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Iron deficiency is often observed in obese individuals. The iron regulatory hormone hepcidin is regulated by iron and cytokines interleukin (IL) 6 and IL1β. We examine the relationship between obesity, circulating levels of hepcidin, and IL6 and IL1β, and other risk factors in patients with nonalcoholic fatty liver disease (NAFLD) with iron deficiency.We collected data on 675 adult subjects (18 years old) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Subjects with transferrin saturation20% were categorized as iron deficient, whereas those with transferrin saturation ≥20% were classified as iron normal. We assessed clinical, demographic, anthropometric, laboratory, dietary, and histologic data from patients, and serum levels of hepcidin and cytokines IL6 and IL1β. Univariate and multivariate analysis were used to identify risk factors for iron deficiency.One-third of patients (231 of 675; 34%) were iron deficient. Obesity, diabetes, and metabolic syndrome were more common in subjects with iron deficiency (P.01), compared with those that were iron normal. Serum levels of hepcidin were significantly lower in subjects with iron deficiency (61 ± 45 vs 81 ± 51 ng/mL; P.0001). Iron deficiency was significantly associated with female gender, obesity, increased body mass index and waist circumference, presence of diabetes, lower alcohol consumption, black or American Indian/Alaska Native race (P ≤ .018), and increased levels of IL6 and IL1β (6.6 vs 4.8 for iron normal, P ≤ .0001; and 0.45 vs 0.32 for iron normal, P ≤ .005).Iron deficiency is prevalent in patients with NAFLD and associated with female gender, increased body mass index, and nonwhite race. Serum levels of hepcidin were lower in iron-deficient subjects, reflecting an appropriate physiologic response to decreased circulating levels of iron, rather than a primary cause of iron deficiency in the setting of obesity and NAFLD.

Background. There is an ongoing clinical need for novel methods to measure hepatic iron content (HIC) noninvasively. Both magnetic resonance imaging (MRI) and superconducting quantum interference device (SQUID) methods have previously shown promise for estimation of HIC, but these methods can be expensive and are not widely available. Room-temperature susceptometry (RTS) represents an inexpensive alternative and was previously found to be strongly correlated with HIC estimated by SQUID measurements among patients with transfusional iron overload related to thalassemia. Aim. The goal of the current study was to examine the relationship between RTS and biochemical HIC measured in liver biopsy specimens in a more varied patient cohort. Material and methods. Susceptometry was performed in a diverse group of patients with hyperferritinemia due to hereditary hemochromatosis (HHC) (n = 2), secondary iron overload (n = 3), nonalcoholic fatty liver disease (NAFLD) (n = 2), and chronic viral hepatitis (n = 3) within one month of liver biopsy in the absence of iron depletion therapy. Results. The correlation coefficient between HIC estimated by susceptometry and by biochemical iron measurement in liver tissue was 0.71 (p = 0.022). Variance between liver iron measurement and susceptometry measurement was primarily related to reliance on the patient’s body-mass index (BMI) to estimate the magnetic susceptibility of tissue overlying the liver. Conclusions. We believe RTS holds promise for noninvasive measurement of HIC. Improved measurement techniques, including more accurate overlayer correction, may further improve the accuracy of liver susceptometry in patients with liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States. The association between NAFLD and quality of life (QOL) remains unclear. These data are important to estimate the burden of illness in NAFLD. The aim was to report QOL scores of adults with NAFLD and examine the association between NAFLD severity and QOL. QOL data were collected from adults with NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network using the Short Form 36 (SF-36) survey, and scores were compared with normative U.S. population scores. Liver biopsy histology was reviewed by a central pathology committee. A total of 713 subjects with NAFLD (male = 269, female = 444) were included. Mean age of subjects was 48.3 years; 61% had definite nonalcoholic steatohepatitis (NASH), and 28% had bridging fibrosis or cirrhosis. Diabetes was present in 27% of subjects. Subjects with NAFLD had worse physical (mean, 45.2) and mental health scores (mean, 47.6) compared with the U.S. population with (mean, 50) and without (physical, 55.8; mental, 52.5) chronic illness. Subjects with NASH reported lower physical health compared with subjects with fatty liver disease without NASH (44.5 versus 47.1, P = 0.02). Subjects with cirrhosis had significantly (P < 0.001) poorer physical health scores (38.4) than subjects with no (47.6), mild (46.2), moderate (44.6), or bridging fibrosis (44.6). Cirrhosis was associated with poorer physical health after adjusting for potential confounders. Mental health scores did not differ between participants with and without NASH or by degree of fibrosis. Conclusion: Adults with NAFLD have a significant decrement in QOL. Treatment of NAFLD should incorporate strategies to improve QOL, especially physical health. (HEPATOLOGY 2009.)

