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

Causality assessment methods in drug induced liver injury: Strengths and weaknesses

Do Hepatotoxicity Registries Have a Role in Health Care?

BackgroundDurvalumab is approved for the treatment of lung cancer, advanced biliary tract cancers, and is also being evaluated in many other solid organ tumors. The aim of our study is to define the incidence, etiology, and outcomes of liver injury in consecutive patients receiving durvalumab-based immunotherapy.Patients and methodsDurvalumab treated patients between 1/2016 – 7/2020 were identified from the electronic medical record. Liver injury was defined as serum AST or ALT ≥ 5x upper limit of normal (ULN), ALP ≥ 2x ULN, bilirubin ≥ 2.5 mg/dl, or INR ≥ 1.5. Potential drug induced liver injury (DILI) cases were adjudicated using expert opinion scoring and confirmed with Roussel Uclaf Causality Assessment Method (RUCAM).ResultsAmongst 112 patients, 58 (52%) had non-small cell lung cancer, the median age was 65 years, and 60% were male. The 21 (19%) liver injury patients were significantly more likely to harbor hepatic metastases (52% vs 17%, p=<0.001), experience tumor progression (67% vs 32%, p=0.01) or die (48% vs 11%, p<0.001) during follow-up compared to the 91 without liver injury. Using multivariate regression analysis, the development of liver injury during treatment as well as baseline hepatic metastases were independently associated with mortality during follow-up. Six of the 21 (29%) liver injury cases were adjudicated as probable DILI with four attributed to durvalumab and two due to other drugs (paclitaxel, pembrolizumab). Durvalumab was permanently discontinued in two DILI patients, three received corticosteroids, and one was successfully rechallenged. Only one patient with DILI developed jaundice, and none required hospitalization. Liver biochemistries normalized in all 6 DILI cases, while they only normalized in 27% of the 15 non-DILI cases (p=0.002). The 6 DILI patients also had a trend towards improved survival compared to those with other causes of liver injuryConclusionLiver injury was observed in 19% of durvalumab-treated patients and is associated with a greater likelihood of tumor progression and death during follow-up. The four durvalumab DILI cases were mild and self-limited, highlighting the importance of causality assessment to determine the cause of liver injury in oncology patients receiving immunotherapy.

Idiosyncratic drug-induced liver injury (DILI) is an important cause of liver injury that is difficult to diagnose and identify in the electronic medical record (EMR). Our objective was to develop a computerized algorithm that can reliably identify DILI cases from the EMR. The EMR was searched for all encounters with an International Classification of Diseases, Tenth Revision (ICD-10) T code for drug toxicity and a K-71 code for toxic liver injury between 1 October 2015 and 30 September 2018. Clinically significant liver injury was defined using predetermined laboratory values. An expert opinion causality score (1-3 = probable DILI, 4/5 = non-DILI), Roussel Uclaf Causality Assessment Method (RUCAM) score, and severity score was assigned to each case. Among the 1,211,787 encounters searched, 517 had both an ICD-10 T code and a K-71 code, with 257 patients meeting the laboratory criteria. After excluding 75 cases of acetaminophen hepatotoxicity, the final study sample included 182 cases of potential DILI, with antineoplastics and antibiotics being the most frequently implicated agents. Causality assessment identified probable DILI in 121 patients (66.5%), whereas 61 (33.5%) had an alternative cause of liver injury. Although age, sex, race, and suspect drugs were similar, the probable DILI cases were more likely to present with a hepatocellular injury profile and have more severe liver injury than the non-DILI cases (p < 0.05). A computerized algorithm based on a combination of ICD-10 codes identified 182 potential DILI cases with 121 true positives, 61 false positives, and a positive predictive value of 66.5%. Future studies incorporating natural language processing may further improve the utility of this algorithm in identifying high-causality idiosyncratic DILI cases.

