Risk Factors For Advanced Fibrosis Research Articles

Risk factors for biopsy-proven advanced non-alcoholic fatty liver disease in the Veterans Health Administration.

With its increasing incidence, nonalcoholic fatty liver disease (NAFLD) is of particular concern in the Veterans Health Administration (VHA). To evaluate risk factors for advanced fibrosis in biopsy-proven NAFLD in the VHA, to identify patients at risk for adverse outcomes. In randomly selected cases from VHA databases (2005-2015), we performed a retrospective case-control study in adults with biopsy-defined NAFLD or normal liver. Of 2091 patients reviewed, 399 met inclusion criteria. Normal controls (n=65) had normal liver function. The four NAFLD cohorts included: NAFL steatosis (n=76), nonalcoholic steatohepatitis (NASH) without fibrosis (n=68), NAFLD/NASH stage 1-3 fibrosis (n=82), and NAFLD/NASH cirrhosis (n=70). NAFLD with hepatocellular carcinoma (HCC) was separately identified (n=38). Most patients were older White men. NAFLD patients with any fibrosis were on average severely obese (BMI>35kg/m2 ). Diabetes (54.4%-79.6%) and hypertension (85.8%-100%) were more common in NAFLD with fibrosis or HCC. Across NAFLD, 12.3%-19.5% were enrolled in diet/exercise programs and 0%-2.6% had bariatric surgery. Hispanics exhibited higher rates of NASH (20.6%), while Blacks had low NAFLD rates (1.4%-11.8%), particularly NAFLD cirrhosis and HCC (1.4%-2.6%). Diabetes (OR 11.8, P<.001) and BMI (OR 1.4, P<.001) were the most significant predictors of advanced fibrosis. In the VHA, diabetes and severe obesity increased risk for advanced fibrosis in NAFLD. Of these patients, only a small proportion (~20%) had enrolled in diet/exercise programs or had bariatric surgery (~2%). These results suggest that providers should focus/tailor interventions to improve outcomes, particularly in those with diabetes and severe obesity.

Involvement of Porphyromonas gingivalis in the progression of non-alcoholic fatty liver disease.

The risk factors in the progression of nonalcoholic fatty liver disease (NAFLD) have not been fully clarified. Porphyromonas gingivalis (P.g) has been considered to be a confounding risk factor for systemic diseases. We aimed to evaluate the effect of P.g infection on risk of progression to NASH. (1) Serum IgG antibody titers against P.g fimbriae (fimA) in 200 biopsy-proven NAFLD patients were measured by ELISA and compared with histological findings. (2) C57BL/6J mice were fed a control diet (CD) or high-fat diet (HFD) with or without P.g-odontogenic infection and analyzed histologically. Mouse livers were analyzed using CE-TOFMS and LC-TOFMS. (1) A significant correlation between fibrosis progression and antibody titers against P.g possessing fimA type 4 was identified (P=0.0081). Multivariate analysis identified older age and type 4 P.g-positivity as risk factors for advanced fibrosis. (2) Fibrosis and steatosis were more severe in HFD P.g(+) mice compared with HFD P.g(-) mice. In metabolome analysis, fatty acid metabolism was significantly disrupted with HFD in P.g-infected mouse livers. Monounsaturated/saturated fatty acid ratios were significantly higher in the HFD P.g(+) group than in the HFD P.g(-) group (P<0.05). Moreover, expression levels of SCD1 and ELOVL6 were significantly reduced. These results suggest that P.g infection is an important risk factor for pathological progression in NAFLD. Increase in the monounsaturated/saturated fatty acid ratio may be an important change that facilitates progression of NAFLD.

Stage of liver fibrosis in patients with congenital bleeding disorders and infected with hepatitis C virus.

