Hepatitis: Roncalli M

Park YN, Roncalli M. · Department of Pathology, Center for Chronic Metabolic Disease, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea. · J Hepatol. · Pubmed #16982109 No free full text.

Abstract: Large cell change (LCC) is a noncommittal term used today to indicate liver cell dysplasia of the large cell type. Dysplasia was deleted from the original definition because not enough evidence has been collected over time to support premalignancy. LCC is a microscopically well-defined lesion, usually found in cirrhosis, whose origin, natural history, and fate are still debated. Different morphologic, phenotypic, molecular and clinical studies have been performed to address the issue of the dysplastic versus reactive nature of this lesion. The aim of this review is to critically evaluate the contributions to the topic and to underline that the heterogeneity of the lesion is an important issue to be taken into account for our biological understanding of it. While LCC has important morphologic analogies in experimental liver carcinogenesis, no comparable lesions are known in solid non-liver parenchymal human tissues that morphologically feature dysplasia, but in which it is uncertain whether the lesions are reactive or preneoplastic. The debate over the lesion may be useful in learning the actual limits of morphology and how additional information can be gained by looking inside the cells.

Dioguardi N, Grizzi F, Bossi P, Roncalli M. · Department of Pathology, Istituto Clinico Humanitas, Rozzano, Milan, Italy. · Anal Quant Cytol Histol. · Pubmed #10560501 No free full text.

Abstract: OBJECTIVE: To evaluate the usefulness of a reliable and reproducible mathematical scoring system based on fractal geometry for quantifying the irregular pattern in fibrosis commonly seen in liver biopsy specimens from chronic liver diseases. STUDY DESIGN: The study used 26 standard liver biopsy specimens obtained from patients with chronic hepatitis C virus-related liver disease. The degree of fibrosis in each specimen was estimated using a quantitative scoring system based on the computer-assisted evaluation of both the fractal and spectral dimensions of deposited collagen. The fractal dimension was then compared with the percent area of collagen measured using an image analysis system. RESULTS: The fractional dimension of its irregular shape defines fibrosis as a natural fractal structure. The complex distribution of its collagenous components (unmeasurable by means of the usual morphometric parameters) can be optimally quantified using a single numerical score that seems to be a better alternative to the semiquantitative methods adopted so far. The proposed method is reproducible, rapid and inexpensive; furthermore, supported by specific software, its mathematical approach excludes subjectivity and eliminates the external factors capable of influencing staging and classification. CONCLUSION: This study demonstrated that it is possible to quantify the irregularity of the structures of the liver in an objective manner and that the box-counting fractal dimension does not depend on the amount of collagen deposited on the slide. Furthermore, as has been found in other fields of investigation, study of the fractal properties of the liver is likely to reveal more about its structure and the pathogenesis of liver diseases.

Borroni G, Ceriani R, Cazzaniga M, Tommasini M, Roncalli M, Maltempo C, Felline C, Salerno F. · Dipartimento Dipendenze, ASL Provincia di Milano 1, Legnano (MI), Italy. · Aliment Pharmacol Ther. · Pubmed #16918883 No free full text.

Abstract: BACKGROUND: Biopsy is the gold standard for assessing cirrhosis in patients with chronic hepatitis C virus infection, but it is expensive and at risk of complications. Alternative non-invasive methods have been developed but their usefulness remains uncertain. AIM: To compare the accuracy of five non-invasive scores in detecting cirrhosis. METHODS: We reviewed the charts and liver biopsies of 228 consecutive, treatment-naïve, hepatitis C virus-positive patients, 13.2% of whom with histological diagnosis of cirrhosis. The five alternative scores were age-platelet index, cirrhosis discriminant score, aspartate transaminases to platelet ratio index, Pohl's index, and aspartate transaminases/alanine transaminases ratio. RESULTS: The specificities of the scores were good (87-100%), but not so their sensitivities (17-67%). Accordingly positive likelihood ratios were generally good but negative likelihood ratios were suboptimal. Combinations of the scores independently related to cirrhosis only slightly change this diagnostic accuracy. Using double cut-offs to exclude/diagnoses cirrhosis, cirrhosis discriminant score classified 21% of patients without misdiagnoses and aspartate transaminases to platelet ratio index classified 85% of case with 9% of misdiagnoses. CONCLUSIONS: The five scores showed variable sensitivities and specificities in detecting liver cirrhosis, both individually and in combination. The use of double cut-off points may make the cirrhosis discriminant score and aspartate transaminases to platelet ratio index useful to reduce the number of patients submitted to liver biopsy.

