Abstract: BACKGROUND/AIMS: Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, being a putative steatogenic factor, may promote liver fibrosis progression in patients with chronic hepatitis C. This study aimed to verify the role of recipient MTHFR polymorphism in favouring graft fibrosis progression in patients with recurrent HCV after orthotopic liver transplantation (OLT). METHODS: We studied 63 such patients, followed for >1 year. MTHFR allelic variants were determined by a polymerase chain reaction/restriction fragment length polymorphism method. RESULTS: Recipients carrying the TT genotype had more frequently, 1-year post-OLT, homocysteine serum levels >23 micromol/L (P<0.05), serum triglycerides >180 mg/dL (P<0.02) and de novo diabetes mellitus (P<0.05) but not a higher frequency of graft steatosis. Time-to-event analysis in reaching an Ishak staging score >2 was performed by stratifying the recipients as follows: (a) patients with donor age < or =45 years, (b) patients with donor age >45 and C/(*) genotype, and (c) patients with donor age >45 years and TT genotype. A significant linear trend was observed, with increasing frequencies as follows: (a) 8/37, (b) 10/19 and (c) 6/7 (P=0.0005). CONCLUSION: The MTHFR C677T polymorphism may play a role in influencing liver fibrosis progression in patients with recurrent hepatitis C, in conjunction with donor age, but not via steatosis promotion.

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Abstract: BACKGROUND: The aim of the study was to perform a comprehensive diagnostic evaluation of six popular, non-proprietary, indirect markers of liver fibrosis in a cohort of patients with chronic hepatitis C representing the full spectrum of disease severity. METHODS: A total of 167 consecutive, hepatitis C virus RNA positive, untreated patients with chronic hepatitis C were studied. Liver biopsy with histological evaluation and age/platelet index, aspartate aminotransferase/alanine aminotransferase ratio, aspartate aminotransferase to platelet ratio index, Bonacini's discriminant score, Forn's fibrosis index and FibroIndex were assessed in all patients. RESULTS: The area under the receiver operating characteristic curves of the six tests was always greater when performed to discriminate patients with METAVIR score F4 than when assessed to discriminate patients with METAVIR score > or =F2. At step-wise discriminant analysis the only indirect marker of fibrosis entered was FibroIndex, with the following correct classification of the patients: total=52.1, patients with scores F0-F1=62.2, patients with scores F2-F3=26.0 and patients with score F4=68.4. CONCLUSIONS: The ability to correctly classify patients using a panel of non-proprietary indirect markers of liver fibrosis is far from being ideal. Among them, FibroIndex appears to possess the best discriminating capacity. The simultaneous use of several indirect markers of liver fibrosis does not improve their diagnostic accuracy.

Abstract: Idenix Pharmaceuticals Inc and Novartis AG are codeveloping valopicitabine dihydrochloride, a once-daily oral nucleoside for the potential treatment of HCV infection. In January 2005, a phase IIa clinical trial comparing valopicitabine dihydrochloride with pegylated IFN in treatment-naive HCV patients was ongoing, in addition to a phase IIb trial in patients that had previously failed pegylated IFN and ribavirin combination therapy. In January 2006, an international phase III trial in treatment-refractory patients was planned for the first half of the year, with a phase III trial in treatment-naive individuals planned for the second half of the year.

Abstract: To ascertain whether single nucleotide polymorphisms (SNPs) regulating the expression of interferon-gamma (IFN-gamma), IFN-gamma receptor-1 (IFNGR-1), interleukin-6 (IL-6), IL-10, IL-18, and tumor necrosis factor-alpha (TNF-alpha) may be associated with early fibrosis progression of recurrent hepatitis C, 50 liver transplantation recipients (32 men, 18 women, median age 56 years) with a median histologic follow-up time of 54 months were studied; 98 healthy blood donors served as controls. Cytokine SNPs were determined by means of previously described PCR-based methods. On the basis of the SNP studies, a low, intermediate, or high producer cytokine phenotype was attributed to each patient. Only 1 of the 17 low IL-10 producers reached an Ishak staging score > 2, in contrast to 20 of the 33 patients who were intermediate or high IL-10 producers (Mantel-Cox, p < 0.005). Recipients who were low IL-10 producers and high IFN-gamma producers had significantly slower fibrosis progression in comparison to intermediate/high IL-10 producers and low IFN-gamma producers (p < 0.005). In conclusion, cytokine SNPs resulting in high and low producer phenotypes of both Th1 and Th2 cytokines appear to modulate the course of recurrent hepatitis C. Low IL-10 producers are those with the slowest histologic fibrosis progression.

Abstract: Hepatitis C virus (HCV) infection is a major public health problem around the world and it is estimated that there are about 200 million infections globally. The majority of HCV infected patients develop chronic infection, which can progress to liver cirrhosis, hepatocellular carcinoma, and liver failure. Since the discovery of the virus in 1989, impressive progress has been made in the treatment of HCV hepatitis. However, the actual standard of care in treating HCV infection, represented by the combination therapy of pegylated interferon alpha 2a or 2b with ribavirin, fails to cure near half of treated patients. This paper aimed to trace a brief overview of the progress made by interferon-based treatments for HCV hepatitis since their introduction in the early 1990s, and to highlight the results of recent clinical studies concerning new and emerging drugs.

Abstract: BACKGROUND AND AIM: Per protocol annual liver biopsy represents the gold standard in the assessment of graft fibrosis progression due to recurrent hepatitis C after liver transplantation. Non-invasive liver fibrosis tests have been proposed as surrogate markers of liver fibrosis in hepatitis C virus (HCV)-positive immune-competent patients. No data are available in the literature on the usefulness of non-invasive liver fibrosis tests in liver transplanted patients with recurrent HCV infection. METHODS: A total of 102 annual per protocol liver biopsies performed in 51 consecutive HCV-positive recipients (31 men), with a follow-up period lasting up to 5 years, were included and evaluated in this study. At each time point, the following non-invasive liver fibrosis tests were calculated: aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, age-platelet index, AST to platelet ratio index (APRI), Forns' fibrosis index and Bonacini's discriminant score. RESULTS: In discriminating patients with histological fibrosis score >2, APRI provided the best area under the receiver operating characteristic curves (AUROC) (0.801), in comparison to the other four non-invasive liver fibrosis tests. The AUROC of APRI was better in female (0.871) than in male (0.753) recipients. Among female recipients, an APRI value >1.4 was 91% sensitive and 75% specific in detecting a staging score >2. The corresponding values among male recipients were 60% and 77%, respectively. CONCLUSIONS: Among non-invasive liver fibrosis tests, APRI has the highest diagnostic value in discriminating liver transplanted patients with progression to significant liver fibrosis, although its accuracy is influenced by recipient sex.

Abstract: BACKGROUND: Experimental evidence and clinical studies suggest that the renin-angiotensin system and its inhibitors may play a role in regulating the mechanisms of liver fibrosis development. The present study aimed to verify whether carriage of specific angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) allelic variants, modulating angiotensin II generation, could affect the outcome of recurrent hepatitis C after liver transplantation, via several metabolic pathways. METHODS: Forty-five (29 men) recipients, with a median histological follow-up of 60 months after orthotopic liver transplantation (OLT), were studied. ACE gene I/D polymorphism was assessed by means of a polymerase chain reaction procedure. Fibrosis progression was evaluated annually during the follow-up. RESULTS: Weight gain 1 year post-OLT (defined as an increase in body mass index, BMI, of >0.5 kg/m(2)) was significantly more common among D/ carriers (22/22 vs. 16/23, P < 0.005); patients who 1 year after OLT had an increase in their BMI value of >0.5 kg/m(2) more frequently had a triglycerides/cholesterol ratio of <or= 0.7 (16/22 vs. 8/23, chi-squared test P < 0.02). This association was stronger in men. Female D/D homozygotes had the highest probability of showing significant liver fibrosis (7/10) in comparison with men (11/29) and I/ women (1/6) (P < 0.01). CONCLUSIONS: In patients with recurrent hepatitis C, carriers of the D allele appeared to gain more weight after liver transplantation, and in male liver recipients, the D allele was associated with a peculiar lipid profile that was associated with a slower rate of allograft fibrosis progression. Among female recipients, carriage of the D allele may favor more severe allograft fibrosis.

Abstract: The prevalence and associated factors of chronic uncomplicated strongyloidiasis were estimated among 200 consecutive elderly patients (aged >or= 60 years) admitted to a general hospital in northern Italy. One-hundred patients had a peripheral eosinophil concentration >or= 500 cells/microL (group A), and 100 were age- and gender-matched controls (group B). Measurements included serum IgG anti-Strongyloides antibody titre by an indirect immunofluorescence assay, combined with faecal culture for Strongyloides stercoralis. Anti-Strongyloides antibodies were detected in 28 patients (at high titre in 11 patients). Seropositivity was significantly more common among group A than among group B patients (OR 4.85). Strong seropositivity for anti-Strongyloides antibodies was associated with farm work (p < 0.001), but not with other patient characteristics or with signs and symptoms of strongyloidiasis. In conclusion, strongyloidiasis was relatively common among elderly in-patients; eosinophilia and a history of farm work were the most useful indications for this diagnosis.

Abstract: OBJECTIVES: To verify the value of indirect serum markers in the non-invasive assessment of liver fibrosis in patients with persistently normal or near normal alanine aminotransferases levels (NALT). DESIGN AND METHODS: Forty HCV RNA positive, untreated patients with NALT (30 non-drinkers) underwent two liver biopsies, with a median interval of 78.5 months. The AST/ALT ratio, age-platelet index, AST to platelet ratio index (APRI), Forns fibrosis index and Bonacini's discriminant score were simultaneously determined. RESULTS: In 19 patients, worsening of fibrosis was observed at the second biopsy in comparison to the index biopsy. Among non-drinkers, an APRI >0.4 had a 100% sensitivity in identifying subjects with significant liver fibrosis (Ishak staging score >2) and an APRI < or =0.4 had a 100% negative predictive value in excluding significant liver fibrosis. CONCLUSIONS: APRI performs better, in comparison to all other markers, in correctly classifying patients with NALT with no progression to significant liver fibrosis.

Abstract: Autocrine/paracrine stimulation of KIT has been observed in colorectal carcinoma (CRC) cell lines. We investigated the expression of KIT and stem cell factor (SCF) in CRC in comparison with premalignant colon lesions and normal colonic mucosa to assess the prognostic and therapeutic relevance of this receptor/ligand system in CRC. Transcript levels of c-kit and the two SCF splicing variants were determined quantitatively by real-time RT-PCR using cDNA obtained from normal, premalignant and malignant snap frozen colon tissue specimens. Immunohistochemistry with specific anti-KIT and anti-SCF antibodies was performed on paraffin-embedded tissue sections in order to localize the relative protein expression in epithelial compartments. Approximately 10% of patients expressed KIT in their adenoma or primary tumor. The majority of KIT-positive carcinomas co-expressed SCF. Real-time RT-PCR showed expression of c-kit and SCF transcripts in all cDNA specimens examined. A significant association between the co-expression of KIT/SCF and a worse clinical outcome was found. In conclusion, KIT expression was observed in a proportion of premalignant and malignant colonic lesions, while it was virtually absent in normal colon mucosa. Moreover, the majority of KIT-positive carcinomas co-expressed SCF, suggesting the possibility of aberrant signaling by an autocrine loop, as confirmed by the negative prognostic value of this association. Therefore, in the subset of CRC patients with concomitant KIT/SCF expression, the activity of Imatinib mesylate, a selective inhibitor of specific tyrosine kinases including KIT, may be exploited in combination with standard therapy.

Abstract: Therapy of hepatitis C virus (HCV) infection may prevent progression to cirrhosis, hepatocellular carcinoma and end-stage liver disease. The cornerstone of treatment has long been standard IFN-alpha, the use of which was associated with a sustained biochemical and viral response in only a small proportion of patients. More recently, the success of interferon-based regimens has substantially improved due to the combination with the guanosine analogue ribavirin and to the advent of pegylated interferon formulations. However, even the most up-to-date regimens fail to cure the infection in many cases and are limited by side effects and high costs. A better understanding of the HCV genomic organisation, the elucidation of the three-dimensional structures of virally encoded enzymes and the recent development of a HCV-replicon system in human hepatoma (Huh-7) cells have led to significant advances in the development of new antiviral compounds, many of which are under evaluation in clinical trials. The aim of this review is to trace a brief overview of the progress made by interferon-based treatments for hepatitis C since their introduction in the early 1990s, and to highlight the results of recent clinical studies concerning new and emerging drugs.

