Altered lipid metabolism and the development of metabolic-associated fatty liver disease.

PURPOSE OF REVIEW: An increasing amount of research has underscored the significant role of lipoproteins in the pathogenesis of metabolic-associated fatty liver disease (MAFLD). This comprehensive review examines the intricate relationship between lipoprotein abnormalities and the development of MAFLD. RECENT FINDINGS: Atherogenic dyslipidemia seen in insulin resistance states play a significant role in initiating and exacerbating hepatic lipid accumulation. There are also specific genetic factors ( PNPLA3 , TM6SF2 , MBOAT7 , HSD17B13 , GCKR- P446L) and transcription factors (SREBP-2, FXR, and LXR9) that increase susceptibility to both lipoprotein disorders and MAFLD. Most monogenic primary lipid disorders do not cause hepatic steatosis unless accompanied by metabolic stress. Hepatic steatosis occurs in the presence of secondary systemic metabolic stress in conjunction with predisposing environmental factors that lead to insulin resistance. Identifying specific aberrant lipoprotein metabolic factors promoting hepatic fat accumulation and subsequently exacerbating steatohepatitis will shed light on potential targets for therapeutic interventions. SUMMARY: The clinical implications of interconnection between genetic factors and an insulin resistant environment that predisposes MAFLD is many fold. Potential therapeutic strategies in preventing or mitigating MAFLD progression include lifestyle modifications, pharmacological interventions, and emerging therapies targeting aberrant lipoprotein metabolism.

Epigenetic age in African American adolescents with type 2 diabetes: A cross-sectional case-control study protocol.

Background and Aims: Type 2 diabetes (T2D) is a disease caused by a relative insulin deficiency compared to the significant insulin requirement needed by the body to achieve glycemic control. T2D in adolescence appears to be increasing in prevalence over the past several decades, necessitating studies to understand for the onset of the disease to occur early in the lifespan. Given the high burden of disease, specifically in young African American adolescents, our study chose to focus initially on feasibility of recruitment of this population. Methods: Data was collected at a single study center at Children's of Alabama. The protocol was completed as part of routine care or at a study visit. The study team was able to leverage the Electronic Medical Record to prescreen eligible patients to discuss the study. A variety of times of day were utilized to improve likely of success with reaching potential participants. Inclusion criteria for patients with T2D was focused on the adolescent population (ages 12-18 years), with no history of an obesity syndrome. DNA methylation age will be calculated using the EPIC 850K array. Statistical analysis will be done using linear regression analysis, adjusting for covariates. Conclusions: This study's aim was to screen and enroll young African American adolescents for a study investigating epigenetic aging and T2D. Our study found that more direct contact (face-to-face- or phone call) improve success of recruitment. Leveraging the electronic medical record also helped improve success with pre-screening participants. Challenges included recruiting participants who might come from long distances to a tertiary care center. Consolidating appointments helped improve the success of reaching these participants. Other challenges included frequent address changes and changed phone numbers. Close attention to the barriers as well as the successes will aid in understanding effective strategies for this important population.

Lipid Disorders and Metabolic-Associated Fatty Liver Disease.

Dyslipidemia has been linked metabolic-associated fatty liver disease (MAFLD). Several genes and transcription factors involved in lipid metabolism can increase susceptibility to MAFLD. Multiple parallel 'hits' have been proposed for developing hepatic steatosis, NASH, and MAFLD, including insulin resistance and subsequent free fatty acid excess, de novo lipogenesis, and excessive hepatic triglyceride and cholesterol deposition in the liver. This lead to defective beta-oxidation in the mitochondria and VLDL export and increased inflammation. Given the significant cardiovascular risk, dyslipidemia associated with MAFLD should be managed by lifestyle changes and lipid-lowering agents such as statins, fenofibrate, and omega-3 fatty acids, with judicious use of insulin-sensitizing agents, and adequate control of dysglycemia.

Epigenetic age acceleration correlates with BMI in young adults.

