Impact of elexacaftor/tezacaftor/ivacaftor on lipid and fat-soluble vitamin levels and association with body mass index.

INTRODUCTION: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve gastrointestinal absorption of nutrients and may result in changes in body mass index (BMI), serum lipids, and fat-soluble vitamin levels. We hypothesized that serum lipids and vitamin levels would increase with CFTR modulator therapy and that greater increase in lipids and vitamin levels would be related to greater increase in BMI. METHODS: A retrospective study was performed to evaluate the impact of elexacaftor/tezacaftor/ivacaftor (ETI) on nutritional parameters, serum lipids, and fat-soluble vitamin levels. Pre-ETI values (<2 years prior) and post-ETI values (>1 month after) were compared. Linear regression was used to evaluate whether change in BMI is associated with the change in lipid and/or vitamin levels and whether modulator duration is associated with the degree of rise in lipid and/or vitamin levels. RESULTS: Adults and adolescents with CF (n = 137) were evaluated before and 31-300 days after starting ETI. Median BMI (adults 21.9 vs. 23.5 kg/m2 ; adolescents 48 vs. 63 percentile) increased after initiation of ETI. Total cholesterol (126 vs. 154 mg/dL), low-density lipoprotein cholesterol (63 vs. 78 mg/dL), non-high-density lipoprotein cholesterol (84 vs. 102 mg/dL), and high density lipoprotein cholesterol (43 vs. 49 mg/dL) increased after ETI, while triglycerides and very low density lipoprotein did not change. Median values for vitamin D (34.5 vs. 38.0 ng/mL) and vitamin A (40.1 vs. 47.9 µg/dL) increased, while vitamin E did not change significantly. There was no significant correlation between BMI change or duration of modulator therapy with vitamin levels or lipid changes. CONCLUSION: After initiation of ETI therapy, serum lipids increased in our population, but most values remained within the normal range. Vitamins A and D levels increased post-ETI and no changes were noted in vitamin E. No significant correlation between the degree of BMI change and the magnitude of increase in lipids or vitamin levels was found.

Reproducibility of in-home CFRD screening using continuous glucose monitoring and mixed meal tolerance test.

Background: Cystic fibrosis related diabetes (CFRD) is associated with insulin-remediable pulmonary decline, so early detection is critical. Continuous glucose monitors (CGM) have shown promise in screening but are not recommended by clinical practice guidelines. Little is known about the reproducibility of CGM results for a given patient. Methods: Twenty non-insulin treated adults and adolescents with CF placed an in-home CGM and wore it for two 14-day periods. Participants underwent a mixed meal tolerance test (MMTT) on day 5 of each 14-day period. Glycemic data from CGM 1 and CGM 2 were compared regarding published thresholds to define abnormality: percent time >140 mg/dL of ≥4.5%, percent time >140 mg/dL of >17.5%, and percent time >180 mg/dL of >3.4%. Results of the repeat MMTT were compared for peak glucose and 2-hour glucose thresholds: >140 mg/dL, >180 mg/dL, and >200 mg/dL. Results: For percent time >140 mg/dL of ≥ 4.5%, five of 20 subjects had conflicting results between CGM 1 and CGM 2. For percent time >140 mg/dL of >17.5% and >180 mg/dL of >3.4%, only one of 20 subjects had conflicting results between CGM 1 and CGM 2. On the MMTT, few participants had a 2-hour glucose >140 mg/dL. Peak glucose >140 mg/dL, 180 mg/dL, and 200 mg/dL were more common, with 10-37% of participants demonstrating disagreement between CGM 1 and CGM 2. Conclusions: Repeated in-home CGM acquisitions show reasonable reproducibility regarding the more stringent thresholds for time >140 mg/dL and >180 mg/dL. More data is needed to determine thresholds for abnormal mixed meal tolerance tests in CFRD screening.

Trajectories of eGFR and risk of albuminuria in youth with type 2 diabetes: results from the TODAY cohort study.

