PNPLA3 rs738409 I748M is associated with steatohepatitis in 434 non-obese subjects with hepatitis C.

BACKGROUND: The PNPLA3/Adiponutrin rs738409 C/G single nucleotide polymorphism is associated with the severity of steatosis, steatohepatitis and fibrosis in patients with non-alcoholic fatty liver disease, as well as the severity of steatosis and fibrosis in patients with chronic hepatitis C (CHC). AIM: To test in genotype 1(G1)-CHC patients, the putative association between the PNPLA3 variant and histological features of steatohepatitis, as well as their impact on the severity of fibrosis. METHODS: Four hundred and thirty-four consecutively biopsied Caucasian G1-CHC patients were genotyped for PNPLA3 rs738409, its effect evaluated by using an additive model. Histological features of steatohepatitis in CHC were assessed using the Bedossa classification. Hepatic expression of PNPLA3 mRNA was evaluated in 63 patients. RESULTS: The prevalence of steatohepatitis increased from 16.5% in patients with PNPLA3 CC, to 23.2% in CG and 29.2% in the GG genotype (P = 0.02). By multiple logistic regression, PNPLA3 genotype (OR 1.54, 95% CI 1.03-2.30, P = 0.03), together with age (OR 1.03, 95% CI 1.00-1.05, P = 0.02), BMI ≥ 30 (OR 2.06, 95% CI 1.04-4.10, P = 0.03) and homoeostasis model assessment (HOMA, OR 1.18, 95% CI 1.04-1.32, P = 0.006) were independently linked to steatohepatitis. When stratifying for obesity, PNPLA3 was associated with NASH in non-obese patients only (12.0% in CC vs. 18.3% in CG vs. 27.3% in GG, P = 0.01), including after correction for metabolic confounders (OR 2.06, 95% CI 1.26-3.36, P = 0.004). We showed an independent association between steatohepatitis (OR 2.05, 95% CI 1.05-4.02, P = 0.003) and severe fibrosis. Higher liver PNPLA3 mRNA was associated both with the severity of steatosis (adjusted P = 0.03) and steatohepatitis after adjusting for gender, age, BMI and HOMA (P = 0.002). CONCLUSION: In patients with genotype 1 hepatitis C, the PNPLA3 G variant is associated with a higher risk of steatosis severity and steatohepatitis, particularly among non-obese subjects.

Venesection for non-alcoholic fatty liver disease unresponsive to lifestyle counselling--a propensity score-adjusted observational study.

BACKGROUND/AIM: To test the short-term clinical usefulness of venesection associated with lifestyle counselling as against counselling alone on insulin resistance and liver enzymes in subjects with non-alcoholic fatty liver disease (NAFLD), using a propensity score approach. METHODS: We carried out a 6- to 8-month observational analysis of 198 NAFLD patients in three Italian referral centres (79 venesection and 119 counselling alone). Insulin resistance was measured by the homeostasis model assessment (HOMA) method. Logistic regression was used to identify factors associated with normal HOMA and normal alanine aminotransferase (ALT) at the end of observation. The results were adjusted for the propensity score to be enrolled in the venesection programme, based on clinical and laboratory data, including common HFE polymorphisms and liver biopsy (available in 161 cases). RESULTS: After adjustment for propensity and changes in BMI, venesection was significantly associated with normal HOMA [all cases: odds ratio (OR) 3.00; 95% confidence interval (CI) 1.51-5.97; cases with histology: OR 2.29; 95% CI 1.08-4.87] and ALT within normal limits (all cases: OR 2.56; 95% CI 1.29-5.10; cases with histology: OR 2.81; 95% CI 1.20-5.24). The results were confirmed in an analysis of 57 pairs matched for propensity, where venesection similarly increased the probability of normal HOMA (OR 3.27; 95% CI 1.16-7.84) and normal ALT (OR 5.60; 95% CI 2.09-15.00). Similar data were obtained in the subset of cases with normal basal ferritin (<350 ng/ml). CONCLUSION: Iron depletion by venesection favours the normalization of insulin resistance and raised liver enzymes in non-haemochromatosis patients with NAFLD.

Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms.