INTRODUCTION: Obesity increases the risk of Type 2 diabetes, cardiovascular disease, several types of cancer, and other age-related disorders. Among older adults, obesity is also related to epigenetic age, typically measured with DNA methylation (DNAm). Because less is known about obesity and epigenetic aging earlier in the lifespan, this study examined the relationship between obesity and DNAm in young adulthood and whether these relationships vary by sex. METHODS: A cross-sectional community sample of 290 healthy young adults (mean age 27.39 years, 60% female; 80% African American, 18% White) had their BMI and waist circumference measured. Four epigenetic age estimators were derived from salivary DNA: Hannum DNAm, Horvath DNAm, Phenoage DNAm, and GrimAge DNAm. Sociodemographic covariates included age, sex, race, parental education, and income-to-needs ratio. RESULTS: After adjusting for covariates, higher BMI and waist were associated with higher DNAm PhenoAge in both sexes, with a stronger effect on BMI in males (ß = 0.35, p < .001) compared to females (ß = 0.13, p = .002). Higher waist, but not BMI, was associated with higher Horvath DNA methylation age. Both BMI and waist circumference were associated with higher Hannum DNAm age in men but not in women. Neither BMI nor waist circumference were related to GrimAge. DISCUSSION: This study extends prior research by linking obesity with accelerated epigenetic aging in young adulthood, replicating the associations across two measures of obesity and four indices of salivary epigenetic aging. The results add to evidence that higher BMI accelerates aging early in the lifespan.

Cushing syndrome as a failed cardiac screen in a patient with McCune-Albright syndrome: a case report.

BACKGROUND: McCune-Albright syndrome is a complex disorder encompassing multiple endocrinopathies. These manifestations are secondary to a mutation in the stimulatory G-protein alpha subunit. Cushing syndrome is due to autonomous secretory function of the adrenal gland and is present in 7.1% of patients with McCune-Albright syndrome. Cardiac newborn screenings assist in the identification of critical congenital heart disease. These screenings have become part of routine postnatal care nationwide. CASE REPORT: A 6-week-old Caucasian male presented to a cardiologist at the University of Tennessee Health Science Center with left ventricular hypertrophy and poor feeding after a failed cardiac newborn screen. He had been previously seen at 2 weeks by a cardiologist on follow-up for abnormal critical congenital heart disease screening. Electrocardiogram and echocardiographic studies identified hypertrophic cardiomyopathy. Other examination findings revealed multiple characteristic café-au-lait lesions along with hypotonia and rounded facies. Given his cardiac disease, he was admitted to the hospital, where an evaluation was done for Cushing syndrome, showing elevated cortisol by immunoassay of 38 µg/dL (1.7-14.0 µg/dL, Vitros 5600) after a dexamethasone suppression test and urinary cortisol elevated to 35 µg/dL/24 hours (reference range 3-9 µg/dL/24 hours) (Esoterix; Calabasas, CA). He was started on metyrapone therapy to block synthesis of cortisol. His cortisol improved and was suppressed less than 2 µg/dL. His hypertension and clinical features of Cushing syndrome improved. CONCLUSIONS: This case demonstrates a unique presentation of Cushing syndrome in a young infant. This is the first case to our knowledge showing significant left ventricular hypertrophy resulting from Cushing syndrome identified following a failure on a critical congenital heart disease screen. It highlights the importance of considering of McCune-Albright syndrome in patients with Cushing syndrome, especially if other clinical features are present. Medical therapy can be used to treat Cushing syndrome and can result in improvement in the cardiovascular pathology.

Novel therapeutic targets and agents for pediatric dyslipidemia.

