Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown. METHODS: In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). RESULTS: A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting. CONCLUSIONS: Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.).

Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: new evidence on the potential therapeutic mechanism.

UNLABELLED: Pentoxifylline (PTX) improved the histological features of nonalcoholic steatohepatitis (NASH) in a recent randomized placebo-controlled trial. However, the underlying mechanism responsible for the beneficial effects of PTX in NASH remains unidentified. A key role of lipid oxidation in the pathogenesis and progression of NASH has been established. PTX is known to decrease free-radical-mediated oxidative stress and inhibit lipid oxidation. The primary aim of this study was to evaluate the effects of PTX on levels of lipid oxidation products in patients with NASH. Levels of multiple structurally specific oxidized fatty acids including hydroxy-octadecadienoic acids (HODEs), oxo-octadecadienoic acids (oxoODEs), and hydroxy-eicosatetraenoic acids (HETEs) were quantified by mass spectrometry in plasma obtained at baseline and at study completion in patients who completed 1 year of therapy with PTX or placebo in a randomized controlled trial. Therapy with PTX resulted in significant decreases in 9-HODE and 13-oxoODE, oxidized lipid products of linoleic acid (LA) linked to histological severity in nonalcoholic fatty liver disease. Similarly, PTX therapy was associated with significant decreases in 8-HETE, 9-HETE, and 11-HETE compared to placebo. Statistically significant correlations were demonstrated between the decrease in HODEs and oxoODEs and improved histological scores of fibrosis and between the decrease in HETEs and improved lobular inflammation. CONCLUSION: Therapy with PTX compared to placebo was associated with a significant reduction of oxidized fatty acids. This novel evidence supports that the beneficial effects of PTX in patients with NASH are likely partly mediated through decreasing lipid oxidation, largely free-radical-mediated lipid oxidation. Additionally, this is the first report on the link between decreased oxidized lipid products and improved histological disease in the setting of a therapeutic trial in NASH.

Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial.

UNLABELLED: The primary aim of this study was to compare the effects of pentoxifylline (PTX) versus placebo on the histological features of nonalcoholic steatohepatitis (NASH). In all, 55 adults with biopsy-confirmed NASH were randomized to receive PTX at a dose of 400 mg three times a day (n = 26) or placebo (n = 29) over 1 year. The primary efficacy endpoint was defined as improvement in histological features of NASH through reduction in steatosis, lobular inflammation, and/or hepatocellular ballooning as reflected by a decrease of ≥ 2 points in the nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 1 year, intention-to-treat analysis showed a decrease of ≥ 2 points in the NAS in 38.5% of patients on PTX versus 13.8% of those on placebo (P = 0.036). Per protocol analysis, a decrease of ≥ 2 points in the NAS from baseline was observed in 50% of the patients on PTX versus 15.4% of those on placebo (P = 0.01). The mean change in NAS score from baseline was -1.6 in the PTX group, versus -0.1 in the placebo group (P < 0.001). PTX significantly improved steatosis (mean change in score -0.9 versus -0.04 with placebo, P < 0.001) and lobular inflammation (median change -1 versus 0 with placebo, P = 0.02). No significant effects in hepatocellular ballooning were observed. PTX also improved liver fibrosis (mean change in fibrosis score was -0.2 among those on PTX versus +0.4 among those on placebo, P = 0.038). Although not statistically significant (P = 0.17), improvement in fibrosis was observed in a greater proportion (35%) of patients in the PTX group compared to placebo (15%). Adverse effects were similar in both groups. CONCLUSION: PTX improved histological features of NASH compared to placebo. PTX was well tolerated in patients with NASH.

Prevalence of hypothyroidism in nonalcoholic fatty liver disease.

