[Cyclosporin for steroid refractory ulcerative colitis. Results of a study conducted at Turin General Hospital between 1990 and 1997]. / La ciclosporina nel trattamento della rettocolite ulcerosa refrattaria al cortisone. Risultati dello studio condotto dal 1990 al 1997 all'Ospedale San Giovanni Battista di Torino.

BACKGROUND: Four every ten patients receiving high-dose parenteral steroids for severe ulcerative colitis fail and may have their colon removed. Intravenous followed by oral cyclosporin has been shown to initially rescue approx. 70% of these non-responder patients, but dosages and long term-efficacy are still debated. We reviewed the clinical outcomes of patients treated with cyclosporin for refractory ulcerative colitis at our Center in the last 7 years. METHODS: Fifty-four patients destined to colectomy because of refractory ulcerative colitis (previous failure to respond to 7 days of 1 mg/kg/day steroids) were enrolled to initially receive a two-week continuous infusion of 2 mg/kg/day cyclosporin. Responders (showing at least a 50% reduction of activity) were meant to be treated with oral drug at 6-8 mg/kg/day for 6 months with the maintenance of remission and the spare of steroids being the end-points. RESULTS: Data are available for 47 patients followed-up for a minimum of 6 months up to 6 years. Of these 47, 14 did not respond to the intravenous drug and were submitted to surgery; of the remaining 33 responders (70%) entering the oral 6-month phase, 17 relapsed before end or on leaving the drug and were considered as failures. The remaining 16 (34% of the 47) left cyclosporin in remission and in need of less than 20 mg steroids daily. Of them, 12 avoided colectomy in a follow-up of 6 months-6 years. CONCLUSIONS: Intravenous cyclosporin may be rapidly effective in 7 every 10 patients whose acute ulcerative colitis fails a full-dose steroid course. However, only 3 of the initial 10 may maintain remission over a 6-month oral course. Further efforts should concentrate on improving the long term efficacy of cyclosporin.

Prolonged treatment (2 years) with different doses (3 versus 6 MU) of interferon alpha-2b for chronic hepatitis type C. Results of a multicenter randomized trial.

BACKGROUND/AIMS: To examine the effect of prolonged treatment with different doses of interferon alpha-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 alpha-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, 35/54 patients of the group 3 MU and 21/34 patients of the group 6 MU showed normal ALT levels (65% vs 62%, p=N.S.). After 2 years of follow-up, 24/35 (69%) patients of the group 3 MU and 16/21 (76%) of the group 6 MU were still in remission (p=N.S.). In an intention-to-treat analysis, 48/171 (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 significantly better to prolonged interferon therapy than highly viremic patients with genotype 1b.

IgM antibody against measles virus in patients with inflammatory bowel disease: a marker of virus-related disease?

OBJECTIVE: Viral infections of the mesenteric microvascular endothelium have been hypothesized as pathogenetic factors in inflammatory bowel diseases. The aim of this study was to determine whether immunoglobulin M (IgM) antibody against measles virus is associated with disease. PATIENTS AND METHODS: The IgM antibody was detected by indirect antibody test in 36 patients with evidence of Crohn's disease (23 males and 13 females, median age 40 years, range 20-66), 22 patients with ulcerative colitis (14 males and 8 females, median age 42 years; range 19-65), 59 patients with a chronic active hepatitis (35 males and 24 females, median age 56 years, range 38-77) and 30 blood donors (20 males and 10 females, median age 45 years, range 29-62). RESULTS: Twenty-eight of 36 patients (78%) with Crohn's disease and 13 of 22 patients (59%) with ulcerative colitis tested positive as compared to only 3 of 89 (3.3%) controls (P < or = 0.001). CONCLUSION: The detection of IgM anti-measles virus in the majority of patients with Crohn's disease and in about half of ulcerative colitis patients as compared to a very low prevalence in patients with other chronic inflammatory disease is consistent with the hypothesis that the measles virus has pathogenetic implications in inflammatory bowel diseases.

