Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease.
Chu Huikuan,Duan Yi,Yang Ling,Schnabl Bernd
Gut
The spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from simple hepatic steatosis, commonly associated with obesity, to non-alcoholic steatohepatitis, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD pathophysiology involves environmental, genetic and metabolic factors, as well as changes in the intestinal microbiota and their products. Dysfunction of the intestinal barrier can contribute to NAFLD development and progression. Although there are technical limitations in assessing intestinal permeability in humans and the number of patients in these studies is rather small, fewer than half of the patients have increased intestinal permeability and translocation of bacterial products. Microbe-derived metabolites and the signalling pathways they affect might play more important roles in development of NAFLD. We review the microbial metabolites that contribute to the development of NAFLD, such as trimethylamine, bile acids, short-chain fatty acids and ethanol. We discuss the mechanisms by which metabolites produced by microbes might affect disease progression and/or serve as therapeutic targets or biomarkers for NAFLD.
10.1136/gutjnl-2018-316307
Sex differences between parental pregnancy characteristics and nonalcoholic fatty liver disease in adolescents.
Ayonrinde Oyekoya T,Adams Leon A,Mori Trevor A,Beilin Lawrence J,de Klerk Nicholas,Pennell Craig E,White Scott,Olynyk John K
Hepatology (Baltimore, Md.)
Nonalcoholic fatty liver disease (NAFLD) is a complex chronic liver disorder. Examination of parental pregnancy-related characteristics may provide insights into the origins of risk of NAFLD in offspring. We examined relationships between parental pregnancy-related characteristics and NAFLD in 1,170 adolescent offspring aged 17 years participating in the Western Australian Pregnancy (Raine) Cohort Study. Fatty liver was diagnosed using liver ultrasound. NAFLD was diagnosed in 15.2% of adolescents at age 17 years. In univariate analysis, maternal factors associated with NAFLD in female offspring were younger maternal age (P = 0.02), higher maternal prepregnancy BMI (P < 0.001), higher maternal weight gain by 18 weeks' gestation (P < 0.001), and maternal smoking during pregnancy (P = 0.04). Paternal age or body mass index (BMI) were not associated with NAFLD in female offspring. In contrast, higher paternal BMI (P < 0.001), maternal prepregnancy BMI (P < 0.001), and lower family socioeconomic status (SES) at time of birth (P = 0.001), but not parental age nor maternal gestational weight gain, were associated with NAFLD in male offspring. Using multivariate logistic regression, factors independently associated with NAFLD after adjusting for obesity in adolescent females included maternal obesity (odds ratio [OR], 3.46; 95% confidence interval [CI], 1.49-8.05; P = 0.004) and maternal weight gain ≥6.0 kg by the 18th week of gestation (OR, 1.10; 95% CI, 1.04-1.15; P < 0.001). In adolescent males, family SES at the time of birth (OR, 9.07; 95% CI, 1.54-53.29; P = 0.02) remained significantly associated with NAFLD after multivariate modeling adjusted for adolescent obesity. CONCLUSION:Early-life contributors to NAFLD show considerable sexual dimorphism. Maternal obesity and higher early-mid gestational weight gain were associated with NAFLD in female offspring, whereas lower family SES at birth was associated with NAFLD in male offspring independent of adolescent obesity. (Hepatology 2018;67:108-122).
10.1002/hep.29347
Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives.
Arab Juan P,Karpen Saul J,Dawson Paul A,Arrese Marco,Trauner Michael
Hepatology (Baltimore, Md.)
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches to prevent disease progression to advanced fibrosis or cirrhosis and cancer. In recent years, bile acids have emerged as relevant signaling molecules that act at both hepatic and extrahepatic tissues to regulate lipid and carbohydrate metabolic pathways as well as energy homeostasis. Activation or modulation of bile acid receptors, such as the farnesoid X receptor and TGR5, and transporters, such as the ileal apical sodium-dependent bile acid transporter, appear to affect both insulin sensitivity and NAFLD/NASH pathogenesis at multiple levels, and these approaches hold promise as novel therapies. In the present review, we summarize current available data on the relationships of bile acids to NAFLD and the potential for therapeutically targeting bile-acid-related pathways to address this growing world-wide disease. (Hepatology 2017;65:350-362).
