[11C]acetate PET as a tool for diagnosis of liver steatosis.

PURPOSE: To investigate [11C]acetate PET-surrogate parameter of fatty acid synthase activity-as suitable tool for diagnosis and monitoring of liver steatosis. METHODS: In this retrospective study, data were obtained from 83 prostatic carcinoma patients from 1/2008 to 1/2014. Mean HU was calculated from unenhanced CT of all patients from liver with liver HU less than 40 as threshold for liver steatosis. SUVmax of the liver and of the blood pool in thoracic aorta (as background for calculation of a liver/background ratio [SUVl/b]) was measured. t test was used with a P < 0.05 considered as statistically significant difference and ROC analysis was used for calculating specificity and sensitivity. RESULTS: 19/83 patients (20%) had diagnosis of hepatic steatosis according to CT. Uptake of [11C]acetate was significantly higher in patients with hepatic steatosis as compared to control group (SUVmax 7.96 ± 2.0 vs. 5.48 ± 2.3 [P < 0.001]). There was also a significant correlation between both SUVmax (r = - 0.52, P < 0.001) and SUVl/b (r = - 0.59, P < 0.001) with the density (HU) of the liver. In ROC analysis for detection of liver steatosis SUVmax (threshold: 5.86) had a sensitivity of 94% and specificity of 69% with an AUC of 0.81. Increasing body mass index is correlated with the severity of steatosis. CONCLUSION: We showed for the first time that hepatic steatosis associates with increased [11C]acetate uptake. Also, severity of steatosis correlates with [11C]acetate uptake. [11C]acetate uptake PET seems promising for the assessment of liver steatosis.

Ultra-high-field magnetic resonance spectroscopy in non-alcoholic fatty liver disease: Novel mechanistic and diagnostic insights of energy metabolism in non-alcoholic steatohepatitis and advanced fibrosis.

BACKGROUND & AIMS: With the rising prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) non-invasive tools obtaining pathomechanistic insights to improve risk stratification are urgently needed. We therefore explored high- and ultra-high-field magnetic resonance spectroscopy (MRS) to obtain novel mechanistic and diagnostic insights into alterations of hepatic lipid, cell membrane and energy metabolism across the spectrum of NAFLD. METHODS: MRS and liver biopsy were performed in 30 NAFLD patients with NAFL (n=8) or NASH (n=22). Hepatic lipid content and composition were measured using 3-Tesla proton (1 H)-MRS. 7-Tesla phosphorus (31 P)-MRS was applied to determine phosphomonoester (PME) including phosphoethanolamine (PE), phosphodiester (PDE) including glycerophosphocholine (GPC), phosphocreatine (PCr), nicotinamide adenine dinucleotide phosphate (NADPH), inorganic phosphate (Pi), γ-ATP and total phosphorus (TP). Saturation transfer technique was used to quantify hepatic ATP flux. RESULTS: Hepatic steatosis in 1 H-MRS highly correlated with histology (P<.001) showing higher values in NASH than NAFL (P<.001) without differences in saturated or unsaturated fatty acid indices. PE/TP ratio increased with advanced fibrosis (F3/4) (P=.002) whereas GPC/PME+PDE decreased (P=.05) compared to no/mild fibrosis (F0-2). γ-ATP/TP was lower in advanced fibrosis (P=.049), while PCr/TP increased (P=.01). NADPH/TP increased with higher grades of ballooning (P=.02). Pi-to-ATP exchange rate constant (P=.003) and ATP flux (P=.001) were lower in NASH than NAFL. CONCLUSIONS: Ultra-high-field MRS, especially saturation transfer technique uncovers changes in energy metabolism including dynamic ATP flux in inflammation and fibrosis in NASH. Non-invasive profiling by MRS appears feasible and may assist further mechanistic and therapeutic studies in NAFLD/NASH.

Low hepatic copper content and PNPLA3 polymorphism in non-alcoholic fatty liver disease in patients without metabolic syndrome.

