Liver cholestatic

Liver and Gallbladder. High dosages of oral estrogens have been reported to increase the risk for jaundice, cholestatic hepatitis, gallstones, and hepatic vein blood clots. Estrogens promote the development of hepatic neoplasms associated with increased hepatic cell regenerative activity (186,187). 

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). 

Ursodiol may slow progression of liver disease. It improves bile flow and may displace toxic bile acids that accumulate in a cholestatic liver, stimulate bicarbonate secretion into the bile, offer a cytoprotective effect, and reduce elevated liver tests. Ursodiol is typically dosed at 15 to 20 mg/kg per day in two divided doses and may be rounded to the nearest tablet size.5,7... 

Diagnosing viral hepatitis may be difficult because most infected individuals are asymptomatic. Because symptoms cannot identify the specific type of hepatitis, laboratory serologies must be obtained (Table 21-2). In addition, liver function tests may be obtained to assess the extent of cholestatic and hepatocellular injury. However, the definitive test to determine the amount of damage and inflammation of hepatic cells is a liver biopsy. 

Cholestatic liver disease/cirrhosis (e.g., primary biliary cirrhosis)... 

Alderman S, Kailas S, Goldfarb S, et al. Cholestatic hepatitis after ingestion of chaparral leaf confirmation by endoscopic retrograde cholangiopancreatography and liver biopsy. J Clin Gastro 19(3) 242-247, 1994. 

Cholestatic liver diseases Primary biliary cirrhosis... 

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. 

The levels of GGT in plasma correlate well with elevations of alkaline phosphatase and are a sensitive marker for cholestatic liver disease. 

Intermittent EN is similar to bolus EN except that the feeding is administered over 20 to 60 minutes, which improves tolerability but requires more equipment (e.g., reservoir bag and infusion pump). Like bolus EN, intermittent EN mimics normal eating patterns. As compared with continuous EN, bolus or intermittent EN minimizes the development of cholestatic liver disease. 

Requirements for trace elements during organ failure are not clearly defined. Manganese and copper should be restricted or withheld in patients with cholestatic liver disease. Chromium, molybdenum, and selenium should be restricted or withheld in patients with renal failure. 

Cholestatic hepatitis has been reported with risperidone, and liver function test abnormalities (mostly transient) have been reported with olanzapine and clozapine. 

PXR has been demonstrated to act as an LCA sensor and plays an essential role in detoxification of cholestatic bile acids [11,61]. Studies in different animal models showed that activation of PXR protected against severe liver damage induced by LCA. Pretreatment of wild-type mice, but not the PXR-null mice, with PCN reduced the toxic effects of LCA. Moreover, genetic activation of PXR by expressing the activated... 

Stedman, C.A., Hddle, C., Coulter, S.A., Sonoda, J., Alvarez, J.G., Moore, D.D., Evans, R.M. and Downes, M. (2005) Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury. Proceedings of the National Academy of Sciences of the United States of America, 102, 2063-2068. 

Dormer, M.G. and Keppler, D. (2001) Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver. Hepatology, 34, 351-359. 

These studies were generally carried out at bile-acid concentrations that occur naturally in humans e.g. for colon cells, after a high-fat meal for esophageal cells, in individuals with repeated heartburn due to duodeno-gastroesophageal reflux or in cholestatic liver disorders). Taken together, these studies indicate that induction of apoptosis by bile acid is likely a frequent challenge for cells throughout the GI tract. 

Phenothiazines Use phenothiazines with caution in patients with cardiovascular disease, liver dysfunction, or ulcer disease. Promethazine has been associated with cholestatic jaundice. 

Liver injury is clinically defined as an increase of serum alanine amino transferase (ALT) levels of more than three times the upper limit of normal and a total bilirubin level of more than twice the upper limit of normal [4]. The clinical patterns of liver injury can be characterized as hepatocellular (with a predominant initial elevation of ALT), cholestatic (with an initial elevation of alkaline phosphatase) or mixed. The mechanisms of drug-induced hepatotoxicity include excessive generation of reactive metabolites, mitochondrial dysfunction, oxidative stress and inhibition of bile salt efflux protein [5]. Better understandings of these mechanisms in the past decades led to the development of assays and models suitable for studying such toxic mechanisms and for selecting better leads in the drug discovery stage. 

