Drug-induced Liver Injury Recognition Research Articles

Possible cholestatic hepatitis with clindamycin therapy: A case report

Introduction: Clindamycin is a lincosamide antibiotic that is effective against streptococci, staphylococci, and anaerobic bacteria. Though it predominantly undergoes hepatic metabolism, no dose adjustments are recommended for patients with hepatic dysfunction. Hepatotoxicity is a rare side effect and even though transient elevation of liver enzymes has been reported, there are very few cases of acute idiosyncratic liver injury. Case Presentation: A 49-year-old male from Sri Lanka, with no knowncomorbidities, was treated with oral clindamycin for left lower limb cellulitis. He was investigated for a low platelet count and was diagnosed to have chronic liver cell disease (CLCD) on day two of admission following an ultrasound scan of the liver. On day four of treatment, the patient developed deep icterus and asterixis. The serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels rose from normal levels to 681 U/L and 1100 U/L respectively. Total bilirubin had risen to 158.5 micromole/L with a high direct fraction of 116.1 micromole/L and alkaline phosphatase (ALP) was 108 U/L. Drug induced liver injury (DILI) was suspected immediately and clindamycin treatment was withheld. The patient’s symptoms improved over the next few days and the AST, ALT levels dropped immediately and returned to normal within three weeks. Serum anti-nuclear antibody and anti-mitochondrial antibody were negative. IgM antibodies for hepatitis A, C, E, and Epstein-Barr virus were negative and the test for hepatitis B surface antigen was negative. The serum ferritin and transferrin saturation were normal and there were no Kayser–Fleischer rings in the eyes. The urine toxicology screen was negative. Conclusion: This case highlights a rare but important complication of clindamycin treatment. Clinicians should be vigilant when starting clindamycin in a patient diagnosedor suspected to have CLCD and such patients should be monitored for DILI. Early recognition of DILI is essential and immediate discontinuation of drug is the most important intervention which alone can lead to resolution of the injury.
 Keywords: Clindamycin, Cholestasis, Hepatitis

Characterization of drug-induced liver injury associated with drug reaction with eosinophilia and systemic symptoms in two prospective DILI registries.

Idiosyncratic drug-induced liver injury (DILI) associated with drug reactions with eosinophilia and systemic symptoms (DRESS) is poorly characterized among patients of Western countries. We aimed to comprehensively assess the clinical characteristics, outcomes, and causative agents in a prospective, well-vetted cohort of DILI patients with DRESS (DILI-DRESS). We identified 53 DILI-DRESS cases from the Spanish DILI Registry and the Latin American DILI Network. For comparison purposes, we defined a group of DILI patients (n = 881). DILI-DRESS cases were younger (47 vs. 53years, respectively; p = 0.042) and presented more frequently with cholestatic/mixed damage (p = 0.018). Most DILI-DRESS patients showed moderate liver injury, 13% developed severe damage, and only one patient (with hepatocellular injury due to anti-tuberculosis drugs) progressed to acute liver failure and died. DILI-DRESS cases showed a distinctive causative drug pattern compared to DILI cases. The most frequent drugs were carbamazepine (13%), anti-tuberculosis drugs (13%), amoxicillin-clavulanate (11%), and allopurinol and lamotrigine (7.6% each). Among all cases of DILI due to allopurinol and lamotrigine, 67% presented with a DILI-DRESS phenotype, respectively. Higher total bilirubin (TBL) levels at DILI recognition (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.04-1.45) and absence of eosinophilia (OR 8.77; 95% CI 1.11-69.20) increased the risk for developing a severe-fatal injury in DILI-DRESS patients. DILI-DRESS patients have a more frequent cholestasis/mixed pattern of injury at presentation, with antiepileptics as distinctive causative drug class. Most of the lamotrigine and allopurinol cases present with this phenotype. Higher TBL levels and absence of eosinophilia at DILI recognition are markers of poor outcomes.

