Small (

PURPOSE: We prospectively compared gadoliniumenhanced magnetic resonance imaging (dynamic MRI), superparamagnetic iron oxide (SPIO) (ferucarbotran) MRI and multidetector-row computed tomography (MDCT) and the combination of dynamic MRI plus MDCT vs. dynamic MRI plus SPIO-MRI (double-contrast MRI: DC-MRI) for the detection of small (1 cm and the highest specificity (83.3%) superior to dynamic MRI (p<0.0001). In the per-lesion analysis, SPIO-MRI demonstrated a positive predictive value higher than dynamic MRI (p=0.0059) and than both the combinations dynamic MRI/MDCT and DC-MRI (p=0.0021 and p=0.0087, respectively). DC-MRI showed the highest sensitivity (97.7%) and accuracy (78.9%), detecting hypovascular and atypical HCCs >1 cm. Furthermore its per-patient negative predictive value was the highest (100%), and significantly higher than all the other methods. CONCLUSIONS: DC-MRI is the most sensitive and accurate method and can be confidently used as a single-step procedure for the detection of small HCCs, with the exception of lesions <1 cm.

Clinical trial: peg-interferon alfa-2b and ribavirin for the treatment of genotype-1 hepatitis C recurrence after liver transplantation.

BACKGROUND: Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is difficult with low response rates. AIM: To assess the safety and efficacy of pegylated-interferon (PEG-IFN) alfa-2b + ribavirin (RBV) in patients with post-LT recurrent genotype-1 HCV and to establish stopping rules according to response. METHODS: Fifty-three patients with post-LT HCV recurrence were enrolled. Patients received PEG-IFN alfa-2b 1.0 micro/kg/week plus RBV 8-10 mg/kg/day for 24 weeks. Those with 'early virological response at week 24' (EVR24) continued treatment for 24 weeks (group A). Patients without EVR24 were randomized to continue (group B) or to discontinue (group C). RESULTS: Overall sustained virological response (SVR) was 26% (14/53). Alanine aminotransferase, rapid virological response, EVR12, EVR24, undetectable serum HCV-RNA at weeks 12 (cEVR12) and 24 (cEVR24) were related to SVR. cEVR12 and cEVR24 (OR: 14.7; 95% CI: 2.02-106.4) were independent predictors of SVR. All patients with SVR, had cEVR12. No patient in groups B and C achieved end-of-treatment response. One patient in group B had SVR. CONCLUSIONS: Pegylated-interferon alfa-2b was effective in one of four of patients with HCV genotype 1 after LT. Treatment should be discontinued in patients with no virological response at week 12. Further studies are needed to evaluate whether a longer treatment period may be beneficial in patients with > or =2 log10 drop in HCV-RNA at week 24.

Meta-analysis: the efficacy of proton pump inhibitors for laryngeal symptoms attributed to gastro-oesophageal reflux disease.

BACKGROUND: Many investigators have proposed an association between gastro-oesophageal reflux disease and laryngo-pharyngeal symptoms, suggesting that medical or surgical therapy for reflux may be useful. AIM: To perform a meta-analysis assessing the effectiveness of medical or surgical therapy for reflux disease in adult patients with laryngeal or pharyngeal symptoms presumed to be due to gastro-oesophageal reflux disease. METHODS: Randomized controlled trials comparing medical or surgical treatments for gastro-oesophageal reflux disease against placebo were identified by searching MEDLINE (1966-September 2005), EMBASE (1974-September 2005), the CCRCT (until September 2005) and abstracts from gastroenterology and ENT meetings. The relative risks of reporting symptomatic improvement or resolution of symptoms was evaluated using a random-effects model. RESULTS: Five studies using high-dose proton pump inhibitor as intervention met the inclusion criteria and were included in the meta-analysis. No surgical studies met inclusion criteria. The pooled relative risk was 1.18 (95% confidence interval: 0.81-1.74). There was no heterogeneity between studies but evidence of significant publication bias. Sub-group analysis performed evaluating Jadad scores and symptom type, did not change the relative risk. CONCLUSIONS: Therapy with a high-dose proton pump inhibitor is no more effective than placebo in producing symptomatic improvement or resolution of laryngo-pharyngeal symptoms. Further studies are necessary to identify the characteristics of patients that may respond to proton pump inhibitor therapy.

