Immune checkpoint inhibitor use and the incidence of hepatitis B virus reactivation or immune-related hepatitis in non-small cell lung cancer patients with chronic hepatitis B.

BACKGROUND: The safety of immune-checkpoint inhibitors (ICIs) has not been thoroughly investigated in non-small cell lung cancer (NSCLC) patients with chronic hepatitis B (CHB) or occult hepatitis B infection (OBI). The authors analyzed the incidence of hepatitis B virus (HBV) reactivation, immune-related hepatitis and jaundice in NSCLC patients in a real-world setting. METHODS: A total of 1277 NSCLC patients treated with ICIs were analyzed. Among them, 52 patients were hepatitis B surface antigen (HBsAg) (+) (group A, CHB), 759 patients were HBsAg (-)/hepatitis B core antibody immunoglobulin G (anti-HBc IgG) (+) (group B, OBI), and 466 patients were HBsAg (-)/anti-HBc IgG (-) (group C). Among the 52 patients with CHB, 38 (73.1%) were receiving antiviral therapy. The primary end point was HBV reactivation, immune-related hepatitis, and jaundice. The secondary end points included other immune-related adverse events and efficacy. RESULTS: HBV reactivation was observed in two patients (0.2%) who were both in group A (CHB). Among CHB patients who were not receiving antiviral therapy, HBV reactivation was observed in 14.3% (2 of 14 patients). The incidences of immune-related hepatitis and jaundice were comparable among the three groups. The incidence of ≥grade 3 other immune-related adverse events and efficacy were all comparable among the three groups (p > .05 for all comparisons). CONCLUSIONS: In this large, real-world cohort study, the safety and efficacy of ICIs were comparable in patients with CHB and OBI. HBV reactivation was observed in patients with CHB without antiviral therapy indicating antiviral prophylaxis should be required for them. For patients with OBI, the risk of HBV reactivation was minimal.

Immunoglobulin for hemolytic jaundice in Japan: A retrospective survey.

BACKGROUND: Intravenous immunoglobulin G (IVIG) is used to treat blood-type incompatibility hemolytic disease of newborns (BTHDN). Although IVIG's efficacy for treating BTHDN has been challenged, as an updated systematic review suggests, IVIG could significantly reduce exchange transfusions. We conducted a mail-in questionnaire survey to ascertain actual use of IVIG for BTHDN in Japan. METHODS: The survey, conducted in 2014, included infants born between January 1, 2009, and December 31, 2013. Questionnaires were sent to the heads of neonatal intensive care units (NICUs) at perinatal centers of the Japan Neonatologist Association. RESULTS: A total of 195 centers (64.6%) responded to the questionnaire. During the study period, 170 centers (87.2%) reported incidences of BTHDN. Among these centers, there were 1726 diagnosed cases of BTHDN in neonates. Of these cases, 419 infants were treated with IVIG in 127 centers, representing approximately 74.7% of all centers. After the exclusion of cases with missing data and those where consent for data usage was not obtained, a total 916 infants were included in this study. Of these, 219 (23.9%) were treated with IVIG after phototherapy, and 187 (20.4%) of these infants did not require further blood exchange transfusion. The IVIG dosages ranged from 40 to 1200 mg/kg/dose, but the majority were between 500 and 1000 mg/kg/dose, with a median of 800 mg/kg/dose. About 20% of the infants treated with IVIG showed late-onset anemia and required treatment. Adverse events were reported in less than 1% of infants. CONCLUSIONS: For the treatment of BTHDN, IVIG administration was widely used in NICUs in Japan without severe adverse events.

Serious liver injury induced by Nimesulide: an international collaborative study.

