Cases Of Drug-induced Liver Injury Research Articles

Combination of Neoadjuvant Therapy and Liver Transplantation in Pediatric Multisystem Langerhans Cell Histiocytosis With Liver Involvement.

Background: Langerhans cell histiocytosis (LCH) is characterized by misguided myeloid differentiation, whose prognosis was poor with involvement of risk organs. Remaining issues include how to improve the outcomes of patients with risk-organ involvement.Methods: A retrospective study was conducted in Renji Hospital exploring the effects of neoadjuvant therapy in combination with pediatric liver transplantation (LT) for LCH patients based on data collected between October 2006 and October 2019.Results: We presented here five cases of multisystem LCH patients underwent systemic chemotherapy to control active lesions, followed by LT to treat end-stage liver diseases. Manifestations before LT included elevated transaminase levels (n = 5, 100%), jaundice (n = 4, 80%), ascites (n = 3, 60%), and variceal hemorrhage (n = 1, 20%). Three patients underwent orthotopic liver transplantation (OLT) and two underwent living donor liver transplantation (LDLT). Until December 2019, median follow-up time was 32 months (range, 2–67 months). Liver functions significantly improved compared with pre-operative conditions. One patient had perioperative hepatic artery complications and one patient had a recurrence in the lung. EBV infection occurred in four (80%) patients and CMV infection occurred in one (20%). There was one case of drug-induced liver injury diagnosed on biopsy 13 months after LT. None underwent re-transplantation and there were no rejection or portal vein and biliary complications.Conclusion: Combination of neoadjuvant therapy and LT is an effective paradigm in treatment of multisystem LCH with severe liver dysfunction. With advances in chemotherapy regimen for multisystem LCH and LT surgery, perspectives on prognosis for LCH children are promising.

S2399 RAD-140: An Emerging Cause of Drug-Induced Liver Injury

INTRODUCTION: Selective androgen receptor modulators (SARMs) include Ligandrol, enobosarm, and RAD-140. Their tissue-selective activity is thought to promote anabolic actions without significant androgenic effects. Despite lacking FDA approval, these products are widely accessible, and have been gaining popularity as alternatives to traditional androgenic anabolic steroids (AAS). Unlike AAS, only limited human hepatic safety data are available for SARMs. We report a case of drug-induced liver injury (DILI) from RAD-140. CASE DESCRIPTION/METHODS: A healthy 24-year-old Asian male presented to the emergency department with a 2-week history of diffuse abdominal pain, jaundice, scleral icterus and worsening pruritus. He did not take any prescription medications, drink alcohol, or use recreational drugs. His only over the counter medication was RAD-140, which he took for 5 weeks and stopped 2 weeks prior to the presentation due to elevated liver enzymes, noted on routine laboratory tests. Evaluation was incomplete as he left against medical advice. Three weeks later, he was hospitalized with worsening jaundice and pruritus. His mental status remained unchanged. Initial pattern of hepatocellular injury was subsequently followed by a significant cholestasis, with total bilirubin peak around the 11th week after initiating RAD-140 intake. The trend of liver tests and international normalized ratio (INR) are summarized in Table 1. Acute and chronic liver disease evaluations were all unremarkable. Despite mildly elevated alkaline phosphatase, gamma-glutamyl transpeptidase remained normal. Ferritin was significantly elevated at 1523 ng/mL but transferrin saturation was normal. Urine toxicology drug screen was also negative. Liver imaging revealed hepatomegaly and some focal fatty infiltration but excluded biliary or vascular obstruction (Figure 1, A&B). A Liver biopsy revealed blank canalicular cholestasis without remarkable inflammation consistent with drug-induced intrahepatic cholestasis (Figure 1, C&D). Currently, he remains asymptomatic with steady improvement in liver tests after being off RAD-140 for the past 5 months. DISCUSSION: Our patient represents the second reported case of significant DILI due to RAD-140, and the third case of DILI due to SARMs requiring supplement discontinuation. This case raises concerns regarding SARMs advertised selectivity and safety. Until further data is available, these agents should be used with caution.Table 1Figure 1.: A: Contrasted cross sectional imaging showing hepatomegaly and focal fatty infiltration (white arrow). B: Magnetic resonance cholangiopancreatography showing hepatomegaly and patent biliary tree. C: Liver histology showing intrahepatic cholestasis (black arrow). D: Liver histology showing minimal portal inflammation (black arrow).

