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Biomedical subjects

Ran Oren

Publications and source records attributed to Ran Oren.

At least 19 recordsLinked to original sources
PubMed2006

NAFLD and hyperinsulinemia are major determinants of serum ferritin levels.

BACKGROUND/AIMS: There is an increasing body of evidence that serum ferritin is associated with the metabolic syndrome. However, no study has tested for NAFLD. The aim was to test the assumption that the association between serum ferritin and the metabolic syndrome is mediated by NAFLD. METHODS: A cross-sectional study of a sub-sample of the first Israeli national health survey. Exclusion criteria were any known etiology for secondary NAFLD. Participants underwent an abdominal ultrasound (US), biochemical tests, and dietary and anthropometric evaluations. RESULTS: Three hundred and forty-nine subjects were included in the analysis. Serum ferritin was higher in the NAFLD group (92.4+/-63.1 vs. 65.1+/-58.0, P<0.001). After adjusting for age and gender, the following variables were significantly associated with increased ferritin levels: abdominal obesity, hyperglycemia, hyperinsulinemia, HOMA, hypertriglyceridemia and the metabolic syndrome itself. After further adjusting for NAFLD, only abdominal obesity [2.1 (1.1-3.9)] and hyperinsulinemia [2.3 (1.3-4.2)] were still significantly associated with ferritin. In a multivariate analysis the interaction between NAFLD and hyperinsulinemia was the second strongest predictor of serum ferritin (P=0.005). CONCLUSIONS: The association between serum ferritin and the metabolic syndrome is mediated by undiagnosed NAFLD. The interaction between NAFLD and hyperinsulinemia is a major determinant of serum ferritin levels at the population level.

Abdominal Fat↗
PubMed2006

A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Few controlled studies have addressed the issue of effective medical treatment for nonalcoholic fatty liver disease (NAFLD). We herein assessed the effect of orlistat in patients with NAFLD. METHODS: We performed a randomized, double-blind, placebo-controlled study on 52 patients with NAFLD diagnosed by ultrasound (US) and confirmed by liver biopsy (40 patients). The patients were randomized to receive either orlistat (120 mg 3 times daily for 6 months) or placebo. All patients participated in an identical behavioral weight loss program. All patients underwent monthly evaluation by abdominal US; liver enzyme levels, lipid profiles, insulin levels, and anthropometric parameters were monitored, and all patients underwent nutritional follow-up evaluation. Twenty-two patients underwent a second liver biopsy examination at the end of the study. RESULTS: Fifty-two patients were recruited and 44 (mean age, 47.7 y; mean body mass index, 33) completed the study. Serum glucose and insulin levels (P<.03) were significantly higher in the orlistat group, which also presented a higher degree of fibrosis. Body mass index was reduced significantly in each group, with a nonsignificant difference between the groups. Serum alanine transaminase (ALT) levels decreased significantly in both groups, with an almost 2-fold reduction in the orlistat group (48% vs 26.4%). There was a statistically significant reversal of fatty liver by US only in the orlistat group (P<.05). CONCLUSIONS: Orlistat improves serum ALT levels and steatosis on US in NAFLD patients, beyond its effect on weight reduction.

Adolescent↗
PubMed2006

Budd-Chiari syndrome and acute portal vein thrombosis: management by a transjugular intrahepatic portosystemic shunt (TIPS) and portal vein interventions via a TIPS.

