Prevalence of Adolescents Meeting Criteria for Metabolic and Bariatric Surgery.

BACKGROUND AND OBJECTIVES: The American Academy of Pediatrics endorses metabolic and bariatric surgery (MBS) as a safe and effective treatment of severe obesity in children with class 3 obesity or with class 2 obesity and qualifying comorbidities. The study objective was to determine eligibility and characteristics of adolescents who qualify for MBS based on American Academy of Pediatrics guidelines. METHODS: This retrospective cohort study analyzed electronic health record data of 603 051 adolescents aged 13 to 17 years between January 1, 2018, and December 31, 2021. Centers for Disease Control and Prevention criteria were used to define obesity classes 2 and 3. Multivariable logistic regression was used to evaluate the factors associated with meeting MBS eligibility criteria. RESULTS: Of the 603 041 adolescents evaluated, 22.2% had obesity (12.9% class 1, 5.4% class 2, and 3.9% class 3). The most frequently diagnosed comorbid conditions were gastroesophageal reflux disease (3.2%), hypertension (0.5%), and nonalcoholic fatty liver disease (0.5%). Among adolescents with class 2 obesity, 9.1% had 1 or more comorbidities qualifying for MBS, and 4.4% of all adolescents met the eligibility criteria for MBS. In multivariable modeling, males, Black and Hispanic adolescents, and those living in more deprived neighborhoods were more likely to meet MBS eligibility criteria. CONCLUSIONS: Overall, 1 in 23 adolescents met the eligibility criteria for MBS. Demographic and social determinants were associated with a higher risk for meeting these criteria. The study suggests that the health care system may face challenges in accommodating the demand for MBS among eligible adolescents.

Distinguishing Autoimmune Hepatitis From Steatohepatitis in Adolescents With Obesity and Positive Screening Alanine Aminotransferase.

Screening children with obesity for nonalcoholic fatty liver disease leads to identification of elevated alanine aminotransferase (ALT) and is a common cause for referral to pediatric gastroenterology. Guidelines recommend that children with positive screening ALT be evaluated for causes of ALT elevation beyond nonalcoholic fatty liver disease. One clinical challenge is that autoantibodies can be present in patients with obesity and thus may or may not represent autoimmune hepatitis. This case series highlights the importance of a comprehensive evaluation to reach an accurate diagnosis.

Recent advances in the epidemiology of nonalcoholic fatty liver disease in children.

Children with obesity are at risk for numerous health problems, including nonalcoholic fatty liver disease (NAFLD). This review focuses on progress made in the epidemiology of NAFLD in children for the years 2015-2020. The estimated prevalence of NAFLD in children with obesity is 26%. The incidence of NAFLD in children has risen rapidly over the past decade. An understanding of the reasons for this rise is incomplete, but over the past 5 years, many studies have provided additional insight into the complexity of risk factors, diagnostic approaches, and associated comorbidities. Risk factors for NAFLD are wide-ranging, including perinatal factors involving both the mother and newborn, as well as environmental toxin exposure. Progress made in the noninvasive assessment will be critical to improving issues related to variability in approach to screening and diagnosis of NAFLD in children. The list of serious comorbidities observed in children with NAFLD continues to grow. Notably, for many of these conditions, such as diabetes and depression, the rates observed have exceeded the rates reported in children with obesity without NAFLD. Recent advancements reviewed show an increased awareness of this problem, while also calling attention to the need for additional research to guide successful efforts at prevention and treatment.

Incidence of Nonalcoholic Fatty Liver Disease in Children: 2009-2018.

BACKGROUND AND OBJECTIVES: In 2007, the American Academy of Pediatrics recommended that children with obesity should be screened for nonalcoholic fatty liver disease (NAFLD). Population epidemiology reveals that NAFLD is common in children; however, little is known about rates of clinical diagnosis. In this study, we aim to determine screening practices, annual incidence, and clinical characteristics of NAFLD in children within an integrated community health system. METHODS: Using electronic health records, we identified patients newly diagnosed (aged 5-18) with NAFLD on the basis of diagnostic codes from the 9th and 10th revisions of the International Classification of Diseases. We calculated screening rates and annual incidence rates of NAFLD from January 1, 2009, to December 31, 2018. RESULTS: In this study, we evaluated 7 884 844 patient-years. Screening was performed in 54.0% of children with obesity and 24.0% of children with overweight. The results revealed 36 658 children aged 9 to 18 with overweight or obesity and alanine aminotransferase >30 U/L. Of these children, 12.3% received further workup for NAFLD. The incidence of an NAFLD diagnosis significantly increased over time, with 36.0 per 100 000 in 2009 and 58.2 per 100 000 in 2018 (P < .0001). CONCLUSIONS: Our study of a large integrated health care system in southern California revealed that the incidence of NAFLD in children is increasing, although many children may remain undiagnosed.