S2438 A Novel Case of Drug-Induced Liver Injury Following Intravenous Buprenorphine Use Without Concomitant Hepatitis C Viremia

S2438 A Novel Case of Drug-Induced Liver Injury Following Intravenous Buprenorphine Use Without Concomitant Hepatitis C Viremia

S2481 A Case of Sertraline-Induced Hepatotoxicity Correlated With Pharmacogenomic Testing

INTRODUCTION: Sertraline is a commonly used medication for depression and anxiety and is a type of selective serotonin reuptake inhibitor (SSRI). SSRIs are generally well tolerated, but there have been a few reports of drug induced liver injury (DILI) from this exposure. There is no reliable mechanism to predict the risk of DILI from SSRIs. Pharmacogenomic (PGx) testing is a form of genetic testing analyzing alleles of enzymes involved in metabolism. This is a case of Sertraline-induced DILI further correlated by PGx testing. CASE DESCRIPTION/METHODS: A 73 year old woman with fibromyalgia and anxiety presented for evaluation of cholestatic hepatitis. 2 months prior to presentation, she was started on sertraline 75 mg daily for chronic anxiety. 4 weeks after starting the medication, she noticed pruritus and dark urine. The SSRI was discontinued, but she continued to have symptoms. Her physical exam was notable for normal vital signs with a BMI of 20.90 kg/m2, scleral icterus and excoriations but no hepatospenomegaly or stigmata of chronic liver disease. Prior to presentation, she had normal liver function testing. Her labs were notable for total bilirubin 4.7 mg/dL, direct bilirubin 3.1 mg/dL, ALP 509 U/L, AST 280 U/L, ALT 468 U/L, INR 0.9. Viral hepatitis serologies, ANA, ASMA, ceruloplasmin, liver kidney microsomal antibody, SPEP were all unremarkable. MRCP showed no biliary ductal dilation. A liver biopsy was done showing resolving cholestatic hepatitis with no evidence of autoimmune liver disease or fibrosis. Given the slow improvement in enzymes, she was referred for PGx testing. Testing revealed that the patient was an intermediate metabolizer of serotonin with an allelic variation of the SLC6A4 as well as the HTR2A gene. Eventually, her liver enzymes normalized, and she was recommended to avoid SSRIs. DISCUSSION: Sertraline is a rare yet known culprit of DILI. There is no current reliable way of predicting one’s risk of developing DILI from SSRIs. PGx testing showed that she two polymorphisms in sertraline metabolism. SLC6A4 encodes a serotonin transporter and augments the synaptic concentration of the drug. HTR2A changes also are associated with an increase in antidepressant response of higher serotonin levels. This possibly led to increased drug levels and side effects from poor metabolism of SSRIs. With further affordability, PGx testing can be considered prior to starting medications associated with DILI to avoid prescribing it to those who may be higher risk of developing it.

S2718 Harmful Gains: Drug-Induced Liver Injury From Selective Androgen Receptor Modulators

INTRODUCTION: Hepatotoxicity associated with androgenic anabolic steroids (AASs) is well-recognized. Selective androgen receptor modulators (SARMs) such as RAD-140 (Testolone) are a novel class of agents being marketed by some supplement manufacturers as “legal steroids” that carry the advantage of androgen receptor specificity, tissue selectivity and lack of undesired AAS side effects. Data on the association of SARMs with drug-induced liver injury (DILI) is limited. Here, we present a rare case of drug-induced liver due to SARM use. CASE DESCRIPTION/METHODS: A 31-year-old male with asthma presented with 3 days of epigastric pain, jaundice and pruritis. He reported using a SARM supplement (RAD-140) for 12 weeks prior to admission. He denied alcohol use. Vital signs were normal. Physical exam was notable for scleral icterus and jaundice without other stigmata of chronic liver disease. Admission labs showed total bilirubin 8.4 mg/dL (unconjugated 2.1,conjugated), alkaline phosphatase 122 mg/dL, ALT 293 mg/dL, AST 145 mg/dL. Work-up for causes of liver injury including viral hepatitis, Wilson’s disease, hemochromatosis, autoimmune hepatitis and alpha-1-antitrypsin was unremarkable. MRI abdomen showed normal liver parenchyma, patent portal and splenic vasculature, no ductal dilatation or cholelithiasis. The cause of liver injury was thought to be SARM use. His pruritis was treated with cholestyramine. The bilirubin peaked at 20.3 mg/dL on day 15 and trended down on repeat labs 1 month after admission to 15.1 mg/dL. DISCUSSION: Despite FDA-issued public advisories regarding safety concerns associated with SARMs, they continue to be promoted for use particularly as a body building supplement. While the reported tissue selectivity of SARMs can be promising for therapeutic use in hormonal and age-related disorders, this case among others brings the aspect of tissue selectivity into question. Cases of SARM-related DILI are likely underreported and underrecognized. SARMs are thought to activate the intracellular androgen receptor that influences transcription of genes that result in androgen-stimulated cell growth. As such, they are thought to have similar consequences as AAS, which results in three types of liver injury related to augmented cell growth: peliosis hepatis, hepatic tumors and nodular regenerative hyperplasia. As SARM use becomes more prevalent, it is crucial to report these cases for earlier identification and offending agent cessation and for a better understanding of long-term consequences.

