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Drug-Induced Cholestatic Liver Disease

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Summary

Drug induced cholestatic liver disease is a subtype of liver injury that is characterized by predominant elevations of alkaline phosphatase and bilirubin secondary to the administration of a hepatotoxic agent. It can manifest itself as a cholestatic hepatitis or as bland cholestasis, depending upon the causative agent and the mechanism of injury. Drugs that typically cause cholestasis with hepatitis include psychotropic agents, antibiotics and nonsteroidal antiinflammatory drugs (NSAIDs). The mechanism is immunoallergic and results from hypersensitivity. Pure cholestasis without hepatitis is observed most frequently with contraceptive and 17α-alkylated androgenic steroids and the mechanism most likely involves interference with hepatocyte canalicular efflux systems for bile salts, organic anions and phospholipids. The rate-limiting step in bile formation is considered to be the bile salt export pump (BSEP) mediated translocation of bile salts across the canalicular hepatocyte membrane. Inhibition of BSEP function by metabolites of cyclosporine A, troglitazone, bosentan, rifampicin and sex steroids is an important cause of drug induced cholestasis. Appropriate screening systems for inhibition of BSEP by drug metabolites have been established in membrane vesicles from Sf9 insect cells overexpressing the BSEP protein. A newly recognized mechanism of drug interactions that could cause cholestasis involves the activation of nuclear receptor signaling cascades which affect the transcription of hepatocyte transporter genes critical for bile formation. The multiple factors that regulate transcription of, for example, the BSEP, multidrug resistance protein 2 (MRP2) and multidrug resistance gene product 3 (MDR3) genes are likely targets for untoward effects of xenobiotics on hepatocyte transport function and disposal of toxic metabolites from the liver.

Introduction

The liver plays a predominant role in drug biotransformation and disposition from the body. In view of its barrier function between the gastrointestinal tract and systemic blood, it is constantly exposed to ingested xenobiotics entering the portal circulation. Drug-induced liver injury accounts for up to 7% of all reports of adverse drug effects voluntarily reported to pharmacovigilance registries. Drugs cause direct damage to hepatocytes, bile ducts or vascular structures or may interfere with bile flow. The phenotypes commonly encountered thus include hepatitis, cholestasis, steatosis, cirrhosis, vascular and neoplastic lesions and even fulminant hepatic failure.

Almost every drug has the potential to cause hepatic injury, be it through direct toxicity of the agent or through an idiosyncratic response of the individual. The susceptibility of the liver to injury by drugs is influenced by various factors such as age, sex, pregnancy, comedication, renal function and genetic factors. The latter variable is exemplified by slow metabolizers of debrisoquine, who exhibit a gene polymorphism in the cytochrome P450 2D6 gene and are more susceptible than fast metabolizers to perhexiline maleate toxicity. Other genetically determined enzyme deficiencies that predispose to drug toxicity have been described for cytochrome P450 2C9 (phenytoin toxicity), N-acetyltransferase 2 (sulfonamides, dihydralazine), epoxide hydrolase (phenytoin, halothane), glutathione synthetase (paracetamol) and glutathione S transferase type T (tacrin).1,2