Clinical Practice Approach to Nonalcoholic Fatty Liver Disease by Pediatric Gastroenterologists in the United States.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is common; however, no information is available on how pediatric gastroenterologists in the United States manage NAFLD. Therefore, study objectives were to understand how pediatric gastroenterologists in the US approach the management of NAFLD, and to identify barriers to care for children with NAFLD. METHODS: We performed structured one-on-one interviews to ascertain each individual pediatric gastroenterologist's approach to the management of NAFLD in children. Responses were recorded from open-ended questions regarding screening for comorbidities, recommendations regarding nutrition, physical activity, medications, and perceived barriers to care. RESULTS: Response rate was 72.0% (486/675). Mean number of patients examined per week was 3 (standard deviation [SD] 3.5). Dietary intervention was recommended by 98.4% of pediatric gastroenterologists. Notably, 18 different dietary recommendations were reported. A majority of physicians provided targets for exercise frequency (72.6%, mean 5.6 days/wk, SD 1.6) and duration (69.9%, mean 40.2 minutes/session, SD 16.4). Medications were prescribed by 50.6%. Almost one-half of physicians (47.5%) screened for type 2 diabetes, dyslipidemia, and hypertension. Providers who spent more than 25 minutes at the initial visit were more likely to screen for comorbidities (P = 0.003). Barriers to care were reported by 92.8% with 29.0% reporting ≥3 barriers. CONCLUSIONS: The majority of US pediatric gastroenterologists regularly encounter children with NAFLD. Varied recommendations regarding diet and exercise highlight the need for prospective clinical trials. NAFLD requires a multidimensional approach with adequate resources in the home, community, and clinical setting.

The safety and tolerability of ferric citrate as a phosphate binder in dialysis patients.

BACKGROUND: A phase II open-label study was conducted in hemodialysis patients evaluating the short-term safety, tolerability, and iron absorption with ferric citrate when used as a phosphate binder. METHODS: Enrollment occurred in two periods. Period 1 recruited patients taking 6-15 pills/day of binder with phosphorus of ≥2.5 mg/dl. Period 2 recruited patients taking ≥12 pills/day of binder with phosphorus of ≥3.5 mg/dl. Participants with ferritin ≥1,000 µg/l or transferrin iron saturation (TSAT) ≥50% at screening were excluded. Subjects discontinued their previous binders and started 4.5 g/day of ferric citrate (period 1) or 6 g/day (period 2) and were titrated for 4 weeks to maintain a phosphorus of 3.5-5.5 mg/dl. Chemistries and complete blood count were obtained weekly and a gastrointestinal questionnaire was administered at drug initiation and final visit. Iron therapy was permitted if the ferritin was <500 µg/l and TSAT <30%. RESULTS: Fifty-five subjects were enrolled. Four serious adverse events were reported; none were related to the study drug. Findings from the gastrointestinal questionnaire included stool discoloration (69%), constipation (15%), and bloating (7%). Mean iron parameters at the beginning of the study were ferritin 554 ± 296 µg/l, iron 68 ± 21 µg/dl, and iron saturation 30 ± 7.8%. At the end of study, mean ferritin was 609 ± 340 µg/l (p = 0.02), iron 75 ± 27 µg/dl (p = 0.04), and TSAT was 35 ± 13% (p = 0.001). Mean phosphorus and calcium levels were unchanged from baseline at the end of study. CONCLUSION: Ferric citrate was well tolerated by patients after 4 weeks with no significant clinical or biochemical adverse events related to exposure.

Antilipolytic effect of calcimimetics depends on the allelic variant of calcium-sensing receptor gene polymorphism rs1042636 (Arg990Gly).