Abstract: To verify prospectively the usefulness of the furosemide-induced natriuresis test in predicting ascites control by medical treatment, 15 stable cirrhotics (9 male) with ascites were studied. Sodium excretion was measured after this test and after volume expansion with saline associated with intravenous infusion of octreotide; 6 months later, response to medical treatment was rated as good (N=9) or poor (N=6). Patients with poor ascites control had lower sodium excretion with the furosemide-induced natriuresis test (median, 88 vs 201 mmol; P < 0.01). Poor control was observed in four of four patients with sodium excretion < or =125 mmol, and good control in six of six patients with sodium excretion >175 mmol (P < 0.002). Volume expansion was followed by limited natriuresis (median, 20 mmol), in inverse relationship with plasma active renin concentration (P < 0.001). In conclusion, long-term ascites control is well predicted by the furosemide-induced natriuresis test.

Abstract: Cytokine shedding by tumor cells into the local microenvironment modulates host immune response, tumor growth, and metastasis. The study aimed to verify the hypothesis that the immunological microenvironment of pancreatic carcinoma exists in a prevalently immunosuppressive state, influencing survival. We analyzed expression profiles of pro-inflammatory (IL-1beta, IL-2, IL-6, IL-8, IL-12 p40, IL-18 and IFN-gamma) and anti-inflammatory (IL-10, IL-11, IL-13 and TGF-beta isoforms) cytokines. The study was performed both in vitro, in five pancreatic carcinoma cell lines (real time RT-PCR), and in specimens from 65 patients, comparing tumoral versus non-tumoral pancreatic tissues (real time RT-PCR and immunohistochemistry). Furthermore, cytokines were measured in supernatants and sera (from patients and controls) by ELISA. All cell lines expressed IL-8, IL-18, TGF-beta1, TGF-beta2 and TGF-beta3, but not IFN-gamma and IL-2 transcripts. Expression of IL-1beta, IL-6, IL-10, IL-11, IL-13 and IL-12 mRNA was variable. All the above cytokines were detected as soluble proteins in supernatants, except IL-13. Tumor tissues overexpressed IL-1beta, IL-6, IL-8, IL-10, IL-11, IL-12 p40, IL-18, IFN-gamma, TGF-beta1, TGF-beta2 and TGF-beta3 at the mRNA level and IL-1beta, IL-18, TGF-beta2 and TGF-beta3 also at the protein level. Conversely, non-tumor tissues had stronger RNA and protein expression of IL-13. Survival was significantly longer in patients with high IL-1beta and IL-11 and moderate IL-12 expression. Serum IL-8, IL-10, IL-12, IL-18, TGF-beta1 and TGF-beta2 were higher in patients than in controls, as opposed to IL-1beta and IL-13. Patients with low circulating levels of IL-6, IL-18 and TGF-beta2 survived longer. Pancreatic cancer is characterized by peculiar cytokine expression patterns, associated with different survival probabilities.

Abstract: BACKGROUND: Subjects who carry the D allele of the angiotensin-converting enzyme (ACE) gene have higher plasma and tissue angiotensin II levels, possibly concurrent with the development of obesity. In transplant recipients, treatment with calcineurin antagonists would magnify these effects. The present study verifies whether the allelic variants of ACE are a factor involved in excess weight gain after liver transplantation. METHODS: A consecutive series of 108 liver transplant recipients (73 males) were studied. Recipient ACE genotypes, determined by a polymerase chain reaction-based method, were related to body mass changes 1 year after transplant. RESULTS: Body mass index (BMI) increased from the pretransplant value of 25.1+/-3.3 kg/m2 to 25.9+/-3.5 kg/m2 (P<0.005). The difference was mainly attributable to recipients carrying 1 D allele or more (N=88) in whom the BMI increased from 25.3+/-3.1 kg/m2 to 26.3+/-3.3 kg/m2 (P<0.005). A BMI of 25 kg/m or greater was measured in 30 of 45 deletion/deletion homozygotes and 25 of 43 insertion/deletion heterozygotes; in contrast, 14 of 20 insertion/insertion homozygotes had a normal body mass (P<0.01). Among patients with normal body mass pretransplant (N=56), none of 13 insertion/insertion homozygotes reached a BMI value 25 kg/m or greater posttransplant (P<0.005). At multivariate analysis, pretransplant body mass and carriage of 1 D allele or more were independent predictors of body mass gain greater than 2 kg/m. CONCLUSIONS: Carriage of the D allele of the ACE gene is a strong, independent risk factor for excess weight gain after liver transplantation.

Abstract: BACKGROUND: Hyponatremia represents a frequent complication of liver cirrhosis, associated with adverse events and death. It is caused either by excessive water retention or solute depletion, or a combination of both. AIMS: To determine the cause of hyponatremia clinically and to examine the usefulness of quantitative calculations of water excess and Na deficit to guide treatment. METHODS: We studied 23 patients with liver cirrhosis and PNa < or =131 meq/L to determine the cause of hyponatremia and results of quantitative treatment. RESULTS: The most frequent cause of hyponatremia was diuretic-induced Na depletion, which occurred in 14 out of 23 instances, while four patients had water excess. Hyponatremia was corrected after a quantitative estimate of the Na deficit or relative water excess by algebraic formulas. The former was quantitatively replenished as 3% NaCl, the latter was excreted with the technique of furosemide-induced diuresis and re-infusion of solute, but not water, losses. After quantitative replacement, there was a significant correlation (R=0.98, P< 0.001) between the Na concentration predicted mathematically and that actually measured. CONCLUSIONS: The hyponatremia of cirrhosis is frequently caused by diuretics. Its treatment can be effectively guided with the aid of quantitative estimates of Na deficit and/or water excess in all instances, although the methods of correction described are indicated in severe clinical conditions.

Abstract: BACKGROUND: In the treatment of hepatitis C virus (HCV) infection, regimens including pegylated interferon-alpha are superior to those including standard interferon; the present retrospective study was performed to verify whether the same is applicable to biopsy-proven recurrent hepatitis C (genotype 1b) after liver transplantation (OLT). METHODS: Twenty-four patients (16 male) were studied. Twelve had received interferon-alpha(2b) (IFN), 9 MU weekly and 12 received pegylated interferon-alpha(2b) (PEG-IFN), 0.5 microg/kg weekly. All had received oral ribavirin 600-800 mg/day. Treatment duration was intended for 12 months. A repeat liver biopsy, with evaluation of the Ishak grading and staging scores, was obtained at 1 year. RESULTS: Only 12/24 patients (50%) completed a full year of therapy; 17 (71%) experienced side-effects requiring a 50% dosage reduction or discontinuation of the IFN, PEG-IFN and/or ribavirin. This was observed in 6/12 patients (50%) treated with IFN in comparison to 11/12 patients (92%) treated with PEG-IFN (P < 0.05). The difference was mainly accounted for by anemia and leukopenia that were reported in 4/12 IFN patients (33%) versus 9/12 PEG-IFN patients (75%; P < 0.05), respectively. End-of-treatment viral response (ETVR) and histological response were always associated and occurred in 4/24 patients (17%), two in each treatment arm. Patients with ETVR were younger, had always completed 1 year of therapy, had had recurrent hepatitis later after transplantation and presented a higher baseline grading score. CONCLUSIONS: In the OLT setting, the potential benefits of antiviral treatments including PEG-IFN may be limited by the poor tolerability of the adopted drugs.

Abstract: Hyponatremia is common in cirrhosis, where it impairs encephalopathy. It could be either due to excess water, or reduced Na, or a combination of both. The diagnosis can be established with clinical skills aided by simple data like weight, blood pressure and plasma electrolytes. The quantitative estimates of the water surfeit or solute deficit, easily performed with simple formulas and measurements, guide accurate and programmed treatment procedures, avoiding the occurrence of the ominous central pontine myelinolysis.

Abstract: The course of hepatitis C virus (HCV) infection carriers with normal/near-normal aminotransferases (NALT) is usually mild; however, in a few, fibrosis progression occurs. We aimed to verify whether monitoring by liver biopsy might be replaced by noninvasive methods and to identify factors associated with fibrosis progression in patients with persistently normal alanine aminotransferases. We studied 40 untreated HCV-RNA-positive subjects (22 male; median age, 44 years), who underwent two liver biopsies, with a median interval of 78.5 months, during which alanine aminotransferase concentrations (median number of determinations: 12) never exceeded 1.2 times the upper normal limit. Within 9 months from the second biopsy, they were tested by the shear elasticity probe (Fibroscan) and the artificial intelligence algorithm FibroTest. METAVIR fibrosis scores were analyzed in relationship to demographic, clinical, and viral parameters. Weighted kappa analysis was used to verify whether the results of noninvasive methods agreed with histology. Significant fibrosis (> or = F2), present at the first biopsy in only one patient (2.5%), was observed at the second biopsy in 14 patients (35%). At multivariate analysis, excess alcohol consumption in the past (>20 g/d; P = .017) and viral load (>8.0 x 10(6) copies/mL; P = .021) were independent predictors of progression. In identifying patients with significant fibrosis, inter-rater agreement was excellent for Fibroscan (weighted kappa = 1.0), and poor for FibroTest (weighted kappa = -0.041). In conclusion, among HCV carriers with NALT, Fibroscan is superior to the FibroTest in the noninvasive identification of fibrosis, for which excess alcohol consumption in the past and high viral load represent risk factors.

Abstract: BACKGROUND: The histological outcome of chronic hepatitis C is better among carriers of the apolipoprotein E (ApoE) epsilon4 allele, for reasons unknown. The orthotopic liver transplantation (OLT) setting allows to separate the role played by liver-derived ApoE (graft) from ApoE of different origin (recipient). Patients and METHODS: Forty-six OLT recipients with recurrent hepatitis C were studied. Grafts and recipients were genotyped for ApoE. In a follow-up extending up to 4 years, the serum triglycerides-to-cholesterol ratio (T/C ratio) was measured 1 year after OLT, whereas fibrosis progression was assessed yearly and expressed as fibrosis units/month (FU/mo). RESULTS: A T/C ratio < or =0.75 was observed in 13/15 cases in which both donor and recipient were epsilon4 carriers, 10/19 cases in which epsilon4 alleles were of exclusive recipient's origin and 5/12 cases in which epsilon4 alleles were of exclusive donor's origin or absent (P<0.02). One year after OLT, a fibrosis progression < or =0.100 FU/mo was associated with a low T/C ratio (24/34 vs. 4/12, P<0.05). An Ishak staging score >2 was reached later by male recipients who were epsilon4 carriers (P<0.002). CONCLUSIONS: Recipient's carriage of ApoE epsilon4 affects fibrosis progression of recurrent hepatitis C through gender-specific mechanisms, associated with a peculiar, ApoE-associated, lipid profile.

Abstract: AIM: To investigate how weight gain after OLT affects the speed of fibrosis progression (SFP) during recurrent hepatitis C virus (HCV) infection of the graft. METHODS: Ninety consecutive patients (63 males, median age 53 years; 55 with HCV-related liver disease), transplanted at a single institution, were studied. All were followed for at least 2 years after OLT and had at least one follow-up graft biopsy, performed not earlier than 1 year after the transplant operation. For each biopsy, a single, experienced pathologist gave an estimate of both the staging according to Ishak and the degree of hepatic steatosis. The SFP was quantified in fibrosis units/month (FU/mo). The lipid metabolism status of patients was summarized by the plasma triglycerides/cholesterol (T/C) ratio. Body mass index (BMI) was measured before OLT, and 1 and 2 years after it. RESULTS: In the HCV positive group, the highest SFP was observed in the first post-OLT year. At that time point, a SFP <=0.100 FU/mo was observed more frequently among recipients who had received their graft from a young donor and had a pre-transplant BMI value >26.0 kg/m(2). At completion of the first post-transplant year, a BMI value >26.5 kg/m(2) was associated with a T/C ratio <=1. The proportion of patients with SFP >0.100 FU/mo descended in the following order: female recipients with a high T/C ratio, male recipients with high T/C ratio, and recipients of either gender with low T/C ratio. Hepatic steatosis was observed more frequently in recipients who, in the first post-transplant year, had increased their BMI >=1.5 kg/m(2) in comparison to the pre-transplant value. Hepatic steatosis was inversely associated with the staging score. CONCLUSION: Among HCV positive recipients, excess weight gain post-OLT does not represent a factor favoring early liver fibrosis development and might even be protective against it.

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Abstract: Adefovir-dipivoxil has been shown to be effective against lamivudine-resistant mutants in immunocompetent patients and in a small number of liver transplant recipients with recurrent hepatitis B virus (HBV) infection. The therapeutic role of adefovir-dipivoxil in acute de novo HBV infection after transplantation is uncertain. We describe a case of acute de novo HBV infection that occurred after liver transplantation and that was treated with lamivudine followed (when viral escape mutants emerged) by adefovir-dipivoxil rescue. Treatment outcome was excellent, with complete viral clearance and development of a protective titer of antibodies to anti-hepatitis B surface antigen. Because the donor was vaccinated against HBV, it is conceivable that clearance of HBV infection in the recipient might have been favored by adoptive transfer of immunity to HBV. The immune status of the donor might be a factor to consider when determining the treatment options for de novo hepatitis B.

