Clonal analysis of macronodules in cirrhosis

Several arguments suggest that most hepatocellular carcinomas (HCCs) occurring in human cirrhotic livers arise from large hepatocellular nodules or macronodules. Except for nodules with obvious features of HCC, there exist no consistent criteria enabling the differentiation between benign regenerative and neoplastic, potentially malignant macronodules. Surrogate markers able to accurately discriminate those lesions that will evolve toward a HCC are required. In this study, we investigated the clonality of 26 macronodules isolated from eight cases of explanted cirrhotic livers in women by analyzing X-chromosome inactivation, as indicated by the methylation status of the human androgen receptor gene (HUMARA). For each macronodule, a large set of pathological features was evaluated and used to classify the macronodules into four groups: entirely benign-looking nodule (type 1), low-grade dysplastic nodule (type 2), high-grade dysplastic nodule (type 3), and HCC (type 4). Clonal analysis showed that 14 macronodules (54%) were monoclonal and 12 (46%) were polyclonal. Monoclonality was detected in 5 of 11 (45%) nodules from groups of entirely benign-looking and low-grade dysplastic nodules (types 1 and 2) and in 9 of 15 (60%) nodules from the group of high-grade dysplastic nodule and HCC (types 3 and 4). Neither the etiology of cirrhosis nor the size or histological classification of macronodules was correlated with the clonal status. In conclusion, clonal analysis of macronodules enables the differentiation between mono- and polyclonal macronodules in cirrhosis. Because monoclonal macronodules are prone to evolve to HCC, the determination of the clonal status of a macronodule could provide additional information for evaluating the prognosis of these lesions.     

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The blood supply of hepatocellular carcinoma (HCC) is primarily arterial. Recent studies reported differences of vascular, especially arterial, supply among low- and high-grade dysplastic nodules and HCC. We assessed arterialization using monoclonal antibody specific for smooth muscle actin as well as simultaneous changes in sinusoidal capillarization in cirrhotic nodules, dysplastic nodules, and HCC. We immunohistochemically stained 56 cirrhotic nodules, 20 low-grade dysplastic nodules, 27 high-grade dysplastic nodules, and 20 HCCs for alpha smooth muscle actin (to identify unpaired arteries (i.e., arteries not accompanied by bile ducts) and CD34 (indicating sinusoidal capillarization). Distribution and number of unpaired arteries and distribution of sinusoidal capillarization were graded semiquantitatively. Unpaired arteries were rare in cirrhotic nodules, significantly more common in dysplastic nodules of both types (p < 0.00001), and most common in HCC. Sinusoidal capillarization was least common in cirrhotic nodules, significantly more common in dysplastic nodules (p < 0.0035), and most common in HCC. No topographic relationship between unpaired arteries and sinusoidal capillarization was identified. These findings showed that (1) distributions of sinusoidal capillarization and unpaired arteries in dysplastic nodules are intermediate between those in cirrhotic nodules and HCC, supporting dysplastic nodules as premalignant lesions; (2) unpaired arteries are histologically useful for distinguishing dysplastic nodules from large cirrhotic nodules; and (3) areas of sinusoidal capillarization within dysplastic nodules are unrelated to location of arterialization.     

Rates of change in peak expiratory flow and in diurnal variation in peak flow in patients recovering from acute severe asthma

Reexpression of the insulin-like growth factor type II (IGF-II) gene has recently been described in hepatocellular carcinoma (HCC). In this study, we used a nonisotopic in situ hybridization method to analyze the expression of IGF-II mRNA in a series of 28 HCCs arising on cirrhotic and noncirrhotic livers. An immunohistochemical method was used to detect IGF-II peptide. Hepatitis B virus (HBV) status and the histological differentiation degree were also evaluated. Increased expression of IGF-II mRNA was found in 4 of 28 HCCs, and 7 of 17 cirrhotic patients showed IGF-II mRNA in the cirrhotic nodules surrounding the HCC. A slightly higher rate of positivity for IGF-II mRNA was found in the HBV-negative patients than in HBV-positive ones. Positive immunostaining for the IGF-II peptide in the HCC and/or in surrounding cirrhotic nodules was found in 10 of 28 cases. The normal hepatocytes of the noncirrhotic patients were always negative for IGF-II peptide and mRNA. The similarities between our results and those from experimental models in woodchucks seem to support the concept that heterogeneous phenotypic groups could exist in human HCCs.     

