Types of Liver Injury

The types of injury to the liver depend on the type of toxic agent, the severity of intoxication, and the type of exposure, whether acute or chronic. The main types of liver damage are discussed briefly in this section. Whereas some types of damage—for example, cholestasis—are liver specific, others such as necrosis and carcinogenesis are more general phenomena. 

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Hepatitis is an inflammation of the liver and is usually viral in origin however, certain chemicals, usually drugs, can induce a hepatitis that closely resembles that produced by viral infections (Table 14.1). This type of liver injury is not usually demonstrable in laboratory animals and is often manifest only in susceptible individuals. Fortunately, the incidence of this type of disease is very low. 

Many types of liver injury are caused by a number of biochemical reactions of toxicants or their active metabolites. Such reactions inclnde covalent binding, lipid peroxidation, inhibition of protein synthesis, pertnrbation of calcium homeostasis, disturbance of biliary prodnction, and a variety of immunologic reactions. The types of liver injury from such biochemical reactions include steatosis (fatty liver), liver necrosis, cirrhosis, cholestasis, hepatitis, and carcinogenesis. The toxicants that cause these injuries are discussed in brief. 

As will be discussed in a later section, patients with certain types of liver injury have chenodeoxycholate as the predominant primary bile salt in their serum. Primary bile salt concentration ratios in serum are a fairly accurate reflection of the primary bile salt concentration ratio in bile. The evidence for this is given in Fig. 3, in which the primary bile salt concentration ratio in serum is plotted against that in bile in 14 patients. The correlation coefficient for these two variables is 0.86 (p<0.01). When chenodeoxycholate predominates in bile its metabolites (lithocholate and others) predominate in feces, and when cholate predominates in bile its metabolites (de-oxycholate and others) predominate in feces (27). This relationship is shown in Fig. 4. It thus appears that primary bile salt concentrations in blood and bile are related to their relative synthesis rates and that the predominant bile salt in blood and bile has the greater synthesis rate, since its metabolites predominate in feces. This assumes of course that there is a steady state and... 

Mechanisms of liver injury have been divided into two categories intrinsic and idiosyncratic. Intrinsic injury may lead to steatosis, necrosis, cholestasis, or a mixed form of damage, often with minimal inflammation (Sturgill and Lambert, 1997). Intrinsic liver injury is a predictable, reproducible, dose-dependent reaction to a toxicant (Dahm and Jones, 1996 Sturgill and Lambert, 1997 Zimmerman, 1999 Pineiro-Carrero and Pineiro, 2004). A threshold dose exists for xenobiotics causing intrinsic liver injury. There is commonly a predictable latent period between the time of exposure and clinical evidence of liver injury. This type of liver injury accounts for the vast majority of toxic liver injury and is often caused by reactive products of xenobiotic metabolism, most commonly electrophiles and free radicals. A few drugs cause intrinsic liver injury without bioactivation. An abbreviated summary of mechanisms of intrinsic liver injury is illustrated in Figure 42.1. 

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. 

Type rV Liver injuries combined with lesions of the vena cava... 

Carbon tetrachloride-induced liver injury is another animal model for studying free-radical injury to tissues. Animals maintained on high zinc regimen are resistant to this type of biochemical injury, thus suggesting that zinc may be protective against free-radical injury. More recent studies have shown that zinc also inhibits the analogous metro-midazole-dependent, free-radical sequence. 

AIH is associated with the presence of liver- and nonliver-related autoantibodies m plasma. These are helpful in diagnosis, but are not likely to be the cause of liver injury. The most important antibodies for diagnosis include antinuclear antibody (ANA), antismooth muscle antibody (ASMA), and antiliver-kidney microsomal antigen type 1 (LKMi). A variety of other autoantibodies are found frequently in AIH, some of which are found in other disorders. A summary of the most common autoantibodies, their associations, and their molecular targets (when known) is given... 

Fig. 1.1 Morphological and biochemical studies (a) One biochemical approach to study enzymes is to analyze the activity levels with results plotted on a graph and to include error bars from multiple assays. The morphological approach gives information about where the enzyme is located. Three different types of liver cells are shown here as circular, elongated, and rectangular, (b) The enzyme (dark cells) can be located in all the different types of liver cells, (c) More likely the enzyme is found in only one cell type, the rectangular cells, (d) As a result of disease, the enzyme may be expressed in only a small number of cells in a single cell type, (e) Following an injury, the enzyme may be expressed in multiple cell types located near the injury sites...

A Spanish study examined causes of amoxicillin/clavulanate-induced liver injury to determine the role of HLA class 1 and 11 alleles in characteristics of this effect. It was found that different alleles may influence the type of presentation of liver injury (hepatocellular vs cholestatic), severity and timing of onset [29 ]. 

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. 

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