S2637 Whey Protein-Associated Liver Injury

INTRODUCTION: Drug-induced liver injury (DILI) is a common cause of liver injury and failure. Injury from dietary supplements is increasing, with an estimated rise from 8% to 20% over a ten year period from 2004 to 2014. While potential toxicity of some supplements is well documented, the potentially damaging effects of whey protein are not. Here we document a case of severe DILI caused by ingestion of whey protein. CASE DESCRIPTION/METHODS: A 44-year-old incarcerated male with no medical history presented to an outside hospital after two weeks of worsening fatigue and jaundice. He had nausea, vomiting and forty-pound weight loss over the previous month. Imaging indicated a bile duct stricture prompting transfer to our institution. On admission, ALT and AST were mildly elevated to 53U/L and 64U/L, respectively. Alkaline phosphatase was 312IU/L and total bilirubin was 26.86mg/dL with a direct bilirubin of 19.01mg/dL. Endoscopic retrograde cholangiopancreatography revealed no stricture, obstruction or mass. Viral, autoimmune and other causes of liver injury were ruled out. Although he had a strong family history of lymphoma and was subsequently found to have a mass behind his right eye, no source of malignancy could be found, as imaging was unremarkable and orbital mass was determined to be a hematoma secondary to a burst vessel. Subsequent liver biopsy suggested a drug-induced origin. He denied any medication use but admitted to taking whey protein daily for several months. A month prior to symptom onset, he increased his usage, consuming a minimum of five scoops at once, up to three times a day, well above the recommended dosage. Supportive care was provided. Over the next two weeks, he improved and was discharged. DISCUSSION: DILI is the most common cause of acute liver failure in the western world. Incidence secondary to dietary supplements is on the rise. Supplement-induced injury can lead to more severe and prolonged cases of liver injury and is also more often in a cholestatic pattern, as seen here. While no active ingredients of his supplementation are on the National Institute of Health liver toxicology list, with no other discernable cause of liver injury, whey protein was determined to be the most likely culprit. Liver injury from whey protein is poorly described with only two reported cases. Determining the causative reason for liver injury can be convoluted. When faced with DILI from an unknown source, all avenues should be explored and protein supplementation, including whey, should be considered.Figure 1.: Canalicular and hepatic perivenular cholestasis with minimal lobular and portal inflammation.Figure 2Figure 3