Abstract: BACKGROUND/AIMS: Hepatic iron may act as an important co-morbid factor in non-hemochromatotic liver diseases, but whether it may favour fibrogenesis after liver transplantation is not known. To verify whether the hepatic iron concentration of the graft might play a role in the rapid fibrotic progression frequently observed after liver transplantation for chronic hepatitis C. METHODS: The hepatic iron concentration, measured at the time of the donor operation, was retrospectively related to the histological follow-up data of 68 recipients (49 males, 19 females), of whom 38 were hepatitis C virus positive. RESULTS: The hepatic iron concentration in donor liver biopsies ranged from 25 to 7,100 microg/gdw. After a median follow-up of 19 months, nine patients (five HCV positive) had a staging score >3. There was a significant association between a higher frequency of increasing staging and donor age >50 years. In female HCV-positive recipients, a graft hepatic iron concentration >1,200 microg/gdw was associated with fibrosis progression >0.15 fibrosis units per month (4/4 vs. 1/7, p<0.01). CONCLUSIONS: The graft hepatic iron concentration may be one of the factors involved in early fibrosis progression due to recurrent hepatitis C in female recipients.

Abstract: Carriage of the epsilon4 allelic variant of the apolipoprotein E (ApoE) gene might affect the outcome of hepatitis C virus (HCV) infection. The liver transplantation setting offers the opportunity to verify the role of the donor's vs recipient's ApoE polymorphism. Twenty-four patients (16 men) with recurrent hepatitis C, all infected by HCV-1b and treated with interferon and ribavirin, were genotyped for ApoE variants. Liver biopsies were done at baseline and 12 months later After treatment, staging scores improved in 10 of 24 patients. Staging improvement was associated with recipient sex, completion of the full antiviral schedule, and recipient's epsilon4 carriage. The beneficial effect of epsilon4 carriage toward the progression of fibrosis was due entirely to the contribution given by male patients and was independent of the viral response. Recipients', but not donors', carriage of at least 1 epsilon4 allele might be associated with a better histologic outcome in recurrent HCV infection.

Abstract:

Abstract: When Budd-Chiari syndrome (BCS) is due to occlusion of all three hepatic veins, the standard transjugular intrahepatic portosystemic shunt (TIPS) technique can be extremely laborious. A feasible alternative is to use the direct transcaval approach, by which a shunt can be created directly between the intrahepatic inferior vena cava and the portal vein. We describe two patients (one with acute BCS and one with hyperacute BCS) who were successfully managed with this modified technique. Both patients recovered; one of them underwent elective liver transplantation 15 months after the procedure, whereas the other still had good hepatic function and a patent stent 24 months after the procedure. We conclude that, in selected patients with acute and hyperacute BCS, placement of a TIPS by the direct transcaval approach is a rapid and effective emergency procedure, which can either be curative or function as a bridge for elective liver transplantation.

Abstract:

Abstract: Serum iron indices are believed to be elevated in patients with hepatitis C virus (HCV) infection in connection to the presence of hepatic inflammation, though this hypothesis has never been formally tested. We studied 69 consecutive, unselected anti HCV antibody positive patients, aged 14 to 70 years. Iron, transferrin saturation and ferritin were measured in fasting serum samples. Histologically detectable iron (HDI) as well as histologic grading and staging were estimated semiquantitatively in liver biopsy samples. The median values for serum iron, transferrin saturation and serum ferritin were 24 micromol/l (range, 8-61), 29 percent (range, 6-77) and 170 microg/l (range, 1-954), respectively. At univariate analysis, all three serum iron indices were positively correlated with grading and staging scores, as well as with HDI in the liver; only serum iron was positively correlated with transaminases. At multivariate analysis, independent associations were found between serum iron and the grading score; ferritin and sinusoidal and portal HDI; transferrin saturation and total hepatic HDI. In conclusion, in hepatitis C, serum iron reflects the degree of current hepatic inflammation and necrosis, whereas the extent of progressive deposition of iron in sites of fibrosis is best reflected by serum ferritin. Transferrin saturation is the best predictor of the status of hepatic iron deposits.

Abstract: Empyemas are usually of infectious origin. Noninfectious causes of empyema may be a considerable diagnostic challenge, as exemplified in the present case report. A 21-year-old male presented with high fever, sore throat and myalgias of 1 week duration. In the following days, bilateral pleural effusions developed, with cellular counts in the pleural fluid up to 117 x 10(9)/liter (98% neutrophils). Despite institution of empiric antibiotic therapy, spiking fever continued. All culture studies resulted in being negative. Following the report of a serum ferritin concentration of 6,975 microg/l, adult-onset Still's disease was diagnosed and successfully treated with anti-inflammatory drugs. This case adds adult-onset Still's disease to the list of noninfectious causes of empyema and underlies the value of measuring serum ferritin as a diagnostic tool.

Abstract: During the last two decades, owing to advances in immunosuppressive pharmacotherapy, liver transplantation has been increasingly accepted by the medical community as an effective treatment for patients with end-stage liver disease. Successful transplantation of the liver, however, requires frequent monitoring. Most of the serious infectious complications and allograft dysfunction occur during the early post-transplantation period (i.e., first six months). Blood levels of cyclosporine or tacrolimus, the two major calcineurin inhibitors currently in use, need to be frequently checked. Drug dosage is adjusted in order to maintain target serum concentrations and the patients free of side-effects. In the time, the risk of acute allograft rejection decreases considerably, whereas the proportion of patients with fibrosis or cirrhosis increases, particularly among hepatitis C virus carriers. Graft loss may occur, secondary to recurrent disease or chronic rejection. Patients with well-functioning grafts may still be affected by significant comorbidities, such as hypertension, diabetes, obesity, hyperlipidemia and osteoporosis, which appear to be related to long-term immunosuppression. The incidence of lymphoma, skin and colorectal cancers in liver transplantation recipients exceeds those found in the general population and requires early detection. The principles of the management of medical problems after liver transplantation are a careful clinical assessment of the patient and a judicious use of laboratory tests, radiological evaluation and liver biopsy.

Abstract: Recent years have witnessed tremendous advances in the fields of pathophysiology, diagnosis and management of hereditary hemochromatosis (HH) and other iron overload syndromes, the dreadful consequences of which are fully preventable by early diagnosis and treatment. Missense mutations in HFE, a newly discovered gene encoding for a major histocompatibility class-I like molecule, have been found to be strictly associated with most cases of HH. The mechanisms by which a dysfunctional HFE molecule determines increased absorption of iron in HH are on the way to be fully clarified, due to the availability of a knockout mouse model. Epidemiologic studies have shown that HH is one of the most common human hereditary disorders. The possibility to identify HFE heterozygotes by means of a simple genetic test have prompted studies on the association between HFE mutations and iron overload syndromes different from HH. In the era of the historic completion of the human genome projects, genetic testing for HH may soon qualify for being adopted in universal population screening policies. In the present paper, the recent advances in the fields of genetics and pathophysiology of HH and other iron overload syndromes will be summarized. Furthermore, its clinical features, pathology and treatment will be reviewed, and the emerging issues of cost-effective diagnosis and of possible population screening strategies will be succintly discussed.

Abstract: A series of bis(benzo[g]indoles) bridged by CX-(CH2)nN(Me)(CH2)n-CX (X = O, S, H2; n = 2,3) was synthesized as bifunctional antitumor agents and evaluated for cytotoxic activity against diverse human cancer cell lines by the National Cancer Institute. The parent compounds 2a,b exhibited a good level of activity and derivates 2c-g,i,k demonstrated significant inhibitory effects, all with IC50 values in the low micromolar range. The thioamide analogue 2j showed less potency. It is interesting to note that introduction of substituents on the benzene ring of the benzo[g]indole portion of 2a,b did not affect activity, with the only exception of the 7,8-dichloro derivative 2h which became less potent. One member of this series, 2i, was then tested in the hollow fiber cell assay to evaluate, in a preliminary fashion, its in vivo antineoplastic activity. Molecular modelling studies were performed on amide 2a and thioamide 2j to explain the loss of activity of 2j as to 2a. Finally, compound 2a behaved as a typical DNA intercalating agent, as judged from viscosity measurements with Poly(dA-dT)...poly(dA-dT).

Abstract: Histologically detectable iron (HDI) and HFE mutations were searched for in liver biopsy specimens from 58 Italian patients with chronic hepatitis C, and morphologic features were compared to examine their reciprocal relation and their contribution to disease progression. HDI was evident in 48% of cases with features of nonhemochromatosis iron overload. Total, sinusoidal, and portal HDI increased with stage; grade was related to all iron scores because of the contribution of portal inflammation and interface hepatitis. HFE mutations were seen in 47% of patients with chronic hepatitis C and in 28% of control subjects; they were related to stage and the His63Asp mutation to portal HDI. On multivariate analysis, grade but not stage or HFE mutations was associated with HDI in all sites. Interface hepatitis with its sequelae (sinusoidal capillarization and microshunting) represents a major factor in iron deposition in chronic hepatitis C and justifies the features of HDI. HFE mutations are not responsible for HDI deposition but could favor the progression of virus-induced damage independently from interference with iron metabolism.

Abstract: Because in experimental hepatocarcinogenesis apoptosis increases from normal to preneoplastic to carcinoma tissue, proapoptotic factors, such as activin-A, may represent useful markers for hepatocellular carcinoma (HCC). In this study, serum activin-A was measured in 99 cirrhotic patients, of whom 55 had HCC. Activin-A concentrations were higher in HCC patients (median, 2.33 ng/ml; range, 0.41-8.12) than in patients with nonmalignant cirrhosis (1.28 ng/ml; range, 0.35-6.25) (P < .05). All 12 patients with activin-A greater than 3 ng/ml and serum alpha-fetoprotein greater than 30 ng/ml had HCC, in comparison to 32 of 41 patients who had only one and to 11 of 46 patients who had both markers below these cutoffs (P < .0001). No correlation was found between activin-A and alpha-fetoprotein in the two groups, whereas in patients with HCC, activin-A was strictly correlated with serum aspartate aminotransferase (P < .001). Activin-A mRNA for inhibin betaA subunit was expressed both in tumor and nontumor liver tissues in a case of HCC superimposed on cirrhosis and was not expressed in a case of HCC without cirrhosis. In conclusion, cirrhotic patients with HCC have high serum activin-A, to the production of which both the cirrhotic liver and the liver tumor are likely to contribute.

Abstract: To verify whether endotoxin (LPS) might act as a priming cofactor of liver injury caused by obstructing the duodenum, four groups of male Wistar rats were studied. The first two groups comprised rats in which a closed duodenal loop (CDL) was created: CDL, n = 6 and CDL + LPS, n = 7; the next two groups comprised sham-operated animals: Sham n = 6 and Sham + LPS, n = 6. LPS, 400 microg/kg bodyweight, was administered i.p. to the rats belonging to groups CDL + LPS and Sham + LPS, 24 h before laparotomy. Twenty-four hours after laparotomy the animals were killed. Damage to bile ducts, extent and grading of coagulative and lytic spotty necrosis in liver tissue were evaluated morphologically. Coagulative necrosis was severe in four of seven rats of the group CDL + LPS, mild in six of six rats of group CDL, and absent in four of six and five of six rats of groups Sham and Sham + LPS (chi2 32.8, P = 0.0001). The animals of group CDL + LPS had more frequently diffuse lytic spotty necrosis than the animals in the three other groups (chi2 9.57 P<0.01). The results of our study indicate that, in rodents subjected to a closed duodenal loop, priming with LPS exacerbates liver injury due to cholate stasis.

Abstract: BACKGROUND: Aggressive hepatocellular carcinoma (HCC) complicates frequently hereditary hemochromatosis, a disease for which a strong candidate gene, named HFE, has recently been identified. Patients with HCC who are heterozygotes for mutations in the HFE gene might have distinct features and a distinct disease course. METHODS: The presence of the 2 mutations associated with hereditary hemochromatosis (C282Y and H63D) was sought by restriction fragment length polymorphism in 61 cirrhotic patients (46 males and 15 females) who underwent resection for HCC at a single institution. RESULTS: There were 4 heterozygotes for the C282Y mutation and 6 homozygotes + 20 heterozygotes for the H63D mutation, with no compound heterozygotes. Carriage of >/= 1 HFE mutated allele was significantly more frequent in HCC patients than in 149 control subjects (44% vs. 29%, P = 0.005). Among C282Y heterozygotes, 3 of 4 were female, compared with 12 of 57 wild-type carriers (P = 0.015); no gender distribution existed among patients carrying H63D alleles (6 of 26 vs. 9 of 35, P = 0.813). Survival was longer for patients with wild-type HFE than for those with mutated HFE (67% vs. 22% at 3 years; hazard ratio = 0.42, 95% confidence interval = 0.21-0.80) (P < 0.01). The negative effect on survival that resulted from possessing >/= 1 HFE mutated allele was maintained even after adjustment for gender, age, presence of tumor capsule, presence of comorbid factors, Okuda stage, Edmonson grading, and number of lesions (P = 0.01). CONCLUSIONS: Testing for HFE mutations may help identify HCC patients with dismal prognoses for whom surgical resection may not represent the best treatment option.

