HCV genotype 3 and squamous cell carcinoma antigen (SCCA)-IgM are independently associated with histological features of NASH in HCV-infected patients.

Nonalcoholic steatohepatitis (NASH) enhances the risk of progressive liver disease. In chronic hepatitis C (CHC), liver steatosis is frequent, especially in genotype 3, but its clinical significance is debated. As squamous cell carcinoma antigen (SCCA)-IgM has been associated with advanced liver disease and risk of tumour development, we evaluated its occurrence in CHC and the possible relation with NASH at liver biopsy. Using a validated ELISA, serum SCCA-IgM was measured in 91 patients with CHC at the time of liver biopsy performed before antiviral treatment, at the end of treatment and 6 months thereafter, and in 93 HCV-negative patients with histological diagnosis of nonalcoholic fatty liver disease, as controls. SCCA-IgM was detected in 33% of CHC patients and in 4% of controls. This biomarker was found more elevated in CHC patients with histological NASH, and at multivariate analysis, SCCA-IgM and HCV genotype 3 were independently associated with NASH [OR (95% CI): 6.94 (1.21-40) and 27.02 (4.44-166.6)]. As predictors of NASH, HCV genotype 3 and SCCA-IgM had a specificity and a sensitivity of 97% and 44%, and of 95% and 27%, respectively. PPV and NPV were 80% and 86% for HCV genotype 3 vs 73% and 72% for SCCA-IgM. In patients with sustained virologic response to therapy, SCCA-IgM levels decreased significantly, while these remained unchanged in nonresponders. In conclusion, SCCA-IgM is detectable in one-third of patients with CHC and significantly correlates with histological NASH.

Who is more likely to respond to dual treatment with pegylated-interferon and ribavirin for chronic hepatitis C? A gender-oriented analysis.

We assessed, in real-life practice, viral, demographic, genetic and metabolic factors influencing the sustained virologic response (SVR), with a gender-oriented analysis, in patients with chronic hepatitis C virus (HCV) treated with pegylated interferon and ribavirin. Six hundred and seventy naïve patients were treated with dual therapy and evaluated by gender and HCV genotype. Associations between baseline variables and SVR were assessed by multivariate logistic regression analysis. Among 362 genotype 1 patients, SVR was achieved in 158 patients (44%), and SVR was independently associated with age less than 50 years (OR 2.12; 95% CI 1.09-4.30; P=0.039) and C/C genotype rs12979860 SNP (OR 2.83; 1.19-6.74; P=0.002) in 163 females, while absence of visceral obesity (OR 2.491; 1.131-5.487; P=0.023), HCV-RNA lower than 400,000 IU/mL (OR 2.66; 1.273-5.558; P=0.009) and C/C genotype rs12979860 SNP (OR 4.969; 2.401-10.283; P<0.001) were independently associated with SVR in 199 males. Combining favourable baseline variables, the probability of obtaining SVR ranged from 27.6% to 84.2% in females, and from 14.3% to 85.7% in males. The rate of SVR was 81.1% in 175 genotype 2 patients, and 69% in 100 genotype 3 patients. Rapid virologic response was the only valid predictor of SVR regardless of other features. In conclusions, in the setting of HCV genotype 1, chronic hepatitis, combining rapid virologic response and predictive factors, which are different for females and males, allows clinicians to single out a group of patients whose likelihood of SVR exceeds 80%. For these patients, triple therapy with first-generation protease inhibitors may be unwarranted.

Carriage of the EGF rs4444903 A>G functional polymorphism associates with disease progression in chronic HBV infection.