Hepatitis C virus (HCV) is the major cause of chronic liver disease in patients with hemophilia. However, since liver biopsy should not be routinely used in these patients, the accurate assessment of the stage of fibrosis has been limited so far. The aim of this study was to determine the stage of liver fibrosis in HCV‑infected patients with hemophilia by using noninvasive methods of fibrosis assessment, and to analyze the influence of risk factors on liver fibrosis. The study included 71 HCV‑infected patients with hemophilia and other congenital bleeding disorders. Patients were divided into 3 groups: HCV-RNA negative after successful treatment, HCV-RNA negative after spontaneous elimination of infection, and HCV‑RNA positive. Liver fibrosis was measured with shear wave elastography and FibroTest. The risk factors for liver fibrosis were analyzed, including demographic factors, HCV genotype, coinfections, and comorbidities. Cirrhosis or significant fibrosis (METAVIR score >F2) was observed in 26.8% of the patients. The stage of fibrosis was associated with age and estimated duration of infection (P <0.001). Active and past HBV infection did not affect fibrosis. The stage of liver fibrosis was lower in patients with spontaneous clearance of HCV (P = 0.007). Patients in our study had a similar stage of liver fibrosis to that reported by other studies on hemophilia. The older age and long duration of infection are the main risk factors for advanced fibrosis. Noninvasive methods such as shear wave elastography and FibroTest may allow a proper assessment of the fibrosis stage in hemophilia patients, particularly when used together and in correlation with other clinical parameters. They may also be useful in other groups of HCV‑infected patients.

Prevalence of non-alcoholic fatty liver disease and risk factors for advanced fibrosis and mortality in the United States.

In the United States, non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and associated with higher mortality according to data from earlier National Health and Nutrition Examination Survey (NHANES) 1988–1994. Our goal was to determine the NAFLD prevalence in the recent 1999–2012 NHANES, risk factors for advanced fibrosis (stage 3–4) and mortality. NAFLD was defined as having a United States Fatty Liver Index (USFLI) > 30 in the absence of heavy alcohol use and other known liver diseases. The probability of low/high risk of having advanced fibrosis was determined by the NAFLD Fibrosis Score (NFS). In total, 6000 persons were included; of which, 30.0% had NAFLD and 10.3% of these had advanced fibrosis. Five and eight-year overall mortality in NAFLD subjects with advanced fibrosis was significantly higher than subjects without NAFLD ((18% and 35% vs. 2.6% and 5.5%, respectively) but not NAFLD subjects without advanced fibrosis (1.1% and 2.8%, respectively). NAFLD with advanced fibrosis (but not those without) is an independent predictor for mortality on multivariate analysis (HR = 3.13, 95% CI 1.93–5.08, p<0.001). In conclusion, in this most recent NHANES, NAFLD prevalence remains at 30% with 10.3% of these having advanced fibrosis. NAFLD per se was not a risk factor for increased mortality, but NAFLD with advanced fibrosis was. Mexican American ethnicity was a significant risk factor for NAFLD but not for advanced fibrosis or increased mortality.

Prevalence of Liver Fibrosis and its Association with Non-invasive Fibrosis and Metabolic Markers in Morbidly Obese Patients with Vitamin D Deficiency.

BackgroundMorbidly obese patients are at risk for non-alcoholic fatty liver disease (NAFLD) and vitamin D deficiency (VDD). Non-alcoholic steatohepatitis (NASH) is the progressive variant of NAFLD and can advance to fibrosis, cirrhosis, and liver cancer. We aimed to examine prevalence of liver fibrosis and its non-invasive predictors in bariatric patients with VDD (<75 nmol/l).MethodsBaseline liver biopsy of a randomized controlled trial was performed in 46 patients with omega loop gastric bypass. Clinical, laboratory, and histological data were examined and tested with univariate and multivariable analysis.ResultsIn total, 80 % were females, aged 42 (SD 13) years with BMI 44 (4) kg/m2. Twenty-six percent had diabetes mellitus (DM) and 44 % metabolic syndrome (MeS). Seventy-two percent had NASH, 11 % simple steatosis, and 17 % normal liver. In total, 30 % demonstrated significant fibrosis (F ≥ 2) with 9 % of advanced (F3) and 4 % cirrhosis (F4). Increased stages of fibrosis were primarily associated with higher levels of HOMA2-insulin resistance (IR), procollagen type I propeptide (P1NP), lower osteocalcin, albumin-corrected calcium, parathyroid hormone, vitamin D, male sex, and higher age. Other independent risk factors for advanced fibrosis were MeS (OR = 9.3 [0.99–87.5], p = 0.052) and DM (OR = 12.8 [1.2–137.4], p = 0.035). The fibrosis FIB-4 index <10.62 and NAFLD fibrosis score <−26.93 had a negative predictive value of 100 and 96 %, respectively.ConclusionsLiver fibrosis is frequent in morbidly obese patients with concurrent DM and/or MeS. Increased serum levels of IR, P1NP, lower osteocalcin, and VDD are clinically relevant predictors of fibrosis. Consequently, we suggest that patients with preoperative presence of these markers are at increased risk for liver fibrosis and should be monitored closely.