10.1002/hep.28709
Modulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease.
Khan Reenam S,Bril Fernando,Cusi Kenneth,Newsome Philip N
Hepatology (Baltimore, Md.)
Nonalcoholic fatty liver disease (NAFLD) has an estimated prevalence of 25% in the general population, and cirrhosis secondary to nonalcoholic steatohepatitis (NASH) is predicted to become the leading cause of liver transplantation, yet there is a lack of effective licensed treatments for these conditions. There is a close relationship between insulin resistance (IR) and NAFLD, with prevalence of NAFLD being 5-fold higher in patients with diabetes compared to those without. IR is implicated both in pathogenesis of NAFLD and in disease progression from steatosis to NASH. Thus, modulation of IR represents a potential strategy for NAFLD treatment. This review highlights key proposed mechanisms linking IR and NAFLD, such as changes in rates of adipose tissue lipolysis and de novo lipogenesis, impaired mitochondrial fatty acid β-oxidation (FAO), changes in fat distribution, alterations in the gut microbiome, and alterations in levels of adipokines and cytokines. Furthermore, this review will discuss the main pharmacological strategies used to treat IR in patients with NAFLD and their efficacy based on recently published experimental and clinical data. These include biguanides, glucagon-like peptide 1 receptor (GLP-1) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, peroxisome proliferator-activated receptor (PPAR-γ/α/δ) agonists, sodium glucose cotransporter 2 (SGLT2) inhibitors, and farnesoid X receptor (FXR) agonists, with further novel treatments on the horizon. Ideally, treatment would improve IR, reduce cardiovascular risk, and produce demonstrable improvements in NASH histology-this is likely to be achieved with a combinatorial approach.
10.1002/hep.30429
Diet, weight loss, and liver health in nonalcoholic fatty liver disease: Pathophysiology, evidence, and practice.
Marchesini Giulio,Petta Salvatore,Dalle Grave Riccardo
Hepatology (Baltimore, Md.)
Fatty liver accumulation results from an imbalance between lipid deposition and removal, driven by the hepatic synthesis of triglycerides and de novo lipogenesis. The habitual diet plays a relevant role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), and both risky (e.g., fructose) and protective foods (Mediterranean diet) have been described, but the contribution of excess calories remains pivotal. Accordingly, weight loss is the most effective way to promote liver fat removal. Several controlled studies have confirmed that an intense approach to lifestyle changes, carried on along the lines of cognitive-behavior treatment, is able to attain the desired 7%-10% weight loss, associated with reduced liver fat, nonalcoholic steatohepatitis (NASH) remission, and also reduction of fibrosis. Even larger effects are reported after bariatric surgery-induced weight loss in NAFLD, where 80% of subjects achieve NASH resolution at 1-year follow-up. These results provide solid data to evaluate the safety and effectiveness of the pharmacological treatment of NASH. The battle against metabolic diseases, largely fueled by increased liver fat, needs a comprehensive approach to be successful in an obesiogenic environment. In this review, we will discuss the role of hepatic lipid metabolism, genetic background, diet, and physical activity on fatty liver. They are the basis for a lifestyle approach to NAFLD treatment. (Hepatology 2016;63:2032-2043).
10.1002/hep.28392
Past, present and future perspectives in nonalcoholic fatty liver disease.
