Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by ...a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov). According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab.
An important element in assessing causality in drug‐induced liver injury is whether the implicated agent is known to cause hepatotoxicity. We classified drugs into categories based on the number of ...published reports of convincingly documented, clinically apparent, idiosyncratic liver injury. Drugs described in the website LiverTox (http://livertox.nih.gov) were classified into five categories based on the number of published cases (category A, ≥50; category B, 12‐49; category C, 4‐11; category D, 1‐3; category E, none). Case reports in categories C and D were individually reanalyzed using the Roussel Uclaf Causality Assessment Method. Drugs with fatal cases or with rechallenge were noted. Among 671 individual drugs or closely related agents, 353 (53%) were considered convincingly linked to liver injury in published case reports; 48 (13%) were assigned to category A, 76 (22%) were assigned to category B, 96 (27%) were assigned to category C, and 126 (36%) were assigned to category D. Another 7 (2%) were direct hepatotoxins but only in high doses and placed in a separate category (T). The remaining 318 (47%) drugs had no convincing case report of hepatoxicity in the literature (category E). All except one in category A have been available since 1999, 98% had at least one fatal case and 89% a positive rechallenge. In category B, 54% had a fatal case and 41% a rechallenge. Drugs in categories C and D less frequently had instances of fatal (23% and 7%) or rechallenge cases (26% and 11%). Conclusion: Documentation of hepatoxicity in the medical literature is variable, and many published instances do not stand up to critical review. A standardized system for categorizing drugs for hepatotoxicity potential will help develop objective and reliable, computer‐based instruments for assessing causality in drug‐induced liver injury. (Hepatology 2016;63:590–603)
Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver disorders faced by hepatologists, because of the myriad of drugs used in clinical practice, available ...herbs and dietary supplements with hepatotoxic potential, the ability of the condition to present with a variety of clinical and pathological phenotypes and the current absence of specific biomarkers. This makes the diagnosis of drug-induced liver injury an uncertain process, requiring a high degree of awareness of the condition and the careful exclusion of alternative aetiologies of liver disease. Idiosyncratic hepatotoxicity can be severe, leading to a particularly serious variety of acute liver failure for which no effective therapy has yet been developed. These Clinical Practice Guidelines summarize the available evidence on risk factors, diagnosis, management and risk minimization strategies for drug-induced liver jury.
Statins are generally well tolerated and adverse effects are relatively rare. Clinical trials are underpowered to detect uncommon adverse effects such as idiosyncratic drug‐induced liver injury. This ...review is aimed at covering the current knowledge on the hepatotoxicity associated with statins and other lipid lowering drugs. Both atorvastatin and simvastatin have been associated with more than 50 case reports of liver injury and other statins have been implicated in this type of liver injury as well. Idiosyncratic liver injury due to statins has been reported to occur 1.9%‐5.5% of patients in prospective series of drug‐induced liver injury. Atorvastatin and simvastatin have been associated with positive rechallenge and some case reports have described liver injury following dose escalation of the implicated statin. Mortality from liver injury and/or liver transplantation has been documented in a few patients with statin induced liver injury although the vast majority of patients with liver injury have recovered after cessation of therapy.
Drug-induced liver injury (DILI) is an important differential diagnosis in patients with abnormal liver tests and normal hepatobiliary imaging. Of all known liver diseases, the diagnosis of DILI is ...probably one of the most difficult one to be established. In all major studies on DILI, antibiotics are the most common type of drugs that have been reported. The clinical phenotype of different types of antibiotics associated with liver injury is highly variable. Some widely used antibiotics such as amoxicillin-clavulanate have been shown to have a delayed onset on liver injury and recently cefazolin has been found to lead to liver injury 1-3 weeks after exposure of a single infusion. The other extreme is the nature of nitrofurantoin-induced liver injury, which can occur after a few years of treatment and lead to acute liver failure (ALF) or autoimmune-like reaction. Most patients with liver injury associated with use of antibiotics have a favorable prognosis. However, patients with jaundice have approximately 10% risk of death from liver failure and/or require liver transplantation. In rare instances, the hepatoxicity can lead to chronic injury and vanishing bile duct syndrome. Given, sometimes very severe consequences of the adverse liver reactions, it cannot be over emphasized that the indication for the different antibiotics should be evidence-based and symptoms and signs of liver injury from the drugs should lead to prompt cessation of therapy.
The liver has a range of responses to drug-induced injury, with a number of phenotypes. In addition, idiosyncratic reactions may occur as a consequence of both direct drug action and indirect drug ...effects. Antibiotics are the most common cause of drug-induced liver injury.