The Score Model Containing Chinese Medicine Syndrome Element of Blood Stasis Presented a Better Performance Compared to APRI and FIB-4 in Diagnosing Advanced Fibrosis in Patients with Chronic Hepatitis B.

This study aims to explore a useful noninvasive assessment containing TCM syndrome elements for liver fibrosis in CHB patients. The demographic, clinical, and pathological data were retrospectively collected from 709 CHB patients who had ALT less than 2 times the upper limit of normal from April 2009 to October 2012. Logistical regression and area under receiver-operator curve (AUROC) were used to determine the diagnostic performances of simple tests for advanced fibrosis (Scheuer stage, F ≥ 3). Results showed that the most common TCM syndrome element observed in this CHB population was dampness and Qi stagnation, followed by blood stasis, by heat, and less by Qi deficiency and Yin deficiency. The logistical regression analysis identified AST ≥ 35 IU/L, PLT ≤ 161 × 109/L, and TCM syndrome element of blood stasis as the independent risk factors for advanced fibrosis. Therefore, a score model containing these three factors was established and tested. The score model containing blood stasis resulted in a higher AUC (AUC = 0.936) compared with APRI (AUC = 0.731) and FIB-4 (AUC = 0.709). The study suggested that the score model containing TCM syndrome element of blood stasis could be used as a useful diagnostic tool for advanced fibrosis in CHB patients and presented a better performance compared to APRI and FIB-4.

Donor-Specific Anti-HLA Antibodies and Endothelial C4d Deposition-Association With Chronic Liver Allograft Failure.

The significance of humoral immune response for allograft survival after liver transplantation (LT) is still a matter of debate. The aim of this cross-sectional study was to assess immunological and clinical factors associated with advanced fibrosis (F3-F4) and chronic graft failure in LT recipients. Serum samples from 174 patients prospectively enrolled and followed up for 12 months were tested for anti-HLA antibodies and compared against donor HLA types. Immunohistochemical C4d staining was performed on formalin-fixed, paraffin-embedded liver tissue. Mean time period from LT to enrollment was 66.9 ± 51.9 months. Independent predictive factors for graft failure included donor-positive cytomegalovirus serostatus (P = 0.02), donor-specific antibodies (DSA) against HLA class II (P = 0.03), donor age (P = 0.01), hepatitis C virus allograft reinfection (P = 0.0008), and biliary complications (P = 0.003). HLA class II DSA and HLA class I antibody positivity, hepatitis C virus reinfection, and mycophenolate mofetil-free regimens were significant risk factors for advanced fibrosis after LT. There was a significant association between C4d deposition on allograft endothelial cells and presence of class II DSA (P < 0.0001). Patients with C4d deposits had a 4.3 times higher risk of graft failure than those with negative staining and a significantly lower median time to graft failure (94.6 months [range, 3.6-158.9 months] vs 176.4 months [range, 9.4-217.8 months], P < 0.0001). Screening for HLA DSA might be useful for early identification of LT recipients at increased risk of graft failure who could benefit from closer surveillance and tailored immunosuppressive regimens.

