Epidemiology and outcome of hepatocellular carcinoma in Lombardy.

BACKGROUND AND AIMS: Information on the impact of therapeutic strategies of hepatocellular carcinoma is still incomplete due to the lack of surveys involving primary-care centres. PATIENTS AND METHODS: The Gruppo Epatologico Lombardo (GEL) carried out a study on 361 incident hepatocellular carcinoma observed from January to December 1998 in 22 hospitals in Lombardy. The clinical, pathological and therapeutic data were collected from all patients; 5-year survival and factors related to outcome were analysed. RESULTS: Two hundred and ninety-seven patients were male (M/F: 4.6/1, mean age 66); 61% were HCV-pos, 15% HBV-pos, 17% alcoholic. Cirrhosis was present in 333 (92%) and was classified as Child-A in 197 (59%), Child-B in 85 (26%) and Child-C in 51 (15%) cases. Hepatocellular carcinoma was multifocal/diffuse (more than three nodules) in 91 (25%), less than three nodules in 86 (24%) and monofocal in 184 (51%) (

A morphometric study of liver cell dysplasia.

Thirty-seven cases of cirrhosis with large liver cell dysplasia (LLCD) were evaluated by morphometric analysis and the results compared with those in 11 cases of hepatitis B surface antigen (HBsAg)-positive cirrhosis, 12 cases of cirrhosis with nodules of active regeneration, 15 cases of hepatocellular carcinomas, and 15 cases of inactive cirrhosis. The nuclear-cytoplasmic, nucleolar-cytoplasmic, and nucleolar-nuclear ratios of LLCD were significantly higher than those observed in all other nonneoplastic groups. Whereas the nuclear-cytoplasmic and nucleolar-cytoplasmic ratios of hepatocellular carcinoma cells were significantly higher than those measured in dysplastic cells, the latter had a nucleolar-nuclear ratio similar to that of neoplastic cells. These results show that, in contrast to previously accepted criteria, the nuclear-cytoplasmic ratio of LLCD is increased and that some morphometric features of LLCD are consistent with its supposed premalignant nature. The usefulness of a morphometric analysis in evaluating any group of abnormal-appearing hepatocytes is stressed.

Role of IgM antibody to hepatitis B core antigen in the diagnosis of hepatitis B exacerbations.

IgM anti-HBc levels were measured by the IMx Core-M Abbott assay in 939 serum samples in order to define a specific and sensitive cut-off value for diagnosis of chronic hepatitis B. The sera used were obtained from 52 chronic HBV patients and 10 HBV carriers with HCV or HDV co-infections and 155 asymptomatic subjects without evidence of liver disease. A Youden index value of 95.4% with 98% sensitivity and 97.4% specificity was obtained for an IMx Index value of 0.204 as cut-off. A one-year follow-up study with monthly tests has shown that quantitative analysis of IgM anti-HBc can serve as a noninvasive tool for monitoring HBV infection, and provides an accurate diagnosis of hepatitis B exacerbations. Significant elevations of IgM anti-HBc levels were associated with hepatitis B exacerbations in 96.2% of the cases but with none of the ALT flare-ups observed in HCV or HDV infected individuals. These results suggest that quantitative analysis of IgM anti-HBc provides the highest degree of confidence in definition of spontaneous and therapy-induced exacerbations or remissions of hepatitis B.

Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study.

AIMS: To evaluate the prevalence, incidence and clinical relevance of bacterial infection in predominantly non-alcoholic cirrhotic patients hospitalised for decompensation. PATIENTS/METHODS: A total of 405 consecutive admissions in 361 patients (249 males and 112 females; 66 Child-Pugh class B and 295 class C) were analysed. Blood, urine, ascitic and pleural fluid cultures were performed within the first 24 hours, during hospitalisation whenever infection was suspected, and again before discharge. RESULTS: Over a one year period, 150 (34%) bacterial infections (89 community- and 61 hospital-acquired) involving urinary tract (41%), ascites (23%), blood (21%) and respiratory tract (17%) were diagnosed. The prevalence of bacterial peritonitis was 12%. Infections were asymptomatic in 69 cases (46%) and 130 (87%) involved a single site. Enteric flora accounted for 62% of infections, Escherichia Coli being the most frequent pathogen (25%). Community-acquired infections were associated with more advanced liver disease (Child-Pugh mean score 10.2+/-2.1 versus 9.5+/-1.9, p<0.05), renal failure (p<0.05), and high white blood cell count (p<0.01). Hospital-acquired infections occurred more frequently in patients admitted for gastrointestinal bleeding (p<0.05). The in-hospital mortality was significantly higher in infected than in non-infected patients (15% versus 7%, p<0.05), and infection emerged as an independent variable affecting survival. Moreover bacterial infection accounted for a significantly prolonged hospital stay. CONCLUSIONS: Bacterial infection, regardless of the aetiology, is a severe complication of decompensated cirrhosis, and, although frequently asymptomatic, accounts for both longer hospital stay and increased mortality.