High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis?

BACKGROUND: Interferon may trigger autoimmune disorders, including autoimmune hepatitis, in immunocompetent patients. To date, no such disorders have been described in liver transplanted patients. METHODS: 9 of 44 liver transplanted patients who had been receiving pegylated-interferon alpha-2b and ribavirin for at least 6 months for hepatitis C virus (HCV) recurrence, developed graft dysfunction despite on-treatment HCV-RNA clearance in all but one case. Laboratory, microbiological, imaging and histological evaluations were performed to identify the origin of graft dysfunction. The International Autoimmune Hepatitis scoring system was also applied. RESULTS: In all cases infections, anastomoses complications and rejection were excluded, whereas the autoimmune hepatitis score suggested a "probable autoimmune hepatitis" (score from 10 to 14). Three patients developed other definite autoimmune disorders (overlap anti-mitochondrial antibodies (AMA)-positive cholangitis, autoimmune thyroiditis and systemic lupus erythematosus, respectively). In all cases, pre-existing autoimmune hepatitis was excluded. Anti-lymphocyte antibodies in immunosuppressive induction treatment correlated with the development of the disorder, whereas the use of granulocyte colony-stimulating factor to treat interferon-induced neutropenia showed a protective role. Withdrawal of antiviral treatment and treatment with prednisone resulted in different outcomes (five remissions and four graft failures with two deaths). CONCLUSIONS: De novo autoimmune hepatitis should be considered in differential diagnosis along with rejection in liver transplanted patients developing graft dysfunction while on treatment with interferon.

Pulmonary complications of liver transplantation: radiological appearance and statistical evaluation of risk factors in 300 cases.

The aim of this study was to evaluate the incidence, radiographic appearance, time of onset, outcome and risk factors of non-infectious and infectious pulmonary complications following liver transplantation. Chest X-ray features of 300 consecutive patients who had undergone 333 liver transplants over an 11-year period were analysed: the type of pulmonary complication, the infecting pathogens and the mean time of their occurrence are described. The main risk factors for lung infections were quantified through univariate and multivariate statistical analysis. Non-infectious pulmonary abnormalities (atelectasis and/or pleural effusion: 86.7%) and pulmonary oedema (44.7%) appeared during the first postoperative week. Infectious pneumonia was observed in 13.7%, with a mortality of 36.6%. Bacterial and viral pneumonia made up the bulk of infections (63.4 and 29.3%, respectively) followed by fungal infiltrates (24.4 %). A fairly good correlation between radiological chest X-ray pattern, time of onset and the cultured microorganisms has been observed in all cases. In multivariate analysis, persistent non-infectious abnormalities and pulmonary oedema were identified as the major independent predictors of posttransplant pneumonia, followed by prolonged assisted mechanical ventilation and traditional caval anastomosis. A "pneumonia-risk score" was calculated: low-risk score ( < 2.25) predicts 2.7% of probability of the onset of infections compared with 28.7% of high-risk (> 3.30) population. The "pneumonia-risk score" identifies a specific group of patients in whom closer radiographic monitoring is recommended. In addition, a highly significant correlation (p < 0.001) was observed between pneumonia-risk score and the expected survival, thus confirming pulmonary infections as a major cause of death in OLT recipients.

[Hepatic and pancreatic disease in patients with acquired immunodeficiency syndrome (AIDS)]. / Patologie epatiche e pancreatiche in pazienti con sindromi da immunodeficienza acquisita (AIDS).