Because epidermal growth factor (EGF) up-regulation is characteristic of the cirrhotic liver, we hypothesised that the EGF rs4444903 A > G functional polymorphism might be associated with a worse disease course in patients with chronic HBV infection. To verify this hypothesis, 170 HBV-positive patients (125 males) with a median age of 52 years were studied. Sixty-two of these patients were followed longitudinally for a median time of 21 years. Genotyping for the EGF rs4444903 A > G polymorphism was performed by the polymerase chain reaction-based restriction fragment length polymorphism assay. In the cross-sectional study, the EGF rs4444903 A > G polymorphism genotypic frequencies significantly differed between transplant patients (A/A = 20·4%, A/G = 52·3%, G/G = 27·3%) and HBsAg+ carriers (active and inactive: A/A = 35·7%, A/G = 47·6%, G/G = 16·7%, P = 0·036 for the linear trend). In the longitudinal study, the EGF rs4444903 A > G polymorphism was found to be an independent predictor of cirrhosis development (O.R. 7·73, 95% C.I. 1·21-49·5, P = 0·007). Three groups of patients were identified: A/A female homozygotes (n = 9), A/A male homozygotes (n = 13) and carriers of the G allele of either gender (n = 40). Cirrhosis did not occur among A/A females (n = 0/9), seldom occurred among A/A males (n = 2/13) and reached the highest frequency among G/* patients (n = 13/40, P = 0·026). In conclusion, the EGF rs4444903 A > G polymorphism appears to be associated with an unfavourable disease course of chronic HBV infection and cirrhosis development. This effect might be modulated, at least in part, by the gender of the patient.

Accuracy of VirtualTouch Acoustic Radiation Force Impulse (ARFI) imaging for the diagnosis of cirrhosis during liver ultrasonography.

PURPOSE: VirtualTouch is a new technique recently proposed to evaluate liver stiffness during B-mode ultrasonography. The goal of the present study was to analyze the diagnostic accuracy of VirtualTouch in the diagnosis of cirrhosis and its correlation with transient elastography (Fibroscan). MATERIALS AND METHODS: A total of 133 patients with chronic liver disease were enrolled. 90 of 133 underwent VirtualTouch and transient elastography and 70 patients assessed with VirtualTouch were submitted to liver biopsy. Stiffness was assessed by both techniques in the right liver lobe. The diagnostic accuracy for cirrhosis was first assessed in the 90 patients submitted to transient elastography with > 13 kPa (47 % of patients) as diagnostic for cirrhosis values. The best cut-off for cirrhosis with VirtualTouch was then tested in the 70 patients with biopsy (cirrhosis in 38 % of patients). 41 patients were assessed by VirtualTouch by two different operators. RESULTS: The VirtualTouch values in controls, chronic hepatitis and cirrhosis were respectively 113, 147 and 255 cm/sec. The AUROC of liver VirtualTouch for the diagnosis of cirrhosis (reference Fibroscan) was 0.941 with 175 cm/sec as the best cut-off (sensitivity 93.0 %; specificity 85.1 %). VirtualTouch confirmed good performance also in patients with bioptic diagnosis of cirrhosis (AUROC 0.908, sensitivity 81.5 %, specificity 88.4 %,). The correlation of VirtualTouch with transient elastography was strict (r = 0.891) and the correlation in VirtualTouch measurements between two operators was also good (r = 0.874). CONCLUSION: VirtualTouch is able to identify the presence of cirrhosis with good accuracy, shows good interobserver reproducibility and the correlation of its values with those obtained by transient elastography with Fibroscan is good.

Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years.

OBJECTIVE: To assess risk factors for liver-related death, we re-evaluated, after a median follow-up of 25 years, a cohort of 70 Caucasian patients with hepatitis B e antigen (HBeAg) positive chronic hepatitis (CH) at presentation. METHODS: Follow-up studies included clinical and ultrasound examinations, biochemical and virological tests, and cause of death. RESULTS: Sixty-one (87%) patients underwent spontaneous HBeAg seroconversion. During a median period of 22.8 years after HBeAg seroclearance, 40 (66%) patients became inactive carriers, whereas the remaining 21 (34%) showed alanine aminotransferase elevation: one (1%) had HBeAg reversion, nine (15%) detectable serum HBV DNA but were negative for HBeAg, eight (13%) concurrent virus(es) infection and three (5%) concurrent non-alcoholic fatty liver disease. Liver-related death occurred in 11 (15.7%) patients, caused by hepatocellular carcinoma in five and liver failure in six. The 25-year survival probability was 40% in patients persistently HBeAg positive, 50% in patients with HBeAg negative CH or HBeAg reversion and 95% in inactive carriers. Older age, male sex, cirrhosis at entry and absence of sustained remission predicted liver-related death independently. The adjusted hazard ratios (95% CI) for liver related death were 33 (3.01-363) for persistently HBeAg positive patients and 38.73 (4.65-322) for those with HBeAg negative CH or HBeAg reversion relative to inactive carriers. CONCLUSION: Most patients with HBeAg seroconversion became inactive carriers with very good prognosis. The risk of liver-related mortality in Caucasian adults with CH is strongly related with sustained disease activity and ongoing high level of HBV replication independently of HBeAg status.

