Hepatotoxicity cholestasis

Azathioprine is indicated in renal homotransplantation (five-year patient survival rate of 35%) in rheumatoid arthritis (for patients with severe, active, and erosive disease not responding to conventional therapies) and in chronic ulcerative colitis, myasthenia gravis, and Behcet s syndrome (adverse effects may offset its limited value). As with other cytotoxic drugs, azathioprine can affect rapidly growing cells, resulting in leukopenia, thrombocytopenia, and gastrointestinal toxicity. In addition, hepatotoxicity (cholestasis) has been reported. Many of the general problems of immunosuppression, such as increased risk of infections, can also occur. 

Yellow phosphorus was the first identified liver toxin. It causes accumulation of lipids in the liver. Several liver toxins such as chloroform, carbon tetrachloride, and bromobenzene have since been identified. I he forms of acute liver toxicity are accumulation of lipids in the liver, hepartxiellular necrosis, iii-trahepatic cholestasis, and a disease state that resembles viral hepatitis. The types of chrome hepatotoxicity are cirrhosis and liver cancer. 

Oral testosterone-replacement regimens can cause hepatotoxicity, ranging from mildly elevated hepatic transaminases to serious liver diseases (e.g., peliosis hepatitis, hepatocellular and intrahepatic cholestasis, and benign or malignant tumors). 

Testosterone (T.) derivatives for clinical use. T. esters for im. depot injection are T. propionate and T. heptanoate (or enanthate). These are given in oily solution by deep intramuscular injection. Upon diffusion of the ester from the depot, esterases quickly split off the acyl residue, to yield free T. With increasing lipophilicity, esters will tend to remain in the depot, and the duration of action therefore lengthens. A T. ester for oral use is the undecanoate. Owing to the fatty acid nature of undecanoic acid, this ester is absorbed into the lymph, enabling it to bypass the liver and enter, via the thoracic duct, the general circulation. 17-0 Methyltestosterone is effective by the oral route due to its increased metabolic stability, but because of the hepatotoxicity of Cl 7-alkylated androgens (cholestasis, tumors) its use should be avoided. Orally active mesterolone is 1 a-methyl-dihydrotestosterone. Trans-dermal delivery systems for T. are also available. 

Hepatotoxicity Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis, have been reported rarely in postmarketing data in patients receiving infliximab. Autoimmune hepatitis has been diagnosed in some of... 

The best clinical evidence that BSEP is involved in hepatotoxicity is provided by human genetic studies which found four highly conserved non-synonymous mutations in two hepatobiliary transporters (BSEP and MDR3) that were specific for drug-induced liver injury [118]. Recently, a consortium of investigators identified a remarkable 82 different ABCBll mutations in 109 families that caused severe BSEP deficiency [119]. It is therefore expected that at least some of these genetic mutations and polymorphisms will put patients at an increased risk of drug-induced cholestasis. Does this justify the implementation of a simple BSEP inhibition screen for all new chemical entities The answer is not quite that simple. 

The introduction of cyclosporin, a peptide derived from a fungus, revolutionised immunosuppressive therapy, and was one of the major influences in the improvement of early graft survival in transplant surgery when introduced in the 1980s. The main action is a relatively selective inhibition of IL-2 production and consequently a decreased proliferation of T cells. A major advantage of cyclosporin is that it does not cause myelosuppression in therapeutic doses. The major side effect is nephrotoxicity, which occurs in about 20% of patients, and about 50% of patients develop moderate hypertension. The other major side effect is hepatotoxicity with cholestasis and hyperbilirubinaemia. 

Cunningham and Matthews (1991) treated male Fischer 344 rats with 0.5, 1 or 2 mmol/kg bw 2-nitropropane daily for 10 days by gavage. At the higher dose levels, but not at 0.5 mmol/kg bw, increased hepatic DNA synthesis was found, together with moderate signs of cholestasis and hepatotoxicity. 