INTRODUCTION: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is multifactorial including metabolic, genetic (e.g. PNPLA3 [patatin-like phospholipase domain-containing 3 gene]), viral factors and drugs. Besides, there is evidence for a role of copper deficiency. Aim of the study was to evaluate the role of hepatic copper content, PNPLA3 in NAFLD patients with and without metabolic syndrome (MetS). METHODS: One-hundred seventy-four NAFLD patients, who underwent liver biopsy for diagnostic work-up, were studied. Diagnosis of MetS was based on the WHO Clinical Criteria. Steatosis was semiquantified as percentage of fat containing hepatocytes and was graded according to Brunt. Histological features of non-alcoholic steatohepatitis (NASH) were assessed using the Bedossa classification. Hepatic copper content (in µg/g dry weight) was measured by flame atomic absorption spectroscopy. SNP rs738409 in PNPLA3 was investigated by RT-PCR. RESULTS: Mean hepatic copper content was 22.3 (19.6-25.1) µg/g. The mean percentage of histologically lipid containing hepatocytes was 42.2% (38.3-46.0) and correlated inversely with hepatic copper content (ρ=-0.358, P<0.001). By subgroup analysis this inverse correlation remained significant only in patients without MetS (OR: 0.959 [CI95%: 0.926-0.944], P=0.020). Presence of minor allele (G) of PNPLA3 was also associated with moderate/severe steatosis (≥33%) both in patients with (OR: 2.405 [CI95%: 1.220-4.744], P=0.011) and without MetS (OR: 2.481 [CI95%: 1.172-5.250], P=0.018), but was only associated with NASH (OR: 2.002 [CI95%: 1.062-3.772], P=0.032) and liver fibrosis (OR: 2.646 [CI95%: 1.299-5.389], P=0.007) in patients without MetS. CONCLUSION: Hepatic copper content and PNPLA3 mutations are associated with disease activity in NAFLD patients without MetS. Presence of MetS appears to mask the effects of hepatic copper and PNPLA3.

Vitamin D3 Loading Is Superior to Conventional Supplementation After Weight Loss Surgery in Vitamin D-Deficient Morbidly Obese Patients: a Double-Blind Randomized Placebo-Controlled Trial.

BACKGROUND: Bariatric patients often suffer from vitamin D deficiency (VDD), and both, morbid obesity and VDD, are related to non-alcoholic fatty liver disease. However, limited data are available regarding best strategies for treating VDD, particularly, in bariatric patients undergoing omega-loop gastric bypass (OLGB). Therefore, we examined the efficacy and safety of a forced vitamin D dosing regimen and intervention effects in liver fibrotic patients. METHODS: In this double-blind, randomized, placebo-controlled trial, 50 vitamin D-deficient patients undergoing OLGB were randomly assigned to receive, in the first month postoperatively, oral vitamin D3 (≤3 doses of 100,000 IU; intervention group) or placebo as loading dose (control group) with subsequent maintenance dose (3420 IU/day) in both groups until 6-month visit. RESULTS: Compared with control group, higher increase of 25(OH)D (67.9 (21.1) vs. 55.7 nmol/L (21.1); p = 0.049) with lower prevalence of secondary hyperparathyroidism (10 vs. 24 %; p = 0.045) was observed in intervention group. No (serious) adverse events related to study medication were found. The loading dose regimen was more effective in increasing 25(OH)D in patients with significant liver fibrosis while this was not the case for conventional supplementation (placebo with maintenance dose) (71.5 (20.5) vs. 22.5 nmol/L (13.8); p = 0.022; n = 14). CONCLUSIONS: Our findings indicate that a high vitamin D3 loading dose, in the first month postoperatively, with subsequent maintenance dose is effective and safe in achieving higher vitamin D concentrations in OLGB patients. Unexpectedly, it is more effective in patients with significant liver fibrosis which is of potentially high clinical relevance and requires further investigation.

The Effect of Roux-en-Y vs. Omega-Loop Gastric Bypass on Liver, Metabolic Parameters, and Weight Loss.

BACKGROUND: Omega-loop gastric bypass (OLGB) results in weight loss (WL) but data on its impact on liver and glucose metabolism compared to Roux-en-Y gastric bypass (RYGB) is lacking. Therefore, the aim of this study was to compare the development of hepatic and metabolic markers as well as WL between the above-mentioned surgical groups during the first postoperative year. METHODS: We retrospectively evaluated the respective parameters in non-diabetic morbidly obese patients who underwent either RYGB (n = 25) or OLGB (n = 25). RESULTS: Compared to RYGB, OLGB showed a greater WL percentage. Liver transaminases dropped in RYGB, while rose in OLGB. No correlation between aspartate transaminase, alanine transaminase, and WL could be detected. Gamma-glutamyltransferase decreased significantly in RYGB over the first 3 months, while it increased in OLGB. We found higher levels of triglycerides, insulin, homeostasis model assessment of insulin resistance (HOMA2-IR), and liver fat percentage in RYGB at baseline, despite matching the groups for age, sex, and BMI. Those differences disappeared, except for triglycerides, within 1 year. All metabolic parameters correlated with WL. CONCLUSION: OLGB results in greater WL but transiently deteriorated several liver parameters in the first postoperative year. This was not associated with WL. The impact of these results on hepatic outcomes such as non-alcoholic steatohepatitis and fibrosis progression requires further studies. In both groups, improved insulin resistance and sensitivity were correlated with higher WL and lower liver fat percentage, respectively.

