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Background/Aims: To examine the effect of prolonged treatment with different doses of interferon α-2b on the relapse rate in patients with chronic hepatitis C. Methods: One hundred and seventy-one patients with non-cirrhotic chronic hepatitis C were enrolled in an Italian multicenter trial. All patients were treated for 3 months with 3 000 000 Units (3 MU) of interferon α-2b given subcutaneously three times a week (t.i.w.). Patients with abnormal alanine aminotransferase (ALT) values were given 6 MU of interferon for an additional 3 months. If ALT remained persistently abnormal, therapy was then suspended. If ALT levels were normal, therapy was continued (6 MU t.i.w.) for an additional 18 months (total = 2 years). Patients with normal ALT were randomly assigned to two groups, one receiving 3 MU and the other receiving 6 MU t.i.w. for an additional 21 months (total = 2 years). Follow-up continued for 2 years after therapy withdrawal. Results: Seven patients stopped treatment during the first 3 months. Of the remaining 164 patients, 76 (46%) showed abnormal ALT levels after 3 months of therapy: 11 of these (14%) normalized ALT values when given 6 MU and a sustained response was maintained in eight during the follow-up. Overall, 54 and 34 patients were allocated respectively to the groups receiving the 3 MU and 6 MU long-term treatment. At the end of therapy, 3554 patients of the group 3 MU and 2134 patients of the group 6 MU showed normal ALT levels (65% vs 62%, p =N.S.). After 2 years of follow-up, 2435 (69%) patients of the group 3 MU and 1621 (76%) of the group 6 MU were still in remission ( p =N.S.). In an intention-to-treat analysis, 48171 (28%) patients showed a long-term response (normal ALT values, HCV-RNA negative). About 65% of the sustained responders showed low baseline viremia compared with 33% of non-responders ( p =0.005) while genotype 1b was more frequently found among non-responders than in long-term responders (84% vs 25%, p =0.0001). Conclusions: About 14% of patients who do not respond to a 3-month course of 3 MU of interferon normalize ALT levels when given 6 MU. In prolonged treatment, there is no significant difference between 3 and 6 MU in inducing a sustained response. Patients with low baseline viremia and genotype 2a respond signifiantly better to prolonged interferon therapy than highly viremic patients with genotype 1b.

Alpha-interferon (IFN-α) is an effective treatment for chronic hepatitis C, but only 20% to 30% of patients are apparently cured with the currently recommended schedule of 3 MU given three times a week for 6 months. To evaluate the efficacy of more aggressive treatment regimens, we have conducted a randomized trial in 174 patients with chronic hepatitis C using three different schedules: (1) 12-month treatment starting with 6 MU/three times a week and decreasing the dose on the basis of serum alanine transaminase (ALT) activities (group A: 59 cases); (2) fixed dose of 3 MU three times a week for 12 months (Group B: 61 cases), (3) fixed dose of 6 MU three times a week for 6 months (Group C: 54 cases). Patients were evaluated during therapy for biochemical and virological response and followed for at least 12 months after therapy to assess long-term efficacy and liver histological outcome. The genotype of infecting HCV was also analyzed in all patients, and predictors of response were determined by multivariate analysis. Serum ALT became normal during therapy in 76% of patients (95% confidence interval [CI]: 63 to 86), 65% (CI: 52 to 77), and 74% (CI: 60 to 85) in groups A, B, and C, respectively (P = NS). The corresponding figures for sustained response 12 months after therapy were 49% (CI: 36 to 62), 31% (CI: 20 to 44), and 28% (CI: 16 to 42) (A vs. B, P = .06; A vs. C, P = 0.03). Eighty-six percent of patients with sustained response cleared HCV-RNA from serum and 72% improved histologically. Patients infected with HCV genotypes 2a and 3 had higher sustained response rates than those with 1b, independent of treatment schedule. In patients infected with genotype 1b, the rate of sustained response was related to dose and duration of therapy being 28% with schedule A, 16% with schedule B, and 9% with schedule C. Multivariate analysis indicated that younger age (P = .016), shorter disease duration (P = .003), and infection with HCV genotypes 2a (P = .0017) and 3 (P = .0083) were independent predictors of sustained response. These results indicate that sustained response to IFN-α in chronic hepatitis C is affected by dose and duration of therapy, particularly in patients infected with HCV genotype 1b.