Nimesulide is a non-steroidal anti-inflammatory drug still marketed in many countries. We aim to analyze the clinical phenotype, outcome, and histological features of nimesulide-induced liver injury (nimesulide-DILI). We analyzed 57 cases recruited from the Spanish and Latin American DILI registries. Causality was assessed by the RUCAM scale. Mean age of the whole case series was 59 years (86% women) with a median time to onset of 40 days. A total of 46 patients (81%) were jaundiced. Nimesulide-DILI pattern was hepatocellular in 38 (67%), mixed in 12 (21%), and cholestatic in 7 (12%) cases. Transaminases were elevated with a mean of nearly 20-fold the upper limit of normality (ULN), while alkaline phosphatase showed a twofold mean elevation above ULN. Total bilirubin showed a mean elevation of 13-fold the ULN. Liver histology was obtained in 14 cases (25%), most of them with a hepatocellular pattern. Median time to recovery was 60 days. Overall, 12 patients (21%) developed acute liver failure (ALF), five (8.8%) died, three underwent liver transplantation (5.3%), and the remaining four resolved. Latency was ≤ 15 days in 12 patients (21%) and one patient developed ALF within 7 days from treatment initiation. Increased total bilirubin and aspartate transaminase levels were independently associated with the development of ALF. In summary, nimesulide-DILI affects mainly women and presents typically with a hepatocellular pattern. It is associated with ALF and death in a high proportion of patients. Shorter (≤ 15 days) duration of therapy does not prevent serious nimesulide hepatotoxicity, making its risk/benefit ratio clearly unfavorable.

Acute Liver Injury After Long-Term Herbal "Liver Cleansing" and "Sleep Aid" Supplement Use.

BACKGROUND: Acute liver injury is reported in association with toxins, pharmaceuticals, and viral infections. Increasingly prevalent are cases of herbal- and dietary supplement-related hepatotoxicity. Early recognition of this potentially life-threatening complication by emergency care providers leads to more appropriate management and disposition. CASE REPORT: A 53-year-old woman presented to the emergency department with a 3-day history of jaundice and increased abdominal girth after a month-long use of a combination herbal "liver-cleansing" compound and a nightly herbal "sleep aid." The "Liver Detoxifier and Regenerator" listed multiple constituents, including concentrated scute root and turmeric root; "Restful Sleep" listed multiple constituents, including valerian. Emergency department evaluation revealed marked hyperbilirubinemia with liver enzyme elevations indicative of cholestatic jaundice. Imaging studies, including ultrasound and abdominal magnetic resonance imaging, revealed hepatomegaly and steatosis without biliary dilatation; a biopsy specimen was obtained, and the results were consistent with drug-induced liver injury. The patient's liver function abnormalities gradually improved with discontinuation of the products as well as a tapered course of corticosteroid therapy. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: A significant proportion of the U.S. adult population uses herbal and dietary supplements. Most patients do not discuss nonprescription medication use with their providers and many physicians will not specifically ask about herbal supplements. It is important for emergency physicians to be aware of the potential for herbal supplements to contribute to acute liver injury and be able to investigate the active agents reported in these formulations. The diagnostic criteria for cholestatic jaundice and drug-induced liver injury are discussed.

Caution With the Use of Lopinavir/Ritonavir in Severely Ill Patients for the Treatment of SARS-CoV-2: A Report of Severe Jaundice.

INTRODUCTION: We investigated the potential hepatotoxicity of lopinavir/ritonavir recently used in the treatment of Severe Acute Respiratory Syndrome Coronavirus. METHODS: This is a retrospective cohort of critical patients in a teaching hospital: 12 treated with lopinavir/ritonavir and 30 in the standard-of-care group. RESULTS: Elevation occurred more frequently in patients treated with lopinavir/ritonavir (33% vs 6.7%). DISCUSSION: Caution is advised regarding the use of lopinavir/ritonavir in the most severe cases of Severe Acute Respiratory Syndrome Coronavirus.

The role of roughage provision on the absorption and disposition of the mycotoxin deoxynivalenol and its acetylated derivatives in calves: from field observations to toxicokinetics.

