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Background & AimsMacrophage inducible C-type lectin (Mincle) is expressed on Kupffer cells and senses ethanol-induced danger signals released from dying hepatocytes and promotes IL-1β production. However, it remains unclear what and how ethanol-induced Mincle ligands activate downstream signaling events to mediate IL-1β release and contribute to alcohol-associated liver disease (ALD). In this study, we investigated the association of circulating β-glucosylceramide (β-GluCer), an endogenous Mincle ligand, with severity of ALD and examined the mechanism by which β-GluCer engages Mincle on Kupffer cells to release IL-1β in the absence of cell death and exacerbates ALD.Approach and ResultsConcentrations of β-GluCer were increased in serum of patients with severe AH and correlated with disease severity. Challenge of Kupffer cells with LPS and β-GluCer induced formation of aMincleandGsdmd-dependent secretory complex containing chaperoned full-length GSDMD (Hsp90-CDC37-NEDD4) with polyubiquitinated pro-IL-1β and components of the Casp8-NLRP3 inflammasome loaded as cargo in small extracellular vesicles (sEV). Gao-binge ethanol exposure to wild-type, but notMincle-/-andGsdmd-/-, mice increased release of IL-1β containing sEVs from liver explant cultures. Myeloid-specific deletion ofGsdmdsimilarly decreased the formation of sEVs by liver explant cultures and protected mice from ethanol-induced liver injury. sEVs collected from ethanol-fed wild-type, but notGsdmd-/-, mice promoted injury of cultured hepatocytes and, when injected into wild-type mice, aggravated Gao-binge ethanol-induced liver injury.Conclusionβ-GluCer functions as a DAMP activating Mincle-dependent GSDMD-mediated formation and release of IL-1β-containing sEVs, which in turn exacerbate hepatocyte cell death and contribute to the pathogenesis of ALD.

Mixed lineage kinase domain-like pseudokinase (MLKL), a key terminal effector of necroptosis, also plays a role in intracellular vesicle trafficking that is critical for regulating liver inflammation and injury in alcohol-associated liver disease (ALD). Although receptor interacting protein kinase 3 (Rip3)Bone marrow transplants between MlklTogether, these data indicate that myeloid MLKL restricts ethanol-induced liver inflammation and injury by regulating hepatic immune cell homeostasis and macrophage phagocytosis.

Hepatocellular death contributes to progression of alcohol-associated (ALD-associated) and non-alcohol-associated (NAFL/NASH) liver diseases. However, receptor-interaction protein kinase 3 (RIP3), an intermediate in necroptotic cell death, contributes to injury in murine models of ALD but not NAFL/NASH. We show here that a differential role for mixed-lineage kinase domain-like protein (MLKL), the downstream effector of RIP3, in murine models of ALD versus NAFL/NASH and that RIP1-RIP3-MLKL can be used as biomarkers to distinguish alcohol-associated hepatitis (AH) from NASH. Phospho-MLKL was higher in livers of patients with NASH compared with AH or healthy controls (HCs). MLKL expression, phosphorylation, oligomerization, and translocation to plasma membrane were induced in WT mice fed diets high in fat, fructose, and cholesterol but not in response to Gao-binge (acute on chronic) ethanol exposure. Mlkl-/- mice were not protected from ethanol-induced hepatocellular injury, which was associated with increased expression of chemokines and neutrophil recruitment. Circulating concentrations of RIP1 and RIP3, but not MLKL, distinguished patients with AH from HCs or patients with NASH. Taken together, these data indicate that MLKL is differentially activated in ALD/AH compared with NAFL/NASH in both murine models and patients. Furthermore, plasma RIP1 and RIP3 may be promising biomarkers for distinguishing AH and NASH.

Case Presentation A 39-year-old male presented to the ED with a 2-day history of fever (Temperature-Maximum 39°C), nonbloody productive cough, and worsening right-sided pleuritic chest pain. The patient denied shortness of breath, nausea, vomiting, sinus symptoms, and abdominal pain. His medical history included type 2 diabetes mellitus (glycated hemoglobin, 11.1), hyperlipidemia, and depression. He smoked marijuana but denied tobacco or illicit drug use. He reported no recent travels. He reported a 1-week history of left molar pain that began after he siphoned stagnant water with a straw from a refrigerator drip pan. He lived in Ohio all of his life. He denied any sick contacts. His medications include Lantus insulin at night, metformin, glimepiride, pravastatin, and Remeron.

