Sequential treatment with lamivudine and alpha-interferon in anti-HBe-positive chronic hepatitis B patients: a pilot study.

BACKGROUND: In chronic hepatitis B, long-term use of alpha interferon is hampered by side effects, and long-term treatment with nucleos(t)ide analogues is burdened by drug-resistant mutants. We hypothesized that alternate rounds of lamivudine and alpha interferon might circumvent previous shortcomings. AIM: To evaluate efficacy of sequential lamivudine or IFN-alpha2b monotherapies in preventing occurrence of tyrosine-methionine-aspartate-aspartate (YMDD) mutants and achieving virological and biochemical response. METHODS: Fifteen patients with hepatitis B surface antigen, anti-HBe-positive chronic hepatitis received four consecutive rounds of monotherapy with lamivudine (100 mg/day), IFN-alpha2b (5MU/tiw), lamivudine, IFN-alpha2b. Serum HBV-DNA levels were evaluated during and off treatment, HBV polymerase and pre-core/core regions sequenced. RESULTS: End-of-treatment response was achieved in 10 patients (67%). One patient did not respond, a second developed genotypic resistance at week 24. A rebound in viremia occurred in three patients at week 48. Six patients (40%) remained sustained responders. Triple promoter mutations at nucleotides 1762-1764-1896 prevailed in non-responders (60%) as compared to responders (20%). L180M/M204V mutations were identified during virological breakthrough. CONCLUSION: Sequential approach of alternate rounds of lamivudine or interferon may help patients to tolerate a prolonged schedule of therapy and protect them from emergence of viral strains.

Ultrasonographic and biochemical parameters in the non-invasive evaluation of liver fibrosis in hepatitis C virus chronic hepatitis.

BACKGROUND: Prior studies suggest that platelet counts of <140 000/microL can discriminate patients with different stages of fibrosis. AIM: To determine the added value of abdominal ultrasound analysis of morphological liver features in increasing the diagnostic accuracy of platelet counts for the prediction of liver fibrosis at histology. METHODS: In a retrospective study, clinical records of 1143 chronic hepatitis C patients at their first presentation, naives to both liver biopsy and anti-viral treatment, were reviewed. Sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios of following indices were evaluated singularly or in combination: platelet counts <140 000/microL; nodular liver surface, spleen and portal vein size. RESULTS: All indices had specificity rate of > or =90% in excluding bridging fibrosis/cirrhosis, whereas sensitivity was acceptable (51%) for only platelet counts <140 000/microL. None of the ultrasonographic parameters singularly evaluated and reached an acceptable sensitivity rate. For ruling cirrhosis in or out, specificity rate was > or =82% for all tests, with the highest value reported by portal vein size. Low platelet counts plus nodular liver surface had the best sensitivity. CONCLUSIONS: No additional significant predictive value was given by adding ultrasonographic parameters to low platelet counts, whereas only a mild non-significant improvement in sensitivity was obtained combining platelet counts <140 000/microL with the presence of nodular liver surface. The platelet counts <140 000/microL showed the best predictive value for including both significant fibrosis and cirrhosis.

Treatment of chronic hepatitis D with thymus-derived polypeptide thymic humoral factor-gamma 2: a pilot study.

BACKGROUND: Thymic humoral factor-gamma 2 is a thymus-derived synthetic octapeptide, shown to be effective in chronic hepatitis B virus infection; as the latter is needed to support hepatitis D virus, thymic humoral factor-gamma 2 may have a therapeutic role in hepatitis D. AIM: To evaluate tolerability and efficacy of thymic humoral factor-gamma 2 in chronic hepatitis D. METHODS: Intramuscular thymic humoral factor-gamma 2, 40 microg, was given for 15 consecutive days and twice weekly for 22 additional weeks to adult patients with chronic hepatitis D virus hepatitis. RESULTS: A total of 11 patients (male/female 9/2, mean age 45.9 years] completed the treatment period, 10 the 6-month follow-up. At baseline, hepatitis D virus-RNA was positive in 8/11 (73%) patients. During treatment, hepatitis D virus-RNA became undetectable in 3/8 (37%), decreased in 1/8 (13%), remained unchanged in 4/8 (50%) and persisted undetectable in 3 patients, negative at baseline. During follow-up hepatitis D-viraemia relapsed in all patients but 2, one already negative at baseline. No changes in hepatitis B virus markers occurred. Mean serum alanine aminotransferase levels did not change significantly None of the patients reached normal serum alanine aminotransferase levels. CONCLUSION: At the doses given, thymic humoral factor-gamma 2 has been of limited efficacy A possible role of thymic humoral factor-gamma 2 in the treatment of chronic hepatitis D requires further dose-finding studies and/or combination with other antivirals.