Sa1036 Hepatic Fibrosis After Small-for-Size Liver Transplantation in Rats: Possible Role of TGFβ/SMAD Signaling

this study, we explored whether concomitant medication altered the risk of hepatic fibrosis in NAFLD. Specifically, we sought to ascertain the association between RAS blocking agents (angiotensin converting enzyme blocker or angiotensin II receptor blocker) and severity of hepatic fibrosis in NAFLD patients with hypertension. Methods: This study cohort consisted of 259 hypertensive patients with biopsy proven NAFLD prospectively followed up in hepatology outpatient clinics in Cleveland, OH. Clinical data including demographics, anthropometry, medical history, medication history, biochemical and liver biopsy findings were evaluated. Patients with and without RAS blocker use were compared in relation to liver fibrosis stage. Utilizing electronic medical records, risk factors for advanced fibrosis were explored, in particular, the association between commonly used medications and advanced fibrosis. Independent risk factors for advanced fibrosis were ascertained using binary regression. Results: The mean age of the cohort was 52.2 years and mean BMI was 37.33 kg/m2. Females, diabetics and patients with advanced fibrosis comprised 64.9%, 60.2% and 35.9% of the cohort respectively. Patients treated with RAS blockers had significantly less ballooning (1.05 vs. 1.33, p=0.002) and lower fibrosis stage (1.64 vs. 2.24, p=0.001) on liver biopsy compared to patients not treated with RAS blockers. Compared to patients without advanced fibrosis, patients with advanced fibrosis were older (54.6 vs. 50.9 years, p=0.014), more often diabetic (76.3 vs. 50.9%, p=0.000), had more ballooning on histology (1.57 vs. 0.93, p=0.000), more likely to be on insulin (22.6 vs. 11.5%, p=0.018), and sulfonylureas (29.0 vs. 15.8%, p=0.011) while less likely to be on RAS blockers (49.5 vs. 70.3%, p=0.001). On multivariate analysis, grade of ballooning had an independent positive association with advanced fibrosis (OR 7.539; 95%CI 3.402-16.706, p=0.000) while usage of RAS blockers had a negative association with advanced fibrosis (OR 0.293; 95%CI 0.1090.787, p=0.015). Conclusion: Hypertensive patients with NAFLD treated with RAS blockers had less advanced hepatic fibrosis, suggesting a beneficial role for angiotensin blockers to protect against NASH fibrosis. Prospective clinical trials are warranted to explore this association in greater detail.

Diabetes Mellitus, Insulin, Sulfonylurea and Advanced Fibrosis in Non-Alcoholic Fatty Liver Disease

Background & aims: Diabetes mellitus is a risk factor for advanced fibrosis in non-alcoholic fatty liver disease. However, not all non-alcoholic fatty liver disease patients with diabetes develop advanced fibrosis. We hypothesised that prescription medications used by these patients influence the development of advanced fibrosis. We investigated the association of commonly used medications and advanced fibrosis in non-alcoholic fatty liver disease patients with diabetes. Methods: Clinical information including demographics, medical history, medication history, biochemical and histologic variables were ascertained in 459 patients with biopsy proven non-alcoholic fatty liver disease. We compared characteristics of patients with and without diabetes and explored potential associations between classes of drugs as risk factors and advanced fibrosis among the diabetic patients with NAFLD. Results: Presence of diabetes was an independent risk factor for advanced fibrosis. In diabetic patients, age (OR 1.09; 95%CI 1.04-1.15, p=0.000) and grade of ballooning (OR 5.59; 95%CI 2.69-11.61, p=0.000) had a positive relationship with advanced fibrosis. The use of insulin (OR 4.95; 95%CI 1.65-14.88, p=0.004) and sulfonylurea (OR 5.07; 95%CI 1.87-13.75, p=0.001) were positively associated while statin use (OR 0.31; 95%CI 0.12-0.78, p=0.013) was negatively associated with advanced fibrosis. Conclusion: Among non-alcoholic fatty liver disease patients with diabetes, the prevalence of advanced fibrosis was higher in patients treated with insulin and sulfonylurea, but lower in patients on statins. These findings provide support for a greater role of statin use in non-alcoholic fatty liver disease patients with diabetes while limiting the use of insulin and sulfonylurea.