Whether to screen for prostate cancer using PSA testing is a difficult decision for many men. Here's the information you need to help them make an educated choice.

Nonalcoholic liver disease (NAFLD) is manifested with a wide spectrum of clinical symptoms and is closely associated with the metabolic syndrome, inflammation, and mitochondrial dysfunction. Although the mechanism of mitochondrial dysfunction in NAFLD is still not fully elucidated, multiple studies have demonstrated evidence of molecular, biochemical, and biophysical mitochondrial abnormalities in NAFLD. Given the association between NAFLD and mitochondrial dysfunction, the aim of this study is to analyze circulating levels of Krebs cycle intermediates in a cohort of NAFLD-affected individuals and matching healthy controls and to correlate our findings with the liver function metrics. Standard serum biochemistry and Krebs cycle intermediates were analyzed in NAFLD (n = 22) and matched control (n = 67) cohorts. Circulating levels of isocitrate and citrate were significantly (p &lt, 0.05) elevated in the NAFLD cohort of patients. The area under the curve (AUROC) for these two metabolites exhibited a moderate clinical utility. Correlations between plasma Krebs cycle intermediates and standard clinical plasma metrics were explored by Pearson&rsquo, s correlation coefficient. The data obtained for plasma Krebs cycle intermediates suggest pathophysiological insights that link mitochondrial dysfunction with NAFLD. Our findings reveal that plasma isocitrate and citrate can discriminate between normal and NAFLD cohorts and can be utilized as noninvasive markers of mitochondrial dysfunction in NAFLD. Future studies with large populations at different NAFLD stages are warranted.

Altered lipid metabolism and inflammation are involved in the pathogenesis of both nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). Even though high-density lipoprotein (HDL), a CVD protective marker, is decreased, whether HDL metabolism and function are perturbed in NAFLD are currently unknown. We examined the effect of NAFLD and disease severity on HDL metabolism and function in patients with biopsy-proven simple steatosis (SS), nonalcoholic steatohepatitis (NASH), and healthy controls. HDL turnover and HDL protein dynamics in SS ( n = 7), NASH ( n = 8), and healthy controls ( n = 9) were studied in vivo. HDL maturation and remodeling, antioxidant, cholesterol efflux properties, and activities of lecithin-cholesterol ester acyltransferase and cholesterol ester transfer protein (CETP) were quantified using in vitro assays. All patients with NAFLD had increased turnover of both HDL cholesterol (HDLc; 0.16 ± 0.09 vs. 0.34 ± 0.18 days, P < 0.05) and apolipoprotein A1 (ApoAI) (0.26 ± 0.04 vs. 0.34 ± 0.06 days, P < 0.005) compared with healthy controls. The fractional catabolic rates of other HDL proteins, including ApoAII (and ApoAIV) were higher ( P < 0.05) in patients with NAFLD who also had higher CETP activity, ApoAI/HDLc ratio ( P < 0.05). NAFLD-induced alterations were associated with lower antioxidant (114.2 ± 46.6 vs. 220.5 ± 48.2 nmol·mL−1·min−1) but higher total efflux properties of HDL (23.4 ± 1.3% vs. 25.5 ± 2.3%) (both P < 0.05), which was more pronounced in individuals with NASH. However, no differences were observed in either HDL turnover, antioxidant, and cholesterol efflux functions of HDL or HDL proteins’ turnover between subjects with SS and subjects with NASH. Thus, HDL metabolism and function are altered in NAFLD without any significant differences between SS and NASH.

BACKGROUND AND AIMS Sarcopenia or skeletal muscle loss adversely affects outcomes in cirrhosis. The impact of aetiology of liver disease on the severity or the rate of muscle loss is not known. METHODS Consecutive, well-characterized adult patients with cirrhosis due to viral hepatitis (VH), alcoholic liver disease (ALD) or non-alcoholic fatty liver disease (NAFLD) and non-diseased controls with at least two temporally distinct abdominal CT (computed tomography) scans were evaluated. Psoas, paraspinal and abdominal wall muscle areas at the L3 vertebra level were quantified on the CT scans. Standardized rate of change in muscle area was expressed as change in area/100 days. Univariate and multivariable analyses were performed to identify contributors to rate of muscle loss and survival. RESULTS Among 83 cirrhotics (NAFLD n = 26, ALD n = 39, VH n = 18), there were 20 (24.1%) deaths over 62.7 ± 41.3 months. The mean percentage change in psoas area was -0.03 ± 0.05/100d in controls and -3.52 ± 0.45/100d in cirrhosis (P