Clearance of hepatitis B surface antigen in chronic carriers of hepatitis delta antibodies.

BACKGROUND/AIMS: We evaluated the rate of seroclearance of the hepatitis B surface antigen (HBsAg) and its clinical significance in patients with chronic hepatitis delta virus (HDV). METHODS: Antibody to HDV was tested in HBsAg-positive subjects admitted to our Hospital from 1991 to 1995. In 1997, a biochemical and virologic study was performed in the surviving anti-HD-positive patients who had not undergone transplantation. As a control, a cohort of 106 HBsAg-positive, anti-HD-negative patients was studied. RESULTS: One hundred and forty-one subjects were originally positive for anti-HD. After 4 years of follow-up, six of the 60 patients who underwent re-evaluation (10%) had cleared the HBsAg: three of the six patients had minimal changes at the initial liver histology and normal ALT, whereas in the remaining three patients with chronic active hepatitis ALT normalized during the observation. Anti-HD persisted in five of the six patients. Only one patient had raised anti-HBs. In contrast, three of 106 HBsAg carriers without HDV infection (2.8%) cleared the HBsAg within the same time and seroconverted to anti-HBs (p=0.002). CONCLUSION: HBsAg clearance is increased over the years in HDV patients compared to ordinary HBsAg carriers, and is often associated with improvement of HDV disease without seroconversion to anti-HBs.

Antineutrophil cytoplasmic antibodies in inflammatory bowel disease: clinical role and review of the literature.

PURPOSE: Perinuclear antineutrophil cytoplasmic antibodies have been found consistently in patients with ulcerative colitis; however, their pathogenetic and clinical role is still uncertain. In this study we tested the prevalence of perinuclear antineutrophil cytoplasmic antibodies in a large population of patients with ulcerative colitis and Crohn's disease, with particular attention to the possible correlation with clinical features. METHODS: Perinuclear antineutrophil cytoplasmic antibody reactivity was investigated with indirect immunofluorescence in 279 patients with ulcerative colitis, 110 patients with Crohn's disease, and 252 unrelated healthy subjects. RESULTS: Perinuclear antineutrophil cytoplasmic antibodies were found in 84 of 279 patients with ulcerative colitis (30 percent), 10 of 110 patients with Crohn's disease (9 percent), and 2 of 252 healthy subjects (<1 percent; P < 0.001), respectively. Perinuclear antineutrophil cytoplasmic antibodies were significantly more frequent in patients with ulcerative colitis with higher relapse rate (43 vs. 27 percent; P < 0.002), and patients with Crohn's disease with colitis (27 vs. 2.5 percent; P < 0.0003). Perinuclear antineutrophil cytoplasmic antibodies were also significantly less frequent in patients with ulcerative colitis in remission (18 vs. 34 percent; P < 0.0025). CONCLUSIONS: In this study we confirm the relative specificity of perinuclear antineutrophil cytoplasmic antibodies, either for ulcerative colitis or for Crohn's disease involving the colon. Perinuclear antineutrophil cytoplasmic antibodies were more frequently found in patients with ulcerative colitis with a more aggressive clinical behavior; however, their presence had a limited value in identifying homogeneous subgroups of patients in our population.

Pharmacologic treatment can prevent pancreatic injury after ERCP: a meta-analysis.