Landmark studies have convincingly demonstrated that atherosclerosis begins in youth. While generally asymptomatic, an increasing number of youth with disorders of lipid and lipoprotein metabolism, such as familial hypercholesterolemia, are being identified through selective and universal screening. While a heart healthy lifestyle is the foundation of treatment for all youth with dyslipidemia, lipid-lowering therapy may be required by some to prevent morbidity and premature mortality, especially when initiated at a young age. When appropriate, use of statins has become standard of care for reducing low-density lipoprotein cholesterol, while fibrates may be beneficial in helping to lower triglycerides. Many therapeutic options commonly used in adults are not yet approved for use in youth less than 18 years of age. Although currently available lipid-lowering therapy is well tolerated and safe when administered to youth, response to treatment may vary and some conditions lack an efficient therapeutic option. Thus, newer agents are needed to aid in management. Many are in development and clinical trials in youth are currently in progress but will require FDA approval before becoming commercially available. Many utilize novel approaches to favorably alter lipid and lipoprotein metabolism. In the absence of long-term outcome data of youth who were treated beginning at an early age, clinical registries may prove to be useful in monitoring safety and efficacy and help to inform clinical decision-making. In this manuscript, we review currently available and novel therapeutic agents in development for the treatment of elevated cholesterol and triglycerides.

Lipoprotein(a) Concentrations Correlate With LDL-C in Children With Type 1 and 2 Diabetes.

CONTEXT: Elevated levels of lipoprotein(a) (Lp[a]) is an independent risk factor for atherosclerotic cardiovascular disease especially in patients with diabetes. Adult levels of Lp(a) are thought to be is expressed by the second year of life. OBJECTIVE: We hypothesized that Lp(a) would be influenced by low density lipoprotein cholesterol (LDL-C), race, and HbA1C. METHODS: Retrospective electronic medical record review of children and adolescents with type 1 diabetes (T1D) (n = 607) and type 2 diabetes (T2D) (n = 93). RESULTS: Total of 700 subjects, ages 12-19 years with T1D (n = 607) and T2D (n = 93), 49% were male, mean age was 13.2 ±â€…3.08 years, and the median Lp(a) was 8.00 mg/dL, IQR 5.00-12.00. The Black subjects had an increased relative risk (RR) of higher Lp(a) compared with White subjects (RR 1.25, P < .0001). Among patients with T1D, Black people had an increased relative risk of higher Lp(a) than White people (RR 1.23, P = .0002). In T2D, Black subjects have 43% higher risk of having elevated Lp(a) than White subjects (RR 1.43, P = .268). In T1D, a 5 mg/dL increase in LDL-C results in 2% increase in Lp(a) (P < .0001). In T2D, a 5 mg/dL increase of LDL-C results in an increase of Lp(a) by 3%. LDL-C and BMI are independently associated with Lp(a) (RR = 1.02, P < .001; RR = 0.98, P < .001). CONCLUSION: Our data suggest that Lp(a) is associated with LDL-C in children with diabetes. Lp(a) is differentially increased at higher concentrations of LDL-C. Black children with diabetes have a significant burden of Lp(a) concentrations compared with White children.

Excess serum uric acid is associated with metabolic syndrome in obese adolescent patients.

PURPOSE: Obesity is a significant cause of morbidity in adolescents. Excess serum uric acid (SUA) has been associated with metabolic syndrome (MS) among adults. We evaluated the relationship among SUA and markers of insulin resistance (IR) and low-grade inflammation in obese adolescents with and without MS. METHODS: The study was a retrospective chart review of obese patients seen in the LeBonheur Endocrine clinic seen in clinic between September 2016 and December 2017. MS was defined as according to the International Diabetes Federation. Body mass index standard deviation score (BMI SDS), systolic blood pressure (SBP), diastolic blood pressure (DBP), body composition, fasting lipids, glucose, high sensitivity c-reactive protein (hs-CRP), serum uric acid (SUA), HbA1c, alanine transferase (ALT), aspartate transferase (AST), insulin and homeostatic model assessment for insulin resistance (HOMA-IR) were extracted from the charts of the 100 obese adolescents (57% female). RESULTS: Hyperuricemia (SUA >357 umol/L) was present in 41.8% of entire cohort without significant ethnic/racial and/or gender differences. Adolescents with HUA had higher FM, SBP, HbA1c, insulin and HOMA-IR (p < 0.05). While SUA was positively correlated with FM, SBP, HOMA-IR and HbA1c, and triglyceride:HDL-C ratio (TG:HDL-C) (p < 0.05). MS was identified in 32.8% of cohort. MS showed significantly higher FM, SBP, DBP, SUA, ALT, insulin, HOMA-IR, and TG:HDL-c ratio than non-MS subgroup (p < 0.05). FM was positively correlated with SUA, HOMA-IR and hsCRP (p < 0.01). CONCLUSIONS: In our study, those with hyperuricemia (HUA) showed elevated markers of metabolic syndrome including BP, serum glucoses, IR and triglycerides. In our cohort, SUA appears to correlate with MS comorbidities.

