Cholestasis/cholestatic

Tab. 13.5 Drugs known to cause cholestasis/cholestatic hepatitis (s. figs. 29.3, 29.4) (s. tab. 29.10)...

There is very little evidence relating to the role of ROMs in cholestatic liver disease. Serum selenium and glutathione peroxidase activity are decreased in humans with intrahepatic cholestasis of pregnancy (Kauppila et al., 1987). Low levels of vitamin E have been reported in patients with primary biliary cirrhosis, and in children with Alagille s syndrome or biliary atresia (Knight et al., 1986 Jeffrey etal., 1987 Lemonnier etal., 1987 Babin etal., 1988 Kaplan et al., 1988 Sokol etal., 1989). Serum levels of Mn-SOD are increased in patients with all stages of primary biliary cirrhosis compared with patients with other forms of chronic liver disease, although whether this causes or results from the disease process is unclear (Ono etal., 1991). 

Alkaline phosphatase levels and GGT are elevated in plasma with obstructive disorders that disrupt the flow of bile from hepatocytes to the bile ducts or from the biliary tree to the intestines in condition such as primary biliary cirrhosis, sclerosing cholangitis, drug-induced cholestasis, gallstone disease, and autoimmune cholestatic liver disease. 

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. 

Cholestatic. Pertaining to or characterized by suppression or stopping of the flow of bile (cholestasis), having intrahepatic or extra-hepatic causes. 

During cholestasis, the metabolism of tolbutamide is greatly altered, thus, tolbutamide (100 mg/kg) injected i.v. into rats with experimental cholestasis was eliminated more rapidly than in control animals, this increase was owing to the increase in liver weight and microsomal protein (25). In patients with recurrent intrahepatic cholestasis no differences in tolbutamide metabolism were noted as compared to the control group. In cholestatic hepatitis the plasma half-life of tolbutamide appeared unchanged. The... 

Dose-independent, drug-induced liver dysfunction (cholestatic jaundice) is not an unusual adverse reaction. Caused by a number of different, commonly used drugs, cholestasis is a hypersensitivity reaction that primarily affects the biliary canaliculi, causing an intrahepatic obstructive jaundice. An alteration in... 

Cholestatic Alagille s syndrome Progressive familial intrahepatic cholestasis... 

GGT does not nsnally form part of the standard LFTs in most laboratories. It is an enzyme fonnd in hepatocytes and biliary epithelial cells, and also in kidney, pancreas, intestine and prostate. It has a higher sensitivity for indicating a problem of liver origin than alkaline phosphatase, but tends to follow a similar pattern. It is released in all types of liver dysfunction and therefore cannot generally be used to differentiate between types. However, a raised GGT with an isolated raised alkaline phosphatase can be suggestive of cholestasis. GGT levels can be ten to 20 times normal in cholestatic disease. 

If a patient has cholestasis careful consideration must be given to the use of any drug that can cause biliary problems. Several drugs are known to cause cholestatic hepatitis, including the antibiotics flucloxacillin, erythromycin and co-amoxiclav (amoxicillin/clavulanic acid). Although a patient with cholestasis is no more likely to suffer from this idiosyncratic reaction than a patient without liver impairment, it will be of greater concern if it does occur. 

Patient 1 has been gradually becoming more cholestatic over the last few weeks. Her results suggest that because of the cholestasis the absorption of lipid-soluble drugs and the elimination of biliary cleared drugs may be affected. She has pruritus associated with the cholestasis, so drugs that cause itching are best avoided. 

Hepatic adverse effects secondary to antiemetic therapy are usually asymptomatic. Metoclopramide has been reported as causing cholestasis and the formation of arteriovenous shunts in the liver [12]. The 5HTj-receptor antagonists have all been documented as occasionally causing mild increases in liver fimction tests. Cholestatic jaundice has been reported with cyclizine, prochlorperazine and promethazine, and hepatitis has been reported with cyclizine. 

Kreek MJ, Sleisenger MH, Jeffries GH (1967) Recurrent cholestatic jaundice of pregnancy with demonstrated oestrogen sensitivity. Am J Med 43 79-203. Weden M, Glaumann H, Einarsson K (1992) Protracted cholestasis probably induced by oral contraceptive. J Intern Med 231 561-565. 