AIMS/HYPOTHESIS: Non-alcoholic fatty liver disease (NAFLD) has been associated with the metabolic syndrome. However, it is not clear whether insulin resistance is an independent feature of NAFLD, and it remains to be determined which of the in vivo actions of insulin are impaired in this condition. METHODS: We performed a two-step (1.5 and 6 pmol min(-1) kg(-1)) euglycaemic insulin clamp coupled with tracer infusion ([6,6-2H2]glucose and [2H5]glycerol) and indirect calorimetry in 12 non-obese, normolipidaemic, normotensive, non-diabetic patients with biopsy-proven NAFLD and six control subjects. RESULTS: In NAFLD patients, endogenous glucose production (basal and during the clamp) was normal; however, peripheral glucose disposal was markedly decreased (by 30% and 45% at the low and high insulin doses, respectively, p<0.0001) at higher plasma insulin levels (p=0.05), due to impaired glucose oxidation (p=0.003) and glycogen synthesis (p<0.001). Compared with control subjects, glycerol appearance and lipid oxidation were significantly increased in NAFLD patients in the basal state, and were suppressed by insulin to a lesser extent (p<0.05-0.001). The lag phase of the in vitro copper-catalysed peroxidation of LDL particles was significantly shorter in the patients than in the control subjects (48+/-12 vs 63+/-13 min, p<0.04). Lipid oxidation was significantly related to endogenous glucose production, glucose disposal, the degree of hepatic steatosis, and LDL oxidisability. CONCLUSIONS/INTERPRETATION: Insulin resistance appears to be an intrinsic defect in NAFLD, with the metabolic pattern observed indicating that adipose tissue is an important site.

Non-alcoholic fatty liver and insulin resistance: a cause-effect relationship?

The role of insulin resistance in non-alcoholic fatty liver disease is suggested by laboratory data (hyperinsulinemia and decreased sensitivity to endogenous and exogenous insulin). The clinical association with features of the metabolic syndrome, particularly in the most aggressive stages of the disease, further confirms a causative role. Fat accumulation in the liver may stem either from genetic defects, primarily responsible for insulin resistance, or excessive calorie intake and visceral obesity, and is mediated by adipocytokines (leptin, adiponectin, tumour necrosis factor-alpha). Progression of fatty liver to steatohepatitis may be the result of an imbalance between pro-inflammatory and anti-inflammatory cytokines, triggering the formation of reactive oxygen species and intrahepatic lipid peroxidation. This process may also be promoted or accelerated by pro-oxidant xenobiotics or environmental factors. Insulin resistance provides a target for specific treatment of non-alcoholic fatty liver, and insulin-sensitising agents (metformin or thiazolidinediones) as well as lifestyle changes to reduce visceral adiposity are the most promising therapeutic options. Future trials need to be performed in order to test the long-term effectiveness of these treatments on the basis of clinically relevant histological outcomes.

Low ghrelin concentrations in nonalcoholic fatty liver disease are related to insulin resistance.

Several physiological and pathophysiological conditions, including changes in body fat, food intake, and insulin resistance, are known to be associated with variations in plasma ghrelin concentrations. We tested the hypothesis that insulin resistance exerts a primary role by measuring ghrelin in 86 patients with nonalcoholic fatty liver disease (NAFLD), a condition in which insulin resistance is relatively independent of obesity. Compared with 40 matched healthy subjects, patients with NAFLD had similar glucose levels and higher plasma insulin and insulin resistance [homeostasis model assessment (HOMA)-R index] by over 60%. Ghrelin was reduced (mean +/- SD, 226 +/- 72 pmol/liter in NAFLD vs. 303 +/- 123 in controls; P < 0.0001). In relation to quartiles of body mass index, ghrelin progressively decreased in controls (P = 0.003), but not in patients (P = 0.926). In relation to quartiles of HOMA-R, ghrelin decreased in both groups, and significantly correlated with HOMA-R. After adjustment for age and sex, HOMA-R was the sole factor significantly associated with low ghrelin in the whole group (odds ratio, 5.79; 95% confidence interval, 2.62-12.81; P < 0.0001) and specifically in NAFLD (2.96; 1.12-7.79; P = 0.028). The study suggests that insulin resistance is a major factor controlling ghrelin levels in subjects with and without NAFLD.

[Lithiasis of the gallbladder and biliary ducts: from epidemiology to therapy]. / Litiasi della colecisti e delle vie biliari: dall'epidemiologia alla terapia.

The diagnosis of cholelitiasis, more and more common with the wide diffusion of abdominal ultrasound, is often a surprise for the patient as well as for the physician who is sometimes forced to take a therapeutical decision. In the case of dilatation of the biliary duct, the cholangioRM is assuming an increasingly important role, especially before a therapeutical ERCP. The best therapeutical approach seems to be the surgical ablation in laparoscopy in presence of specific signs and symptoms. Indication to surgical ablation is a symptomatic or complicated cholelithiasis, or the history of obstructive pancreatitis. A preventive cholecystectomy can be useful for precancerous lesions.