A clinical case in Belgium demonstrated that feeding a feed concentrate containing considerable levels of deoxynivalenol (DON, 1.13 mg/kg feed) induced severe liver failure in 2- to 3-month-old beef calves. Symptoms disappeared by replacing the highly contaminated corn and by stimulating ruminal development via roughage administration. A multi-mycotoxin contamination was demonstrated in feed samples collected at 15 different veal farms in Belgium. DON was most prevalent, contaminating 80% of the roughage samples (mixed straw and maize silage; average concentration in positives: 637 ± 621 µg/kg, max. 1818 µg/kg), and all feed concentrate samples (411 ± 156 µg/kg, max. 693 µg/kg). In order to evaluate the impact of roughage provision and its associated ruminal development on the gastro-intestinal absorption and biodegradation of DON and its acetylated derivatives (3- and 15-ADON) in calves, a toxicokinetic study was performed with two ruminating and two non-ruminating male calves. Animals received in succession a bolus of DON (120 µg/kg bodyweight (BW)), 15-ADON (50 µg/kg BW), and 3-ADON (25 µg/kg) by intravenous (IV) injection or per os (PO) in a cross-over design. The absolute oral bioavailability of DON was much higher in non-ruminating calves (50.7 ± 33.0%) compared to ruminating calves (4.1 ± 4.5%). Immediately following exposure, 3- and 15-ADON were hydrolysed to DON in ruminating calves. DON and its acetylated metabolites were mainly metabolized to DON-3-glucuronide, however, also small amounts of DON-15-glucuronide were detected in urine. DON degradation to deepoxy-DON (DOM-1) was only observed to a relevant extent in ruminating calves. Consequently, toxicity of DON in calves is closely related to roughage provision and the associated stage of ruminal development.

Race/ethnicity difference in the pharmacogenetics of bilirubin-related atazanavir discontinuation.

BACKGROUND: Atazanavir causes plasma indirect bilirubin to increase. We evaluated associations between Gilbert's polymorphism and bilirubin-related atazanavir discontinuation stratified by race/ethnicity. PATIENTS AND METHODS: Patients had initiated atazanavir/ritonavir-containing regimens at an HIV primary care clinic in the southeastern USA, and had at least 12 months of follow-up data. Metabolizer group was defined by UGT1A1 rs887829 C→T. Genome-wide genotype data were used to adjust for genetic ancestry in combined population analyses. RESULTS: Among 321 evaluable patients, 15 (4.6%) had bilirubin-related atazanavir discontinuation within 12 months. Homozygosity for rs887829 T/T was present in 28.1% of Black, 21.4% of Hispanic, and 8.6% of White patients. Among all patients the hazard ratio (HR) for bilirubin-related discontinuation with T/T versus C/C genotype was 7.3 [95% confidence interval (CI): 1.7-31.5; P=0.007]. Among 152 White patients the HR was 14.4 (95% CI: 2.6-78.7; P=0.002), but among 153 Black patients the HR was 0.8 (95% CI: 0.05-12.7; P=0.87). CONCLUSION: Among patients who initiated atazanavir/ritonavir-containing regimens, UGT1A1 slow metabolizer genotype rs887829 T/T was associated with increased bilirubin-related discontinuation of atazanavir in White but not in Black patients, this despite T/T genotype being more frequent in Black patients.

Liver injury from herbal and dietary supplements.

Herbal and dietary supplements (HDS) are used increasingly both in the United States and worldwide, and HDS-induced liver injury in the United States has increased proportionally. Current challenges in the diagnosis and management of HDS-induced liver injury were the focus of a 2-day research symposium sponsored by the American Association for the Study of Liver Disease and the National Institutes of Health. HDS-induced liver injury now accounts for 20% of cases of hepatotoxicity in the United States based on research data. The major implicated agents include anabolic steroids, green tea extract, and multi-ingredient nutritional supplements. Anabolic steroids marketed as bodybuilding supplements typically induce a prolonged cholestatic but ultimately self-limiting liver injury that has a distinctive serum biochemical as well as histological phenotype. Green tea extract and many other products, in contrast, tend to cause an acute hepatitis-like injury. Currently, however, the majority of cases of HDS-associated liver injury are due to multi-ingredient nutritional supplements, and the component responsible for the toxicity is usually unknown or can only be suspected. HDS-induced liver injury presents many clinical and research challenges in diagnosis, identification of the responsible constituents, treatment, and prevention. Also important are improvements in regulatory oversight of nonprescription products to guarantee their constituents and ensure purity and safety. The confident identification of injurious ingredients within HDS will require strategic alignments among clinicians, chemists, and toxicologists. The ultimate goal should be to prohibit or more closely regulate potentially injurious ingredients and thus promote public safety. (Hepatology 2017;65:363-373).

