Drug-Induced Cholestasis

Abstract

Intrahepatic cholestasis, defined as arrested bile flow, mimics extrahepatic obstruction in its biochemical, clinical and morphological features. It may be due to hepatocyte lesions of which there are three types, termed canalicular, hepatocanalicular and hepatocellular, respectively; or it may be due to ductal lesions at the level of the cholangiole or portal or septal ducts. Defective bile flow due to hepatic lesions reflects abnormal modification of the ductular bile. Defective formation of canalicular bile may involve bile acid-dependent or independent flow. It appears to result most importantly from defective secretion of bile acid-dependent flow secondary to defective uptake from sinusoidal blood, defective transcellular transport and defective secretion; or from regurgitation of secreted bile via leaky tight junctions. An independent defect in bile acid-independent flow is less clear. Defective flow of bile along the canaliculus may reflect increased viscosity and impaired canalicular contractility secondary to injury of the pericanalicular microfibrillar network. Impaired flow beyond the canaliculus may result from ductal injury. Sites of lesions that contribute to cholestasis include the sinusoidal and canalicular plasma membrane, the pericanalicular network and the tight junction and, less certainly, microtubules and microfilaments and Golgi apparatus. A number of drugs that lead to cholestasis have been found to lead to injury at one or more of these sites. Other agents (alpha-naphthylisothiocyanate, methylenedianiline, contaminated rapeseed oil, paraquat) lead to ductal injury resulting in cholestasis. Reports of inspissated casts in ductules (benoxaprofen jaundice) and injury to the major excretory tree (5-fluorouridine after hepatic artery infusion) have led to other forms of ductal cholestasis. Most instances of drug-induced cholestasis present as acute, transient illness, although important chronic forms also occur. The clinical features include the reflection of the cholestasis (pruritus, jaundice), systemic manifestations and extrahepatic organ involvement. While nearly all classes of medicinal agents include some that can lead to cholestasis, there are differences among the various categories. Phenothiazines and related antipsychotic and 'tranquillizer' drugs characteristically lead to cholestatic hepatic injury. The tricyclic antidepressants may lead to cholestatic or hepatocellular injury.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkaline Phosphatase Is Increased in both Brain and Plasma in Alzheimer’s Disease

“…None of the subjects had an acute cholestatic injury. In terms of medications associated with drug-induced cholestasis [28] , there were insufficient numbers of subjects taking any such medications (maximally 1 or 2 cases in each group taking any one medication) for any meaningful statistical analysis to be performed. The most significant difference between the groups in terms of medications taken was acetylcholinesterase inhibitors: 90% of the AD subjects were taking these medications (99 of 110 AD subjects compared with 0 out of 110 control subjects; p !…”

Effects of <i>Plasmodium berghei</i>Infection on Arteether Metabolism and Disposition

“…Drug-in duced cholestasis has been documented for the antimalarial drug, mefloquine [25,26]; however, preliminary studies in our laborato ry demonstrate that AE does not affect bile production (data not shown). Although drugEtYects of Plasmodium berghei on Artccthcr Metabolism induced cholestasis is usually clinically insig nificant, fatal instances reflect serious un derlying disease or other systemic effects of the drug [27], More extensive changes would be expected in multiple drug dose systems with both disease-and drug-induced choles tatic changes, i.e. MI with drug therapy.…”

Isolated idiopathic bile ductular hyperplasia in patients with persistently abnormal liver function tests

“…Fifteen cases (six males, aged 32^8.5 years, range 16 -55) were then selected, allowing an overall analysis of 158 portal spaces; on average, there were 15 portal tracts per specimen (range [8][9][10][11][12][13][14][15][16][17][18]. We have also considered 39 patients staged for haematological malignancies in stable clinical remission from January 1998 to December 2002 as source of control needle biopsies.…”

“…In addition, drug intake was carefully investigated by clinical chart examination supported by a detailed patients' interview so that previous or ongoing use of any hepatotoxic drug or herbal medicine known to cause cholangiopathies and ductopenia [12][13][14] and any professional exposure to xenobiotic agents were excluded.…”