Liver targeting of nucleoside analogues coupled to galactosyl terminating macromolecules: a new approach to the treatment of a chronic viral hepatitis.

In order to reduce the extrahepatic side effects of antiviral nucleoside analogues in the treatment of chronic viral hepatitis, these drugs are conjugated with galactosyl-terminating macromolecules. The conjugates selectively enter hepatocytes after interaction of the carrier galactose residues with a receptor present in large amounts and high affinity only on these cells. Within hepatocytes the conjugates are delivered to lysosomes where enzymes split the bond between the carrier and the drug, allowing the latter to become concentrated in the liver. The majority of experiments referred to in this paper were performed employing a conjugate of lactosaminated human albumin with adenine arabinoside monophosphate (ara-AMP), a phosphorylated nucleoside analogue active against hepatitis B virus. This conjugate administered for 28 days to patients with chronic hepatitis B exerted the same antiviral activity as that of the free drug without producing any clinical side effects, including the severe neurotoxicity caused by free ara-AMP. This result demonstrates the validity of the liver targeting approach which enhances the therapeutic possibilities of nucleoside analogues. Coupling to galactosyl terminating carriers may be a way of obtaining higher drug concentrations within hepatocytes and permitting the use of nucleoside analogues, the administration of which would otherwise be impossible due to extrahepatic toxicity.

Quantitative detection of hepatitis C virus RNA in the serum of patients with chronic hepatitis C treated with interferon: a pilot study.

BACKGROUND: It is not known whether the measurement of serum hepatitis C virus (HCV) RNA by reverse transcription polymerase chain reaction (RT-PCR) could improve the management of patients with chronic hepatitis C being treated with interferon. OBJECTIVES: We analysed, in a pilot study, the relations between the variations of HCV-RNA and alanine aminotransferase (ALT) serum levels in 18 anti-HCV positive patients treated with interferon. STUDY DESIGN: Serum HCV-RNA was measured, using a non competitive coamplification assay (Amplicor HCV Monitor), before (at 3, 2 and 1 months and baseline), during (first, third and sixth month) and after treatment for at least 8 months (range 8-17 months). HCV-RNA levels fluctuations were correlated with those of ALT and treatment outcome. According to the ALT pattern, four patients were non responders, seven partial responders, four relapsers and two long term responders. RESULTS: The median and mean baseline HCV-RNA levels were significantly different in patients infected by HCV type 1, 2 and 3, being 248,449, 235,506; 4170, 17,866 and 22,315, 79,273 molecules per ml, respectively (P < 0.0001). We did not find any significant difference between median and mean baseline viremia of responders and non responders. After 1 month of treatment viremia was below the sensitivity levels of the assay in 77.7% (14/18) of the patients who normalized ALT, at least temporarily. On the contrary, HCV-RNA remained detectable in non responders. CONCLUSIONS: Our data suggest that HCV-RNA detection using Amplicor Monitor at the first month of treatment can be useful to identify non responders, avoiding three additional months of treatment as would be required by ALT monitoring alone. During the post-treatment follow-up, persistence of undetectable HCV-RNA and normal ALT levels helps to identify long term responders from patients with the risk of relapse in spite of biochemical remission.

[Chronic diarrhea: a difficult diagnosis. A rare cause: lymphocytic colitis]. / Diarrea cronica: una diagnostica difficile. Una causa rara: colite linfocitica.

Lymphocytic colitis is a clinicopathological entity, characterized by chronic watery diarrhea, not bloody. Previously termed microscopic, it is now named lymphocytic for histological features, the most important seems to be the diffuse infiltration of intraepithelial lymphocytes, that must be investigated in multiple biopsies during colonoscopy. This review evidences that during endoscopy the mucosa is normal, but this does not exclude a biopsy, only way for take a diagnosis. Ethiologies are unknown too although a correlation with autoimmune diseases as possible. Lymphocytic colitis is a definition histological entity, while the term ''microscopic'' includes different histological entities under the same ''umbrella'', in relation to the concept of no macroscopic changes and multiple different histological specimens. The treatment is based for the first time on mesalazine or sulphasalazine and then in case of non responders, on corticosteroids.