BACKGROUND Non-alcoholic steatohepatitis (NASH) is an advanced and aggressive form of non-alcoholic fatty liver disease (NAFLD), which remains difficult to diagnose without a liver biopsy. Hyperferritinemia has increasingly been associated with the presence of NASH. Hence, we sought to explore the relationship between ferritin and NASH and to develop a composite model based on ferritin to predict the presence of NASH. METHODS A total of 405 patients with biopsy-proven NAFLD were enrolled in the study. Comparison was explored to assess differences between patients with and without NASH, upon which a scoring model was established using variables found to be independent predictors of NASH. RESULTS Among all patients with NAFLD, 291 (72%) had biopsy-proven NASH, and 114 (28%) had non-NASH. Mean age was 48 ± 12 years, and 56% were female. Ferritin was significantly higher in NASH compared with non-NASH patients (184 vs 126, respectively; P

The USPSTF recommends the AUDIT, the AUDIT-C, or the single-question NIAAA screen. The CAGE screening tool has low sensitivity at lower levels of alcohol intake.

Background: According to 2011 CDC data, more than 2.6 million adults aged 60 and older with cognitive impairment reported difficulty performing one or more ADLs. There are studies that link cognitive decline and physical impairment in terms of low-level chronic inflammation, oxidative stress, and depression. Skeletal muscle can produce IL-1, IL-6 and other important myokines that have been implicated in cognitive and physical functional degenerative processes. Oxidative stressors have been linked to physical frailty and sarcopenia as well as neurodegenerative processes further worsening cognitive impairment. What are Sarcopenia and Sarcopenic Obesity and its impacts on elders? Sarcopenia is a primary disease of the elderly population, characterized by loss of skeletal muscle mass and function. Sarcopenia is correlated with physical disability, poor quality of life, frailty, cognitive impairment, and death. Age, gender, and level of physical activity are the risk factors for the Sarcopenia. In addition to aging, malignancy and rheumatoid arthritis causes loss of lean body mass and even increase in body fat mass. The loss of muscle mass associated with increased body fat mass i.e. sarcopenic obesity causes weakness in aging. Sarcopenia, with or without obesity, results in impairment of IADL (Instrumental Activity of Daily Living) and eventually ADLs (Activities of Daily Living) among elders and results in need for long-term care and increased cost of health care. What is the link between Sarcopenia and Cognitive Impairment? Sarcopenia has not only has a greater effect on survival but also on cognitive impairment. Sarcopenia has been linked to global cognitive impairment and dysfunction in specific cognitive skills including memory, speed, and executive functions. While obesity may impair the executive functions of aging, the exact mechanism linking obesity to cognitive dysfunction is not clear. Improvement in muscular function of obese older adults has been linked to improvement of executive functions. Obesity and Sarcopenia were associated with the lower executive function such as working memory, mental flexibility, self-control and orientation when assessed independently and even more so when they occurred together. Sarcopenia is highly correlated with frailty and risk of falls in elders; it also represents an important risk factor for disability and mortality. Frailty is an independent predictor of dementia. How do you assess for the Sarcopenia? Sarcopenia with or without obesity can be used in clinical practice to assess the potential risk of cognitive impairment in elders. There are several ways to measure Sarcopenia – DEXA (Dual-Energy X-ray Absorptiometry), biometric impedance analysis (BIA), CT (Computed Tomography) scan and MRI (Magnetic Resonance Imaging). However, assessing BMI and testing grip strength by dynamometry can be easily administered during annual wellness visits to assess the risk of sarcopenic related cognitive impairments. Sarcopenia can be assessed using parameters such as 1) Measure walking speed in elderly (>65 years). If the walking speed is below 0.8 m/s at the 4-m walking test, measure the muscle mass. 2) Hand- grip strength if this value is lower than 20kg in women and 30kg in man then muscle mass must be analyzed. 3) Defining Fat mass and lean body mass using BIA 4) Muscle Mass assessment by DEXA or CT. What is the significance of assessing the Sarcopenia? It is important to identify the risk of cognitive impairment by assessing for the onset of this condition. Preventing or delaying onset will likely enhance survival and reduce the demand for long-term care. Increasing resistance physical training will help to improve physical deconditioning, strengthen skeletal muscle hypertrophy, overcome the pain syndrome and enhance overall mental well-being. Interventions such as resistance exercise and nutritional therapy need to be developed specifically to delay the onset of Sarcopenia. What is the need in the future? Team-based approach including multidisciplinary model involving primary care physicians, geriatric psychiatrists, pain management physicians and physical therapists is required to combat the complex interlinked Sarcopenia associated cognitive impairment. Screening programs that include identification of cognitive and functional impairment in the office setting will serve as the starting point for specific interventions. The training regimen that includes supervision and correct equipment with resistance exercise will be necessary to get proper training and delay the muscle loss in elderly. References: 1) Cruz-Jentoft et al; Prevalence of and interventions for sarcopenia in aging adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS). Age Ageing. 2014 Nov;43(6):748-59. 2) Tolea MI, Galvin Sarcopenia, and impairment in cognitive and physical performance.Clin Interv Aging. 2015 Mar 30;10:663-71. 3) Zembron-Łacny A, Dziubek W, Rogowski Ł, Skorupka E, Dąbrowska G. Sarcopenia: monitoring, molecular mechanisms, and physical intervention. Physiol Res. 2014;63(6):683-91. 4) Chang KV Hsu TH Wu WT Huang KC, Han DS. Association Between Sarcopenia and Cognitive Impairment: A Systematic Review and Meta-Analysis. J Am Med Dir Assoc. 2016 Dec 1;17(12):1164.e7-1164.e15.