Pantoprazole-induced autoimmune chronic hepatitis.

BACKGROUND: Although very rare, pantoprazole can result in acute hepatitis. It has yet to be reported, however, that it can also cause chronic autoimmune hepatitis. AIM, METHOD AND RESULTS: We report the case of a patient in whom pantoprazole administration for 2 months was followed by acute liver injury with severe jaundice and features of autoimmunity. A liver biopsy revealed acute hepatocellular lesions associated with cholestasis, acute cholangitis and polymorphous inflammatory infiltration suggestive of drug-induced liver injury. The jaundice disappeared following discontinuation of the pantoprazole. There was, however, chronic autoimmune liver injury, with the occurrence of extensive liver fibrosis within a few months. This led to the administration of immunosuppressive agents, which led to progressive and complete recovery associated with the disappearance of autoantibodies. CONCLUSION: This observation further supports the notion that pantoprazole can induce acute hepatocellular hepatitis, and it strongly suggests that it may trigger acute cholangitis and autoimmune liver injury. This case also helps document that some drugs can induce chronic autoimmune hepatitis that can resolve with immunosuppressive treatment.

Drug-induced liver injury: a cohort study on patients referred to the Danish transplant center over a five year period.

OBJECTIVE: The idiosyncratic subtype of drug-induced liver injury (DILI) is a rare reaction to medical treatment that in severe cases can lead to acute liver failure and death. The aim of this study was to describe the presentation and outcome of DILI and to identify potential predictive factors of poor outcome. MATERIALS AND METHODS: We identified all patients diagnosed with DILI at the Department of Hepatology, Rigshospitalet, from March 2007 to November 2012. The following parameters were registered from patient files: drug causing DILI, symptoms, comorbidity, biochemistry, treatment and outcome. RESULTS: Of 43 patients, 25 (58%) were female with a mean age of 54 years. The two most frequent causes of DILI were Disulfiram (30%) and antibiotics (19%). The most common symptoms were jaundice, nausea, fatigue and gastrointestinal discomfort. At the time of admission, the most frequent biochemical findings included bilirubin elevated to above 3.2 × ULN, ALT elevated to above 9 × ULN in 86%, INR above 1.4 in 70%. Twenty two patients needed treatment in the liver intensive care unit. Fifteen patients developed acute liver failure with a severe outcome. Six patients were liver transplanted and nine patients died. Jaundice, a moderately elevated bilirubin level or INR at presentation was predictive of severe outcome. CONCLUSION: In this retrospective study, 35% of patients with DILI developed severe acute liver failure and were either liver transplanted or died. Our results underline that DILI may be severe and run a fatal course, and that bilirubin and INR levels may predict poor outcome.

Drug-induced liver injury due to antibiotics.

Drug-induced liver injury (DILI) is an important differential diagnosis in patients with abnormal liver tests and normal hepatobiliary imaging. Of all known liver diseases, the diagnosis of DILI is probably one of the most difficult one to be established. In all major studies on DILI, antibiotics are the most common type of drugs that have been reported. The clinical phenotype of different types of antibiotics associated with liver injury is highly variable. Some widely used antibiotics such as amoxicillin-clavulanate have been shown to have a delayed onset on liver injury and recently cefazolin has been found to lead to liver injury 1-3 weeks after exposure of a single infusion. The other extreme is the nature of nitrofurantoin-induced liver injury, which can occur after a few years of treatment and lead to acute liver failure (ALF) or autoimmune-like reaction. Most patients with liver injury associated with use of antibiotics have a favorable prognosis. However, patients with jaundice have approximately 10% risk of death from liver failure and/or require liver transplantation. In rare instances, the hepatoxicity can lead to chronic injury and vanishing bile duct syndrome. Given, sometimes very severe consequences of the adverse liver reactions, it cannot be over emphasized that the indication for the different antibiotics should be evidence-based and symptoms and signs of liver injury from the drugs should lead to prompt cessation of therapy.