Acute portal vein thrombosis (PVT) is a devastating complication of Budd-Chiari syndrome (BCS). Conservative approach, anticoagulation, systemic or transarterial thrombolysis, and urgent liver transplantation were applied in this scenario but with poor results. We present and discuss an approach to treat BCS complicated by acute PVT. Two young female patients presented with acute liver failure, rapidly progressive tense ascites, renal- and respiratory failure. The diagnosis of chronic BCS complicated by acute PVT was confirmed with ultrasound Doppler. Initial treatment was supportive. Right portal vein localization was by transarterial portogram or by computed tomography-guided microcoil placement. Transjugular intrahepatic portosystemic shunt (TIPS) was performed and included Wallstents and a Jograft in one case and Viatorr stentgraft that was extended later with a Hemobahn stentgraft in another. Mechanical clot removal from the portal system was performed in the primary procedure and in a revision procedure in the following few days. Stents were placed precisely with no extension into the inferior vena cava or deeply into the main portal vein. Patients were fully anticoagulated and patency was assessed by ultrasound Doppler. The procedures were performed on days 5 and 10 following admission. In both cases, successful thrombectomies were revised and maintained. Partial occlusion of the TIPS and reaccumulation of ascites were reversed with repeated procedure. Both patients were discharged without ascites and normal liver function. In conclusion, urgent TIPS and portal vein thrombectomy via TIPS are emerging therapeutic options that offer a safe and effective treatment to patients with BCS complicated by acute portal vein thrombosis.

Acute Disease↗
PubMed2006

Role of CYP2D6 polymorphism in predicting liver fibrosis progression rate in Caucasian patients with chronic hepatitis C.

OBJECTIVE: Previous studies have demonstrated that CYP2D6 polymorphism is associated with liver cirrhosis. The aim of the present study was to find out whether CYP2D6*4, the poor metabolizer allele can predict fibrosis progression rate. METHODS: Seventy-five Caucasian patients with chronic hepatitis C infection were recruited. They were divided into two groups, 'fast fibrosers' and 'slow fibrosers', according to Poynard's fibrosis progression curves. Sixty-two patients underwent liver biopsy. Twenty healthy neonates were included as control population. DNA was extracted from peripheral blood and CYP2D6*4 was tested by polymer chain reaction using fluorescent hybridization probes in a lightCycler instrument. RESULTS: Forty-two patients were classified as 'fast fibrosers' and 33 patients as 'slow fibrosers'. The frequency of CYP2D6*4 allele in the 'fast fibrosers' (34.5%) was significantly higher compared with the 'slow fibrosers' (15%) (P-value=0.007). There was no significant difference between the frequency of CYP2D6*4 in the 'slow fibrosers' (15%) compared with the controls (12.5%). Carrier state of CYP2D6*4 was the only covariate that was significantly positively correlated with fast progression to cirrhosis (odds ratio=6.5, P=0.01). CONCLUSION: This study indicates for the first time that CYP2D6 genotype might be a significant predictor of liver fibrosis progression rate in chronic hepatitis C patients.

Adult↗
PubMed2006

Re-evaluation of serum alanine aminotransferase upper normal limit and its modulating factors in a large-scale population study.

BACKGROUND: The upper normal limit (ULN) of serum alanine-aminotrasferase (ALT) normal range was recently challenged, because patients diagnosed with liver diseases may have 'normal' or near-'normal' ALT levels, and because possible modulators are often ignored in determining normal range. AIM: To estimate the ULN for serum ALT and to identify factors modulating it. SUBJECTS AND METHODS: We reviewed medical records of subjects aged 15-90, who underwent standard panels of laboratory tests, including serum ALT, over 6 months at a central laboratory. Three groups were defined: Group 1, comprised total study population (N=272 273). Group 2 (N=87 020) comprised total study population, excluding those receiving potentially hepatotoxic drugs, or diagnosed with liver disease, or had any abnormal laboratory test results other than for triglycerides, cholesterol, glucose, or HbA1c. Group 3 (N=17 496) the 'healthy' population, from whose ALT values we established the new ULN, comprised Group 2 subjects with normal triglycerides, cholesterol, glucose, and HbA1c levels. RESULTS: The 95th percentile ALT values, corresponding to the ULN, in groups 1, 2, and 3 were 50.1, 40, and 37.5 U/l, respectively. 6.2% (16 943/273 273) of subjects whose ALT was below ULN listed by the test manufacturer (52 U/l), had ALT level above our new ULN. Linear and logistic-regression analyses showed that ALT levels were significantly modified by gender, age, glucose, cholesterol, triglycerides, and overweight/obesity diagnosis. Significant interaction was found between gender, glucose and cholesterol levels. CONCLUSIONS: In this first large-scale study of 'healthy' population, serum ALT ULN was far lower than currently accepted value. Age and gender may be considered when determining the ULN for ALT.