Background While non-alcoholic fatty liver disease (NAFLD) has been well characterised in patients with diabetes mellitus (DM), less is known about NAFLD in non-DM patients. We investigated the clinical characteristics of NAFLD patients with and without DM and accuracy of the NAFLD fibrosis score (NFS) in these two NAFLD groups. Methods Clinical, biochemical and histological variables were evaluated in this prospective cross-sectional study of 503 patients with biopsy proven NAFLD. Comparisons between patients with and without DM were analysed. NFS was correlated with liver histology to assess its robustness in patients with and without DM. Results There were 503 biopsy proven NAFLD patients with 48% of the cohort being diabetic. Relative to patients without DM, patients with DM were older (52 vs. 46 years, p, Highlights • Patients with diabetes have more severe NAFLD based on histology. • Severe NAFLD can occur in a considerable proportion of non-diabetic NAFLD patients. • The NAFLD fibrosis score may be less accurate in non-diabetics.

While histological differences have been reported between pediatric and adult nonalcoholic fatty liver disease (NAFLD), potential age-related changes in serum transaminases and liver histology remain largely unexplored. Our study sought to investigate the clinical and histological characteristics of NAFLD across age. This was a prospective cross-sectional study of 502 biopsy-proven NAFLD patients. Clinical data were evaluated and compared among different age groups; group A (ages 18–44), B (ages 45–64), and C (≥ages 65). 34.9, 56.0, and 9.1 % of the cohort were distributed among group A, B, and C, respectively. While the prevalence of nonalcoholic steatohepatitis (NASH) was comparable across age groups, the prevalence of advanced fibrosis increased with age (p = 0.000). Although the mean ALT progressively decreased with age; 87, 64, 56 U/L in group A, B, and C, respectively (p = 0.000), there was no difference in mean AST (p = 0.939) across age. The AST:ALT ratio (AAR) progressively increased from 0.7, 0.9, and 1.1 in group A, B, and C, respectively (p = 0.000). In group C, an AAR ≥1 was found in 74 and 40 % of patients with and without advanced fibrosis. With advancing age, ALT levels progressively declined while AST levels remained stable, leading to a higher AAR. Although higher AAR is often used as a surrogate measure of advanced fibrosis, advancing age can also contribute to increased AAR. In fact, an AAR ≥1 was found in significant number of elderly patients without advanced fibrosis. Consequently, an increased AAR may be a function of decreasing ALT with age in addition to progressive fibrosis.