Hepatic lipase activity influences high density lipoprotein subclass distribution in normotriglyceridemic men. Genetic and pharmacological evidence

Inhibin is a heterodimeric glycoprotein originally detected in gonadal tissues. One report described inhibin immunopositivity in 17 of 19 hepatocellular carcinomas (HCCs) and the hepatocytes of the surrounding nonneoplastic parenchyma. The reported immunohistochemical method, which used avidin-biotin complex, did not describe blocking endogenous biotin. Since liver tissue may contain high levels of biotin, endogenous biotin may result in false-positive immunostaining. We wondered whether this reported immunopositivity represented a false-positive result due to unblocked endogenous biotin. By using a similar antigen retrieval technique and the same specificity, titer, and clonal source of primary antibody as the aforementioned study, we performed immunostaining for inhibin with and without an endogenous biotin blocking step on 23 cases of HCC and the surrounding cirrhotic liver. In all cases, the HCC and the hepatocytes in the cirrhotic nodules were negative for inhibin when the endogenous biotin blocking step was used. When the blocking step was omitted, apparent immunostaining was noted in 20 of 23 HCCs and in the hepatocytes in all cases. Accordingly, HCC and the hepatocytes of the surrounding cirrhotic liver are immunohistochemically negative for inhibin. The previously reported immunopositivity of HCC and nontumoral hepatocytes for inhibin represents a false-positive result due to endogenous biotin.     

Liver cell dysplasia in liver cirrhosis and hepatocellular carcinoma

The aim of the study was to assess the incidence of both types of liver cell dysplasia and concomitance with cirrhosis, hepatocellular carcinoma (HCC) and positive reaction for HBsAg in the autopsy material and an attempt to determine a relationship between these two types of liver cell dysplasia and hepatocellular carcinoma. Autopsy material included 102 cases of hepatocellular carcinoma, 101 cases of hepatocirrhosis without accompanying cancer and 106 control cases. Histological specimens stained with HE were analyzed for the presence of large liver cell dysplasia (LLCD) according to Anthony et al., small liver cell dysplasia (SLCD) according to Watanabe et al., the presence of macroregenerative nodules (< 8 mm) and antigen HBs (stained with orcein according to Shikata). The detected LLCD were also assessed semiquantitatively taking into account the number of dysplastic areas in a given case. Statistical significance of the results was tested with the chi square test. LLCD was most frequently detected in HCC with concomitant cirrhosis (55.3%), then in cirrhosis without HCC (40.6%), and in HCC without cirrhosis only in 12.5%. LLCD was found significantly more frequently (p < 0.05) in cirrhosis with HCC than in cirrhosis without HCC. Antigen HBs was found in 25.6% of cirrhoses and/or HCC. No significant differences in the presence of HBsAg were seen between the analyzed groups. The incidence of LLCD and HBsAg in controls was significantly lower than in other groups. A mean age at death in case of cirrhosis with HCC subdivided into that with or without LLCD was not significantly different, whereas in case with cirrhosis with LLCD age at death was 10.8 years higher (the difference statistically significant). Analysis of material with respect to gender revealed a high proportion of men in case of HCC with concomitant cirrhosis but without LLCD (13:1). A strong relationship was seen between the presence of positive reaction for HBsAg and LLCD (p < 0.001). Also the intensity of LLCD positively correlated with the presence of HBsAg. Furthermore, a positive correlation was seen between the presence of LLCD and macronodular cirrhosis (posthepatitic). The present findings suggest a closer relation between HBV infection and LLCD than between cirrhosis or HCC and LLCD. Also morphological patterns of LLCD foci do not confirm the hypothesis of some investigators about the precancerous character of these lesions. In the whole current material only seven cases of SLCD were detected. They were all present in cirrhotic livers with concomitant HCC. Both the morphological pattern of these lesions and their sometimes discerned close spatial relation with HCC foci indicate that SLCD is an alternative way of HCC development.     

