Cirrhosis aminotransferases

Percutaneous Hver biopsy after each 1.5 g of total accumulated methotrexate dosage to detect hepatic fibrosis or cirrhosis not rehably predicted by semm aminotransferase tests are recommended (1,50). Concurrent use of NSAIDs may increase toxicity of methotrexate, although toxicity may be avoided if the dmgs are separated by 12 h. 

General outcomes for treating hepatitis are to (1) prevent the spread of the disease (2) prevent and treat symptoms (3) suppress viral replication (4) normalize hepatic aminotransferases (5) improve histology on liver biopsy and (6) decrease morbidity and mortality by preventing cirrhosis, hepatocellular carcinoma, and ESLD. 

Toxicities are GI (stomatitis, diarrhea, nausea, vomiting), hematologic (thrombocytopenia, leukopenia), pulmonary (fibrosis, pneumonitis), and hepatic (elevated enzymes, rare cirrhosis). Concomitant folic acid may reduce some adverse effects without loss of efficacy. Liver injury tests (aspartate aminotransferase or alanine aminotransferase) should be monitored periodically, but a liver biopsy is recommended during therapy only in patients with persistently elevated hepatic enzymes. MTX is teratogenic, and patients should use contraception and discontinue the drug if conception is planned. 

Viral hepatitis or cirrhosis produces an increase in both direct and indirect bilirubin. Aminotransferase levels will also be elevated. 

Hepatic Effects. Carbon tetrachloride has been known for many years to be a powerful hepatotoxic agent in humans and in animals. The principal clinical signs of liver injury in humans who inhale carbon tetrachloride are a swollen and tender liver, elevated levels of hepatic enzyme (aspartate aminotransferase) in the serum, elevated serum bilirubin levels and the appearance of jaundice, and decreased serum levels of proteins such as albumin and fibrinogen (Ashe and Sailer 1942 McGuire 1932 New et al. 1962 Norwood et al. 1950 Straus 1954). In cases of acute lethal exposures, autopsy generally reveals marked liver necrosis with pronounced steatosis (Jennings 1955 Markham 1967 Smetana 1939), and repeated or chronic exposures leads in some cases to fibrosis or cirrhosis (McDermott and Hardy 1963). 

Typical side effects are constitutional in nature, including a flu-like syndrome within 6 hours after dosing in more than 30% of patients that tends to resolve upon continued administration. Other potential adverse effects include thrombocytopenia, granulocytopenia, elevation in serum aminotransferase levels, induction of autoantibodies, nausea, fatigue, headache, arthralgias, rash, alopecia, anorexia, hypotension, and edema. Severe neuropsychiatric side effects may occur. Absolute contraindications to therapy are psychosis, severe depression, neutropenia, thrombocytopenia, symptomatic heart disease, decompensated cirrhosis, uncontrolled seizures, and a history of organ transplantation (other than liver). Alfa interferons are abortifacient in primates and should not be administered in pregnancy. 

Milk thistle has been used to treat acute and chronic viral hepatitis, alcoholic liver disease, and toxin-induced liver injury in human patients. Milk thistle has most often been studied in the treatment of alcoholic hepatitis and cirrhosis. In both of these disorders, outcomes have been mixed and reports include significant reductions in markers of liver dysfunction and in mortality, as well as no effect. In acute viral hepatitis, studies have generally involved small sample sizes and have shown mixed outcomes of improved liver function (eg, aminotransferase values, bilirubin, prothrombin time) or no effect. Studies in chronic viral hepatitis and toxin-induced injury have also been of small size but have reported mostly favorable results. Parenteral silybin is marketed and used in Europe as an antidote in Amanitaphalloides mushroom poisoning, based on favorable outcomes reported in case-control studies. 

Transaminases Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) Liver, heart, skeletal muscle 0 0 lU/L 0 0 lU/L Raised levels indicate hepatocyte damage/necrosis ALT is more liver specific but has a longer half-life, so less sensitive May be normal in compensated liver cirrhosis... 

Tarao, K., Rino, Y., Ohkawa, S., Tamai, S., Miyakawa, K., Takakura, H., Endo, O., Yoshitsugu, M., Watanabe, N., Matsuzaki, S. Close association between high serum alanine aminotransferase levels and multicentric hepatocarcinogenesis in patients with hepatitis C virus-associated cirrhosis. Cancer 2002 94 1787-1795... 

Water retention due to sodium chloride (salt) is a common manifestation that leads to weight gain. Edema is also found in patients with cardiac heart failure, renal insufficiency, liver cirrhosis, and hypo-proteinemia. When large doses are used to treat neoplastic diseases, compounds with 17-alkyl substitutions can cause cholestatic hepatitis at high doses, jaundice is the most common clinical feature with accumulation of bile in the bile capillaries. Jaundice usually develops after 2-5 months of therapy. It can be detected by increases in plasma aspartate aminotransferase and alkaline phosphatase. 