S3188 The Tale of an Ancient Herb: A Stress Reliever or a Liver Stressor

Introduction: Ashwagandha is found in several herbal products today. However, there is a paucity of literature regarding its safety. Our case serves to remind physicians about the potential liver toxicity of Ashwagandha and to illustrate how early recognition of drug-induced liver injury (DILI) and discontinuation of the offending substance can be lifesaving. Case Description/Methods: A 58-year-old man with a remote history of hepatitis B and C presented with nausea, vomiting, and right upper quadrant abdominal pain of one day duration. He reported using an herbal supplement called “Primal Male,” which contained Ashwagandha as a main ingredient, over the past two weeks. He was normotensive, tachycardic up to 120 beats per minute (bpm), and febrile. The initial laboratory studies were notable for elevated AST level of 954 U/L, ALT level of 860 U/L, and a normal alkaline phosphatase level of 101 U/L. He had a normal total bilirubin level and an international normalized ratio of 1.3. His complete blood count and renal function were unremarkable. His creatinine kinase (CK) level was also within the normal range. His drug test, alcohol level, and acetaminophen level were unremarkable. The viral panel did not suggest active viral infections. His autoimmune panel was negative. An abdominal CT scan did not reveal any acute abnormality. In the following days, his symptoms worsened, and he became more encephalopathic. His AST, ALT, total bilirubin, and INR levels continued to rise. He developed hypotension and received intravenous fluids and midodrine. He also completed a course of N-acetylcysteine treatment. On the fifth day of admission, he underwent a transjugular liver biopsy. Liver histology showed active lymphocytic hepatitis with moderate inflammation (primarily lymphocytes, abundant neutrophils, and occasionally eosinophils) around the portal tract. On the sixth day of hospitalization, he reported decreasing pain and was more hemodynamically stable. His liver enzymes also showed improvement. The cause of acute liver injury was suspected to be drug-induced liver injury from Ashwagandha use. He was counseled to avoid the use of the herbal supplement and other hepatotoxic products. One month later, his liver enzymes were in normal range. Discussion: DILI is a less common form of liver injury but is a leading cause of acute liver failure in the United States. Ashwagandha has been reported in a few cases of DILI. It is important to have an early suspicion of the offending agent and avoid further substance exposure.

Development of peroxynitrite-responsive fluorescence probe for recognition of drug-induced liver injury

Peroxynitrite (ONOO−) as an active substance, is produced during normal physiological process, which plays an important role in maintaining cell REDOX balance and cell function. Moreover, the peroxynitrite is involved in many diseases and especially can be used as a biomarker of drug-induced liver injury (DILI). Therefore, in this work, we synthesized a fluorescent probe JQ-3 for detecting ONOO−. The results showed the probe JQ-3 possessed excellent selectivity, fast response time (10 min) and low detection limit (32 nM). The probe JQ-3 is almost unaffected by pH, showing the potential application in biological systems. Moreover, the probe JQ-3 can be successfully used for the detection of exogenous and endogenous ONOO− in living cells and zebrafish. At the same time, the DILI was successfully recognized by visualizing ONOO− with JQ-3 in living cells and zebrafish. Therefore, the probe JQ-3 provides a potential tool for detecting ONOO− to understand physiological and pathology processes of disease.

Drug properties and host factors contribute to biochemical presentation of drug-induced liver injury: a prediction model from a machine learning approach

Drug-induced liver injury (DILI) presentation varies biochemically and histologically. Certain drugs present quite consistent injury patterns, i.e., DILI signatures. In contrast, others are manifested as broader types of liver injury. The variety of DILI presentations by a single drug suggests that both drugs and host factors may contribute to the phenotype. However, factors determining the DILI types have not been yet elucidated. Identifying such factors may help to accurately predict the injury types based on drugs and host information and assist the clinical diagnosis of DILI. Using prospective DILI registry datasets, we sought to explore and validate the associations of biochemical injury types at the time of DILI recognition with comprehensive information on drug properties and host factors. Random forest models identified a set of drug properties and host factors that differentiate hepatocellular from cholestatic damage with reasonable accuracy (69-84%). A simplified logistic regression model developed for practical use, consisting of patient's age, drug's lipoaffinity, and hybridization ratio, achieved a fair prediction (68-74%), but suggested potential clinical usability, computing the likelihood of liver injury type based on two properties of drugs taken by a patient and patient's age. In summary, considering both drug and host factors in evaluating DILI risk and phenotypes open an avenue for future DILI research and aid in the refinement of causality assessment.