Sanyal Arun J
Nature reviews. Gastroenterology & hepatology
Nonalcoholic fatty liver disease (NAFLD) was first described as a distinct clinical entity four decades ago. However, the condition has become the centre of attention within hepatology owing to its high prevalence and growing contribution to the burden of end-stage liver disease in the general population. This Perspective provides an overview on the development of knowledge related to NAFLD with a focus on landmark findings that have influenced current paradigms and key knowledge gaps that need to be filled to make progress. Specifically, a timeline of scientific discovery of both basic disease mechanisms (with a focus on human data) and the evolution of knowledge about the clinical course of the disease is provided and related to current approaches to treat and eventually prevent NAFLD.
10.1038/s41575-019-0144-8
Out of the frying pan: dietary saturated fat influences nonalcoholic fatty liver disease.
Parks Elizabeth,Yki-Järvinen Hannele,Hawkins Meredith
The Journal of clinical investigation
Nonalcoholic fatty liver disease (NAFLD) is characterized by excess accumulation of fat in the liver. In some cases, NAFLD is also accompanied by insulin resistance, resulting in metabolic dysfunction. Dietary fat content probably influences both NAFLD and insulin resistance; however, the immediate effects of fat consumption have not been fully explored. In this issue of the JCI, Hernández et al. evaluated hepatic glucose and lipid metabolism in humans and mice following a single oral dose of saturated fat. This one bolus of fat resulted in a measurable increase in insulin resistance, hepatic triglycerides, and gluconeogenesis. In mice, the saturated fat bolus resulted in the induction of several NAFLD-associated genes. Together, the results of this study indicate that saturated fat intake has immediate effects on metabolic function.
10.1172/JCI92407
Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease.
Castera Laurent,Friedrich-Rust Mireen,Loomba Rohit
Gastroenterology
Nonalcoholic fatty liver disease (NAFLD) is estimated to afflict approximately 1 billion individuals worldwide. In a subset of NAFLD patients, who have the progressive form of NAFLD termed nonalcoholic steatohepatitis (NASH), it can progress to advanced fibrosis, cirrhosis, hepatocellular carcinoma, and liver-related morbidity and mortality. NASH is typically characterized by a specific pattern on liver histology, including steatosis, lobular inflammation, and ballooning with or without peri-sinusoidal fibrosis. Thus, key issues in NAFLD patients are the differentiation of NASH from simple steatosis and identification of advanced hepatic fibrosis. Until now, liver biopsy has been the gold standard for identifying these 2 critical end points, but has well-known limitations, including invasiveness; rare but potentially life-threatening complications; poor acceptability; sampling variability; and cost. Furthermore, due to the epidemic proportion of individuals with NAFLD worldwide, liver biopsy evaluation is impractical, and noninvasive assessment for the diagnosis of NASH and fibrosis is needed. Although much of the work remains to be done in establishing cost-effective strategies for screening for NASH, advanced fibrosis, and cirrhosis, in this review, we summarize the current state of the noninvasive assessment of liver disease in NAFLD, and we provide an expert synthesis of how these noninvasive tools could be utilized in clinical practice. Finally, we also list the key areas of research priorities in this area to move forward clinical practice.
10.1053/j.gastro.2018.12.036
Burden of Future Liver Abnormalities in Patients With Intrahepatic Cholestasis of Pregnancy.
The American journal of gastroenterology
INTRODUCTION:There are limited data on the incidence, predictors, and time to future liver abnormalities in patients with intrahepatic cholestasis of pregnancy (ICP). METHODS:Single-center retrospective study of pregnant women with and without ICP who delivered from 2005 to 2009 evaluating incidence and time to future liver abnormalities. Women returning for care with liver function tests at a minimum of 6 months postpartum were included. Liver disease diagnoses and liver functions test abnormalities were compared. Time to development of alanine aminotransferase (ALT) >25 U/L, alkaline phosphatase (ALP) >140 U/L, and diagnosis of liver disease (through imaging or clinical evaluation) were compared between women with and without ICP using Kaplan-Meier methods and Cox regression models. RESULTS:A total of 255 women with ICP and 131 age-matched control subjects with delivery during the same period were identified. Subjects in both groups were similar in follow-up time, age at pregnancy, prepregnancy body mass index, and ethnicity (≥75% were Hispanic in both groups). On univariate analyses, ICP was associated with increased incidence of ALT >25 U/L P < 0.01 ALP >140 U/L (P < 0.01) and liver disease (P = 0.03). Adjusting for metabolic factors, ICP diagnosis was associated with risk of future liver abnormalities: postpartum ALT >25 U/L (hazard ratio [HR] 1.9, P < 0.01), ALP >140 U/L (HR 3.4, P < 0.01), and liver disease (HR 1.5, P = 0.05). DISCUSSION:In our cohort of urban women, ICP diagnosis predicted risk of future liver disease and abnormal liver tests. Women with pregnancies complicated by ICP may benefit from surveillance for postpartum liver abnormalities.