Low prevalence of organic pathology in a predominantly black population with premature adrenarche: need to stratify definitions and screening protocols.

BACKGROUND: Premature adrenarche has been described as clinical and biochemical hyperandrogenism before the age of 8 years in girls and 9 years in boys and absence of signs of true puberty. Adrenal pathology such as adrenal tumors or non-classical congenital adrenal hyperplasia (NCCAH) and exogenous androgen exposure need to be excluded prior to diagnosing (idiopathic) premature adrenarche. Premature adrenarche is more common among black girls compared to white girls and other racial groups. Adrenal pathology such as NCCAH is less common as a cause for premature adrenarche compared with idiopathic premature adrenarche. The evaluation guidelines for premature adrenarche however are not individualized based on racial/ethnic differences. Few studies have been done to evaluate a largely black population with premature adrenarche to assess the incidence of adrenal pathology. METHODS: This cross-sectional retrospective study evaluated characteristics of prepubertal patients seen in an endocrine clinic for premature adrenarche. RESULTS: Two hundred and seventy three subjects had signs of early adrenarche. Three subjects were found to have CAH (2 with NCCAH and 1 with late diagnosis classical CAH). None were black. Exogenous androgen exposure was etiology in 4 additional subjects. These 7 patients were excluded from further analysis. The remaining subjects had idiopathic PA (n = 266); 76.7% were females. The mean age at initial visit was 6.42 +/- 1.97 years (with no racial difference) although black subjects were reported symptom onset at a significantly younger age compared to non-Hispanic white patients. CONCLUSIONS: Our study showed organic pathology was very uncommon in a predominantly black population with premature adrenarche. Patient factors that influence the probability of an underlying organic pathology including race/ ethnicity should be considered to individualize evaluation.

Menstrual Irregularities.

Irregular menstrual cycles are a common complaint among adolescents. There are multiple etiologies for menstrual irregularities. It is important to have a stepwise approach, including obtaining a thorough medical history and performing a physical examination, when patients present. Understanding the characteristics of the menstrual cycle helps determine the etiology. This article discusses the differential diagnosis of irregular menstrual cycles, as well as the approach to evaluation and management. The common conditions and defining characteristics are also discussed. [Pediatr Ann. 2018;47(1):e23-e28.].

Diabetes Control and Adherence in Adolescence.

Type 1 diabetes is a chronic disease that can lead to severe complications if poorly controlled. Adolescents are particularly vulnerable to worsening diabetes control due to changes in physiology, family dynamics, and social interactions. Good diabetes control requires following a regimen of frequent blood glucose checks, accurate carbohydrate counts, and compliance with insulin administration. Patients who are challenged in controlling their diabetes do tend to respond to behavioral interventions; however, the effect of the intervention wanes over time. Using technology to provide interventions has shown promise in terms of improving compliance. Positive family support and adequate knowledge of the developmental stages is important to ensure a successful transition from childhood to adolescence. Providers should also incorporate a structured transition from adolescent to adult diabetes care. [Pediatr Ann. 2016;45(9):e327-e331.].

Severe malnutrition causing superior mesenteric artery syndrome in an adolescent with Triple A syndrome.

Triple A syndrome, formerly known as Allgrove syndrome (AS), is characterized by achalasia, alacrima and adrenal insufficiency. Here we report an adolescent male with adrenal insufficiency who developed severe malnutrition secondary to a delayed diagnosis of achalasia. The severe malnutrition in our patient led to superior mesenteric artery (SMA) obstruction syndrome. Severe malnutrition to the point of SMA syndrome has not been previously described in the literature in Triple A syndrome.

Lipid patterns in treated growth hormone deficient children vs. short stature controls.