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

BACKGROUND: Morbidly 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). METHODS: Baseline 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. RESULTS: In total, 80 % were females, aged 42 (SD 13) years with BMI 44 (4) kg/m(2). 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. CONCLUSIONS: Liver 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 link between obesity and vitamin D in bariatric patients with omega-loop gastric bypass surgery - a vitamin D supplementation trial to compare the efficacy of postoperative cholecalciferol loading (LOAD): study protocol for a randomized controlled trial.

BACKGROUND: Beyond its classical role in calcium homoeostasis and bone metabolism, vitamin D deficiency has been found to be associated with several diseases, including diabetes, non-alcoholic fatty liver disease, and even obesity itself. Importantly, there are limited data on therapeutic strategies for vitamin D deficiency in bariatric patients, and the procedure-specific guidelines may not be sufficient. To improve long-term outcomes, nutritional screening and appropriate supplementation to prevent nutrient deficiencies are urgently needed. Therefore, the aim of this study is to examine effects and safety of a forced dosing regimen of vitamin D versus conventional dose supplementation on vitamin D levels and other parameters in bariatric patients. METHODS/DESIGN: The study includes loading plus repeat dosing compared with repeated administration of vitamin D without a loading dose, according to guidelines, in a prospective, double-blind, randomized controlled trial. Up to a triple oral loading dose is given on day 1, then 2 and 4 weeks after surgery (100,000 IU dose each time), followed by an oral maintenance dose (3420 IU/day). The control group (n = 25) will receive placebo, followed by administration of a standard dose (3420 IU/day). We hypothesize that a significant increase in vitamin D levels will occur in patients in the treatment group (n = 25) by 24 weeks after surgery. Further measurements are aimed at evaluating changes in inflammation, bone turnover, insulin resistance, blood pressure, liver, mental health, and gut microbiota of patients undergoing omega-loop gastric bypass surgery. Furthermore, possible associations between concentrations of vitamin D, the involved enzymes, or vitamin D receptor in adipose and/or liver tissues will be determined. DISCUSSION: To our knowledge, this trial is the first of its kind with this type of vitamin D supplementation in bariatric patients. Its major strength is the design and implementation of evaluation of influencing factors such as liver function, bone health, inflammation, insulin resistance, blood pressure, symptoms of depression, or microbiota. This alternative vitamin D dosing regimen has the potential to be a safe, fast, evidence-based treatment of vitamin D deficiency in bariatric patients. Owing to the increasing number of bariatric patients, it is also of interest to elucidate the link between obesity and vitamin D. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02092376 . Registered on 17 March 2014.

Challenges and Management of Liver Cirrhosis: Practical Issues in the Therapy of Patients with Cirrhosis due to NAFLD and NASH.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and comprises a liver disease spectrum ranging from steatosis to nonalcoholic steatohepatitis (NASH) with risk of progression to liver cirrhosis and hepatocellular carcinoma (HCC). Associated metabolic conditions and comorbidities such as obesity, diabetes and cardiovascular diseases are common and require concerted management. Adiponutrin (PNPLA3) variants may help to identify NAFLD patients at higher risk for liver disease progression towards advanced fibrosis and HCC. The therapeutic options in NAFLD/NASH include lifestyle modification, pharmacological treatment, bariatric surgery for patients with morbid obesity and treatment of complications of liver cirrhosis and HCC, including liver transplantation. Insulin sensitizers and antioxidative treatment strategies with vitamin E are among the best-established pharmacological approaches, but both drugs have long-term safety issues and there is limited evidence in cirrhotic patients. Treatment of concomitant/underlying metabolic conditions with statins or metformin may also have beneficial effects on portal hypertension, complications of liver cirrhosis and HCC prevention. The bile acid receptor FXR may be a promising novel therapeutic target for the treatment of NAFLD/NASH, fibrosis and portal hypertension, but the prognostic implications of associated changes in low- and high-density lipoprotein cholesterol require further studies. Morbidly obese NASH patients can benefit from bariatric surgery which may reduce liver fibrosis but carries a risk of decompensation in patients with advanced liver cirrhosis. When carefully selected, patients with NASH cirrhosis undergoing liver transplantation have a good outcome. This review summarizes recent progress in the management of patients with liver cirrhosis due to NASH.