BACKGROUND: A possible association between nonalcoholic fatty liver disease (NAFLD) and hypothyroidism has been suggested. The recognized link between hypothyroidism and elements of the metabolic syndrome may explain this association. AIM: The purpose of this study was to determine the prevalence of hypothyroidism in a cohort of patients with NAFLD and analyze the potential factors associated with hypothyroidism in this patient population. METHODS: Two hundred forty-six patients with biopsy-proven NAFLD attending hepatology clinics at the Cleveland Clinic between October 2006 and June 2009, and 430 age-, gender-, race- and BMI-matched control subjects seen in the general internal medicine clinic were included. Patients with a clinical diagnosis of hypothyroidism who were on thyroid replacement therapy were considered to be hypothyroid. RESULTS: Hypothyroidism was more frequent among patients with NAFLD (21% vs. 9.5%; P < 0.01) compared to controls, and was higher in NASH patients than NAFLD patients without NASH (25% vs. 12.8%, P = 0.03). Subjects with hypothyroidism were 2.1 (95% CI 1.1-3.9, P = 0.02) and 3.8 (95% CI 2-6.9, P < 0.001) times more likely to have NAFLD and NASH, respectively. By multivariate analysis, female gender (P < 0.001) and increased BMI (P = 0.03) were associated with hypothyroidism. NAFLD subjects who reported mild alcohol consumption were less likely to have hypothyroidism compared to those who reported complete abstinence (OR 0.37, P = 0.008). CONCLUSIONS: A higher prevalence of hypothyroidism was demonstrated in patients with NAFLD compared to controls. Among subjects with NALFD, female gender, increased BMI and history of abstinence from alcohol were associated with hypothyroidism. Patients with hypothyroidism were also more likely to have NASH.

Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Although many predictors of disease severity of nonalcoholic fatty liver disease (NAFLD) have been proposed, studies of the potential effects of specific environmental exposures on human NAFLD are lacking. Smoking increases insulin resistance. Given the pathophysiological role of insulin resistance in NAFLD, characterization of the influence of smoking in NAFLD is warranted. The aim of this paper was to study the potential association between cigarette smoking and advanced fibrosis in NAFLD. METHODS: All adults enrolled in the NASH CRN studies, between October 2004 and February 2008, who had liver biopsies, were included (n=1091). Advanced fibrosis was defined as stages 3-4. Analyses were performed. RESULTS: Significant bivariate associations were demonstrated between advanced fibrosis and age, gender, ethnicity, diabetes, and smoking history. History of smoking ≥ 10 pack-years was more common (p <0.0001) among patients with advanced fibrosis. Multivariate analysis demonstrated an association between smoking history of ≥ 10 pack-years and advanced fibrosis (OR=1.63). Among non-diabetics, history of ≥ 10 pack-years was associated with an OR of 2.48 for advanced fibrosis. High frequencies of advanced fibrosis were observed among diabetics (with or without ≥ 10 pack-years history) and non-diabetics with ≥ 10 pack-years history as compared to non-diabetics without significant smoking history. CONCLUSIONS: Smoking history was associated with advanced liver fibrosis in this large multicenter cohort of NAFLD patients. The results indicate that smoking may enhance the progression of NAFLD partly through its effect on insulin resistance. Our results are consistent with recent animal studies suggesting that cigarette smoke may aggravate fatty liver. To our knowledge, this is the first study to show that cigarette smoking is associated with increased fibrosis severity in human NALFD, suggesting it may accelerate disease progression. These results may support a formal recommendation of smoking cessation in patients with NAFLD.

Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease.

UNLABELLED: The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) was formed to conduct multicenter studies on the etiology, contributing factors, natural history, and treatment of nonalcoholic steatohepatitis (NASH). The aim of this study was to determine the associations of readily available demographic, clinical, and laboratory variables with the diagnosis of NASH and its key histological features, and determine the ability of these variables to predict the severity of nonalcoholic fatty liver disease (NAFLD). A total of 1266 adults were enrolled in NASH CRN studies between October 2004 and February 2008, of whom 1101 had available liver histology. The median age was 50 years; 82% were white and 12% Hispanic. The median body mass index was 33 kg/m(2); 49% had hypertension and 31% had type 2 diabetes. On liver biopsy, 57% were judged to have definite NASH and 31% bridging fibrosis or cirrhosis. Using data from the 698 patients with liver biopsies within 6 months of clinical data, patients with definite NASH were more likely to be female and have diabetes, higher levels of aspartate and alanine aminotransferases, alkaline phosphatase, gamma glutamyl transpeptidase, and homeostasis model assessment of insulin resistance (HOMA-IR). Progressive models for predicting histological diagnoses performed modestly for predicting steatohepatitis or ballooning (area under receiver operating characteristic curves [AUROC] ranged from 0.70-0.79), and better for advanced fibrosis (AUROC 0.73-0.85). CONCLUSION: Readily available clinical and laboratory variables can predict advanced fibrosis in adults with NAFLD, but additional information is needed to reliably predict the presence and severity of NASH. Prospective studies of this well-characterized population and associated tissue bank samples offer a unique opportunity to better understand the cause and natural history of NAFLD and develop more precise means for noninvasive diagnosis.

