction can affect both organs concurrently. The association of drug‐induced liver injury (DILI) and Stevens‐Johnson syndrome (SJS) or toxic epidermal necrosis (TEN) is even rarer and not well studied. We describe our experience of DILI occurring in association with SJS/TEN including the etiologic agents, clinical and biochemical characteristics, and outcome. We identified patients who developed DILI in association with SJS/TEN from a registry of DILI patients from a single center. Causality assessment for DILI and SJS/TEN was carried out with the Roussel Uclaf Causality Assessment Method and the Algorithm for Drug Causality for Epidermal Necrolysis, respectively. Among 748 consecutive patients with DILI from 1997 to March 2015, 36 (4.8%) had associated features of SJS/TEN. The mean age was 32 years (females 19). Children and patients with human immunodeficiency virus constituted 25% (n = 9) and 22% (n = 8), respectively. Only a small number of “high‐risk” drugs such as antiepileptic agents, sulfonamides, and antiretroviral drugs accounted for the majority of cases. Overall mortality was 36% (n = 13), which rose to 45.5% in the presence of jaundice. Mortality was less in children 11% (n = 1) and human immunodeficiency virus patients 12.5% (n = 1). Conclusions: DILI associated with SJS/TEN is rare and associated with a high death rate, particularly in those with jaundice; however, children and human immunodeficiency virus–infected individuals have a favorable outcome; a small group of drugs contributed to a disproportionate number of cases, and causality with Roussel Uclaf Causality Assessment Method and the Algorithm for Drug Causality for Epidermal Necrolysis was highly probable or probable in all cases. (Hepatology 2016;63:993–999)

HIV/AIDS cholangiopathy: clinical spectrum, cholangiographic features and outcome in 30 patients.

Background and Aims:  AIDS cholangiopathy is presently considered rare and has been reported mainly from the West. With the HIV epidemic in India, we have encountered an increasing number of patients. We aimed to study these patients and determine differences from earlier experiences.

Drug-induced liver injury due to antimicrobials, central nervous system agents, and nonsteroidal anti-inflammatory drugs.

Antimicrobial agents including antituberculosis (anti-TB) agents are the most common cause of idiosyncratic drug-induced liver injury (DILI) and drug-induced liver failure across the world. Better molecular and genetic biomarkers are acutely needed to help identify those at risk of liver injury particularly for those needing antituberculosis therapy. Some antibiotics such as amoxicillin-clavulanate and isoniazid consistently top the lists of agents in retrospective and prospective DILI databases. Central nervous system agents, particularly antiepileptics, account for the second most common class of agents implicated in DILI registries. Hepatotoxicity from older antiepileptics such as carbamazepine, phenytoin, and phenobarbital are often associated with hypersensitivity features, whereas newer antiepileptic drugs have a more favorable safety profile. Antidepressants and nonsteroidal anti-inflammatory drugs carry very low risk of significant liver injury, but their prolific use make them important causes of DILI. Early diagnosis and withdrawal of the offending agent remain the mainstays of minimizing hepatotoxicity.

Factors That Predict 1-Month Mortality in Patients With Pregnancy-Specific Liver Disease

BACKGROUND & AIMS Pregnancy-specific liver diseases such as acute fatty liver of pregnancy; hemolysis, elevated liver enzymes and low platelet syndrome; and preeclampsia-associated liver disease are associated with considerable morbidity and mortality. We investigated the ability of the model for end-stage liver disease (MELD) to predict 1-month mortality among patients with pregnancy-specific liver diseases. We also developed and tested a model to predict mortality based on features of pregnancy-specific liver diseases. METHODS We performed a retrospective study, analyzing hospital admission, clinical, hematologic, and biochemical data collected from 130 patients with pregnancy-specific liver diseases admitted to the St. Johns Medical College Hospital (Bangalore, India) from January 2000 through April 2011. Patients were followed up until 3 months after delivery or death. Logistic regression models were fitted using the MELD score and other variables identified as clinically or statistically significant. The predictive accuracy and calibration of the models were assessed by receiver operating characteristic curves and the Hosmer-Lemeshow goodness-of-fit test. RESULTS Thirty-two patients (24.6%) died. Mortalities from pregnancy-specific liver diseases within 1 month of admission among patients with MELD scores of 20 to 29, 30 to 39, or 40 or greater were 24.2%, 45.45%, and 90.9%, respectively. Univariate analysis identified encephalopathy, ascites, serum total protein, bilirubin, platelet count, alkaline phosphatase, serum creatinine, and international normalized ratio (INR) as significant variables. Multivariate analysis identified total bilirubin (P < .001) and INR (P < .003) as significant predictors of mortality. MELD score and a model based on only 2 variables (bilirubin level and INR) accurately predicted mortality (C statistics, 0.83 and 0.86, respectively) and were well calibrated (Hosmer-Lemeshow χ(2) = 9.7 [P = .28] and 1.9 [P = .98], respectively). CONCLUSIONS A new logistic model based on only 2 variables (INR and total bilirubin) was comparable with the MELD model in predicting mortality among women with pregnancy-specific liver diseases.

Factors that predict mortality in children with Wilson disease associated acute liver failure and comparison of Wilson disease specific prognostic indices

Wilson disease (WD) associated acute liver failure (ALF) affects children more than adults. The predictors of mortality and outcome in patients without encephalopathy are not clear. We investigated the ability of prognostic factors and various models including model for end‐stage liver disease (MELD) to predict mortality among children with WD and ALF.

Systemic Inflammatory Response Syndrome in Acute on Chronic Liver Failure- Relevance of ‘Golden Window’- a Prospective Study

Systemic inflammatory response syndrome (SIRS) is an early marker of sepsis and ongoing inflammation and has been reported in large proportion of acute‐on‐chronic liver failure (ACLF) patients. Whether sepsis is the cause or the result of liver failure is unclear and is vital to know. To address this, the study investigated the course and outcome of ACLF patients without SIRS/sepsis.