A new hepatitis C virus-like flavivirus in patients with cryptogenic liver disease associated with elevated GGT and alkaline phosphatase serum levels.

The intriguing co-infection of two flaviviruses (GBV-A and GBV-B) in tamarins and the recent discovery of another flavivirus (GBV-C/HGV) in humans raises the question of the relations between hepatitis C virus (HCV) and GBV-C/HGV. To address this issue the sera of 285 patients with liver disease (102 patients with cryptogenic and 183 with known forms of chronic liver disease) and 19 patients without liver disease were tested for HGV-RNA. GBV-C/HGV-RNA was detected by RT-PCR using primers encompassing 5'NC and NS5 regions and hybridization with specific biotinilated and radiolabelled probes. GBV-C/HGV RNA was found in 11 of 20 (55%) acute hepatitis C patients, in 13 of 117 (11.1%) patients with chronic hepatitis C, in 11 of 27 patients with a liver transplant (40.7%), one of 19 (5.3%) patients with chronic HBV infection, 15 out of 102 (14.7%) patients with cryptogenic liver disease and two out of 19 patients with inflammatory bowel disease. In cryptogenic patients, elevated serum gammaglutamyl transpeptidase (GGT, higher than twice the normal values) and alkaline phosphatase (ALP, above normal values) levels were significantly associated with GBV-C/HGV-RNA infection (P < 0.001). In conclusion GBV-C/HGV appears to be transmitted in humans by blood exposure and to be associated with liver disease in HCV co-infected patients and in a minority of patients with cryptogenic disease. The virus is only occasionally pathogenic for the liver and when liver damage is present; the association with the combined elevation of GGT and APH serum levels might represent a specific feature of the liver tropism of the agent.

Liver targeting of antiviral nucleoside analogues through the asialoglycoprotein receptor.

In order to reduce the extrahepatic side-effects of antiviral nucleoside analogues in the treatment of chronic viral hepatitis, these drugs are conjugated with galactosyl-terminating macromolecules. The conjugates selectively enter hepatocytes after interaction of the carrier galactose residues with the asialoglycoprotein receptor present in large amounts and high affinity only on these cells. Within hepatocytes the conjugates are delivered to lysosomes where enzymes split the bond between the carrier and the drug, allowing the latter to become concentrated in the liver. The validity of this chemotherapeutic strategy has been endorsed by a clinical study. Adenine arabinoside monophosphate (ara-AMP), conjugated with lactosaminated human serum albumin (L-HSA) and administered to hepatitis B virus (HBV)-infected patients for 28 days, exerted an antiviral activity to the same extent as the free drug without producing any clinical side-effects, including the severe neurotoxicity caused by the free drug. Preclinical studies are now underway with conjugates obtained using lactosaminated poly-L-lysine (Lac-poly(Lys)) as the hepatotropic carrier. These new conjugates have some advantages over those prepared with L-HSA: they can be administered by the intramuscular route; they are obtained entirely by chemical synthesis, thus eliminating the problems involved in the use of haemoderivatives; they have a heavy drug load, which permits administration of smaller quantities of conjugate that are more easily digested in lysosomes; and they enable higher quantities of drug to be introduced into hepatocytes. The results of the experiments with two Lac-poly(Lys) conjugates, one with ara-AMP and one with ribavirin, are reported in this review.

Monoethyl glycine xylidide (MEGX) test evaluation in primary biliary cirrhosis: comparison with Mayo score.