10.14309/ajg.0000000000001132
From Pruritus to Cholestasis: Building a Statistical Model and Online Application to Predict a Diagnosis Prior to Bile Acid Determination.
Ramirez Zamudio Andres F,Monrose Erica,Pan Stephanie,Ferrara Lauren
American journal of perinatology
OBJECTIVE:This study aimed to create a statistical model using clinical and laboratory parameters to predict which patients presenting with pruritus in pregnancy will have elevated total bile acids (TBA) and thus, have a high risk of intrahepatic cholestasis of pregnancy (ICP). STUDY DESIGN:Retrospective cohort study of patients presenting with pruritus in pregnancy and had TBA sent from a single public hospital from January 1, 2017, to December 31, 2017. Primary outcome is TBA ≥ 10 µmol/L. Multivariate logistic regression with stepwise and backward variable selection were used to create predictive models. Four models were compared using Akaike information criterion (AIC), C-statistic, and the DeLong nonparametric approach to test for differences between area under the curve (AUC) of receiver operating characteristic (ROC) curves. Internal validation was performed via fivefold cross-validation technique on the best-fitting, most parsimonious model. RESULTS:Of the 320 patients with pruritus, 153 (47.8%) had elevated bile acid levels ≥10 µmol/L. Sixty-nine variables were assessed for association with the primary outcome. Five variables were significantly associated with elevated TBA: pruritus of palms and soles (adjusted odds ratio [aOR]: 2.35 [95% confidence interval, CI: 1.22, 4.54]), gestational hypertension (aOR: 0.10 [95% CI: 0.02, 0.60]), log of total bilirubin (aOR: 4.71 [95% CI: 2.28, 9.75]), systolic blood pressure (aOR: 0.97 [95% CI: 0.94, 0.99]), and alanine aminotransferase (aOR: 1.05 [95% CI: 1.02, 1.07]). The final model was chosen for being parsimonious while having the lowest AIC with highest AUC (0.85; 95% CI: 0.81, 0.89). Internal validation using a probability threshold of 50% demonstrated a sensitivity of 65.5%, specificity of 83.5%, and accuracy of 75.1%. CONCLUSION:We provide a predictive model using five simple variables to determine the probability that a patient presenting with pruritus in pregnancy carries the diagnosis of ICP. This tool, available via a web app, is designed to aid providers and enhance clinical judgment in difficult triage situations. KEY POINTS:· Currently, no standard method to triage pruritus in pregnancy exists.. · We present a predictive statistical model using five readily available clinical variables.. · Final calculator yields probability of having intrahepatic cholestasis of pregnancy..
10.1055/s-0041-1729160
Maternal obesity increases the risk and severity of NAFLD in offspring.
