Liver fibrosis progression is related to CD4 cell depletion in patients coinfected with hepatitis C virus and human immunodeficiency virus.

A total of 204 patients with liver biopsy-proven hepatitis C virus (HCV) infection, 84 with and 120 without human immunodeficiency virus (HIV) coinfection, were studied, to evaluate variables possibly associated with the stage of liver fibrosis. All patients were injection drugs users, with a mean age of 32 years and an estimated duration of HCV infection of 12 years. Twenty-four patients (11%) had many fibrous septa with (5%) or without (6%) cirrhosis, 56 (27%) had few fibrous septa, and 124 (60%) had no fibrous septa. In all patients, an association was found between CD4 cell counts <500 cells/mm(3)and the presence of many fibrous septa (odds ratio, 3.2; P=.037), independent of HIV infection and other factors. These results suggest that HIV infection-induced CD4 depletion is independently associated with the severity of liver fibrosis in chronic HCV infection.

Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy.

OBJECTIVE: Intrahepatic cholangiocarcinoma (ICC) is a rare type of primary liver cancer (PLC) arising from intrahepatic bile ducts. We carried out a case-control study to assess the association between ICC and hepatitis B and C virus (HBV and HCV) infections, alcohol intake, and hepatolithiasis in Brescia, North Italy. METHODS: Among 370 subjects with histology-based diagnosis of PLC who were resident in the area and hospitalized in 1995-2000, 26 (7%) ICC cases were identified. A total of 824 subjects unaffected by hepatic diseases and frequency-matched with PLC cases by age, sex, date, and hospital of admission were recruited as controls. RESULTS: Among ICC cases the mean age was 65 years, 80.8% were males, and 38.5% had cirrhosis. Seropositivity for anti-HCV, HBsAg, alcohol intake >80 g/day and history of hepatolithiasis were found in 25%, 13%, 23.1%, and 26.9% of ICC cases and in 5.8%, 6.7%, 32.9%, and 10.6% of controls, respectively. The odds ratios adjusted for demographic factors by logistic regression (95% confidence interval; 95% CI) were 9.7 (1.6-58.9) for anti-HCV, 2.7 (0.4-18.4) for HBsAg, and 6.7 (1.3-33.4) for hepatolithiasis, whereas no association was found with alcohol drinking. CONCLUSIONS: HCV and hepatolithiasis may be risk factors for ICC in Western countries.

Etiology of hepatocellular carcinoma in Italian patients with and without cirrhosis.

We performed a case-control study to assess the role of hepatitis B virus (HBV), hepatitis C virus (HCV), GB virus C/hepatitis G virus (HGV), TT virus, alcohol intake, and tobacco smoking as risk factors for hepatocellular carcinoma (HCC) in the presence or absence of cirrhosis. We prospectively recruited 174 patients with a first diagnosis of HCC admitted to the main hospitals in Brescia, North Italy. On the basis of histological, clinical, and radiological criteria, the presence of cirrhosis was established in 142 cases, excluded in 21 cases, and remained undefined in 11 cases. Among the HCC cases without cirrhosis, a histological picture of normal liver was found in a single patient, chronic viral hepatitis was found in 11 patients, alcoholic hepatitis was found in 5 patients, nonspecific reactive hepatitis was found in 3 patients, and hemochromatosis was found in 1 patient. As controls, we also included 610 subjects unaffected by hepatic diseases and admitted to the same hospitals as cases. The odds ratios for having HCC according to positivity for HCV RNA, HBsAg and/or HBV DNA, and alcohol intake > 80 g/day (95% confidence interval) were as follows, in the presence and absence of cirrhosis, respectively: (a) 33.5 (17.7-63.4) and 19.7 (6-64.8) for HCV RNA; (b) 17.6 (9.0-34.4) and 20.3 (5.7-72.6) for HBsAg; and (c) 5.5 (3.1-9.7) and 4.6 (1.5-13.8) for alcohol intake. No association was found with HGV or TT virus infections or tobacco. This study has shown that most HCC cases arising in the area are due to HBV, HCV, or alcohol intake, in both the presence and absence of cirrhosis.