Calcium-sensing receptor polymorphism rs1042636 (Arg990Gly) affects the response to the calcimimetic cinacalcet, used to treat hypercalcemia in secondary hyperparathyroidism (sHPT) or parathyroid carcinoma. Carriers of the Arg allelle, show less parathyroid hormone secretion suppression in response to the drug. This effect was reproducible in transfected cultured human embryonic kidney cells, supporting a causal relationship on the protein level. We previously established that cinacalcet has an antilipolytic effect in isolated human adipocytes; however, there were a number of samples that did not respond to the treatment. The present work aimed to investigate whether the variable antilipolytic response to cinacalcet in adipocytes was consistent with the effect reported for the rs1042636 polymorphism. Lipolysis was assessed by measuring glycerol release after exposure to cinacalcet (10 µM) or vehicle in adipocytes isolated from 38 donors. Responsiveness was defined as lipolysis suppression (cinacalcet vs vehicle control) greater than 20%. Genotype analysis showed that 23 adipocyte donors were homozygous for Arg at position 990, 14 heterozygous and 1 homozygous Gly-Gly. Among the Arg homozygotes, one was responsive to cinacalcet, whereas five Gly carriers responded to the calcimimetic. In all, 83% of adipocytes showing response to cinacalcet carried the glycine allele, whereas in 96% of Arg-Arg individuals adipocytes did not respond to the calcimimetic (P=0.027, Fisher's exact test). Confirming sHPT observations, adipocytes from rs1042636 Gly-allele carriers show higher sensitivity to the antilipolytic action of cinacalcet. The potential benefit of cinacalcet as a suppressor of basal lipolysis and free fatty acid release in uremic patients needs to consider the rs1042636 single-nucleotide polymorphism.

Restoration of vagal tone: a possible mechanism for functional abdominal pain.

Functional abdominal pain (FAP) causes disruption of daily activities/missed school days, over utilization of healthcare, unnecessary surgeries, and anxiety in 10-15% of children. Its etiology is not clearly understood, however the success of several clinical protocols suggests that autonomic dysregulation is a factor. In this study autonomic activity, including heart rate variability (HRV), was compared between children with FAP and a comparison group. Twenty children with FAP and 10 children without FAP between the ages of 5 and 17 years old were compared on autonomic regulation using an ambulatory system at baseline and 8 weeks later. Children with FAP participated in 6 sessions of HRV biofeedback aimed at normalizing autonomic balance. At baseline, children with FAP appear to have more autonomic dysregulation than children without FAP. After completing HRV biofeedback, the FAP group was able to significantly reduce their symptoms in relation to significantly increasing their autonomic balance. In a sample of children with FAP, it appears that HRV biofeedback treatment improved their symptoms and that a change in vagal tone was a potential mediator for this improvement. The present study appears to point to excessive vagal withdrawal as an underlying mechanism of FAP.

Cinacalcet HCl and concurrent low-dose vitamin D improves treatment of secondary hyperparathyroidism in dialysis patients compared with vitamin D alone: the ACHIEVE study results.

BACKGROUND AND OBJECTIVES: Patients with chronic kidney disease (CKD) receiving dialysis often develop secondary hyperparathyroidism with disturbed calcium and phosphorus metabolism. The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (KDOQI) was established to guide treatment practices for these disorders. The ACHIEVE study was designed to test two treatment strategies for achieving KDOQI goals. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: Individuals on hemodialysis treated with vitamin D sterols were enrolled in this 33-week study. Subjects were randomly assigned to treatment with either cinacalcet and low-dose vitamin D (Cinacalcet-D) or flexible vitamin D alone (Flex-D) to achieve KDOQI-recommended bone mineral targets. ACHIEVE included a 6-week screening phase, including vitamin D washout, a 16-week dose-titration phase, and an 11-week assessment phase. RESULTS: Of 173 subjects enrolled, 83% of Cinacalcet-D and 67% of Flex-D subjects completed the study. A greater proportion of Cinacalcet-D versus Flex-D subjects had a >30% reduction in parathyroid hormone (PTH) (68% versus 36%, P < 0.001) as well as PTH <300 pg/ml (44% versus 23%, P = 0.006). The proportion of subjects simultaneously achieving targets for intact PTH (150-300 pg/ml) and calcium-phosphorus product (Ca x P) (<55 mg2/dl2) was also greater (21% versus 14%), but this was not statistically significant. This was attributable to 19% of Cinacalcet-D subjects with a PTH value below the KDOQI target range. CONCLUSIONS: Achievement of KDOQI targets was difficult, especially with Flex-D. Maintaining calcium and phosphorus target values precluded the use of vitamin D doses necessary to lower PTH to within the narrow target range and highlighted limitations inherent to the KDOQI treatment algorithm.

CaSR polymorphism Arg990Gly and response to calcimimetic agents in end-stage kidney disease patients with secondary hyperparathyroidism and in cell culture.