BACKGROUND: We conducted exploratory analyses to identify distinct trajectories of estimated glomerular filtration rate (eGFR) and their relationship with hyperfiltration, subsequent rapid eGFR decline, and albuminuria in participants with youth-onset type 2 diabetes enrolled in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. METHODS: Annual serum creatinine, cystatin C, urine albumin, and creatinine measurements were obtained from 377 participants followed for ≥ 10 years. Albuminuria and eGFR were calculated. Hyperfiltration peak is the greatest eGFR inflection point during follow-up. Latent class modeling was applied to identify distinct eGFR trajectories. RESULTS: At baseline, participants' mean age was 14 years, type 2 diabetes duration was 6 months, mean HbA1c was 6%, and mean eGFR was 120 ml/min/1.73 m2. Five eGFR trajectories associated with different rates of albuminuria were identified, including a "progressive increasing eGFR" group (10%), three "stable eGFR" groups with varying starting mean eGFR, and an "eGFR steady decline" group (1%). Participants who exhibited the greatest peak eGFR also had the highest levels of elevated albuminuria at year 10. This group membership was characterized by a greater proportion of female and Hispanic participants. CONCLUSIONS: Distinct eGFR trajectories that associate with albuminuria risk were identified, with the eGFR trajectory characterized by increasing eGFR over time associating with the highest level of albuminuria. These descriptive data support the current recommendations to estimate GFR annually in young persons with type 2 diabetes and provide insight into eGFR-related factors which may contribute to predictive risk strategies for kidney disease therapies in youth with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00081328, date registered 2002. A higher resolution version of the Graphical abstract is available as Supplementary information.

Initial Insights into the Genetic Variation Associated with Metformin Treatment Failure in Youth with Type 2 Diabetes.

Metformin is the first-line treatment for type 2 diabetes (T2D) in youth but with limited sustained glycemic response. To identify common variants associated with metformin response, we used a genome-wide approach in 506 youth from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study and examined the relationship between T2D partitioned polygenic scores (pPS), glycemic traits, and metformin response in these youth. Several variants met a suggestive threshold (P < 1 × 10-6), though none including published adult variants reached genome-wide significance. We pursued replication of top nine variants in three cohorts, and rs76195229 in ATRNL1 was associated with worse metformin response in the Metformin Genetics Consortium (n = 7,812), though statistically not being significant after Bonferroni correction (P = 0.06). A higher ß-cell pPS was associated with a lower insulinogenic index (P = 0.02) and C-peptide (P = 0.047) at baseline and higher pPS related to two insulin resistance processes were associated with increased C-peptide at baseline (P = 0.04,0.02). Although pPS were not associated with changes in glycemic traits or metformin response, our results indicate a trend in the association of the ß-cell pPS with reduced ß-cell function over time. Our data show initial evidence for genetic variation associated with metformin response in youth with T2D.

Cystic fibrosis-related liver disease is an independent risk factor for mortality and increased health care resource utilization in hospitalized pediatric patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis-related liver disease (CFLD) is more prevalent in recent decades due to the increasing life expectancy of patients with cystic fibrosis (CF). There is paucity of population-level data on the impact of CFLD on hospital outcomes. METHODS: We interrogated nonoverlapping years (2003-2016) of the National Inpatient Sample and Kids' Inpatient Database to include all hospitalized patients <21 years of age with a primary diagnosis of CF within the United States. A concomitant diagnosis of cirrhosis, liver fibrosis, chronic liver disease, portal hypertension, hepatomegaly, splenomegaly, hypersplenism, and liver transplant status was considered as surrogates for the diagnosis of CFLD and was compared with CF-related hospitalizations without these diagnoses (controls) for demographics, comorbid conditions, in-hospital mortality, length-of-stay, and hospital charges. RESULTS: We evaluated 94,374 CF-related hospitalizations. The prevalence of CFLD was 5.8%. The prevalence increased from 3.1% (2003) to a peak of 7.3% (2014) with an overall increasing trend, p < 0.001. Hospitalizations with CFLD had an increased prevalence of significant comorbidities: respiratory failure,lung transplant, pulmonary hypertension, diabetes mellitus, malnutrition, Clostridioides difficile infection, cholelithiasis, anemia, and need for parenteral nutrition, p < 0.001. Multivariate regression models showed CFLD as independently associated with 2.1 (95% confidence interval [CI]: 1.5 to 2.8) times increased risk of inpatient mortality, contributed to 1.1 (95% CI: 0.89 to 1.37) additional days of hospitalization, and incurring $14,852 (95% CI: 12,204 to 17,501) excess hospital charges, p < 0.001. CONCLUSION: CFLD is associated with multiple comorbidities and is independently associated with increased risk of mortality and increased health care resource utilization in pediatric CF-related hospitalizations.