Ultrasound evaluation of hepatic lymph nodes in patients with anti-hepatitis C virus antibody reactivity.

BACKGROUND: Portal lymphadenopathy is frequently found in inflammatory liver diseases. However, the mechanisms underlying portal lymphadenopathy are unknown. AIMS: To evaluate the prevalence of portal lymphadenopathy in patients with serum anti-hepatitis C Virus antibody reactivity and its relationship to clinical parameters. PATIENTS AND METHODS: The presence of portal lymphadenopathy was evaluated by upper abdominal Ultrasound by the same examiner in 114 patients with anti-hepatitis C Virus reactivity: 56 patients with normal liver enzyme activity and 58 randomly selected patients with increased liver enzyme activity undergoing liver biopsy. Laboratory tests were then performed in all patients the following day. RESULTS: Portal lymph nodes were found in a significantly higher percentage of patients with increased liver enzymes (74%) than in patients with persistently normal liver enzymes (29%: p < 0.01). Aminotransferases, gamma glutamyl transpeptidase levels and the percentage of patients with HCVRNA in serum and histological scores for piecemeal and lobular necrosis were significantly higher in patients showing hepatic lymph nodes. Multivariate analysis showed that only alanine aminotransferase and lobular necrosis were independently related to the presence of hepatic lymph nodes. A significant correlation was found between lymph node size, aminotransferase activity and lobular necrosis. CONCLUSION: Ultrasound-proven portal lymph node enlargement is an indirect sign of hepatocellular damage in patients with positive serum anti-hepatitis C Virus antibodies.

[Intestinal brushing. Technical-cytological contribution in the pathological study of Vater's ampulla, common bile duct, and pancreatic system]. / Il brushing intestinale. Apporto tecnico-citologico nello studio della patologia della papilla di Vater, della via biliare principale e del sistema pancreatico.

OBJECTIVE: This experience shows the effectiveness of the cytological examination in the diagnosis of biliary and pancreatic neoplasm on samples obtained from Vater's papilla through endoscopic intestinal brushing. STUDY DESIGN: From June 1997 to October 1998, 28 patients, suffering from suspicious neoplasm of Vater's papilla or biliary system, were studied. Each sample was obtained through intestinal brushing during an Endoscopic Retrograde Colangio-Pancreatography (ERCP) and processed with the technique of direct smear stained with Papanicolaou's method. The sample was followed by the corresponding biopsy in 16 cases and by surgical specimens in 8 cases. RESULTS: 27 patients out of 28 were correctly classified by the intestinal brushing. The method carried out a positive predictive value of 100% and a sensitivity of 93%. The sensitivity of biopsy turned out to be 80%. CONCLUSIONS: The intestinal brushing is an effective method of diagnosis, which turned out to be relevant as a support and, in several cases, as a substitute of the biopsy. We think, therefore, that the brushing should be carried out whenever a lesion of the Vater's papilla or of the biliary system is suspected during an ERCP.

Recurrent Salmonella sepsis and aortitis in a patient with hepatocellular carcinoma.

A 62 years old man was admitted to hospital because of fever; a small superficial hepatic nodule was showed by ultrasonography. Blood cultures grew Salmonella enteritidis. Cefotaxime was administered for ten days. Fever promptly disappeared but one week later recurred with abdominal and back pain. Cultures grew again Salmonella enteritidis. Biopsy of the hepatic nodule showed hepatocarcinoma. Computed abdominal tomography showed a paraaortic mass. Angiography demonstrated hematoma communicating with the aortic lumen. The patient underwent revascularization of the involved aortic tract and resection of the hepatic nodule. Histology showed suppurative aortic endarteritis and a well-differentiated hepatocellular carcinoma with a large area of suppurative necrosis. The recovery of Salmonella species as of any uncommon bacteria from blood should warrant a through research of underlying disease, especially cancer.

Segment 4 (the quadrate lobe): a barometer of cirrhotic liver disease at US.