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Abstract: To verify whether a solid-phase enzyme immunoassay for serum IgM antibodies to the hepatitis C virus (HCV) core protein (IgM anti-HCVcore) might be proposed as a surrogate test for serum HCV RNA, we studied 86 anti-HCV antibody-positive intravenous drug users. Serum HCV RNA was demonstrated by RT-PCR with primers derived from the 5' non-coding and the core region. IgM anti-HCVcore antibodies were found in 62/86 (72%) subjects; circulating HCV RNA was detected by the 5' noncoding assay in 53/86 samples (62%) and by the core region assay in 35/86 samples (41%). IgM anti-HCVcore reactivity was associated with core HCV RNA seropositivity (p < 0.05) but not with 5' noncoding HCV RNA seropositivity (p = NS). Patients infected by HCV type 1a were more-often positive for IgM anti-HCVcore (p < 0.05) and for core HCV RNA (p = 0.005) than patients infected by other HCV genotypes. IgM anti-HCVcore reactivity was significantly more common in subjects positive for core HCV RNA (p < 0.005) and in subjects aged > 30 years (p < 0.05). In conclusion, the IgM anti-HCVcore assay frequently tests positive in intravenous drug users, particularly when infected by HCV 1a, but is not a surrogate of testing for serum HCV RNA.

Abstract: The hepatitis G virus (HGV) polyprotein was scanned by computer-aided prediction of antigenicity to search for B-cell epitopes. Four polypeptide sequences, V37D (amino acids [aa] 1685 to 1721), V36S (aa 2102 to 2137), P37R (aa 2156 to 2192), and C40P (aa 2280 to 2319), were identified and synthesized for use in immunoassays. Antibodies to these peptides were searched for in a panel of 239 serum samples, which were also tested for anti-E2 antibodies and HGV RNA. Furthermore, the course of HGV markers was studied prospectively in four patients who had been transfused with HGV RNA-positive blood. There was a negative association between immunoreactivity to V37D and P37R and presence of HGV RNA (2 of 53 and 1 of 53, respectively; P < 0.05); none of the subjects with dual antibody positivity was HGV RNA positive. Anti-V37D and anti-P37R antibodies compared favorably with anti-E2 antibodies as markers of recovery from HGV infection. These results might be useful for the development of new, more sensitive diagnostic assays.

Abstract: Circulating soluble TNF receptors, which act as TNF inhibitors, increase following the administration of IFN-alpha. Whether this is due to a direct IFN action or to indirect mechanisms involving the release of other cytokines is unclear. The kinetics of serum IFN, TNF, IL-6, IL-10, soluble TNF receptor type-I (sTNF-RI) and sTNF-RII were evaluated by enzyme immunoassays in 11 patients with chronic hepatitis C, following the first dose of recombinant human IFN-alpha2b (3 MU given subcutaneously). sTNF-RI concentrations paralleled IFN concentrations, rising from a mean +/- s.e.m. value of 3.5 +/- 0.3 ng/ml at baseline to a peak value of 5.5 +/- 0.5 ng/ml after 9 h, followed by a return to 4.1 +/- 0.4 ng/ml after 24 h (P = 0.0001). sTNF-RII concentrations, which were 7.6 +/- 0.5 ng/ml at baseline, fell initially to 6.9 +/- 0.5 ng/ml, to reach a peak at 24 h of 9.0 +/- 0.7 ng/ml (P < 0.0001). In contrast, the concentrations of TNF, IL-6 and IL-10 fluctuated with no significant changes at any time point. The area under the curve (AUC) of incremental IFN values had a strong positive correlation with the AUC of incremental sTNF-RI values (r = 0.75, P < 0.01). In patients with hepatitis C, IFN concentrations reached after a single dose of IFN were paralleled by correlationally increased concentrations of sTNF-RI, which are a much better marker of administered IFN than sTNF-RII, IL-6 or IL-10.

Abstract: OBJECTIVES: To ascertain the effects of eating on plasma antioxidant capacity in patients with liver disease. DESIGN AND METHODS: Eighteen cirrhotic patients were compared to 18 age and sex-matched controls. TRAP was measured by a fluorometric assay after a 12 h fast, and 60, 120, and 180 min after the study participants had taken a drink formula food. RESULTS: In the fasting state, TRAP was higher in patients with alcoholic cirrhosis (847+/-39 micromol/L, mean +/- SEM) in comparison to patients with viral cirrhosis (653+/-41) and to controls (758+/-26) (p<0.005). In cirrhotic patients, TRAP did not change in the post-absorptive state. In controls, TRAP decreased progressively, to a value of 719+/-21 (p<0.02), and the AUC of the delta-values of TRAP and of plasma insulin showed an inverse correlation (r = -0.52, p<0.05). CONCLUSIONS: In normal subjects, but not in cirrhotics, TRAP decreases in the post-absorptive state, probably in relationship with the activation of metabolic pathways.

Abstract: Serum hepatitis C virus (HCV) RNA, HCV genotypes and liver function tests were evaluated in a series of 189 unselected, consecutive anti-HCV positive intravenous drug users (IVDUs). Serum HCV RNA was detected in 106/189 patients. Abnormal liver function tests were associated with alcohol abuse, but not with the presence of serum HCV RNA. Among 109 patients retested after a mean follow-up of 21 months, 41 were intermittently serum HCV RNA positive. Patients persistently negative had more commonly a past history of acute hepatitis. A history of prostitution and/or a pattern of abuse involving >30 injections per week were related to infection by genotype 3a. In conclusion, serum HCV RNA is either transiently or persistently detectable in most anti-HCV positive IVDUs, but bears no association with abnormal liver biochemistry. Infection by HCV-3a is more common in IVDUs with more deviant life styles. In those cases where serum HCV RNA is found repeatedly negative, HCV infection may have been cleared, possibly through an episode of acute hepatitis.

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Abstract: OBJECTIVE: We report the results of a combined immunosuppressive schedule for the treatment of patients with idiopathic nephrotic syndrome, in which prednisone and cyclophosphamide were given in four phases: induction, maintenance, tapering and discontinuation. Patients and Outcome Measures: Sixty-seven patients with nephrotic syndrome, followed for an average of 7.1 +/- 4.5 years, were studied. Treatment outcomes were remission, progression, end-stage renal disease and death. RESULTS: At the end of the follow-up, 72% of patients maintained a complete remission. Stepwise logistic regression showed that the cumulative dose of cyclophosphamide was the only independent predictor of a favourable outcome, being associated both with complete remission of the nephrotic syndrome and with lack of progression to chronic renal failure. CONCLUSION: We suggest that the combination treatment may be indicated in all histological subgroups of nephrotic syndrome, provided that prednisone is given at high doses on alternate days, cyclophosphamide is given for 6 months, and relapses are treated with the same schedule. The adverse effects of treatment, however, require the adoption of a programme to prevent bone loss, infertility, bladder cancer and infections.

Abstract: BACKGROUND/AIMS: The pathogenic role of hepatitis G virus, the recently discovered blood-borne agent, is controversial. Our aim was to ascertain the prevalence of hepatitis G virus infection in hepatic and in extrahepatic malignancies. METHODS: We studied 166 Italian patients (112 male, 54 female, mean age 61.8+/-9.3, mean+/-SD, range 34-85). One hundred and eighteen had cirrhosis, which was complicated by hepatocellular carcinoma in 66 cases. Forty-eight patients had extra-hepatic malignancies. Circulating HGV RNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) of both the nonstructural-3 and 5'noncoding regions of the hepatitis G virus genome. Antibodies to the E2 protein of hepatitis G virus were detected by means of an enzyme-linked immunosorbent assay. RESULTS: Ongoing HGV infection was detected in 30/66 (46%) patients with hepatocellular carcinoma, 12/52 (23%) patients with cirrhosis, and 14/48 (29%) patients with extrahepatic malignancies (p<0.05). Evidence of exposure to hepatitis G virus (detection of either HGV RNA or anti-E2 antibodies) was found in 46% of patients with cirrhosis, 66% of patients with hepatocellular carcinoma, and 39% of patients with extrahepatic malignancies. Serum HGV RNA positivity was associated with a hematocrit value < or = 0.35 and with history of exposure to blood products (p<0.005). CONCLUSIONS: Ongoing hepatitis G virus infection is detected at a very high rate in patients with hepatocellular carcinoma, but is also fairly common in extrahepatic malignancies. Hepatitis G virus infection in these patients is likely to originate from exposure to blood products, and to persist because of deficient immune surveillance.

Abstract: To investigate the relationship among circulating cytokines, inflammation in the liver, and kind of response to interferon-alpha (IFN-alpha) in hepatitis C, we studied 63 consecutive patients (38 male, 25 female), treated with IFN for up to 1 year. Serum tumor necrosis factor-alpha (TNF-alpha) was measured at baseline and after 3 months of treatment. Transient (TR) or sustained response (SR) was observed in 29 and 16 patients, respectively. Baseline levels of TNF < or = 22 ng/L were observed in 69% of patients with SR, 55% of patients with TR, and 22% of nonresponders (p < 0.01). There was a significant correlation between baseline TNF levels and histologic grading score of hepatitis (p < 0.01). After 3 months of treatment, TNF levels >22 ng/L were observed in 63% of patients with SR, 69% of patients with TR, and 83% of nonresponders (p NS). Independent of the treatment outcome, TNF levels were lower at baseline and increased significantly with treatment in patients with lower histologic grading (p < 0.005). In conclusion, in patients with chronic hepatitis C, circulating TNF levels correlate with the degree of inflammation in the liver. Response to IFN is accompanied by an inflammatory response involving the release of TNF.

Abstract: The purpose of this work was to investigate the prevalence, associated features and effect on survival of portal vein thrombosis (PVT) complicating hepatocellular carcinoma (HCC). The autopsy data of a series of 72 consecutive patients (57 male, 15 female) with HCC were reviewed. PVT was found in 32/72 patients (44%), and tended to be more common in female patients (10/15 versus 22/57, P = 0.052). Stratifying the data according to gender, it appeared that the mean age of patients with PVT compared to those without was greater in woman (71.9 +/- 5.9 versus 63.2 +/- 6.9 years, P = 0.024) and younger in men (58.8 +/- 8.9 versus 66.0 +/- 9.9 years, P = 0.007). When PVT was present, it was more likely that a definite diagnosis of HCC had been obtained before autopsy (P = 0.0001) and that death had been caused by bleeding complications (P = 0.007). Median survival times were similar, irrespective of the presence of PVT. During the natural history of HCC, PVT occurs in a substantial proportion of patients. Hormonal factors may have a permissive role in thrombus formation or neoplastic vascular invasion. Although in the presence of PVT a diagnosis of HCC is rarely missed and bleeding complications are likely to occur, patient survival does not seem to be significantly affected.

Abstract: AIMS/BACKGROUND: Soluble ICAM-1 may act as an antagonist of the membrane bound form, which is essential for the adhesion of leucocytes to endothelial cells. The aim of this study was to investigate whether the presence of high concentrations of soluble ICAM-1 are related to the impairment of delayed-type hypersensitivity reactions. METHODS: The study population comprised 73 patients (53 men and 20 women) with chronic liver disease (19 with chronic hepatitis, 36 with cirrhosis and 18 with hepatocellular carcinoma), and 21 age-matched controls (11 men and 10 women). Serum soluble ICAM-1 was measured using an enzyme immunoassay. Skin tests for seven different antigens (tetanus, diphtheria, streptococcus group C, tuberculin, Candida, tricophyton, and proteus) were considered positive when diameters > or = 2 mm were recorded; the diameters of positive tests were added to calculate a cumulative score. RESULTS: Patients with chronic liver disease had fewer positive skin tests (median 2) and a lower cumulative score (median 7) than controls (median 3 and 12, respectively). Multivariate analysis suggested the existence of an independent association between alkaline phosphatase and anergy to skin tests and between soluble ICAM-1 concentrations and the cumulative score. CONCLUSIONS: The strong association observed between increased soluble ICAM-1 concentrations and impairment of delayed-type hypersensitivity skin tests suggests that soluble ICAM-1 may be implicated in the immune depression seen in patients with chronic liver disease.