[Topical beclomethasone dipropionate (BDP) in intestinal inflammatory diseases: the results of a multicentre trial]. / Beclometasone dipropionato topico nelle malattie infiammatorie intestinali: risultati di un'indagine multicentrica.

The authors assessed the efficacy and tolerability of BDP in an open protocol using rectal enemas and suppositories and in a double-blind protocol vs mesalazine using rectal enemas. A total of 47 patients suffering from ulcerous rectocolitis were enrolled in the study and treated for 42 days while undergoing endoscopic, histologic and clinical controls. In conclusion, the authors affirm that BDP may represent a useful new therapeutic instrument in the treatment of slight to moderately severe forms of inflammatory intestinal disease.

Comparison of spontaneous ascites filtration and reinfusion with total paracentesis with intravenous albumin infusion in cirrhotic patients with tense ascites.

OBJECTIVE: To compare the effectiveness and safety of spontaneous ascites filtration and reinfusion and total paracentesis plus intravenous albumin infusion in cirrhotic patients with tense ascites. DESIGN: Randomised trial of the two treatments. SETTING: Teaching hospital and district general hospital in Milan. PATIENTS: 45 consecutive cirrhotic patients with recurrent tense ascites and urinary sodium excretion rate less than 20 mmol/day. 35 fulfilled admission criteria and completed the study. 17 received spontaneous ascites filtration and 18 paracentesis plus albumin infusion. MAIN OUTCOME MEASURES: Body weight; urinary volume; serum and urinary electrolyte, serum fibrinogen, and plasma aldosterone concentrations; and plasma renin activity before the procedure and 24 hours and eight days afterwards. RESULTS: Both procedures were effective in all patients. Weight decreased in both groups and showed no substantial increase after eight days. In patients receiving ascites filtration, values decreased significantly (p less than 0.01) after 24 hours for platelet count (mean relative change 0.92; 99% confidence interval 0.86 to 0.98) and serum fibrinogen concentration (0.92; 0.88 to 0.98) but returned to pretreatment values after eight days; no laboratory and clinical signs of disseminated intravascular coagulation were noted. Three patients in this group had fever, which receded spontaneously. One patient in each group had dilutional hyponatraemia. CONCLUSIONS: Spontaneous ascites filtration and reinfusion is an effective treatment for tense ascites. Reinfusion of the patient's concentrated proteins provides savings without compromising safety.

[Role of surgical therapy in the treatment of refractory ascites]. / Ruolo della terapia chirurgica nel trattamento dell'ascite refrattaria.

In 5-10% of cases ascites is not controlled by medical therapy and is defined refractory. These patients may be submitted to one of the four following surgical options: portal-systemic shunt, peritoneo-venous shunt, transjugular intrahepatic portal-systemic shunt, orthotopic liver transplantation. Although the portal-systemic shunt is efficient in clearing ascites, it does not improve the survival, which depends on liver function, and it is complicated by an important incidence of encephalopathy. Since the patients with refractory ascites and good hepatic risk are not usually many, it is possible to understand why derivative surgery has been disappointing with this indication. Although the peritoneo-venous shunt is associated with a significant rate of valve obstruction, it is an easy, effective and not expensive treatment. So, till now, it has been considered the first choice procedure of refractory ascites, if any situations, determinating the onset of postoperative complications, are not present. Recently a new method has been introduced in the therapy of portal hypertension, the transjugular intrahepatic portal-systemic shunt. This is a bloodless portal-systemic derivation and so it has caused great enthusiasm even if the available data are insufficient to give a definitive opinion on its role in management of ascites. Certainly the liver transplantation, which presents the great advantage to treat both the cirrhosis and its complications, seems to be the most rational therapy for these patients. However, at least for this moment, the well-known absence of organ donors makes still actual the palliative surgical measures.