Patients with hepatitis C virus infection may have circulating antibodies to various structural and nonstructural antigens of the virus. To assess whether the antibody profile is related to epidemiological or clinical features of chronic infection or to viral replication, sera from 172 consecutive patients with biopsyproven chronic non-A, non-B hepatitis were studied for antibodies to nonstructural and structural hepatitis C virus antigens and for serum hepatitis C virus RNA with the polymerase chain reaction using primers derived from the 5′ noncoding region. Three subgroups could be identified on the basis of their seroreactivity to hepatitis C virus: 133 cases (77.3% [group A]) were positive on first- and second-generation assays and had antibodies to C100-3 and to C22, C33c or both identified on recombinant immunoblot assay; 23 cases (13.4% [group B]) were positive only on second-generation assay and reacted with C22, C33c or both but not with C100-3; and 26 cases (9.3% [group C]) were negative for all hepatitis C virus antibodies. Mean age and sex distributions were similar among the three groups; a history of transfusion was more frequent among cases in group B (p = 0.06). These patients also had the highest serum aminotransferase values (p = 0.001). Liver histological studies showed active necroinflammatory changes in 69.2% of patients in group A and 52.2% of those in group B but only in 25% of cases in group C. Serum hepatitis C virus RNA was frequently detected in patients of groups A and B, independent of their recombinant immunoblot assay profiles. Hepatitis C virus RNA was also detected in 57% of cases with indeterminate patterns of reactivity on recombinant immunoblot assay. However, none of the patients without hepatitis C virus antibody reactivity had detectable hepatitis C virus RNA in serum. These results identify different subgroups of patients with chronic hepatitis C and indicate that chronic non-A, non-B, non-C hepatitis does exist in our region and that it appears to cause less severe liver injury than does documented hepatitis C. (HEPATOLOGY 1993;17:179–182.)

Background: Previous studies have reported the association between type 2 diabetes mellitus (DM2) and hepatocellular carcinoma (HCC). Aims: To explore the relationships among DM2, antidiabetic therapy and HCC risk. Methods: We recruited 610 HCC patients compared with 618 matched cirrhotic patients and 1696 Controls. The odds ratio (OR) for HCC in diabetic subjects treated with insulin, sulphonylureas and metformin was calculated. Results: DM2 prevalence was 31.2% in HCC, 23.3% in cirrhotic patients and 12.7% in Controls (P

The relationship between urinary albumin excretion rate (UAE) and some metabolic and haemodynamic characteristics was studied in 62 (50 male, 12 female) type 2 (non-insulin-dependent) diabetic patients, with (26 male, 5 female) and without (24 male, 7 female) ischaemic heart disease (IHD), free from overt diabetic nephropathy. The overall population was subdivided into quartiles on the basis of UAE values (mg/24h): group 1 (16 subjects), 3.3–7 (range); group 2 (15 subjects), 7.22–11.8; group 3 (15 subjects), 11.9–30; group 4 (16 microalbuminuric subjects), 31.7–226. The groups were comparable with regard to age, duration of diabetes and prevalence of smokers. From group 1 to group 4 we found increasing levels of body mass index (BMI) (24.2±0.6, 26.6±0.7, 27.6±0.7, 27.6±0.9 kg/m2;P=0.007), HbA1c (5.99±0.2, 6.45±0.35, 7.02±0.41, 7.4±0.39%;P=0.017), total cholesterol (5.30±0.26, 5.51±0.34, 6.14±0.21, 6.32±0.26 mmol/l;P=0.026), triglycerides (1.37±0.20, 1.67±0.21, 2.07±0.29, 2.55±0.45 mmol/l;P=0.034) and prevalence of hypertension (50%, 67%, 67%, 81%;P=0.088). No significant differences were found between C-peptide, insulin resistance (K index of insulin tolerance test) and high-density lipoprotein (HDL)-cholesterol levels. Groups 1+2 had a lower prevalence of IHD in comparison with groups 3+4 (42% vs 58%,P=0.069). Using multiple regression analysis, only HbA1c was independently associated with log10 UAE in the overall population (P=0.002), including as independent variables age, duration of diabetes, BMI, total cholesterol, triglycerides and mean arterial pressure. In conclusion: (1) type 2 diabetic patients show higher BMI, HbA1c, total cholesterol, triglyceride levels and prevalence of hypertension with increasing UAE, even in the normoalbuminuric range; (2) the prevalence of IHD is higher in the groups with elevated UAE; (3) glycaemic control is the only metabolic characteristic independently associated with UAE.