Adolescent↗
PubMed2006

Prevalence of primary non-alcoholic fatty liver disease in a population-based study and its association with biochemical and anthropometric measures.

BACKGROUND/AIMS: Only a few studies have assessed the epidemiology of non-alcoholic fatty liver disease (NAFLD). The aim was to evaluate the prevalence of primary NAFLD in a population-based study in Israel and to determine independent risk factors. METHODS: A cross-sectional study of a subsample of the Israeli national health survey (n=352). Individuals with a known etiology for secondary NAFLD were excluded. Each participant underwent an abdominal ultrasound, biochemical tests and an anthropometric evaluation. RESULTS: Three hundred and twenty-six subjects (53.4% male, mean age 50.5+/-10.3 standard deviaton [SD]) met the inclusion criteria. The prevalence of primary NAFLD was 30% (25-35% 95% confidence intervals [CI]). NAFLD was more prevalent in men than women (38% vs. 21%; P=0.001). Compared with ultrasonography, the sensitivity of serum alanine transaminase (ALT) for the diagnosis of primary NAFLD was 8.2%. Risk factors independently associated with NAFLD included male gender (odds ratios (OR)=2.8, 95% CI 1.5-5.3), abdominal obesity (OR=2.9, 95% CI 1.3-6.4), homeostasis model assessment (OR=5.8, 95% CI 2.0-17.2), hyperinsulinemia (OR=2.3, 95% CI 1.2-4.3, P=0.01) and hypertriglyceridemia (OR=2.4, 95% CI 1.3-4.5). CONCLUSIONS: NAFLD is prevalent in the general Israeli population and closely related to the metabolic syndrome. The use of ALT as a marker for NAFLD seriously underestimates its prevalence.

Adult↗
PubMed2006

Is the model of end-stage liver disease (MELD) valid in Israel? A critical analysis of liver transplant waiting list mortality.

BACKGROUND: The model for end-stage liver disease is the best available predictor of waiting list mortality among liver transplant candidates. OBJECTIVES: To validate the applicability of MELD in Israel. METHODS: All candidates awaiting liver transplantation in our institution were followed prospectively since 2002. We measured the concordance (c-statistic) equivalent to the area under the receiver operating characteristic curve in order to assess the predictive power of MELD. Other independent mortality risk factors were identified by a separate multivariate analysis. Mortality rates within different MELD and Child-Pugh-Turcotte scores were compared to the original (United States) MELD data. RESULTS: Of 86 patients listed for transplantation, 40 were transplanted (36 in Israel and 4 abroad). Of the other 46 patients, 24 are alive and still listed, and 22 died (25%, approximately 7%/year). The area under the ROC curve for MELD score was 0.79 (0.83 USA) compared to a CPT score of 0.71 (0.76 USA). High MELD scores, occurrence of spontaneous bacterial peritonitis, and diagnosis of hepatocellular carcinoma were independent risk factors of mortality. Death rates per mid-MELD score (20-29) were significantly higher than the USA results. CONCLUSIONS: MELD is valid in Israel and superior to CPT in predicting waiting list mortality. Although longer waiting time due to organ scarcity is a key factor, death rates in the mid-range (10-29) MELD groups indicate further audit of the care of patients with end-stage liver disease.

Female↗
PubMed2005

Whole fetal liver transplantation--a new approach to cell therapy.

We recently developed a novel rat model for liver repopulation, heterografting of microliver slices, aimed at overcoming the limitations inherent in both whole liver and hepatocyte transplantations. The aim of the present study was to evaluate the potential of whole fetal liver transplantations to survive and differentiate within the adult liver, using the adult liver slice transplantation model. Embryonic day 14 whole fetal livers from dipeptidyl peptidase IV+/+ wild-type Fischer 344 rats were transplanted into the livers of dipeptidyl peptidase IV-/- mutant rats. Adult hepatic markers, dipeptidyl peptidase IV, albumin, glycogen, and proliferation cell nuclear antigen- proliferation cell nuclear antigen (PCNA) were assessed in the transplanted liver tissue by immunohistochemistry. Two groups of 9 rats each were transplanted with 3 fetal livers per recipient. Two months later the rats were sacrificed and the markers were detected in the transplanted tissues. In conclusion, the results of this study raise the possibility that fetal liver transplantation could serve as a model for genetic metabolic liver diseases.