PURPOSE: To evaluate the dimensions of segment 4 of the liver in patients with cirrhosis by using ultrasonography (US). MATERIALS AND METHODS: The transverse diameter of segment 4 was measured in 125 control subjects without liver disease and 167 patients with cirrhosis. The size of segment 4 was measured on oblique subcostal US scans obtained between the left wall of the gallbladder (or the main fissure after cholecystectomy) and the ascending or umbilical portion of the left portal vein at the point where it gives rise to the branch to segment 4. RESULTS: In the control subject group, the mean diameter of segment 4 was 43 mm +/- 8 (standard deviation). In the patient group, the mean diameter of segment 4 was 28 mm +/- 9. The cause or severity of cirrhosis had no influence on the size of segment 4. CONCLUSION: A decreased diameter of segment 4 may be a helpful adjunct sign of cirrhosis in the US investigation of chronic liver disease.

Primary liver cancer in a high-incidence area in north Italy: etiological hypotheses arising from routinely collected data.

The incidence rate for primary liver cancer (PLC) was investigated in the Health Unit of Brescia (about 325,000 inhabitants), North Italy, in the 5-year period 1986-90, in order to ascertain whether there was a high risk for developing the disease in the area as suggested by mortality data. A total of 349 incident cases were observed (male: female ratio = 3.4: 1), of which 182 (52.1%) were diagnosed through histology. The cumulative risk was about 5% and 1% in males and females, respectively. The crude incidence rates were 34.5/100,000 in males and 9.4/100,000 in females, and the age-standardized rates were the highest among all those observed in the 9 Italian areas covered by Cancer Registries. Although about half of the cases in males can be attributed to either chronic alcoholic disease or HBV infection or both, further research is needed to investigate the role of known risk factors for PLC in the Health Unit.

Pathology of hepatocellular carcinoma.

This study provides a guideline to a dynamic approach toward the diagnosis of hepatocellular carcinoma (HCC). Bile production, fibrinogen synthesis, Mallory body, fibrinogen ground-glass and abnormal glycogen bodies as a reflection of "clone" selection, and hepatitis B virus (HBV) antigen expression in tumor cells can be considered as markers for the morphological diagnosis of HCC. The demonstration in tumor cells of these diagnostic features requires a careful screening of routinely stained preparations in search of suggestive, characteristic, specific, or pathognomonic features further supplemented by ancillary techniques, such as histochemistry, immunocytochemistry, and electron microscopy.

Biosynthesis of thiopeptide antibiotic A10255: incorporation of isotopically-labeled precursors.

The biosynthetic origin of antibiotic A10255 was investigated using 14C- and 13C-labeled amino acids. DL-[1-(13)C]Serine labeled 15 of the 17 amino acid residues present in A10255G. These included the oxazole, thiazole, dehydroalanine, masked glycine, masked alanine and pyridine moieties. The same 15 residues labeled by serine were labeled by [2-(13)C]glycine, apparently by conversion of the glycine to [2,3-(13)C]serine. Formation of the pyridine ring occurred via a C3 to C3 condensation of two serines. The results indicated origin of the masked alanine from alanine; the masked glycine from glycine; the thiazole residues from cysteine; and the threonine, masked dehydrobutyrine, masked dehydronorvaline and masked dehydroleucine residues from threonine. L(-)[CH3-(13)C]Methionine labeled the methyl carbon of the masked dehydronorvaline moiety in factor B and the two methyl carbons of the masked dehydroleucine moiety in factor E. The results demonstrate that A10255 originates exclusively from amino acids in a manner similar to the closely related thiopeptide antibiotics nosiheptide and thiostrepton.

Biosynthesis of thiopeptide antibiotic A10255 in stirred reactors using a chemically defined medium supplemented with continuous nutrient feeds.

A10255 is a complex of new thiopeptide antibiotics produced by Streptomyces gardneri. When stirred reactors were operated in batch mode using a defined medium with a glucose feed, 250 micrograms/ml of A10255 were produced during a four-day fermentation cycle. The linear growth phase of S. gardneri was extended through seven days by supplementing the defined medium with continuous feeds of hydrolyzed casein and methyl caprate. With the supplementary feeds, antibiotic biosynthesis paralleled growth during the extended cycle and attained levels of 1,750 micrograms/ml. Increasing the standard glucose feed rate increased titers principally by increasing cell mass. Supplementing the standard glucose feed with lipids such as caprylate or caprate, and decyl alcohol, affected cell mass minimally but produced higher titers by increasing the specific biosynthesis of A10255 per unit of biomass.