Latest and emerging therapies for primary biliary cirrhosis and primary sclerosing cholangitis.

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the two most common causes of chronic cholestatic liver disease in adults. In PBC, therapy with ursodeoxycholic acid (UDCA) is safe and has been associated with tangible biochemical, histologic, and survival benefits. However, a need for different or adjuvant therapies remains for specific subsets of PBC patients, including those who do not respond to UDCA and those who have advanced histologic disease at presentation. Similarly, beneficial therapies for disease-related symptoms that do not typically respond to UDCA (eg, fatigue and pruritus) are still needed. In contrast to PBC, no medical therapy of proven benefit has been identified for patients with PSC. In PBC and PSC, adequate management of complications of chronic cholestasis is important. For both diseases, liver transplantation is the only curative option.

Diabetes mellitus is associated with impaired response to antiviral therapy in chronic hepatitis C infection.

UNLABELLED: Insulin resistance may promote hepatic fibrosis in chronic hepatitis C (HCV) and has emerged as a cofactor in failure to achieve sustained viral response (SVR). AIMS: (1) To assess the association of diabetes mellitus (DM) in HCV patients to the severity of hepatic fibrosis and to the response to antiviral treatment. (2) To assess the safety of pegylated interferon and ribavirin combination therapy (Peg IFN/RBV) in diabetic HCV patients. Methods HCV diabetics (n=61) were identified. A 2:1 matching control group was used to identify independent factors of advanced fibrosis and treatment failure. RESULTS: Compared to HCV non-diabetics, HCV diabetics were more likely to have steatosis (P<0.0001) and advanced fibrosis (P=0.003). Patients' age, Caucasian ethnicity, obesity, and histologic activity index were independently associated with advanced fibrosis (P<0.05). Only 23% of HCV diabetics achieved SVR compared to 46% of HCV non-diabetics (P=0.003). DM, genotype 1, high baseline viral load, and African- American ethnicity were independently associated with less SVR (P<0.05). Significant adverse events were more common in HCV diabetics compared to HCV non-diabetics (P=0.001). Side effects did not increase in patients receiving PEG IFN/RBV and insulin sensitizers. Conclusion DM was associated with impaired virologic response to PEG IFN/RBV in HCV patients. Adverse events during therapy were more frequent in diabetic compared to non-diabetic HCV patients.

Clinical significance of metabolic syndrome in the setting of chronic hepatitis C virus infection.

BACKGROUND & AIMS: The metabolic syndrome (MS) is a unique condition in which the underlying mechanism is related to insulin resistance. In hepatitis C virus (HCV) patients, insulin resistance has been linked to treatment failure. The aim of this study was to estimate the prevalence of MS in HCV patients undergoing antiviral therapy and to assess its predictive value in treatment outcome. METHODS: All HCV treatment-naive patients who met the inclusion/exclusion criteria were studied (n = 228). MS was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. A logistic regression analysis was performed to study multivariable associations. The final model contained sex, ethnicity, body mass index, viral load, genotype, steatosis, fibrosis stage, and MS. RESULTS: MS was present in 59 of 228 (26%) patients. Genotype 1 (P = .002) and presence of steatosis (P < .001) were found to be associated significantly with MS. Overall, sustained virologic response (SVR) was achieved in 108 of 228 (47%) patients. Male sex, non-Caucasian ethnicity, higher body mass index, high viral load, genotype 1, higher fibrosis stage, and MS were associated significantly with a lack of SVR. After adjusting for confounding variables, MS remained independently associated with a lack of SVR (P < .01). Specifically, subjects with MS were 3.8 (95% confidence interval, 1.4-10.5) times more likely to fail treatment than those without MS. CONCLUSIONS: MS is seen frequently in patients with chronic HCV and is associated independently to lack of SVR. These findings support the concept that an aggressive intervention approach comprising lifestyle modification alone or in combination with drug treatment of the MS components may play an important role in improving antiviral responses in these patients.