In some studies, women taking estradiol or conjugated estrogens for hormone replacement therapy had no cholestasis or hepatotoxicity, as assessed by rises in serum alkaline phosphatase, bilirubin, or transaminases, whereas these effects did occur with ethinylestradiol. 

The antipsychotic chlorpromazine is a prototype heptotoxicant for production of cholestasis. Pleiotropic effects of chlorpromazine on membrane permeability and associated ion gradients and microfilament-mediated canalicular contraction have been attributed to detergent effects. Valproic acid, an anticonvulsant, is associated with microvesicular steatosis. Inhibition of mitochondial fatty acid (S-oxidation is an important component of this toxic effect and is apparently related to carnitine availability as evidenced by the protection afforded by L-carnitine supplements. The hypolipidemic drugs clofibrate, fenofibrate, and gemfibrozil are peroxisome prolif-erators in rodent liver, but not in humans. Isoniazid, an antibiotic used to treat tuberculosis, exhibits an approximately 1 % incidence of hepatotoxicity. Although toxicity is known to be metabolism-dependent and protein adduction has been well-... 

Hepatotoxicity has been associated with moclobemide, including fatal intrahepatic cholestasis in an 85-year-old woman 7 days after switching to moclobemide from fluoxetine (13). 

Herbal medicines are becoming more and more popular, and indeed some herbal products may be considered to benefit people with liver disease, e.g. Silybum marianum (milk thistle), Picrorhiza kurroa, Phyllanthus, etc. Herbal hepatotoxicity is increasingly being recognised, for example, with kava kava, black cohosh, and many traditional Chinese remedies. The range of liver injury includes minor transaminase elevations, acute and chronic hepatitis, steatosis, cholestasis, zonal or diffuse hepatic necrosis, veno-occlusive disease and acute liver failure. In addition to the potential for hepatotoxicity, herb-drug interactions may affect the safety and efficacy of concurrent medical therapy [15]. 

All fibrates can cause an increase in the cholesterol saturation of bile. An increase in gallstone formation has been reported. This is a class effect. The fibrates may cause altered LFTs, including GGT and ALP. Use of a fibrate may make it difficult to distinguish between hepatotox-icity and worsening cholestasis. 

Two small studies have examined the effect of HRT on liver function tests in healthy women. The women had regular assessment of their liver function tests during therapy. Hepatotoxicity and cholestasis were not observed [10, 11]. 

Farrell, G.C., Duddy, S.K., Kass, G.E., Llopis, J., Gahm, A., Orrenius, S. (1990) Release of calcium from the endoplasmic reticulum is not the mechanism for bile acid induced cholestasis and hepatotoxicity in the intact rat liver. J. Clin. Invest. 85 1255-9. 

I7(x-Methyl-17 -hydroxy-estra-4,9,l l-trien-3-one (Methyltrienolone, N-99). In the course of a steroid total synthesis [293] this compound (Methyltrienolone, N-99) was prepared it was reported [55] to possess 6000% of the androgenic (ventral prostate index), 7500% of the androgenic (seminal vesicles index), and 12,000% of the anabolic (levator ani index) activity of methyltestosterone. Later the anabolic activity was reported [74] to be 30,000% of that of methyltestosterone. As measured by multiple parameters methyltrienolone turned out to be the most hepatotoxic steroid, causing biochemical symptoms of intrahepatic cholestasis [75]. It was also reported [74] to reduce the excretion of 17-ketosteroids and 17-hydroxycorticosteroids and to cause enhancement of the blood coagulation factors V, VII, and X. It also increases the prothrombin content of the plasma [74]. 

In each form of cholestasis, atypical bile adds, such as monohydroxy bile acids, aUo-bile adds, 1- or 6-hydroxylated bile acids and their sulphated or glucuronidated derivatives, are found in the sermn and/or urine. In cholestasis, the increase in the neosynthesis of atypical bile adds that pass into the kidney can be seen as a compensatory mechanism which eliminates potentially hepatotoxic bile acids by renal clearance. The highest renal excretion quota is demonstrated by tetrahydroxy bile acids. 