Abstract: With the aim of morphologically characterizing chronic sialoadenitis in patients with hepatitis C virus (HCV) chronic liver disease, labial salivary gland biopsies from 22 chronic HCV liver disease and from 10 primary Sjögren's syndrome patients were compared. Only focus score (number of aggregates with more than 50 lymphocytes per 4 mm2 of glandular tissue) and grading of inflammation were able to discriminate significantly between the two patient groups. Duct ectasia, acinar depletion, presence of lymphoid aggregates with less than 50 lymphocytes and of lymphoid infiltration within intralobular salivary duct epithelium were evident in both disease groups and appeared to be non-specific, mostly age-related changes. In both patient groups plasma cell and lymphocyte typing showed similar features: T-lymphocytes represented most of the lymphoid population, B lymphocytes were few unless follicles were present. Higher focus score values were associated with a plasma cell switch from an IgA to an IgM and/or IgG predominance. A greater morphological similarity was seen between biopsies of the primary Sjögren's syndrome group and those of female rather than male chronic HCV liver disease patients. Salivary gland tissue in HCV patients responds to damage in a fashion similar to primary Sjögren's syndrome, the only difference being a lesser degree of inflammation.

Abstract: C-terminal peptide of procollagen I, N-terminal peptide of procollagen III, collagen IV and serum prolyl hydroxylase were measured in 100 patients with cirrhosis and 71 patients with noncirrhotic chronic liver disease. Patients with cirrhosis had significantly higher mean values of prolyl hydroxylase, collagen IV, N-terminal peptide of procollagen III and C-terminal peptide of procollagen I as compared to noncirrhotic patients. This difference was maintained for collagen products even after stratification for alcohol intake, although all markers of fibrosis were higher in alcoholics. Stepwise logistic regression analysis showed that collagen IV, and N-terminal peptide of procollagen III were independently associated with cirrhosis. Receiver-operating characteristic (ROC) curves showed that collagen IV and N-terminal peptide of procollagen III perform more efficiently than C-terminal peptide of procollagen I and prolyl hydroxylase in identifying cirrhosis.

Abstract: OBJECTIVES: To verify the diagnostic usefulness of soluble CD44 (sCD44) in liver diseases. METHODS: We studied 142 subjects (90 male, 52 female): 14 had acute hepatitis (AH); 45, noncirrhotic chronic liver disease (CLD); 34, cirrhosis; 35 had extrahepatic diseases (EHD); and 14 were healthy controls. sCD44, soluble intercellular adhesion molecule-1 (slCAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured immunoenzymatically. RESULTS: Patients with AH or cirrhosis had higher sCD44 in comparison to CLD, EHD, and controls (p < 0.01). On univariate analysis, sCD44 was associated with sVCAM-1, sICAM-1, bilirubin, cholinesterase, aspartate aminotransferase, and alkaline phosphatase (p < 0.001). By stepwise discriminant analysis, a set of variables, including sCD44 and sVCAM-1, were entered into a model that allocated correctly 79% of observations (p < 0.0001). However, when adhesion molecules were excluded, the model could still allocate correctly 72% of observations. CONCLUSION: Although sCD44 concentration increases during severe acute or chronic liver disease, its measurement adds little to the clinical information provided by traditional liver biochemistry.

Abstract: To verify its value with regard to the outcome of therapy in chronic hepatitis C, serum interferon-alpha (IFN) was measured by ELISA in 70 patients (43 male, 27 female) with chronic hepatitis C, treated with IFN 9 MU/week subcutaneously for up to one year. Serum IFN was detectable in 49/70 patients, 16 of whom had IFN values >125 pg/ml. Only 1/22 patients who maintained a sustained response six months after the end of treatment had pretreatment serum IFN > 125 pg/ml, in comparison to 15/48 patients who did not respond or who relapsed (chi2 6.1, P < 0.02). At multivariate analysis the predictive value of serum IFN was independent of age, sex, presence of cirrhosis, infection by genotype 1b (improvement chi2 7.1, P < 0.01). In patients with chronic hepatitis C, measurement of serum IFN at baseline might be useful for the selection of patients with higher probability of long-term response.

Abstract: OBJECTIVE: To explore the hypothesis that a relationship exists between free radical activity and abnormalities in hemostasis in NIDDM. RESEARCH DESIGN AND METHODS: The use of the total radical-trapping antioxidant parameter (TRAP) has very recently been proposed to explore the antioxidant property of a plasma and their mutual cooperation. In the present study, TRAP, vitamin E, vitamin C, vitamin A, uric acid, protein-bound SH (thiol) groups, fibrinogen, prothrombin fragments F1 + 2, and D-dimer have been evaluated in 46 NIDDM patients and 47 healthy matched control subjects. RESULTS: In NIDDM patients, TRAP, vitamin A, SH groups, and uric acid were significantly reduced, whereas the level of vitamin E was significantly increased. Vitamin C was similar in the two groups. Fibrinogen, prothrombin fragment 1 + 2, and D-dimer were increased in diabetic patients. TRAP, but no single other antioxidant, had a strong inverse association with fibrinogen, prothrombin fragment 1 + 2, and D-dimer. CONCLUSIONS: These findings are consistent with the hypothesis that oxidative stress may condition coagulation activation in diabetics. However, the data suggest that it is the total antioxidant capacity rather than any single plasma antioxidant that is the most relevant parameter.

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Abstract: In order to investigate whether a difference might exist in blood cholesterol and its subtractions between patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, serum cholesterol, HDL-cholesterol, triglycerides and common liver function tests were measured in 138 patients (92 male, 46 female) with biopsy-proven chronic viral hepatitis without cirrhosis. Twenty-four had hepatitis B and 114 hepatitis C. Mean serum cholesterol was lower in HCV-infected in comparison to HBV-infected patients (175 +/- 36 mg/dl vs. 189 +/- 28 mg/dl, p < 0.05). On multivariate analysis, etiology of hepatitis appeared to be associated with the value of serum cholesterol, independently of age, sex and liver synthetic function (improvement of chi-square 4.40, p < 0.05). In patients with HBV infection, circulating tumor necrosis factor-alpha demonstrated a correlation with serum triglycerides (p = 0.618) and an inverse correlation with serum HDL-cholesterol (p = -0.456); in the group of patients with HCV infection, interleukin-6 correlated with triglycerides (p = 0.370) and HDL-cholesterol (p = -0.355). Thus, differences in the mechanisms of liver damage and of viral clearance in hepatitis C in comparison to hepatitis B, reflected in these patients by the levels of circulating cytokines, may be mirrored by differences in their blood lipid composition.

Abstract: To evaluate serum alpha-1-antitrypsin (A1AT) as a prognostic factor in hepatocellular carcinoma, we studied 75 consecutive patients (60 male, 15 female, mean age +/- SD 63.0 +/- 9.3 years) in whom hepatocellular carcinoma developed with pre-existing cirrhosis. Median survival time was 245 days (range 4-1568+). 30 patients had serum A1AT concentration of < or = 2.20 g/l (Group A) while 45 (Group B) had alpha-1-antitrypsin > 2.20 g/l. Median survival was 518 days in Group A and 81 days in Group B (Mantel-Cox 20.95, P < 0.0001; hazard ratio 0.26, 95% confidence limits 0.15-0.46). By stepwise survival analysis, alpha-1-antitrypsin together with bilirubin, tumour size and blood urea nitrogen were chosen among 17 variables as the only independent predictors of survival. We conclude that measurement of serum A1AT concentration might be useful as an inexpensive, widely available prognostic marker of hepatocellular carcinoma.

Abstract: Recently, endotoxaemia has been reported as a prognostic marker in acute pancreatitis. However, the role of endotoxin in inducing or aggravating acute pancreatitis is not fully understood. We administered endotoxin 400 micrograms/kg i.p. to rats 24 h before performing either a closed duodenal loop (group B) or a sham operation (group D). Pancreatic damage and overall survival were compared with the results obtained in rats not exposed to endotoxin undergoing either closed duodenal loop (group A) or sham treatment (group C). In a first set of experiments, 24 h after laparotomy blood samples were collected and the animals were sacrificed; survival up to 8 days was estimated in a second set of experiments. Group B had higher lipase concentrations and more severe tissue damage than group C (P < 0.05). A larger number of abscesses was observed in both group B and group D as compared to group C (P < 0.05). Survival was significantly shorter in group B (P < 0.0001). We conclude that priming with endotoxin worsens the extent of pancreatic damage induced by the closed duodenal loop procedure in the rat, possibly favouring selective homing of neutrophils to the site of inflammation, in similarity to what happens in the Shwartzman phenomenon.

Abstract: To compare the diagnostic usefulness as markers of hepatocellular carcinoma (HCC) of alpha1-antitrypsin, C-reactive protein, and alpha1-acid glycoprotein (all determined by nephelometric methods), we studied 132 subjects (74 male, 58 female): 43 had mild chronic liver disease, 32 cirrhosis, 24 HCC; 33 were controls. A total of 29.2% of the patients with HCC had alpha1-acid glycoprotein > 100 mg/dl, 75.0% had alpha1-antitrypsin > 220 mg/dl, 70.8% had C-reactive protein > 5 mg/L. In cirrhotics, frequencies were 3.1, 50.0 and 59.4%, respectively; in patients with mild chronic liver disease, 14.0, 11.6, and 32.6% (chi2 12.3, p < 0.01; chi2 47.3, p < 0.0001; chi2 38.0, p < 0.0001, respectively). alpha1-fetoprotein performed better than all acute-phase proteins. We conclude that, due to their low specificity and/or sensitivity, none of the three acute-phase reactants tested can be recommended for diagnostic use as biological markers of HCC in Western patients.

Abstract: It has been previously demonstrated that hyperglycaemia activates haemostasis; diabetes mellitus is considered a thrombosis-prone state. Acarbose, by inhibiting dietary carbohydrate absorption, reduces post-meal hyperglycaemia. In this study we evaluated the effect of post-meal hyperglycaemia on two markers of coagulation activation: prothrombin fragments 1 + 2 and D-dimer. Seventeen non-insulin-dependent diabetic patients maintained on diet therapy alone were randomly assigned to receive- with a cross-over study design-acarbose (100 mg orally) or placebo before a standard meal. Blood samples for measurement of plasma glucose, insulin, prothrombin fragments 1 + 2 and D-dimer were drawn at 0, 60, 120 and 240 min. After both placebo and acarbose, hyperglycaemia and hyperinsulinaemia which followed a standard meal were accompanied by a significant increase of plasma concentration of prothrombin fragments 1 + 2 and D-dimer in comparison to their baseline values. Acarbose administration significantly reduced the rise of glucose, insulin, prothrombin fragments 1 + 2 and D-dimer from 0 to 240 min in comparison to placebo. We conclude that post-meal hyperglycaemia, at the level reached by many diabetic patients on diet therapy alone, induces a coagulation activation. Acarbose, by decreasing post-meal hyperglycaemia, may be useful in reducing meal-induced activation of haemostasis in diabetic patients.

Abstract: Molecules governing cellular interactions have been suggested to be involved in the spurious elevation of alpha 1-fetoprotein (AFP) in non-neoplastic liver disease. To explore this controversial issue, we measured AFP, circulating intercellular adhesion molecule 1 (cICAM-1), and common liver function tests in 111 patients (71 male, 40 female). Eighty-four patients had non-neoplastic chronic liver disease and 27 had hepatocellular carcinoma. The concentration of cICAM-1 was determined immunoenzymatically. In patients with non-neoplastic chronic liver disease, univariate analysis demonstrated a significant correlation between AFP and cholinesterase (R = -0.397, P < 0.001), aspartate aminotransferase (R = 0.421, P < 0.001), bilirubin (R = 0.231, P < 0.05) and cICAM-1 (R = 0.430, P < 0.001). Multivariate analysis among these variables and AFP indicated cICAM-1 to be the strongest independent predictor of AFP. We conclude that cICAM-1 compares favourably with liver function tests in predicting non-specific AFP variations in non-neoplastic chronic liver disease, suggesting a link between targeting of the inflammatory damage to the hepatocyte and development of neoplasia.