Application of localized ³¹P MRS saturation transfer at 7 T for measurement of ATP metabolism in the liver: reproducibility and initial clinical application in patients with non-alcoholic fatty liver disease.

OBJECTIVES: Saturation transfer (ST) phosphorus MR spectroscopy ((31)P MRS) enables in vivo insight into energy metabolism and thus could identify liver conditions currently diagnosed only by biopsy. This study assesses the reproducibility of the localized (31)P MRS ST in liver at 7 T and tests its potential for noninvasive differentiation of non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH). METHODS: After the ethics committee approval, reproducibility of the localized (31)P MRS ST at 7 T and the biological variation of acquired hepato-metabolic parameters were assessed in healthy volunteers. Subsequently, 16 suspected NAFL/NASH patients underwent MRS measurements and diagnostic liver biopsy. The Pi-to-ATP exchange parameters were compared between the groups by a Mann-Whitney U test and related to the liver fat content estimated by a single-voxel proton ((1)H) MRS, measured at 3 T. RESULTS: The mean exchange rate constant (k) in healthy volunteers was 0.31 ± 0.03 s(-1) with a coefficient of variation of 9.0 %. Significantly lower exchange rates (p < 0.01) were found in NASH patients (k = 0.17 ± 0.04 s(-1)) when compared to healthy volunteers, and NAFL patients (k = 0.30 ± 0.05 s(-1)). Significant correlation was found between the k value and the liver fat content (r = 0.824, p < 0.01). CONCLUSIONS: Our data suggest that the (31)P MRS ST technique provides a tool for gaining insight into hepatic ATP metabolism and could contribute to the differentiation of NAFL and NASH. KEY POINTS: • 1D localized (31) P MRS saturation transfer in the liver is reproducible at 7 T • NASH patients have decreased hepatic Pi-to-ATP exchange rate • In this study, hepatic metabolic activity correlates with liver fat content.

Prevalence and predictors of emotional and behavioural functioning of children where a parent has cancer: a multinational study.

BACKGROUND: This study aimed to evaluate prevalence and risk factors for emotional and behavioral problems in dependent children of cancer patients using a multinational research design. METHODS: The sample comprised 350 ill parents, 250 healthy partners, and 352 children. Parents assessed the child's psychological functioning using the Child Behavior Checklist, parental depression using the Beck Depression Inventory, family functioning using the General Functioning subscale of the Family Assessment Device, quality of life using short-form questionnaire, and adolescents (N = 168) self-reported psychological functioning using the Youth Self Report. RESULTS: Children and adolescents, in particular latency-aged boys and adolescent girls, were of higher risk of psychosocial problems than norms. There was a higher risk of problems when the father was ill than when the mother was ill, but it remains unclear whether this difference was due to the different diagnoses of fathers and mothers, gender or other factors. The best predictor of internalizing problems in children and adolescents was parental depression, and the best predictor of externalizing problems in children and adolescents was family dysfunction. CONCLUSIONS: The results indicate the need for a family-oriented approach to psychological support of cancer patients.

Multinational study of cancer patients and their children: factors associated with family functioning.

PURPOSE: This study examined factors associated with family functioning in cancer patients' families with dependent children. PATIENTS AND METHODS: A sample of 381 families (639 parents and 489 children) was recruited simultaneously in six European countries. Patients and family members completed a background questionnaire, the Family Assessment Device (FAD), the Beck Depression Inventory, and the short form version of the Medical Outcomes Health Survey. Descriptive statistics and a multilevel model that allowed a multi-informant design were used. Analyses were carried out with all participants, and separately with parent-rated and children-rated FAD scores. RESULTS: In descriptive analyses, children reported more impairment in family functioning than parents, but the difference was not significant. Depression prevalence was 35% for ill mothers and 28% for ill fathers. In the multilevel analyses with all participants (ie, adults and children) the ill parent's depression was significantly associated with impaired family functioning on five of seven FAD subscales. In analyses with only children, the perception of impairment of family functioning was not associated with parental depression. Additionally, poorer physical status of the ill parent was significantly associated with impairment on roles and communication. CONCLUSION: The ill parent's depression was the most significant factor associated with impairment in family functioning. Screening for depression, active diagnostics, and appropriate treatment of cancer patient's and partner's depression may be important to protect their children from mental disorders. Therefore, support systems need to be more family-oriented and child-centered in their approaches to cancer psychosocial care.