[The topical therapy of ulcerative colitis. A multicenter study with beclomethasone dipropionate foam]. / Terapia topica della colite ulcerosa. Studio multicentrico con beclometasone dipropionato schiuma.

BACKGROUND AND AIMS: The use of steroids was recently extended to the various forms of ulcerative rectocolitis by the introduction of topical formulations, above all steroids with an hepatic "first pass" devoid of systemic interference. The aim of this study was to evaluate the efficacy and tolerability of Beclomethasone dipropionate (BDP) in a rectal foam formulation, in the treatment of patients suffering from ulcerative colitis. METHODS: The experimental protocol took the form of a 28-day open prospective trial using BDP rectal foam in patients suffering from ulcerative colitis. Endoscopic, histological, clinical and tolerability parameters were evaluated. The centres taking part in the trial collected data for 60 cases out of a total of 80 patients enrolled in the study, of both sexes and aged between 20 and 81 years old, suffering from proctosigmoiditis (46.7%) and ulcerative rectocolitis (53.3%). RESULTS: Endoscopic parameters showed an improvement after 28 days of treatment in 74.5% of patients; a clinical improvement was achieved in 65.2% of cases. In percentage terms of the mean value of all the improved parameters, histological parameters were altered in 56.9% of patients. With regard to tolerability 82% of patients judged the treatment to be good/excellent. CONCLUSIONS: In conclusion, in line with recent reports regarding other pharmaceutical forms of BDP, including the use of rectal foam, these data confirm the efficacy and tolerability of this molecule and emphasise the validity of its use in the treatment of ulcerative colitis and proctosigmoiditis.

[A case of intestinal schistosomiasis with hepatic involvement: interdisciplinary diagnostic approach and peculiarity of the echographic and histologic findings]. / Un caso di schistosomiasi intestinale con interessamento epatico: approccio diagnostico interdisciplinare e peculiarità dei reperti ecografico e istologico.

We report a case of intestinal schistosomiasis; secondary hepatic involvement is particularly described, with a very distinctive ecographic feature of portal hypertension and a bioptic picture stressing a granulomatous periportal inflammation. In the work we emphasize the importance of a multidisciplinary approach (physicians working in the fields of internal medicine, infectious disease, gastrointestinal diseases, radiologist, pathologist) in the course of diagnostic investigation. Finally, we confirm the effectiveness of praziquantel against Schistosoma mansoni.

Translocation of gut bacteria in rats with cirrhosis to mesenteric lymph nodes partially explains the pathogenesis of spontaneous bacterial peritonitis.

Spontaneous bacterial peritonitis is a common infection of ascitic fluid that develops in cirrhosis. The offending organisms are predominantly of enteric origin. However, the mechanism and route by which bacteria exit from the gut and enter the fluid remain unclear. "Translocation" of bacteria from the gut to extraintestinal sites has been postulated in the pathogenesis of gram-negative sepsis in intensive care unit patients, burn-wound sepsis, and sepsis associated with chemotherapy. Translocation is defined by culture-positivity (with enteric flora) of mesenteric lymph nodes. In this study we assessed the frequency of translocation in a carbon tetrachloride-induced rat model of cirrhosis, ascites, and spontaneous bacterial peritonitis. We determined that translocation was more common in rats with cirrhosis (78.1%) than in normal controls (4.3%) (p < 0.001). Escherichia coli and other gram-negative enteric organisms were cultured. Translocation of enteric bacteria in rats with cirrhosis to extraintestinal sites may be an important early step in the pathogenesis of spontaneous bacterial peritonitis.

Thyroid function tests in chronic liver disease: evidence for multiple abnormalities despite clinical euthyroidism.

