Acute liver injury in pregnancy.

A woman in her fifth month of pregnancy presented to the outpatient department with vomiting, generalised itching and yellowish discolouration of the skin for 1 week. No history of rashes, fever, pain abdomen or altered stools. In view of four pregnancy losses previously, she was evaluated to have antiphospholipid antibody syndrome and was advised low molecular weight heparin. She was a known type-II diabetic on insulin. Prophylactic oral dydrogesterone and natural micronised progesterone were started at a local hospital 2 months prior, in view of threatened abortion. Investigations revealed grossly elevated serum bilirubin and liver enzymes. Other blood investigations were unremarkable and abdominal ultrasonography was normal. The most likely diagnosis in this case, is drug-induced liver injury due to oral progestin consumption. Causality assessment by Roussel Uclaf Causality Assessment Model was used to establish the diagnosis. High doses of progestin over a prolonged period resulted in acute hepatic toxicity causing itching, jaundice and transaminitis. Cautious use of progestins in appropriate dosage is recommended during pregnancy.

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.

Indirect hyperbilirubinemia and jaundice during chronic hepatitis C in an HIV-infected patient treated with glecaprevir/pibrentasvir (GLE/PIB) and antiretroviral therapy (ART). The first reported case in Italy.

Glecaprevir (GLE)/pibrentasvir (PIB) is a pangenotypic direct-acting antiviral regimen approved for treating chronic hepatitis C virus. Primary treatment and re-treatment with GLE/PIB are effective and safe for patients without decompensated liver cirrhosis and chronic hepatitis C in a real-world clinical setting. However, in the context of compensated cirrhosis and concomitant administration of inhibitors of cytochromes, a careful monitoring of liver biomarkers, as well as therapeutic drug monitoring (TDM), may be advisable during GLE/PIB therapy. The GLE / PIB combination is very effective and safe in achieving a sustained virological response, but it can be associated with the development of severe hepatic adverse events, which require virological and serum concentration monitoring of the two drugs to prevent a serious liver damage. The possible onset of hyperbilirubinemia must not necessarily lead to the suspension of therapy, because the phenomenon may be transient. We report what is likely the first known case of severe jaundice after treatment with GLE/PIB in Italy in a patient with compensated chronic hepatitis in the context of HIV disease.

L-carbocisteine can cause cholestasis with vanishing bile duct syndrome in children: A case report.

RATIONALE: Vanishing bile duct syndrome (VBDS) is the acquired progressive destruction and disappearance of intrahepatic interlobular bile ducts in the absence of underlying liver or biliary tract disease, causing chronic cholestasis. Infections, drugs, toxins, malignant diseases, and certain immunological processes are associated with the development of this syndrome. There have been no reports of children developing VBDS as a consequence of the administration of L-carbocisteine. PATIENT CONCERNS: A 9-year-old Japanese girl presented with fever, jaundice, and skin rash. Laboratory investigations revealed elevated levels of serum transaminases, γ-glutamyltransferase, and bilirubin. Histopathological features were consistent with a diagnosis of VBDS. Drug-induced lymphocyte stimulation tests (DLST) were positive for L-carbocisteine. DIAGNOSIS: VBDS caused by L-carbocisteine. INTERVENTIONS: Ursodeoxycholic acid and discontinuation of L-carbocisteine. OUTCOMES: The patient responded to treatment based upon discontinuation of L-carbocisteine and administration of ursodeoxycholic acid. Her transaminase and bilirubin levels were normalized gradually. LESSONS: Physicians should be aware of the fact that L-carbocisteine can cause cholestasis with VBDS in children.

Therapeutic efficacy and safety of Yinzhihuang granules with phototherapy in neonatal pathologic jaundice: An updated systematic review and meta-analysis.

BACKGROUND: Yinzhihuang granule, consisting of extracts of Artemisia capillaris Thunb., Gardenia jasminoides Ellis, Lonicera japonica Thunb., and Scutellaria baicalensis Georgi is a well-known traditional Chinese patent medicine for patients with liver injury in China. However, the effects and safety of its use for pathologic jaundice in newborns require further systematic evaluation. PURPOSE: To systematically evaluate the efficacy and safety of Yinzhihuang granules for the treatment of neonatal pathologic jaundice and to provide clinical evidence. METHODS: Chinese databases (China Network Knowledge Infrastructure, Wan Fang Database, and VIP Database) and English databases (PubMed, EmBase, and the Cochrane Library) were thoroughly investigated through screening randomized controlled trials on Yinzhihuang granules for neonatal pathologic jaundice from the establishment of all databases to November 18, 2021. A meta-analysis was performed for selected data using STATA software. TSA software was used for trial sequential analyses of the total effective rate and adverse reactions. RESULTS: A total of 19 trials and 2,221 newborns with pathologic jaundice were included in this study. Outcome measures of clinical efficacy in the experimental group were higher than in controls, including total bilirubin (WMD = -30.34, 95% CI = -35.44 to -25.23, p < 0.001), direct bilirubin (WMD = -15.03, 95% CI = -23.54 to -6.52, p < 0.001), indirect bilirubin (WMD = -11.22, 95% CI = -17.50 to -4.95, p < 0.001), recovery time (WMD = -2.96, 95% CI = -3.92 to -2.00, p < 0.001), hospitalization time (WMD = -3.83, 95% CI = -4.89 to -2.76, p < 0.001), and liver function indices. There were statistically significant differences between the two groups. Likewise, the incidence of adverse reactions, including diarrhea, erythra, and fever decreased remarkably in the trial group (RR = 0.44, 95% CI =  0.33 to 0.59, p < 0.001). Publication bias did not exist. We verified the efficacy and safety of Yinzhihuang granules with phototherapy for pathologic jaundice in newborns according using TSA analysis. CONCLUSION: Yinzhihuang granules with phototherapy for neonatal pathologic jaundice are more effective than phototherapy alone. The incidence of ADRs does not increase with the application of Yinzhihuang granules. Due to the heterogeneity across the included studies, additional multicenter clinical trials with follow-ups are needed to confirm our findings.