Cirrhosis of the liver. A regenerative process.

The ancient story of Prometheus, chained to a rock for defying Zeus by stealing fire from Mount Olympus and subjected to daily tearing at his liver by an eagle, attests to the early recognition of the extraordinary regenerative capacity of the human liver. This process had remained an intriguing mystery over the millennia. In the last 20 years, following the pioneering work of Bucher (1) and Moolten et al (2), there has been an explosion of research that has clarified some of the mechanisms underlying the process of hepatic regeneration. Regeneration implies proliferation and regeneration. After the fetal and postnatal growth of the liver is completed, hepatocytes no longer proliferate actively, but they can proliferate in response to cell death or loss (3). Hepatocyte growth responses are of particular research interest because they occur in vivo and involve cells that are normally quiescent. Hepatic regeneration constitutes a highly regulated process that is best shown by the arrest of liver growth following a partial hepatectomy precisely at the moment the hepatic mass reaches the mass of the original intact liver (3). This suggests that hepatic regeneration after a partial hepatectomy is a strictly regulated nonautonomous growth process that is controlled by the same factors that are responsible for the determination and maintenance of hepatic mass in a normal individual. In response to a partial hepatectomy, hepatocytes enter the cell cycle and progress to DNA synthesis and replication but only in numbers sufficient to restore the hepatic mass. The regeneration response is both synchronized and universal in that it affects all intrahepatic cell lines, including nonparenchymal cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Basement membrane components in normal, dysplastic, neoplastic laryngeal tissue and metastatic lymph nodes.

The immunohistochemical localization of the basement membrane (BM) components laminin, type IV collagen and fibronectin was analyzed in normal, dysplastic and neoplastic laryngeal specimens. The distribution of these macromolecules was also investigated in metastatic lymph nodes. A regular and continuous staining for laminin and type IV collagen was present in normal and mild dysplastic epithelium (LIN I); interruptions and reduplications were more evident in severe dysplasia (LIN III), together with an increased positivity for fibronectin in the subepithelial connective tissue. In squamous cell carcinomas the distribution of BM components was related to the degree of cellular differentiation, with a decreased immunostaining being evident in moderately and poorly differentiated carcinomas. Furthermore, the positivity for laminin and type IV collagen was influenced by the pattern of neoplastic growth, being continuous around the "pushing" border and discontinuous where the neoplastic front had an "invading" appearance. Similar changes were present in cervical metastatic lymph nodes. These observations tend to support the theory that the neoplastic growth is a cyclic process, with BM component synthesis and reabsorbtion related to the shifts of cellular metabolism.

[Eosinophilic gastritis. Clinico-pathologic considerations on a case and review of the literature]. / Gastrite eosinofila. Considerazioni clinico-patologiche su di un caso e revisione della letteratura.

The clinical, radiographic and histological features of a case of eosinophilic gastritis in a 26 year old-man without personal or familial signs of allergy are reported. The Authors pointed out the importance of radiographic and histological aspects of the case studied. Therefore they represent essential methods for a correct diagnosis and an appropriate management that in this case is only pharmacological. The diagnosis of eosinophilic gastritis is, however, important for the recognition of specific allergens.

[Immunohistochemical localization of laminin, collagen IV and fibronectin in dysplasias and neoplasms of the cervix uteri]. / Localizzazione immunoistochimica di laminina, collagene IV e fibronectina nelle displasie e neoplasie della cervice uterina.