AIDS is frequently expressed through gastrointestinal o abdominal symptoms. In addition, patients with AIDS or ARC frequently have hepatic and biliary symptoms, while pancreatic alterations are found in 4-30% of patients hospitalised for AIDS. Since AIDS patients are immunodepressed, they are subject to opportunistic infection often multifocal and the pathological processes can be present simultaneously. About 2/3 of patients have enlarged liver, steatosis, splenomegaly, lymphoadenopathy, cholecystic and biliary tract abnormalities, alterations of liver function tests, and abdominal discomfort in the upper right quadrant. Jaundice is rare and hepatic failure is not common. Hepatic biopsy is often necessary to establish the diagnosis. The hepatic localisation of an opportunistic pathogenic agent is generally a sign of systemic dissemination which is expressed as granulomatous hepatitis (atypical mycobacteria, frequently mycobacterium avium, or M. tuberculosis representing the reactivation of latent diseases), peliosis hepatis, infection from CMV, HSV, EBV, Pneumocystis carinii, and mycotic infections. Coinfections with the hepatic virus (HBV, HDV, HCV) are also often present. Pharmacological damage may also be present (mainly caused by antibiotic therapies). Neoplasia are rare (hepatic Kaposi's sarcoma associated with cutaneous and gastrointestinal manifestations, or generally metastatic lymphoma). Damage of the biliary tract usually develops after other manifestations of the illness; the most frequent pictures are cholestatic syndromes and cholangitis, while cholecystitis and jaundice are rare. Pancreatic lesions are generally asymptomatic. They are diagnosed during autopsy and are caused principally by opportunistic agents.

Serum pancreatic enzyme concentrations in chronic viral liver diseases.

Serum amylase and lipase concentrations were determined in 78 patients with chronic liver diseases [26 chronic active hepatitis (CAH) and 52 liver cirrhosis] and in 15 healthy subjects. Pancreatic isoamylase concentrations and macroamylase complexes were assayed in hyperamylasemic sera. Serum amylase levels were abnormally elevated in 27 patients (35%; 22 liver cirrhosis, 5 CAH), whereas serum lipase levels were elevated in 16 patients (21%; 15 liver cirrhosis, 1 CAH). In 9 of the 27 hyperamylasemic patients, the hyperamylasemia was of pancreatic type. Macroamylasemic complexes were not detected in hyperamylasemic sera. Patients with liver cirrhosis had serum levels of amylase and lipase significantly higher than both the healthy subjects and the patients with CAH, while no significant differences were found in serum levels of these enzymes in patients with CAH as compared to the healthy subjects. A decreased liver metabolism of serum amylase and lipase in patients with chronic infective liver disease, especially in those having liver cirrhosis, may lead to an accumulation of these enzymes in the blood.

Factors associated with gallstone disease in the MICOL experience. Multicenter Italian Study on Epidemiology of Cholelithiasis.

The epidemiological associations of gallstone disease were evaluated in a general population sample of 29,584 individuals (15,910 men and 13,674 women; age range, 30-39 years) belonging to 14 cohorts examined between December 1984 and April 1987. Subjects were screened for the presence of gallstones by gallbladder ultrasonography, completed a questionnaire, and underwent a physical examination and blood chemistry tests. Participants were considered to have gallstone disease if they had already had cholecystectomy or gallstones. Statistical associations were established by univariate analysis of the age-standardized data and by stepwise multiple logistic regression. Increasing age and body mass index and a maternal family history of gallstone disease were the most consistent associations (both at univariate and multivariate analysis and in both sexes) found in this study. Personal history of dieting was associated with gallstone disease in men, and at univariate analysis, in women. Decreasing serum total cholesterol levels and increasing serum triglycerides were associated with gallstone disease in both sexes in the multivariate analysis. In women, associations were also found with a number of pregnancies and paternal family history of gallstone disease. A slight but negative association with contraceptive pill use was identified only at multivariate analysis. Associations (investigated at univariate analysis) were also found with diabetes, cirrhosis, angina or myocardial infarction, and peptic ulcer. There was no association with smoking habits and use of aspirin or antirheumatic drugs.

Serum lipid and lipoprotein patterns in patients with liver cirrhosis and chronic active hepatitis.

BACKGROUND: An impaired lipid metabolism is often found in patients with chronic liver diseases. Unfortunately, few studies are available concerning serum lipid and lipoprotein levels in patients with liver cirrhosis and chronic active hepatitis (CAH). OBJECTIVES: To evaluate low-density lipoprotein (LDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and total cholesterol serum levels in patients with cirrhosis and CAH and control patients and to relate the findings to the severity of the cirrhosis (Child classification). METHODS: We measured the serum lipid pattern in 34 consecutive patients with liver cirrhosis (15 men and 19 women; mean [+/-SD] age, 55 +/- 14 years; Child classes: 14 in A, 9 in B, 11 in C; patients with biliary cirrhosis were excluded), 34 patients with CAH, and 34 control patients. The 3 groups were matched for sex and age. Total serum, HDL cholesterol, and triglyceride levels were measured by enzymatic methods; serum LDL and VLDL levels were calculated. RESULTS: In patients with cirrhosis, there was a significant decrease in LDL, HDL, and total cholesterol serum levels compared with both the patients with CAH and the control patients, while the VLDL cholesterol level in patients with cirrhosis was significantly lower compared with the control patients alone. A significant decrease in total cholesterol levels was also observed in the CAH group when compared with the control patients. In patients with cirrhosis, levels of LDL, HDL, and total serum cholesterol were progressively lower when comparing patients in Child class A with patients in class C. CONCLUSIONS: In this study, the striking decrease in the level of serum LDL cholesterol in patients with liver disease was related to the increasing severity of the disease. Accordingly, the assessment of the serum LDL cholesterol level is important for an effective treatment and prognostic evaluation of patients with chronic liver disease.