BACKGROUND: The identification of therapeutic agents that can prevent the pancreatic injury after endoscopic retrograde cholangiopancreatography (ERCP) is of considerable importance. METHODS: We performed a meta-analysis including 28 clinical trials on the use of somatostatin (12 studies), octreotide (10 studies), and gabexate mesilate (6 studies) after ERCP. Outcome measures evaluated were the incidence of acute pancreatitis, hyperamylasemia, and pancreatic pain. Three analyses were run separately: for all available studies, for randomized trials only, and for only those studies published as complete reports. RESULTS: When all available studies were analyzed, somatostatin and gabexate mesilate were significantly associated with improvements in all three outcomes. Odds ratios (OR) for gabexate mesilate were 0.27 (95% CI [0.13, 0. 57], p = 0.001) for acute pancreatitis, 0.66 (95% CI [0.48, -0.89], p = 0.007) for hyperamylasemia, and 0.33 (95% CI [0.18, 0.58], p = 0. 0005) for post-procedural pain. Somatostatin reduced acute pancreatitis (OR 0.38: 95% CI [0.22, 0.65], p < 0.001), pain (OR 0. 24: 95% CI [0.14, 0.42], p < 0.001), and hyperamylasemia (OR 0.65: 95% CI [0.48, 0.90], p = 0.008). Octreotide was associated only with a reduced risk of post-ERCP hyperamylasemia (OR 0.51: 95% CI [0.31, 0.83], p = 0.007) but had no effect on acute pancreatitis and pain. The statistical significance of data did not change after analyzing randomized trials only or studies published as complete reports. For each considered outcome, the publication bias assessment and the number of patients that need to be treated to prevent one adverse effect were, respectively, higher and lower for somatostatin than for gabexate mesilate. CONCLUSIONS: The pancreatic injury after ERCP can be prevented with the administration of either somatostatin or gabexate mesilate, but the former agent is more cost-effective. Additional studies comparing the efficacy of short-term infusion of somatostatin versus gabexate mesilate in patients at high risk for post-ERCP complications seem warranted.

Changing pattern of chronic hepatitis D in Southern Europe.

BACKGROUND & AIMS: The aim of this study was to assess changes in the clinical pattern of hepatitis D virus (HDV) infection in Italy, brought about by improved control of hepatitis B and D viruses, and to establish the natural history of chronic hepatitis D. METHODS: Histological diagnosis and clinical features of 122 patients with HDV recruited from 1987 to 1996 in three Italian tertiary referral centers (Torino, northern Italy; San Giovanni Rotondo and Castellana Grotte, southern Italy) were compared with those of 162 patients collected in the same centers in the previous decade. Patients from both groups with at least 6 months of follow-up were included in a new subgroup to assess the natural history of the disease. RESULTS: Among 162 patients referred from 1977 to 1986, 9 (6%) had mild hepatitis at histology vs. 9 (8%) of 122 patients referred in the second decade; 105 (65%) vs. 21 (17%) had severe hepatitis; 46 (28%) vs. 38 (31%) had histological asymptomatic cirrhosis; and 2 (1%) vs. 54 (44%) had clinically overt cirrhosis. For 159 patients (121 men and 38 women; mean age, 34 +/- 11), a follow-up of more than 6 months was documented, and they were included in the natural history subgroup. After 78 +/- 59 months of follow-up, 112 (70%) survived free of liver transplantation: 9 underwent transplantation, 32 died of liver failure, and 6 of acquired immunodeficiency syndrome. Estimated 5- and 10-year probability of survival free of orthotopic liver transplantation was 100% and 100% for patients with mild hepatitis, 90% and 90% for severe hepatitis, 81% and 58% for histological asymptomatic cirrhosis, and 49% and 40% for clinical cirrhosis (P < 0.01), respectively. CONCLUSIONS: Occurrence of fresh and severe forms of hepatitis D has diminished greatly in Italy. Contemporary patients represent cohorts infected years ago who survived the immediate medical impact of hepatitis D. The disease has been asymptomatic and nonprogressive in a minority; in the majority, it rapidly advanced to cirrhosis but thereafter subsided with stable clinical conditions for more than a decade.

Intrafamilial transmission of hepatitis delta virus: molecular evidence.