Diagnosis of Helicobacter pylori infection: validation of a commercial non invasive salivary test against urea breath test and serology.

BACKGROUND: Helicobacter pylori (H. pylori) infection plays an important role in the pathogenesis of chronic gastritis, peptic ulcer disease, MALT lymphoma and gastric cancer. Recently Helicobacter spp. infection has been correlated with cirrhosis, hepatocellular carcinoma and acute myocardial infarction. Several invasive and non-invasive tests have been proposed for the detection of the bacterium. In clinical practice, the selection of the appropriate test will depend on the disease and on cost-effectiveness. Aim of the study was to validate a rapid, salivary test for detecting the presence of antibodies against H. pylori in a population of patients undergoing to the 13C-urea breath test (13C-UBT). METHODS: Saliva and serum samples were obtained from 91 patients (47 females, mean age 53+/-6.7 years) attending the 13C-UBT service between 15 September and 31 November 1999. Thirty-five of them had had a previous diagnosis of peptic ulcer at endoscopy and 46 out of 91 had a diagnosis of histologically confirmed chronic gastritis. 39 out of 91 were dyspeptic patients with no symptoms suspect for peptic ulcer or cancer. Patients were excluded from the 13C-UBT if they had been treated with inhibitors of acid secretion and antibiotics within 30 days before testing. Breath sample were collected at baseline and 30 minutes after the ingestion of orange juice and a 75 mg dose of 13C-labeled urea. The presence in serum of antibodies (IgG) against the bacterium was assessed by means of a commercial enzyme immunosorbent assay with a reported sensitivity of 94% and specificity of 87%. Saliva was collected using a sterile absorbent pad placed between the mandibular gum and the cheek in the mouth and assayed for H. pylori antibodies by an immunochromatographic rapid method. RESULTS: Thirty-seven of the 91 patients were defined positive by 13C-UBT and serological test. Twenty-nine of these 37 were identified as positive by the salivary test. Fifty-four patients were defined as negative but the salivary test identified 13 of them as positive, thereby sensitivity and specificity were 78.3 and 75.9% respectively. The accuracy was 76.9%. Positive predictive value was 69% and negative predictive value 83.6%. CONCLUSIONS: The salivary test could be considered in the ambulatory setting, as a non-invasive tool for the screening of H. pylori infection, when more accurate methods are not available.

Previous tuberculosis, hepatitis C virus and lichen planus. A report of 10 cases, a causal or casual link?

We report 10 cases of lichen planus (LP) and chronic liver disease linked to HCV. The mean age was 63.4 +/- 5.1 years (range 51-73), five were female; six patients had an established cirrhosis of the liver, as shown by either a liver biopsy or the ultrasonographic and biohumoral evidence. The remaining four patients had chronic hepatitis. Histological examination confirmed the presence of LP: the localization of the dermatosis was restricted to the skin in four patients, to the mucous membranes in five (4 atrophic erosive and one erosive) while the remaining had mucous-cutaneous localization. A type II cryoglobulinemia was demonstrated in two and a type III in one of the patients, while no one had otherwise circulating autoantibodies (anti-nuclear, anti-smooth muscle, anti-liver kidney microsomal type 1 and anti-mitochondrial antigens) such as other etiological factors of liver disease. In six of the patients the history was positive for previous Mycobacterium tuberculosis infection. In clinical practice the patients with chronic liver disease and HCV infection can also suffer from severe extrahepatic manifestations, including lichen planus.

Management of duodenal ulcer disease in the era of H. pylori.

BACKGROUND: Today it is expected that the great majority of patients with duodenal ulcer (DU) respond to H. pylori eradication treatment without DU recurrence. The aim of the research is to identify patients who need a different therapeutic approach and the best management of their disease. METHODS: We examined retrospectively the medical history of 474 patients (326 males, mean age 61 years), followed up in 5 years in the outpatients department of a third level GI Center. From our research, 5 subgroups of patients emerged: 1) 63.5% carrying H. pylori infection, with successful eradication treatment and without DU recurrence; 2) 4% failing 3 courses of H.pylori eradication treatment; 3) 11% with DU lacking evidence of H. pylori infection or relapsing after verified eradication; 4) 8% being treated with NSAIDs; 5) 13% with DU complicated by hemorrhage or perforation. RESULTS: 23% of patients with DU need long-term therapy after H. pylori eradication treatment. Concerning this, the percentage of ulcerous recurrences in patients receiving anti-H2 therapy is 18.5%, but decreases considerably to 2% when PPI were used. CONCLUSIONS: Although representing the mainstay of DU therapy, H. pylori eradication treatment may not abolish all issue in DU management. Actually, of DU patients referred to a third level GI Center, 23% need a different therapeutic approach, which results from a thorough analysis of the medical history of the patient.