CONTEXT: Previous studies in adults with growth hormone (GH) deficiency have substantiated an increased risk of cardiovascular events. This risk has been attributed to an unpropitious lipid profile, increased abdominal mass, and higher incidence of metabolic syndrome. In these studies, a collateral observation has been a negative correlation between IGF-1 levels and lipid profiles. Longitudinal studies are lacking in children with GH-deficiency wherein the various lipid subfractions after GH treatment were compared to matched GH-sufficient short stature controls. Our study examined changes in small lipid particles following GH treatment. OBJECTIVE: The primary objective was to determine the effect of GH treatment on serum lipids in GH-deficient patients vs. short controls. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective, unblinded, case-controlled, 6-month trial conducted at a tertiary pediatric referral center. Patients were referred for short stature. Incorporating accepted criteria, the treatment group (n=18) was found to be GH-deficient, whereas the control group (n=13) was GH-sufficient. The two groups had near-identical short stature along in addition to baseline measurements of weight and BMI. INTERVENTIONS: The treatment arm received 6 months of recombinant GH at standard doses. MAIN OUTCOME MEASURES: The primary endpoint was the comparison of the lipoprotein subclasses and lipids between the two groups after 6 months. RESULTS: With the exception of the intermediate density lipoprotein (IDL), there were no significant differences at baseline in serum lipid profiles between the GH-deficient children and the controls. After 6 months of therapy, there were statistically significant differences in Apo-B, LDL, and smaller lipoparticles (LDL-3 and non-HDL) in GH-treated children compared to untreated GH-sufficient short children. CONCLUSIONS: Our findings indicate that GH replacement may improve cardiovascular outcome by favorably altering lipid profiles.

Evidence that adrenal hexose-6-phosphate dehydrogenase can effect microsomal P450 cytochrome steroidogenic enzymes.

The role of adrenal hexose-6-phosphate dehydrogenase in providing reducing equivalents to P450 cytochrome steroidogenic enzymes in the endoplasmic reticulum is uncertain. Hexose-6-phosphate dehydrogenase resides in the endoplasmic reticulum lumen and co-localizes with the bidirectional enzyme 11ß-hydroxysteroid dehydrogenase 1. Hexose-6-phosphate dehydrogenase likely provides 11ß-hydroxysteroid dehydrogenase 1 with NADPH electrons via channeling. Intracellularly, two compartmentalized reactions generate NADPH upon oxidation of glucose-6-phosphate: cytosolic glucose-6-phosphate dehydrogenase and microsomal hexose-6-phosphate dehydrogenase. Because some endoplasmic reticulum enzymes require an electron donor (NADPH), it is conceivable that hexose-6-phosphate dehydrogenase serves in this capacity for these pathways. Besides 11ß-hydroxysteroid dehydrogenase 1, we examined whether hexose-6-phosphate dehydrogenase generates reduced pyridine nucleotide for pivotal adrenal microsomal P450 enzymes. 21-hydroxylase activity was increased with glucose-6-phosphate and, also, glucose and glucosamine-6-phosphate. The latter two substrates are only metabolized by hexose-6-phosphate dehydrogenase, indicating that requisite NADPH for 21-hydroxylase activity was not via glucose-6-phosphate dehydrogenase. Moreover, dihydroepiandrostenedione, a non-competitive inhibitor of glucose-6-phosphate dehydrogenase, but not hexose-6-phosphate dehydrogenase, did not curtail activation by glucose-6-phosphate. Finally, the most compelling observation was that the microsomal glucose-6-phosphate transport inhibitor, chlorogenic acid, blunted the activation by glucose-6-phosphate of both 21-hydroxylase and 17-hydroxylase indicating that luminal hexose-6-phosphate dehydrogenase can supply NADPH for these enzymes. Analogous kinetic observations were found with microsomal 17-hydroxylase. These findings indicate that hexose-6-phosphate dehydrogenase can be a source, but not exclusively so, of NADPH for several adrenal P450 enzymes in the steroid pathway. Although the reduced pyridine nucleotides are produced intra-luminally, these compounds may also slowly transverse the endoplasmic reticulum membrane by unknown mechanisms.