Sex and sex hormones can affect responses of patients with nonalcoholic fatty liver disease (NAFLD) to metabolic stress and development of hepatocyte injury and inflammation. We collected data from 3 large US studies of patients with NAFLD (between October 2004 and June 2013) to assess the association between histologic severity and sex, menopause status, synthetic hormone use, and menstrual abnormalities in 1112 patients with a histologic diagnosis of NAFLD. We performed logistic or ordinal logistic regression models, adjusting for covariates relevant to an increase of hepatic metabolic stress. We found that pre-menopausal women were at an increased risk of lobular inflammation, hepatocyte ballooning, and Mallory-Denk bodies than men and also at an increased risk of lobular inflammation and Mallory-Denk bodies than post-menopausal women (P

Previous controlled trials are inconclusive regarding the efficacy of ursodeoxycholic acid (UDCA) for treating primary sclerosing cholangitis (PSC). One hundred fifty adult patients with PSC were enrolled in a long-term, randomized, double-blind controlled trial of high-dose UDCA (28-30 mg/kg/day) versus placebo. Liver biopsy and cholangiography were performed before randomization and after 5 years. The primary outcome measures were development of cirrhosis, varices, cholangiocarcinoma, liver transplantation, or death. The study was terminated after 6 years due to futility. At enrollment, the UDCA (n = 76) and placebo (n = 74) groups were similar with respect to sex, age, duration of disease, serum aspartate aminotransferase and alkaline phosphatase levels, liver histology, and Mayo risk score. During therapy, aspartate aminotransferase and alkaline phosphatase levels decreased more in the UDCA group than the placebo group (P0.01), but improvements in liver tests were not associated with decreased endpoints. By the end of the study, 30 patients in the UDCA group (39%) versus 19 patients in the placebo group (26%) had reached one of the pre-established clinical endpoints. After adjustment for baseline stratification characteristics, the risk of a primary endpoint was 2.3 times greater for patients on UDCA than for those on placebo (P0.01) and 2.1 times greater for death, transplantation, or minimal listing criteria (P = 0.038). Serious adverse events were more common in the UDCA group than the placebo group (63% versus 37% [P0.01]).Long-term, high-dose UDCA therapy is associated with improvement in serum liver tests in PSC but does not improve survival and was associated with higher rates of serious adverse events.

Adult nonalcoholic fatty liver disease (NAFLD) is characterized by absent or mild portal chronic inflammation (CI); in children, portal CI may be predominant. This study correlated clinical features with portal CI. Centrally-graded biopsies and temporally-related clinical parameters from 728 adults and 205 children. From the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) were evaluated. Mild, more than mild and no portal CI were found in 60%, 23% and 16% of adult biopsies and 76%, 14% and 10% of pediatric biopsies. Autoantibodies, and elevated alanine aminotransferase were not associated with portal CI. Clinical features associated with “more than mild” in adults were older age (P < 0.0001), female gender (P = 0.001), higher body mass index (P < 0.0001), elevated insulin levels (P = 0.001), higher homeostasis model assessment of insulin resistance score (HOMA-IR) (P < 0.0001), and medications used for NAFLD (P = 0.0004), diabetes (P < 0.0001), and hypertension (P < 0.0001). “More than mild” in the pediatric biopsies correlated with younger age (P = 0.01), but not with body mass index, insulin or HOMA-IR. In both groups, lobular and portal inflammation scores had no association, but there was an association with definite steatohepatitis (P < 0.0001). Features associated in the adult biopsies with “more than mild” were steatosis amount (P = 0.01) and location (P < 0.0001), ballooning (P < 0.0001), and advanced fibrosis (P < 0.0001). In the pediatric biopsies, “more than mild” was associated with steatosis location (P = 0.0008) and fibrosis score (P < 0.0001), specifically, the portal/periportal fibrosis or greater fibrosis) (P < 0.01). Conclusion: Increased portal CI is associated with many clinical and pathologic features of progressive NAFLD in both adults and children, but not with ALT, autoantibodies, or lobular inflammation. More than mild portal CI in liver biopsies of untreated NAFLD may be considered a marker of advanced disease. (HEPATOLOGY 2009.)

Microparticles (MP) are circulating cellular fragments that are increased in thrombotic conditions including TTP, antiphospholipid syndrome, and HIT. Tissue factor (TF)-bearing MP are thought to be procoagulant in these conditions. Hemolytic Uremic Syndrome (HUS) is a thrombotic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and renal failure secondary to glomerular thrombotic microangiopathy. In children, HUS most often occurs after infection with E. coli O157H7. It is hypothesized that E. coli verotoxin injures renal and other endothelium leading to activation of hemostasis, thrombotic microangiopathy and HUS. We studied 56 children at the time of presentation with bloody diarrhea associated with E. coli O157H7 infection (typically day 4 of illness) prior to developing HUS, and 5 healthy children as controls. Subsequently 14 children (Pre-HUS) went on to develop HUS while 42 (Uncomplicated) resolved their illness without developing HUS. We also studied 15 children that presented with already developed HUS (HUS group). We analyzed the total number of MPs, percent of TF-bearing microparticles and their cellular derivation using a 5-color flow cytometry assay. Endothelial-derived MP are identified as positive for CD144 (Ve-Cad)-PE, monocyte-derived MP are positive for CD14-PE-Cy7, and platelet derived MP are positive for CD41a-PerCP. MPs were collected from plasma by ultracentrifugation (100,000g). MPs were defined based on size (0.5–1 um) and strong annexin V binding. The MP distribution in the control group was similar to reports by others: 204 ±98 ×103 MPs/mL of plasma (55% platelet-, 5% endothelial- and 15% monocyte-derived), only 2.6% of MP express TF. The MP distribution in Uncomplicated was 996 ±766 ×103 MPs/mL (36% plat-, 11% endo- and 15% mono-derived) and 5.4% express TF; while pre-HUS showed 1197±1108 ×103 MPs/mL (21% plat-, 12% endo- and 11% mono-derived) and 8.2% express TF. The MP distribution in the HUS group was 1183±949 ×103 MPs/mL (45% plat-, 15% endo- and 19% mono-derived) and 10.9% express TF. Compared to controls, children infected with E. coli O157H7 showed a higher number of total MPs (p