Epidemiology and Taxonomy

The importance of drugs as hepatotoxins lies not in the overall number of cases, which is relatively small, but in the severity of some reactions and in their potential reversibility provided the drug etiology is promptly recognized. Whereas transient elevations in liver function tests are frequent with many drugs, the incidence of severe liver injury is about 1:100,000 for the most common causative agents including NSAIDs, antibiotics, methyldopa, newer antihypertensive agents and H2-receptor blockers, >10:100,000 for amoxicillin-clavulanic acid, 14:100,000 for erythromycin esters, and ∼1:100 for chlorpromazine and isoniazid.3,4 According to a consensus conference of the Council for International Organizations of Medical Sciences (CIOMS), drug induced hepatotoxicity can be divided into the three categories: cholestatic, hepatocellular or mixed type injury, depending upon serum biochemistry.5 Cholestasis with hepatitis is seen with many drugs, notably chlorpromazine, psychotropic agents, erythromycins, clavulanic acid and NSAIDs. Pure cholestasis without hepatitis is observed most frequently with estrogens, oral contraceptive steroids and 17α-alkylated androgenic steroids, and less frequently with cyclosporine A, tamoxifen, griseofulvin, glibenclamide and others. Steroid jaundice caused by methyltestosterone and other C17-alkylated anabolic steroids is dose-related but is also dependent upon the individual susceptibility of the recipient. Whereas hepatic dysfunction is seen in most recipients of steroids, jaundice is seen in only few. A minor degree of hepatic dysfunction in women taking oral contraceptives which contain C-17 ethinyl estrogen and progesterone derivatives is relatively frequent. Women with a personal or family history of cholestatic jaundice of pregnancy are particularly prone to develop jaundice when taking oral contraceptives. In addition to the “cholestatic hepatitis” of the chlorpromazine type and “bland cholestasis” caused by anabolic and contraceptive steroids, a third category of cholestasis that results from injury to bile ducts should be defined. This “cholangiodestructive cholestasis” has been observed following exposure to rapeseed oil contaminated with aniline,6 paraquat,7 α-naphthyl-isothiocyanate8 and intraarterial pump infusions of floxuridine,9 the latter leading to vascular injury.

Although the prognosis of drug-induced cholestasis is generally good with reversibility of symptoms, a chronic cholestatic lesion resembling primary biliary cirrhosis may ensue.10 The worst case involves development of a ductopenic or vanishing bile duct syndrome associated with chlorpromazine and phenothiazines, tricyclic antidepressants, flucloxacillin, thiabendazole, tolbutamide, carbamazepine and organic arsenicals.11 The injury to bile ducts caused by floxuridine may progress to biliary sclerosis.9,12 Other complications of typically cholestatic drugs include the onset of peliosis hepatis in individuals taking contraceptive or anabolic steroids,13-15 tamoxifen16 or azathioprine,17 as well as tumorigenesis.18

From a histologic viewpoint, drug-induced cholestasis can be divided into three categories: hepatocanalicular, canalicular or mixed type injury, depending also upon serum biochemistry. Hepatocanalicular cholestasis is associated with 3- to 10 fold increases of alkaline phosphatase and high serum cholesterol, and is seen in conjunction with phenothiazines and erythromycin estolate. In canalicular cholestasis, typically caused by contraceptive and anabolic steroids, alkaline phosphatase levels are only mildly elevated (up to 3 fold the upper limit of normal) and cholesterol levels are normal or elevated. Mixed-type cholestasis is seen with phenylbutazone, para-aminosalicylic acid and sulfonamides.

Mechanisms of Cholestasis

The following basic mechanisms can be held responsible for the development of drug- or toxin-induced cholestasis (Table 1). The first involves the formation of reactive metabolites19-22 leading to two types of hepatitis:

Table 1. Prototypic cholestatic hepatotoxins and mechanism of injury.

Table 1

Prototypic cholestatic hepatotoxins and mechanism of injury.

  1. toxic hepatitis, typically occurring after overdoses of a given drug (e.g., paracetamol) and,
  2. immunoallergic hepatitis, in which an adverse immune response that is directed against the liver is triggered.