Southern Europe as an example of interaction between various environmental factors: a systematic review of the epidemiologic evidence.

Hepatitis B virus (HBV), hepatitis C virus (HCV) and alcohol consumption are major causes of hepatocellular carcinoma (HCC) worldwide. We performed a systematic review of epidemiologic studies carried out on HCC aetiology in Southern Europe, an area with an intermediate-high prevalence of these agents as well as of putative risk factors such as tobacco smoking, diabetes and obesity. To retrieve the articles, we performed a Medline search for titles and abstracts of articles. After the Medline search, we reviewed the papers and reference lists to identify additional articles. A synergism between HCV infection and HBV infection, overt (hepatitis B virus antigen (HbsAg) positivity) or occult (HBsAg negativity with presence of HBV DNA in liver or serum), is suggested by the results of some studies. The pattern of the risk for HCC due to alcohol intake shows a continuous dose-effect curve without a definite threshold, although most studies found that HCC risk increased only for alcohol consumption above 40-60 g of ethanol per day. Some evidence supports a positive interaction of alcohol intake probably with HCV infection and possibly with HBV infection. A few studies found that coffee has a protective effect on HCC risk due to various risk factors. Some data also support a role of tobacco smoking, diabetes and obesity as single agents or preferably co-factors in causing HCC. In countries with a relatively high alcohol consumption and intermediate levels of HCV and HBV infections (1-3% of population infected by each virus), such as Mediterranean countries, the three main risk factors together account for about 85% of the total HCC cases, leaving little space to other known risk factors, such as haemochromatosis, and to new, still unrecognised, factors as independent causes of HCC.

HCV genotype 1 subtypes (1a and 1b): similarities and differences in clinical features and therapeutic outcome.

AIM: To evaluate similarities and differences in HCV-1 subtypes 1a and 1b in the presenting clinical features and the response to peg-interferon and ribavirin (Peg/RIBA). PATIENTS AND METHODS: A total of 1,233 naïve patients with HCV genotype-1 infection, 159 (13%) with subtype 1a and 1,074 (87%) with subtype 1b were treated with Peg-IFN/RIBA at 12 Italian centers. Covariates included in the logistic model were age, gender, BMI, serum alanine aminotransferase, serum gamma-glutamiltranspeptidase (γGT), platelets counts, liver fibrosis, the occurrence of type 2 diabetes, baseline viremia, and IL28B genotype. RESULTS: At multivariate analysis, baseline characteristics differentiating patients with HCV-1a versus HCV-1b were young age, male gender, no F4 fibrosis, and no diabetes. SVR was achieved by 37% of patients with subtype 1b and 45% of those with subtype 1a, a nonsignificant difference of 8% (p = 0.069). In patients with subtype 1a, predictors of SVR were IL28B CC (OR 5.78, CI 1.98-16.83), RVR (OR 4.18, CI 1.66-10.55), female gender (OR 2.83, CI 1.83-6.78), and HCVRNA (OR 0.55, CI 0.32-0.96). In patients with subtype 1b, the ranking of predictors was levels RVR (OR 6.49, CI 4.32-9.73), IL28B CC (OR 3.32, CI 2.15-4.58), γGT (OR 1.59, CI 0.14-2.22), HCVRNA (OR 0.61, CI 0.47-0.79), and age (OR 0.01, CI 0.02-0.42). CONCLUSION: In Italy HCV-1 subtype 1a prevails in young male patients with less advanced liver damage, findings that imply a more recent spreading of the infection with this viral strain. The two HCV-1 subtypes appear equally responsive to Peg-IFN/RIBA, with IL28B genotyping and monitoring of RVR mostly influencing the therapeutic response.