S2422 Drug Induced Liver Injury Associated With Oral Aloe Vera Use

INTRODUCTION: Herbal preparations and dietary supplements (HDS) use continues to increase over time, due to perceived safety and medicinal benefits. However, there are potential adverse effects associated with HDS such as drug induced liver injury (DILI). We present a case of DILI from the herbal supplement oral Aloe vera ultimately leading to orthotopic liver transplantation (OLT). CASE DESCRIPTION/METHODS: A 64-year-old female patient with a history of obesity, diabetes mellitus type 2, and hyperlipidemia presented to the hospital with jaundice and pruritus. Patient had denied acetaminophen use, alcohol misuse, and had no previous history of chronic liver disease. Patient reported taking daily oral Aloe verasupplement. Notable laboratory values on presentation were aspartate aminotransferase (AST): 1088 U/L, alanine transaminase (ALT): 785 U/L, alkaline phosphatase (ALP): 141 U/L, total bilirubin: 16.6 mg/dL, and international normalized ratio (INR): 3.2. Serological workup for causes of acute hepatitis was negative. She underwent liver biopsy which revealed acute hepatitis without significant fibrosis. Despite discontinuing Aloe vera the patient continued to deteriorate with suspected acute liver failure and ultimately required OLT. The pathological evaluation concluded that the patient had cirrhosis, which was a new finding. Post-transplant course was uneventful. DISCUSSION: DILI is defined as hepatic dysfunction caused by prescription medications, over the counter medications, and HDS after alterative causes have been excluded. Evaluating for DILI can be challenging as its presentation can vary and there are no definitive tests available. Scoring algorithms such as Roussel Uclaf Causality Assessment Model (RUCAM) and Drug-Induced Liver Injury Network (DILIN) expert consensus opinion can help in making the diagnosis of DILI. In our case, the source of hepatotoxicity was likely due to oral Aloe vera. The patient had a RUCAM score of 6 (probable DILI) and DILIN severity grade of 5+ (severe). Liver biopsy also demonstrated acute hepatitis with centrizonal necrosis and cholestasis concerning for DILI. After excluding other etiologies of acute hepatitis the likely source of hepatotoxicity was due to oral Aloe vera. This case highlights the importance of recognizing DILI associated with HDS. The lack of HDS safety regulations and a uniform HDS DILI reporting system, allow for continued HDS DILI outbreaks. Implementing a uniform reporting system can help overcome the obstacles of underreported HDS DILI.Figure 1.: CT abdomen showing an unremarkable liver and spleen.Figure 2.: H&E stain demonstrating acute hepatitis with bridging necrosis associated with canalicular cholestasis and swollen hepatocytes.Figure 3.: Tricome stain showing areas of panacinar necrosis with possible septal fibrosis.

Treatments in Covid-19 patients with pre-existing metabolic dysfunction-associated fatty liver disease: A potential threat for drug-induced liver injury?

Obese patients who often present metabolic dysfunction-associated fatty liver disease (MAFLD) are at risk of severe presentation of coronavirus disease 2019 (COVID-19). These patients are more likely to be hospitalized and receive antiviral agents and other drugs required to treat acute respiratory distress syndrome and systemic inflammation, combat bacterial and fungal superinfections and reverse multi-organ failure. Among these pharmaceuticals, antiretrovirals such as lopinavir/ritonavir and remdesivir, antibiotics and antifungal agents can induce drug-induced liver injury (DILI), whose mechanisms are not always understood. In the present article, we hypothesize that obese COVID-19 patients with MAFLD might be at higher risk for DILI than non-infected healthy individuals or MAFLD patients. These patients present several concomitant factors, which individually can favour DILI: polypharmacy, systemic inflammation at risk of cytokine storm, fatty liver and sometimes nonalcoholic steatohepatitis (NASH) as well as insulin resistance and other diseases linked to obesity. Hence, in obese COVID-19 patients, some drugs might cause more severe (and/or more frequent) DILI, while others might trigger the transition of fatty liver to NASH, or worsen pre-existing steatosis, necroinflammation and fibrosis. We also present the main mechanisms whereby drugs can be more hepatotoxic in MAFLD including impaired activity of xenobiotic-metabolizing enzymes, mitochondrial dysfunction, altered lipid homeostasis and oxidative stress. Although comprehensive investigations are needed to confirm our hypothesis, we believe that the current epidemic of obesity and related metabolic diseases has extensively contributed to increase the number of cases of DILI in COVID-19 patients, which may have participated in presentation severity and death.

Drug induced liver injury: an update.

Drug induced liver injury (DILI) is a relatively rare hepatic condition in response to the use of medications, illegal drugs, herbal products or dietary supplements. It occurs in susceptible individuals through a combination of genetic and environmental risk factors believed to modify drug metabolism and/or excretion leading to a cascade of cellular events, including oxidative stress formation, apoptosis/necrosis, haptenization, immune response activation and a failure to adapt. The resultant liver damage can present with an array of phenotypes, which mimic almost every other liver disorder, and varies in severity from asymptomatic elevation of liver tests to fulminant hepatic failure. Despite recent research efforts specific biomarkers are not still available for routine use in clinical practice, which makes the diagnosis of DILI uncertain and relying on a high degree of awareness of this condition and the exclusion of other causes of liver disease. Diagnostic scales such as the CIOMS/RUCAM can support the causality assessment of a DILI suspicion, but need refinement as some criteria are not evidence-based. Prospective collection of well-vetted DILI cases in established DILI registries has allowed the identification and validation of a number of clinical variables, and to predict a more severe DILI outcome. DILI is also in need of properly designed clinical trials to evaluate the efficacy of new DILI treatments as well as older drugs such as ursodeoxycholic acid traditionally used to ameliorate cholestasis or corticosteroids now widely tried in the oncology field to manage the emergent type of hepatotoxicity related to immune checkpoint inhibitors.