Abstract: To assess the effectiveness of an intensive immunosuppressive regimen on the nephrotic syndrome due to mixed membranous and mesangial lesions, we studied 18 patients with nephrotic syndrome and miscellaneous histologic features characterized by mesangial proliferation and sclerosis, non-specific basement membrane changes such as thickening, fraying and scalloping, in the absence of extensive immune complex deposition by immunofluorescence. The patients were treated with an immunosuppressive regimen that combined prednisone and cyclophosphamide for at least 6 months with the following schedule: 1) induction with prednisone daily 250 to 750 mg i.v. for 3 to 8 days, plus cyclophosphamide 100 to 200 mg p.o. daily; 2) maintenance with prednisone 100 to 200 mg p.o. in alternate days for 30 to 75 days, and cyclophosphamide as before; 3) tapering, with prednisone in alternate day regimen, reduced on average by 25 mg every month, plus cyclophosphamide as before; 4) discontinuation of cyclophosphamide and slow withdrawal of prednisone. Treatment lasted on average 9 months, with an average cumulative dose of prednisone of 9.2 g and of cyclophosphamide of 26.7 g. At the end of treatment, 14 patients had a complete remission and 4 remained stable. On longer follow-up, one out of these 4 patients, who had renal failure before treatment, subsequently progressed to end-stage renal disease. Nine patients relapsed after an average remission of 6 years. Eight of them remitted completely on a repeat cycle. One patient refused the retreatment and progressed to end-stage renal disease within one year. After an average follow-up of 7.3 +/- 1.1 years, plasma creatinine for the whole group had fallen from 138 +/- 26 to 103 +/- 20 mumol/l and proteinuria from 6.7 +/- 0.7 to 0.4 +/- 0.2 g/d (p < 0.001). In conclusion, in patients with these forms of nephrotic syndrome this immunosuppressive regimen is highly effective in inducing remission, in preventing progression to end-stage renal disease and in treating relapses.

Abstract: Our aim was to ascertain the degree of variation of serum soluble vascular cell adhesion molecule-1 (VCAM-1) concentrations according to the nature and the severity of an underlying liver disease. One-hundred forty sera collected from 123 patients (83 male, 40 female) with acute hepatitis (n = 14), mild chronic liver disease (n = 52) or cirrhosis (n = 57) of different etiologies as well as from 17 healthy blood donors (8 male, 9 female) were studied. Soluble VCAM-1 concentration was measured immunoenzymatically. One-way analysis of variance revealed a significant variability of the mean values of soluble VCAM-1 among groups (F = 80.02, p < 0.0001). All groups of patients had higher soluble VCAM-1 than controls; moreover, patients with acute hepatitis and patients with cirrhosis had higher soluble VCAM-1 levels than patients with mild chronic liver disease (Bonferroni's test, p < 0.01). These results did not change after stratification of patients according to the etiology (viral or toxic) of liver disease (two-way analysis of variance: grouping factor diagnosis, F = 60.39, p < 0.0001; grouping factor etiology, F = 1.73, p NS). Cholinesterase, total bilirubin, circulating thrombocytes and blood area nitrogen were the independent predictors of the concentration of soluble VCAM-1. In conclusion, patients with liver disease have high serum soluble VCAM-1, which seems to reflect more the severity of impairment of liver function rather than the etiologic nature of the disease.

Abstract: BACKGROUND: The aim of our study was to determine whether immunosuppressive treatment is effective in preventing and reversing the evolution of Berger's disease toward chronic renal failure. METHODS: We studied 20 unselected, consecutive patients with biopsy-proven Berger's disease who met the criteria for disease progression. They had proteinuria, significant histologic changes, persistent hematuria, and red cell casts. The treatment consisted of prednisone in an alternate-day regimen and cyclophosphamide, either in a daily oral administration or in a monthly intravenous pulse injection, both given for a 6-month cycle. Five patients had chronic renal failure (as disclosed by plasma creatinine of 230 +/- 71 mumol/L), hypertension, and proteinuria (2.7 +/- 0.8 gm/day), whereas the remaining 15 patients had normal renal function (plasma creatinine, 97 +/- 18 mumol/L) and less severe proteinuria (1.9 +/- 1.1 gm/day). However, even these 15 patients had a significant number of risk factors heralding progression to chronic renal failure. RESULTS: Over an average follow-up of 8.7 +/- 3.7 years (range, 5 to 15 years), all patients but one had complete disease remission, including five patients with incipient chronic renal failure. Relapse occurred in two patients who were healed after a repeat treatment cycle. Over the entire follow-up period, no patient progressed to chronic renal failure and plasma creatinine concentration remained stable, even in subjects in whom it was high before treatment (257 +/- 79 versus 230 +/- 71 mumol/L; p > 0.05). CONCLUSION: The immunosuppressive treatment of patients with Berger's disease with high probability of progression appears to be effective in the prevention of end-stage renal disease.

Abstract: OBJECTIVE: To assess the results of a new immunosuppressive cycle, which had given favorable results in other immune-mediated glomerulonephritides, in the treatment of Henoch-Schönlein disease. METHODS: Eight patients (seven male and one female; age range, 13 to 61 years) with biopsy-proved Henoch-Schönlein were treated with the following protocol: (1) induction with 250 to 750 mg intravenous methylprednisolone every day for 3 to 7 days plus 100 to 200 mg oral cyclophosphamide every day, (2) maintenance with 100 to 200 mg oral prednisone on alternate days plus cyclophosphamide, as before, for 30 to 75 days; (3) tapering, with prednisone reduced on average by 25 mg every month while the cyclophosphamide dose remained the same, and (4) discontinuation, after at least 6 months, with abrupt interruption of cyclophosphamide and slow tapering of prednisone. The results were assessed in terms of remission, improvement, progression of disease, kidney failure, and death, unambiguously defined. The follow-up extended up to 12 years. RESULTS: Seven of eight patients had a complete remission that was maintained indefinitely thereafter. Plasma creatinine levels decreased on average from 211 +/- 81 to 92 +/- 27 mumol/L (p < 0.01) and urine protein excretion decreased from 1.9 +/- 0.8 to 0.3 +/- 0.1 gm/day (p < 0.01). One patient died of intestinal infarction caused by atherosclerotic mesenteric artery thrombosis. CONCLUSIONS: Our data suggest that an intensive immunosuppressive regimen that combines prednisone and cyclophosphamide at high doses can be effective in healing Henoch-Schönlein disease.

Abstract: We compared the results of genotyping hepatitis C virus (HCV) either by PCR amplification of the core region or by hybridization of PCR-amplified products of the 5' untranslated region (5'UTR assay). Serum samples from 144 Italian anti-HCV-positive patients (106 drug abusers and 38 patients with chronic viral liver disease but no history of drug abuse) were studied. The original core region assay described by Okamoto et al. (H. Y. Okamoto, Y. Sugiyama, S. Okada, K. Kurai, Y. Akahane, Y. Sugai, T. Tanaka, K. Sato, F. Tsuda, Y. Miyakawa, and M. Mayumi, J. Gen. Virol. 73:673-679, 1992) allowed genotyping of 75 of 144 samples. A modified version of Widell et al. (A. Widell, S. Shev, S. Månsson, Y.-Y. Zhang, U. Foberg, G. Norkrans, A. Frydén, O. Weiland, J. Kurkus, and E. Nordenfelt, J. Med. Virol. 44:272-279, 1994) allowed genotyping of 11 of 79 samples (50 of 79 samples remained unclassified by the method of Okamoto et al. In contrast, all 144 samples were genotyped by the 5'UTR assay. Forty-six of 75 (61 percent) of the samples genotyped by the method of Okamoto et al. and 10 of 11 (91 percent) of the samples genotyped by the method of Widell et al. had results consistent with those obtained by the 5'UTR assay. According to the results of direct sequencing, the method of Okamoto et al. erroneously classified seven samples as having mixed infections. In conclusion, HCV genotyping seems more reliable when it is performed by the 5'UTR assay than by either of two core region assays. The major advantage provided by the 5'UTR assay is a much lower proportion of negative or indeterminate results in younger patients with histories of drug abuse or infection by genotypes other than HCV type 1.

Abstract: To investigate the pathogenesis of fibrinolysis in liver disease, antithrombin III (AT III) activity, prothrombin fragment (F1 + 2) and d-dimer (D-DI) were measured in 50 patients with liver disease and in 17 healthy controls. Moreover, 4 patients with cirrhosis were randomly assigned to receive either an intravenous infusion of AT III (at two different dosages) or placebo, with a crossover design. Increased levels of D-DI were detected in patients with cirrhosis and hepatocellular carcinoma in comparison both with control subjects and with patients with acute hepatitis or mild chronic liver disease. An inverse correlation was observed between AT III and D-DI (r = -0.755, P < 0.001, simple linear regression), while no correlation was found between D-DI or AT III and F1 + 2. The correlation of the deficiency of AT III activity by infusion of human AT III did not result in any significant change (P0.10, analysis of variance for repeated measures) of the plasma concentration of either D-DI or F1 + 2, in comparison to placebo. Thus, advanced forms of chronic liver disease, but not acute hepatitis and mild forms of chronic liver disease, are associated with increased plasma concentrations of markers of fibrinolysis, which are inversely correlated with AT III activity. However, the correction of the deficient AT III activity does not affect the plasma concentration of either D-DI or F1 + 2, thence not supporting the hypothesis that enhanced fibrinolysis in advanced liver disease is the result of low-grade disseminated intravascular coagulation.

Abstract: An immunocompetent man developed malaise, fever, progressive weight loss, eosinophilia, and transient pulmonary infiltrates that responded to steroid treatment but recurred after its discontinuation. Examinations of feces, bronchoalveolar lavage fluid, and pulmonary tissue obtained during a 50-day period of hospitalization yielded negative results. When a new bronchoalveolar lavage sample and a new pulmonary biopsy specimen showed nematode larvae and adult worms, treatment with thiabendazole was started. However, therapy with this agent and then with mebendazole had no impact on the patient's downhill course, which ended in respiratory distress and death. Autopsy documented an overwhelming pulmonary infection with a metastrongylid nematode resembling a species of Angiostrongylus. Histologic study revealed features of necrotizing angiitis closely mimicking those of Wegener's granulomatosis. To our knowledge, this is the first reported instance of patent metastrongylid parasitism of the human pulmonary arteries with necrotizing angiitis caused by a reaction to the parasite and/or its metabolic products.

Abstract: Our aim was to investigate the existence of an association between B cell responsiveness to hepatitis C virus (HCV) core protein and progression of liver disease. In fact, the persistence of HCV infection is permitted by avoidance of viral clearance, despite chronic inflammation in the liver; this process ends with the development of hepatocellular carcinoma in many patients. On the basis of computerized prediction of antigenicity of the genomic sequence of HCV core protein, three 15-mer peptides (named Q15V, R15P, and G15V) were synthesized to be used as antigens in an enzyme immunoassay. Sera from 97 patients (65 males and 32 females) were tested: 43 patients had mild chronic liver disease (steatofibrosis, chronic persistent, or chronic active hepatitis) and 54 had cirrhosis, which was complicated by hepatocellular carcinoma (HCC) in 19. Seventy-six patients were positive to anti-HCV testing by second generation ELISA and 21 were negative. Rates of positivity for synthetic peptides in anti-HCV-positive versus anti-HCV negative patients were as follows: 53 of 76 and 0 of 21 for anti-Q15V; 41 of 76 and 0 of 21 for R15P; and 67 of 76 and 2 of 21 for G15V. Rates of positivity to anti-Q15V and anti-G15V were similar among diagnostic groups (Pearson's chi 2, 1.97, P > 0.10 and 0.45, P > 0.10), whereas anti-R15P antibodies were detected at a significantly lower rate in patients with HCC (2/13) in comparison to mild chronic liver disease (22/35) and cirrhosis (17/28) (Pearson's chi 2, 9.42, P < 0.01). We conclude that anti-R15P antibodies are uncommon in anti-HCV-positive patients with HCC. During the course of chronic HCV infection, anti-R15P testing might help to identify a subgroup at higher risk to develop HCC.