Treatment of cystic fibrosis related bone disease.

The advent of highly effective CFTR modulator therapies has slowed the progression of pulmonary complications in people with cystic fibrosis. There is increased interest in cystic fibrosis bone disease (CFBD) due to the increasing longevity of people with cystic fibrosis. CFBD is a complex and multifactorial disease. CFBD is a result of hypomineralized bone leading to poor strength, structure and quality leading to susceptibility to fractures. The development of CFBD spans different age groups. The management must be tailored to each group with nuance and based on available guidelines while balancing therapeutic benefits to risks of long-term use of bone-active medication. For now, the mainstay of treatment includes bisphosphonates. However, the long-term effects of bisphosphonate treatment in people with CF are not fully understood. We describe newer agents available for osteoporosis treatment. Still, the lack of data behooves trials of monoclonal antibodies treatments such as Denosumab and Romozosumab and anabolic bone therapy such as teriparatide and Abaloparatide. In this review, we also summarize screening and non-pharmacologic treatment of CFBD and describe the various options available for the pharmacotherapy of CFBD. We address the prospect of CFTR modulators on bone health while awaiting long-term trials to describe the effects of these medications on bone health.

Cystic fibrosis related liver disease and endocrine considerations.

Cystic fibrosis-liver disease (CFLD) is one of the most common non-pulmonary complications in the CF population, is associated with significant morbidity and represents the third leading cause of mortality in those with CF. CFLD encompasses a broad spectrum of hepatobiliary manifestations ranging from mild transaminitis, biliary disease, hepatic steatosis, focal biliary cirrhosis and multilobular biliary cirrhosis. The diagnosis of CFLD and prediction of disease progression remains a clinical challenge. The identification of novel CFLD biomarkers as well as the role of newer imaging techniques such as elastography to allow for early detection and intervention are active areas of research focus. Biliary cirrhosis with portal hypertension represents the most severe spectrum of CFLD, almost exclusively develops in the pediatric population, and is associated with a decline in pulmonary function, poor nutritional status, and greater risk of hospitalization. Furthermore, those with CFLD are at increased risk for vitamin deficiencies and endocrinopathies including CF-related diabetes, CF-related bone disease and hypogonadism, which can have further implications on disease outcomes and management. Effective treatment for CFLD remains limited and current interventions focus on optimization of nutritional status, identification and treatment of comorbid conditions, as well as early detection and management of CFLD specific sequelae such as portal hypertension or variceal bleeding. The extent to which highly effective modulator therapies may prevent the development or modify the progression of CFLD remains an active area of research. In this review, we discuss the challenges with defining and evaluating CFLD and the endocrine considerations and current management of CFLD.

Obesity in cystic fibrosis.