This latter form of hepatitis is an idiosyncratic reaction resulting from hypersensitivity and may be associated with the presence of serum autoantibodies (ANA in the case of nitrofurantoin, methyldopa, chlorpromazine, diclofenac, sulfonamides and nimesulide; AMA against the E6 subunit following iproniazide; antibodies against the E2 subunit of the pyruvate dehydrogenase complex following halothane).22-25 The second mechanism of cholestasis involves direct injury to bile ducts, typically seen in conjunction with α-naphthyl-isothiocyanate, aniline-contaminated rapeseed oil, paraquat, 5-floxuridine and sporidesmin. The third and possibly the most important mechanism of cholestasis involves the selective interference of a drug with a bile excretory mechanism. Many cholestatic drugs are substrates for the transport proteins localized at the basolateral and canalicular hepatocyte membrane, the latter class generally belonging to the superfamily of ATP-binding cassette transporters.26 A variation in transporter structure or function may render an individual uniquely susceptible to drug-mediated impairment of bile formation. In analogy to variations in cytochrome P450 function that predispose to altered drug metabolism, variations in transporter function represent a major field of research within the rapidly expanding field of pharmacogenomics.27 Examples for sequence variants of hepatocyte canalicular efflux systems include the mutations of the MDR3 phospholipid export pump that predispose to intrahepatic cholestasis of pregnancy as a result of high circulating levels of progesterone metabolites,28,29 as well as the recently described heterozygous mutations of the bile salt export pump in an adolescent patient suffering from recurrent intrahepatic cholestasis, possibly triggered by the intake of certain NSAIDs.30

Hypersensitivity Associated and Toxic Cholestatic Injury

In this form of liver injury the liver becomes the target of an immune reaction directed against an immunogenic drug or drug component. Various mechanisms may trigger an immune reaction. First, the drug itself may produce the initial liver injury, as exemplified by halothane. The drug complexes with a liver-specific (membrane) protein, yielding an antigenic moiety. This moiety is presented by an antigen presenting cell (e.g., Kupffer cell), leading to a CD4+ helper T cell induced immune response. The prerequisite is surface expression of an alkylated peptide derived from the drug-protein complex together with a class II MHC molecule. This pathway will provide for a B cell response to the drug. Alternatively the drug may be metabolized by a P450 enzyme with the formation of a reactive metabolite complexed with a P450 peptide. This complex can be expressed at the cell surface in association with a class I MHC molecule (endogenous antigen presentation). MHC class I associated antigens are recognized by CD8+ T cells, leading to immune induction for a cytotoxic T cell response upon reexposure to the drug. Fortunately MHC molecules have a low capacity to interact with drugs or to bind epitopes derived from drug-protein complexes. In addition, reactive T cells tend to undergo a tolerance rather than an immune response to the drug-protein complex, resulting in clonal anergy. This may explain the low overall frequency of immunoallergic drug reactions.

Hypersensitivity associated liver injury is usually a mixed type “cholestatic hepatitis” as exemplified by chlorpromazine. Chlorpromazine causes hepatocanalicular jaundice in 1% of patients, usually within 1-5 weeks of the initiation of treatment.18 Severe pruritus is common, and alkaline phosphatase values are elevated 3-10 fold, with transaminases 1-8 fold of the upper limit of normal. Cholestasis is typically seen in zone 3 hepatocytes surrounding the central vein. Eosinophilia occurs in 60% of cases and a rechallenge will lead to a positive recurrence in about 50% of cases.18 This suggests a hypersensitivity reaction as the underlying mechanism, although a toxic component also appears to be involved. Furthermore, chlorpromazine can lead to inhibition of bile flow in the isolated perfused rat liver,31-33 to an inhibition of Na+-K+-ATPase function and an alteration of membrane fluidity.34 Although the prognosis is generally good, a small percentage of patients may develop a prolonged cholestatic syndrome strongly resembling PBC, but without the occurrence of AMA.11,35-37 Risk factors for chlorpromazine-induced liver injury include genetically determined ineffective sulfoxidation 38 and drug interactions with sodium valproate.39 Treatment should include UDCA as well as the supplementation of vitamins in prolonged cholestasis. Intractable pruritus may necessitate plasmapheresis.

Numerous medications may induce cholestatic or mixed type injury through hypersensitivity reactions including all neuroleptics and the cholestatic NSAIDs sulindac, phenylbutazone, indomethacin, fenoprofen and ticlopidine. Two other classes of drugs are commonly associated with cholestatic injury through immunological idiosyncrasy: erythromycin and amoxicillin-clavulanic acid. All erythromycin esters can lead to cholestatic jaundice, which occurs in 1-2% of adult recipients but only rarely in children.18 The pattern of injury is also hepatocanalicular and histology shows bile casts with prominent portal inflammation that is often rich in eosinophils. Cholestasis usually develops within 3 weeks after initiation of therapy and may persist for up to 4 months after cessation.