Abstract: It has been shown previously that erythropoietin expression in vitro by hepatoma cells increases in response to hypoxia. To verify whether hypoxia of the tumor might result in hepatic release of erythropoietin in vivo, serum erythropoietin concentrations were measured immunoenzymatically in 12 patients (5 women, 7 men) who underwent transarterial chemoembolization for hepatocellular carcinoma. Peripheral blood samples were collected at baseline, and after 6 hours and 1, 2, 3, and 7 days after the procedure. In a second set of experiments, performed in three male patients also undergoing chemoembolization for hepatocellular carcinoma, paired blood samples were collected after catheterization of the hepatic veins and of the right antecubital vein. None of the patients had erythrocytosis. In comparison with a baseline mean value +/- SEM of 100.6 +/- 12.6 micrograms/L, serum erythropoietin concentrations were the following; +6 hours, 55.4 +/- 18.0 (P < .001); +1 day, 102.4 +/- 24.7 (P = NS), +2 days, 183.0 +/- 31.1 (P < .05); +3 days, 155.0 +/- 26.0 (P < .05); +7 days, 153.3 +/- 27.4 (P < .05) (matched Student's t-test). The ratio of hepatic vein/antecubital vein serum erythropoietin concentrations increased from 0.85 at baseline to 1.30 at +2 days, paralleling the increase of aspartate transaminase (r = .914, P < .005). After chemoembolization, no correlation was found between serum erythropoietin and alpha-1-fetoprotein concentrations. The concentration of the latter, stable initially, decreased 7 days after the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: Our aim was to verify whether the presence of antibodies to HCV envelope protein might mark the occurrence of liver damage, as recently suggested in the literature. Sera from 104 patients (62 male, 42 female) were tested: 84 were positive and 20 were negative to a second generation enzyme immunoassay for anti-HCV antibodies; 51 patients had mild chronic liver disease (44 chronic hepatitis, seven steatosis), 43 had liver cirrhosis (superimposed by hepatocellular carcinoma in 18) and ten were asymptomatic anti-HCV positive subjects with normal liver function tests. Besides, all sera were tested by means of an enzyme immunoassay for the presence of serum antibodies to the synthetic peptide S24A (SIYPGHVSGH RMAWDMMMNW SPTA) derived from amino acids 307-330 of HCV polyprotein. Anti-S24A antibodies were detected in 40/84 sera positive and 1/20 negative at anti-HCV testing (Pearson chi 2 12.29; p = 0.005). Among anti-HCV positive sera, no significant difference existed in anti-S24A status with regard to clinical evidence of liver disease, ALT concentration or HCV RNA positivity. Thus, anti-S24A antibodies are detectable in approximately half of HCV-positive sera, but they do not seem to add significant clinical information to existing tests or to be useful as putative markers of viraemia.

Abstract: Diabetes is characterized by the existence of a thrombosis-prone condition, possibly related to hyperglycemia. However, the mechanism linking hyperglycemia to the activation of the coagulation cascade is still unclear. It has been recently suggested that diabetes is accompanied by increased oxidative stress. In this work, the possibility that oxidative stress may be involved in the hyperglycemia-induced coagulation activation has been evaluated. Prothrombin fragment 1 + 2 (F1 + 2), which represents a reliable marker of the amount of thrombin released in the circulation, has been chosen for studying thrombin formation in vivo. In nine type II diabetic patients and in seven healthy control subjects, matched for age and body mass index, three different experiments were performed: oral glucose tolerance test (OGTT), intravenous antioxidant glutathione (GSH) administration for 2 h, and OGTT plus intravenous GSH administration. Samples were drawn at -15 min and every 30 min from 0 to 180 min. During the OGTT, F1 + 2 significantly increased in both diabetic and healthy subjects. GSH administration during OGTT normalized this phenomenon. GSH administration alone significantly decreased F1 + 2 in diabetic patients, while no effect was observed in the normal subjects. These data suggest that hyperglycemia may induce thrombin activation, possibly inducing an oxidative stress, and that antioxidant GSH may counterbalance this effect.

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Abstract: Sialyl-Lewisa antigen (SLe(a)), the immune determinant of carbohydrate antigen 19-9 (CA 19-9), is the ligand of E-selectin. To verify the possibility of an association between nonspecific elevation of CA 19-9 and adhesion molecules, sera from 12 patients with acute hepatitis, 55 with non-cirrhotic chronic liver disease, 33 with cirrhosis and 25 with hepatocellular carcinoma, were tested for common liver function tests. Besides, CA 19-9 and soluble forms of E-selectin, VCAM-1 and ICAM-1 were measured immunoenzymatically. One-way analysis of variance demonstrated that mean CA 19-9 concentration differed among groups (F 15.27, P < 0.0001) with the highest values found in patients with acute hepatitis. By univariate analysis, the strongest correlation of CA 19-9 was with soluble ICAM-1, which by stepwise multiple regression analysis was the only independent predictor of elevated CA 19-9 (multiple R 0.560). The association between ICAM-1 and CA 19-9 might originate in the biliary cells where they might be simultaneously overexpressed during inflammatory processes.

Abstract: To assess whether the initial status of lipid metabolism in patients with chronic viral hepatitis might correlate with outcome of therapy, 52 patients (32 males and 20 female) with chronic hepatitis C were studied: 44 were treated with human recombinant interferon-alpha 2b (3 MU three times per week for up to 12 months), and 8 served as controls. At baseline, sera were tested for total and HDL cholesterol, HDL2, HDL3, apolipoprotein A-I, apolipoprotein B, interferon-alpha, tumor necrosis factor, and interleukin-6. Changes in blood lipids were evaluated after 3, 30, and 90 days of treatment. HDL cholesterol, apolipoprotein A-I, and HDL3 decreased by 9.4-11.4% within 4 weeks of starting interferon treatment, but this effect was sustained only in patients with a primary response to interferon. On multivariate analysis, a primary response to interferon correlated with higher apolipoprotein A-I and lower (< 2.23 pg/ml) interleukin-6 levels (p < 0.005 for both). In contrast, a sustained response was significantly more common in patients with low (< or = 13.3 pg/ml) serum interferon-alpha and lower interleukin-6 at baseline but did not correlate with any of the blood lipids. Thus, in chronic hepatitis C, interferon treatment induces specific changes in blood lipids. The concentration of apolipoprotein A-I at baseline is a strong predictor of primary response to treatment, and the likelihood of sustained response seems to be reflected by lower cytokine activation.

Abstract: To evaluate the results, the long-term prognosis and the rates of complication of an immunosuppressive regimen with corticosteroids and cyclophosphamide in the treatment of the nephritis of systemic lupus erythematosus, 21 patients with lupus glomerulonephritis were studied. Renal biopsies were performed in 17/21 of them and indicated diffuse proliferative (6 patients), diffuse mesangial (4) and membranous (7) glomerulonephritis. Treatment was structured in 4 phases: 1) induction with methylprednisolone 250 mg i.v. for 7-14 days, and cyclophosphamide 100-200 mg p.o., q.d., or 20 mg/kg i.v. every 28 days; 2) maintenance with prednisone p.o., 2 mg/kg q.o.d. for 45 days, and cyclophosphamide as before; 3) tapering, with reduction of prednisone by 15% each month for 4 months; 4) indefinite maintenance with prednisone slowly tapered to the least effective q.o.d. dose and cyclophosphamide discontinued after six months of treatment. This cycle was repeated in the event of a relapse. After a first immunosuppressive cycle, 20/21 patients achieved remission of glomerulonephritis. Plasma creatinine fell from 97 +/- 6 to 80 +/- 3 microMol/l (p < 0.01). Proteinuria fell from 2.1 +/- 0.4 to 0.2 +/- 0.4 g/d (p < 0.0001) and the nephrotic syndrome, present in 8 patients, disappeared. After an average of 20 +/- 7 months, 8 patients relapsed: all remitted again after a repeat cycle, but 1 later progressed to end-stage renal failure during pregnancy. After an average of 56 months 4 out of these 8 patients relapsed again: 1 progressed to end-stage renal disease following an abortion and 3 remitted completely after a third cycle. Thus, 18 out of 21 patients are presently in remission with an average dose of prednisone of 13.7 mg/day after an average follow-up of 52 +/- 38 months (range 2 to 156). Three patients are presently off treatment. In 16 patients with extended follow-up of 2 to 13 years, anti-nuclear antibodies, anti-DNA antibodies, albuminuria and cylindruria fell below post-cycle levels (p < 0.001 for all). We conclude that intensive immunosuppression with steroids and cyclophosphamide can achieve excellent long-term results in the treatment of systemic lupus with glomerulonephritis.

Abstract: Fibrinogen has recently emerged as a major risk factor for atherothrombosis. However, the pathophysiologic mechanism linking high fibrinogen concentration to cardiovascular disease is unclear. In this study 136 subjects (75 males, 61 females, age 51.7 +/- 14.4 years, mean +/- standard deviation, range 17-82) were tested for total and HDL-cholesterol, total triglycerides, apolipoprotein AI, apolipoprotein B, fibrinogen, prothrombin fragment and D-dimer. Moreover, 5 subjects who had hyperfibrinogenemia (range 450 to 950 mg/dl) for at least 6 months by repeated measurements, were treated with a short 7-day course of heparin 12,500 U/day subcutaneously. The effect of heparin on all the above mentioned parameters was observed at the end of treatment and after 7 days of wash-out. Simple regression analysis detected a positive correlation between fibrinogen and age, prothrombin fragment and D-dimer, and a negative correlation between fibrinogen and HDL-cholesterol and apolipoprotein AI. A direct correlation between age and both prothrombin fragment and D-dimer was also demonstrated. Multivariate analysis showed a persistent correlation between fibrinogen and prothrombin fragment, D-dimer and age, that was not influenced by sex, smoking habit and body mass index. In the 5 hyperfibrinogenemic subjects, heparin administration significantly reduced fibrinogen (625.4 +/- 211.1 vs 455.2 +/- 112.3 mg/dl, p < 0.03), prothrombin fragment (0.97 +/- 0.1 vs 0.63 +/- 0.2 nM, p < 0.002) and D-dimer (336 +/- 101.8 vs 275.2 +/- 78.5 ng/ml, p < 0.03). All these parameters returned to baseline after 7 days of wash-out (fibrinogen 632.5 +/- 198.2 mg/dl, prothrombin fragment 0.96 +/- 0.2 nM, D-dimer 325.8 +/- 98.65 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: We investigated whether, in Italian patients, C-reactive protein (CRP) determination could be considered a useful adjunct, complementary to alpha 1-fetoprotein, in the detection of liver cancer. CRP was determined by particle-enhanced nephelometry in 171 subjects (102 male, 69 female). Fifty-five patients had mild chronic liver disease (CLD), 45 cirrhosis (CIR), 38 hepatocellular carcinoma (HCC); 33 subjects were healthy controls. Patients with HCC and CIR had higher CRP levels (P < 0.05) than those found in patients with CLD and controls. CRP higher than 5 mg/l was found in 30/38 (78.9%) patients with HCC, 28/45 (62.2%) patients with CIR, 16/55 (29.1%) patients with CLD (chi 2 56.0, P < 0.0001). Sensitivity, specificity and diagnostic accuracy of CRP in diagnosing HCC with respect to CLD+CIR were: 78.9%, 56.0% and 34.9%. However, when considered only in the subgroup of patients with alpha 1-fetoprotein below or equalling 30 ng/ml, they were 50.0%, 54.3% and 4.3% respectively. In conclusion, CRP concentration is frequently elevated in patients with HCC, however, it does not seem to improve the ability of alpha 1-fetoprotein to discriminate HCC from CIR.

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Abstract: The treatment of membranoproliferative glomerulonephritis (MPGN) is considered by most authors as unrewarding, and the disease progresses to end-stage renal disease (ESRD). We studied the effectiveness of a new immunosuppressive (IS) regimen by analyzing the rates of remission, relapse and progression to ESRD in 19 patients with MPGN. The treatment consisted of 4 phases: (1) induction with intravenous boluses of methylprednisolone plus cyclophosphamide (CPM) orally; (2) maintenance with oral prednisone (PDN) in an alternate-day regimen and CPM in a daily oral dose; (3) tapering during which PDN alone was slowly decreased; (4) discontinuation when CPM was omitted and PDN slowly withdrawn according to the steroid withdrawal schedule. At the end of the treatment that lasted on average 10 +/- 1 months, 15 patients remitted, 3 improved and 1 progressed. There were 8 relapses in 6 patients: 4 in 3 patients were treated with repeat cycles and remitted completely. Four patients who had relapsed after 4, 8, 11 and 13 years of remission refused retreatment and progressed rapidly to ESRD. All patients treated and retreated after relapsing had remissions, while renal failure and disease progression occurred in 1 patient only. Plasma creatinine averaged, in the whole group, 165 +/- 26 before, 156 +/- 30 after treatment and 224 +/- 57 microM/l at the end of 7.4 +/- 0.8 years of follow-up. An intensive IS regimen combining steroids and alkylating agents in high doses and for a prolonged time is effective in inducing remission and halting progression to ESRD in patients with MPGN.