Albumins↗
PubMed2005

Optimal dosing frequency of pegylated interferon alfa-2b monotherapy for chronic hepatitis C virus infection.

BACKGROUND & AIMS: Pegylated interferon alfa-2b (PEG-IFN-alfa 2b ) has been shown to provide superior efficacy to IFN-alfa 2b in patients with chronic hepatitis C (predominantly genotype 1) infection as measured by viral clearance. This study was conducted to determine the optimal dosing regimen of PEG-IFN-alfa 2b required to obtain a maximum decrease of hepatitis C viral RNA. METHODS: This was a 24-week, open-label, multicenter, parallel-group, randomized, active-controlled trial in the United Kingdom, France, and Israel. Individuals (n = 61) with chronic hepatitis C infection, genotype 1, received IFN-alfa 2b 3 mIU 3 times weekly for 24 weeks, or PEG-IFN-alfa 2b 1.5 or 3.0 microg/kg/wk, as total weekly full or split doses, for 12 weeks. At week 12, serum RNA titer was measured, and all PEG-IFN-alfa 2b patients continued with 1.5 microg/kg/wk for a further 12 weeks. RESULTS: Mean serum hepatitis C RNA levels decreased in all groups at weeks 12 and 24. PEG-IFN-alfa 2b 1.5 microg/kg/wk was superior to IFN-alfa 2b in decreasing mean serum hepatitis C RNA ( P < .05 at week 12). The efficacy of split-dose PEG-IFN-alfa 2b 1.5 or 3.0 microg/kg/wk regimens was not significantly different from full-dose PEG-IFN-alfa 2b 1.5 microg/kg/wk. However, there was a significant decrease in neutrophil count in groups receiving PEG-IFN-alfa 2b 3.0 microg/kg/wk or lower, multiple-dose per week regimens. CONCLUSIONS: PEG-IFN-alfa 2b 1.5 microg/kg once weekly is the optimal dosing frequency for patients with chronic hepatitis C with predominantly genotype 1 infection. More frequent dosing or increasing the dose to 3.0 microg/kg/wk did not result in improved antiviral effects, but did decrease neutrophil counts.

Adolescent↗
PubMed2005

Nicotinamide induces apoptosis and reduces collagen I and pro-inflammatory cytokines expression in rat hepatic stellate cells.

OBJECTIVE: Nicotinamide has been shown to inhibit proliferation and induce apoptosis in a variety of cells. Moreover, nicotinamide treatment attenuates collagen accumulation and fibrogenesis in the bleomycin model of lung fibrosis. We hypothesized that nicotinamide may be useful as an antifibrotic agent in liver fibrosis and we investigated the in vitro effect of nicotinamide on hepatic stellate cells proliferation, apoptosis and collagen I expression. MATERIAL AND METHODS: Transforming growth factor beta1 (TGF-beta1) was used for activation of the rat HSC-T6 cell line. Apoptosis was determined by fluorescence activated cell sorter (FACS) analysis after propidium iodide staining and by immunohistochemistry showing presence of the active form of caspase 3. Expression of activation marker alpha-smooth muscle actin (alpha-SMA), apoptotic and cell cycle markers cyclin D1, P53 and caspase 3 was determined by Western blotting. Collagen I expression was assessed by Northern blotting. RESULTS: Nicotinamide inhibits hepatic stellate cell proliferation and induces apoptosis with caspase-3 activation. There is no effect of nicotinamide on the levels of cell cycle stimulator cyclin D1. Expression of p53 is induced in the presence of nicotinamide. Nicotinamide reduces activation marker alpha-SMA and decreases both basal and TGFbetaepsilon-induced collagen I expression. Moreover, in TGFbeta-activated cells, nicotinamide reduces expression of pro-inflammatory and pro-fibrotic cytokines TGFbeta2, IL-1beta, TNFalpha and macrophage chemotactic protein-1. CONCLUSIONS: The in vitro effect of nicotinamide on activation and proliferation of hepatic stellate cells suggests that nicotinamide may have a potential beneficial role in attenuation of liver fibrogenesis.

