Occurrence of diffuse, poorly differentiated hepatocellular carcinoma during pegylated interferon plus ribavirin combination therapy for chronic hepatitis C.

Interferon therapy is indicated for the treatment of chronic hepatitis C and prevention of hepatocellular carcinoma. We describe the case of a 66-year-old Italian woman who received pegylated interferon alpha-2a plus ribavirin combined therapy for HCV-related chronic liver disease. Preliminary hematochemical, ultrasound and bioptic investigations did not show liver cirrhosis or hepatocarcinoma. After 24 weeks of treatment transaminase serum levels were in the normal range and circulating HCVRNA was undetectable by PCR qualitative assay. On week 46 a serious adverse event occurred, with rapid transaminase increase, severe hyperpyrexia, and abdominal pain, leading to interruption of interferon and ribavirin. Liver biopsy was repeated and it revealed poorly differentiated hepatocellular carcinoma. Only palliative care could be performed and the patient died of liver failure within 2 months. The present case underlines that hepatocellular carcinoma can be misdiagnosed in spite of laboratory and instrumental follow-up. More sensitive tools are needed for tumor detection, to avoid IFN impairment of the liver, even though it eradicates HCV.

Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study.

BACKGROUND: Recent studies suggest a role of n-3 long-chain polyunsaturated fatty acids (n-3 PUFA) as peroxisome proliferator-activated receptor-alpha ligands in improving non-alcoholic fatty liver disease (NAFLD) in rodents. However, data in humans are still lacking. AIM: To evaluate the efficacy of prolonged PUFA supplementation in patients with NAFLD. METHODS: Fifty-six patients with NAFLD were enrolled. Among the overall eligible patients, 42 assumed n-3 PUFA 1-g capsule daily for 12 months, whereas 14 refused the treatment and were analysed as controls. All patients underwent haematochemical and ultrasound follow-up. RESULTS: Polyunsaturated fatty acid supplementation significantly decreased serum aspartate transaminase (P = 0.003), alanine transaminase (P = 0.002), gamma-glutamyl transpeptidase (P = 0.03), triglycerides (P = 0.02) and fasting glucose (P = 0.02) in comparison with controls. Circulating arachidonate and n-6/n-3 fatty acid ratio was reduced (P = 0.0002, and P = 0.0001 respectively) in treated patients. Moreover, ultrasonography demonstrated improvement of liver echotexture after PUFA (P = 0.0001), and increase of Doppler perfusion index (P = 0.001), whereas no significant changes occurred in controls. CONCLUSIONS: Supplementation with n-3 PUFA improves biochemical, ultrasonographic and haemodynamic features of liver steatosis. Our study supports the efficacy of n-3 PUFA as a new therapeutic approach in the treatment of NAFLD.

Pharmacokinetics of dirithromycin in patients with mild or moderate cirrhosis.

The pharmacokinetics of dirithromycin were determined over a 72-h period following oral administration of a single 500-mg dose to 8 healthy volunteers and to 16 cirrhotic patients (8 patients with class A cirrhosis and 8 patients with class B cirrhosis according to Pugh's & Child's classification). Drug levels in plasma and urine were determined by microbiological assay. The mean maximum concentrations of drug in serum obtained 3 to 4 h after administration were 0.29 +/- 0.22 mg/liter in volunteers and 0.48 +/- 0.21 and 0.52 +/- 0.38 mg/liter in patients with class A and class B cirrhosis, respectively. The elimination half-life (t1/2beta) was 23.3 +/- 7.6 h in healthy subjects and 35.2 +/- 11.8 h and 39.5 +/- 11.0 h in patients with class A and class B cirrhosis, respectively. The mean area under the concentration-time curve (AUC) and t1/2beta were significantly higher in patients with class A and B cirrhosis than in healthy controls, while total and renal clearances were markedly reduced (P < 0.01). The time to the maximum concentration of drug in serum and the volume of distribution values appeared to be similar in all groups, and the mean recovery in urine at 72 h ranged from 3.7 to 5.7%, without significant differences among groups. These results demonstrate that some dirithromycin kinetic parameters are significantly different in cirrhotic patients in comparison to those in healthy volunteers. However, an increase in the t1/2beta or AUC, which is also observed with other semisynthetic macrolides (e.g., azithromycin), does seem to be not clinically relevant if one takes into account both the high therapeutic indices of these antibiotics and the usually short duration of therapy. Therefore, on the limited basis of single-dose administration, no modifications of dirithromycin dosage seem to be required even for patients with class B liver cirrhosis.

