Oyekoya T. Ayonrinde

Gender-Specific Differences in Adipose Distribution and Adipocytokines Influence Adolescent Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a predominantly adult‐diagnosed disorder. Knowledge regarding the epidemiology, phenotype, and metabolic risk factors, during adolescence is limited. We sought to determine the prevalence, phenotype, and predictors of NAFLD in 1170 community‐based adolescents in the Western Australian Pregnancy Cohort (Raine) Study (the Raine Cohort) who underwent a cross‐sectional assessment that included questionnaires, anthropometry, cardiovascular examinations, blood tests, and abdominal ultrasound examinations. Among the 1170 adolescents assessed, the prevalence of NAFLD was 12.8%. Females compared with males had a significantly higher prevalence of NAFLD (16.3% versus 10.1%, P = 0.004) and central obesity (33.2% versus 9.9%, P < 0.05). The severity of hepatic steatosis was associated with the body mass index, waist circumference, subcutaneous adipose tissue thickness (SAT), serum leptin level, homeostasis model assessment for insulin resistance score (P < 0.001 for all), and serum alanine aminotransferase level (P < 0.005) in both genders, but it was associated with increasing visceral adipose tissue thickness (VAT; P < 0.001) and decreasing serum adiponectin levels (P < 0.05) in males alone. Males and females with NAFLD had similar amounts of SAT (P > 0.05); however, in comparison with females with NAFLD, males with NAFLD had greater VAT, a more severe metabolic phenotype with higher glucose levels and systolic blood pressure and lower adiponectin and high‐density lipoprotein cholesterol levels (P < 0.001 for all), and greater measures of liver injury (alanine aminotransferase and aspartate aminotransferase, P < 0.001 for all). Similarly, metabolic syndrome was more common in males than females with NAFLD (24% versus 8%, P = 0.01). Suprailiac skinfold thickness predicted NAFLD independently of the body mass index, insulin resistance, and VAT. Conclusion: Gender differences in adolescent NAFLD are related to differences in adipose distribution and adipocytokines. The male phenotype of NAFLD is associated with more adverse metabolic features and greater visceral adiposity than the female phenotype despite the lower prevalence of NAFLD. (HEPATOLOGY 2011;)

The Western Dietary Pattern Is Prospectively Associated With Nonalcoholic Fatty Liver Disease in Adolescence

OBJECTIVES:Poor dietary habits have been implicated in the development of nonalcoholic fatty liver disease (NAFLD); however, little is known about the role of specific dietary patterns in the development of NAFLD. We examined prospective associations between dietary patterns and NAFLD in a population-based cohort of adolescents.METHODS:Participants in the Western Australian Pregnancy Cohort (Raine) Study completed a food frequency questionnaire at 14 years and had liver ultrasound at 17 years (n=995). Healthy and Western dietary patterns were identified using factor analysis and all participants received a z-score for these patterns. Prospective associations between the dietary pattern scores and risk of NAFLD were analyzed using multiple logistic regression.RESULTS:NAFLD was present in 15.2% of adolescents. A higher Western dietary pattern score at 14 years was associated with a greater risk of NAFLD at 17 years (odds ratio (OR) 1.59; 95% confidence interval (CI) 1.17–2.14; P<0.005), although these associations were no longer significant after adjusting for body mass index at 14 years. However, a healthy dietary pattern at 14 years appeared protective against NAFLD at 17 years in centrally obese adolescents (OR 0.63; 95% CI 0.41–0.96; P=0.033), whereas a Western dietary pattern was associated with an increased risk of NAFLD.CONCLUSIONS:A Western dietary pattern at 14 years in a general population sample was associated with an increased risk of NAFLD at 17 years, particularly in obese adolescents. In centrally obese adolescents with NAFLD, a healthy dietary pattern may be protective, whereas a Western dietary pattern may increase the risk.

Association between liver-specific gene polymorphisms and their expression levels with nonalcoholic fatty liver disease