Interferon therapy for the anti-HBe positive form of chronic hepatitis B.

Two distinct serologic types of chronic hepatitis B have been identified, namely the "classical" HBeAg positive form and the "atypical" HBeAg negative, anti-HBe positive variant which is due to infection by a mutant HBV having a pre-core stop codon that makes the virus unable to produce HBeAg. The anti-HBe positive form is currently the prevalent type of chronic hepatitis B in the Mediterranean area, being associated with a more severe clinical course compared to HBeAg positive cases. The response to interferon therapy in patients with anti-HBe positive chronic hepatitis B has been recently investigated in control trials. These studies have shown that normalization of ALT with efficient suppression of virus activity can be achieved in 50-80% of patients while treated with interferon alpha indicating that also the pre-core mutant of HBV is sensitive to the antiviral effect of interferon. However, reactivation of hepatitis occurs in a variable percentage of initial responders when interferon is stopped. The probability of reactivation increases when the disease is of long duration, when cirrhosis is present and particularly if the pre-core mutant of HBV has become the predominant type of circulating virus, indicating that this HBV variant is more resistant to immunoclearance compared to wild type HBV.

Induction of autoantibodies during alpha interferon treatment in chronic hepatitis B.

Thirty-two patients with chronic hepatitis B treated with alpha interferon were tested for 12 different antibodies. Only a minority (18%) of cases developed antinuclear antibodies and none developed clinical signs of autoimmune disease. These data suggest that, at the dose regimen used, interferon therapy of chronic hepatitis B is not associated with triggering of autoimmunity.

Clinical evolution of HCV-related chronic hepatitis.

Evolution of HCV positive chronic hepatitis to cirrhosis has been reported to occur in about 30% of patients after five years of follow-up. In contrast, evolution of cirrhosis to decompensation and liver failure is slow, with a survival rate at 5 and 10 years of 91% and 79%, respectively. These findings support the hypothesis that histologic cirrhosis and clinical cirrhosis are different facets of the same disease, the latter developing after a long period of time and being related not only to liver disease per se, but also to other factors only partially identified. During this long-term evolution, extrahepatic manifestations may occur due to the formation of antigen-antibody immunocomplexes, which may eventually lead to death due to renal or cardiac complications.

Anti-hepatitis A virus seroprevalence and seroconversion in a cohort of patients with chronic viral hepatitis.

BACKGROUND: Patients with chronic hepatitis C infected by hepatitis A virus have a substantial risk of fulminant hepatitis or death, while the course of hepatitis A virus is uncomplicated in most subjects with chronic hepatitis B. AIM: To evaluate the prevalence of anti-hepatitis A virus antibodies and the incidence of hepatitis A virus seroconversion in a nationwide sample of 530 patients with chronic hepatitis B and/or hepatitis C infection initially susceptible to this infection after a follow-up of some years. RESULTS: The overall anti-hepatitis A virus prevalence was 85.7%, with no difference between males and females. By the age of 50 years, almost all patients were found to have been exposed to hepatitis A virus. After a mean follow-up period of 76 months the overall anti-hepatitis A virus seroconversion rate in the 76 initially susceptible individuals was 1.2 per 100 person/years. However, it was 0.3 per 100 person/years in those hepatitis B surface antigen positive but 3.36 per 100 person/years in those anti-hepatitis C virus positive. None of the seroconverters was affected by a clinically evident disease or showed deterioration of underlying chronic liver disease. CONCLUSIONS: The present study shows that Italian patients >50 years of age with chronic liver disease have already been exposed to hepatitis A virus suggesting that anti-hepatitis A virus screening is not advisable in these subjects.