Tumour necrosis factor alpha and cellular proliferation in primary biliary cirrhosis.

AIMS: 1) To evaluate serum levels and tissue expression of Tumour necrosis factor alpha in primary biliary cirrhosis: 2) to correlate serum tumour necrosis factor alpha levels and cellular proliferation with the severity and prognosis of liver disease. METHODS: Twenty-nine primary biliary cirrhosis patients (6 stage I, 8 II, 8 III, and 7 IV) entered the study. Serum tumour necrosis factor alpha was measured by EIA (Innogenetics, Antwerp, Belgium). Tissue tumour necrosis factor alpha and Ki-67 were tested by indirect immunoperoxidase staining on liver sections. RESULTS: Serum tumour necrosis factor alpha increased with the severity of histological stage (from 10.8 +/- 11 pg/ml in stage II to 17.1 +/- 10 in stage III and 22.8 +/- 8.7 in stage IV, p < 0.036). A positive correlation was also found between tumour necrosis factor alpha serum levels and the Mayo score (p < 0.05). A weak and sporadic expression of tumour necrosis factor alpha was observed in the inflammatory infiltrate around the bile ducts. Tissue Ki-67 (expressed as the labelling index in the hepatocellular nuclei) was evaluated in all stages of the disease (1.09 +/- 0.6% in stage I, 1.14 +/- 0.6% in stage II, 2.11 +/- 1.9% in stage III, and 2.67 +/- 2.8% in stage IV; the labelling index was significantly lower in early stages (I/II) than in late stages (III/IV), p < 0.05. A strong correlation between Ki-67 and the Mayo score was observed (p < 0.0005). CONCLUSIONS: 1) tumour necrosis factor alpha production seems related to the severity and the prognosis of primary biliary cirrhosis; 2) liver mononuclear cells in the inflammatory infiltrate do not seem to be the major site of tumour necrosis factor alpha release; 3) cellular proliferation is correlated with the severity of liver disease.

Serologic detection of CagA positive Helicobacter pylori infection in a northern Italian population: its association with peptic ulcer disease.

BACKGROUND: About 60-70% of Helicobacter pylori strains possess cagA (cytotoxin associated gene A) gene and express its product CagA, a highly immunogenic 128-140 kD protein. Patients infected with CagA positive strains develop serum IgG anti-CagA. A serologic response to CagA has been detected in Helicobacter pylori infected patients with peptic ulcer more frequently than in those with gastritis alone. It is nuclear whether this finding is consistent in different geographical populations. We investigated the relationship between anti-CagA seropositivity and peptic ulcer disease in a Northern Italian population. MATERIALS AND METHODS: We studied 135 H. pylori infected patients: 65 with duodenal ulcer (DU), 28 with gastric ulcer (GU) and 42 with non ulcer dyspepsia (NUD). Sera from these patients were assayed by EIA (enzyme immunoassay) for anti-CagA IgG. RESULTS: A high prevalence of anti-CagA was found associated with DU (86.1%) and GU (96.4%), while NUD patients showed anti-CagA seropositivity of 52.4% (Odd ratio, 5.66; 95% confidence interval, 2.23 to 14.32; p < .001, DU vs. NUD; Odd ratio, 24.5; 95% confidence interval, 3.05 to 197.6; p = .003, GU vs. NUD). DU patients showed anti-CagA seropositivity titer (1.15 (0.61 OD, mean (SD) higher than that of NUD patients (0.78 (0.60 OD, mean (SD) (p < .05). CONCLUSIONS: These data demonstrate in a Northern Italian population that anti-CagA seropositivity is strongly associated with peptic ulcer disease and suggest that CagA might play an important role in ulcer pathogenesis.

Chronic atrophic gastritis and Helicobacter pylori infection in primary biliary cirrhosis: a cross-sectional study with matching.

BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by exocrine gland impairment. Up to now there have been no reports dealing with gastric mucosa involvement in this autoimmune condition, which is frequently associated with Sjögren's syndrome. The aim of this study was to investigate the morphologic, biochemical and immunological features of the gastric mucosa in PBC. METHODS: A cross-sectional study with matching was performed. Thirty-three PBC patients (30 F, 3 M, mean age 58 years; 17 with stage II-III, and 16 with stage IV disease) and 33 sex- and age-matched dyspeptic controls were included. Six biopsy specimens from the fundus (2), body (2) and antrum (2) were taken from all patients and controls. A serological assessment was performed for each subject, i.e. pepsinogen A (PGA), pepsinogen C (PGC), gastrin (G), and antibodies against Helicobacter pylori (anti-Hp IgG). RESULTS: Endoscopic gastritis was found in 22 PBC patients (66.6%). There was no difference between PBC patients and controls regarding the percentage of subjects with mild, moderate, severe or atrophic gastritis (AG). There was no difference in gastric mucosal involvement between PBC subjects with or without secondary Sjögren's syndrome. A discrepancy was observed in the data obtained with respect to Helicobacter pylori (H. pylori) infection. H. pylori colonization was significantly more frequent in controls than in PBC patients (79% vs 49%, p < 0.002), but anti-Hp IgG were detected in the same percentage in the two groups (90% vs 83% respectively). There was no difference between the two groups in the PGA, PGC, PGA/PGC ratio, or gastrin. Eight PBC patients had esophageal varices. CONCLUSIONS: PBC patients are not characterized by chronic atrophic gastritis. Even though they present chronic gastritis with the same prevalence as dyspeptic controls, and show signs of previous H. pylori infection as frequently as dyspeptic patients, they are actually much less frequently infected. The reasons for this observation are unclear.

Incidence of hepatic and extra-hepatic malignancies in primary biliary cirrhosis (PBC).

The aim of this study was to analyze the incidence of malignancies in a large series of PBC patients from Italy. The overall sample included 178 patients (10 M, 168 F). The mean age at presentation was 52 yrs (range 29-74); 17 patients had histological stage I, 52 stage II, 66 stage III, 44 stage IV. The follow-up period ranged from 1 to 16 years (mean 5 years). During the follow-up, extra-hepatic malignancies developed in 6 cases (3.3%), and hepatocellular carcinoma (HCC) in a further 4 patients, all associated with cirrhosis (2.2%). Breast cancer developed only in one patient, resulting in a crude incidence rate of 130/100.000 person years among females. The calculated crude incidence of HCC was 492.4/100.000 person years. Three of the four patients with HCC had a superinfection with HCV. In conclusion, the incidence of breast cancer is not significantly increased. HCC has a relatively high prevalence in PBC and HCV superinfection may play an important role in favouring HCC.

Octreotide inhibits the meal-induced increases in the portal venous pressure of cirrhotic patients with portal hypertension: a double-blind, placebo-controlled study.

The aim of this study was to determine the effects of the long-acting somatostatin analog, octreotide, on portal venous pressure and collateral blood flow in cirrhotic patients with portal hypertension during fasting and postprandial states. In a double-blind, placebo-controlled study, we investigated the effects of octreotide on the hepatic venous pressures and azygos blood flow of 21 patients before and after a standard liquid meal containing 40 gm of protein in 250 ml. Octreotide significantly reduced azygos blood flow from a mean of 499 +/- 65 ml/min to a mean of 355 +/- 47 ml/min (p < 0.01), but it had no effect on the hepatic venous pressure gradient. The hepatic venous pressure gradient of patients in the placebo group increased significantly, from a fasting mean of 16.4 +/- 1.6 mm Hg to a mean of 20.0 +/- 1.7 mm Hg 30 min after the meal (p < 0.01). In a second protocol hepatic venous pressures were measured in 20 patients at 30-min intervals for 2 hr after ingestion of the mixed meal. Again the placebo group showed a significant increase in the hepatic venous pressure gradient 30 min after the meal (20.4 +/- 1.5 mm Hg vs. 18.2 +/- 1.2 mm Hg; p < 0.05), but the group receiving octreotide showed no significant changes during the 2 hr of observation. We conclude that octreotide significantly reduces azygos blood flow, with little effect on portal venous pressure, and that it appears to inhibit postprandial increases in portal pressure in cirrhotic patients with portal hypertension.

Prediction of short-term survival with an application in primary biliary cirrhosis.