Immunohistochemical localization of metallothionein in hepatocellular carcinoma: preferential expression in non-cancerous cirrhotic nodules

Metallothionein (MT), an oncofocal gene product was strongly expressed in 35%-95% of hepatocytes in hepatocellular carcinoma (HCC) and MT-positive hepatocytes were localized mainly in the non-cancerous cirrhotic nodules but not in malignant hepatocytes. On the other hand, <10% hepatocytes showed weak staining for MT in chronic hepatitis and cirrhosis of liver. Strong expressions of MT in non-cancerous cirrhotic nodule in HCC and low expressions in liver cirrhosis without HCC indicate a relationship between malignant transformation of hepatocytes and the expression of MT.     

Cathepsin D serum mass concentrations in patients with hepatocellular carcinoma and/or liver cirrhosis

Cathepsin D serum mass concentrations were determined by enzyme immunoassay in patients with hepatocellular carcinoma (n = 51) and/or liver cirrhosis (n = 92) or benign steatosis (n = 16) and correlated with some biochemical and clinical properties of these diseases. Increased cathepsin D serum mass concentrations (P < 0.001) were observed in all these groups of patients as compared to normal subjects (n = 98). However, patients with steatosis had serum mass concentrations of this enzyme significantly lower (mean 2-3 fold) than those measured in cancer patients (P < 0.05) or cirrhotic patients (P < 0.001). Interestingly, significantly higher cathepsin D serum mass concentrations (mean + 62%) (P < 0.006) were determined in the cirrhosis group as compared to cancer patients. No correlation between cathepsin D and a number of clinical and biochemical properties examined, namely, alpha-foetoprotein, number of neoplastic lesions and tumour size in cancer patients or, Child-Pugh grade of severity of cirrhosis and other enzymes of liver function tests in the cirrhotic group was found. The present data and those from other studies which indicate that cathepsin D may be involved in carcinogenesis suggest that this enzyme may be potentially useful as an additional biochemical marker to identify cirrhotic patients who may develop precancerous hepatic nodules.     

Large cell change (liver cell dysplasia) and hepatocellular carcinoma in cirrhosis: matched case-control study, pathological analysis, and pathogenetic hypothesis

Large cell change (LCC), characterized by cellular enlargement, nuclear pleomorphism and hyperchromasia, and multinucleation of hepatocytes, is a common lesion in cirrhotic livers, but its nature, significance, and pathogenesis remain uncertain. Therefore, we assessed the prognostic value of LCC as a marker of subsequent hepatocellular carcinoma (HCC) through a case-control study that compared pretransplant liver biopsy specimens from 37 cirrhotic liver transplant recipients with HCC to specimens from a control group of recipients without HCC, matched for sex, age (+/-5 years), and cause of cirrhosis. LCC was identified in 16 (43%) of the study and 7 (19%) of the control group biopsy specimens. By matched-pair analysis, LCC conveyed a moderately increased risk of later HCC with an estimated odds ratio of 3.3 (95% CI, 1.2-15; P = .038). However, a pathology review of 45 HCCs showed adjoining LCC in only 12 (27%) and did not suggest a morphological transition or a histogenetic association between the two lesions. LCC hepatocytes displayed a low proliferative rate by Ki-67 or proliferating cell nuclear antigen immunostaining (labeling indices of 0.27 and 0.73) but showed a greater degree of apoptosis than normal hepatocytes (labeling indices of 1.9 and 0.23; P = .03) To reconcile these findings, we propose that LCC derives from derangements in the hepatocyte's normal process of polyploidization. Such derangements, possibly caused by chronic inflammation-induced DNA damage, could yield a population of enlarged liver cells with nuclear atypia and pleomorphism, frequent binuclearity, and minimal proliferation. According to this hypothesis, LCC would be a habitual feature of cirrhosis and a regular accompaniment of HCC but would not represent a direct malignant precursor.     