Flutamide-induced toxic hepatitis. Potential utility of ursodeoxycholic acid administration in toxic hepatitis.

Flutamide is a nonsteroidal antiandrogen commonly used in the treatment of prostate cancer. Hepatic toxicity associated with flutamide has been reported with an incidence from less than 1% to about 5%. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, has been widely used in the treatment of cholesterol gallstones and of several liver diseases, but few data are now available concerning its use in the management of drug-induced hepatitis. The case of a patient who presented severe hepatitis with jaundice following use of flutamide is reported. UDCA treatment was started on admission and, contemporaneously, flutamide was withdrawn. Clinical and biochemical improvement was progressively observed, and the patient was discharged six weeks after the admission. Since fatal flutamide-related hepatitis has been reported, monitoring of serum liver tests is advocated during flutamide administration, and the effectiveness of UDCA in the treatment of drug-induced hepatotoxicity requires further study.

Liver transplantation in HBsAg-positive HBV-DNA--negative cirrhotics: immunoprophylaxis and long-term outcome.

The presence of a positive hepatitis B surface antigen (HBsAg) has been considered a highly questionable indication for orthotopic liver transplantation. We report our experience in the treatment of HBsAg-positive HBV-DNA-negative cirrhotics with liver transplantation, whether or not followed by passive prophylaxis with specific immunoglobulins. Of the 123 cirrhotics who received transplants at our institution since May 1986, 39 (31.7%) were HBsAg positive; of these, 1 was HBV-DNA positive, and 4 were hepatitis Be antigen (HBeAg) positive. Since April 1991, 25 HBsAg-positive HBV-DNA-negative cirrhotics have undergone an original protocol with the periodical intramuscular administration of 5,000 IU of specific immunoglobulins starting in the anhepatic phase and lasting for at least 1 year. There were no differences among cirrhotics in terms of operative mortality and long-term survival with respect to the presence of the HBsAg. Of the 35 HBsAg-positive HBV-DNA-negative patients having a follow-up of 1 month or longer, 12 (34.3%) developed HBsAg recurrence; of them, 4 (33.3%) had received a complete prophylaxis, whereas 8 (66.7%) had not. The recurrence rate was 80% (8 out of 10) in the group of patients who had not received the prophylaxis and 16% (4 out of 25) in the group who had received the prophylaxis (P = .0003). The actuarial recurrence rate in the treated patients was 20.2% and 20.2% after 1 and 3 years, respectively, whereas in the untreated group it was 60.0% and 70.0% (P < .01). The hazard of recurrence of treated patients was reduced to 24.9% compared with untreated patients. Liver transplantation can be performed in HBsAg-positive HBV DNA negative patients without an increase in the operative risk or a worsening of long-term results. Immunoglobulin prophylaxis seems to be effective in preventing hepatitis recurrence after transplantation.

[Pulmonary complications from monoclonal antibody (OKT3) immunosuppression in patients who have undergone an orthotopic liver transplant]. / Complicanze polmonari da immunosoppressione con anticorpi monoclonali (OKT3) nei pazienti sottoposti a trapianto ortotopico di fegato.