Prevalence and predictors of esophageal varices in patients with primary biliary cirrhosis.

BACKGROUND & AIMS: Esophageal varices and bleeding are among the most feared complications of primary biliary cirrhosis (PBC). We aimed to determine the prevalence of esophageal varices in patients with PBC, to evaluate noninvasive markers of esophageal varices in this population, and to validate the results in an independent set of patients. METHODS: Data were collected on all patients with PBC seen for the first time at the University of Florida (study group) and at Case Western Reserve University hospitals (cross-validation group) during 7 consecutive years. Logistic regression analysis was used to identify independent predictors of esophageal varices. The best cut-off values were calculated based on receiver operating characteristic curves. The diagnostic accuracy of the independent predictors of esophageal varices identified in the study group were retested in the cross-validation group. RESULTS: Of 210 patients with PBC seen at the University of Florida, 113 had an endoscopy and 49.6% (56 of 113) were found to have esophageal varices. After excluding 22 patients with a history of variceal bleeding, data on 91 patients were analyzed. Thirty-four patients had esophageal varices (37%). Multivariate analysis revealed that a platelet count of less than 140,000 (odds ratio, 7.6; 95% confidence interval, 1.6-37) and a Mayo risk score of 4.5 or greater (odds ratio, 10.6; 95% confidence interval, 1.8-62) were independent predictors of esophageal varices. The diagnostic accuracy of these predictors was confirmed in an independent set of patients. CONCLUSIONS: Among patients with PBC, a platelet count of less than 140,000 and/or a Mayo risk score of 4.5 or greater appears to identify those patients more likely to benefit from a screening endoscopy.

Advances in therapy for hepatitis C infection.

The first approved therapy for chronic hepatitis C virus (HCV) infection was recombinant interferon. Subsequently, controlled studies demonstrated that the combination of interferon-alpha and ribavirin leads to significantly higher virologic sustained responses in patients with chronic hepatitis C. A novel modification of the interferon molecule resulted in the formulation of pegylated interferons, which have a longer half-life than standard interferon. Two recent trials have established the superiority of pegylated interferons compared with interferon-alpha in inducing sustained virologic responses in patients with chronic HCV infection, with or without cirrhosis. Presumably, pegylated interferons will replace standard interferon in treating HCV infection. Phase 3 trials of pegylated interferons in combination with ribavirin are currently under way. Noninterferon-based therapies for the treatment of HCV infection are also in the developmental and experimental phases. Our aims in this review are to present the currently available therapeutic options for HCV infection and the evidence supporting their use in typical patients with chronic hepatitis C or in patients with special circumstances. We also briefly review novel therapeutic approaches, including noninterferon-based therapies.

Primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic, progressive, cholestatic liver disease characterized by multifocal strictures of intra and extrahepatic bile ducts. PSC occurs more commonly in men and is often associated with inflammatory bowel disease. At present, there is no effective medical therapy for PSC. Current management of patients with PSC is centered on endoscopic therapy of biliary strictures, management of complications of chronic cholestasis and of progressive liver disease, and close clinical monitoring for development of cholangiocarcinoma, as well as for timely referral for liver transplantation.

Predictors of steatohepatitis and advanced fibrosis in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease is the most common cause of chronic liver disease in the United States. The development of non-alcoholic steatohepatitis increases the risk for cirrhosis and its complications. The gold standard for diagnosis is liver biopsy, the costs and risks of which make it impractical. Some demographic factors, blood tests, and imaging studies can be used to predict a higher risk of steatohepatitis or advanced fibrosis, but are of limited sensitivity and specificity. More accurate predictors and scoring systems would allow identifying who would benefit most from liver biopsy and monitor disease progression and response to therapy.

Predictors and noninvasive identification of severe liver fibrosis in patients with chronic hepatitis C.