Hagström Hannes,Simon Tracey G,Roelstraete Bjorn,Stephansson Olof,Söderling Jonas,Ludvigsson Jonas F
Journal of hepatology
BACKGROUND & AIMS:Maternal obesity has been linked to the development of cardiovascular disease and diabetes in offspring, but its relationship to non-alcoholic fatty liver disease (NAFLD) is unclear. METHODS:Through the nationwide ESPRESSO cohort study we identified all individuals ≤25 years of age in Sweden with biopsy-verified NAFLD diagnosed between 1992 and 2016 (n = 165). These were matched by age, sex, and calendar year with up to 5 controls (n = 717). Through linkage with the nationwide Swedish Medical Birth Register (MBR) we retrieved data on maternal early-pregnancy BMI, and possible confounders, in order to calculate adjusted odds ratios (aORs) for NAFLD in offspring. RESULTS:Maternal BMI was associated with NAFLD in offspring: underweight (aOR 0.84; 95% CI 0.14-5.15), normal weight (reference, aOR 1), overweight (aOR 1.51; 0.95-2.40), and obese (aOR 3.26; 1.72-6.19) women. Severe NAFLD (biopsy-proven fibrosis or cirrhosis) was also more common in offspring of overweight (aOR 1.94; 95% CI 0.96-3.90) and obese (aOR 3.67; 95% CI 1.61-8.38) mothers. Associations were similar after adjusting for maternal pre-eclampsia and gestational diabetes. Socio-economic parameters (smoking, mother born outside the Nordic countries and less than 10 years of basic education) were also associated with NAFLD in offspring but did not materially alter the effect size of maternal BMI in a multivariable model. CONCLUSIONS:This nationwide study found a strong association between maternal overweight/obesity and future NAFLD in offspring. Adjusting for socio-economic and metabolic parameters in the mother did not affect this finding, suggesting that maternal obesity is an independent risk factor for NAFLD in offspring. LAY SUMMARY:In a study of all young persons in Sweden with a liver biopsy consistent with fatty liver, the authors found that compared to matched controls, the risk of fatty liver was much higher in those with obese mothers. This was independent of available confounders and suggests that the high prevalence of obesity in younger persons might lead to a higher risk of fatty liver in their offspring.
10.1016/j.jhep.2021.06.045
Association between birth weight, preterm birth, and nonalcoholic fatty liver disease in a community-based cohort.
Hepatology (Baltimore, Md.)
BACKGROUND AND AIMS:The association between birth weight (BW) and metabolic outcomes has been described since the 1980s but NAFLD has been rarely studied. This study aimed to investigate the association between BW and NAFLD occurrence in adult subjects. APPROACH AND RESULTS:The study population consisted of participants from the French nationwide Constances cohort from 2012 to 2019. Participants with a history of chronic viral hepatitis or excessive alcohol consumption were excluded. Noninvasive diagnosis of NAFLD and fibrosis was performed using a combination of the Fatty Liver Index (FLI) and the Forns Index. The relationship between BW and NAFLD was analyzed with a sex-stratified logistic regression model adjusted for sociodemographic parameters, lifestyle, and birth term, whereas liver fibrosis was analyzed with a sex-stratified linear regression model. In total, 55,034 individuals with reliable BW were included (43% men, mean age: 38 years). NAFLD (FLI ≥ 60) was present in 5530 individuals (10%). Multivariate logistic regression showed a significant U-shaped relationship between BW and NAFLD, with no significant interaction with sex. A significant and slightly decreasing association was found between BW and Forns Index (β = -0.05; p = 0.04). Premature birth (OR, 1.23; 95% CI, 1.03-1.48 for birth between 33 and 37 weeks versus ≥ 37 weeks) was associated with NAFLD, with a significant direct effect of premature birth, and without an indirect effect of low BW in mediation analysis. Forns Index was not significantly higher in participants with preterm birth compared to full-term birth. CONCLUSIONS:This large prospective adult-based cohort confirms the relationship between BW and NAFLD occurrence.
10.1002/hep.32540
Childhood predictors of adult fatty liver. The Cardiovascular Risk in Young Finns Study.