Hepatocellular carcinoma (HCC) ranks as the fifth most common malignancy worldwide, and its incidence is especially increasing in male populations of Western countries [1]. Recognized risk factors ...

The aim of this study was to investigate the role of alcohol dehydrogenase type 3 (ADH3), glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) polymorphisms in modifying hepatocellular carcinoma (HCC) risk according to alcohol intake. A hospital-based case–control study was conducted in two areas of North Italy. Two-hundred cases hospitalized for HCC and 400 controls were recruited. Genotypes were determined using PCR and the PCR/restriction fragment length polymorphism-based method. There was no association of the putative risk genotypes ADH31-1, GSTM1 null and GSTT1 null with HCC (odds ratio [OR], 0.8; 95% confidence interval [CI], 0.5–1.3; OR, 1.0; 95% CI, 0.6–1.5; OR, 0.8; 95% CI, 0.4–1.4, respectively). A steady increase in HCC risk with increasing alcohol intake, which did not vary according to ADH3 and GSTT1 genotypes, was observed. Nevertheless, the OR for HCC due to an alcohol intake of >100 g of ethanol per day increased in subjects with GSTM1 null genotype (OR, 8.5; 95% CI, 3.9–18.6) compared to GSTM1 non-null genotype (OR, 4.5; 95% CI, 2.0–10.0). ADH31-1 and GSTT1 null genotypes did not modify the risk of HCC due to alcohol intake whereas an influence of GSTM1 null genotype for high ethanol consumption was suggested.

Only a small fraction of patients with hepatitis C virus (HCV) positive mixed cryoglobulinemia achieve longterm recovery after interferon (IFN) therapy; we evaluated the effectiveness and safety of combination therapy (interferon plus ribavirin) in nonresponders or those who relapsed after one or more courses of IFN.Twenty-seven patients with HCV positive mixed cryoglobulinemia were studied. All were treated with IFN-a2b (3 MU 3 times weekly) for one year, plus daily oral ribavirin 1000 or 1200 mg.Five patients (18.5%) obtained complete recovery from viral infection and from all signs and symptoms of disease. During treatment, most patients (85%) improved clinically. All 5 responders were "relapsers" to the first treatment(s).Combination therapy of IFN plus ribavirin could be useful for patients with mixed cryoglobulinemia resistant to IFN as monotherapy.

To the Editor: Interferon (IFN) monotherapy in chronic hepatitis C is associated with a low rate of sustained biochemical and virological response, which usually ranges between 15% and 25%.[1][1] Recent studies indicate that the combination of IFNα plus ribavirin may increase the success of

Objective : To identify the best time-frame for defining bleeding-related death after variceal bleeding in patients with cirrhosis. Design : Prospective long-term evaluation of a cohort of 155 patients admitted with variceal bleeding. Setting : Eight medical departments in seven hospitals in north-eastern Italy. Methods : Non-linear regression analysis of a hazard curve for death, and Cox's multiple regression analyses using different zero-time points. Results : Cumulative hazard plots gave two slopes, the first corresponding to the risk of death from acute bleeding, the second a baseline risk of death. The first 30 days were outside the confidence limits of the regression curve for the baseline risk of death. Using Cox's regression analysis, the significant predictors of overall mortality risk were balanced between factors related to severity of bleeding and those related to severity of liver disease. If only deaths occurring after 30 days were considered, only predictors related to the severity of liver disease were found to be of importance. Conclusion : Thirty days after bleeding is considered to be a reasonable time-frame for the definition of bleeding-related death in patients with cirrhosis and variceal bleeding.