Hepatocellular carcinoma in an orthotopic mouse model metastasizes intrahepatically in cirrhotic but not in normal liver

Prognosis of hepatocellular carcinoma (HCC) still remains poor mainly because of intrahepatic metastasis. In the majority of cases, HCC is found in conjunction with liver cirrhosis. It is, therefore, of great importance to investigate the invasive and metastatic behavior of HCC in cirrhotic liver. To examine this, a liver cirrhosis model was produced by injecting thioacetamide i.p. into mice. Murine HCC cells were labeled with the fluorescent carbocyanine dye, DiI, and implanted directly under the capsule of cirrhotic and normal livers of syngeneic mice. DiI-labeled HCC cells in the liver were observed under fluorescent and confocal microscopy. Histological analysis of cirrhotic and normal livers revealed that implanted HCC cells migrated to and invaded the adjacent periportal regions, but not the adjacent centrolobular areas. This characteristic behavior of HCC was more evident in cirrhotic liver than in normal liver. Furthermore, intrahepatic metastasis to unimplanted hepatic lobes was observed in cirrhotic liver as early as 7 days after implantation, while it was not detected in normal liver even 4 weeks later. Thus, an orthotopic animal model for HCC with cirrhosis described here may be suitable for investigating the invasive and metastatic behavior of HCC. Importantly, labeling tumor cells with a fluorescent dye before orthotopic implantation may be a convenient and useful method to investigate the invasive and metastatic behavior of various types of cancer.     

Tenascin and type IV collagen expression in liver cell dysplasia and in hepatocellular carcinoma

The extracellular matrix (ECM) located in and around tumors is different from normal organ stroma, and there is evidence that it is critically involved in carcinogenesis and malignant growth. Whereas an abnormal composition of ECM in hepatocellular carcinomas (HCC's) has previously been demonstrated, not much is known so far with respect to putative HCC precursor lesions. We have, therefore, systematically analyzed the immunohistochemical reactivity for two major ECM components, tenascin and type IV collagen, in three types of liver cell dysplasia (LCD), and compared the findings with patterns observed in HCC's of different types and grades. Tenascin reactivity was generally stronger in HCC's than in cirrhosis. In cirrhotic nodules harboring areas of LCD, tenascin expression was significantly lower in small cell LCD than in large cell LCD. Type IV collagen reactivity in and around HCC's decreased as a function of a lower differentiation grade. In both groups of cirrhosis, i.e. with or without HCC, cirrhotic nodules occupied by the small cell variant of LCD exhibited a significantly lower type IV collagen reactivity than those with large cell LCD or simple regenerative cells. Taken together these findings suggest that, similar to adenomatous hyperplasia, small cell LCD is characterized by an abnormal tenascin and type IV collagen expression, thus reflecting the defective ECM pattern observed in HCC's.     

Long-term results of percutaneous ethanol injection therapy for hepatocellular carcinoma in cirrhosis: a European experience

The objective of our work was to evaluate the long-term results of percutaneous ethanol injection (PEI) for the treatment of hepatocellular carcinoma (HCC) in patients with liver cirrhosis. A total of 184 cirrhotic patients with HCC underwent PEI as the only anticancer treatment over an 8-year period. Patients were followed after therapy by means of clinical examinations, laboratory tests, and US and CT studies performed at regular time intervals. Survival rates were determined according to the Kaplan-Meier method. The overall survival was 67% at 3 years, 41% at 5 years, and 19% at 7 years. The 3-, 5-, and 7-year survival rates of patients with single HCC < or = 3 cm (78, 54, and 28%, respectively) were significantly higher (p < 0.01) than those of patients with single HCC of 3.1-5 cm (61, 32, and 16, respectively) or multiple HCCs (51, 21, and 0%, respectively). Survival of Child-Pugh A patients (79% at 3 years, 53% at 5 years, and 32% at 7 years) was significantly longer (p < 0.01) than that of Child-Pugh B patients (50% at 3 years, 28% at 5 years, and 8% at 7 years). A selected group of 70 patients with Child-Pugh A cirrhosis and single HCC < or = 3 cm had a 7-year survival of 42%. Long-term survival of cirrhotic patients with HCC treated with PEI is comparable to that reported in published series of matched patients submitted to surgical resection.     

