Chapter 5

Trend of liver cirrhosis as precancerous lesions

Viral hepatitis is the most significant predisposing factor for hepatocellular carcinoma (HCC). Liver cancer grows silently with mild or no symptoms until the disease is advanced and with little hope of cure. Early recognition of the onset of HCC would help to select more effective therapies for patients leading to a better prognosis and life span. The current study aims to evaluate two diagnostic and prognostic markers – Prothrombin induced by vitamin K absence-II (PIVKA-II) and macrophage migration inhibitory factor (MIF) in the serum of patients with HCC and those with a high risk of developing hepatic cancers. Serum samples from hepatocellular carcinoma, hepatitis C and normal subjects were subjected to quantitative determinations of different parameters including alpha-fetoprotein (AFP), PIVKA-II and MIF. Significant differences between the various groups were recorded. PIVKA-II and AFP showed a higher specificity and sensitivity compared to MIF, and there was considerable correlation between AFP and both PIVKA and MIF. It is concluded that analysis of PIVKA-II and AFP can serve as useful non-invasive markers for the early detection of HCC with good sensitivity and specificity.

Chronic viral infection is the most important oncogenetic factor, and hepatitis B virus (HBV) plays an important role in the development of hepatocellular carcinoma (HCC).

HBV-related carcinogenesis is a multi-step process, encompassing the combination of different, not mutually exclusive effects such as the induction of chronic liver inflammation and regeneration, its integration into the hepatocyte genome and the transactivating and transforming activity of several viral proteins (HBx and truncated Pre-S2/S) that may stimulate cellular oncogenes or suppress growth-regulating genes. Data related to the influence of different hepatitis B virus genotypes and the emergence of selective variants as biomarkers of HCC development still remain controversial. At last, recent studies on occult HBV infection, as defined by serologically undetectable hepatitis B surface antigen (HBsAg–), despite the presence of circulating HBV DNA, suggest that the occult viral strains, maintaining the transcriptional activity and the pro-oncogenetic assets of the clear HBV infection (HBsAg+), may harbour a potential risk for liver cancer development.

The development of hepatocellular carcinoma (HCC), the mechanisms of hepatocarcinogenesis, the prevention of HCC, and screening for HCC will be discussed. Cirrhosis has been considered as a pre-neoplastic condition for the development of HCC. The worldwide incidence of HCC differs according to different hepatitis viruses, and information is lacking. Hepatocarcinogenesis is a multistep process involving a number of different genetic alterations and is poorly understood. Interferon should help prevent the development of HCC in patients with chronic hepatitis C. Screening is the only practical approach for improving the management of HCC patients, as early detection increases the application of curative treatments. However, the cost-effectiveness of various screening strategies needs to be analysed.

We investigated correlations between laboratory test results and multicentric development of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) in 202 patients who underwent liver resection. Two types of HCC were considered to meet multicentricity criteria: in one, at least one tumor was well-differentiated, with at least one other being less differentiated; in the other, all tumors included well-differentiated HCC with or without less differentiated components. Forty-five patients had multicentric HCC. Platelet counts were lower in patients with multicentric HCC than in others. Serum concentrations of type IV collagen 7s domain and α-fetoprotein, histologic hepatitis activity score, and histologic hepatic fibrosis score were higher in patients with multicentric HCC. By multiple logistic regression analysis, low platelet count was an independent risk factor for multicentric HCC. The proportion of patients with multicentric HCC was significantly higher among patients with low platelet counts (below 10⁵/mm³) than in patients with a higher count. Thus, HCC patients with a platelet count below 10⁵/mm³ may require particularly careful examination for multicentricity.

Hepatic functional reserve can be evaluated in a noninvasive way by scintigraphy with ^99mTc-DTPA-galactosyl human serum albumin (^99mTc-GSA). We monitored hepatic functional reserve in patients with chronic hepatitis and cirrhosis using scintigraphy with ^99mTc-GSA to determine the natural course of changes in their hepatic functional reserve. Computer acquisition of gamma-camera data was started before the injection of 185 MBq of ^99mTc-GSA and was stopped 20 min later. Time-activity curves were generated from ROI for the heart and liver. A receptor index and index of blood clearance were calculated from radioactivity in the heart and liver. Scintigraphy with ^99mTc-GSA was performed in 12 healthy subjects, 86 patients with chronic hepatitis, and 226 patients with cirrhosis. Seventy-two patients (23 with chronic hepatitis, 32 with cirrhosis in Child-Pugh stage A, 15 in stage B, and 2 in stage C) were examined at least twice with 12–72 months intervening. The receptor index was lower for more severe disorders, decreasing in the order of chronic hepatitis and cirrhosis in stages A, B, and C. The index of blood clearance was higher for more severe disorders, increasing in the order of chronic hepatitis and cirrhosis in stages A, B, and C. The mean annual change in the receptor index with chronic hepatitis was −0.0007, that with cirrhosis in stage A was −0.0023, and that with cirrhosis in stage B or C was −0.0117. The difference between the median annual change with cirrhosis in stage B or C and that with chronic hepatitis or cirrhosis in stage A was not significant (P=0.064 and 0.251, respectively). The mean annual change in the index of blood clearance with chronic hepatitis was 0.0018, that with cirrhosis in stage A was 0.0060, and that with cirrhosis in stage B or C was 0.0330. The difference between the median annual change in the index of blood clearance with cirrhosis in stage B or C and that with chronic hepatitis or cirrhosis in stage A was significant (P=0.004 and 0.007, respectively). Hepatic receptor imaging with ^99mTc-GSA could be used to noninvasively evaluate the hepatic reserve of various liver diseases. Changes in hepatic functional reserve were not steady; it decreased gradually as disease advanced from chronic hepatitis to cirrhosis in Child-Pugh stage A, and decrease rapidly after development of stage B cirrhosis.