Diagnosis of severe fibrosis (stages III and IV) in hepatitis C has clinical implications. Our objective was to distinguish independent predictors of severe fibrosis and use them to identify patients with severe fibrosis without a liver biopsy. One hundred ninety-nine hepatitis C patients were included in the initial analysis to identify predictors of severe fibrosis. Univariate and multivariate analyses of 26 predetermined variables for significance in predicting severe fibrosis were performed. Based on the coefficient regression and P values, a scoring system was developed and applied to a second independent cohort (137 patients) for validation. In multivariate analysis, low platelet count, low albumin, aspartate transaminase level, history of blood transfusion, and hepatitis B core antibody were significant independent predictors of severe fibrosis. A scoring system (range, 0-9) was developed from the three variables with the lowest P values (platelet count, aspartate transaminase, and albumin). A cutoff point of 4 had 99% specificity and 94% positive predictive value. A cutoff point of 2 had 87% sensitivity and 95% negative predictive value. We conclude that severe fibrosis in hepatitis C may potentially be identified with a high degree of certainty in a substantial number of patients with a simple noninvasive scoring system.

Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: A cross validated retrospective assessment.

An epidemiological association between cigarette smoking and primary biliary cirrhosis (PBC) has been demonstrated. Our aim was to determine the relationship between smoking and severity of liver fibrosis at presentation in patients with PBC. All patients with PBC seen at the three major teaching hospitals of Case Western Reserve University between October 1998 and December 2005 were identified. Data obtained at the time of the first evaluation leading to the PBC diagnosis on 97 patients were collected. The cumulative number of cigarette packs smoked per year (pack-years) was calculated. Advanced histological disease was defined as Ludwig stages 3 or 4. Analyses were performed to determine associations between advanced histological disease, smoking and other variables related to liver fibrosis. Smoking history was more common (P = .0008) in patients with advanced histological disease at presentation compared to those with early disease. Among smokers, mean lifetime tobacco consumption was higher (P = .04) in cases with advanced histological disease at presentation (30 pack-years) compared to cases with early disease (17 pack-years). Logistic regression demonstrated a significant association between a lifetime tobacco consumption of > or =10 pack-years and advanced histological disease at presentation (OR = 13.3). The association remained significant after adjusting for age, gender, and alcohol intake. The validity of these results was corroborated by cross-validation in an independent confirmatory set of 172 patients with PBC. In conclusion, smoking may accelerate the progression of PBC. This could be induced by exposure to chemicals in cigarette smoke.

Chronic hepatitis C and type II diabetes mellitus: a prospective cross-sectional study.

An epidemiologic link between chronic hepatitis C (HCV) and type II diabetes mellitus (DM) has been established. Our aims were to prospectively determine the prevalence of DM in interferon-naive patients with HCV in comparison with the general population, and to determine the association between DM and impaired fasting glucose (IFG) with histological stage in patients with HCV. A consecutive sample of 179 patients was included in this prospective cross-sectional study. The crude percentage of DM for the cohort was 14.5%, different from the crude rate of 7.8% for the general population (p= 0.0008) and from the rate of 7.3% observed in a matched control group with non-HCV liver disease. The prevalence of DM and IFG (DM/IFG) was higher among HCV-infected patients with advanced versus those with early histological disease (p= 0.0004). Advanced histological disease predicted DM/IFG after controlling for other identified risk factors for DM. Family history was the only other independent predictor of DM/IFG in HCV-infected patients. In conclusion, patients with HCV had a higher prevalence of DM compared to the general population. The presence of advanced histological disease in genetically predisposed HCV-patients is associated with a higher prevalence of DM/IFG. DM and IFG were not associated with anthropomorphic markers of obesity in HCV patients, suggesting a unique multifactorial pathogenesis of DM in HCV.

Alendronate improves bone mineral density in primary biliary cirrhosis: a randomized placebo-controlled trial.