Suomela Emmi,Oikonen Mervi,Pitkänen Niina,Ahola-Olli Ari,Virtanen Johanna,Parkkola Riitta,Jokinen Eero,Laitinen Tomi,Hutri-Kähönen Nina,Kähönen Mika,Lehtimäki Terho,Taittonen Leena,Tossavainen Päivi,Jula Antti,Loo Britt-Marie,Mikkilä Vera,Telama Risto,Viikari Jorma S A,Juonala Markus,Raitakari Olli T
Journal of hepatology
BACKGROUND & AIMS:Fatty liver is a potentially preventable cause of serious liver diseases. This longitudinal study aimed to identify childhood risk factors of fatty liver in adulthood in a population-based group of Finnish adults. METHODS:Study cohort included 2,042 individuals from the Cardiovascular Risk in Young Finns Study aged 3-18years at baseline in 1980. During the latest follow-up in 2011, the liver was scanned by ultrasound. In addition to physical and environmental factors related to fatty liver, we examined whether the genetic risk posed by a single nucleotide polymorphism in the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3) (rs738409) strengthens prediction of adult fatty liver. RESULTS:Independent childhood predictors of adult fatty liver were small for gestational age, (odds ratio=1.71, 95% confidence interval=1.07-2.72), variant in PNPLA3 (1.63, 1.29-2.07 per one risk allele), variant in the transmembrane 6 superfamily 2 gene (TM6SF2) (1.57, 1.08-2.30), BMI (1.30, 1.07-1.59 per standard deviation) and insulin (1.25, 1.05-1.49 per standard deviation). Childhood blood pressure, physical activity, C-reactive protein, smoking, serum lipid levels or parental lifestyle factors did not predict fatty liver. Risk assessment based on childhood age, sex, BMI, insulin levels, birth weight, TM6SF2 and PNPLA3 was superior in predicting fatty liver compared with the approach using only age, sex, BMI and insulin levels (C statistics, 0.725 vs. 0.749; p=0.002). CONCLUSIONS:Childhood risk factors on the development of fatty liver were small for gestational age, high insulin and high BMI. Prediction of adult fatty liver was enhanced by taking into account genetic variants in PNPLA3 and TM6SF2 genes. LAY SUMMARY:The increase in pediatric obesity emphasizes the importance of identification of children and adolescents at high risk of fatty liver in adulthood. We used data from the longitudinal Cardiovascular Risk in Young Finns Study to examine the associations of childhood (3-18years) risk variables with fatty liver assessed in adulthood at the age of 34-49years. The findings suggest that a multifactorial approach with both lifestyle and genetic factors included would improve early identification of children with a high risk of adult fatty liver.
10.1016/j.jhep.2016.05.020
Gestational exercise protects adult male offspring from high-fat diet-induced hepatic steatosis.
Sheldon Ryan D,Nicole Blaize A,Fletcher Justin A,Pearson Kevin J,Donkin Shawn S,Newcomer Sean C,Rector R Scott
Journal of hepatology
BACKGROUND & AIMS:Mounting evidence indicates that maternal exercise confers protection to adult offspring against various diseases. Here we hypothesized that maternal exercise during gestation would reduce high-fat diet (HFD)-induced hepatic steatosis in adult rat offspring. METHODS:Following conception, pregnant dams were divided into either voluntary wheel running exercise (GE) or wheel-locked sedentary (GS) groups throughout gestation (days 4-21). Post-weaning, offspring received either normal chow diet (CD; 10% fat, 70% carbohydrate, 20% protein) or HFD (45% fat, 35% carbohydrate, and 20% protein) until sacrificed at 4- or 8-months of age. RESULTS:GE did not affect offspring birth weight or litter size. HFD feeding in offspring increased weight gain, body fat percentage, and glucose tolerance test area under the curve (GTT-AUC). Male offspring from GE dams had reduced body fat percentage across all ages (p<0.05). In addition, 8-month male offspring from GE dams were protected against HFD-induced hepatic steatosis, which was associated with increased markers of hepatic mitochondrial biogenesis (PGC-1α and TFAM), autophagic potential (ATG12:ATG5 conjugation) and hepatic triacylglycerol secretion (MTTP). CONCLUSIONS:The current study provides the first evidence that gestational exercise can reduce susceptibility to HFD-induced hepatic steatosis in adult male offspring.