Kava extracts can, if overdosed (>60-120 mg kavapyr-ones/day) and/or taken over a longer period (>3 months), cause hepatotoxicity in the form of hepatic reactions and liver cell necrosis in rare cases, they may even cause cholestasis and acute liver failure (possibly leading to liver transplantation). Risk factors include the concomitant intake of medicaments and alcohol as well as a genetically based deficiency of cytochrome P450 2D6. (99, 116)... 

Ciclosporin can cause cholestasis and cellular necrosis by an inhibitory effect on hepatocyte membrane transport proteins at both sinusoidal and canalicular levels. It induces oxidative stress by accumulation of various free radicals. Ademetionine (5-adenosylmethionine) is a naturally occurring substance that is involved in liver detoxification processes. The efficacy of ademetionine in the treatment and prevention of ciclosporin-induced cholestasis has been studied in 72 men with psoriasis (89). The patients who were given ciclosporin plus ademetionine had low plasma and erythrocyte concentrations of oxidants and high concentrations of antioxidants. The authors concluded that ademetionine may protect the hver against hepatotoxic substances such as ciclosporin. 

Cholestasis from other causes can increase the accumulation of ciclosporin or its metabolites, which in turn worsens hepatic cholestasis. This mechanism has been suggested in patients with bowel diseases who experienced an aggravation of hyperbilirubinemia or an increased incidence of hepatotoxicity from the combination of total parenteral nutrition and ciclosporin (SEDA-19, 348) (288). 

The authors noted that two other patients in the Australian adverse reactions database also appeared to have had hepatotoxicity related to entacapone. In response, representatives of the manufacturers (Novartis) strongly contested the conclusion that any of the three reported cases demonstrated entacapone-induced hepatotoxicity, and concluded that two of the three patients had cholestasis, which is unlikely to be related to entacapone, while the third had no real evidence of hepatic dysfunction (10). These arguments were in turn rebutted by the original authors, and the possible hepatotoxicity of entacapone remains a matter of debate, although there can be no doubt that it is safer than tolcapone. 

Fatal cholestatic hver failure occurred in a 45-year-old woman with metastatic breast cancer who was given gemcitabine and carboplatin and pre-existing liver damage. After four courses of gemcitabine -I- carboplatin she developed severe decompensated cholestatic hepatitis (9). Liver biopsy showed marked cholestasis and hepatocellular injury consistent with drug-induced hepatotoxicity. 

There have been several reports of hepatotoxicity of iodipamide, variously characterized by epigastric pain, nausea and vomiting, jaundice, pyrexia, and tenderness over the liver, with abnormal liver function tests. Biopsy has shown centrilobular necrosis (154). The incidence of abnormal liver function tests may be as high as 18% after a dose of 40 ml, and the quantity given should be as small as possible. Prior administration of glucocorticoids or sulfonylureas impairs hepatic excretion of ioglycamide. Both iodoxamate and iotroxate can affect liver function tests in a small series of cases, the degree of intrahepatic cholestasis appeared to be relatively more marked after iodoxamate than after iotroxate (SED-12, 1168) (155). 

Nadir A, Reddy D, Van Thiel DH. Cascara sagrada-md xced intrahepatic cholestasis causing portal hypertension case report and review of herbal hepatotoxicity. Am J Gastroenterol 2000 95(12) 3634-7. 

FlncloxacUUn is the most important cause of antimicrobial dmg-indnced hepatotoxicity in varions countries (69-71). The risk has been estimated in some countries to be in the range of 1 in 10000 to 1 in 30000 prescriptions (72-74). The hepatic injnry is often severe and deaths have occnrred (73). The course can be prolonged. Cholestasis is the most freqnent and prominent feature and the so-called vanishing bile dnct syndrome can develop. Female sex, increasing age, and dnration of therapy are risk factors (75). High daily doses increase the risk (74). 

The authors rated the likelihood that benzylpenicillin had caused cholestasis as probable and referred to three previous reports in which penicillin was claimed to cause hepatotoxicity. 

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