Many long-term follow-up studies for survival accumulate repeated measurements of prognostic factors. Survival models which include only covariate values at baseline do not use all available information, and do not relate to survival predictions for times other than at that baseline. Time-dependent covariate models (which update covariate values as measurements occur through time) might be used, though limitations of software for estimating the underlying hazard functions and difficulty in relating hazard function changes to survival prediction present serious drawbacks. By dividing each patient's follow-up into successive intervals of equal length (using a length of interest for prediction) and with measurements available at the start of each, we describe how an analysis taking person-intervals as the observation units can be undertaken using readily available software to produce short-term survival models. We show that this approach is related to both the baseline and time-dependent covariate models. The method is illustrated using data from a long-term study of patients with primary biliary cirrhosis, where interest is in short-term survival predictions to aid the decision when to undertake liver transplantation.

Duodenal ulcer and Sjogren's syndrome in patients with primary biliary cirrhosis: a casual association?

Peptic ulcer has been reported in patients with primary biliary cirrhosis (PBC), but its frequency and pathogenesis are still poorly defined. We have analyzed the occurrence of duodenal ulcer in 37 female patients affected by PBC and in 35 with chronic liver disease of various etiologies. An active ulcer was found in seven patients with PBC and in one with chronic autoimmune hepatitis. The presence of an exocrine gland defect, as indicated by clinical signs of Sjogren's syndrome (SS), was found in six patients with PBC and duodenal ulcer (85%), but in only eight (26.6%) of those without ulcer (p less than 0.02). Therefore, in our patients, duodenal ulcer occurs more often in PBC than in other types of chronic liver disease. The association of SS with PBC, significantly higher in patients with than without ulcer, supports the hypothesis that the underlying exocrine gland defect is involved in the development of duodenal ulcer.

Prognosis in primary biliary cirrhosis. A review.

Recent progress has been made in estimating prognosis in primary biliary cirrhosis using Cox models. These models have also demonstrated the therapeutic value of liver transplantation by comparing the observed survival for a group after transplantation with the expected survival without transplantation calculated from the Cox prognostic model. However, good risk patients and those not transplanted principally for hepatocellular failure may not have a survival advantage for many years. Cox models have several limitations: the selection criteria for the patient populations used to derive the models, the selection of the time at which the patients are evaluated, the poor prognostic accuracy for individual patients rather than patient groups and lastly the fact that they use variables derived at only one time point-time independent Cox models. Thus new statistical tools must be used to improve prediction of survival in individual patients with PBC in order to optimize timing of liver transplantation. In addition a more precise definition of the natural history of both symptomatic and asymptomatic forms of this disease is needed to evaluate the efficacy of therapeutic agents in randomized clinical trials. However, although use and timing of therapeutic intervention, including liver transplantation, still requires good clinical experience and judgement, statistical modelling does give some objective measurement of prognosis, which is useful for the clinician treating patients with PBC. At the same time that new treatments are being evaluated, there is an obvious need to improve prognostic tools for application to individual patients with PBC. This may be achieved by using serial data in a different form of modelling-time dependent Cox models.

Effects of plasma exchange (PE) in primary biliary cirrhosis (PBC). A pilot study.

Six patients were studied to evaluate the efficacy and safety of plasma exchange (PE) in the treatment of primary biliary cirrhosis (PBC). All patients were affected by PBC at stage III-IV and presented symptoms refractory to pharmacologic therapy. Patients underwent PE for a mean period of 40 weeks (range 10-88). A mean of 33 liters (range 17-64) of plasma per patients was removed. Patients reported less fatigue (4/6), pruritus (5/5), nausea (3/3), Sjogren's syndrome (2/6), and painful neuropathy (2/3). A reduction of xanthomata was noted in one of the three affected patients. Definitive improvement was seen in the patient with Raynaud's phenomenon. A significant reduction was noted for serum cholesterol and gammaglobulins. ALT, AST, gamma-GT, alkaline phosphatase, bilirubin, prothrombin activity, AMA titers were not affected by PE. All patients suffered some mild adverse effects during PE. Two patients (IV stage) developed late edema and ascites after 34 and 44 weeks of treatment. We conclude that PE can be considered effective chronic treatment for advanced symptomatic PBC refractory to pharmacological therapy.