Actins↗
PubMed2005

Solid splenic masses: evaluation with 18F-FDG PET/CT.

UNLABELLED: Our objective was to assess the role of (18)F-FDG PET/CT in the evaluation of solid splenic masses in patients with a known malignancy and in incidentally found lesions in patients without known malignancy. METHODS: Two groups of patients were assessed: (a) 68 patients with known malignancy and a focal lesion on PET or a solid mass on CT portions of the PET/CT study; and (b) 20 patients with solid splenic masses on conventional imaging without known malignancy. The standard of reference was histology (n = 16) or imaging and clinical follow-up (n = 72). The lesion size, the presence of a single versus multiple splenic lesions, and the intensity of (18)F-FDG uptake expressed as a standardized uptake value (SUV) were recorded. The ratio of the SUV in the splenic lesion to the background normal splenic uptake was also calculated. These parameters were compared between benign and malignant lesions within each of the 2 groups of patients and between the 2 groups. RESULTS: The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of (18)F-FDG PET/CT in differentiating benign from malignant solid splenic lesions in patients with and without malignant disease were 100%, 100%, 100%, and 100% versus 100%, 83%, 80%, and 100%, respectively. In patients with known malignant disease, an SUV threshold of 2.3 correctly differentiated benign from malignant lesions with the sensitivity, specificity, PPV, and NPV of 100%, 100%, 100%, and 100%, respectively. In patients without known malignant disease, false-positive results were due to granulomatous diseases (n = 2). CONCLUSION: (18)F-FDG PET can reliably discriminate between benign and malignant solid splenic masses in patients with known (18)F-FDG-avid malignancy. It also appears to have a high NPV in patients with solid splenic masses, without known malignant disease. (18)F-FDG-avid splenic masses in patients without a known malignancy should be further evaluated as, in our series, 80% of them were malignant.

Adolescent↗
PubMed2005

Donor recruitment and selection for adult-to-adult living donor liver transplantation in urgent and elective circumstances.

BACKGROUND: Adult-to-adult living donor liver transplantation is becoming an alternative to cadaveric transplantation in urgent and elective settings. Donor selection crucially affects donor safety and recipient outcome. OBJECTIVE: To present our algorithm of urgent and elective donor selection. METHODS: Urgent selection is expeditious and protocol-based. Elective selection permits a comprehensive process. Both include medical, psychosocial and surgical-anatomic evaluations. Liver volumes and vascular anatomy are evaluated with computerized tomographic angiography. Informed consent is obtained after painstaking explanations. Independent institutional committees review and approve all cases. RESULTS: Between July 2003 and June 2004 we evaluated 43 potential live donors for 12 potential recipients (fulminant hepatic failure, n = 5; chronic end-stage liver disease, n = 6; primary graft non-function, n = 1). Thirty-three candidates (76%) were excluded due to blood type incompatibility (n = 14, 42%), incompatible anatomy (n = 8, 24%)--including problematic volume distribution (n = 2) or vascular anatomy (n = 6)--psychosocial issues (n = 4, 12%), or medical co-morbidity (n = 7, 22%). Five recipients (FHF, n = 4; chronic ESLD, n = 1) were successfully transplanted from living donors. In the acute setting, two patients (FHF, PGNF) died in the absence of an appropriate donor (cadaveric or living donor). In the elective group, one patient died of unexpected variceal bleeding and one received a cadaveric graft just before the planned living donor transplantation was performed. One candidate was transplanted overseas and two cases are scheduled. The ratio of compatibility for donation was 34% (10/29) for blood type-compatible candidates. CONCLUSIONS: Donor selection for living donor liver transplantation is a complex, labor-intensive multidisciplinary process. Most exclusions are due to blood type incompatibility or anatomic details. Psychosocial aspects of these donations warrant special attention.