Phosphodiesterase type 5 inhibitors (PDE5I) are prescribed for erectile dysfunction and pulmonary hypertension. Despite its widespread use, there are only seven cases of drug-induced liver injury (DILI) associated with PDE5I, none associated with vardenafil or avanafil. We report a patient who had taken vardenafil and tadalafil individually for several years without developing symptoms of liver injury. However, after taking vardenafil and tadalafil together on 2 consecutive days, he developed severe cholestasis. Causality was determined using Roussel Uclaf causality assessment method (RUCAM). The patient is a 72-year-old White man in excellent health who drank 2 units of alcohol, three times/week. Previously, he had used vardenafil for more than 2 years and tadalafil for 3 months as single agent for erectile dysfunction without any complications. He took vardenafil and tadalafil for 2 consecutive days and 5 days later, he developed dyspepsia, loss of appetite, jaundice, and intense itching. Liver tests showed mixed cholestatic/hepatocellular pattern of injury. Histology showed marked cholestasis with minimal inflammation. He remained cholestatic for 5 weeks before a full recovery 2 months later. The patient then resumed vardenafil monotherapy with no recurrent liver dysfunction. RUCAM causality score 7 indicates that the combination of PDE5I is probable cause of liver injury. The similarities among the eight cases of PDE5I DILI include a relatively short latency, cholestatic histological features, and complete recovery. Biochemical pattern of liver injury is variable. PDE5I DILI is a rare event that can result in severe acute liver injury.

Heart-leaved Moonseed- Innocuous or Baneful

High Prevalence of Ibuprofen Drug-Induced Liver Injury in Spanish and Latin-American Registries

Liver Injury Associated With Drugs and Complementary and Alternative Medicines in India

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.

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

Introduction: The diagnosis of drug induced liver injury (DILI) is difficult as it is largely a clinical diagnosis of exclusion. To aid in diagnostic decision making, we reviewed cases enrolled in DILIN with an initial diagnosis of DILI that were ultimately adjudicated as unlikely with alternative etiologies accounting for the abnormal liver tests. Methods: The DILIN is an ongoing NIH observational trial in which hepatologists enrolled patients from 2004 to the present with a high suspicion of DILI. Cases were adjudicated by a panel of experts through a structured process and scored from 1 (definite DILI) to 5 (unlikely DILI). Cases that were scored at least probable DILI (1-3) were compared to unlikely DILI (5). Unlikely cases were further reviewed for salient features and trends over time. Results: From 9/04 to 12/21, 1916 cases were adjudicated; 134 (7%) were unlikely DILI. There were no demographic features to distinguish at least probable cases from unlikely cases. Unlikely cases more often had renal disease (18% vs 9%, p=0.005), HIV (7% vs 2% p< 0.001), hepatitis C (HCV) (12% vs 3% p< 0.001), and hepatitis B (5% vs 1 % p< 0.001). Unlikely DILI vs. true DILI was higher for brief latency between drug use and liver injury (< 1 week 9% vs 5%) or very long latency ( >24 weeks 28% vs 16%) p=0.002 overall. The most common alternative diagnoses for unlikely cases were autoimmune hepatitis (AIH) (20%) and HCV (20%) (Table). Among white patients, carriage frequency of two copies of HLA-DQA1*03:01 was greater among those with AIH (13%) compared to DILI (3%) and population controls (1%). Patients with unlikely DILI had greater all-cause (16% vs 7%, p< 0.001) and liver related mortality (10% vs 3%, p< 0.001). Unlikely DILI cases died within six months at a higher rate (14% vs 6%, p=0.004). Transplant rates, hospitalization, and duration of illness were similar. Conclusion: DILI is difficult to diagnose, even among experienced hepatologists. Demographic factors are not helpful in the initial diagnosis. Very short or very long latency between suspect drug and initial liver injury decreases likelihood of true DILI. HCV PCR testing is critical in presumed DILI. Genetic testing in white patients with AIH vs. DILI may be useful. Longitudinal follow up of patients with DILI is essential to refine the diagnosis, treat an alternative disease, and potentially absolve a medication presumed to have caused DILI. Table 1. - Alternative Diagnoses in 134 Unlikely DILI cases Diagnosis N % Comments Autoimmune hepatitis 27 20.1 The most common incorrectly implicated class of medications were antibiotics (9/27) followed by HDS products (8/27). Nearly all had a liver biopsy, but findings were neither diagnostic for DILI nor classic for AIH. Other common themes included 1) prevalent systemic immune mediated disease (systemic lupus erythematous, hypothyroidism, inflammatory bowel disease, etc.) in 8/27 cases; 2) negative or relatively low antinuclear antibody titers (< 1:80) which increased on follow up; 3) a response to steroids in 14/27 with six of these having a flare in enzymes after immunosuppression titration or withdrawal. Hepatitis C 27 20.1 Of the 24 that were acute cases, 17 were enrolled prior to 2011 and none since 2017. Most of these cases had negative HCV antibodies and were discovered to have a positive HCV viral load later in their clinical course. Three patients had prevalent detectable HCV virus which later cleared spontaneously on follow up. Gallstones/BiliaryDisease 18 13.4 Eight cases with biliary tract malignancy.Three cases with primary sclerosing cholangitis. Normal imaging in some patients who acutely passed a stone.No differences in the presence of stones (3.3% vs. 6.7% p=0.32), or ductal dilation (3.3% vs. 2.5% p=0.89) between unlikely DILI and probable and higher DILI cases. Hepatitis E 11 8.2 Diagnosis often delayed as test is a send-out in most centers. Sepsis 7 5.2 Frequently in Intensive Care Unit on multiple drugs and hypotensive. Other ( >20 diverse etiologies) 44 32.8 Etiologies included alcohol, myopathy, Epstein Barr virus, cytomegalovirus, nonalcoholic steatohepatitis, metastatic cancer, and granulomatous liver disease.