Background: Hypovitaminosis D is associated with an increased severity of nonalcoholic fatty liver disease (NAFLD), but reports on the response to cholecalciferol (vitamin D3) supplementation are conflicting.Objective: The objective of this study was to determine if standard vitamin D3 supplementation is effective in NAFLD with hypovitaminosis D.Methods: Sixty-five well-characterized adults [age (mean ± SD): 51.6 ± 12.3 y] with biopsy-proven NAFLD were screened. Forty-two patients (the ratio of men to women was 13:29) had hypovitaminosis D (plasma 25-hydroxyvitamin D [25(OH)D]

Background & Aims Therapeutic options are limited for patients with non-alcoholic fatty liver disease (NAFLD). One promising approach is the attenuation of necroinflammation and fibrosis by inhibition of the renin-angiotensin system (RAS). We explored whether the risk of fibrosis was associated with the use of commonly used medications in NAFLD patients with hypertension. Specifically, we sought to determine the association between RAS blocking agents and severity of hepatic fibrosis in NAFLD patients with hypertension. Methods Cross-sectional study where clinical information including demographics, anthropometry, medical history, concomitant medication use, biochemical and histological features were ascertained in 290 hypertensive patients with biopsy proven NAFLD followed at two hepatology outpatient clinics. Stage of hepatic fibrosis was compared in patients with and without RAS blocker use. Other risk factors for fibrosis were evaluated from the electronic medical records and patient follow-up. Results Baseline characteristics of hypertensive patients treated with and without RAS blockers were similar except for less ballooning (1.02 vs. 1.31, P = 0.001) and lower fibrosis stage (1.63 vs. 2.16, P = 0.002) in patients on RAS blockers On multivariate analysis, advancing age (OR: 1.04; 95%CI: 1.01–1.06, P = 0.012) and presence of diabetes (OR: 2.55; 95%CI: 1.28–5.09, P = 0.008) had an independent positive association, while use of RAS blockers (OR: 0.37; 95%CI: 0.21–0.65, P = 0.001) and statins (OR: 0.52; 95%CI: 0.29–0.93, P = 0.029) had a negative association with advanced fibrosis. Conclusion Hypertensive patients with NAFLD on baseline RAS blockers had less advanced hepatic fibrosis suggesting a beneficial effect of RAS blockers in NAFLD.

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 & AIMS: Noninvasive methods are needed to determine disease stage in patients with nonalcoholic fatty liver disease (NAFLD). We evaluated the diagnostic performance of several widely available fibrosis models for the assessment of hepatic fibrosis in patients with NAFLD. METHODS: We performed a retrospective analysis of data from individuals enrolled in the NIDDK NASH Clinical Research Network, from 2004 through 2018. Using biopsy as the reference standard, we determined the diagnostic performance of the aspartate aminotransferase (AST):platelet ratio (APRI), FIB-4, ratio of AST:alanine aminotransferase (ALT) and the NAFLD fibrosis score (NFS) in a cross-sectional study of 1904 subjects. The ability of these models to detect changes in fibrosis stage was assessed in a longitudinal data set of 292 subjects with 2 biopsies and accompanying laboratory data. Outcomes were detection of fibrosis of any stage (stages 0 to 4), detection of moderate fibrosis (stages 0–1 vs 2–4), and detection of advanced fibrosis (stages 0–2 vs 3–4). Diagnostic performance was evaluated using the C-statistic, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) analyses. RESULTS: In the cross-sectional study, FIB-4 and NFS outperformed other non-invasive models for detecting advanced fibrosis; the C-statistics were 0.80 for FIB-4 and 0.78 for NFS. In the longitudinal study, 216 patients had non-advanced fibrosis at baseline and 35 patients progressed to advanced fibrosis after median follow up of 2.6 years. After we adjusted for fibrosis stage and model score at initial biopsy, change in APRI, FIB-4, and NFS were significantly associated with change in fibrosis. A unit change in APRI, FIB-4, or NFS was associated with changes in fibrosis stage of 0.33 (95% CI, 0.20-0.45; P