Mirtazapine-induced steatosis
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Mirtazapine is a commonly used drug indicated for the treatment of severe depression. It works as a presynaptic α2-adrenoreceptor antagonist that increases central noradrenergic and serotonergic neurotransmission, and it is metabolized by the p450 cytochrome oxidase system. There is evidence within the literature to suggest a link between antidepressants and increased liver enzymes, although case reports demonstrating a link between mirtazapine specifically and steatosis are sparse. Here, we present a case of mirtazapine-induced steatosis in a 48-year-old office worker. She presented with painless jaundice of 2 days duration and generalized lethargy and peripheral edema present for 3 weeks beforehand. Extensive investigations were undertaken to identify the cause of her jaundice but no biochemical, blood-borne, or anatomical cause could be found. Mirtazapine was subsequently stopped, and her liver function, both clinically and biochemically, improved rapidly. She made a full recovery after discontinuation of her mirtazapine.
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Drug Induced Liver Injury at a Tertiary Hospital in India: Etiology, Clinical Features and Predictors of Mortality.

INTRODUCTION AND AIMS: Drug-induced liver injury (DILI) is rare; however, it is one of the important causes of acute liver failure which results in significant morbidity or mortality. MATERIAL AND METHODS: Patients with suspected DILI were enrolled based on predefined criteria and followed up for at least 6 months or until normalization of liver tests. Causality assessment was done by applying the Roussel Uclaf Causality Assessment Method model. RESULTS: We collected data from 82 individuals diagnosed with DILI at our hospital from 2014 through 2015 (41 men; median age, 38 years). The most commonly implicated drugs were antitubercular therapy (ATT) (49%), antiepileptic drugs (12%), complementary and alternative medicine (CAM) in 10%, antiretroviral drugs (9%) and non-steroidal anti-inflammatory drugs (6%). 8 out of 13 deaths were liver related. Also, liver related mortality was significantly higher for ATT DILI (17.5%) vs. those without (2.4%) (P = 0.02). There was no significant difference in overall as well as liver related mortality in hepatocellular, cholestatic or mixed pattern of injury. Laboratory parameters at one week after discontinuation of drug predicted mortality better than those at the time of DILI recognition. On multivariate logistic regression analysis, jaundice, encephalopathy, MELD (Model for end stage liver disease) score and alkaline phosphatase at one week, independently predicted mortality. CONCLUSION: DILI results in significant overall mortality (15.85%). ATT, anti-epileptic drugs, CAM and antiretroviral drugs are leading causes of DILI in India. Presence of jaundice, encephalopathy, MELD score and alkaline phosphatase at one week are independent predictors of mortality.

Acute Cholestatic Liver Injury From Hydralazine Intake.

Hydralazine is a commonly used oral antihypertensive agent. We report a rare case of hydralazine-induced hepatotoxicity in the form of subacute hepatic necrosis. A 75-year-old African American woman presented with jaundice of 7-day duration. She was started on hydralazine 100 mg 3 times a day 10 weeks before presentation. On physical examination, scleral icterus was noted. Workup revealed elevated liver transaminases, alkaline phosphatase, and conjugated bilirubin. She had no history of liver disease, and liver function tests had been normal before starting hydralazine. Other etiologies, including viruses, common toxins, drugs, autoimmune, and copper-induced hepatitis, were excluded. Abdominal imaging studies did not show any evidence of intrahepatic or extrahepatic biliary ductal dilatation, and no pathologies were seen in the liver and pancreas. The patient's liver biopsy revealed extensive lobular hepatitis, significant necrosis, mixed inflammatory infiltrate, and no significant fibrosis, supporting a diagnosis of drug-induced liver injury. Hydralazine was immediately discontinued. She showed improvement of clinical and laboratory abnormalities within 5 days after discontinuation of hydralazine. To establish the diagnosis of hydralazine-induced liver injury, we used assessment tool outlined by the Council for International Organization of Medical Sciences (CIOMS) scale that led to "high probable" relationship. Although rare, clinically significant, and potentially life-threatening liver injury can result from use of hydralazine. Both clinical and histological presentations in our patient suggest acute liver injury. The hydralazine-induced hepatitis seems to be reversible as discontinuation of the drug improves clinical outcomes. We highly recommend monitoring of the liver function during hydralazine treatment.