Serum ALP and total bilirubin (unconjugated and conjugated fractions) are traditionally used to monitor cholestatic injury. The ALP families of enzymes are zinc metalloproteases that are present in nearly all tissues. In the liver, ALP is immu-nolocalized to the microvili of the bile canaliculus [124]. Increased synthesis of ALP and its release into the circulation occurs within hours of cholestatic injury [129]. Serum assays of 5 -nucleotidase (5 -NT) or y-glutamyltransferase activity (GGT) are used to confirm the liver as the specific origin for the elevation of ALP. Increases in serum bilirubin or bile acids are usually the result of bile retention subsequent to impaired bile flow, increased production associated with accelerated erythrocyte destruction, or altered bilirubin metabolism [129]. 

Drug-induced hepatotoxicity can present in variable manifestations, such as cell death (necrosis, apoptosis), infiammation, degeneration (steatosis), fibrosis/cirrho-sis and the development of tumors. The manifestations of drug toxicity may not be mutually exclusive and may occur sequentially, or in combination. ALT and ALP can be used to generally classify the pattern of liver injury as either hepatocellular (ALT >3x ULN), cholestatic (ALP >2x ULN, ALT/ALP <2) or mixed (elevated ALP and ALT). The successful monitoring of hepatotoxicity would identify cases before irreversible injury occurs. The activity levels of ALT, AST and ALP only increase after hepatic or cholestatic injury has occurred. Waiting for activity levels to exceed the established thresholds may be too late [3]. New biomarkers are needed to monitor/predict the specific sequence of events for different classes of hepatotoxic compounds. 

May LD, Lefkowitch JH, Kram MT, Rubin DE. Mixed hepatocellular-cholestatic liver injury after pioglita-zone therapy. Ann Intern Med 2002 136 449-52. 

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 hepatitis may occur when drug therapy lasts longer than 10 days or repeated courses are prescribed. The hepatitis is characterized by fever, enlarged and tender liver, hyperbilirubinemia, dark urine, eosinophilia, elevated serum bilirubin, and elevated transaminase levels. Hepatitis has been associated with the estolate salt of erythromycin but not with other formulations. Although the hepatitis usually occurs 10 to 20 days after the initiation of therapy, it can occur within hours in a patient who has had such a reaction in the past. The hepatitis is believed to be the result of both a hepatotoxic effect and a hypersensitivity reaction this latter effect is reversible on withdrawal of the drug. Erythromycin and derivatives induce hepatic microsomal enzymes and interfere with the actions of various drugs, including theophylline and carbamazepine. 

Deems, R. O., and M. I. Friedman. Macronutrient selection in an animal model of cholestatic liver disease. Appetite 1988 11(2) 73-80. 

Cholestatic jaundice can occur during treatment with antipsychotics, and is most often reported in chlorpromazine-treated patients (Hansen et ah, 1997). Elevations in liver transaminases have also been observed in a few cases of children treated with risperi-... 

Except for one case/° recent clinically oriented MRS studies of human liver have been at 1.5T. Several studies applied in vivo MRS to diffuse liver disease. ° °" The PDE intensity was lower in cirrhosis than in controls ° and served to distinguish the alcoholic, viral, and cholestatic etiologies of diffuse liver disease. ° However, there was no difference between patients with non-alcoholic fatty liver disease (NAFLD) and controls. Sharma et al., using the relative PME intensity as a measure of altered gluconeogenesis (this peak can contain glucose-6-P and 3-phos-phoglycerate in addition to PC and PE), found that hepatic gluconeogenesis was altered in both obese and non-obese Asian Indians with NAFLD, relative to non-obese subjects without NAFLD. 

Adverse effects include gastrointestinal symptoms like nausea, vomiting, epigastric pain, diarrhoea, hypersensitivity reactions like rash, urticaria, angioedema, exceptionally bronchospasm, anaphylactic shock dizzy sensations (caution in driving or use of machinery) moderate increase in ASAT, ALAT and/or alkaline phosphatases cholestatic or more rarely acute liver injury. 

Among the more severe adverse reactions, Stevens-Johnson epidermal necrolysis syndrome, thrombocytopenia, agranulocytosis, and nephrotic syndrome have all been observed. Like diclofenac, sulindac may have some propensity to cause elevation of serum aminotransferases it is also sometimes associated with cholestatic liver damage, which disappears when the drug is stopped. 

Erythromycins, particularly the estolate, can produce acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction. Most patients recover from this, but hepatitis recurs if the drug is readministered. 

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