Hepatotoxicity of metronidazole in Cockayne syndrome: A clinical report.

Cockayne syndrome (CS) is a rare autosomal recessive genetic disorder characterized by growth failure and progressive multisystem dysfunction caused by deficient nucleotide excision repair. Whereas metronidazole (MTZ) hepatotoxicity is quite rare in the general population, cases of severe hepatic reaction to MTZ have been reported in CS patients. We report here the case of a 21-year-old CS patient who presented with jaundice following one week of treatment with MTZ combined with spiramycin for dental care. This case is the first one documented with a liver biopsy. Histopathological analysis revealed portal and lobular inflammation with predominance of neutrophils, ballooning degeneration and severe cholestasis without bile duct damage. The outcome was marked by regression of jaundice over 6 weeks. Analysis of this case highlights the probable responsibility of MTZ and adds support to the recommendation to strictly avoid the prescription of this drug in CS patients.

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.

Clinical management of patients with drug-induced liver injury (DILI).

Drug-induced liver injury (DILI) should be considered in all patients with recent elevation of liver tests without obvious etiology and normal hepatobiliary imaging. There is currently no biomarker that is helpful in diagnosis which relies on clinical and laboratory findings. Diagnosis is dependent on temporal relationship with a recently started drug or herbal and dietary supplement and elevated liver tests with exclusion of competing etiologies. The implicated agent should be discontinued and the patient should be observed closely. This is particularly important in patients with jaundice who have approximately 10% risk of liver related mortality and/or need for liver transplantation. There is no specific therapy for DILI which is only symptomatic such as for itching. Patients with jaundice and coagulopathy usually require hospitalization.

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.

Daño hepático inducido por mesterolona: a propósito de un caso / Drug-induced liver injury due to mesterolone: A case report

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Hepatotoxicity and hematologic complications induced by fusidic acid in a patient with hepatitis B cirrhosis: A case report.

RATIONALE: Fusidic acid (FA) is an active agent against gram-positive bacteria such as Staphylococcus, it is generally well tolerated and the major adverse effects are mild gastrointestinal discomfort, diarrhea, and headache. However, some rare side effects such as granulocytopenia and thrombocytopenia have also been reported. Here we report a case of FA-induced hepatotoxicity and hematologic toxicity. PATIENT CONCERNS: A 54-year-old woman with hepatitis B cirrhosis was referred to us because of fever, Staphylococcus aureus was identified in the twice blood culture, and intravenous FA was given (0.5 g, q8 hours). Twelve days after FA therapy, she developed nausea and jaundice. Meanwhile, complete blood cell count showed neutropenia (white blood cell count of 1360/µL, neutrophil of 619/µL) and aggravated thrombocytopenia (platelet count of 18,000/µL). Adverse drug reaction was suspected, and FA was stopped immediately, after 1 day of discontinuation of FA, nose bleeding occurred and the platelet count declined further and reached the lowest value of 4000/µL. DIAGNOSES: Hepatotoxicity and hematologic complications induced by FA were diagnosed. INTERVENTIONS AND OUTCOMES: The FA was stopped immediately, and concentrated platelet transfusion was used. Five days after withdrawal of FA, jaundice resolved and the hematologic index returned to the level before the medication. LESSONS: Hematologic adverse effect accompanying with hepatotoxicity may be induced by FA. Though the risk is rather low, it should not be overlooked.

Toxicidad hepática inducida por terbinafina / Terbinafine-induced hepatotoxicity

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Immune-mediated Drug-induced Liver Injury Caused by Laninamivir Octanoate Hydrate.

We herein report the first case of immune-mediated drug-induced liver injury that may have been caused by laninamivir. A 15-year-old girl was diagnosed with influenza and prescribed 40 mg laninamivir. Six weeks later, she was admitted to our hospital because of jaundice and fatigue. Laboratory examinations revealed elevated levels of hepatobiliary enzymes, and acute liver injury was suspected. Laboratory examinations and histological findings were characteristic of autoimmune hepatitis. Steroid treatment was ineffective, and azathioprine was added to the treatment. Twenty-two months after the onset, a second biopsy revealed the absence of inflammatory infiltrations, and the drugs were withdrawn. Liver function tests remained normal nine months after withdrawal.

Severe cholestasis due to azathioprine in Behcet's disease.

Azathioprine (AZA) is an immunosuppressive drug that is widely used in the treatment of autoimmune diseases. Although AZA is used widely, many studies reported that AZA-related hepatotoxicity is rather rare. We aimed to present a case with severe cholestatic hepatitis due to AZA use for Behcet's disease. Three weeks after starting AZA for the treatment of uveitis, the patient was admitted to our clinic with cholestasis and constitutional symptoms. In liver biopsy, findings were in accordance with drug reaction, and the AZA treatment was stopped. After 2 months, bilirubin levels and liver tests results became normal. As a result, given that AZA may cause severe cholestasis, the drug should be stopped if idiosyncrasy or hypersensitivity develops. If there is a debate in the diagnosis, histopathological evaluation of the liver would be the major issue because of the correct diagnosis of the drug toxicity and excluding other aetiologies.

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.