[A 22-year-old mother with severe pruritus and increasing jaundice two weeks after starting hormonal contraception]. / Eine 22-jährige Mutter mit starkem Juckreiz und zunehmendem Ikterus zwei Wochen nach Beginn der hormonalen Kontrazeption.

Intermittent cholestatic liver disease may indicate an inherited deficiency of bile salt transport proteins. Episodes of cholestasis may start during pregnancy or during use of oral contraceptives or other medication. We describe the case of a 22-year-old mother with increasing jaundice and severe pruritus two weeks after starting hormonal contraception. A few months before she was suffering from intrahepatic cholestasis of pregnancy (ICP). Liver biopsy showed bland cholestasis with canalicular bile plugs. Treatment with ursodeoxycholic acid was not effective. Finally, rifampicin induced a complete remission of the cholestasis. Genetic testing showed a heterozygous mutation in the ABCB11 gene encoding the bile salt export pump (BSEP). Rifampicin activates nuclear receptors and may induce alternative pathways for the excretion of bile salts in patients with ABCB11 deficiency.

An unusual case of prolonged post-endoscopic retrograde cholangiopancreatography jaundice.

Despite the effectiveness of endoscopic retrograde cholangiopancreatography (ERCP) for the treatment of choledocholithiasis, various complications have been described. We herein report the first case of prolonged post-ERCP jaundice due to toxicity of the contrast agent Iobitridol (®XENETIX, Guerbet, Roissy CdG Cedex, France) in a patient who underwent ERCP with sphincterectomy and common bile duct stone removal. While clinical improvement and normalization of aminotransferases and cholestatic enzymes after the procedure, an unexplained increase of direct bilirubin was noticed. A second ERCP was performed one week later, excluding possible remaining choledocholithiasis. Nevertheless, serum direct bilirubin increased further up to 15 mg/dL. Other potential causes of direct hyperbilirubinemia were ruled out and patient's liver biopsy was compatible with drug-induced liver toxicity. Additionally, the cause-result time connection between the use of Iobitridol and bilirubin increase indicated the possibility of a toxic effect related to the repeated use of the particular contrast agent. Iobitridol, a contrast agent, can induce prolonged direct hyperbilirubinemia.

Fluorescein-related extensive jaundice.

Fluorescein is a chemical dye frequently used in eye diseases to assess blood flow in the retina, choroid tissue, and iris. Although it has many known adverse effects, it has not previously been reported to lead to jaundice. The purpose of this case report was to emphasize that for patients presenting at the emergency department with jaundice symptoms, it should not be forgotten by emergency physicians that jaundice can develop after fluorescein angiography. Case: A 65-year-old woman presented at the emergency department with extensive jaundice that had developed on her entire body a few hours after fluorescein angiography applied because of vision impairment. The test results for all the diseases considered to cause jaundice were normal,and fluorescein-related jaundice was diagnosed. Conclusion: A detailed anamnesis should be taken when jaundice is seen in patients who have undergone fluorescein angiography, and it should not be forgotten that fluorescein dye is a rare cause of jaundice.

Glucose-6-phosphate dehydrogenase deficiency: an unusual cause of acute jaundice after paracetamol overdose.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest human enzyme defect causing haemolytic anaemia after exposure to specific triggers. Paracetamol-induced haemolysis in G6PD deficiency is a rare complication and mostly reported in children. We report the first case (to the best of our knowledge) of acute jaundice without overt clinical features of a haemolytic crisis, in an otherwise healthy adult female following paracetamol overdose, due to previously undiagnosed G6PD deficiency. It is important that clinicians consider this condition when a patient presents following a paracetamol overdose with significant and disproportionate jaundice, without transaminitis or coagulopathy.