Despite advances in treatment of alcohol use disorders that focus on increasing abstinence and reducing recidivism, alcoholic liver disease is projected to be the major cause of cirrhosis and its complications. Malnutrition is recognized as the most frequent complication in alcoholic liver disease (ALD) and despite the high clinical significance, there are no effective therapies to reverse malnutrition in ALD. Malnutrition is a relatively imprecise term and sarcopenia or skeletal muscle loss, the major component of malnutrition, is primarily responsible for the adverse clinical consequences in patients with liver disease. It is, therefore, critical to define the specific abnormality (sarcopenia) rather than malnutrition in ALD, so that therapies targeting sarcopenia can be developed. Skeletal muscle mass is maintained by a balance between protein synthesis and proteolysis. Both direct effects of ethanol and its metabolites on the skeletal muscle and the consequences of liver disease result in disturbed proteostasis (protein homeostasis) and consequent sarcopenia. Once cirrhosis develops in patients with alcoholic liver disease, abstinence is unlikely to be effective in completely reversing sarcopenia, since other contributors including hyperammonemia, hormonal and cytokine abnormalities aggravate sarcopenia and maintain a state of anabolic resistance initiated by ethanol. Cirrhosis is also a state of accelerated starvation, with increased gluconeogenesis that requires amino acid diversion from signaling and substrate functions. Novel therapeutic options are being recognized that are likely to supplant the current “deficiency replacement” approach and instead focus on specific molecular perturbations, given the increasing availability of small molecules that can target specific signaling components. Myostatin antagonists, leucine supplementation, and mitochondrial protective agents are currently in various stages of evaluation in preclinical studies to prevent and reverse sarcopenia, in cirrhosis in general, and alcoholic liver disease, specifically. Translation of these data to human studies and clinical application requires priority for allocation of resources.

Depigmented patches covering approximately 15% of newborn's body, surrounded by areas of thickened skin. Mild scaling and hyperpigmentation.

Lifestyle changes and metabolic syndrome management are the best interventions for NAFLD. Less clear is which agents to use for liver-directed pharmacotherapy.

Change in body composition with reduced muscle mass with or without loss of fat mass occurs in 60-90% of patients with cirrhosis. This has an adverse impact on the outcome of these patients and is an understudied area. Transjugular intrahepatic portosystemic stent (TIPS) is now a standard therapy for portal hypertension but its beneficial impact on nutritional indices is not well recognized. We included all publications on TIPS that had any nutritional index as an outcome measure or end point. Given the heterogeneity of the patient population, differences in study design and outcome measures, a meta-analysis was not feasible. Data were summarized and interpreted. A total of eight studies have been published on the changes in body composition after TIPS in cirrhosis in a total of 152 patients followed for 3-12 months. Improvement in fat-free mass and fluid-free or ascites-free body weight was reported in all studies. Plasma leptin, IGF1, insulin sensitivity, rate of glucose disposal and growth hormone did not change after TIPS. One study measured muscle strength that improved. Direct measurement of skeletal muscle mass was not performed in any study. TIPS resulted in an improvement in body composition. Given the clinical significance of skeletal muscle and fat mass in cirrhosis, nutritional indices should be considered to be an important outcome measure in patients with TIPS. The mechanism of these is unclear, but its clinical implication is that this may contribute to the improved survival after TIPS.

The objective of this study was to determine if primary care providers (PCPs) screen for sleep disorders during clinical evaluation of new patients, and to compare this to likely sleep diagnoses as assessed by validated questionnaires.Adult patients evaluated as new patients in a primary care clinic at a tertiary care center were included in a prospective study. Following their appointment, patients completed the Cleveland Sleep Habits questionnaire (CSHQ), Berlin questionnaire, Epworth Sleepiness Scale (ESS), and STOP questionnaire. The encounters were subsequently reviewed for elements of a sleep history, sleep review of systems, and/or sleep workup.101 patients participated in the study.58 (52%) females, mean age 38 ± 12.9 years, body mass index (BMI) 29.5 ± 8.3 kg/m² (BMI30 kg/m² in 44%), 46% Caucasian, 38% African American, 11% Hispanic, and 5% other. House staff evaluated 57.4%; faculty evaluated the remainder. The ESS was10 in 28% of subjects. High risk for obstructive sleep apnea (OSA) risk was found in 33% (Berlin) and 34% (STOP) (24.8% by both). The CSHQ suggested possible diagnoses of insomnia in 30% and restless legs syndrome in 22%. In the clinic encounters, a limited sleep history was found in 24.8%, documentation of a sleep disorder in 8.9%, referral to sleep clinic in 2%, and referral to psychiatry clinic in 6.9%.Symptoms suggestive of sleep disorders are common but are not routinely screened for in the primary care setting. Validated questionnaires can efficiently identify patients at risk for common sleep disorders in this setting.