BACKGROUND/AIMS: Epidemiologic studies have suggested that transmission of hepatitis delta virus (HDV) occurs by intrafamilial routes in some populations in southern Italy, where HDV infection is endemic. To further evaluate intrafamilial transmission of HDV, we obtained the partial sequence of the viral genome from HDV-RNA positive members of families in which two or more immediate family members were positive for HDV-RNA. METHODS: The region analyzed was the semi-conserved region from nucleotides 908 to 1265. Sequences obtained from family members were compared with those obtained from a control group of 20 unrelated patients. RESULTS: The mean genetic divergence among HDV isolates was 2.8 +/- 1.7% within the 9 families analyzed, and 7.6 +/- 2.2% among the control group of unrelated individuals (p < 0.0001). A Receiver Operating Characteristic curve and Youden Index were used to define a cut-off value of 3.5% to discriminate sequence variations calculated within families and in the control group. CONCLUSIONS: The data indicate that in most family units, HDV-infected members harbored nearly identical strains of HDV, and provide molecular support that HDV infection can be transmitted within the family. Such spreading among family members highlights the role of inapparent transmission through personal contacts.

Helicobacter pylori infection may undergo spontaneous eradication in children: a 2-year follow-up study.

BACKGROUND: Helicobacter pylori infection is generally acquired early in life. However, it is still unknown whether a spontaneous eradication can occur. The purpose of this study was to evaluate whether H. pylori infection can undergo spontaneous eradication in children. METHODS: Three hundred and four Italian children (age range, 4.5 to 18.5 years) were tested for H. pylori by means of 13C-urea breath test. Infected children were followed up every 6 months for as long as 2 years. Parents were instructed to record consumption of antibiotics. At each visit, children underwent a repeat 13C-urea breath test. RESULTS: Eighty-five out of 304 (27.9%) children were H. pylori infected. Forty-eight out of 85 infected children (56.4%) participated in the follow-up study. After 2 years, 8 (16.6%) infected children had negative results on 13C-urea breath tests; 2 of them were given antibiotics for concomitant infections. One child was negative at 6 months but became positive again at the next 6-month 13C-urea breath test. Forty children remained persistently positive; of them, 10 were treated with a short course of antibiotics. CONCLUSIONS: Our findings support the hypothesis that, at least during childhood, H. pylori infection may be a fluctuating disease with spontaneous eradication and possible recurrence.

Relationship between the results of pre-treatment urea breath test and efficacy of eradication of Helicobacter pylori infection.

AIMS: This study was carried out to evaluate whether the 13C-urea breath test could assess the intragastric Helicobacter pylori load and predict the outcome of infected subjects undergoing short-term triple therapy. METHODS: A total of 108 infected patients underwent upper endoscopy with antral biopsies and histological grading of Helicobacter pylori density. These patients received omeprazole 20 mg b.i.d., clarithromycin 500 mg b.i.d., and amoxycillin 1000 mg b.i.d. or tinidazole 500 mg b.i.d. for one week. 13C-urea breath test (75 mg 13C-urea; results expressed as Delta Over Baseline values at 30') was performed before and after therapy. According to pre-treatment Delta Over Baseline at 30' values, patients were assigned to low (< 16/1000), intermediate (16-35/1000) and high (> 35/1000) Delta Over Baseline at 30' groups. RESULTS: A significant correlation was found between pre-treatment Delta Over Baseline at 30' values and the density of Helicobacter pylori (rs = 0.76). The eradication rates were 82%, 67%, and 17% in the low, intermediate, and high Delta Over Baseline at 30' groups, respectively (p = 0.0001). When classified according to the outcome of therapy, the median pre-treatment Delta Over Baseline at 30' value was 15.7 in eradicated subjects vs 21.6 in non eradicated patients (p = 0.002). In patients who failed eradication, a significant difference was also observed between pre- and post-treatment Delta Over Baseline at 30' values (21.6 vs 15.6, p = 0.019). CONCLUSIONS: The 13C-urea breath test can be used to evaluate the intragastric bacterial load and to predict the outcome of standard eradication treatment.