Drug-Induced Liver Injury After Liver Transplantation.

Drug-induced liver injury (DILI) is an adverse reaction to many drugs in common use that in a liver transplantation (LT) recipient may cause graft dysfunction and may even lead to graft loss and the need for retransplantation. However, several potential clinical scenarios, such as graft rejection and infection, can confound the diagnosis of suspected DILI in the setting of LT. This makes causal assessment of a new liver injury more uncertain and has traditionally precluded collection of bona fide cases of DILI affecting LT patients in prospective DILI registries and cohorts. Although no studies have yet determined a greater susceptibility of the transplant patient to DILI, these patients nevertheless present certain risk factors that can theoretically increase the risk of DILI. These include the fact that these patients are polymedicated, use drugs that are potentially hepatotoxic, and can have coexisting hepatitis B or C viruses in addition to other factors found in nontransplant patients, such as genetic variants. Therefore, awareness is crucial of any potential hepatotoxic effect of drugs used in the LT recipient and their possible implication in any case of liver dysfunction. In the present article, we review the most common drugs used in LT recipients from a liver safety perspective and address the main pitfalls in attributing causality in this clinical setting. We also affirm the need for further research and collaboration in this somewhat neglected topic in the field of DILI.

Systematic evaluation of clinical trial protocols of new drugs as a cure of chronic hepatitis B

Objective: To describe the current status of registration and design characteristics of clinical trials of new drugs for curing hepatitis B through domestic and foreign websites, so as to provide references for the follow-up clinical trials of new hepatitis B drugs. Methods: A search was conducted on the US Clinical Trials Database and the Chinese Clinical Trial Registry Center. The search date was from the establishment of the database to May 26, 2020, and the registration trials of new drugs for curing hepatitis B at home and abroad were included. Two researchers independently searched and screened the literature and extracted the data. Results: A total of 106 registered clinical trials of new drugs for curing hepatitis B were included (94 English registration websites and 12 Chinese registration websites), and the number of registrations had increased year by year. Among them, the proportion of therapeutic vaccines and core protein inhibitors were the highest, accounting for 27.4% (n = 29) and 22.6% (n = 24), respectively. The vast majority of clinical trials (n = 96, 90.6%) were in the early stages (Phase I and II). The subjects in phase I clinical trial were mainly healthy people and treated CHB patients, while the subjects in phase II clinical trial were mainly CHB patients who had achieved viral suppression after initial or post-treatment. The main evaluation indicators of Phase I clinical trials were the safety and tolerability of new drugs. The main evaluation indicators in about half of Phase II clinical trials were HBsAg negative conversion/quantitative decline. Overall, the number of clinical trials with the new design was small, accounting for 3.8% (4 / 106). There were relatively few trials of new drugs for curing hepatitis B on domestic registration websites, and the information provided was incomplete. Conclusion: The number of clinical trials of new hepatitis B drugs at home and abroad is increasing year by year, but most of them are in phase I and II, with few adopting new designs. In addition, the information integrity of the domestic website registration center needs to be improved.

Histopathological analysis of autoimmune hepatitis with "acute" presentation: Differentiation from drug-induced liver injury.

Presently, no standardized definition or acceptable diagnostic criteria have been established for acute presentation of autoimmune hepatitis (AP-AIH), making it difficult to differentiate that condition from drug-induced liver injury (DILI). This study aimed to characterize clinical and histological features for distinguishing between AP-AIH and DILI. Clinical, biochemical, and histological characteristics of AP-AIH and DILI in clinically well-characterized cases were compared in a standardized manner to clarify differences. In clinical evaluations, immunoglobulin G level and rate of anti-nuclear antibody positivity were greater in AP-AIH than DILI cases. As for diagnosis of each condition, significant (P < 0.01) differences were found for 10 features: lobular necrosis/inflammation, cobblestone appearance of hepatocytes, plasma cell infiltration in liver parenchyma, centrilobular fibrosis, hepatic rosette formation in areas with cobblestone appearance, portal inflammation, interface hepatitis, prominent plasma cells in portal areas, bile duct injury, and hepatic rosette formation in periportal areas. The area under the curve and cut-off values for the combination of these 10 features were 0.95 and 9 (sensitivity 86%, specificity 90%), respectively. Combinations of histological features were found to be helpful for differentiating AP-AIH from DILI, but we were not able to statistically identify an individual feature as definitive.