10.1016/j.jhep.2015.08.022
Weight trajectories through infancy and childhood and risk of non-alcoholic fatty liver disease in adolescence: the ALSPAC study.
Anderson Emma L,Howe Laura D,Fraser Abigail,Callaway Mark P,Sattar Naveed,Day Chris,Tilling Kate,Lawlor Debbie A
Journal of hepatology
BACKGROUND & AIMS:Adiposity is a key risk factor for NAFLD. Few studies have examined prospective associations of infant and childhood adiposity with subsequent NAFLD risk. We examined associations of weight-for-height trajectories from birth to age 10 with liver outcomes in adolescence, and assessed the extent to which associations are mediated through fat mass at the time of outcome assessment. METHODS:Individual trajectories of weight and height were estimated for participants in the Avon Longitudinal Study of Parents and Children using random-effects linear-spline models. Associations of birthweight (adjusted for birth length) and weight change (adjusted for length/height change) from 0-3 months, 3 months-1 y, 1-3 y, 3-7 y, and 7-10 y with ultrasound scan (USS) determined liver fat and stiffness, and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) at mean age 17.8 y were assessed with linear and logistic regressions. Mediation by concurrent fat mass was assessed with adjustment for fat mass at mean age 17.8 y. RESULTS:Birth weight was positively associated with liver stiffness and negatively with ALT and AST. Weight change from birth to 1 y was not associated with outcomes. Weight change from 1-3 y, 3-7 y, and 7-10 y was consistently positively associated with USS and blood-based liver outcomes. Adjusting for fat mass at mean age 17.8 y attenuated associations toward the null, suggesting associations are largely mediated by concurrent body fatness. CONCLUSIONS:Greater rates of weight-for-height change between 1 y and 10 y are consistently associated with adverse liver outcomes in adolescence. These associations are largely mediated through concurrent fatness.
10.1016/j.jhep.2014.04.018
The metabolic profile of intrahepatic cholestasis of pregnancy is associated with impaired glucose tolerance, dyslipidemia, and increased fetal growth.
Martineau Marcus G,Raker Christina,Dixon Peter H,Chambers Jenny,Machirori Mavis,King Nicole M,Hooks Melissa L,Manoharan Ramya,Chen Kenneth,Powrie Raymond,Williamson Catherine
Diabetes care
OBJECTIVE:Quantification of changes in glucose and lipid concentrations in women with intrahepatic cholestasis of pregnancy (ICP) and uncomplicated pregnancy and study of their influence on fetal growth. RESEARCH DESIGN AND METHODS:A prospective study comparing metabolic outcomes in cholestastic and uncomplicated singleton pregnancies was undertaken at two university hospitals in the U.K. and U.S. from 2011-2014. A total of 26 women with ICP and 27 control pregnancies with no prior history of gestational diabetes mellitus were recruited from outpatient antenatal services and followed until delivery. Alterations in glucose, incretins, cholesterol, and triglycerides were studied using a continuous glucose monitoring (CGM) system and/or a standard glucose tolerance test (GTT) in conjunction with GLP-1 and a fasting lipid profile. Fetal growth was quantified using adjusted birth centiles. RESULTS:Maternal blood glucose concentrations were significantly increased in ICP during ambulatory CGM (P < 0.005) and following a GTT (P < 0.005). ICP is characterized by increased fasting triglycerides (P < 0.005) and reduced HDL cholesterol (P < 0.005), similar to changes observed in metabolic syndrome. The offspring of mothers with ICP had significantly larger customized birth weight centiles, adjusted for ethnicity, sex, and gestational age (P < 0.005). CONCLUSIONS:ICP is associated with impaired glucose tolerance, dyslipidemia, and increased fetal growth. These findings may have implications regarding the future health of affected offspring.
10.2337/dc14-2143