AIMS: Calcimimetics are effective in reducing parathyroid hormone (PTH) levels in patients with secondary hyperparathyroidism, but variability in dose response has been noted. We examined SNP Arg990Gly of the calcium-sensing receptor as a possible cause. MATERIALS & METHODS: We performed a dose-response study with cinacalcet on 23 hemodialysis patients (with PTH >300 pg/ml). Intact (i)PTH levels were measured at baseline and over time post-dose; 17 patients had iPTH measured at 24 h post-dose (60 mg). Arg990Gly status was established by sequencing a section from exon 7 of the CaSR gene. RESULTS: Only 33% of patients homozygous for the arginine allele showed an iPTH suppression of at least 5% of baseline at 24 h, while 88% of patients with one or two glycine alleles achieved this target (p < 0.05). CONCLUSION: We conclude that Arg990Gly influences the response to calcimimetics in patients with secondary hyperparathyroidism with an odds ratio of 2.6. This corresponds with in vitro data testing the effect of calcimimetic agent R-568 in HEK-293 cells transfected with the two alleles of Arg990Gly: HEK-293 cells expressing glycine-type CaSR were more sensitive to R-568 than arginine-type CaSR (p = 0.0001).

Calcium-sensing receptor gene polymorphism Arg990Gly and its possible effect on response to cinacalcet HCl.

Cinacalcet, a novel calcimimetic compound, is effective in reducing parathyroid hormone (PTH) levels in approximately 70% of patients with secondary hyperparathyroidism. However, interindividual variations in the dose required to achieve the treatment goal have been noted in clinical studies. Our investigation examined the genetic polymorphisms of the calcium-sensing receptor (CaSR) gene as one possible cause of the different responses to cinacalcet. We report data on seven end-stage renal failure patients who were treated with regular haemodialysis and who participated in clinical trials of cinacalcet. All patients had secondary hyperparathyroidism with baseline intact PTH (iPTH) levels greater than 600 pg/ml. Three patients were male and four female with a mean+/-SD age of 60+/-12 years. DNA was extracted from peripheral lymphocytes. An area in exon 7 of the CaSR gene was amplified by the polymerase chain reaction and sequenced. Mean+/-SD baseline iPTH was 1086+/-189 pg/ml. The five patients without Arg990Gly demonstrated a 29.7+/-4.0% (+/-SEM) reduction in iPTH from individual baseline. One patient was found to be homozygous for the Arg990Gly polymorphism and another was heterozygous for both arginine and glycine alleles. The homozygous patient showed a significantly higher sensitivity to cinacalcet compared to the other patients (P=0.003) with a 76.3+/-7.7% reduction in iPTH from baseline. No polymorphisms were noted in codons 986 or 1011. This preliminary study points to the possibility that patients homozygous for glycine at the 990 position in exon 7 of the CaSR may be more sensitive to the calcimimetic drug cinacalcet compared to those who are homozygous for arginine at that location.

Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism in hemodialysis and peritoneal dialysis: a randomized, double-blind, multicenter study.

Management of secondary hyperparathyroidism is challenging with traditional therapy. The calcimimetic cinacalcet HCl acts on the calcium-sensing receptor to increase its sensitivity to calcium, thereby reducing parathyroid hormone (PTH) secretion. This phase 3, multicenter, randomized, placebo-controlled, double-blind study evaluated the efficacy and safety of cinacalcet in hemodialysis (HD) and peritoneal dialysis (PD) patients with PTH > or =300 pg/ml despite traditional therapy. A total of 395 patients received once-daily oral cinacalcet (260 HD, 34 PD) or placebo (89 HD, 12 PD) titrated from 30 to 180 mg to achieve a target intact PTH (iPTH) level of < or =250 pg/ml. During a 10-wk efficacy assessment phase, cinacalcet was more effective than control for PTH reduction outcomes, including proportion of patients with mean iPTH levels < or =300 pg/ml (46 versus 9%), proportion of patients with > or =30% reduction in iPTH from baseline (65 versus 13%), and proportion of patients with > or =20, > or =40, or > or =50% reduction from baseline. Cinacalcet had comparable efficacy in HD and PD patients; 50% of PD patients achieved a mean iPTH < or =300 pg/ml. Cinacalcet also significantly reduced serum calcium, phosphorus, and Ca x P levels compared with control treatment. The most common side effects, nausea and vomiting, were usually mild to moderate in severity and transient. Once-daily oral cinacalcet was effective in rapidly and safely reducing PTH, Ca x P, calcium, and phosphorus levels in patients who received HD or PD. Cinacalcet offers a new therapeutic option for controlling secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.