To further evaluate thyroid function in patients with liver disease, we have measured total and free T3 and T4, thyroxine binding globulin, basal and thyrotropin releasing hormone-stimulated thyrotropin and thyroglobulin antibodies in 33 patients with liver cirrhosis, in 22 with chronic hepatitis and in 30 healthy controls. All the patients but one were clinically euthyroid. T3, FT3, T3/thyroxine binding globulin and T4/thyroxine binding globulin ratios and thyrotropin after thyrotropin releasing hormone were significantly reduced, while FT4, thyroxine binding globulin and thyrotropin were significantly increased in liver cirrhosis. In chronic hepatitis group, FT3 and T3/thyroxine binding globulin ratio were significantly lower and thyroxine binding globulin and FT4 were higher than in healthy controls. The between patients comparison revealed a significantly lower T3, FT3, T3/thyroxine binding globulin and T4/thyroxine binding globulin ratios and delta thyrotropin in cirrhotics. Thyroglobulin antibodies were present at high titre only in two patients one of whom having evidence of Hashimoto's thyroiditis with subclinical hypothyroidism. The correlation coefficient between T4/thyroxine binding globulin ratio and FT4 were lower in patients than in controls. Furthermore an abnormal thyrotropin response to thyrotropin releasing hormone was shown in 10 cirrhotics and in four patients with chronic hepatitis. Serum T3 significantly correlated with serum bilirubin, albumin, and prothrombin time in both groups of patients. The present data confirm the existence of several abnormalities of thyroid function tests in patients with chronic liver disease, although showing that euthyroidism is almost always maintained, probably as a result of low-normal FT3 and high-normal FT4. Furthermore, T3 serum levels appear to parallel the severity of liver dysfunction.

Metabolic effects of chronic prazosin treatment.

The effects of chronic (3 mg/day for 1 week) administration of the vasodilator drug prazosin on several metabolic and endocrine variables were evaluated in 12 hypertensive patients, 6 with normal and 6 with abnormal oral glucose tolerance test (OGTT). After 1 week prazosin treatment there were no significant modifications in fasting plasma glucose, serum free fatty acids (FFA), cholesterol, triglycerides, insulin (IRI), growth hormone (GH), prolactin (PRL) and gastrin levels; oral glucose tolerance and IRI response to glucose were unchanged in normal subjects, while in chemical diabetics there was a significant improvement in glucose tolerance and a slight increse in IRI secretion. Therefore, the untoward metabolic effects of acute prazosin administration, i.e. increased plasma glucose and serum FFA, are not sustained during chronic treatment, which may even improve glucose metabolism in diabetic patients.

Efficacy of oral ciprofloxacin as selective intestinal decontaminant in cirrhosis.

BACKGROUND: Selective intestinal decontamination has been proposed to prevent bacterial infection in cirrhosis. AIMS: To evaluate the efficacy of ciprofloxacin as selective intestinal decontaminant. PATIENTS AND METHODS: Quantitative microbiological studies on serial faeces were carried out in 15 cirrhotic patients. Ciprofloxacin was given orally at the starting dose of 250 mg every 12 hours for 7 days followed by a single dose of 250 mg/day from day 7 to day 14 and 125 mg/day for the next 3 weeks. Total stool samples were examined in basal conditions and on days 7, 14, 21, 28 and 35 of treatment and 3 and 7 days after treatment withdrawal. RESULTS: Gram-negative flora was completely eliminated in all patients by ciprofloxacin given at doses of 500 and 250 mg/day. When the drug was tapered to 125 mg/day, Escherichia coli reappeared in stools of 7 patients (antibiotic-resistant in one patient) and Klebsiella oxytoca in two patients (antibiotic-resistant in one patient). Faecal concentration of Group D Streptococcus was significantly increased at the end of therapy (basal mean 7.7 +/- 1.2 log CFU vs post treatment mean 9.6 +/- 0.5 log CFU, p < 0.05) while the faecal concentration of anaerobic flora and Candida albicans showed no change. CONCLUSIONS: Results of this study demonstrate the efficacy of oral ciprofloxacin as a selective intestinal decontaminant and ciprofloxacin 250 mg/day is the recommended dose for maintaining Selective Intestinal Decontamination. However, the risks of inducing antibiotic resistance in Gram-negative flora and promoting overgrowth of Gram-positive flora must be carefully considered in all patients chronically treated with oral quinolones.

Abnormal DNA content in liver-cell dysplasia: a flow cytometric study.

To clarify the true nature of liver-cell dysplasia (LCD), a flow cytometric study has been performed. The DNA content of hepatocytes from 26 cases of cirrhosis with diffuse areas of LCD was investigated and compared to that of hepatocytes from 21 control patients with non-neoplastic and neoplastic liver conditions. Flow cytometric analysis was performed on propidium-stained nuclei from archival paraffin-embedded material. Analysis was directed to assessment of diploid as well as non-diploid peaks by calculation of DNA index (DI), using normal hepatocytes present in each sample as individual and specific references. Since only samples containing at least 10,000 nuclei were considered suitable for analysis, 4 of the 26 LCD cases were discarded. Eight of 22 LCD cases had an abnormal DNA content compared with 0/11 non-neoplastic cases (p less than 0.05) and 8/10 hepatocellular carcinomas (p less than 0.05). Non-neoplastic control cases displayed uniformly diploid stemlines whereas hepatocellular carcinomas had in 8/10 cases bimodal or trimodal populations. Thus, LCD is a heterogeneous lesion in terms of ploidy, and the abnormal DNA content observed in some cases supports its pre-neoplastic nature.