A retrospective case-controlled cohort study of inpatient drug induced liver injury: the RIDDLE study.

Identification of risk factors for drug-induced liver injury (DILI) has been hindered by the unpredictable incidence and idiosyncratic nature of DILI. The aim of this study was to identify characteristic host risk factors for DILI. A retrospective cohort study was performed examining all patients admitted with a diagnosis of DILI over a 5.5-year period. Cases were compared to a control group non-exposed to DILI using propensity score-derived inverse probability weights. Patients with DILI due to alcohol or paracetamol were excluded from analysis. Seventy-two cases of DILI admitted to hospital were identified. Antimicrobials caused 56.9% of cases, with amoxicillin-clavulanate the single most common agent, responsible for 13.9% of cases. DILI cohort median age (50.2±36 years) was significantly younger than controls (65.0±38 years) (P<0.001). Pre-existing chronic liver disease (OR, 3.44; 95% CI, 1.38-8.59; P=0.008), length of stay (P<0.001) and in-hospital death (P=0.009) were more likely to be associated with DILI cases. There was no correlation with sex (OR male, 0.92; 95% CI, 0.50-1.67; P=0.78), presence of comorbid autoimmune disease (OR, 1.44; 95% CI, 0.68-3.05; P=0.35), past drug allergies (OR, 1.71; 95% CI, 0.92-3.16; P=0.09), or atopy (OR, 0.87; 95% CI, 0.42-1.82; P=0.72). Younger age and presence of chronic liver disease were associated with an admission with DILI; however, it remains difficult to predict the population at risk of DILI on clinical grounds and putative risk factors such as female gender, and history of other drug allergies and autoimmunity, were not demonstrated in this study.

Liver injury caused by oral anticoagulants: A population-based retrospective cohort study.

Idiosyncratic drug-induced liver injury (DILI) is a rare adverse event. DILI caused by direct oral anticoagulants (DOACs) has been reported, however, data on the risk of DILI are limited. The aim of the study was to evaluate the frequency of DILI caused by oral anticoagulants (OACs) in a population-based setting. A computerized database search in The National Prescription Database was performed identifying all patients in Iceland who were prescribed OACs (rivaroxaban, apixaban, dabigatran, edoxaban or warfarin) in 2008-2017. Personal identification numbers of these patients were linked with a database containing laboratory results for all hospitals and most outpatient clinics in Iceland. A medical chart review was performed in all cases where onset of liver injury followed intake of OACs. Patients with other specific causes of liver injury were excluded. Causality assessment with the RUCAM method was undertaken in cases with suspected DILI. Three cases of suspected DILI were identified. In all cases, rivaroxaban was the implicated agent among patients prescribed this product (n=3446). All were women with a hepatocellular type of liver injury. One patient developed a suspected drug-induced autoimmune hepatitis and was treated with corticosteroids. No cases of DILI in patients on warfarin (n=9101), apixaban (n=1903), dabigatran (n=1335) and edoxaban (n=34) were identified. Rivaroxaban was the only OAC associated with DILI during the 10-year study period. Approximately 1 in 1100 patients treated with rivaroxaban developed DILI. Other OACs were not associated with liver injury in this population-based study.

Drug Induced Liver Injury (DILI) due to variability in monacolin K content in Red Yeast Rice (RYR): An expert opinion

IntroductionRed yeast rice (RYR) is an effective cholesterol-lowering nutraceutical reversibly inhibiting 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase. As liver damage is a possible (albeit rare) side effect of HMG-CoA inhibitors, it make sense to focus on the tolerability of the liver to RYR extracts. The aim of this paper is to offer an expert opinion on the risk of liver damage by the use of RYR extract. MethodsA review of the available literature has been carried out and critically reviewed by the authors. ResultsAccording to a large meta-analysis of 53 randomized clinical trials comprising 112 treatment arms, which included 8535 subjects with 4437 in the RYR arm and 4303 in the control arm of the study, RYR administration was not associated with increased risk of Drug Induced Liver Injury (DILI) during RYR treatment. Single cases of DILI have been associated with the use of RYR supplements. Even if the causal relationship is hardly demonstrable, it is possible that products containing impurities or toxic elements such as citrinin or unstandardized dosages of bioactive compounds like monacolins, could be implicated in liver toxicity. ConclusionDILI associated with RYR intake are exceptional and hardly associated to RYR per se rather than to low-quality products. Nutrivigilance and stricter manufacturing regulations should be implemented and are recommended in order to protect consumers from low quality and potentially dangerous dietary supplements.

