Hepatocellular staging

Mehendale HM. 1991. Role of hepatocellular regeneration and hepatolobular healing in the final outcome of liver injury A two-stage model of toxicity. Biochem Pharmacol 42(6) 1155-1162. 

Sirica AE, Wilkerson CS, Wu LL, et al. 1989. Evaluation of chlordecone in a two-stage model of hepatocarcinogenesis A significant sex difference in the hepatocellular carcinoma incidence. Carcinogenesis 10(6) 1047-1054. 

This pattern of results is typical of hepatocellular damage (necrosis). The high activity of AST and ALT are due to leakage from damaged cells the normal albumin value indicates that this is an acute (recent) condition. The modest rise in bilirubin concentration in plasma is not itself diagnostic at this stage. 

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. 

Hepatic cirrhosis is an end stage process of hepatic inflammation characterised by lobular scarring, distortion of the hepatocellular architecture and disordered function, frequently with associated portal hypertension. 

Hepatocellular carcinoma (HCC) is the fifth most common and the third most deadly cancer. One million patients with HCC die each year. One of the major causes of HCC is infection with the hepatitis C virus (HCV), and the pathogenesis of HCV-related HCC in its incipient stage from the infection to the onset of cancer is being researched. 

Foci A small group of cells occurring e.g. in the liver distinguishable, in appearance or histochemically, from the surrounding tissue. They are indicative of an early stage of a lesion which may lead to the formation of neoplastic nodules or hepatocellular carcinomas. 

Steatohepatitis is the accumulation of lipids and the presence of inflammatory cells within hepatic parenchyma. Steatohepatitis is usually the next stage of steatosis if untreated (Bautista, 2002 French, 2003 Lieber, 1994). The inflammatory cells are usually neutrophils and mononuclear leukocytes. Conditions usually associated with steatohepatitis are alcoholic liver disease, NAFLD, and endotoxemia secondary to intestinal disease. Any toxic compounds that cause steatosis can also result in steatohepatitis if the condition is left untreated. Steatohepatitis may progress to flbrosis/cirrhosis and hepatocellular carcinoma if the inciting cause is not removed or treated (Diehl, 2002). 

False-normal GPT values are often found - despite the presence of liver damage - in (7.) haemochroma-tosis, (2.) ileo-jejunal bypass, (2.) marked (e. g. alcohol-induced) deficiency of pyridoxal phosphate (Bg), 4.) severe loss of liver parenchyma, and (5.) during the terminal stages of liver disease with exhaustion and/or blockage of hepatocellular enzyme synthesis caused by toxins. (31) In healthy persons, slightly elevated GPT values were detected in 0.5% of cases. 

Miller, W.J., Federle, M.P., Campbell, W.L. Diagnosis and staging of hepatocellular carcinoma comparison of CT and sonography in 36 liver transplantation patients. Amer. J. Roentgenol. 1991 157 303-306... 

The clinical picture of chronic liver insufficiency comprises both a compensated and decompensated form. These two stages of manifest chronic liver insufficiency affect the hepatocellular area or the portal system either exclusively or predominantly (= cellular or portal compensation or decompensation) mostly they occur as a combined form of disease. The resulting spectrum of clinical and laboratory findings will reflect either a global or partial insufficiency of the liver, (s. p. 376)... 

Fulminant or protracted liver failure is caused by medicaments in 10-15% of cases. A reduction in the functional liver mass to < 20-35% is deemed to be a critical stage. However, the death of the patient may already occur due to secondary metabolic disorders (so-called exogenous hepatic coma) before the extent of the parenchymal loss has fallen below the critical threshold (so-called endogenous hepatocellular disintegration coma), (s. tab. 29.10)... 

Tab. 37.7 Classification of the stages of hepatocellular carcinoma and survival time in months (untreated) (K. Okuda et af, 1985)...

Kim, R.D., Nazarey, R, Katz, E., Chari, R.S. Laparoscopic staging and tumor ablation for hepatocellular carcinoma in Child C cirrhotics evaluated for orthotopic liver transplantation. Surg. Endosc. 2004 18 39-44... 

Llovet, J.M., Bru, C., Bruix, J. Prognosis of hepatocellular carcinoma The BCLC staging classification. Semin. Liver Dis. 1999 19 329-338... 

A classical example is alcoholic cirrhosis, which in the case of chronic alcohol abuse, leads to multiple, polyclonal areas of liver cell hyperplasia and an increased risk for development of hepatocellular neoplasia. In both preneoplasia and certain forms of hyperplasia, the antecedent lesions typically have a higher rate of cell proliferation than the surrounding normal cells and, thus, these cells are at increased risk to sustain additional genetic damage and progress to the next stage in the carcinogenic process. 

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