Type 2 diabetes mellitus is associated with the fibrosis severity in patients with nonalcoholic fatty liver disease in a large retrospective cohort of Japanese patients

The prevalence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome have been increasing worldwide. The associations between metabolic factors and the histologic severity of NAFLD have not yet been clarified. Therefore, we studied the relationships between relevant metabolic factors and the histological severity of NAFLD. In a cross-sectional multicenter study conducted in Japan, we examined 1,365 biopsy-proven NAFLD patients. The frequencies of underlying lifestyle-related diseases and their relationships to the NAFLD histology were investigated. The hepatic fibrosis stages (Stage 0/1/2/3/4) were 22.6/34.1/26.7/14.5/2.1 (%) in the male patients, and 16.2/31.7/23.9/21.6/6.6 (%) in the female patients. Dyslipidemia was present in 65.7% (hypertriglyceridemia, 45.3%; increased low-density lipoprotein cholesterol, 37.5%; decreased high density lipoprotein cholesterol, 19.5%) of patients. Hypertension was present in 30.2%, and diabetes mellitus (DM) in 47.3%. The fibrosis stage increased with age, especially in postmenopausal females. The body mass index was positively correlated with the fibrosis stage. Deterioration of glucose control was positively correlated with the fibrosis stage, this correlation being more prominent in females. Multivariate analysis identified age and DM as significant risk factors for advanced fibrosis. No significant correlation of the fibrosis stage was observed with hypertension. There was a negative correlation between the serum triglyceride levels and the fibrosis stage. DM appeared to be a significant risk factor for advanced fibrosis in patients with NAFLD, and would therefore need to be properly managed to prevent the progression of NAFLD.

Association Between Appendectomy and Fibrosis Progression in Nonalcoholic Fatty Liver Disease.

BackgroundA two-hit theory explaining the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) and fibrosis is widely accepted. Endotoxins entering the portal vein from the gut are thought to be one cause of this second hit, and the literature frequently mentions associations between gut-derived endotoxins and progression of fibrosis in NAFLD. The appendix regulates intestinal immunity to protect the gut from the invasion of bacteria and antigens. Appendectomy may thus contribute to progression of fibrosis in NAFLD, but this association has not yet been clarified. We therefore investigated the association between appendectomy and progression of fibrosis in NAFLD.MethodsFifty two patients with NAFLD who underwent liver biopsy in our department were included in this study. Based on Brunt’s scores, patients with NAFLD were classified into a mild fibrosis group and advanced fibrosis group.ResultsHistory of appendectomy was found to be significantly more frequent in patients with advanced fibrosis than in patients with mild fibrosis (P = 0.014). Multivariate logistic analysis was conducted with age, sex, albumin, platelet count, steatosis grade, and history of appendectomy as covariates and advanced fibrosis as the dependent variable. Significant differences were identified for platelet count and history of appendectomy, identifying these as independent risk factors for advanced fibrosis in NAFLD patients. The odds ratio for appendectomy history was 39.415 (P = 0.044).ConclusionsHistory of appendectomy was significantly more frequent in NAFLD patients with advanced fibrosis, suggesting that appendectomy may represent a risk factor for advanced fibrosis in NAFLD.

The BARD score and the NAFLD fibrosis score in the assessment of advanced liver fibrosis in nonalcoholic fatty liver disease

SummaryBackgroundNon-alcoholic fatty liver disease (NAFLD) refers to a very wide clinical spectrum. Advanced fibrosis that accompanies disease leads to the development of cirrhosis and hepatocellular carcinoma. Thus, identification of patients with advanced fibrosis is essential. The aim of the present study was to compare the usefulness of NAFLD fibrosis and BARD scores in predicting fibrosis in NAFLD and to determine the risk factors of advanced fibrosis.Material/MethodsThe study included 126 patients with NAFLD. Fibrosis in liver biopsy was scored on a 5-point scale. The BARD and the NAFLD fibrosis scores were compared with the biopsy findings.ResultsLiver biopsy revealed 27 patients with advanced and 99 with mild/moderate fibrosis. Advanced fibrosis was statistically significantly more common in older patients with obesity, AST/ALT ratio ≥0.8, diabetes mellitus, and thrombocytes ≤200×103/L. Positive predictive value, negative predictive value and AUROC curve for BARD score, and NAFLD fibrosis score were 68.57%, 96.70%, 0.865 and 70.59%, 98.11%, 0.919, respectively.ConclusionsBoth scores are capable of ruling out advanced fibrosis and markedly reducing the need for liver biopsies in patients with NAFLD. Obesity, diabetes mellitus, thrombocytes ≤200×103/L, advanced age and AST/ALT ratio ≥0.8 are the risk factors of advanced fibrosis.