Gastric emptying of solids in patients with nonobstructive Crohn's disease is sometimes delayed.

To date, only a few studies of gastric emptying in Crohn's disease have been published in the literature. This might be clinically important because slow-release drug formulations are increasingly available for treatment. Studies in children with gastric involvement suggest that gastric emptying may be delayed in this condition. We studied the scintigraphic gastric emptying of 21 adult patients with nonobstructive Crohn's disease and without gastric or duodenal involvement by the disease, compared with that of 20 healthy volunteers. Overall, no significant differences were found, but subgroup analysis showed that symptomatic patients [half-time (t1/2) 133 +/- 75.9] and those with colonic involvement (t1/2 127.2 +/- 64) had a significantly (p < 0.01) delayed gastric emptying over controls (t1/2 85.5 +/- 15.4). Such a difference was also observed between symptomatic and asymptomatic patients (p < 0.05). We conclude that gastric emptying is slowed in symptomatic patients with nonobstructive Crohn's disease and in those with colonic involvement. This may have therapeutic implications.

Segmental motor abnormalities of the distal oesophagus.

Patients with chest pain and/or dysphagia may present non-specific motor abnormalities that do not fit into classical categories of primary motor disorders. Two such patients are described, both with segmental aperistalsis of the distal oesophagus and with fairly normal proximal motility and LES function. Delayed radionuclide oesophageal transit was noted in both cases. Medical treatment was only partially effective and one patient required pneumatic dilatation. The aperistaltic segments have remained unchanged over 3-4 year follow-ups. These patients account for less than 1% of all those diagnosed with oesophageal motor abnormalities in our hospital in the last ten years.

[Peptic ulcer in liver cirrhosis]. / La malattia peptica nella cirrosi epatica.

The frequency of peptic ulcer and the role of ulcerogenic risk factors in cirrhotic patients were evaluated in a retrospective study. Peptic disease was observed in 18.2% of the cirrhotic patients examined. When compared to the prevalence of ulcerative lesions in the general population, this finding suggests that cirrhotic patients have the same probability of being affected by peptic ulcer as non-cirrhotic subjects. The analysis of ulcerogenic risk factors highlighted the importance of alcohol and smoking. The etiology of cirrhosis and portal hypertension were not found to be important. In conclusion, peptic disease is not more frequent in cirrhotic patients than in the general population.

Evaluation of the use of ultrasonography in the study of liquid gastric emptying.

Gastric emptying of two different test liquid meals (500 ml isotonic saline and 500 ml skimmed milk, 1.8% fat) has been measured in 10 (saline) and in 19 (milk) normal volunteers by means of real-time ultrasonography (RUS) and scintigraphy, employed simultaneously. In each subject, saline and milk contained 37 MBq of diethylenetriaminopentacetic acid (DPTA) marked with 99mTc. Determinations were made thereafter every 5 min up to 45 min with saline and every 30 min up to a maximum of 220 min with milk. The determination of gastric emptying by RUS was obtained indirectly through the measurement of gastric dimensions, with a single scan performed at the epigastrium, while the subject was kept in a standing position. At each observation, the percent decrease of gastric measurements and the decay in radioactivity over the gastric region were calculated, blind, by two independent examiners. Linear regression and correlation coefficient were subsequently computed for gastric measurements and decay in radioactivity. The results show that the values obtained with RUS do not differ grossly from the ones obtained with scintigraphy. This suggests that the ultrasonographic determination of gastric dimensions with a single section of the stomach may be a valuable method for use in the evaluation of gastric emptying of liquids.

Granular cell tumor of the esophagus.

Granular cell tumor (GCT) of the esophagus is a rarely-met-with neoplasm. It is almost invariably benign in character and is of still-disputed histogenesis. Small lesions are asymptomatic. Those over 1 cm in diameter may be accompanied by painful swallowing or retrosternal discomfort. Local resection is the treatment of choice for lesions that are accompanied by symptoms, or that are larger than 1 cm. A tumor incidentally encountered in an asymptomatic patient may be safely followed endoscopically. A successful endoscopic removal of such a lesion is described.