Hepatocellular injury, liver function

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. 

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. 

Response is dose related (as is hepatocellular injury), and both response and increased liver function tests (LFTs) resolve with stopping the drug. 

Injury to the hepatocytes, for example by hepatotoxins or viruses, will result in hepatocellular damage. This generally manifests itself as fatty infiltration (steatosis), inflammation (hepatitis) or cell death (necrosis). If the assault is mild and remits, the liver will recover and overall liver function will remain normal. Snstained injnry causing hepatocyte cell death will, however, nltimately lead to fibrosis and cirrhosis and potentially severe liver dysfimction. 

Reversible hepatocellular injury has been reported with naltrexone in doses of up to 300 mg/day, which is five times that usually used for opioid blockade (SED-11, 147) (17). Five of twenty-six patients treated with naltrexone for obesity developed raised serum transaminase activities after 3-8 weeks of treatment. In another study in which 60 obese subjects received naltrexone for 8 weeks, there were abnormal liver function tests in six patients. Three patients failed to complete the course. Nausea and vomiting occurred within the first 24 hours of treatment but responded to a reduction in dose. There were also changes in mentation such as decreased mental acuity, depression, and anxiety, all of which resolved after withdrawal. This is significant, as adverse effects from naltrexone have previously been attributed to mild physical withdrawal syndromes. 

Several cases of ticlopidine-induced hepatotoxicity have been reported (27). Between 10 days and 12 weeks after the start of treatment, patients develop jaundice, usually without fever, eosinophilia, or pain. Laboratory tests show a cholestatic or mixed cholestatic-hepatocellular pattern of injury. There is usually clinical and biochemical recovery within 1-11 months. Frank ticlopidine-associated liver injury is uncommon, but in one study, 44% of patients had abnormal liver function tests and about one-half of them had to stop taking the drug (22). 

A 27-year-old Hispanic man presented with nausea and vomiting, diarrhea, and upper abdominal pain 12 months after starting to take chaparral capsules. A liver biopsy showed hepatocellular injury with necrosis and periportal inflammation. His liver function stabilized after withdrawal of chaparral. 

There are no laboratory or radiographic tests of hepatic function despite the commonly ordered liver function tests. These commonly measured markers are substances produced by the liver and released into the bloodstream during hepatocellular injury, and are more correctly termed liver dysfunction tests. True liver function tests that assess the ability of the liver to eliminate substances that undergo hepatic metabolism, such as the " C-aminopyrine breath tesfi are limited by complexity and availability. 

The liver is a central organ in metabolism that serves multiple functions such as protein synthesis, glycogen storage, hormone production, and detoxification [149]. Fatty liver is the earliest and the most common form of both nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) [150, 151]. Hepatocellular injury, inflammation and fibrosis are hallmarks of NASH, which are observed in only a fraction of subjects with NAFLD, although the exact mechanisms leading from NAFLD to NASH are still largely unknown [152]. Several lines of evidence indicate the importance of both quantitative and qualitative (e.g. saturated vs unsaturated) changes in dietary FAs as relevant mechanisms for the development of NAFLD both in rodent models and in humans [150, 153, 154, 155]. 

Some injuries may be transient, while others are irreversible. For example, fatty change is often transient and not necessarily indicative of functional compromise under certain conditions, hepatocytes with accumulated fat function normally. Malignant transformation, on the other hand, is irreversible and seriously disrupts hepatocellular function. Necrosis (cell death) may or may not be life-threatening, depending on its extent (see previous discussion of liver regeneration). 

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