Genetic factors account for a significant proportion of the phenotypic variance of nonalcoholic fatty liver disease (NAFLD); however, very few predisposing genes have been identified. We aimed to (1) identify novel genetic associations with NAFLD by performing a genome‐wide association study (GWAS), and (2) examine the biological expression of the strongest genetic associations in a separate cohort. We performed GWAS of a population‐based cohort (Raine Study) of 928 adolescents assessed for NAFLD by ultrasound at age 17. Expression of genes with single nucleotide polymorphisms (SNPs) that were associated with NAFLD at a significance level of P < 10−5 was examined in adults with NAFLD and controls by quantifying hepatic messenger RNA (mRNA) expression and serum levels of protein. After adjustment for sex and degree of adiposity, SNPs in two genes expressed in liver were associated with NAFLD adolescents: group‐specific component (GC) (odds ratio [OR], 2.54; P = 1.20 × 10−6) and lymphocyte cytosolic protein‐1 (LCP1) (OR, 3.29; P = 2.96 × 10−6). SNPs in two genes expressed in neurons were also associated with NAFLD: lipid phosphate phosphatase‐related protein type 4 (LPPR4) (OR, 2.30; P = 4.82 × 10−6) and solute carrier family 38 member 8 (SLC38A8) (OR, 3.14; P = 1.86 × 10−6). Hepatic GC mRNA was significantly reduced (by 83%) and LCP1 mRNA was increased (by 300%) in liver biopsy samples from patients with NAFLD compared to controls (P < 0.05). Mean serum levels of GC protein were significantly lower in patients with NAFLD than controls (250 ± 90 versus 298 ± 90, respectively; P = 0.004); GC protein levels decreased with increasing severity of hepatic steatosis (P < 0.01). Conclusion: The association between GC and LCP1 SNPs and NAFLD as well as altered biological expression implicate these genes in the pathogenesis of NAFLD. (HEPATOLOGY 2013;)

Importance of cardiometabolic risk factors in the association between nonalcoholic fatty liver disease and arterial stiffness in adolescents

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and is regarded as the hepatic manifestation of the metabolic syndrome. In adults, NAFLD is a determinant of arterial stiffness and cardiovascular risk, independent of the metabolic syndrome. Our aim was to ascertain if NAFLD is associated with arterial stiffness, independent of cardiometabolic factors in a population‐based cohort of adolescents. The 17‐year‐olds (n = 964) from an Australian birth cohort had measures of anthropometry, blood pressure, fasting insulin, glucose, lipids, and NAFLD by ultrasound. Two‐step cluster analysis identified youth at high metabolic risk. Measures of arterial stiffness (pulse wave velocity [PWV] and augmentation index corrected for heart rate [AI@75]) were obtained using applanation tonometry. The overall prevalence of NAFLD was 13.3%. The “high risk” metabolic cluster at age 17 years included 16% males and 19% females. Compared to “low risk,” the “high risk” cluster participants had greater waist circumference, triglycerides, insulin, systolic blood pressure, and lower high‐density lipoprotein (HDL) cholesterol (all P < 0.0001). Those who had NAFLD but were not in the “high risk” metabolic cluster did not have increased PWV or AI@75. However, males and females who had NAFLD in the presence of the metabolic cluster had greater PWV (b = 0.20, 95% confidence interval [CI] 0.01 to 0.38, P = 0.037). Males who had NAFLD in the presence of the metabolic cluster had greater AI@75 (b = 6.3, 95% CI 1.9 to 10.7, P = 0.005). Conclusion: NAFLD is only associated with increased arterial stiffness in the presence of the “high risk” metabolic cluster. This suggests that arterial stiffness related to the presence of NAFLD is predicated on the presence of an adverse metabolic profile in adolescents. (Hepatology 2013;58:1306–1314)

The impact of phlebotomy in nonalcoholic fatty liver disease: A prospective, randomized, controlled trial

Iron is implicated in the pathogenesis of liver injury and insulin resistance (IR) and thus phlebotomy has been proposed as a treatment for nonalcoholic fatty liver disease (NAFLD). We performed a prospective 6‐month randomized, controlled trial examining the impact of phlebotomy on the background of lifestyle advice in patients with NAFLD. Primary endpoints were hepatic steatosis (HS; quantified by magnetic resonance imaging) and liver injury (determined by alanine aminotransaminase [ALT] and cytokeratin‐18 [CK‐18]). Secondary endpoints included insulin resistance measured by the insulin sensitivity index (ISI) and homeostasis model of assessment (HOMA), and systemic lipid peroxidation determined by plasma F2‐isoprostane levels. A total of 74 subjects were randomized (33 phlebotomy and 41 control). The phlebotomy group underwent a median (range) of 7 (1‐19) venesection sessions and had a significantly greater reduction in ferritin levels over 6 months, compared to controls (−148 ± 114 vs. −38 ± 89 ng/mL; P < 0.001). At 6 months, there was no difference between phlebotomy and control groups in HS (17.7% vs. 15.5%; P = 0.4), serum ALT (36 vs. 46 IU/L; P = 0.4), or CK‐18 levels (175 vs. 196 U/L; P = 0.9). Similarly, there was no difference in end‐of‐study ISI (2.5 vs. 2.7; P = 0.9), HOMA (3.2 vs. 3.2; P = 0.6), or F2‐isoprostane levels (1,332 vs. 1,190 pmmol/L; P = 0.6) between phlebotomy and control groups. No differences in any endpoint were noted in patients with hyperferritinemia at baseline. Among patients undergoing phlebotomy, there was no correlation between number of phlebotomy sessions and change in HS, liver injury, or IR from baseline to end of study. Conclusion: Reduction in ferritin by phlebotomy does not improve liver enzymes, hepatic fat, or IR in subjects with NAFLD. (Hepatology 2015;61:1555–1564)