The distribution of intrinsic components (Laminin and Type IV Collagen) and extrinsic component (Fibronectin) of the Basement Membrane (BM) has been studied in normal uterine cervix (16 cases), in cervical dysplasia (14 cases) and in invasive carcinoma (45 cases). We found that BM staining for Laminin and Type IV collagen is linear and continuous underlying normal and dysplastic epithelium (CIN 1-CIN 2), it shows minor breaks in continuity and alterations of linearity in situ carcinomas (CIN 3), and it disappears in microinvasive areas. In well differentiated invasive carcinomas only focal disruptions of BM around neoplastic nests is noted; in contrast, in moderately and poorly differentiated neoplasias, is found a progressive reduction and loss of staining for Laminin and Type IV Collagen. The results of this study suggest that the distribution patterns of BM intrinsic components are in relation to the histological grade of cervical neoplasias and their invasion ability. On the contrary Fibronectin doesn't show any distribution pattern related to the grade of cervical neoplasias, its immunostaining increased with the rise of both connective tissue stroma production and of vascularity.

Incidence and clinicopathological heterogeneity of HIV-related non-Hodgkin's lymphoma.

The characteristics of 14 HIV-seropositive patients with NHL consecutively observed between 1984 and 1988 at our Institution are described. Patients belonged to a known population of 1242 HIV-seropositive individuals in whom the incidence of NHL was 1.13%, significantly higher than in age-matched controls (P less than .0001). Within this population, a previous diagnosis of ARC or AIDS, but not of LAS, was the only significant risk factor for the development of NHL (P less than .0001). According to the status of HIV infection at the time of NHL diagnosis, two groups of patients could be clearly identified with different clinicopathological features and prognosis. In fact, NHL developing in 7 patients previously affected by ARC or AIDS, presented as localized, extranodal disease, predominantly in the CNS; large cell histology, peripheral blood cytopenia, severe immunodeficiency and poor prognosis further distinguished this subgroup. Conversely, NHL developing in 7 patients with either asymptomatic HIV-seropositivity or LAS, more often presented as disseminated disease both in nodal and extranodal sites, with Burkitt's-type histology. Cytopenia was uncommon and immunodeficiency was significantly less severe. In this subgroup complete remission (CR) was achieved with aggressive treatment in 6 of 7 patients. No relapses occurred but two opportunistic infection-related deaths were observed. Four patients are alive 6-34 months after CR, two of whom show newly developed opportunistic infections.

[Distribution of laminin, type IV collagen and fibronectin in normal, dysplastic and neoplastic laryngeal tissue]. / Distribuzione di laminina, collagene di tipo IV e fibronectina nel tessuto laringeo normale, displastico e neoplastico.

The main components, both intrinsic (laminin and type IV collagen) and extrinsic (fibronectin), of the basement membrane (BM) were analyzed by immunohistochemical methods in normal, dysplastic and neoplastic laryngeal mucosa specimens. The material was obtained from 35 patients who had undergone surgery for glottic or supraglottic cancer. Fibronectin proved to be absent from normal mucosa whereas an immunopositivity was observed close to the dysplastic epithelium, especially around inflammatory cells. Positivity increased as the degree of dysplasia increased from LIN I to LIN III. A strong staining was also seen around nests of well and moderately differentiated squamous cell carcinoma. These findings are in agreement with the theories about the main sites of origin for fibronectin, both from plasma and connective tissue. Laminin and type IV collagen showed the same staining characteristics. In normal and mild dysplastic samples a regular and continuous positivity was found at the boundaries between the epithelium and the mesenchymal stroma. Focal discontinuities were present in areas of intense subepithelial inflammation only. Interruptions and reduplications were more evident in severely dysplastic epithelium. In invasive squamous cell carcinomas a strong correlation has been found between the degree of cell differentiation and the pattern of distribution of the intrinsic BM components. Immunostaining was usually evident and continuous around nests of well differentiated squamous cell carcinoma, whereas positivity progressively decreased in moderately and poorly differentiated neoplasms. Furthermore, staining for intrinsic BM components was also related to the pattern of tumor growth: continuous around the "pushing" edge of neoplastic growth and discontinuous when the neoplastic front had an "invading" appearance. These observations tend to support the theory which considers neoplastic growth a cyclic process. BM components are most likely synthesized during the phases of quiescence and reabsorbed during the phase of invasiveness, following shifts in neoplastic cell metabolism.