To investigate the relationships between Type 2 diabetes mellitus (DM2) and the risk of hepatocellular carcinoma (HCC).We studied the association between DM2 and HCC in a large case-control study that enrolled 465 consecutive Caucasian patients with HCC (78.3% males, mean age 68.5 +/- 8.9 years) compared with an age and sex matched control group of 490 subjects.Prevalence of DM2 was significantly higher in HCC patients (31.2% vs 12.7%; OR = 3.12, 95% CI: 2.22-4.43) and in HCC cases with alcohol abuse. DM2 has been diagnosed before the appearance of HCC in 84.1% of diabetic HCC subjects with mean duration of 141.5 mo, higher in cases treated with insulin than in those with oral antidiabetic agents (171.5 vs 118.7 mo). Compared to controls, males DM2 with HCC were more frequently treated with insulin (38.1% vs 17.6%, P = 0.009) and with sulfonylurea with or without metformin than with diet with or without metformin (84% vs 68.3%, P = 0.049).DM2 in our patients is associated with a 3-fold increase risk of HCC. In most of our cases DM2 pre-existed to HCC. Patients with DM2 and chronic liver disease, particularly insulin treated males, should be considered for HCC close surveillance programs.

It is known that pentamidine can cause severe pancreatic toxicity in patients with the acquired immunodeficiency syndrome.1The most frequent and severe adverse event is hypoglycemia that occurs in 6% to 35% of patients assuming pentamidine with a higher incidence in those who are seropositive for the human immunodeficiency virus.2Occasionally, hyperglycemia and acute pancreatitis have also been reported.3Diabetes mellitus is a much less commonly recognized complication. Only a few cases have been reported in the literature and the real incidence of diabetes mellitus developing after intravenous pentamidine therapy is unknown.2,4,5 We describe a case of transient diabetes mellitus presenting after pentamidine therapy in a patient with the acquired immunodeficiency syndrome. Report of a Case. A 29-year-old man who was an intravenous drug user became infected with the human immunodeficiency virus in 1986. He was admitted to our hospital with a diagnosis ofPneumocystis carinii

Because insulin shows an antinatriuretic effect in healthy humans, insulin therapy resulting in circulating hyperinsulinemia may lead to sodium retention and in turn to hypertension in individuals with insulin-dependent diabetes mellitus (IDDM). Moreover, it has been proved that atrial natriuretic peptide (ANP) plays a major role in modulating natriuresis in humans. This study investigated the relationship between insulin and ANP in modulating sodium metabolism in normotensive and hypertensive IDDM subjects compared with control groups of normotensive and hypertensive nondiabetic subjects. IDDM normotensive and hypertensive subjects had mean ± SE duration of IDDM of 7 ± 2 and 8 ± 2 yr, respectively, and had no clinical features of diabetic nephropathy. All subjects received a saline infusion (2 mmol · kg−1 · 90 min−1) during euglycemia. IDDM normotensive and hypertensive subjects received a subcutaneous insulin infusion (15 mU · kg−1 · h−1), resulting in twofold higher plasma free-insulin levels (16 ± 2 and 19 ± 3 μU/ml, respectively) than in nondiabetic normotensive and hypertensive subjects (7 ± 2 and 8 ± 2 μU/ml, respectively). During saline challenge, sodium excretion increased by 22 ± 4% in normotensive and 49 ± 9% in hypertensive nondiabetic subjects but by only 11 ± 0.4% in normotensive (P < 0.01) and 8 ± 2% in hypertensive (P < 0.01) IDDM subjects. The impaired natriuretic response to saline challenge was mainly due to greater rates of sodium reabsorption by kidney proximal tubules in IDDM than nondiabetic subjects. At baseline, plasma ANP concentrations were significantly higher in both IDDM groups than in control groups (normotensive IDDM and control subjects: 38 ± 4 and 19 ± 2 pg/ml, respectively, P < 0.01 ; hypertensive IDDM and control subjects: 45 ± 6 and 27 ± 4 pg/ml, respectively, P < 0.05). After saline challenge, ANP concentrations rose to 39 ± 4 pg/ml in normotensive and 49 ± 5 pg/ml in hypertensive control subjects, whereas no significant change above baseline value was seen in IDDM subjects. Both IDDM groups showed a 10–12% greater exchangeable Na+pool than control subjects regardless of the presence of hypertension. Subcutaneous insulin infusion, resulting in circulating plasma free-insulin levels in normotensive control subjects comparable to those in IDDM patients, inhibited natriuresis, increased proximal tubule sodium reabsorption at the level of the kidney, and inhibited an adequate ANP stimulation by saline challenge. We conclude that hyperinsulinemia leads to increased proximal tubule sodium reabsorption and impaired ANP response during saline administration. Both mechanisms account for sodium retention in normotensive and hypertensive IDDM patients. Sodium retention seems to characterize insulin-treated diabetes regardless of the presence of hypertension, suggesting that insulin-induced expansion of the Na+ pool alone cannot produce hypertension and requires the concomitant interaction of other pathogenetic factors.