Bone loss is a well-recognized complication of primary biliary cirrhosis (PBC). Although it has been suggested that alendronate might improve bone mineral density (BMD) in PBC, no randomized placebo-controlled trial has been conducted. The primary aim of this study was to compare the effects of alendronate versus placebo on BMD and biochemical measurements of bone turnover in patients with PBC-associated bone loss. We conducted a double-blinded, randomized, placebo-controlled trial. Patients with a PBC and BMD t score of less than -1.5 were randomized to receive 70 mg per week of alendronate or placebo over 1 year. BMD of the lumbar spine and proximal femur were measured at entry and at 1 year. Changes from baseline in BMD and biochemical measurements of bone turnover were assessed. Thirty-four patients were enrolled. Seventeen patients were randomized to each arm. After 1 year, a significantly larger improvement (P = .005) in spine BMD was observed in the alendronate group (0.09 +/- 0.03 g/cm2 SD from baseline) compared with the placebo group (-0.003 +/- 0.02 g/cm2 SD from baseline). A larger improvement (P = .046) was also observed in the femoral BMD of alendronate patients versus placebo. BMD changes were independent of concomitant estrogen therapy. The rate of adverse effects was similar in both groups. In conclusion, in patients with PBC-related bone loss, alendronate significantly improves BMD compared with placebo. Although in this study oral alendronate appears to be well tolerated in patients with PBC, larger studies are needed to formally evaluate safety.

Prevalence and predictors of esophageal varices in patients with primary sclerosing cholangitis.

Patients with primary sclerosing cholangitis (PSC) may develop and bleed from esophageal varices. However, the exact prevalence of esophageal varices in patients with PSC remains unknown and potential predictors of esophageal varices in this population have not been identified. Our aim was to determine the prevalence of esophageal varices in patients with PSC and the variables that predict their presence. Data were collected on 283 patients with PSC treated for the first time at the Mayo Clinic (Rochester, MN) during 8 consecutive years. Thirty-six percent (102 of 283) of patients had esophageal varices including 56% (57 of 102) with moderate/large varices. After excluding 28 patients with a history of variceal bleeding, data on 183 patients were analyzed to identify independent predictors of esophageal varices and of moderate/large size varices. Platelet count, albumin level, and advanced histologic disease were independent predictors of esophageal varices (area under the receiver operator characteristic [ROC] curve = 0.88). After controlling for the presence of advanced histologic stage and albumin levels, the odds ratios (OR) of platelet count less than 150 x 10(3)/dL for the presence of esophageal varices was 6.3 (95% CI: 2.6-15.8). The diagnostic accuracy of these results was corroborated by cross-validation of the data in an independent set of 72 patients with PSC (area under the ROC = 0.90). In conclusion, in patients with PSC, noninvasive markers of portal hypertension and of advanced liver disease predict the presence of esophageal varices. Our results suggest a clinically applicable and useful approach to identify patients with PSC who are more likely to benefit from endoscopic screening for esophageal varices.

Clinical significance of hepatic iron deposition and serum iron values in patients with chronic hepatitis C infection.

OBJECTIVES: To assess the potential association between hepatic iron deposition or serum iron values and hepatic fibrosis and inflammatory activity in patients with chronic hepatitis C virus infection. METHODS: In 100 consecutive patients with hepatitis C virus infection, tissue iron deposition was assessed by quantifying iron stain on liver biopsy specimens. Serum iron, ferritin, and transferrin saturation were determined by standard laboratory procedures. Statistical analyses incorporated potential confounders associated with hepatic fibrosis. RESULTS: Twenty-one patients had no fibrosis (stage 0), 13 had portal fibrosis (stage 1), 31 had periportal fibrosis (stage II), 10 had bridging fibrosis (stage III), and 25 had cirrhosis (stage IV). Positive iron stain found in liver biopsy specimens of 19 patients was associated with stage III or IV fibrosis (p = 0.004). No significant difference was found between the iron concentration or the hepatic iron index in patients with stage III or IV fibrosis compared with patients with stage I or II fibrosis. At least 1 of 3 serum iron values assessed was abnormal in 55 patients. In univariate analysis, elevated serum iron (p = 0.01), serum ferritin (p < 0.001), and transferrin saturation (p = 0.002) were associated with stage III or IV fibrosis. In multivariate analysis, the only independent predictive factor of severe hepatic fibrosis was serum ferritin (p < 0.02; odds ratio = 11.35). The serum ferritin value and tissue iron stain had a significant positive correlation (p < 0.001). CONCLUSIONS: Increased hepatic iron deposition may be associated with more advanced hepatic fibrosis in patients with chronic hepatitis C virus infection. The serum ferritin value, an independent predictor of severe hepatic fibrosis in patients with chronic hepatitis C virus infection, may predict hepatic iron deposition and severity of fibrosis.