Kalyan Ram Bhamidimarri, MD, MPH and Eugene Schiff, MD∗ESchiff@med.miami.edu,     University of Miami, 1500NW 12th Avenue, Suite 1101, Miami, FL 33136, USA

∗Corresponding author.

Drug-induced cholestasis manifests as an acute self-limiting injury or as a chronic perpetuating injury, resulting in duct loss and cirrhosis. The number of drugs implicated in drug-induced cholestasis grows every year as new drugs are developed and approved. Other agents such as herbals, nutritional supplements, and complementary and alternative medicines are also reported to cause cholestatic liver injury. Recent literature on molecular transporters involved in bile transport has improved our understanding of patterns of drug-induced liver injury and the mechanisms of cholestasis. This article summarizes the probable offending drugs, and the diagnosis and management of drug-induced cholestasis.

Keywords

Drugs• Cholestasis• Liver injury• Bile duct injury• Management

Key points

Introduction

Drug-induced liver injury (DILI) poses a significant health and economic burden in the modern health care system.1 Despite the advancements in health care, DILI is often a diagnosis of exclusion, and the current data on understanding of the pathogenesis, recognition of risk factors, and tools for diagnosis are limited. Heterogeneity of clinical presentation, lack of standardized diagnostic criteria, delay in diagnosis, and the recognition of culprit drugs, and underreporting of cases and outcomes are some of the important reasons for the paucity of data in this field.2

There are 3 clinical patterns of DILI: hepatocellular, cholestatic, and mixed. Hepatocellular injury appears distinct from cholestatic and mixed patterns, with predominant cytolytic injury resulting in elevation of serum transaminases before jaundice. Although cholestatic and mixed patterns of injury are theoretically different, they resemble each other in several aspects. The term cholestasis refers to stagnant bile or the failure of bile to reach the small intestine.3 Cholestatic injury is defined as an elevation of alkaline phosphatase (ALP) greater than 2 times the upper limit of normal (ULN) and/or the ratio of serum alanine aminotransferase (ALT)/serum activity of ALP of less than 2 (both enzymes are expressed as multiples of the ULN).4 As there is no gold standard for diagnosis, drug-induced cholestasis is usually a diagnosis of exclusion.4

Drug-induced cholestasis can be broadly classified into acute and chronic liver injury, the former being more common than the latter.5

Epidemiology

DILI accounts for approximately 13% of cases of acute liver failure in the United States, and is a major reason for drug abandonment by the drug regulatory agencies during the developmental phases of several candidate molecules.5,6 The true incidence of drug-induced cholestasis cannot be estimated with accuracy because of the limited number of population-based studies, heterogeneity in geographic distribution, and underreporting of the cases. A French population-based study showed an annual crude incidence rate of DILI to be around 13.9 cases per 100,000 inhabitants, of which 47% were due to cholestatic or mixed injury.7 A recent review of major DILI case series reported a rate of 20% to 40% for a cholestatic pattern of DILI and 12% to 20% for a mixed pattern of DILI.8 Drugs can cause cholestatic liver injury in a dose-dependent or idiosyncratic manner, the latter being more common. Idiosyncratic DILI from a single drug is rare and unpredictable, and its frequency is less than 1 per 10,000 to 100,000 subjects.9

Risk factors

The risk factors for drug-induced cholestasis are poorly understood. Age, gender, ethnicity, comorbidities, drug composition, and use of concomitant drugs or interplay of 1 or more factors can predispose the risk for DILI.10 Cholestatic and mixed pattern of DILI is predominantly reported in older males, whereas hepatocellular injury is commonly reported in younger females.9–11 Age older than 60 years is conferred as an independent risk factor for cholestatic DILI, irrespective of the drug involved.10 Older age is also implicated as a risk factor for drug-induced cholestasis from amoxicillin-clavulanate.10 Although the age and gender associations are ill conceived, it is speculated that age-related physiologic changes in receptor/transporter expression, body-fat content, volumes of distribution, and hormone status are responsible for such observations.10

Genome-wide association studies have enabled the identification of certain genetic determinants that can influence a disease state. One such breakthrough is in the identification of human leukocyte antigen (HLA) B*5701, which is strongly associated with flucloxacillin-induced cholestatic DILI.12 Similar genetic associations for amoxicillin-clavulanate–induced DILI are HLA haplotypes -DRB and -DQB which were described in a few earlier studies but were not corroborated in later studies.13 Women with intrahepatic cholestasis of pregnancy appear to be susceptible to drug-induced cholestasis from steroids (oral contraceptives or hormone replacement therapy), which again illustrates a common genetic determinant, the MDR3/BSEP polymorphism.14 Evidence from such data appears promising, but genome-wide testing in epidemiologic proportions for numerous implicated drugs is impractical.

Drugs can cause liver injury in a dose-dependent or idiosyncratic manner. The mechanism of idiosyncratic drug injury is unpredictable and uncertain, but a component of dose dependency has been postulated in recent studies.10,15 Individuals taking drug doses of more than 50 mg per day had increased propensity to sustain serious liver injury than those who were taking lower daily doses. Cholestatic or mixed DILI was observed in 30% to 50% of patients who were taking medications at doses greater than 50 mg per day.10,15

Apart from drug dosage, chemical composition of the drugs plays an important role in the causation of DILI. Estrogens and its metabolites have been known for a long time to modulate cholangiocyte functions, thereby playing a pathogenic role in intrahepatic cholestasis.16 Oral contraceptives especially high in estrogen content have been implicated in various studies as a cause of drug-induced cholestasis. The estimated prevalence rates in Europe and North America in the past were reported to be approximately 1 in 10,000 but current reported rates have declined to less than 1%, which parallels the use of contraceptives with lower estrogen doses.9,11 Anabolic steroids with 17α carbon substitutions (particularly alkyl or methyl substitution) are well known to induce a bland type of cholestatic injury. Other anabolic steroids and dietary supplements predominantly used for body building have also been implicated in the causation of drug-induced cholestasis.5 Drugs that have greater than 50% hepatic metabolism have a greater propensity to cause DILI, and those that are highly lipophilic are prone to cause cholestatic DILI.10,15

Pathogenesis

Drugs and toxins that are absorbed into the portal circulation are taken up by the transporters at the basolateral membrane of the hepatocytes. Detoxification of the drugs involve phase I and II reactions in the hepatocytes, and the metabolites are then effluxed into the canaliculi to be excreted in the bile. The efflux of bile is facilitated by the canalicular transporters of the multidrug-resistance protein (MRP) family, which includes other glycoproteins, MRP2 (ABCC2), MDR1 (ABCB1), MDR3 (ABCB4), and BSEP (ABCB11).17 Drugs and metabolites that affect these canalicular efflux transporters are particularly involved in cholestatic DILI. The bile salt export pump (BSEP), discovered in 1998, plays a critical role in the secretion of bile into the canaliculi and in the physiologic maintenance of the bile acids by modulating the enterohepatic circulation. Several variant mutations of BSEP are now identified, of which the V444A polymorphism is particularly associated with drug-induced cholestasis. Most drugs implicated in cholestatic injury are reported to inhibit BSEP and, conversely, most patients with mutations in MDR3 or BSEP are...