In the case of amoxicillin-clavulanic acid, the causative agent appears to be the clavulanic acid component.18,40 Cholestasis occurs within 2 weeks of initiation of treatment, although it may only appear several weeks after withdrawal. Another class of antibiotics that can cause severe cholestasis are the oxacillins.18,40 Flucloxacillin-induced cholestasis can persist for years after withdrawal of the drug and cases of vanishing bile duct syndrome have been reported.18,40-43

Interference with Bile Excretory Mechanisms

A simplified term to characterize this form of “bland” cholestasis could be “steroid jaundice”, since the most important causative agents are the C17-alkylated and the contraceptive steroids. Steroids that possess an alkyl or ethinyl group on carbon atom 17 can lead to hepatic dysfunction in almost all recipients at high doses. However, at the doses normally implemented the overall incidence is low. The duration of intake that precedes the onset of cholestasis is usually 1-6 months. The development of a prolonged cholestatic syndrome that resembles PBC has been reported.44

Contraceptive steroid associated cholestasis exhibits similarities with intrahepatic cholestasis of pregnancy, in which the plasma levels of steroid sulfates, in particular sulfated progesterone metabolites, are markedly elevated.45 Intrahepatic cholestasis of pregnancy has even been postulated to result from a selective biliary excretory defect for sulfated steroids.46 Interestingly, treatment with ursodeoxy cholic acid (UDCA) reduces plasma concentrations of sulfated steroid metabolites.47

The rate-limiting step for bile formation in man is the efflux of bile salts across the hepatocyte canalicular membrane via the bile salt export pump or Bsep.48 This protein, which has been isolated and functionally characterized in rat and mouse liver,49-51 can be expressed at high levels in Sf9 insect cells following baculovirus-mediated gene transfer. By isolating plasma membrane vesicles from Bsep-expressing insect cells, Bsep transport function can be studied directly. In this assay, it was found that cyclosporine A, rifamycin SV, rifampicin, glibenclamide and the endothelin antagonist bosentan cis-inhibited Bsep-mediated [3H]taurocholate transport, providing a potential mechanism for intrahepatic cholestasis caused by these agents (Table 2).27,52 Moreover, the thiazolidinedione insulin sensitizer drug troglitazone, which was withdrawn from the market in March 2000 due to its considerable hepatotoxic potential,53-55 was shown to competitively inhibit rat Bsep with Ki values of 1.3 μM for troglitazone and 0.23 μM for troglitazone sulfate.56 In one study, the substrate specificity of Bsep was shown to extend not only to bile salts but also to vinblastine, calcein-acetoxymethyl ester and the linear hexapeptide ditekiren.50 Interaction of these compounds with the canalicular efflux of bile salts is an important mechanism of drug-induced cholestasis.

Table 2. Inhibitors of hepatocellular bile salt efflux: comparison of inhibitory constants in hepatocyte canalicular plasma membrane vesicles and Bsep-overexpressing Sf9 insect cell membrane vesicles.

Table 2

Inhibitors of hepatocellular bile salt efflux: comparison of inhibitory constants in hepatocyte canalicular plasma membrane vesicles and Bsep-overexpressing Sf9 insect cell membrane vesicles.