Blood flow rate: an important determinant of urea clearance and delivered Kt/V

PURPOSE: To compare the magnetic resonance (MR) imaging findings of primary hepatocellular carcinoma (HCC) in cirrhotic versus noncirrhotic livers. MATERIALS AND METHODS: MR images in 36 patients with HCC (30 men and she women aged 42-84 years [mean age, 65 years]) were retrospectively reviewed. The number and size of hepatic lesions were assessed. Lesion margins were categorized as well circumscribed or ill defined. The presence of a capsule, intratumoral high signal intensity on T1-weighted MR images, and a stellate scar were determined. RESULTS: Eleven (31%) patients had MR imaging evidence of cirrhosis, and 25 (69%) did not: Lesions in cirrhotic livers differed significantly from those in noncirrhotic livers in terms of size (22 cm2 vs 99 cm2, P < .05), frequency of a solitary lesion (27% vs 72%, P < .05), and frequency of a central scar (6% vs 50%, P < .05). There was no difference between the cirrhotic and noncirrhotic livers with regard to tumor margin, intratumoral high signal intensity on T1-weighted images, or tumor capsule. CONCLUSION: Differences exist in the MR imaging appearance of HCC between patients with and those without cirrhosis, although there is overlap of imaging findings.     

Hepatitis, cirrhosis, and hepatoma

Virus hepatitis and liver cirrhosis are found at high incidence in Asia, and they require not only biochemical examination of blood but also subsequent imaging, because they are often complicated by hepatocellular carcinoma (HCC). It is, therefore, very important to know the specific appearances of hepatitis, liver cirrhosis, and HCC when we diagnose these diffuse liver diseases. Liver necrosis due to severe hepatitis is seen as high intensity on T2-weighted spin echo images. Regeneration is seen as low intensity on T2-weighted images. Morphologic and pathologic changes of cirrhotic liver are well demonstrated by MR imaging techniques. Fibrotic septum with inflammatory cell infiltration or rich pseudo bile duct show high intensity on T2-weighted images, and regenerating nodules shows low intensity. Gradient echo images show regenerating nodules with iron deposition as low-intensity nodules due to susceptibility artifact. MRI also has the potential to evaluate function of diffuse liver disease, cirrhosis, and hepatitis. MRI can visualize and diagnose HCC objectively. Dynamic MRI is very useful for diagnosing HCC. It is also applied for evaluation of effect after transcatheter arterial chemoembolization, because it shows enhancement only in the viable region at an arterial phase. MRI is less invasive and is thus an extremely important form of liver imaging.     

Dissociation between anxiolytic and hypomnestic effects for combined extracts of zingiber officinale and ginkgo biloba, as opposed to diazepam