Background/Aims Ultrasound is used to screen for hepatic steatosis, the most common liver disease in the United States. However, few studies have prospectively evaluated the accuracy of ultrasound to diagnose hepatic steatosis. Therefore, a double blinded prospective study was performed in consecutive patients undergoing liver biopsy to evaluate the accuracy of ultrasound to diagnose hepatic steatosis. Methods Real time ultrasound was performed just prior to the biopsy by a single investigator masked to the clinical diagnosis. The liver biopsy was reviewed by a pathologist masked to the clinical indication or sonographic findings. Results Of 73 consecutive patients studied, macrovesicular steatosis of any severity on biopsy was found in 46 (63%) and micro vesicular fat found in 51 (69.9%). The overall impression of the sonographer for the presence of macrovesicular hepatic steatosis of any degree had a sensitivity of 60.9% and a specificity of 100%. The sensitivity increased to 100% and the specificity to 90% when there was⩾20% of fat. The zonular distribution of the fat did not alter the diagnostic accuracy of ultrasound. Ultrasound had a poor yield in the diagnosis of microvesicular fat with an overall sensitivity of 43% and a specificity of 73%. The combination of increased echogenicity and portal vein blurring on ultrasound had the greatest sensitivity in the diagnosis of hepatic steatosis. Conclusion Real time ultrasound using a combination of sonographic findings has a high specificity but underestimates the prevalence of hepatic steatosis when there is

Background Identifying changes in the epidemiology of liver disease is critical for establishing healthcare priorities and allocating resources to develop therapies. The projected contribution of different etiologies toward development of cirrhosis in the United States was estimated based on current publications on epidemiological data and advances in therapy. Given the heterogeneity of published reports and the different perceptions that are not always reconcilable, a critical overview rather than a formal meta-analysis of the existing data and projections for the next decade was performed. Methods Data from the World Health Organization Global Status Report on Alcohol and Health of 2014, Scientific Registry of Transplant Recipients from 1999 to 2012, National Institute on Alcohol Abuse and Alcoholism, and the Centers for Disease Control and Prevention were inquired to determine future changes in the epidemiology of liver disease. Results Alcohol consumption has increased over the past 60 years. In 2010, transplant-related costs for liver recipients were the highest for hepatitis C (~$124 million) followed by alcohol-related cirrhosis (~$86 million). We anticipate a significant reduction in incidence cirrhosis due to causes other than alcohol because of the availability of high efficiency antiviral agents for hepatitis C, universal and effective vaccination for hepatitis B, relative stabilization of the obesity trends in the United States, and novel, potentially effective therapies for nonalcoholic steatohepatitis. The proportion of alcohol-related liver disease is therefore likely to increase in both the population as a whole and the liver transplant wait list. Conclusions Alcohol-related cirrhosis and alcohol-related liver disorders will be the major cause of liver disease in the coming decades. There is an urgent need to allocate resources aimed toward understanding the pathogenesis of the disease and its complications so that effective therapies can be developed.

Non-alcoholic steatohepatitis (NASH) is an advanced and aggressive form of non-alcoholic fatty liver disease (NAFLD), which remains difficult to diagnose without a liver biopsy. Hyperferritinemia has increasingly been associated with the presence of NASH. Hence, we sought to explore the relationship between ferritin and NASH and to develop a composite model based on ferritin to predict the presence of NASH.A total of 405 patients with biopsy-proven NAFLD were enrolled in the study. Comparison was explored to assess differences between patients with and without NASH, upon which a scoring model was established using variables found to be independent predictors of NASH.Among all patients with NAFLD, 291 (72%) had biopsy-proven NASH, and 114 (28%) had non-NASH. Mean age was 48 ± 12 years, and 56% were female. Ferritin was significantly higher in NASH compared with non-NASH patients (184 vs 126, respectively; P 0.001) but lacked diagnostic accuracy for predicting NASH alone (area under the curve [AUC 0.62]). The addition of other significant variables such as aspartate aminotransferase, body mass index, platelet count, diabetes, and hypertension to ferritin improved the prediction of NASH with an AUC 0.81 (95% confidence interval: 0.76-0.86). Internal validation of the model using imputed data sets demonstrated that AUC did not change materially.While higher ferritin was significantly associated with NASH, ferritin alone lacked diagnostic accuracy to predict NASH. However, incorporating several easily obtainable variables with ferritin allowed the construction of a novel scoring system that can be easily applied in the clinical setting to guide management of NAFLD.