Estradiol-17β-D-glucuronide (E217G) has also been found to inhibit Bsep function in vesicles from transfected Sf9 cells, but only in double transfectants that also expressed the canalicular conjugate export pump Mrp2.27 This suggests that E217G first needs to be exported into the canalicular lumen, from where it exerts a trans-inhibitory effect on Bsep, a mechanism of inhibition that has also been postulated for lithocholate. This also explains why E217G is not cholestatic in GY/TR- rats that lack Mrp2 expression.57 In contrast to E217G induced trans-inhibition of Bsep, the mechanism of ethinyl estradiol (EE) induced cholestasis is also a reduction of ATP-dependent canalicular taurocholate transport, however with kinetic parameters that suggest a reduction in the number of ATP-dependent bile salt carriers at the canalicular membrane.58 Accordingly, in rats treated with EE, Bsep protein levels were decreased to 53% and Mrp2 protein levels to 20% of controls.59

The nonsteroidal anti-inflammatory agent sulindac, an established hepatotoxin,60 may also cause cholestasis by interference with the canalicular excretion of bile salts. Sulindac has been shown to follow the cholehepatic shunt pathway and induce choleresis.61 However, when coinfused with taurocholate in the isolated perfused rat liver, sulindac causes cholestasis by reducing taurocholate secretion. Sulindac appears to be secreted into the bile canaliculus in unconjugated form via a canalicular bile salt export system and is passively absorbed by the bile duct epithelium, thereby inducing a bicarbonate-rich choleresis. Due to continuous cycling within the cholehepatic shunt pathway, high local concentrations of sulindac could be reached within the hepatocyte that cause cholestasis by inhibition of canalicular bile salt efflux.

An important form of intrahepatic cholestasis is the cholestasis of sepsis, which is caused by the effect of endotoxin on hepatocellular bile formation. In experimental sepsis secondary to lipopolysaccharide (LPS) administration, ATP-dependent uptake of 5 μM taurocholate in canalicular plasma membrane vesicles was reduced to 53% of controls without an apparent change in Km, suggesting a decrease in the number of Bsep molecules in the canalicular membrane.62 A reduction of Bsep protein levels to 52% of controls following LPS administration was confirmed by western blot analyses.59 The expression of the canalicular organic anion transporter Mrp2 was decreased even more profoundly, amounting to 11% of controls in the LPS model.59 LPS was shown to induce an early and selective but reversible retrieval of Mrp2 from the canalicular membrane,63 whereas phalloidin induced an unselective and irreversible loss of Mrp2 and other proteins from the canalicular membrane.64

Selective interference with the sinusoidal uptake of substances destined for biliary secretion such as bilirubin and bromosulphophthalein has been shown for the tuberculostatic agents rifamycin SV and rifampicin.65 Both are mainly eliminated by hepatic uptake, metabolism and excretion into bile. Rifampicin increases serum bile salt concentrations in 72% of patients after the first dose,66 suggesting acute interference with sinusoidal uptake of bile salts. The major bile salt uptake system of rat liver is the Na+-taurocholate cotransporting polypeptide or Ntcp, whereas Na+-independent uptake of bile salts is mediated by several organic anion transporting polypeptides including Oatp1 and Oatp2.48 When selectively expressed in Xenopus laevis oocytes by injection of cRNA, rifampicin potently inhibited Oatp2 mediated taurocholate uptake, but did not interfere with Oatp1 mediated taurocholate uptake. Both Oatp1 and Oatp2 were inhibited by 10 μmol/l rifamycin SV, whereas significantly higher concentrations of rifamycin SV and rifampicin were required to inhibit Ntcp.67 For the human liver OATPs, it was shown that 10 μmol/l rifampicin inhibited OATP8 mediated bromosulphophthalein transport by 50%, whereas inhibition of OATP-A, OATP-B and OATP-C was below 15%. In contrast, all human OATPs were inhibited by more than 50% in the presence of 10 μmol/l rifamycin SV.68 Inhibition of OATPs can partly explain the known effects of rifamycin SV and rifampicin on hepatic organic anion elimination.