Extrahepatic biliary atresia is a severe neonatal liver disease resulting from a sclerosing cholangiopathy of unknown etiology. Although biliary obstruction may be surgically corrected by a "Kasai" hepatoportoenterostomy, most patients still develop progressive hepatic fibrosis, although the source of increased collagen deposition is unclear. This study examined the role of hepatic stellate cells (HSCs) and assessed the source of transforming growth factor-beta (TGF-beta) production in hepatic fibrogenesis in patients with biliary atresia. Liver biopsies from 18 biliary atresia patients (including 5 pre- and post-Kasai) were subjected to immunohistochemistry for alpha-smooth muscle actin and in situ hybridization for either procollagen alpha1 (I) mRNA or TGF-beta1 mRNA. Sections were also subjected to immunohistochemistry for active TGF-beta1 protein. The role of Kupffer cells in TGF-beta1 production was assessed by immunohistochemistry for CD68. Procollagen alpha1 (I) mRNA was colocalized to alpha-smooth muscle actin-positive HSCs within the region of increased collagen protein deposition in fibrotic septa and surrounding hyperplastic bile ducts. The number of activated HSCs was decreased in only one post-Kasai biopsy. TGF-beta1 mRNA expression was demonstrated in bile duct epithelial cells and activated HSCs and in hepatocytes in close proximity to fibrotic septa. Active TGF-beta1 protein was demonstrated in bile duct epithelial cells and activated HSCs. This study provides evidence that activated HSCs are responsible for increased collagen production in patients with biliary atresia and therefore play a definitive role in the fibrogenic process. We have also shown that bile duct epithelial cells, HSCs, and hepatocytes are all involved in the production of the profibrogenic cytokine, TGF-beta1.     

The usefulness of determining des-gamma-carboxy prothrombin by sensitive enzyme immunoassay in the early diagnosis of patients with hepatocellular carcinoma

BACKGROUND: Measurements of serum concentrations of des-gamma-carboxy prothrombin (DCP) are widely used for diagnosing hepatocellular carcinoma (HCC). However, the DCP is not always sensitive enough to detect small HCCs. In the current study, the authors investigated the usefulness of DCP in the early diagnosis of HCC, using a more sensitive enzyme immunoassay than is conventionally employed. METHODS: The authors examined 148 serum samples with DCP concentrations from a conventional assay of less than 100 mAU (arbitrary unit)/mL from 91 patients with HCC and 57 with cirrhosis. DCP concentrations were determined by a more sensitive enzyme immunoassay (ED-036 kit, Eisai Laboratory, Tokyo, Japan) with a minimal detection level of 10 mAU/mL. Ninety-one HCC patients had 43 solitary small HCCs (with a greatest dimension of less than 2 cm). Of these 43 HCCs, 12 were well differentiated. RESULTS: The mean serum concentration of DCP in HCC (48.3 +/- 24.3, mean +/- standard deviation [SD]) was higher than in cirrhosis (20.3 +/- 10.3); this difference was statistically significant. When the tentative cutoff level of 40 mAU/mL (almost corresponding to the mean value + 2SD in patients with cirrhosis) was used as the level of discriminating HCC from cirrhosis, 62% of patients (56 of 91) with HCC had DCP values above this level (sensitivity). However, only three patients with cirrhosis had higher DCP levels. Thus, the specificity of this test was 95% (54 of 57 patients). The total accuracy was 74% (56 + 54/91 + 57). Twenty-three of 43 solitary small HCCs (53%) had DCP values above the cutoff level. Furthermore, 7 of 12 (58%) small, well-differentiated HCCs less than 2 cm in greatest dimension had higher DCP values. CONCLUSIONS: The results of this study indicate that DCP determination by sensitive enzyme immunoassay is useful in the early diagnosis of HCC because a high specificity is maintained.     

Insulin-degrading activity in experimental liver cirrhosis of the rat

Liver cirrhosis in man is often associated with hyperinsulinemia but its pathogenesis is still unexplained. To investigate whether insulin degradation is impaired in cirrhotic liver, the specific insulin-degrading enzyme activity (EC 3.4.22.11) was assayed in liver cytosol of rats with CCl4-induced liver cirrhosis. No difference was found between liver cytosol of cirrhotic and control rats. The results show that experimental CCl4-induced liver cirrhosis does not damage the specific insulin-degrading activity and support the hypothesis that impaired hepatic insulin handling is not an important cause of hyperinsulinemia in liver cirrhosis.     

