Hepatocellular cholestasis

A 49-year-old man with alcoholic cirrhosis developed jaundice, fatigue, and choluria after he started to take celecoxib 200 mg/day for musculoskeletal pain (9). There were increases in transaminases, alkaline phosphatase, and bilirubin (to 547 pmol/l). Liver biopsy showed cirrhosis and marked hepatocellular cholestasis. On withdrawal of celecoxib the bilirubin began to fall very slowly 1 year later he was well, with a total bilirubin concentration of 44 pmol/l. 

Inflammatory conditions of the liver, in particular inflammatory hepatocellular cholestasis, are one of the most frequent causes of jaundice in the clinic. The major underlying denominator of this disorder is the inhibition of transporter expression and function by proinflammatory cytokines, which are either induced systemically or within the liver. Alcoholic hepatitis accounts for up to two-thirds of patients and is the most frequent trigger, followed by idiosyncratic drug reactions, sepsis or other extrahepatic bacterial infections, some variants of viral hepatitis, and total parenteral nutrition [95, 96]. 

Herbal remedies that have been reported to be he-patotoxic include chaparral (Larrea tridentata), germander (Teucrium chamaedrys), and life root (Senecio aureus) [18]. Cases reported patients developing jaundice, fatigue, pruritus, markedly elevated serum liver enzyme levels, severe cholestasis, hepatitis, and hepatocellular injury or necrosis documented by serial liver biopsies [19-21]. Signs and symptoms may occur as early as 3 weeks to as late as 7 months following ingestion [20,21]. 

J., Kuliak-Ublick, G. A., Meier, P. J., Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver, Gastroenterology 2000, 118, 422-430. 

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). 

Allergic reactions to drugs produce foci of necrosis that are scattered throughout the liver. Other agents cause severe (chlorpromazine) or mild (estrogens) cholestatic liver damage, including cholestasis and inflammation of the portal triad and hepatocellular necrosis. 

A 64-year-old woman who was twice treated with pravastatin had cholestasis on both occasions with minimal hepatocellular injury (6). 

A 25-year-old woman developed abdominal pain, jaundice, and vomiting 5 days after consuming ecstasy. She had hepatocellular failure with a prothrombin ratio of 6.5, cytolysis, cholestasis, renal insufficiency, and encephalopathy. She had a liver transplant 2 days later and recovered fully. 

Other general effects include cholestasis, hepatocellular toxicity, thrombocytopenia, neutropenia, red cell aplasia, and haemolytic anaemia. Ovulation may be reduced or delayed (reversibly). 

Hepatocellular damage Cholestasis Hepatic function Mesenchymal activity Immunology ... 

Hyperbilirubinaemia relates to functional disorders in the hepatocellular metabolism of bilirubin - with and without cholestasis (W. Siede, 1957). This means either dysfunctions regarding bilirubin conjugation (= conjugation jaundice) or bilirubin excretion (= excretion jaundice). 

In classifying cholestasis, the cause, localization and duration of the disease as well as the involvement of bilirubin metabolism must be considered. Laboratory parameters of liver cell damage (increased activity of GPT, GOT and GDH) may be attributed to the underlying liver disease, but can also appear subsequently during the course of cholestasis-related hepatocellular damage, (s. tab. 13.1)... 

Beuers, U., Nathanson, M.H., Isales, C.M., Boyer, J.L. Taurourso-deoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca++ mechanisms defective in cholestasis. X. Clin. Invest. 1993 92 2984-2993... 

A 67-year-old man with Sjogren s sjmdrome took cyclophosphamide for 2 years, a cumulative dose of 40.5 g. He then developed severe progressive jaundice due to acute hepatocellular injury. Gallstones and acute viral hepatitis were excluded, and only anti-smooth muscle antibodies were weakly positive. Liver histology showed marked ballooning of the hepatocytes and cell loss, cytoplasmic and canahcular cholestasis, and infiltration of the portal tract with inflammatory cells. Complete resolution occurred 6 weeks after cyclophosphamide withdrawal. 

Liver damage was reported in 22 (0.35%) of 6294 patients given disopyramide, with jaundice in 6 (0.09%) (17). Liver damage due to disopyramide can be associated with direct hepatocellular damage (18) and intrahepatic cholestasis (19,20). However, it can also occur indirectly, because of heart failure and hepatic congestion (21). Thus, the incidence of direct liver damage quoted above may be an overestimate. 

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. 

In 20 cases of kebuzone-induced liver damage, biopsy showed hepatocellular damage with or without cholestasis, reactive hepatitis, or cholangiolitis (3). There was hepatitis with central lobular necrosis in one case. In five patients, a lymphocyte proliferation test was positive. 

In four patients with cholestatic hepatitis associated with terbinafine, all presented with jaundice and direct hyperbilirubinemia, various other clinical signs of hepatitis, and mild to moderate rises in alkahne phosphatase and hepatic transaminase activities (34,39). Biopsies in two patients showed cellular infiltrates in the portal tracts and hepatocellular and canalicular cholestasis (n — 1) and hepatocyte degeneration (n — 1). In the two cases with long-term follow-up, hepatitis was reversible after withdrawal of terbinafine and liver tests normalized within 6 months. 

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