The prevalence of obesity in patients with cystic fibrosis (CF) is increasing and around one-third of adults with CF are now overweight or obese. The causes of excess weight gain in CF are likely multifactorial, including: adherence to the high-fat legacy diet, reduced exercise tolerance, therapeutic advances, and general population trends. Increased weight has generally been considered favorable in CF, correlating with improved pulmonary function and survival. While the optimal BMI for overall health in CF is unknown, most studies demonstrate minimal improvement in pulmonary function when BMI exceeds 30 kg/m2. Dyslipidemia and cardiovascular disease are important co-morbidities of obesity in the general population, but are uncommon in CF. In people with CF, obesity is associated with hypertension and higher cholesterol levels. With longer life expectancy and rising obesity rates, there may be an increase in cardiovascular disease among people with CF in coming years. Overweight CF patients are more likely to be insulin resistant, taking on features of type 2 diabetes. Treating obesity in people with CF requires carefully weighing the metabolic risks of overnutrition with the impact of low or falling BMI on lung function. This article describes current knowledge on the epidemiology, causes, consequence, and treatment of obesity in people with CF.

COVID-19: Pathophysiology and implications for cystic fibrosis, diabetes and cystic fibrosis-related diabetes.

The novel SARS-CoV-2 coronavirus (COVID-19) has become a global health crisis since its initial outbreak in Wuhan, China in December 2019. On January 30, 2020, the WHO recognized the COVID-19 outbreak as a Public Health Emergency, and on March 11, 2020, it was declared a pandemic. Although all age groups have been affected, patients with cystic fibrosis (CF) and patients with type 1 or type 2 diabeteshave been categorized as highly vulnerable to SARS-CoV-2 infection. Thus far, studies have found that the incidence of SARS-CoV-2 in the CF population is lower than the general population. We review the underlying protective mechanisms which may reduce inflammation and lung damage in CF patients, thus decreasing their risk of severe COVID-19. While the effect of SARS-CoV-2 in those with diabetes related to CF is unknown, other forms of diabetes have been associated with more severe disease. To further understand the potential impact of SARS-CoV-2 in cystic fibrosis-related diabetes, we provide a comprehensive overview of the potential factors contributing to COVID-19 severity in other forms of diabetes, including direct viral effect on the pancreas and indirect effects related to hyperglycemia and immune dysregulation.

Rapid B1-Insensitive MR Fingerprinting for Quantitative Kidney Imaging.

Background MR fingerprinting (MRF) provides rapid and simultaneous quantification of multiple tissue parameters in a single scan. Purpose To evaluate a rapid kidney MRF technique at 3.0 T in phantoms, healthy volunteers, and patients. Materials and Methods A 15-second kidney MRF acquisition was designed with 12 acquisition segments, a range of low flip angles (5°-12°), multiple magnetization preparation schema (T1, T2, and fat suppression), and an undersampled spiral trajectory. This technique was first validated in vitro using standardized T1 and T2 phantoms. Kidney T1 and T2 maps were then obtained for 10 healthy adult volunteers (mean age ± standard deviation, 35 years ± 13; six men) and three pediatric patients with autosomal recessive polycystic kidney disease (ARPKD) (mean age, 10 years ± 3; two boys) between August 2019 and October 2020 to evaluate the method in vivo. Results Results in nine phantoms showed good agreement with spin-echo-based T1 and T2 values (R2 > 0.99). In vivo MRF kidney T1 and T2 assessments in healthy adult volunteers (cortex: T1, 1362 msec ± 5; T2, 64 msec ± 5; medulla: T1, 1827 msec ± 94; T2, 69 msec ± 3) were consistent with values in the literature but with improved precision in comparison with prior MRF implementations. In vivo MRF-based kidney T1 and T2 values with and without B1 correction were in good agreement (R2 > 0.96, P < .001), demonstrating limited sensitivity to B1 field inhomogeneities. Additional MRF reconstructions using the first nine segments of the MRF profiles (11-second acquisition time) were in good agreement with the reconstructions using 12 segments (15-second acquisition time) (R2 > 0.87, P < .001). Repeat kidney MRF scans for the three patients with ARPKD on successive days also demonstrated good reproducibility (T1 and T2: <3% difference). Conclusion A kidney MR fingerprinting method provided in vivo kidney T1 and T2 maps at 3.0 T in a single breath hold with improved precision and no need for B1 correction. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Laustsen in this issue.