Progression of hepatitis B and C to hepatocellular carcinoma in Western countries.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major causes of chronic liver disease and hepatocellular carcinoma (HCC) worldwide. In Western countries most HCC associated with HBV or HCV infection occurs in the cirrhotic liver. In a longitudinal studies of series of a Caucasian patients with compensated cirrhosis the incidence of HCC was approximately 2 and 2.5 per 100 person-years for HBV-related and HCV-related cirrhosis, respectively. The host factors of age, age at infection and male sex as well as parameters reflecting the severity of liver disease, such as bilirubin and platelets, appear to be significant predictors of liver cancer in patients with cirrhosis. It is still controversial whether HCV genotype 1b has a specific oncogenic potential. Studies from Europe have shown a low risk for HCC in patients with compensated cirrhosis type B who achieve a sustained virological and disease remission. Overall these data strengthen the epidemiological evidence of the association among HBV infection, cirrhosis and HCC in the West, indicating a similar risk for liver cancer in Caucasian patients with cirrhosis type B or C and suggest that tumors occur mainly in patients with long-standing disease. Additional factors that may promote liver cancer include concurrent HBV and HCV infection (approximately 5 fold-increase in risk) or concomitant heavy alcohol intake (synergism).

Effect of exogenous gastrointestinal peptides containing the C-terminal tetrapeptide of gastrin on calcium, calcitonin and parathormone serum levels in man.

Gastrointestinal hormones containing the C-terminal tetrapeptide of gastrin are involved in calcium homeostasis. The aim of this study was to investigate: 1) the effect of a standard meal (schedule a) and of a duodenal infusion of 5% aminoacid solution (schedule b) on calcium, CT and PTH serum levels in man; 2) the behaviour of these parameters during I.V. infusions of pentagastrin (mcg 1.5/Kg-hour), sincalide (mcg 0.04/Kg-hour) and caerulein (ng 75/Kg-hour) (schedule c). In order to avoid any possible interference by endogenous secretin release, schedule c was performed in 5 patients previously submitted to total gastrectomy. Schedule a and b were studied in 5 healthy volunteers. After a standard meal a slight increase of CT and PTH was measured. Duodenal infusion of aminoacid was followed by hypocalcaemia and slight but constant rise of CT levels, without significant variations of circulating PTH. Pentagastrin, sincalide and caerulein induced a slight but significant hypocalcaemia and a rise of serum CT levels, together with a significant increase of serum PTH. These findings suggest that peptides containing the C-terminal tetrapeptide of gastrin directly affect calcium homeostasis in the absence of secretin release.

[Relationships between clinico-therapeutic parameters and immunological status in patients with lung cancer]. / Rapporti tra parametri clinico-terapeutici e stato immunitario nel paziente portatore di cancro del polmone. Analisi di 150 casi.

150 patients with lung cancer have been studied from the immunological point of view: the two years that elapsed between the study and processing of the data permitted an evaluation of the prognosis in terms of immunology also. This study has been carried out in vivo by means of skin tests (BCG, PPD, Candida, Varidase, CCB, Mumps, BNCB) and in vitro with lymphocyte blastization in the presence of PHA and dependent antibody cytotoxicity. Serum factors which can interfere with lymphocyte cytotoxicity have also been studied. Peri- and intra-tumour lymphocyte infiltration and the lymph node activation stage have been analyzed in patients who underwent surgery. A real depression of the cell mediated immunity observed in the negative response to skin tests has been found. The study of in vitro parameters showed a deficient blast response in 86% of the cases examined, decreased cytotoxicity in 62% and the presence of inhibiting serum factors in 53%. No correlation was observed between positivity to skin tests, normal response to PHA, normal concentration of inhibiting serum factors on the one hand and survival on the other. The only finding which seems to be correlated with survival is lymphocyte infiltration; its peri- and intrastromal presence on the neoplasia may be associated with a significantly better prognosis.

[Papillary carcinoma in thyroglossal duct cyst remnant: review of the literature and presentation of a clinical case]. / Carcinoma papillare in cisti del residuo del dotto tireoglosso: revisione della letteratura e presentazione di un caso clinico.

The authors report a case of papillary carcinoma arising from thyroglossal duct remnant. It was the only case observed in the last 20 years among 9000 thyroidectomies performed. After a survey of Literature, the role of total thyroidectomy combined to Sistrunk's technique is underlined.