Smoking as an independent risk factor of liver fibrosis in primary biliary cirrhosis

Smoking has been identified as a potential predisposition factor for primary biliary cirrhosis (PBC). However, it remains unclear whether it is associated with more active and severe disease. Our aim was to assess the relationships between smoking and the severity of the elementary histological lesions, as well as the biochemical and immunological features of PBC. Smoking history data were collected from 223 PBC patients using a standardized questionnaire. Histological data were available in 164 patients at presentation. Liver fibrosis and histological inflammatory activity were semi-quantified according to a METAVIR-based classification system. Odds ratios (OR) were assessed using a logistic regression analysis. Smoking history prior to diagnosis was reported in 58 patients (26%). Twenty-five patients (11%) were active smokers at diagnosis. Male gender (OR, 4.5), alcohol intake >20 g/d (OR, 4.2), and F3-F4 fibrosis stage (OR, 2.7), but not inflammatory grade, bile duct changes, biochemical or immunological features, were associated with smoking history. Smoking intensity was significantly higher in patients with F3-F4 stage (8.1±14.2 pack-years vs. 3.0±7.0 pack-years; p=0.01). Adjusted logistic regression identified smoking history and smoking intensity as independent risk factors of advanced fibrosis. Each pack-year of increase in smoking intensity was associated with a 5.0% (95% CI, 1.3-8.7%) increased likelihood of advanced fibrosis. Smoking increases, in a dose-dependent fashion, the risk of liver fibrosis in PBC without apparent increase in the histological inflammatory activity, bile duct lesions, biochemical, and immunological features of the disease. PBC patients should be strongly encouraged not to smoke.

487 ATP-Binding Cassette Transporter Gene Polymorphisms and Insulin Resistance as Risk Factors for Advanced Fibrosis Following Liver Transplantation for HCV Infection

487 ATP-Binding Cassette Transporter Gene Polymorphisms and Insulin Resistance as Risk Factors for Advanced Fibrosis Following Liver Transplantation for HCV Infection

Influence of age and gender in Japanese patients with non‐alcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is considered to be a manifestation of metabolic syndrome. Because prevalence and severity of metabolic syndrome are different according to ages, gender and ethnic group, it is speculated that the clinicopathological features of NASH may also vary in relation to these factors. The present study was performed to clarify the influence of age and gender on the development of Japanese NASH. One hundred 93 biopsy-proven NASH patients (86 women and 107 men) were included in this cross-sectional study. The patients were separately analyzed by generation; a younger group (<55 years old) and an older group (>/=55 years old). These groups were compared for their clinical and histological features. Independent risk factors for advanced fibrosis were also analyzed. Comparison of our younger and older groups showed that older patients had much more advanced fibrosis than the younger ones (advanced fibrosis: 23.8%; youngergroup vs. 54.3%; older group, P < 0.001). Women were predominant in the older group (23.8%; younger group vs. 67.4%; older group, P < 0.001). According to the multivariate analysis for risk factors for advanced fibrosis, age (P = 0.007) and BMI (P = 0.028) were independent predictors of advanced fibrosis in the younger group. In contrast, the absence of hyperlipidemia (P = 0.042) was the only significant independent predictor of advanced fibrosis in the older group. Gender was not a risk factor for the severity of NASH. Clinicians need to be aware of age- and gender-specific differences when assessing the characteristics of NASH, and the findings may be useful for prevention and treatment of this disease.