Incidence and Sequelae of Liver Injury Among Children Treated for Solid Tumors: Analysis of a Large Single-Center Prospective Cohort.

Pediatric oncology patients are at risk of adverse drug events. The incidence and etiologies of liver injury in this population are not well characterized. We utilized a large, single-center pediatric oncology registry to investigate the incidence, causes, and outcomes of liver injury during treatment for solid tumor malignancies. We reviewed all young individuals (age <25 years) who received treatment for any solid tumor at the University of Michigan between January 2004 and July 2016. Subjects with liver injury meeting predetermined laboratory criteria were identified. Cases were independently reviewed by 2 expert hepatologists to assign a cause of liver injury. Clinical characteristics of drug-induced liver injury (DILI) and non-DILI cases were compared. Cases of liver injury occurring after bone marrow or liver transplant were excluded. Of 1136 solid tumor patients, 160 (14%) experienced liver injury, and the overall frequency of DILI was 4%. DILI was the leading identified cause of liver injury (31%), followed by infection (17%), metastatic/malignant biliary disease (13%), and perioperative liver injury (13%). Most DILI cases (>90%) were mild acute hepatocellular injury episodes that did not result in modification to the chemotherapy plan, and all DILI eventually resolved. Severe presentations involving jaundice and/or prolonged hospital course were significantly more common among non-DILI versus DILI cases (23% vs 2%, P < 0.001). DILI is the leading cause of liver injury events among pediatric solid tumor patients. In our registry, DILI was of mild severity and did not result in an alteration of the treatment plan in most patients. In contrast, non-DILI-related liver injury events, including infection, were more likely to have a more severe presentation and a complicated course with a greater mortality during follow-up.

Role of liver biopsy in the era of clinical prediction scores for “drug-induced liver injury” (DILI): experience of a tertiary referral hospital

The clinical implications of the biopsy findings in cases of drug-induced liver injury (DILI) are not fully elucidated. The aim of this study was to evaluate the histopathological findings of cases diagnosed as DILI and to correlate them with clinical and biochemical findings (such as causality assessment algorithms). We searched our department database for all cases of liver biopsy with findings consistent with toxic liver disease and selected those with a clinical diagnosis of DILI. The causative relationships were established according to Roussel Uclaf Causality Assessment Method (RUCAM). A total of 53 cases of DILI were reviewed, most of them diagnosed in hospitalized patients (83%). The analytical toxicity profile was hepatocellular (R > 5) in 60% of the cases and cholestatic (R < 2) in 26.4% of cases. The group of drugs most implicated was the anti-microbials (18, 34%). The predominant histological patterns were "necroinflammation" (67.9%) and "cholestasis" (28.3%). The hepatocellular biochemical pattern was not associated with the presence of predominantly necroinflammatory findings in the biopsy (p = 0.44), and the biochemical cholestatic pattern was not associated with the presence of predominantly cholestatic findings in the biopsy (p = 0.51). This study supports that a better insight into the pathologic mechanisms associated with DILI should be based on liver biopsy due to the lack of a uniform correlation between clinical and biochemical patterns. Also, a liver biopsy may be used in those cases where clinical suspicion of DILI persists despite a low score on current causality assessment algorithms.

Herb-induced Liver Injury in Asia and Current Role of RUCAM for Causality Assessment in 11,160 Published Cases.