The novel ss469415590 variant predicts virological response to therapy in patients with chronic hepatitis C virus type 1 infection.

BACKGROUND: A novel dinucleotide variant TT/∆G (ss469415590) has been associated with hepatitis C virus clearance. AIM: To assess the role of the ss469415590 variant, compared with the known IL28B polymorphisms (rs8099917, rs12979860 and rs12980275) for predicting virological response to therapy in chronic hepatitis C, and its association with the CXCL10 chemokine serum levels - a surrogate marker of interferon-stimulated genes activation. METHODS: Multivariate analysis of factors predicting rapid and sustained virological response in 280 consecutive, treatment-naïve, nondiabetic, Caucasian patients with chronic hepatitis C treated with peginterferon alpha and ribavirin. RESULTS: In hepatitis C virus genotype 1, the OR (95% CI) for rapid and sustained virological response for the wild-type ss469415590 TT was 9.88 (1.99-48.99) and 7.25 (1.91-27.51), respectively, similar to those found for rs12979860 CC [9.55 (1.93-47.37) and 6.30 (1.71-23.13)] and for rs12980275 AA [9.62 (1.94-47.77] and 7.83 (2.02-30.34)], but higher than for rs8099917 TT [4.8 (1.73-13.33) and 4.75 (2.05-10.98)]. In hepatitis C virus genotype 1, mean (SD) CXCL10 levels in patients with the TT/TT, TT/∆G and ∆G/∆G variants were, respectively, 355.1 (240.6), 434.4 (247.4) and 569.9 (333.3) (P = 0.04). In patients with genotypes 2 and 3 no significant association was found for TT/∆G with viral response. The predictive value of ss469415590 was stronger in patients with advanced fibrosis. CONCLUSIONS: The novel IL28B variants at marker ss469415590 predict response to IFN alpha in chronic hepatitis C patients, especially in those with advanced fibrosis. Their determination may be superior to that of known IL28B variants for patient management using IFN-based regimens.

IL28B polymorphisms, IP-10 and viral load predict virological response to therapy in chronic hepatitis C.

BACKGROUND: Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma and the identification of the predictors of response to antiviral therapy is an important clinical issue. AIM: To determine the independent contribution of factors including IL28B polymorphisms, IFN-gamma inducible protein-10 (IP-10) levels and the homeostasis model assessment of insulin resistance (HOMA-IR) score in predicting response to therapy in chronic hepatitis C (CHC). METHODS: Multivariate analysis of factors predicting rapid (RVR) and sustained (SVR) virological response in 280 consecutive, treatment-naive CHC patients treated with peginterferon alpha and ribavirin in a prospective multicentre study. RESULTS: Independent predictors of RVR were HCV RNA <400 000 IU/mL (OR 11.37; 95% CI 3.03-42.6), rs12980275 AA (OR 7.09; 1.97-25.56) and IP-10 (OR 0.04; 0.003-0.56) in HCV genotype 1 patients and lower baseline γ-glutamyl-transferase levels (OR=0.02; 0.0009-0.31) in HCV genotype 3 patients. Independent predictors of SVR were rs12980275 AA (OR 9.68; 3.44-27.18), age <40 years (OR=4.79; 1.50-15.34) and HCV RNA <400 000 IU/mL (OR 2.74; 1.03-7.27) in HCV genotype 1 patients and rs12980275 AA (OR=6.26; 1.98-19.74) and age <40 years (OR 5.37; 1.54-18.75) in the 88 HCV genotype 1 patients without a RVR. RVR was by itself predictive of SVR in HCV genotype 1 patients (OR 33.0; 4.06-268.32) and the only independent predictor of SVR in HCV genotype 2 (OR 9.0, 1.72-46.99) or genotype 3 patients (OR 7.8, 1.43-42.67). CONCLUSIONS: In HCV genotype 1 patients, IL28B polymorphisms, HCV RNA load and IP-10 independently predict RVR. The combination of IL28B polymorphisms, HCV RNA level and age may yield more accurate pre-treatment prediction of SVR. HOMA-IR score is not associated with viral response.