Adolescent↗
PubMed2004

Chimeric molecule IL-6/soluble IL-6 receptor is a potent mitogen for fetal hepatocytes.

A novel recombinant molecule, termed IL-6c and consisting of a chimera of interleukin 6 (IL-6) and its soluble receptor is extremely potent in stimulating proliferation of hematopoietic progenitors. We investigated the effect of the IL-6c on the proliferation and differentiation of E14 fetal hepatocytes. IL-6c, in a dose-dependent manner, stimulated proliferation of E14 fetal rat hepatocytes. Adult hepatocyte mitogens together with IL-6c showed no further effect on proliferation. Hematopoietic stem cells mitogens SCF and flt3 ligand (FL) were also mitogenic for fetal hepatocytes, but did not further enhance the effect of IL-6c on cell proliferation. IL-6c decreased expression of fetal markers alpha-fetoprotein (AFP) and gamma-glutamyltranspeptidase, and induced expression of adult enzyme glucose-6-phosphatase (Gluc-6-P) in E14 hepatocytes. On the other hand, IL-6c strongly reduced, in a dose-dependant manner, expression of albumin and tyrosine aminotransferase (TAT). However, when the cells were grown for 3 days with IL-6c, and IL-6c was removed for the next 5 days, expression of albumin and TAT returned to levels found in control cultures. In conclusion, IL-6c stimulated proliferation and affected gene expression in fetal hepatocytes in culture.

Adenosine Triphosphatases↗
PubMed2004

Initial experience with urgent adult-to-adult living donor liver transplantation in fulminant hepatic failure.

BACKGROUND: The prognosis of patients with fulminant hepatic failure without timely liver transplantation is dismal. Given the limited availability of cadaveric organs for urgent transplantation in Israel, adult-to-adult living donor segmental liver transplantation may be the only alternative. OBJECTIVES: To report our initial experience with urgent lifesaving LDLT in this unique scenario. METHODS: Three adult patients with FHF (two of unknown etiology, one with paracetamol intoxication) were transferred from other institutions and admitted to our intensive care unit. Initial treatment and monitoring included intracranial pressure monitoring and hepatic dialysis using the Molecular Adsorbent Recirculating System. Expeditious potential donor selection included medical, psychosocial and surgical evaluation. Liver volume and vascular anatomic compatibility were assessed with computed tomography angiography. RESULTS: Between July and October 2003 we performed three procedures of urgent adult-to-adult LDLT. The donors (two uncles, one sister) underwent hepatic resection (two right lobes, one left lateral segment) and recovered well. The recipients underwent total hepatectomy with caval preservation, followed by lobar grafting. All recipients recovered and are alive with good liver function and without any neurologic complications. CONCLUSIONS: Urgent adult-to-adult living donor segmental liver transplantation can be performed safely and timely as a lifesaving procedure in the setting of comatose patients with FHF.

Adolescent↗
PubMed2003

Gliotoxin ameliorates development of fibrosis and cirrhosis in a thioacetamide rat model.

Activation of hepatic stellate cells causes most of the pathological changes in cirrhosis. The fungal metabolite gliotoxin was shown to induce apoptosis of hepatic stellate cells in vitro. We examined whether gliotoxin may prevent or reverse liver fibrosis in a rat model of thioacetamide-induced cirrhosis, and whether gliotoxin administration in vivo causes apoptosis of activated stellate cells. Gliotoxin treatment resulted in a significant decrease in liver fibrosis in rats, but did not improve liver functions. We observed a significant reduction in the numbers of activated hepatic stellate cells in the gliotoxin-treated rats. Gliotoxin administration also resulted in parenchymal apoptosis of hepatocytes and hepatic stellate cells. In conclusion, gliotoxin reduces hepatic fibrosis, an effect accompanied by reduction of the numbers of activated hepatic stellate cells in the liver.

Animals↗