Herb-induced liver injuries (HILI) by traditional herbal medicines are particular challenges in Asian countries, with issues over the best approach to establish causality. The aim of the current analysis was to provide an overview on how causality was assessed in HILI cases from Asian countries and whether the Roussel Uclaf Causality Assessment Method (RUCAM) was the preferred diagnostic algorithm, as shown before in worldwide evaluated cases of drug-induced liver injury (DILI). Using the PubMed database, publications in English language were preferred to allow for reevaluation by peers. Overall 11,160 HILI cases have assessed causality using RUCAM and were published by first authors working in Asian countries. With 21 evaluable reports, most publications came from mainland China, with Hong Kong and Taiwan, followed by Korea (n=15), Singapore (n=2), and Japan (n=1), while other Asian countries were not contributory. Most publications provided case and RUCAM data of good quality. For better presentation of future cases, however, the following recommendations are given: (1) preference of prospective study design with use of the updated RUCAM version; (2) clear separation of HILI cohorts from those of other herbal products or DILI; (3) case series for epidemiology studies should contain many essential data, possibly also as supplementary material; (4) otherwise, preference of single case reports providing individual case data and RUCAM-based causality gradings, and applying liver test threshold values; and (5) publication in English language journals. In conclusion, China and Korea are top in presenting RUCAM-based HILI cases, other Asian countries are encouraged to follow.

Drug induced liver injury is associated with high mortality-A study from a tertiary care hospital in Pakistan.

In light of few established drug induced liver injury (DILI) registries, this study aims to evaluate the clinical spectrum and predictors of mortality and morbidity of hospitalized patients with suspected DILI. DILI cases were identified and categorized on basis of COIMS/RUCAM score and the exclusion of other liver diseases. Clinical and laboratory parameters were analyzed to identify the predictors of morbidity (prolonged hospital stay > 5 days) and mortality. Out of 462 patients, there were 264 (57.6%) males and the mean age of the cohort was 50.83 years (range: 20-94 years). DILI was classified as definite or highly probable in 31.1%, probable in 62.5%, and possible in 7.4% of cases. Pattern of liver injury was hepatocellular in 25.1%, cholestatic in 56.17%, and mixed in 18.72% of patients. Anti-tuberculosis drugs (ATDs) were found to be the most common category of drugs causing DILI, in 295 (63.9%) patients. Clinically, encephalopathy was present in 21.6% patients; other presenting symptoms included abdominal pain (57.1%), vomiting (57.1%), jaundice (54.1%) and pruritus (42.3%). In-hospital mortality was 26.5% and prolonged hospital stay (> 5 days) was observed in 35.93% of patients. Mortality was significantly greater in patients with encephalopathy, male gender, hepatocellular pattern of DILI, increased INR and use of ventilator support. In our study, the most frequent cause of DILI in hospitalized patients was ATDs. More than a quarter of patients died during hospital stay. A close control of clinical and biochemical parameters are required to prevent and monitor DILI, especially in patients taking ATDs in our region.

Drug-induced liver injury: an analysis of 384 cases

Objective To analyze the causes, clinical characteristics and treatment outcomes of drug-induced liver injury (DILI). Methods The general information, medication history, clinical classification, grade of liver injury and clinical outcome of 384 patients with drug-induced liver injury admitted in Changjiang River Hospital during January 2014 to December 2018 were retrospectively analyzed. Results Among 384 cases of drug-induced liver injury, there were 191 cases aged ≥60 (49.7%). The top three drugs inducing liver injury were antibiotics, anti-tuberculosis drugs and immune-enhancing Traditional Chinese Medicine (TCM) decoction, accounting for 40.6%(156/384), 20.3%(78/384)and 15.6% (60/384), respectively. In 60 cases of TCM decoction-induced liver injury, 39 cases were cholestatic liver injury (65.0%,39/60), 11 cases were hepatocellular liver injury (18.3%,11/60) and 10 were mixed liver injury (16.7%,10/60) (χ2=40.650, P<0.01). In 44 cases of DILI caused by anti-cancer chemotherapeutic drugs, 25 cases were hepatocellular liver injury (56.8%,25/44), 12 cases were cholestatic liver injury (27.3%,12/44) and 7 cases were mixed liver injury (15.9%,7/44) (χ2=17.659, P<0.01). The proportion of treatment failure in patients with grade 4 liver injury was 5/10 and the proportion of mortality in patients with grade 5 liver injury was 8/8, which were significantly higher than those with lower grade liver injury (χ2=157.218, P<0.01; χ2=320.917, P<0.01). Conclusion The development of drug-induced liver injury and its clinical classification are related to the types of drug, and the prognosis of drug-induced liver injury is depended on the degree of liver injury. Key words: Drug-induced liver injury; Anti-bacterial agents; Antitubercular agents; Drugs, Chinese herbal