Canalicular cholestasis

Fig. 22.13 Late stage of acute viral hepatitis B moderate roundcell infiltration of the lobular parenchyma with small aggregates of Kupffer cells and Kupffer cell activation slight disarray of liver cell trabeculae minimal canalicular cholestasis (— ) liver cell mitosis ( ) and binuclear hepatocytes...

Fig. 29.3 Mixed (intracellular and canalicular) cholestasis following the use of dextropropoxyphene hydrochloride (s. tab. 29.10)...

Canalicular cholestasis with portal fibrosis and ductal proliferation has been reported after 24 years of azathioprine in a 57-year-old woman with myasthenia gravis (34). 

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. 

A 41-year-old man developed severe hepatic dysfunction following a 3.5-week course of terbinafine (250 mg/ day) (40). He had marked pruritus, jaundice, malaise, anorexia, and loin pain. His serum bilirubin rose to a peak of 718 pmol/l with alkahne phosphatase 569 U/1, alanine transaminase 90 U/1, aspartate transaminase 63 U/1, and a prolonged prothrombin time of 21 seconds, unresponsive to vitamin K. Liver biopsy showed canalicular cholestasis consistent with a drug reaction. His symptoms resolved 11 months after drug withdrawal, and his hver function tests normalized after 15 months. 

Liver Severe acute hepatitis with symptomatic cholestasis has again been attributed to atorvastatin. This is a rare adverse effect, which cause mixed hepatotoxicity and canalicular cholestasis [43 ]. In another case, that of a 68-year-old man who was taking... 

Cholestasis may be transient or chronic (Treinen-Moslen, 2001) and may be subdivided into canalicular cholestasis and cholangiodestructive cholestasis. Canalicular cholestasis can be produced by drugs or other chemicals that damage the bile canalicular structure... 

Funk, C. et al. (2001) Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export ofbile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and ihe inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate. Toxicology, 167 (1), 83-98. 

BSEP also known as sister-P-glycoprotein (SPGP) was originally cloned from pig liver (185). BSEP is localized on the canalicular membrane of hepa-tocytes and is responsible for the secretion of bile salts across the canalicular membrane into bile. BSEP appears to be the predominant bile salt efflux system for hepatocytes, and is a critical component in the enterohepatic circulation of bile acids. A number of mutations in the transporter were found to the basis for progressive familial intrahepatic cholestasis type 2 (PFIC2) (186-188). Mutations found in PFIC2 patients include frameshifts, missense mutations, and premature termination codons. Most PFIC2 patients lack immunohistochemically detectable BSEP in their liver. Recently, seven... 

Mottino AD, Cao J, Veggi LM, et al. Altered localization and activity of canalicular Mrp2b in estradiol-17-P-D-glucuronide-induced cholestasis. Hepatology 2002 35 1409-1419. 

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-... 

Morphology The morphologist uses the term cholestasis to describe the presence of bile in the hepatocytes as well as in hypertrophic Kupffer cells (= cellular bilirubino-stasis), particularly in the form of inspissated bile droplets and copper within the more or less dilated canaliculi (= canalicular bilirubinostasis). In extrahepatic cholestasis, bile is additionally found within the likewise mostly dilated interlobular bile ducts (= ductular bilirubinostasis) as well as in the parenchyma in the form of bile infarcts" or bile lakes . 

Inhibition of bile acid transport More than 100 medicaments can cause intrahepatic cholestasis. In this case, the canalicular transport mechanisms are impaired. The retained bile acids damage the cells. 

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. 

Laboratory features of cholestasis vary, depending on whether the process causes complete or partial impairment of biliary drainage. The common feature of aU cholestatic disorders is an increase in plasma activities of canalicular enzymes, such as ALP and GGT. Because this process involves both increased synthesis of enzyme and release of enzyme from its membrane bound forms, there is generally a short lag period between the onset of cholestasis and the increase in plasma activities. In the early stages of an acute mechanical obstruction (especially from gallstones), there may be transient increases in plasma activities of liver cytosolic enzymes, such as AST and ALT. Plasma AST and ALT may exceed 400 lU/L, and in 1% to 2% of cases are more than 2000 lU/L. Even in the presence of continued obstruction, AST and ALT activity gradually decrease, and AST is typically within the reference interval within 8 to 10 days. 

Drugs are a common cause of cholestasis, causing about 15% of cases. Drug reactions are especially common in older individuals, where up to 50% of individuals have increased enzymes because of medications. Drugs can cause a cholestatic picture by two major mechanisms. In some cases, only conjugated bilirubin is increased, whereas canalicular enzymes are not elevated. This picture, often seen... 

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