Lumacaftor/ivacaftor therapy is associated with reduced hepatic steatosis in cystic fibrosis patients.

BACKGROUND: Hepatic steatosis is a common form of cystic fibrosis associated liver disease (CFLD) seen in an estimated 15%-60% of patients with cystic fibrosis (CF). The pathophysiology and health implications of hepatic steatosis in cystic fibrosis remain largely unknown. In the general population, hepatic steatosis is strongly associated with insulin resistance and type 2 diabetes. Cystic fibrosis related diabetes (CFRD) impacts 40%-50% of CF adults and is characterized by both insulin insufficiency and insulin resistance. We hypothesized that patients with CFRD would have higher levels of hepatic steatosis than cystic fibrosis patients without diabetes. AIM: To determine whether CFRD is associated with hepatic steatosis and to explore the impact of lumacaftor/ivacaftor therapy on hepatic steatosis in CF. METHODS: Thirty patients with CF were recruited from a tertiary care medical center for this cross-sectional study. Only pancreatic insufficient patients with CFRD or normal glucose tolerance (NGT) were included. Patients with established CFLD, end stage lung disease, or persistently elevated liver enzymes were excluded. Mean magnetic resonance imaging (MRI) proton density fat fraction (PDFF) was obtained for all participants. Clinical characteristics [age, sex, body mass index, percent predicted forced expiratory volume at 1 s (FEV1), lumacaftor/ivacaftor use] and blood chemistries were assessed for possible association with hepatic steatosis. Hepatic steatosis was defined as a mean MRI PDFF > 5%. Patients were grouped by diabetes status (CFRD, NGT) and cystic fibrosis transmembrane conductance regulator (CFTR) modulator use (lumacaftor/ivacaftor, no lumacaftor/ivacaftor) to determine between group differences. Continuous variables were analyzed with a Wilcoxon rank sum test and discrete variables with a Chi square test or Fisher's exact test. RESULTS: Twenty subjects were included in the final analysis. The median age was 22.3 years (11.3-39.0) and median FEV1 was 77% (33%-105%). Twelve subjects had CFRD and 8 had NGT. Nine subjects were receiving lumacaftor/ivacaftor. The median PDFF was 3.0% (0.0%-21.0%). Six subjects (30%) had hepatic steatosis defined as PDFF > 5%. Hepatic fat fraction was significantly lower in patients receiving lumacaftor/ivacaftor (median, range) (2.0%, 0.0%-6.4%) than in patients not receiving lumacaftor/ivacaftor (4.1%, 2.7-21.0%), P = 0.002. Though patients with CFRD had lower PDFF (2.2%, 0.0%-14.5%) than patients with NGT (4.9%, 2.4-21.0%) this did not reach statistical significance, P = 0.06. No other clinical characteristic was strongly associated with hepatic steatosis. CONCLUSION: Use of the CFTR modulator lumacaftor/ivacaftor was associated with significantly lower hepatic steatosis. No association between CFRD and hepatic steatosis was found in this cohort.

Challenges in the diagnosis and management of disorders of sex development.

Disorders of sex development (DSD) represent a spectrum of uncommon but very complex disorders with medical, psychosexual, and family implications for those affected by them. The diagnosis and management of these disorders requires a coordinated team of multiple specialists. Following an international conference in Chicago in 2005, a consensus statement was created and presented, which has resulted in a new paradigm in the nomenclature, classification, and management of DSDs. Since that time, many improvements have been forthcoming, most notably in the area of molecular genetic technologies. These developments have advanced our understanding of the specific etiologies underlying many of these conditions. In this article, we present an overview of the physiology of sex development, a few clinical vignettes highlighting specific pathologic conditions, discussions regarding the evaluation and management of these disorders, and some thoughts on future directions in this field. Birth Defects Research (Part C) 108:293-308, 2016. © 2016 Wiley Periodicals, Inc.