The role of peripheral opioid receptor subtypes in the modulation of gastric acid secretion and plasma gastrin in dogs.

The peripheral opioid receptor subtypes involved in the regulation of gastric acid secretion were studied in dogs with both a gastric fistula and a Heidenhain pouch, by using the putative mu-opioid receptor agonist dermorphin, the delta-opioid receptor agonist [D-Ala2,D-Leu5]enkephalin (DADLE) and the kappa-opioid receptor agonist dynorphin-(1-13). Dermorphin caused a significant increase in basal acid secretion from both the gastric fistula and the Heidenhain pouch, while DADLE and dynorphin-(1-13) did not. Acid secretion stimulated by 2-deoxy-D-glucose from the gastric fistula was not modified by dermorphin and dynorphin-(1-13), while DADLE significantly inhibited it; at the same time gastric secretion from the Heidenhain pouch was significantly increased by dermorphin and unmodified by DADLE and dynorphin-(1-13). Dermorphin, DADLE or dynorphin-(1-13) did not modify plasma gastrin during basal or 2-deoxy-D-glucose-stimulated conditions. Submaximal bethanechol-stimulated secretion was increased by dermorphin and DADLE but unaffected by dynorphin-(1-13). Acid secretion from the gastric fistula stimulated by pentagastrin was enhanced by dermorphin, inhibited by DADLE and unaffected by dynorphin-(1-13). Dermorphin and DADLE significantly increased acid secretion from the Heidenhain pouch stimulated by pentagastrin, while dynorphin-(1-13) was ineffective. Naloxone prevented the stimulatory effects of dermorphin and DADLE on the Heidenhain pouch, but it reduced acid secretion from the gastric fistula further when given with DADLE. The inhibitory effects of DADLE on secretion from the gastric fistula were prevented by naltrindole, a selective antagonist of delta-opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

[Congenital cysts of the liver. Their instrumental diagnosis and the indications for surgical treatment]. / Cisti congenite del fegato. Diagnosi strumentale e indicazioni al trattamento chirurgico.

The authors report their experience of 8 cases of congenital cysts of the liver describing instrumental examinations used for diagnosis and different surgical operation performed. The Authors believe that the choice of surgical procedure, performed in symptomatic patients and large cysts, has to be according to different parameters as morphology and localization of the cysts and coexisting pathologies. Being non-malignant pathology, conservative surgery often avoids the complications of liver resection.

Surgical management of adrenal cortical carcinoma.

The experience with the surgical management of 14 patients with adrenal cortical carcinoma is presented. Four patients were males and 10 females (mean age: 37 years). Seven patients (50%) has proven hormonal activity and 7 (50%) had "non functioning" tumors. The location of carcinoma involved the left adrenal gland in 9 cases, the right in 3 and it was bilateral in 2. The mean diameter of the mass was 10 cm. The most helpful diagnostic tests were shown to be sonography and computed tomography. The surgical procedure was chosen according to the patients condition: this included resection of primary lesion and excision of local lymph nodes and all involved structures. Adjuvant treatment with either mitotane, 5-FU or local irradiation did not result in any benefit with respect to the expected survival. There was a slightly better survival for functioning versus non functioning tumors. Surgery remains the treatment of choice for these tumors. Prognosis is exceedingly poor: only 5 patients (36%) have survived beyond two years after surgery.

Specific technical note concerning the preparation of distal rectal anastomoses.

The present increase of distal conolorectal anastomoses is certainly due to the desire of surgeons to conserve the natural routes of intestinal transit. With the exception of unusual, and in some cases debateable indications, such as haemorrhagic rectocolitis or Crohn's disease, most distal anastomoses involve cancer. At present, the main interest in distal rectal anastomoses is focussed on the choice of operating technique: manual or mechanical. In the opinion of the author, the decisive factor in favour of the use of Staplers was the substantial reduction of the incidence of dehiscence from 16 to 5 percent.