An unusually impressive atorvastatin-induced elevation of serum alkaline phosphatase

A 90-year-old woman is referred six months after a transient ischaemic attack (TIA) with asymptomatic cholestatic liver function test (LFT) derangement. Following the TIA, atorvastatin and clopidogrel therapy are initiated....

Strategies for Early Prediction and Timely Recognition of Drug-Induced Liver Injury: The Case of Cyclin-Dependent Kinase 4/6 Inhibitors.

The idiosyncratic nature of drug-induced liver injury (DILI) represents a current challenge for drug developers, regulators and clinicians. The myriad of agents (including medications, herbals, and dietary supplements) with recognized DILI potential not only strengthens the importance of the post-marketing phase, when urgent withdrawal sometimes occurs for rare unanticipated liver toxicity, but also shows the imperfect predictivity of pre-clinical models and the lack of validated biomarkers beyond traditional, non-specific liver function tests. After briefly reviewing proposed key mechanisms of DILI, we will focus on drug-related risk factors (physiochemical and pharmacokinetic properties) recently proposed as predictors of DILI and use cyclin-dependent kinase 4/6 inhibitors, relatively novel oral anticancer medications approved for breast cancer, as a case study to discuss the feasibility of early detection of DILI signals during drug development: published data from pivotal clinical trials, unpublished post-marketing reports of liver adverse events, and pharmacokinetic properties will be used to provide a comparative evaluation of their liver safety and gain insight into drug-related risk factors likely to explain the observed differences.

3171 Amoxicillin-Clavulanate Related Mixed Cholestatic-Hepatocellular Injury

INTRODUCTION: Recognition of Drug-induced Liver Injury (DILI) may be challenging as it is often diagnosis of exclusion, unavailability of diagnostic test and variability in presentation. Many antibiotics can cause DILI but Amoxicillin-Clavulanate has rare adverse reaction causing mixed cholestatic-hepatocellular injury. Since amoxicillin alone does not induce liver injury, combination of amoxicillin and clavulanic acid could be responsible for this adverse reaction. It can be due to metabolic idiosyncrasy or hypersensitivity mechanism. CASE DESCRIPTION/METHODS: 64-year-old female with no pertinent PMH presented to ER with abdominal pain and jaundice. She had abdominal pain for 4-5 days. Abdominal pain was constant and located at right upper quandrant and epigastric region. She had associated complaint of nausea, vomiting, metallic taste and chills. Patient had been avoiding eating in fear of vomiting. She also had pale colored stool. Patient did not have any history of gall stones, hepatitis or alcohol use. On further inquiry, she reported being on Amoxicillin-Clavulanate for 4 days, for dental abscess, before onset of symptoms. She stopped taking antibiotic as soon as she started having above-mentioned symptoms. Patient was not on any other new medications during this time-period. On initial evaluation, patient was found to have elevated liver enzymes with T.bilirubin 6.4, AST 218, ALT 288, ALP 331. Due to broad differentials associated with elevated liver enzymes with abdominal pain, further workup was done. Abdominal CT scan and MRCP results were unremarkable. Hepatitis panel was also negative. Patient was provided with supportive care and hydration with IV fluids. Repeat labs done on 4th day after admission showed down trending LFTs – T.bill 3.8, AST 152, ALT 141, ALP 253. DISCUSSION: Amoxicillin-Clavulanate can cause hepatocellular, cholestasis or mix type of liver injuries depending upon genetic factors or pre-existing liver conditions. Early recognition and removal of offending medication is the initial mainstay of treatment along with supportive care. This case signifies proper history taking and review of medications could avoid unnecessary and expensive diagnostic tests for diagnosis. Our case emphasis importance of early recognition of this reversible condition due to Amoxicillin-Clavulanate or other medications to prevent worsening of liver faliure and its complication.

Drug Induced Liver Injury at a Tertiary Hospital in India: Etiology, Clinical Features and Predictors of Mortality.

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. 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. 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. 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.

Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury

Chronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity. 298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or ⩾1year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition. Out of 298 patients enrolled 273 (92%) resolved ⩽1year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p=0.011], dyslipidemia [OR: 4.26, p=0.04] and severe DILI [OR: 14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p<0.001). Main drug classes involved in chronicity were statins (24%) and anti-infectives (24%). Histological examination in chronic patients demonstrated two cases with ductal lesion and seven with cirrhosis. One year is the best cut-off point to define chronic DILI or prolonged recovery, with risk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery. Drug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis.

Drug-Induced Liver Injury in HIV-Infected Patients with Opportunistic Infections: Causes, Clinical Features and Predictors in Chinese Patients

Objective: To evaluate the prevalence, causes, patterns, severity and risk factors of drug-induced liver injury (DILI) in Chinese HIV-infected patients with opportunistic infections. Methods: HIV-infected patients with opportunistic infections with DILI were studied in Beijing Ditan Hospital between Jan.1, 2009 and Nov.30, 2012, and risk factors of DILI were evaluated using multivariate Cox Proportional Hazards Model. Results: In 797 patients, 144 (18.1%) were diagnosed as DILI after receiving treatment of opportunistic infections or antiretroviral therapy. The leading causes were Trimethoprim/sulfamethoxazole (TMP-SMX) (43.9%), anti-tuberculosis medications (13.7%), nevirapine (6.9%), anti-fungal drugs (4.7%) and efavirenz (1.2%). The median duration between agents’ exposure and DILI recognition for hepatocellular, cholestatic and mixed pattern was statistically significant difference among 3 patterns of DILI (p=0.009), and the duration was positively correlated with CD4 count (r=0.223, p=0.007) and R value (r=0.238, p=0.004). Male sex and baseline CD4 counts were significant protective predictors for DILI. Conclusion: TMP-SMX, anti-tuberculosis medications, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and anti-fungal drugs were the leading causes of DILI. The DILI in HIV-infected patients with opportunistic infections was negatively associated with male sex and CD4 counts.

Use of Hy's Law and a New Composite Algorithm to Predict Acute Liver Failure in Patients With Drug-Induced Liver Injury

Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy's Law and to develop a model for predicting ALF in patients with DILI. We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL). Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL greater than 2-fold the upper limit of normal (×ULN) and either ALTlevel greater than 3× ULN, a ratio (R) value (ALT× ULN/alkaline phosphatase× ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest×ULN/ alkaline phosphatase× ULN value) of 5 or greater. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, the level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels greater than 2× ULN. An algorithm based on AST level greater than 17.3× ULN, TBL greater than 6.6× ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity. When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF.

The Characteristics and Clinical Outcome of Drug-induced Liver Injury

The aim of this cohort study was to determine the characteristics and clinical outcome of 170 patients with drug-induced liver injury (DILI) in a single center. Between January 2001 and June 2007, a total of 170 individuals who were diagnosed with DILI were retrospectively analyzed. The median follow-up period was 110.0 days. During the study period, a total of 5471 new patients were assessed for liver test abnormalities. Of those, 170 patients (3.1%) fulfilled the criteria of DILI. A total of 83 different drugs were considered to be related to the hepatotoxicity; a single drug was suspected in 57.6% of individuals. The median interval between the suspicious drug intake and DILI recognition was 15.0 days. Hepatocellular pattern was observed in 50.0% of patients with a mean alanine aminotransferase level of 952.2+/-907.0 U/L. The main causative group of drugs was antibiotics. Sixty-two patients required hospitalization; acute liver failure developed in 14 (8.2%), chronicity was observed in 19 (11.2%), and 7 died (4.1%). Overall, complete recovery occurred in 82% of patients. The presence of jaundice on admission and shorter interval period between drug intake and DILI recognition were identified as risk factors for the development of acute liver failure. DILI is an important cause of liver test abnormalities in outpatient clinics, and antibiotics represent the most common drug group. Overall, complete recovery after the withdrawal of the suspicious drug occurred in the majority of patients, but DILI may progress to acute liver failure, chronicity, and death.

This Month in Gastroenterology

This Month in Gastroenterology