Di Gioia S, Bianchi P, Destro A, Grizzi F, Malesci A, Laghi L, Levrero M, Morabito A, Roncalli M. · Department of Pathology, Humanitas Clinical Institute of Rozzano, Milan, Italy. · BMC Cancer. · Pubmed #16606445 links to  free full text

Abstract: BACKGROUND: Epigenetic changes during ageing and their relationship with cancer are under the focus of intense research. RASSF1A and NORE1A are novel genes acting in concert in the proapoptotic pathway of the RAS signalling. While NORE1A has not been previously investigated in the human liver, recent reports have suggested that RASSF1A is frequently epigenetically methylated not only in HCC but also in the cirrhotic liver. METHODS: To address whether epigenetic changes take place in connection to age and/or to the underlying disease, we investigated RASSF1A and NORE1A gene promoter methylation by conventional methylation specific PCR and Real-Time MSP in a series of hepatitic and non-hepatitic livers harboring regenerative/hyperplastic (cirrhosis/focal nodular hyperplasia), dysplastic (large regenerative, low and high grade dysplastic nodules) and neoplastic (hepatocellular adenoma and carcinoma) growths. RESULTS: In the hepatitic liver (chronic hepatitic/cirrhosis, hepatocellular nodules and HCC) we found widespread RASSF1A gene promoter methylation with a methylation index that increased from regenerative conditions (cirrhosis) to hepatocellular nodules (p < 0.01) to HCC (p < 0.001). In the non-hepatitic liver a consistent pattern of gene methylation was also found in both lesional (focal nodular hyperplasia and hepatocellular adenoma) and non-lesional tissue. Specifically, hepatocellular adenomas (HA) showed a methylation index significantly higher than that detected in focal nodular hyperplasia (FNH) (p < 0.01) and in non-lesional tissue (p < 0.001). In non-lesional liver also the methylation index gradually increased by ageing (p = 0.002), suggesting a progressive spreading of methylated cells over time. As opposed to RASSF1A gene promoter methylation, NORE1A gene was never found epigenetically alterated in both hepatitic and non-hepatitic liver. CONCLUSION: We have shown that in non-lesional, regenerative and neoplastic liver the RASSF1A gene is increasingly methylated, that this condition takes place as an age-related phenomenon and that the early setting and spreading over time of an epigenetically methylated hepatocyte subpopulation, might be related to liver tumorigenesis.

Trerè D, Borzio M, Morabito A, Borzio F, Roncalli M, Derenzini M. · Department of Experimental Pathology, Unit of Clinical Pathology, University of Bologna, Italy. · Hepatology. · Pubmed #12500191 No free full text.

Abstract: Patients with cirrhosis are at significant risk for hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the relationship between the percentage of hepatocytes showing nucleolar hypertrophy and the development of HCC in cirrhosis of different causes. A total of 111 cirrhotic patients were studied, with a mean follow-up period of 83.3 months. Histologic sections from liver biopsy specimens were silver stained for selective visualization of the nucleolus; the nucleolar area was measured by image cytometry. Nucleoli with a size of 7 microm(2) or greater were considered to be hypertrophic. The nucleolar index was obtained by calculating the percentage of hepatocytes disclosing a nucleolar area of 7 microm(2) or greater. During the observation time, HCC was diagnosed in 39 of 111 patients. The incidence rate of HCC was greater in patients with nucleolar indexes of 2.5 or greater than in patients with nucleolar indexes of less than 2.5 (16.49%/y vs. 3.41%/y, respectively; P <.0001). The capacity of the nucleolar index to predict HCC development was separately tested in groups of patients divided by etiology, and it was found to be particularly relevant in hepatitis B virus (HBV)-related cirrhosis (P =.0006). Among patients with hepatitis C virus (HCV) infection, high nucleolar-index values were associated with a greater risk for HCC development, but the difference in the incidence rate of HCC between groups with a nucleolar index of 2.5 or greater and less than 2.5 was not statistically significant (P =.0944). In conclusion, our results have shown that high percentages of hepatocytes showing nucleolar hypertrophy significantly predict HCC development in patients with HBV infection, whereas their predictive value in HCV-related cirrhosis seems to be lower.