OBJECTIVE: To evaluate the clinical and prognostic value of the monoethyl glycine xylidide (MEGX) test in patients with primary biliary cirrhosis (PBC) in comparison with the Mayo score (Mayo). DESIGN: A prospective study. METHODS: MEGX determinations at enrolment were compared to the Mayo score as well as to conventional clinical and laboratory parameters in 92 patients with PBC. RESULTS: The MEGX test yielded higher basal values in long-term survivors compared to patients that were transplanted or died during the follow up; patients belonging to the last two groups displayed significantly higher Mayo scores at baseline. Although values for prothrombin time, serum albumin, alkaline phosphatase, cholesterol, cholinesterase, and gamma-glutamyltranspeptidase were significantly different in survivors compared to either transplanted or dead patients at univariate analysis, the multivariate analysis demonstrated an independent prognostic value for the MEGX and the Mayo score solely. The best discrimination between probability of death or survival was achieved with a cutoff value of 25 ng/ml for the MEGX test and of 6 for the Mayo score. When plotting both MEGX test and Mayo score, the point distribution displayed a bimodal trend, and the wide range of values given by the MEGX test was observed to supply a more precise assessment of liver reservoir and a better discrimination of progressive changes in liver function; the limited range of the Mayo score for values below 6 could only identify gross deteriorations. CONCLUSION: Our data show that the asymptomatic progressive functional deterioration occurring during the natural history of PBC can be monitored by the MEGX test because it appears to be able to identify abnormalities prior to the onset of alterations in conventional laboratory and/or clinical parameters which are likely to affect the Mayo score.

[Recurring duodenal ulcer. Evaluation of previous complications as a predictive factor of ulcer recurrence after eradication of Helicobacter pylori]. / Ulcera duodenale recidivante. Valutazione della pregressa complicanza come fattore predittivo di recidiva ulcerosa dopo eradicazione dell'Helicobacter pylori.

Duodenal ulcer is a chronic disease, punctuated by acute relapses. The pathogenic mechanism in 90-100% of cases is infection by Helicobacter pylori. Two major strains exist of this bacterium: I strain, which secretes a vacuolating cytotoxin (Vac-A), and another protein named cytotoxin-associated (Cag-A) and type II strain, unable to produce both proteins and unable to produce duodenal pathology. We sought to identify the natural history of relapsing duodenal ulcer after cure of the bacterial infection. In particular, we followed the outcome of patients who repeatedly had bled from their recurrent ulcer disease, after success in eliminating the microorganism from the stomach. None of 12 repeated bleeders had an ulcer recurrence after the cure of Helicobacter pylori infection. Only 3 (5%) of 60 frequent relapser had a new episode of duodenal ulcer during a follow-up reinfection by Helicobacter pylori. We demonstrated that the cure of bacterial infection is also the cure of duodenal ulcer recurrence, but for a few cases, in the latter, event one could hypothesize a defect in the production of growth factors (Epidermal Growth Factor, Fibroblast Growth Factor) or of cellular polyamines synthesis. It is important to improve the diagnosis of reinfection by implementing the urea breath test.

Day Bed Unit at the Department of Gastro-enterology. Experience of a study group.

Day Bed Unit at the Department of Gastroenterology. Experience of a study group. We analyzed the activity of the Day-Bed Unit at the Department of Gastroenterology of Turin Hospital (Molinette). The quality of the service provided and the days of stay in hospital for each admission were evaluated in terms of cost benefit ratio. The average stay in hospital for each admission was 2.57 days as opposed to 9.3 in the in patient ward. Patients were divided in subsets according to the cause of admission. Stratifying the patients according to diagnosis showed a hospital stay of 2.73 days for liver disease and of 2.81 for pancreas and biliary disease. Among the admissions for liver disease, pre or posttranspiant patients required 2.89 days as opposed to 2.62 days of those who were treated for esophageal varices. Thus, the cause of admission was a factor influencing length of hospital stay. Patients needing non surgical treatment for liver cancer took 2.22 days if treated with percutaneous ethanol injection; those undergoing chemoembolization required 2.93 days. In conclusion, the day bed unit has proven to be able to provide a service with a good cost benefit ratio. Patients admitted to this service may be withdrawn from the waiting list of the in patient ward, thus reducing the waiting time. Optimization of this service needs integration with the surroudings Units within the Department and in the Hospital.