Low serum 25-hydroxyvitamin D concentrations associate with non-alcoholic fatty liver disease in adolescents independent of adiposity

Non‐alcoholic fatty liver disease (NAFLD) and serum 25‐hydroxyvitamin D (s25[OH]D) concentrations are both associated with adiposity and insulin resistance (IR) and thus may be pathogenically linked. We aimed to determine the prevalence of vitamin D deficiency in adolescents with NAFLD and to investigate the prospective and cross‐sectional associations between s25[OH]D concentrations and NAFLD.

Clinical Perspectives on Hereditary Hemochromatosis

Hereditary hemochromatosis (HH) comprises a group of inherited disorders of iron metabolism that can result in progressive iron overload, morbidity, and mortality, generally in adulthood. HFE-related HH is the most common type of HH and will form the core of this discussion. The discovery of new proteins and gene mutations has defined other types of HH, termed non-HFE HH. The regulatory protein hepcidin has a central role in iron homeostasis in these disorders. While the liver is the predominant organ of iron deposition and iron-overload-related disease in HFE-related HH, involvement of extrahepatic tissue can also result in morbidity and mortality if the disorder is not diagnosed before organ damage develops. This review traverses the road from HFE genotype to phenotype with a focus on clinical penetrance, modifier factors for disease expression, and current thoughts and controversies on HH diagnosis and screening.

Lower Fructose Intake May Help Protect Against Development of Nonalcoholic Fatty Liver in Adolescents With Obesity

Objectives: Although obesity is a major risk factor for nonalcoholic fatty liver (NAFL), not all individuals with obesity develop the condition, suggesting that other factors such as diet may also contribute to NAFL development. We evaluated associations between fructose and total sugar intake and subsequent diagnosis of NAFL in adolescents with obesity and without obesity in a population-based cohort. Methods: Adolescents participating in the Western Australian Pregnancy Cohort (Raine) Study completed 3-day food records and body mass index measurement at age 14 years. At age 17 years, participants underwent abdominal ultrasound to determine NAFL status. Multivariable logistic regression models were used to analyse associations between energy-adjusted fructose and total sugar intake and NAFL status. Food diaries and liver assessments were completed for 592 adolescents. Results: The prevalence of NAFL at age 17 was 12.8% for the total group and 50% for adolescents with obesity. Fructose intake did not significantly differ between adolescents with or without NAFL in our cohort as a whole. Among adolescents with obesity, those without NAFL had significantly lower energy-adjusted fructose intake at age 14 years compared with those with NAFL (mean ± standard deviation [SD] 38.8 ± 19.8 g/day, vs 55.7 ± 14.4 g/day, P = 0.02). Energy-adjusted fructose intake was independently associated with NAFL in adolescents with obesity (OR [odds ratio] 1.09, 95% CI 1.01–1.19, P = 0.03) after the adjustment for confounding factors. Energy-adjusted total sugar intake showed less significance (OR 1.03, 95% CI 0.999–1.07, P = 0.06). No significant associations were observed in other body mass index categories. Conclusions: Lower fructose consumption in adolescents with obesity at 14 years is associated with a decreased risk of NAFL at 17 years. Fructose rather than overall sugar intake may be more physiologically relevant in this association.

Childhood adiposity trajectories and risk of nonalcoholic fatty liver disease in adolescents.

Nonalcoholic fatty liver disease (NAFLD) and its metabolic risk factors are recognized during childhood and adolescence. Identification of adolescents at risk of NAFLD from childhood anthropometry may expose opportunities to influence the hepatic and metabolic destinies of individuals. We sought associations between NAFLD diagnosed during adolescence and earlier life trajectories of anthropometry, in a population‐based cohort of predominantly Caucasian adolescents.

Texture-based classification of liver fibrosis using MRI

To investigate the ability of texture analysis of MRI images to stage liver fibrosis. Current noninvasive approaches for detecting liver fibrosis have limitations and cannot yet routinely replace biopsy for diagnosing significant fibrosis.