Cholestatic injury

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]. 

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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. 

The results instead suggested that infection early in life, when the developing liver may be uniquely sensitive to cholestatic injury and additionally stressed by intravenous nutrition, may play an important role. 

Ramrakhiani S, Brunt EM, Bacon BR. Possible cholestatic injury from ranitidine with a review of the hterature. Am J Gastroenterol 1998 93(5) 822-6. 

The core tests should include those for hepatocellular and cholestatic injury because both or either may occur. Given that it is not always possible to predict whether a xenobiotic will cause either cellular or hiliary injury, the choice of enzymes and bilirubin/bile salts needs to include markers for both of these types of toxicity and to take into consideration the intracellular locations of these enzymes. These common tests are far more effective when used in groups, and reliance should not he placed on any single test for the diagnosis of hepatotoxicity. The recognition of an increase in several of these test values and a pattern of changes offer more evidence of an adverse effect due to a xenobiotic. 

A frequency of ALT elevation >3x ULN of 0-2% was observed among patients treated with the comparators (placebo, warfarin, LMWH/warfarin, aspirin) (Lee et al. 2005). Among 233 patients treated with ximelagatran and 35 patients treated with placebo, the pattern of the hepatic enzyme elevations was evaluated. Of these, 76% (150) and 43% (15) were judged to have hepatocellular injury, while 24% (48) and 57% (20) were judged to have mixed or cholestatic injury (Lewis et al. 2008). 

Other hepatic responses that can be occupationally related include steatosis, cholestatic injury, hepatoportal sclerosis, and hepatic porphyria. The acute care provider should always consider a toxic chemical etiology in the differential diagnosis of liver disease. 

A 48-year-old man developed cholestatic hepatitis, complicated by portal hypertension, after having taken single 425 mg capsules of aged cascara sagrada three times daily for 3 days. Other medications included amitriptyline, cimeti-dine, and baclofen (Nadir et al. 2000). Amitriptyline has been associated with rare but severe incidences of hepatotoxicity, notably, cholestatic injury (Saeian and Rajender-Reddy 2003 Wen et al. 2008). 

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. 

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. 

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. 

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

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. 

This is a chronic lesion resulting from repeated injury and subsequent repair. It may result from either hepatocyte damage or cholestatic damage, each giving rise to a different kind of cirrhosis. Thus, carbon tetrachloride will cause liver cirrhosis after repeated exposure, but also compounds, which do not cause acute necrosis, such as ethionine and alcohol may cause cirrhosis after chronic exposure. 

In a retrospective review of 497 patients taking propylthiouracil for hyperthyroidism, clinically overt hepatitis developed in six patients at 12-49 days after starting the drug (50). Jaundice and itching were present in five, fever in two, rash in two, and arthralgia in one. Serum bilirubin, alanine transaminase, and alkaline phosphatase were increased in five, four, and six patients respectively. The type of hepatic injury was cholestatic in three, hepatocellular in one, and mixed in two. There were no differences in age, sex, drug dose, or serum thyroid hormone concentrations at time of diagnosis in those with hepatic injury compared with those without. Liver function normalized in all patients at 16-145 days after withdrawal of propylthiouracil. In addition to these cases of overt liver injury, 14% of the cohort had mild asymptomatic liver enzyme rises at a mean of 75 days after the start of treatment. 

Chounta A, Zouridakis S, Ellinas C, Tsiodras S, Zoumpouli C, Kopanaks S, Giamoarellou H. Cholestatic liver injury after glimepiride therapy. J Hepatol 2005 42 944-6. 

The incidence of drug-induced liver injury with rosiglitazone has been calculated at 0.02% for alanine transaminase activity 10 times the upper end of the reference range and 0.001% for jaundice (120). The above case report is unusual because, although liver damage is rare, hepatic necrosis occurs more commonly than cholestatic hepatitis. 

Pinto AG, Cummings OW, Chalasani N. Severe but reversible cholestatic liver injury after pioglitazone therapy. Ann Intern Med 2002 137(10) 857. 

Jadallah KA, Limauro DI, Colatrella AM. Acute hepatocellular-cholestatic liver injury after olanzapine therapy. Ann Intern Med 2003 138 357-8. 

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). 

Romagnnolo, J., Sadowskl, D.C., Lalor, E., Jewell, L., Thomson, AJ3.R. Cholestatic hepatocellular injury with azathioprine A case report and review of the mechanisms of hepatotoxicity. Can. J. Gastroenterol. 1998 12 479 -483... 

Hepatic injury is a rare adverse effect of the ACE inhibitors (60,61). Both acute and chronic hepatitis and cholestatic jaundice can occur (62,63), as can cross-reactivity, as identified in a report involving enalapril and captopril (64). 

Prolonged duration of treatment and increasing age were risk factors for flucloxacillin-induced jaundice (181), and cholestatic liver injury has been described most often with flucloxacUhn (182,183) and other isoxazolylpenicillins (184). Whether cholestatic hepatitis after the combination of amoxicUhn with clavulanic acid (co-amoxiclav) is related to one of these categories is not yet clear. 

Co-amoxiclav can cause cholestatic hepatitis. The first report appeared in 1988 (14), since when several hundreds of cases have been reported, for example to health authorities (15), and over 100 cases have been described in detail (16-31). Clavulanic acid is instrumental, either alone or in combination with amoxicillin, since the risk of acute liver injury is much smaller with amoxicillin alone (32). 

These data suggest that bosentan causes cholestatic liver injury due to inhibition of bile-salt efflux and damage due to intracellular accumulation of bile salts. 

Adler E, Benjamin SB, Zimmerman HJ. Cholestatic hepatic injury related to warfarin exposure. Arch Intern Med 1986 146(9) 1837-9. 

Cholestatic hepatitis, which is associated primarily with erjdhromycin estolate, can be caused by all forms of erythromycin, including the base, estolate, ethylsuccinate, propionate, and stearate (39,41). Although it was originally speculated that a hypersensitivity reaction to the estolate ester rather than to the erjdhromycin itself was responsible for this adverse reaction (42), erythromycin does inhibit bile flow (43). Most probably the differences in hepatotoxicity between the various erythromycin derivatives are of a quantitative rather than a qualitative nature (44,45), perhaps because of better intestinal absorption of the estolate. Potentially severe but rare cholestatic liver injury occurs in perhaps up to 2-4% of... 

When B. officinalis was mistaken for a similar plant, Securinega suffruticosa, and was cooked in a soup used for muscle aches, lumbago, or as a tonic by 19 patients, 14 developed diarrhea, 10 had nausea and felt cold, nine had sensations of abdominal fullness, and seven vomited (3). Liver enzymes rose and the median times to median peak activities were 3 days for alanine transaminase, 2 days for aspartate transaminase, 5 days for alkaline phosphatase, and 12 days for gamma glutamyltranspeptidase. The liver damage was hepatocellular liver injury rather than cholestatic and marked jaundice did not develop. 

Hepatic injury has been described from time to time with ACE inhibitors. Severe, prolonged cholestatic jaundice has been reported with fosinopril (3). The evidence of a link to fosinopril was convincing. 

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. 

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