Hepatitis C Virus Infection in the Elderly

A total of 130 million people are presumed to be infected with the hepatits C virus but the infection mostly runs a slow course and only causes problems when people age, have immune impairments or significant cofactors such as excess alcohol consumption or obesity. Age has been determined as a major risk factor for advanced fibrosis and cirrhosis, while treatment, which is needed most for those with cirrhosis, is more difficult once advanced fibrosis is present. The current treatment is thought to be less effective in older people, although few data are available to reliably prove this. As some people with cirrhosis and advanced liver disease can still achieve viral clearance, these patients should be referred to a hepatologist for work-up and treatment decision.

Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver.

The mechanism(s) determining the progression from fatty liver to steatohepatitis is currently unknown. Our goal was to define the relative impact of iron overload, genetic mutations of HFE, and insulin resistance on the severity of liver fibrosis in a population of subjects with nonalcoholic fatty liver disease (NAFLD) who had low prevalence of obesity and no overt symptoms of diabetes. In a cohort of 263 prospectively enrolled patients with NAFLD, 7.4% of patients had signs of peripheral iron overload and 9% had signs of hepatic iron overload, but 21.1% had hyperferritinemia. The prevalence of C282Y and H63D HFE mutations was similar to the general population and mutations were not associated with iron overload. Although subjects were on average only moderately overweight, insulin sensitivity, measured both in the fasting state and in response to oral glucose, was lower. Univariate analysis demonstrated that the presence of severe fibrosis was independently associated with older age, female sex, overweight, aspartate/alanine aminotransferase ratio, serum ferritin level, fasting glucose and insulin levels, decreased insulin sensitivity, and with histologic features (degree of necroinflammation and steatosis). After adjustment for body mass index (BMI), age, sex, and degree of steatosis, ferritin levels (odds ratio [OR] = 1.77; 95% CI = 1.21- 2.58; P =.0032) and the oral glucose insulin sensitivity (OR = 0.53; CI = 0.33-0.87; P =.0113) were independent predictors of severe fibrosis. In conclusion, the current study indicates that insulin resistance is a major, independent risk factor for advanced fibrosis in patients with NAFLD. Increased ferritin levels are markers of severe histologic damage, but not of iron overload. Iron burden and HFE mutations do not contribute significantly to hepatic fibrosis in the majority of patients with NAFLD.

Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome

Objectives The objectives of this study were to determine the following: 1) whether chronic hepatitis C virus (HCV) infection was specifically associated with nonalcoholic fatty liver disease (NAFLD); 2) the factors associated with NAFLD in patients with HCV; and 3) the clinical and histological spectrum of NAFLD occurring together with HCV. Methods A retrospective analysis of 3826 biopsies was performed to compare the prevalence of NAFLD in those with HCV versus that in other liver diseases, e.g., hepatitis B, primary biliary cirrhosis, and α 1-antitrypsin deficiency. Patients with HCV and NAFLD were also compared with an age- and gender-matched control group with HCV and <5% hepatic steatosis. Results The prevalence of NAFLD in patients with HCV was similar to that in hepatitis B, primary biliary cirrhosis, or α 1-antitrypsin deficiency. The risk of having NAFLD in patients with HCV correlated with body weight ( r = 0.7, p < 0.02). Compared with a control group with HCV alone (n = 75), patients with HCV and NAFLD (n = 69) were likely to be heavier (mean BMI 27 vs 30, p < 0.003), diabetic (eight vs 21, p < 0.005), hypertensive (14 vs 25, p < 0.05), and hypertriglyceridemic (15 vs 33, p < 0.05). The HCV viral load, genotype distribution, liver enzymes, liver functions, and ferritin levels were comparable across the study groups. Those with HCV and NAFLD were more likely to have advanced fibrosis (bridging fibrosis or cirrhosis) (26% vs 53%, p < 0.03). Weight, diabetes, and cytological ballooning were independent predictors of advanced fibrosis in those with HCV and NAFLD. Conclusions The presence of NAFLD in patients with HCV is strongly associated with features of the metabolic syndrome and is a risk factor for advanced fibrosis. Advanced fibrosis in such patients is related to weight, presence of diabetes, and presence and degree of cytological ballooning.