Effect of L-dopa with and without inhibition of extra cerebral dopa decarboxylase on gastric acid secretion and gastrin release in man.

The present study was undertaken to investigate the possibility that central nervous system monoaminergic pathways may play a role in the control of gastric acid and gastrin secretion in man. Submaximal pentagastrin stimulated (0.25 micrograms/kg/h) gastric acid secretion, as well as basal gastrin concentrations were studied in two groups of subjects. The first group received oral administration of placebo and the catecholamine precursor L-dopa (500 mg); the second group was treated with placebo and the association of L-dopa (100 mg) plus carbidopa (35 mg) after pretreatment with carbidopa (50 mg every six hours for four doses), a schedule which is known to increase brain catecholamine concentrations. In comparison with placebo, stimulated gastric acid secretion was reduced by L-dopa alone, whereas was not modified by L-dopa plus carbidopa. Basal gastrin concentrations were increased after L-dopa and after L-dopa plus carbidopa. These data show that basal gastrin concentration is raised by central catecholamine augmentation; but gastric acid secretion seems to be influenced by changes of peripheral catecholamine concentrations. It is suggested that dopamine and perhaps noradrenaline, but not adrenaline, are important in these effects.

Effect of selective bowel decontamination with norfloxacin on spontaneous bacterial peritonitis, translocation, and survival in an animal model of cirrhosis.

Selective bowel decontamination with the orally administered quinolone antibiotic, norfloxacin, has been shown to suppress gut gram-negative bacteria and help prevent gram-negative infections in cirrhotic patients who are at high risk of bacterial infection. Because this drug does not eradicate gram-positive organisms, it is conceivable that gram-positives could replace the suppressed gram-negatives in the gut and lead to subsequent infection. Also the effect of norfloxacin on translocation (as defined by culture positivity of mesenteric lymph nodes) has received little attention. In this study, the effect of oral norfloxacin on translocation, bacterial peritonitis, and survival was investigated in an animal model of carbon tetrachloride-induced cirrhosis and ascites. Treated rats received daily doses of orally administered norfloxacin from the onset of cirrhosis until they died or were killed. Controls received no antibiotic. Norfloxacin led to a reduction in bacterial peritonitis from 70% in untreated cirrhotic controls to 28% in treated cirrhotic rats; these data were statistically significant (P = .012). There was no effect on overall translocation rate (28% with norfloxacin vs. 50% without norfloxacin) (P > .1). Gram-positives were isolated in 100% of the bacterial peritonitis episodes and in 71.4% of culture-positive mesenteric lymph nodes in treated animals compared with only 25% of peritonitis episodes and 10% of culture-positive mesenteric lymph nodes of untreated cirrhotic controls (P < .01 for peritonitis and P < .05 for translocation). The survival rate was not different between groups (P > .1).(ABSTRACT TRUNCATED AT 250 WORDS)

A simple method for ascites concentration and reinfusion.

A rapid and simple method for ascites concentration and reinfusion was utilized to treat 103 episodes of tense ascites in 57 patients (38 men and 19 women, mean age 63 +/- 11 years). After a bedside total paracentesis, 6.06 +/- 2.87 liters of ascites were separately ultrafiltrated using a mechanical device during a mean interval of 134 +/- 88 min, and 430 +/- 368 ml of concentrate containing 39 +/- 42 g of albumin were restituted at bedside either intravenously (44 cases) or intraperitoneally (59 cases). Ultrafiltration was successfully and easily completed in all cases. Ascites concentration and reinfusion either intravenously or intraperitoneally did not adversely modify hemodynamic or renal parameters except for a transient decrease in mean arterial pressure (P < 0.05). Transitory hyponatremia and renal failure occurred in two patients. A transient decrease in platelet count and serum fibrinogen levels (P < 0.05) and pyrexia (12%) were observed only in patients reinfused intravenously. In conclusion, this new method for ascites concentration and reinfusion was effective, safe, and, with respect to traditional methods, simpler, faster and more comfortable. Therefore it is proposed for the routine management of tense ascites.