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Abstract: To investigate the possibility of correcting thrombocytopenia of chronic liver disease, 19 patients (6 male and 13 female) with long-term chronic liver disease and platelet count < or = 85,000/microliters were studied. Either a short-term course (7-20 days) of recombinant human erythropoietin, 4000 U daily SQ (12 patients) or placebo (7 patients) was administered. Treatment was interrupted if the platelets rose to > or = 100,000/microliters or if no significant increase was noted after 14 days. After treatment, platelets increased in the recombinant human erythropoietin group (from a baseline value of 70,000 +/- 11,184 to 101,250 +/- 37,625/microliters), while no difference was noted in the placebo group (70,714 +/- 9928 vs 70,000 +/- 10,231/microliters). The increase in the platelet count in the recombinant human erythropoietin group was significant, both compared to baseline values (paired Student's t-test, t = -3.80, p < 0.005) and to the results of treatment in the placebo group (unpaired Student's t-test, t = 2.71, p < 0.02). Eight out of 12 recombinant human erythropoietin-treated patients (66%) reached > or = 100,000/microliters platelets while four (33%) did not. In comparison to responders, non-responders had a significantly lower baseline platelet count (58,500 +/- 7937 vs 75,750 +/- 7498/microliters, t = -3.69, p = 0.004) and failed more frequently than responders to improve their haematocrit in response to recombinant human erythropoietin (Pearson chi 2 = 4.687, p = 0.03). When treatment was discontinued, the platelet count reverted to baseline in a few weeks. In conclusion, recombinant human erythropoietin treatment transiently corrected mild thrombocytopenia in patients with chronic liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: To clarify the link between cytotoxic damage to the hepatocyte and the development of fibrosis, we immunoenzymatically measured serum prolyl hydroxylase (hPH), type IV collagen (CL-IV) and circulating intercellular adhesion molecule-1 (clCAM-1). The population studied was comprised of 122 patients with liver disease (acute hepatitis; mild chronic liver disease; cirrhosis; hepatocellular carcinoma) and 33 patients with extrahepatic diseases. Similar patterns were observed for hPH, CL-IV, and clCAM-1, that were higher in patients with acute hepatitis and hepatocellular carcinoma than in those with mild chronic liver disease (Bonferroni's test for pairwise comparisons, p < 0.01). Liver function tests and markers of fibrosis showed a strict correlation, which disappeared when the linear effect of clCAM-1 was removed. The ability to predict serum hPH and CL-IV from clCAM-1 might suggest the existence of a causal relationship between fibrosis and targeting of cytotoxic damage.

Abstract: The authors measured immunoenzymatically circulating intercellular adhesion molecule-1 (cICAM-1) concentration in 135 patients with liver disease of either viral or toxic etiology: 13 had acute hepatitis; 58 had mild chronic liver disease; and 64 had cirrhosis (superimposed in 30 by hepatocellular carcinoma). Forty patients with extrahepatic diseases (19 with malignancies) and 28 healthy blood donors were tested as controls. One-way analysis of variance demonstrated a significant variability of cICAM-1 concentration among groups (F = 76.67, P < .0001), the highest value being recorded in acute hepatitis (Bonferroni's test for pairwise comparisons, P < .01). Total bilirubin showed a strong correlation with cICAM-1 (R = 0.766, P < .001). By stepwise multiple regression analysis the independent predictors of cICAM-1 concentration were chosen in the following order: total bilirubin; aspartate aminotransferase; cholinesterase; alpha-1-antitrypsin; and immunoglobulins. Thus, in addition to inflammation, cholestasis and decline of functioning hepatic mass may influence cICAM-1 concentration.

Abstract: BACKGROUND: Sjögren's syndrome (SS) is an autoimmune disease of presumed viral origin; sialoadenitis has been reported to occur in hepatitis C virus (HCV) infection. METHODS: Lip biopsy specimens were graded in 32 consecutive patients with either HCV-related chronic liver disease or SS. RESULTS: Seventeen of 22 HCV-positive patients had sialoadenitis, although generally mild (15 of 17, grades I-II). Severe inflammation (grades III-IV) was observed in 8 of 10 patients with SS (chi-square = 12.6; P < 0.0005). Moreover, HCV-positive patients with sialoadenitis differed from patients with SS in female sex prevalence (6 of 17 versus 10 of 10; chi-square = 10.9; P = 0.0001) and presence of serum antinuclear autoantibodies (0 of 17 versus 9 of 10; chi-square = 23.0; P < 0.0001). Five of 13 HCV-positive patients and 7 of 8 patients with SS were HLA-DR3-positive (chi-square = 4.9; P < 0.05). CONCLUSIONS: Sialoadenitis of HCV-related liver disease is common but differs from SS with regard to predisposing genetic factors, expression of autoimmune markers, and histopathologic severity.

Abstract: AIMS--To investigate variations in serum lipid peroxide activities in relation to various clinical entities of liver disease. METHODS--Serum lipid peroxides were measured fluorometrically in eight patients with acute hepatitis, six with liver steatofibrosis, five with chronic persistent hepatitis, 15 with chronic active hepatitis, 28 with liver cirrhosis, 22 with hepatocellular carcinoma; 19 patients with extrahepatic disease (six malignant, 13 benign) were used as controls. RESULTS--Higher serum lipid peroxide concentrations were found in patients with acute hepatitis (4.52 (SEM 0.56)) nmol/ml than in all other groups of patients (p < 0.01). No significant difference was found among the mean values detected in the groups of patients affected by chronic liver disease and extrahepatic diseases. A history of chronic alcohol consumption was not associated with higher lipid peroxide concentrations. A significant correlation (R2 = 0.4538, R = 0.6737, F = 7.617, p = 0.0000) was found between serum lipid peroxides and a set of indices of inflammation (ESR, total leucocyte count, C-reactive protein) and of hepatic function (aspartate aminotransferase (AST) or alkaline phosphatase (ALP) or bilirubin). Of these, bilirubin was the most significant indicator of inflammation. Analysis of covariance showed a significant difference in lipid peroxide values among groups, even when bilirubin was chosen as an independent variable. CONCLUSIONS--Raised serum lipid peroxide concentrations can be found during acute inflammatory liver disease. Acute change in liver function, reflected by high bilirubin concentrations, seems to be more important for intravascular liberation of lipid peroxides than existence of specific aetiological factors or of severe longstanding global liver damage.

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Abstract: We identified four epitopes in hepatitis C virus core protein by using the algorithm of Jameson and Wolf. G15V (amino acids [aa] 31 to 45) appears to be the immunodominant epitope, since it was able to detect antibodies to the core protein in all 40 patients and in 44 of 45 recombinant immunoblot assay-confirmed positive blood donors. This epitope is associated with a low frequency of false-positive results, as found with 522 negative blood donors. A strong reactivity was also observed with the Q15V epitope (aa 7 to 21), although this was associated with low specificity. Occasional reactivity to the R15P (aa 49 to 63) and P15R (aa 99 to 113) epitopes was observed. Q15V and G15V detected antibodies to core protein earlier than the other two epitopes.

Abstract: The red-cell mass is continuously adjusted to the optimal size for its function as an oxygen carrier by messages transmitted to the bone marrow from an oxygen sensor in the kidney. These messages are mediated by the hormone erythropoietin. Erythropoietin is a glycoprotein growth factor synthesized by cells adjacent to the proximal renal tubule in response to signals from a renal oxygen-sensing device, probably a heme protein (1). In the bone marrow, erythropoietin binds to and activates specific receptors on the erythroid progenitor cells (2). In the presence of this erythropoietin-receptor complex the progenitor cells continue their predestined development into mature erythrocytes. Erythropoietin was the first hemopoietic growth factor to be molecularly cloned in 1985 (3). Our understanding of the biology and physiology of erythropoietin has been considerably improved with the advent of recombinant human erythropoietin (rHuEpo). During the past 7 years, rHuEpo has undergone extensive testing in clinical trials. It has been approved for treatment of the anemia of chronic renal failure, both in progressive renal failure and endstage renal failure (ESRD). In these instances, the administration of rHuEpo has been used in effect as a substitutive therapy, since patients' erythropoietin levels are very low despite severe anemia, due to the failure of affected kidneys to produce adequate amounts of the hormone. However, the application of rHuEpo has now moved largely from the primitive indication of renal diseases, and the hormone is currently under study in a number of anemic states of different etiologies, even with relatively high serum erythropoietin levels. Among these, some of the best documented indications are the anemia associated with malignancies, either due to neoplastic bone marrow infiltration or to chemotherapy-related myelosuppression, the anemia of myelodysplastic syndromes and AIDS, the anemia of chronic inflammatory diseases, prematurity, and bone marrow transplantation (4). The purpose of this review is to provide a summary of our present knowledge regarding rHuEpo therapy for the anemia of renal failure. We provide some clues for the correct use of rHuEpo in the treatment of the anemia of chronic inflammatory diseases. In addition, we address a series of new issues in the attempt to better understand the relationship between erythropoietin and liver disease.

Abstract: alpha 1-Acid glycoprotein, an acute phase reactant synthesised by the liver, has been reported to be increased in neoplastic conditions and reduced in chronic liver disease. We measured serum alpha 1-acid glycoprotein by a nephelometric method in 186 subjects (112 males, 74 females): 55 had mild chronic liver disease (chronic hepatitis and steatofibrosis), 45 cirrhosis, 38 hepatocellular carcinoma, 15 extra-hepatic malignant disease; 33 healthy subjects were used as controls. Analysis of variance demonstrated a significant variability among groups (F = 17.08, P = 0.0000). Higher concentrations of alpha 1-acid glycoprotein were detected in malignant extra-hepatic disease than in all other groups (P < 0.01); concentrations of alpha 1-acid glycoprotein were higher in hepatocellular carcinoma than in cirrhosis (P < 0.01). Multiple regression analysis by groups (dependent variable = alpha 1-acid glycoprotein; group 1 = mild chronic liver disease + cirrhosis; group 2 = hepatocellular carcinoma) showed a significant correlation for both group 1 (r = 0.6264, F = 8.005, P = 0.0000) and group 2 (r = 0.8947, F = 13.643, P = 0.0000). The significant standardised regression coefficients were: cholinesterase, C-reactive protein, gamma-glutamyltransferase and iron (negative) for regression upon group 1; C-reactive protein, alpha 1-antiproteinase, gamma-glutamyltransferase, iron (negative) for regression upon group 2. A difference between the 2 regression equation coefficients was detected (F = 5.209, P = 0.0002).(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: We measured serum erythropoietin (EPO) immunoenzymatically in 245 subjects (151 male, 94 female) to investigate the pathophysiology of its liberation in patients with liver disease. Twelve patients had acute hepatitis, 60 mild chronic liver disease (CLD), 50 cirrhosis (CIR), 43 hepatocellular carcinoma (HCC), 16 malignant extrahepatic disease, 32 benign extrahepatic disease (BEN); 32 subjects served as healthy controls. Higher EPO levels were found in all groups of patients as compared with controls (Bonferroni's test, P < 0.01); CIR and HCC had higher values than CLD and BEN (P < 0.01). By multiple regression analysis, EPO correlated with haematocrit, cholinesterase and C-reactive protein (F = 18.63, P < 0.0001). Thus, circulating EPO increases in patients with liver disease, particularly in its more advanced forms. Besides anaemia, both impairment of liver function (possibly via decreased EPO metabolism) and inflammation seem to play contributory roles in elevating serum EPO.

Abstract: Phospholipase A2 (PLA2) modifications were investigated in patients with acute and chronic liver diseases, PLA2 variations were related to indices of liver function as well as to parameters of the acute phase response. Serum PLA2 activity modifications were fluorimetrically measured in 105 patients affected by acute and chronic liver diseases or extra-hepatic diseases. One-way ANOVA demonstrated a significant difference among groups (F = 4.53, P < 0.001); Bonferroni's test for pairwise comparisons showed that patients with hepatocellular carcinoma had higher mean values than subjects with benign extra-hepatic diseases (P < 0.01) and mild chronic liver disease (P < 0.05). Multiple regression analysis, performed choosing PLA2 as the dependent variable and blood urea nitrogen, C-reactive protein, alkaline phosphatase and alpha 1-fetoprotein as predictor variables was significant (multiple R = 0.7056, multiple R2 = 0.4978, F = 15.36, P = < 0.0001). The standardized regression coefficients found to be significant were those of C-reactive protein, blood urea nitrogen and alpha 1-fetoprotein. In conclusion, in patients with chronic liver disease, serum PLA2 activity increases parallel to disease severity and accompanies the expression of proteins of the acute phase response that, like PLA2 activity, increase in serum while liver synthesis declines.

Abstract: There is evidence that tumor necrosis factor (TNF) may be a proliferation and differentiation factor for B lymphocytes. We found that three of four lymphoblastoid cell lines (ADD, IM-9, W1) secreted TNF-beta and expressed TNF receptors, whereas one pre-B cell leukemia and six Burkitt's lymphoma cell lines had no detectable TNF secretion and, except for one Burkitt's cell line (LOU), very low expression of TNF receptors. When IM-9, W1 or LOU cells were cultured over seven days in the presence of either TNF-alpha or antiserum to TNF-beta there was no difference between their growth rate, endogenous TNF-beta secretion or immunoglobulin secretion compared to untreated cells. These findings indicate that TNF does not have a universal role as an autocrine growth factor in transformed B lymphocytes.

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