There has been a substantial interest in drug-induced liver injury (DILI) recently. National Institutes of Health has sponsored a multicenter study in the USA for the last 10 years, which has ...collected valuable information in this context.
Idiosyncratic
DILI is like other adverse effects of drugs underestimated and underreported in most epidemiological studies. A recent prospective population-based study from Iceland found a crude incidence of approximately 19 cases per 100,000 and year. Antibiotic is the class of drugs most commonly implicated in patients with DILI. Amoxicillin–clavulanate continues to be the most commonly implicated agent occurring in approximately 1 out of 2,300 users. Drugs with the highest risk of DILI in the Icelandic study were azathioprine and infliximab. Although rare, statin-induced hepatotoxicity has been well documented. Liver injury associated with the use of herbal medicines and dietary supplements seems to be increasing. Information on the documented hepatotoxicity of drugs has recently been made easier by a website available in the public domain: LiverTox (
http://livertox.nlm.nih.gov
). Unfortunately, at the current time, pre-therapy risk assessment for DILI in the individual patient is difficult but previous well-documented hepatotoxicity is usually a contraindication for a subsequent treatment with the same drug.
Drug-induced liver injury (DILI) has a very variable clinical and biochemical phenotype and differs widely in severity, from mild injury to life-threatening liver failure. Chronic injury has also ...been reported to occur at a variable frequency, ranging from 3.4% to 39%, 6-12 months after discontinuing the implicated agent. This wide range is probably related to various definitions of chronic liver injury and variable selection of patients. The long-term sequalae of this chronic injury in terms of morbidity and mortality are unclear, although rare vanishing bile duct syndrome is associated with an unfavourable prognosis, with increased risk of chronic liver failure and need for liver transplantation. Other forms of long-term sequalae associated with DILI are progressive fibrosis, autoimmune-like hepatitis, secondary sclerosing cholangitis, sinusoidal obstruction syndrome and, as a common final stage, the development of cirrhosis, portal hypertension and its complications. Immune checkpoint inhibitors, which can cause an autoimmune-like phenotype have also recently been shown to cause sclerosing cholangitis with cytotoxic T CD8+ cell infiltration in biliary tracts. DILI has been shown to have a significant impact on health-related quality of life but very little is known about its psychological consequences in the long-term. Further investigations with structured long-term follow-up and periodic quality of life surveys are needed to assess the impact of DILI on psychological outcomes, particularly in those with chronic sequelae.
Background & Aims Little is known about the incidence of drug-induced liver injury (DILI) in the general population. We investigated the incidence and the quantitative risk of DILI in a ...population-based cohort. Methods We performed a prospective study and collected data from 96 individuals diagnosed with DILI in Iceland from 2010 through 2011 (54 women; median age, 55 y). Liver injury was defined based on levels of alanine aminotransferase that were more than 3-fold the upper limit of normal and/or alkaline phosphatase levels more than 2-fold the upper limit of normal. Patients with acetaminophen toxicity were excluded. Drug history and clinical outcome were analyzed. Causality was assessed using the Roussel Uclaf Causality Assessment Method. The patients were registered in prescription databases for outpatients and inpatients. Results The crude annual incidence rate of DILI was 19.1 (95% confidence interval CI, 15.4–23.3) cases per 100,000 inhabitants. DILI was caused by a single prescription medication in 75% of cases, by dietary supplements in 16% of cases, and by multiple agents in 9% of cases. The most commonly implicated drugs were amoxicillin-clavulanate (21 of 96; 22%), diclofenac (6%), azathioprine (4%), infliximab (4%), and nitrofurantoin (4%). The median duration of therapy was 20 days (range, 8−77 days); 26 patients had jaundice (27%) and 22 patients were hospitalized (23%) for a median of 5 days (range, 2−8 days). Overall 35,252 patients received amoxicillin-clavulanate as outpatients, and DILI occurred in 1 of 2350 (43 of 100,000; 95% CI, 24−70). DILI also occurred in 1 of 9480 patients taking diclofenac (11 of 100,000; 95% CI, 4−24), 1 of 133 patients taking azathioprine (752 of 100,000; 95% CI, 205−1914), 1 of 148 patients taking infliximab (675 of 100,000; 95% CI, 184−718), and 1 of 1369 patients taking nitrofurantoin (73 of 100,000; 95% CI, 20−187). Conclusions In a population-based study in Iceland, the incidence of DILI was the highest reported to date. Amoxicillin-clavulanate was the most commonly implicated agent. The highest risk of hepatotoxicity was associated with azathioprine and infliximab, but the actual number of cases attributed to these agents was small.
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