Drug-Induced Liver Injury

Liver Injury Following Tinospora Cordifolia Consumption: Drug-Induced AIH, or de novo AIH?

Introduction: Drug-induced liver injury (DILI) is a common cause of hepatotoxicity that has been associated with multiple medications and supplements. Herein, we present an intriguing case of DILI related to preoperative Cefazolin administration. Case Description/Methods: A 64-year-old female with history of breast cancer presented for right upper quadrant abdominal pain, nausea, vomiting, and jaundice for 1 week. The patient underwent left mastectomy with administration of a single dose of preoperative IV Cefazolin about three weeks prior to presentation. On presentation, vital signs were within normal limits. On physical exam, the patient was noticeably jaundiced with right upper quadrant tenderness. Laboratory studies showed total bilirubin 11.9 mg/dL, direct bilirubin 8 mg/dL, alkaline phosphatase 603 IU/L, AST 165 IU/L, ALT 376 IU/L. Abdominal ultrasound found no biliary obstruction. Magnetic resonance cholangiopancreatography noted mild hepatomegaly with no intrahepatic or extrahepatic ductal dilatation. Workup for autoimmune disease, Wilson disease, and hemochromatosis was negative. Testing for hepatitis A and C was negative. The patient had positive HBcAb, however, HBsAg, HBsAb, and quantitative DNA PCR were negative. Liver biopsy showed cholestatic hepatitis, no significant fibrosis, and prominent eosinophils consistent with DILI. The patient was diagnosed with DILI secondary to Cefazolin administration. She was ultimately discharged home with improvement of symptoms and repeat lab work showing normalization of liver chemistries. Discussion: Cefazolin is an antibiotic that is widely used for surgical prophylaxis, and it can be overlooked when working up acute liver injury, as it is usually a one-time dose. According to LiverTox, the latency period between administration and onset of liver injury is typically 1-4 weeks with most cases causing mild elevations of liver enzymes, however, significant elevations in aminotransferases greater than 5 times the upper limit of normal are rare (< 1%). Hepatotoxicity is likely due to hypersensitivity with primarily cholestatic patterns of liver enzymes, but mixed and hepatocellular patterns have been described. Our patient displayed a mixed pattern after one dose of Cefazolin, and eosinophils were present on biopsy consistent with hypersensitivity. This case highlights the importance of thoroughly reviewing a patient’s history to help diagnose potential causes of liver injury, especially DILI, as it is imperative to the definitive management.Figure 1.: H&E stain (high power) showing intrahepatic cholestasis (A). H&E stain (high power) showing portal inflammation with prominent eosinophils (B).

There are limited data on the causative agents and characteristics of drug-induced liver injury in pregnant individuals. Data from patients with drug-induced liver injury enrolled in the ongoing multicenter Drug-Induced Liver Injury Network between 2004 and 2022 and occurring during pregnancy or 6 months postpartum were reviewed and compared with cases of drug-induced liver injury in nonpregnant women of childbearing age. Among 325 individuals of childbearing age in the Drug-Induced Liver Injury Network, 16 cases of drug-induced liver injury (5%) occurred during pregnancy or postpartum. Compared with drug-induced liver injury in nonpregnant women, pregnancy-related drug-induced liver injury was more severe ( P <.05). One elective termination and three miscarriages were documented; there were no maternal deaths. We recommend that isoniazid for latent tuberculosis be deferred to the postpartum period whenever feasible and that β-blockers or calcium channel blockers rather than methyldopa be used for hypertension management during pregnancy.