Cholangiodestmctive cholestasis is caused by bile duct obstruction which may be intrahepatic or extrahepatic. Bile duct injury may lead to sloughing of epithelial cells into the lumen, cell edema, and inflammation, which may contribute to obstruction (Treinen-Moslen, 2001 Plumlee, 2004). Chronic lesions associated with cholangiodestmctive cholestasis typically include bile duct prohferation and periductular fibrosis. Vanishing bile duct syndrome, characterized by a loss of bile ducts, has been seen in chronic cholestatic disease in humans (Zimmerman, 1999 Treinen-Moslen, 2001) and has been produced experimentally in dogs (Uchida, 1989). 

This chronic cholestatic liver disease affects 1 in 4000 people in the United Kingdom. Pruritus is a common early symptom, and can be helped by colestyramine. Qu-onic cholestasis leads to malabsorption of fat-soluble vitamins, particularly vitamin D, and deficiency of which must be corrected to avoid osteomalacea. 

The Increase In AP activity is stimulated by bile acids. A rise in bile acids, which is considered to be the most sensitive and earliest marker of cholestasis, precedes any elevation in AP. The latter derives from enzyme synthesis with increased secretion into the blood. Under pathological conditions, bile duct AP is formed, which is a sensitive marker for hepatobiliary diseases, cholestasis and space-occupying lesions of the liver. The sensitivity is 80-100% in cholestatic diseases. AP activity is usually higher in obstructive jaundice and cholangitis than in intrahepatic obstructions, and it is highest in the vanishing bile duct disease or in complete obstruction. (13, 39, 41) (s. tabs. 5.9 13.2-13.4)... 

Intracellular transport of bile acids mainly takes place through the cytoskeleton and intracellular structures (Golgi apparatus, endoplasmic reticulum). Here, too, cholestatic factors can prove to be damaging. Microfilaments are contractile elements not only is the intracellular transport of the bile acids disturbed, but the peristaltic activity of the canaliculi (so-called paralytic cholestasis within the lolsules) is also reduced if the functional capacity of those microfilaments becomes diminished. 

Monohydroxy bile acids (such as lithocholic acid produced in the intestine) are deemed to be cholestatic factors. They can, however, also be generated in the liver as a result of damage to the smooth endoplasmic reticulmn, with a decrease in activity of cytochrome P 450-dependent 7a-hydroxylase in cases of cholestasis, 3p-hydroxy-5S-cholic add is formed from cholesterol and converted into lithocholic acid and aUo-lithocholic acid (so-called foetal metabolic pathway of bile acids). (10)... 

However, it is not always clear with regard to the respective cause how the pathogenic mechanism triggers cholestasis. It cannot be adequately explained why one particular cause acts as a cholestatic factor in the individual case or why the same factor possibly has no effect at all. It would appear that genetic disposition is of decisive importance. Influences of everyday life (xenobiotics, drugs, alcohol, etc.), differing performances of biotransforma-... 

Ursodeoxycholic acid was used to treat acute viral hepatitis B without cholestasis for the first time by our working group in 1988. (166) At the time, we attributed the markedly positive effect of treatment in 9 out of 10 patients to the potential immunomodulatory effect of UDCA. (149, 154, 216) In 1993 reports were also published by A. D. Jorge on the good results achieved in 22 patients suffering from acute viral hepatitis and cholestasis. Administration in acute viral hepatitis is therefore recommended in controlled studies, since side effects are not to be expected and the current level of knowledge on the pharmacological effects of UDCA can be deepened. The beneficial effects of UDCA as reported so far in the cholestatic course of acute viral hepatitis are evidence of the success of this treatment. 

More severe liver disease, presenting as hepatitis and/ or intrahepatic cholestasis, has been seen with beta-lactam antibiotics of various classes, the isoxazolyl penicillins being most frequently involved. Co-amoxiclav has repeatedly been associated with cholestatic hepatitis. 

Cholestatic hepatitis occurred in a 61-year-old man with chronic myelocytic leukemia who had taken busulfan for 8 years (27). He presented with fever, abdominal pain, and raised liver enzymes. A liver biopsy showed cellular cholestasis with focal liver cell necrosis accompanied by a mild inflammatory infiltrate. When busulfan was withdrawn, his Uver enzymes normalized and his fever resolved. 

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