Comparative image cytometric DNA ploidy of liver cell dysplasia and hepatocellular carcinoma

Large-cell liver cell dysplasia (LCD), suggested to be a preneoplastic change that progresses to hepatocellular carcinoma (HCC), has a reported frequency of DNA aneuploidy by flow cytometry intermediate between that of nonneoplastic liver (0%) and HCC (80%). We assessed DNA ploidy by image cytometry of Feulgen-stained 5-microns sections of 30 livers with LCD and of 60 HCCs (29 with LCD in adjacent nonmalignant liver). All 30 LCDs were aneuploid, 27 (90%) of which were multiploid--11 (41%) with hyperdiploid and hypertetraploid peaks. Forty-eight (80%) HCCs were aneuploid; in nine of 20 (42%) with a hyperdiploid peak, a hyperdiploid peak was also present in the LCDs, but in none was there less than 0.24 between DNA indices. Besides the 12 (20%) diploid HCCs, a diploid peak was present in four heterogenous, three multiploid, and six HCCs with two phenotypes and two genotypes, one of which was diploid. One aneuploid/hyperdiploid peak in each of 22 nonneoplastic and 24 cirrhotic livers did not have a corresponding LCD or HCC aneuploid peak. These data do not suggest that dysplastic hepatocytes form a single mutant clone that progresses to HCC.     

Disseminated miliary tuberculosis of the skin in patients with AIDS: report of four cases

During the course of long-term follow-up, we examined the efficacy of interferon (IFN) in the improvement of liver function and prevention of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) associated cirrhosis patients. Fifty-five cirrhotic patients, in whom HCC nodules in the liver were not detected by ultrasonography (US) or computed tomography (CT), received 3 or 6 million units of human lymphoblastoid IFN daily for two weeks and 3 times a week for 22 weeks. Complete response (CR) was defined as normalization of serum alanine aminotransferase (ALT) together with negative HCV RNA at 6 months after IFN therapy completion. Any other pattern of response was defined as non-response (NR). After IFN therapy the patients were followed up every 1-3 months for at least 1 year (average follow-up period, about 40 months) with serological tests and US or CT. In the 8 CR patients, the serum ALT levels remained normal and HCV RNA remained negative. Platelet count, white blood cell count, serum albumin and zinc turbidity test have recovered to the normal range at final follow-up. Ten of the 47 patients with NR have developed HCC, whereas no patients with CR has developed HCC during follow-up. We conclude that IFN improves the liver function and may prevent the development of HCC even in cirrhotic patients who show CR to IFN therapy.     

Limited value of fluorine-18-fluorodeoxyglucose PET for the differential diagnosis of focal liver lesions in patients with chronic hepatitis C virus infection

AIM: The differentiation of HCC from liver metastasis or benign disorders by imaging studies based upon morphological aspects may be difficult. METHOD: In order to evaluate the role of tumour metabolism, we performed FDG-PET (whole-body PET and transmission-corrected regional scans of the liver as well as the SUV determined 60 min after injection of FDG) in ten consecutive patients with HCV-associated focal liver lesions. Definite diagnosis was established after ultrasound-guided liver biopsy followed by histopathological examination. These results were compared with ultrasound, computed tomography, serum anti-p53, and p53 protein expression. RESULTS: The histologic examination revealed a HCC in five patients, regenerative nodules in three patients, and liver metastasis (primary malignancy: one adenocarcinoma and one neuroendocrine tumour) in the remaining two patients. Three of ten lesions were detectable by FDG-PET: two HCCs and one metastatic adenocarcinoma. Seven lesions were not distinguishable by FDG-PET (three HCCs, three regeneration nodules and one metastatic neuroendocrine tumour). In each patient hepatic lesions were visible either by ultrasound or CT. Both tumours (metastatic adenocarcinoma, moderately well-differentiated HCC) with the strongest expression of p53 also presented with highly increased FDG uptake. CONCLUSIONS: FDG-PET is not superior to ultrasound or CT and therefore does not allow the non-invasive differentiation of HCV-associated focal liver lesions. Tissue-diagnosis by means of liver-biopsy followed by histopathological examination remains the gold-standard for the differentiation of HCV-related liver lesions. The finding of the relationship of p53 protein overexpression with the SUV needs further confirmation.