The authors investigated the incidence of pulmonary complications following immunosuppression with monoclonal antibodies (OKT3) in a series of 100 consecutive cases of orthotopic liver transplantation (OLT). Of 17 patients treated with OKT3 (16 for acute rejection and 1 for cyclosporine toxicity), 11 pulmonary infections were observed (65%), 9 of which (53%) with onset within a mean of 9 days after OKT3 administration. The infections were severe in all cases and lethal in 8 cases: the most common pathogens were Candida (4 cases) and Pseudomonas aeruginosa (3 cases). On the contrary, of 39 cases of rejection treated with steroids, infections were observed in 3 cases only (8%). The 53% incidence of pulmonary infections in OKT3 patients, significantly higher than in the extant patients (19%), confirms OKT3 treatment as a strong risk factor for severe pulmonary infections. Furthermore, the occurrence of pulmonary edema was directly related to OKT3 administration in 7 OKT3 patients (41%), whereas only 20 cases (24%) occurred in the extant OLT patients (p < 0.001). OKT3-related pulmonary edema was always observed in hyperhydrated patients at the time of drug administration and it seemed to be related to the vasoactive myocardiotoxic agents released by damaged T-cells.

Protease activities, as well as plasminogen activators, contribute to the "lytic" state during orthotopic liver transplantation.

High levels of tissue plasminogen activator (t-PA) have been reported to be the main component of the high fibrinolytic activity measured in patients during orthotopic liver transplantation. However, a previous study of our group suggested that specific t-PA may not completely account for the massive fibrinolytic activities recorded. In the present study we investigated the fibrinolytic patterns in 10 consecutive liver cirrhosis patients undergoing OLT. Euglobulin fibrinolytic activity, measured either on physiologic (fibrin plates) or amidolytic substrates, increased as expected during anhepatic and reperfusion phases, but largely exceeded the specific activity of t-PA, as proved by quenching procedures using anti-t-PA antibodies. The presence of plasmin- and trypsin-like amidolytic activities was detected in native plasmas at the end of anhepatic and reperfusion phases, together with decreased levels of protease inhibitors, especially alpha 1 Antitrypsin. In conclusion, the hyperfibrinolytic pattern recorded in the central OLT phases is not only attributable to an increased t-PA concentration, and is better described as a complex "lytic" state also including the presence of free proteases (plasmin- and trypsin-like), with limited participation of u-PA. Although t-PA increase is probably the main mechanism of stimulation of the fibrinolytic system during OLT, actual and not just potential proteolytic activities can be found in this condition independent of the occurrence of major hemorrhagic complications.

The role of liver transplantation in the treatment of hepatocellular carcinoma.

The role of liver transplantation in the treatment of hepatocellular carcinoma (HCC) is still debated. Overall survival is poor because of the high recurrence rate. Negative prognostic factors are the presence of large, multiple lesions, lymph node involvement, gross vascular invasion and extrahepatic metastases. On the other hand a long term survival (5 yrs), can be achieved in about 30 to 48% of transplanted patients. In the case of incidental tumours, the survival rate can be as high as 90%. Fibrolamellar HCC have a better prognosis than non fibrolamellar HCC. Due to the short supply of donor livers, OLT should be offered to those patients who have the highest probability of surviving.

Reversal of primary liver graft non-function using prostaglandins.

Primary graft non-function remains one of the most life-threatening problems after liver transplantation. Its etiology is still unclear. Liver retransplantation is the only therapeutic alternative to this problem. The PGE1 series of prostaglandins have recently been successfully used in the treatment of transplanted organ dysfunction. In this paper we describe a case of primary graft non-function successfully treated with continuous infusion of prostaglandin PGE1, and we briefly discuss the pathogenetic and therapeutic hypotheses.

Coagulation and fibrinolysis in orthotopic liver transplantation: role of the recipient's disease and use of antithrombin III concentrates. S. Orsola Working Group on Liver Transplantation.

In this study we report the data obtained from extensive haemostatic testing of 25 patients undergoing orthotopic liver transplantation and the results of an open randomized pilot trial of antithrombin III concentrate administration during surgery. Marked differences in transfusional needs and in pre- and intraoperative blood coagulation and fibrinolytic changes were observed between recipients with liver cirrhosis and those with primary biliary cirrhosis. In the former, the increases in tissue-type plasminogen activator activity, total euglobulin fibrinolytic activity, and fibrin-derived degradation products occurred earlier and were more marked, as were the signs of increased thrombin formation. Supplementation of antithrombin III concentrate during surgery failed to induce significant changes in the main parameters studied and in the transfusional needs.