Elevations of LD activity are observed in liver disease, but these elevations are not as great as the increases in aminotransferase activity. Elevations are especially high (10 times normal) in toxic hepatitis with jaundice. Shghtly lower values are observed in viral hepatitis and in infectious mononucleosis, the latter often associated with elevations of LD-3. LD activity is normal or at most twice the upper reference limit in cirrhosis and obstructive jaundice. Serum LD-5 is often notably elevated in patients with either primary fiver disease or fiver anoxia secondary to decreased oxygen perfusion. 

Nonalcoholic steatohepatitis is the most common cause of aminotransferase increases other than viral and alcoholic hepatitis. Increased transaminase concentrations have been observed in extrahepatic cholestasis, with activities tending to be higher the more chronic the obstruction. The aminotransferase activities observed in cirrhosis vary with the status of the cirrhotic process and range from the upper reference limit to four to five times higher, with an AST/ ALT ratio greater than 1. The ratio s elevation can reflect the grade of fibrosis in these patients. This appears to be attributable to a reduction of ALT production in a damaged liver. Twofold to fivefold elevations of both enzymes occur... 

Laboratory findings in cirrhosis reflect ongoing liver injury and decreased hepatic function. The most common laboratory findings in individuals with cirrhosis are summarized in Table 47-9. Activities of aminotransferases are variable in cirrhosis, and reflect activity of underlying necroinflammatory activity. If the cause of cirrhosis has been eliminated (as by abstinence from ethanol or successful treatment of viral hepatitis), aminotransferase activity is often within the reference interval Persistence of elevation is a risk factor for development of HCC. As described earlier, the ratio of AST/ALT activity is often greater than 1 in cirrhosis. The mechanism for the change in... 

Park G, Lin B, Ngu M, Jones D, Katelaris R Aspartate ammotransferase alanine aminotransferase ratio in chronic hepatitis C infection Is it a useful predictor of cirrhosis J Gastroenterol Hepatol 2000 15 386-90. 

Williams A, Hoofnagle J. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterology 1988 95 734-9. 

The liver can be involved in CF. Biliary cirrhosis secondary to bile duct obstruction occurs in as many as 18% of patients, whereas fatty infiltration occurs in about 30% of patients in a pattern unrelated to nutritional status. Bile ducts may be obstructed by inspissated mucus, which may lead to focal or multilobar cirrhosis. Such hepatic involvement can occur at any age but is more common with advancing age and can lead to portal hypertension, esophageal varices, and hypersplenism. The most common laboratory abnormality associated with hepatic involvement is elevated serum hepatic isoenzymes (gamma-glutamyltranspeptidase, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase)." ... 

Elevated liver enzymes may occur in up to 15% of patients cirrhosis is rare. Liver function tests, aspartate aminotransferase (AST) or alanine aminotransferase (ALT), should be performed periodically. Methotrexate should be discontinued if these test values show sustained results greater than twice the upper limits of normal. Serum albumin levels also should be checked periodically, as signs of liver toxicity in some patients may not have liver inflammation manifested by AST or ALT elevation. Liver biopsy is now recommended before beginning methotrexate therapy only for patients with a history of excessive alcohol use, ongoing hepatitis B or C infection, or recurring elevation of AST. Biopsies during methotrexate therapy are recommended only for patients who develop consistently abnormal liver function tests. ... 

Increased serum bile acids, suggesting cholestasis, were observed in rats treated with 1.57 mg selenium/kg/day as sodium selenate in drinking water for 13 weeks, but no effects were noted at 0.92 mg/kg/day (NTP 1994). In a 13-week drinking water study, hepatic effects were not observed in mice treated with sodium selenate at 7.17 mg selenium/kg/day, in mice treated with sodium selenite at doses up to 3.83 mg selenium/kg/day, or in rats treated with sodium selenite at doses up to 1.67 mg selenium/kg/day (NTP 1994). Increased serum aspartate aminotransferase and alanine aminotransferase activities were observed in mice treated by gavage with selenocystine at doses of 9.4 mg selenium/kg/day for 30 days (Sayato et al. 1993) or 4.7 mg selenium/kg/day for 90 days (Hasegawa et al. 1994). No effects on liver enzymes were observed in mice treated with selenocystine at 4.7 mg selenium/kg/day for 30 days (Sayato et al. 1993) or at 2.5 mg selenium/kg/day for 90 days (Hasegawa et al. 1994). Chronic dietary administration of selenium as seleniferous com or wheat at doses ranging from 0.25 to 0.50 mg/kg/day for 24 months produced cirrhosis of the liver in rats (Nelson et al. 1943). 

Various regimens of interferon-a have been attempted (197) and it has been found that longterm (> 1 month) low-dose therapy was more effective and better tolerated than short-term high-dose therapy (195, 198). Similar results were obtained with recombinant and lymphoblastoid preparations (199-201). The success rate was 30-40%, as judged by decreases in serum viral DNA, and patients responding to therapy have shown losses of HBeAg as well as decreased serum aminotransferase levels. Follow-up liver biopsies demonstrate reduced inflammation (198). It is hoped that this reduces the risk of subsequent cirrhosis and carcinoma which is a time-dependent process. Several studies have been performed to evaluate restoration of hepatic markers during and after interferon-a treatment, simply or in combination with other therapies to treat chronic hepatitis B (see section 6.3.5 below). 

---