Grizzi F, Ceva-Grimaldi G, Franceschini B, Roncalli M, Chiriva-Internati M, Dioguardi N. · Scientific Direction Unit, Istituto Clinico Humanitas, Rozzano, Milan, Italy. · Eur J Histochem. · Pubmed #12044042 No free full text.

Abstract: One of the major liver fibrogenic activators is the cellular iron overload that can severely damage parenchymal and non-parenchymal cells. The aim of this study was to investigate a histochemical staining technique that allows the simultaneous detection of the irregular deposition of matrix collagen and both the amount and distribution of iron in liver cells on the same histological section. The method was evaluated using 3-microm histological sections obtained from ten standard liver biopsy specimens taken from patients with hepatitis C virus-related diseases and simultaneous liver cell iron overload. The results indicate that the double-staining technique is simple, sensitive and rapid, and can be routinely applied to liver biopsy specimens for diagnostic purposes. Furthermore, it may also facilitate the study of the complex relationship between hepatic fibrosis and iron overload during common genetic or secondary liver metabolic disorders.

Fracanzani AL, Borzio M, Roncalli M, Derenzini M, Trerè D, Mattioli M, Taioli E, Fiorelli G, Fargion S. · Dipartimento di Medicina Interna, Ospedale Maggiore IRCCS, Università di Milano, Italy. · Am J Gastroenterol. · Pubmed #11051372 No free full text.

Abstract: OBJECTIVE: Patients with hereditary hemochromatosis are at high risk of developing hepatocellular carcinoma. This study was undertaken to define whether large cell change and nucleolar organizer regions proliferative index (marker of high proliferative activity) predict hepatocellular carcinoma development in hereditary hemochromatosis. METHODS: Histological staining for large cell change and high proliferative activity were done on baseline liver biopsies of 74 patients with hereditary hemochromatosis (52 with and 22 without cirrhosis), prospectively followed-up for 83 +/- 53 months (range, 1-230 months). RESULTS: Large cell change and high proliferative activity were found only in cirrhotic patients; 16 of 52 patients (31%) had either the large cell change or high proliferative activity. Large cell change was more frequent in patients with hepatitis B surface antigen than in those positive for hepatitis C virus (57% vs 14%, p = 0.04). Hepatocellular carcinoma developed in 7 of 16 (44%) and in 6 of 36 patients (16%) of the patients positive or negative for these morphological variables. The probability of developing hepatocellular carcinoma at 7 yr of follow-up was significantly higher in patients with large cell change or high proliferative activity than in those without. The length of follow-up from baseline histology to hepatocellular carcinoma occurrence was shorter in patients with large cell change or high proliferative activity than in those without these changes (46 +/- 36 and 109 +/- 34 months, p = 0.01). A multivariate analysis indicated that in patients with cirrhosis, large cell change or high proliferative activity (considered as a single variable), and age >55 yr were the only independent variables significantly associated with the risk of developing hepatocellular carcinoma, with a risk ratio of 4.8 (confidence interval 1.2-18.2) and 4.0 (confidence interval 1.1-15.6), respectively. CONCLUSIONS: In hereditary hemochromatosis, the presence of large cell change or high proliferative activity in patients older than 55 yr with cirrhosis should be considered a strong predictor of hepatocellular carcinoma development, especially if hepatitis B virus infection coexists.