Overall Bottom Line
- DILI is the most common cause of acute liver failure in the USA.
- DILI can be caused by prescription medications, over-the-counter medications, vitamins, hormones, herbs, illicit (“recreational”) drugs and environmental toxins.
- Typically, there are three signature patterns of DILI: hepatocellular, cholestatic, and mixed.
- The diagnosis of DILI often is clinically challenging and therefore providers should maintain a high index of suspicion. It is important to exclude other potential causes of liver injury.
- The treatment of DILI involves discontinuation of the offending agent and supportive care. Patients who develop hepatic failure as a result of DILI should be considered for liver transplant.
Section 1: Background
Definition of disease
- Drug induced liver injury is liver injury due to medications or other toxic agents.
Disease classification
- Jaundice associated with aminotransferase elevation portends a worse prognosis compared with aminotransferase elevation alone.
- Typically, three signature patterns of liver test abnormalities are recognized with DILI: hepatocellular, cholestatic, and mixed. These patterns are generally defined as follows:
- Hepatocellular ALT/ULN ÷ AP/ULN ≥5
- Cholestatic ALT/ULN ÷ AP/ULN ≤2
- Mixed ALT/ULN ÷ AP/ULN >2 to <5
- Hepatocellular ALT/ULN ÷ AP/ULN ≥5
Incidence/prevalence
- DILI is the leading cause of acute liver failure in the USA.
- DILI is infrequent (one in 10 000 to 100 000 persons exposed).
- The majority of patients with symptomatic acute DILI are expected to completely recover with supportive care after discontinuation of the suspect drug.
- Patients with DILI that progress to acute liver failure have only a 25% chance of spontaneous recovery.
Economic impact
- DILI has broad implications for not only patients and healthcare providers but the pharmaceutical industry and policy makers.
- DILI is the major determinant of drug-related regulatory action and can therefore have a tremendous economic impact on the pharmaceutical industry. DILI is the leading cause for termination of clinical drug trials, failure to obtain US Food and Drug Administration (FDA) approval and post-marketing decisions for drug withdrawal.
Etiology
- Many drugs and toxins are capable of evoking some degree of liver injury.
- Drugs that are implicated in DILI include not only prescription medications but also herbal and over-the-counter supplements.
- The liver represents a primary target for adverse drug reactions due to its pivotal role in biotransformation and excretion of drugs and their by-products.
Pathology/pathogenesis
- There are many different proposed mechanisms of action in DILI including: cell membrane disruption, canalicular alterations, formation of drug adducts, apoptosis and formation of free fatty acids.
- Others factors that likely play a role in the development of DILI include genetic and environmental associations.
- The risk factors, pathogenesis and outcomes of idiosyncratic DILI are inadequately understood.
- DILI has been difficult to understand due to the heterogeneity of its clinical presentation and course of injury, ranging from asymptomatic transient elevations in liver enzymes to liver failure and in rare cases chronic liver disease.
- Susceptibility to DILI is thought to be influenced by certain patient characteristics, predominantly age (adults > children) and sex (female > male), although there have been insufficient data to define increased risk in any given patient subpopulation. Other factors including nutrition, concomitant diabetes mellitus or alcohol use may be associated with increased risk of DILI as well as severity.
- Genetic factors may further influence an individual’s susceptibility to adverse drug reactions. There are reports of a relationship between adverse reactions and HLA polymorphisms.
Predictive/risk factors
- Age (adults > children; e.g. isoniazid, halothane, valproic acid).
- Sex (female > male; e.g. halothane, minocycline, nitrofurantoin).
- Malnutrition and fasting (e.g. acetaminophen).
- Concomitant diabetes mellitus (e.g. methotrexate).
- Concomitant alcohol use (e.g. acetaminophen).
- Genetic factors including HLA polymorphisms (e.g. (HLA)-B5701 genotype as a major determinant of flucloxacillin DILI).
- Dose (e.g. acetaminophen).
Section 2: Prevention
Screening
- Having a high index of suspicion for the culprit drug, based on circumstantial evidence and exclusion of other confounding causes of liver injury, usually supports the diagnosis.
Primary prevention
- Avoiding any drugs that are not indicated would be a method of primary prevention.
- Restricted availability and blister packaging of over-the-counter medications.
- Physician and public education about possible drug side effects and dose limitations as well as monitoring for adverse drug reactions.
- Patient adherence to dosing guidelines.
- Baseline and periodic liver tests monitoring for select agents with known increased risk of hepatotoxicity.
- One difficulty associated with prevention of DILI is the relatively underpowered nature of clinical trials.
Secondary prevention
- Avoiding re-exposure to drugs that have precipitated DILI previously.
Section 3: Diagnosis
Clinical Pearls
- Diagnosing DILI can be quite challenging as there is presently no specific diagnostic test or marker for DILI. The diagnosis of DILI is established based on the clinical history, chronology of exposure and injury, exclusion of competing etiologies and subjective assessment based on clinical experience and published data wherever available.
- Idiosyncratic drug reactions are particularly problematic given that these are generally not dose or even time dependent and are instead characterized as reactions unique to the patient.
- Clinically significant DILI is often defined as ALT > 3 times the ULN.
- Clinical features by patient’s history include symptoms of fever, pharyngitis, malaise, headache, rash, dark urine.
- Physical examination findings in severe DILI can include icteric sclerae. In cases of fulminant hepatic failure, signs of hepatic encephalopathy will be present.
- A temporal association between the onset of drug therapy and biochemical evidence of liver injury is helpful as is a temporal association between cessation of drug therapy and improvement in liver biochemistry; and the exclusion of alternative diagnoses.
- Idiosyncratic drug reactions are particularly problematic given that these are generally not dose or even time dependent and are instead characterized as reactions unique to the patient.
- The exclusion of competing etiologies of liver disease is integral to the evaluation of suspected DILI.
Differential diagnosis
| Differential diagnosis | Features |
|---|---|
| Viral/infectious | Evidence of serologic markers or viremia, consistent with viral liver disease Liver biopsy evidence of periportal, not pericentral, mononuclear leukocyte infiltration |
| Autoimmune hepatitis | Presence of serum autoimmune markers and elevated gamma globulin Liver biopsy with plasma cell infiltration and immune cells, interface hepatitis |
| Biliary obstruction | Acute obstruction can lead to liver tests abnormalities Imaging to evaluate for biliary obstruction including ultrasound, EUS, MRI/MRCP, ERCP |
| Metabolic liver diseases | Wilson disease: evidence of serum/urine copper abnormalities, low alkaline phosphatase Alpha-1 antitrypsin deficiency: genetic testing |
| Vascular disorders of liver | Imaging to assess vasculature |
| Alcoholic hepatitis | Evidence of leukocytosis, elevated liver tests Liver biopsy with features of alcoholic steatohepatitis |
Related posts:
24: Portopulmonary Hypertension
25: Pregnancy-Related Liver Disease
38: Liver Transplantation: A Pediatric Perspective
36: Approach to Jaundice in Infancy
53: Recurrent Disease Post-Liver Transplantation: Autoimmune Diseases, Hepatitis B and NASH
34: Diagnosis and Management of Acute Liver Failure: A Pediatric Perspective
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