Hepatitis G virus RNA in the serum of patients with elevated gamma glutamyl transpeptidase and alkaline phosphatase: a specific liver disease? [corrected].

We tested the sera of 67 consecutive patients for hepatitis G virus (HGV) RNA by reverse transcriptase-polymerase chain reaction (RT-PCR). These patients (42 males and 25 females, median age 35 years, range 13-64 years) had liver disease of unknown aetiology and were without markers of hepatitis (A-E) viruses or signs of genetically determined, autoimmune, alcoholic or drug-induced liver disease. The controls in this study were 110 patients (50 females and 60 males, median age 45 years, range 9-65 years) with chronic hepatitis B virus (HBV) infection (19 patients) or hepatitis C virus (HCV) infection (91 patients). Ten of 67 (14.9%) patients with cryptogenic disease were positive for HGV RNA by at least three separate tests; HGV RNA was also detected in one of 19 (5.3%) hepatitis B surface antigen (HBsAg) carriers and in nine of 91 (16.6%) patients with antibody to HCV. These data suggest that HGV occurs as frequently in HCV-infected patients as in those with cryptogenic disease. Elevated serum gamma glutamyl transpeptidase (gamma-GT) (higher than twice the normal value) and alkaline phosphatase levels were found in eight of 10 (80%) HGV RNA positive patients and in six of 57 (10.5%) HGV RNA negative patients (P < 0.0001). Five (50%) HGV RNA positive patients had non-specific inflammatory bile duct lesions. A statistically significant difference was observed between HGV RNA positive and negative patients with chronic HBV or HCV infections (P < 0.029). Therefore, the spectrum of liver disease associated with HGV is wide, but a characteristic lesion of the bile duct leading to elevation of cholestatic enzymes might be specific for this virus.

Recurrent necroinflammatory disease of multiple organs and colon. Systemic presentation of inflammatory bowel disease or gut involvement during systemic disorder.

A 30-year-old man with a recurrent febrile illness resembling infection is described. Because he presented with an acute abdomen, he underwent a laparotomy, which showed the paraaortic and mesenteric lymph nodes to be changed into an abscess-like granulomatous tissue made up of necrotized granulocytes. During further flare-ups, the disease affected the spleen, skin, colon, peripheral nerve, and muscle. Histology on the biopsy materials of both the skin and colon, and on the surgically removed spleen showed the same invading pathologic tissue. Exhaustive investigation disclosed no pathogen, and the flare-ups responded repeatedly to high-dose steroids. This patient's picture has recently been defined as a syndrome of chronic granulomatosis based on several published cases. As a distinctive feature, in our patient the granulomas affected also the colon. For the present, and for another previously described similar case we analyzed the factors that might permit the differential diagnosis between the above-mentioned granulomatous syndrome and Crohn's colitis.

Effect of patient characteristics on hospital costs for cirrhosis: implications for the disease-related group (DRG) reimbursement system.

The Prospective Payment System uses Diagnosis-Related Groups (DRG) as a reimbursement system. DRG 202 is a disease-related group including liver cirrhosis as a whole. Patients referring to the inpatient unit complain of variable severity and complications of cirrhosis, possibly implying different expenditure of resources. Aim of the investigation was to identify factors affecting cost variability in patients with cirrhosis. A total of 73 consecutive, DRG 202-assigned, cirrhotic patients classified according to demographic and clinical variables were evaluated for length and costs of hospitalization calculated on a full-cost basis. Mean length of hospitalization was 10.2 +/- 7 days. Mean cost of hospitalization was Lit. 4.348.000 +/- 2.718.000. Medical, nursing, diagnostic, drug and general charges accounted for 13%, 29%, 37%, 5% and 16% of the cost, respectively. Child-Pugh score significantly correlated with drug consumption (p < 0.005), length (p < 0.01) and costs (p < 0.001) of hospitalization, but not with cost per day. Age, sex, admission status, referral reason, associated diseases and liver transplant susceptibility did not correlate with duration and costs of hospitalization. Disease severity significantly modifies costs of hospital admission in cirrhotic patients mostly on account of longer hospital stay. Surrogate indexes of disease severity, derived from ISTAT/DRG records, cannot identify patients consuming larger resources. In liver cirrhosis, the DRG system could be improved by introducing parameters, such as Child-Pugh score, directly taking into account disease severity.