Little information is available on the hemodynamic response (renal reserve) of the diabetic kidney during an acute amino acid infusion, which has been shown to increase glomerular filtration rate (GFR) in normal humans. We recently found that the infusion of ketone bodies is able to raise GFR in both normal subjects and insulin-dependent diabetes mellitus (IDDM) patients. The aim of this study was to evaluate the renal reserve in 15 IDDM patients with a duration of diabetes of >9 yr [8 with albumin excretion rate 100 μg/min (group 2)] and in 8 normal subjects during amino acid infusion (33 μmol · kg−1 · min−1 , Travasol 10% wt/vol solution containing 0.154 mM sodium chloride concentration; Travenol, Savage, MD) and during acetoacetic sodium salt (25 μmol · kg−1 · min−1) infusion. Blood glucose was clamped at euglycemic levels. The infusion of sodium acetoacetate resulted in a 10- to 15-fold increase in circulating concentrations of ketone bodies, which were similar in magnitude in normal subjects and diabetic patients. The GFR peak increase above baseline after sodium acetoacetate infusion was 28% in normal subjects and 27% in group 1 and 19% in group 2 diabetic patients. The infusion of amino acid solution produced a three- to fivefold increase in plasma concentrations of amino acids in both normal subjects and diabetic patients. The GFR peak increase above baseline after amino acid infusion was significantly lower in diabetic patients (IDDM group 1: 5%, P < .01; IDDM group 2: 6%, P < .01) than in normal subjects (38%). During sodium acetoacetate infusion, proximal sodium reabsorption increased as well as distal sodium delivery in normal subjects and group 1 and group 2 IDDM patients. During amino acid infusion, only normal subjects showed a significant increase in proximal sodium reabsorption and distal sodium delivery, whereas no change was found in group 1 and group 2 IDDM patients. Amino acid infusion resulted in a marked increase in the albumin fractional clearance rate in both normal subjects and diabetic patients. On the contrary, ketone body infusion slightly increased the albumin fractional clearance rate in group 2 diabetic patients but not in group 1 diabetic patients and normal subjects. This study demonstrates that long-standing diabetic patients, irrespective of the presence of impaired renal function, show a peculiar defect in the kidney hemodynamic response to amino acid but not to ketone body infusion. These results question the use of an amino acid load to test for glomerular filtration reserve in diabetic patients, because a lack of response may simply be related to an altered response of the kidney to amino acids. A macula densa feedback mechanism could not account for the increase in GFR after both amino acid and ketone body infusion, because these compounds increase the sodium distal delivery. Amino acids increase albumin excretion rate with a mechanism independent of GFR and renal plasma flow changes, in that this effect occurs even in diabetic patients who showed no changes in these variables.

Since insulin increases renal sodium reabsorption, hyperinsulinaemia in insulin-treated insulin-dependent diabetes mellitus might lead to sodium retention and, in turn, increase atrial natriuretic factor (ANF) values. We investigated ANF levels in insulin-dependent diabetes mellitus with and without hypertension. We infused saline (2 mmol/kg per 90 min) in nine normotensive controls, eight normotensive diabetics, seven hypertensive controls and six hypertensive diabetics during the imposition of a euglycaemic glucose clamp with an artificial pancreas. Baseline ANF values were higher in the normotensive and hypertensive diabetics than in the normotensive and hypertensive controls. During a sodium load the sodium excretion rate increased significantly in controls but not in the diabetic groups. The ANF pattern was similar, values being significantly increased in controls and unchanged in diabetic patients. We conclude that euglycaemic, slightly hyperinsulinaemic, insulin-dependent diabetes mellitus patients with and without hypertension are characterized by higher baseline ANF values and an impaired response to an acute saline load as shown by the sodium excretion rate and the plasma ANF concentration.