Background:Nonalcoholic steatohepatitis (NASH) is common and severe in patients with diabetes mellitus. Although, there are no effective treatments for NASH in diabetic patients, preliminary reports suggest that polyunsaturated fatty acids (PUFA) may be beneficial in these patients.Aim:A prospective

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.

Background & Aims Hypovitaminosis D is common in obesity and insulin-resistant states. Increased fat mass in patients with non-alcoholic fatty liver disease (NAFLD) may contribute to hypovitaminosis D. To determine the relation among plasma vitamin D concentration, severity of disease and body composition in NAFLD. Methods Plasma vitamin D concentration was quantified in 148 consecutive biopsy-proven patients with NAFLD (non-alcoholic steatohepatitis – NASH: n = 81; and hepatic steatosis: n = 67) and healthy controls (n = 39). NAFLD was scored using the NASH CRN criteria. Body composition was quantified by bioelectrical impedance analysis and abdominal CT image analysis. Results Plasma vitamin D concentration was significantly lower in NAFLD (21.2 ± 10.4 ng/ml) compared with healthy controls (35.7 ± 6.0 ng/ml). Higher NAFLD activity scores were associated with lower plasma concentration of vitamin D (r2 = 0.29; P

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

Change in body composition with reduced muscle mass with or without loss of fat mass occurs in 60-90% of patients with cirrhosis. This has an adverse impact on the outcome of these patients and is an understudied area. Transjugular intrahepatic portosystemic stent (TIPS) is now a standard therapy for portal hypertension but its beneficial impact on nutritional indices is not well recognized. We included all publications on TIPS that had any nutritional index as an outcome measure or end point. Given the heterogeneity of the patient population, differences in study design and outcome measures, a meta-analysis was not feasible. Data were summarized and interpreted. A total of eight studies have been published on the changes in body composition after TIPS in cirrhosis in a total of 152 patients followed for 3-12 months. Improvement in fat-free mass and fluid-free or ascites-free body weight was reported in all studies. Plasma leptin, IGF1, insulin sensitivity, rate of glucose disposal and growth hormone did not change after TIPS. One study measured muscle strength that improved. Direct measurement of skeletal muscle mass was not performed in any study. TIPS resulted in an improvement in body composition. Given the clinical significance of skeletal muscle and fat mass in cirrhosis, nutritional indices should be considered to be an important outcome measure in patients with TIPS. The mechanism of these is unclear, but its clinical implication is that this may contribute to the improved survival after TIPS.

Background: Hyperhomocysteinemia during pregnancy, which is a consequence of perturbations in methionine and/or folate metabolism, has been implicated in adverse outcomes such as neural tube defects, preeclampsia, spontaneous abortion, and premature delivery. The adaptive changes in methionine metabolism during pregnancy in humans have not been determined. Objective: Our objective was to examine the kinetics of methionine and its rate of transsulfuration and transmethylation in healthy women with advancing gestation. Design: The whole-body rate of appearance (Ra) of methionine and phenylalanine was measured in healthy pregnant women during the first (n ¼ 10), second (n ¼ 5), and third (n ¼ 10) trimesters of pregnancy. These data were compared with those for nonpregnant women (n ¼ 8). Tracers [1- 13 C]methionine, [C 2 H3]methionine, and [ 2 H5]phenylalanine were administered as prime-constant rate infusions. The effect of enteral high-protein, mixed-nutrient load on tracer-determined variables was also examined. Results: In pregnant women, the Ra of phenylalanine was significantly (P , 0.05) lower in the first trimester than in the second and third trimesters and was significantly lower than that in nonpregnant women. A linear positive correlation was evident between gestational age and phenylalanine Ra. The fractional rate and total rate of transsulfuration of methionine was significantly (P , 0.05) higher during the first trimester, whereas the rate of transmethylation was higher during the third trimester. Plasma concentrations of total cysteine and homocysteine were lower during pregnancy. Conclusions: Uncomplicated pregnancy in humans is associated with a higher rate of transsulfuration early in gestation and a higher rate of transmethylation of methionine in late gestation. These data may have implications for understanding the role of methionine and homocysteine in complications of pregnancy and for the nutritional care of pregnant women. Am J Clin Nutr 2010;91:357‐65.