Levosulpiride in functional dyspepsia: a multicentric, double-blind, controlled trial.

Abnormalities in gastrointestinal motility have been reported in a substantial proportion of patients with functional dyspepsia, supporting the use of prokinetic drugs for treatment of dyspeptic symptoms. To evaluate efficacy and safety of levosulpiride in short-term treatment, 1298 patients were enrolled in a double-blind multicentric study carried out in 45 Italian Gastroenterology Departments. Patients were randomly assigned to either levosulpiride (25 mg tid), domperidone (10 mg tid), metoclopramide (10 mg tid) or placebo (1 tablet tid) for 4 weeks. Patients were selected on the basis of: a) occurrence in the last 4 weeks of at least 5/10 selected symptoms (anorexia, nausea, vomiting, upper abdominal pain, postprandial bloating, abdominal fullness, early satiety, belching, heartburn, regurgitation), severity of which should reach/exceed a total score of 8, as assessed by a specific scale ranging from 0 (absent) to 3 (severe); b) normal results of routine biochemical, ultrasound and endoscopic examinations. In addition, each patient subjectively evaluated efficacy of treatment by a visual analogue scale. Significant improvement was recorded for all symptoms at days 10 and 28 in all groups (p < 0.001), but levosulpiride was significantly (p < 0.01) superior to domperidone, metoclopramide and placebo both in the overall clinical improvement scale as well as in a subgroup of symptoms (postprandial bloating, epigastric pain, heartburn). Active treatments and placebo were comparable as far as concerns occurrence of side-effects (12-20%) including galactorrhoea, breast tenderness and menstrual changes.

Adenine arabinoside monophosphate coupled to lactosaminated human albumin administered for 4 weeks in patients with chronic type B hepatitis decreased viremia without producing significant side effects.

A conjugate of adenine arabinoside monophosphate (ara-AMP) with the liver-targeting molecule lactosaminated human serum albumin (L-HSA) was administered by intravenous infusion for 28 days to eight patients with chronic type B hepatitis. The daily dose varied among the patients, ranging from 34 mg/kg to 53 mg/kg (equal to 1.5 and 2.3 mg/kg ara-AMP, respectively). Pharmacokinetic analysis indicated that, at every dose tested, the conjugate was disposed of without accumulation. Viral DNA serum levels fell markedly during treatment; values rose again when treatment was ceased. The L-HSA-ara-AMP conjugate did not cause either the neurotoxic side effects of free ara-AMP or other adverse clinical reactions. It produced a significant increase both in serum alkaline phosphatase activity and platelet number, and a small but significant decrease in erythrocyte number. These laboratory parameters returned to normal levels within 2 months after treatment. The conjugate induced the production of small amounts of antibodies (approximately 20 pmol of conjugate bound by 1 mL of serum) in one patient only. In conclusion, the present results indicate that the L-HSA-ara-AMP conjugate can exert the antiviral activity of ara-AMP in chronic type B hepatitis patients without producing the neurotoxic side effects which hamper a 4-week period of treatment with the free drug.

[Is HCV RNA detectable in the ultrafiltrate?]. / L'RNA dell'HCV è riscontrabile nell'ultrafiltrato?

We investigated by molecular biology the possibility that the HC virus passes by the dialysis membranes into the ultrafiltrate, making the HD monitor a way of HCV transmission. HCV-RNA was tested in blood and in UF samples during 2 HD sessions at T-0, 30, 60, 120 min and at HD end. HCV-RNA was measured by RT-PCR. Viraemia in patients was > 10(-4) gen Eq/ml and remained unchanged along HD, HCV-RNA was not found in whole UF and its x100 concentrates during the HD. We failed to prove the passage of the HCV into the UF, at least in standard conditions.