Role of Drug Induced Activation of Nuclear Regulatory Cascades

The role of drug mediated changes in cytochrome P450 expression levels has long been recognized as an important mechanism of drug-drug interactions that can cause enhanced metabolism of P450 substrates following gene induction by phenytoin, carbamazepine, rifampicin and others. It is now becoming increasingly evident that the regulatory cascades that affect P450 gene expression can coordinately affect expression of transporter genes involved in bile formation. Numerous drugs are ligands for “orphan” nuclear receptors such as the pregnane X receptor (PXR) which has recently been shown to increase transcription of the human MDR1 gene.69 Increased expression of MDR1 is not a mechanism of drug induced cholestasis, however it can have a major impact on the bioavailability of drugs that are MDR1 substrates such as digoxin or cyclosporine A.70,71 A second hepatocellular transporter gene that is activated by PXR is the rodent organic anion transporting polypeptide Oatp2 (Slc21a5). Hepatic Oatp2 expression is increased in rats treated with the PXR ligand phenobarbital.72 Moreover, the PXR ligand taurolithocholate upregulates Oatp2 expression in mouse liver, an effect that is not observed in PXR-/- mice.73 Oatp2 is an uptake system for bile salts, steroid conjugates and numerous drugs including digoxin.48 Typical PXR ligands that could increase Oatp2 expression include rifampin, RU486, St. John's wort extract, clotrimazole, troglitazone and phenobarbital.70,74-76

Decreased expression of Mrp2 in rats treated with bacterial lipopolysaccharide is also attributable to a direct effect on Mrp2 gene transcription. Lipopolysaccharide administration to rats reproduces the cholestasis which is a common clinical feature of sepsis as well as toxic liver diseases.62 It has been shown that the inflammatory cytokine interleukin-1β inhibits retinoid mediated activation of the rat Ntcp and Mrp2 promoters by reducing nuclear levels of the retinoic acid receptor (RAR) and retinoid X receptor (RXR) and consequently decreasing the binding of RARα/RXRα heterodimers to the Ntcp and Mrp2 retinoid response elements.77 In addition, interleukin-1β decreases nuclear levels of hepatocyte nuclear factor 1 alpha (HNF1α),78 a critical factor required for the transcriptional activation of rat Ntcp,79 human MRP2,80,81 and human OATP-C (SLC21A6).82 In view of these findings it is reasonable to speculate that any form of xenobiotic induced hepatitis is likely to affect the expression of transporter genes via cytokine mediated changes in the nuclear levels of critical transcription factors.

A nuclear receptor that is likely to come into action during cholestatic liver injury is the farnesoid X receptor (FXR), since its natural ligands are hydrophobic bile salts such as chenodexy cholic acid (CDCA).83,84 Increased intracellular bile salt levels secondary to cholestatic liver injury will activate FXR and consequently affect the expression of genes regulated by FXR. Bile salt induced activation of gene transcription through direct binding of FXR to the corresponding promoter element has been shown for the human BSEP85,86 and OATP887 genes. To exert a cholestatic effect through a nuclear receptor mediated mechanism, the drug would need to inhibit gene transcription of an efflux pump such as BSEP, MRP2 or MDR3. A first example for such a mechanism is the bile salt induced activation of the short heterodimeric partner (SHP-1), which leads to reduced binding of the RARα/RXRα heterodimer to the gene promoter of the chief hepatocellular uptake system Ntcp.88 The activation of SHP-1 is also FXR mediated and could contribute to the decreased expression of Ntcp in cholestatic liver injury. Because the Mrp2 gene has also been shown to bind the RARα/RXRα heterodimer,77 it is conceivable that decreased Mrp2 expression in cholestasis also involves a SHP-1 mediated reduction of RARα/RXRα binding, although this remains to be investigated.

Conclusions

In summary, drug-induced cholestatic liver injury can result from direct damage to the hepatic parenchyma by immunoallergic or toxic mechanisms or from impaired transmembrane transport of cholephilic compounds destined for biliary secretion. The rate-limiting step in bile formation is the canalicular excretion of bile salts via the bile salt export pump, which thus represents an especially vulnerable target for drug or toxin mediated injury. The earliest clinical parameter in these patients, which precedes the onset of symptomatic cholestasis, is a rise in serum bile salts. It is likely that individual susceptibility to drug- and toxin-induced cholestasis is conferred by as yet unknown polymorphisms in hepatic transporter genes, that could affect the regulation or secondary structure of the corresponding protein.

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