ABSTRACT
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 5.6âdays/wk, SD 1.6) and duration (69.9%, mean 40.2âminutes/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 (Pâ=â0.003). 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.
Subject(s)
Gastroenterologists/statistics & numerical data , Gastroenterology/methods , Non-alcoholic Fatty Liver Disease , Pediatrics/methods , Practice Patterns, Physicians'/statistics & numerical data , Child , Female , Humans , Male , United StatesABSTRACT
Pediatric nonalcoholic fatty liver disease is an increasingly prevalent disease, but its pathophysiology is not fully elucidated, diagnosis is difficult and invasive, and therapeutic options are limited. This article addresses the recent advancements made in understanding the pathophysiology of nonalcoholic fatty liver disease, the development of less invasive diagnostic modalities, and emerging therapeutic options, including ongoing clinical trials in children.
Subject(s)
Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/therapy , Child , Humans , Non-alcoholic Fatty Liver Disease/diagnosisABSTRACT
Hemojuvelin (Hjv), a member of the repulsive-guidance molecule (RGM) family, upregulates transcription of the iron regulatory hormone hepcidin by activating the bone morphogenetic protein (BMP) signaling pathway in mammalian cells. Mammalian models have identified furin, neogenin, and matriptase-2 as modifiers of Hjv's function. Using the zebrafish model, we evaluated the effects of hjv and its interacting proteins on hepcidin expression during embryonic development. We found that hjv is strongly expressed in the notochord and somites of the zebrafish embryo and that morpholino knockdown of hjv impaired the development of these structures. Knockdown of hjv or other hjv-related genes, including zebrafish orthologs of furin or neogenin, however, failed to decrease hepcidin expression relative to liver size. In contrast, overexpression of bmp2b or knockdown of matriptase-2 enhanced the intensity and extent of hepcidin expression in zebrafish embryos, but this occurred in an hjv-independent manner. Furthermore, we demonstrated that zebrafish hjv can activate the human hepcidin promoter and enhance BMP responsive gene expression in vitro, but is expressed at low levels in the zebrafish embryonic liver. Taken together, these data support an alternative mechanism for hepcidin regulation during zebrafish embryonic development, which is independent of hjv.
Subject(s)
Antimicrobial Cationic Peptides/analysis , Bone Morphogenetic Proteins/metabolism , Signal Transduction , Trans-Activators/physiology , Zebrafish Proteins/physiology , Zebrafish/metabolism , Animals , Anti-Bacterial Agents , Antimicrobial Cationic Peptides/biosynthesis , Antimicrobial Cationic Peptides/genetics , Bone Morphogenetic Protein 2 , Embryo, Nonmammalian , GPI-Linked Proteins , Hemochromatosis/congenital , Hemochromatosis Protein , Hepcidins , Humans , Liver/chemistry , Liver/metabolism , Notochord/chemistry , Promoter Regions, Genetic , Serine Endopeptidases , Somites/chemistry , Zebrafish/geneticsABSTRACT
Juvenile hemochromatosis is an iron-overload disorder caused by mutations in the genes encoding the major iron regulatory hormone hepcidin (HAMP) and hemojuvelin (HFE2). We have previously shown that hemojuvelin is a co-receptor for bone morphogenetic proteins (BMPs) and that BMP signals regulate hepcidin expression and iron metabolism. However, the endogenous BMP regulator(s) of hepcidin in vivo is unknown. Here we show that compared with soluble hemojuvelin (HJV.Fc), the homologous DRAGON.Fc is a more potent inhibitor of BMP2 or BMP4 but a less potent inhibitor of BMP6 in vitro. In vivo, HJV.Fc or a neutralizing antibody to BMP6 inhibits hepcidin expression and increases serum iron, whereas DRAGON.Fc has no effect. Notably, Bmp6-null mice have a phenotype resembling hereditary hemochromatosis, with reduced hepcidin expression and tissue iron overload. Finally, we demonstrate a physical interaction between HJV.Fc and BMP6, and we show that BMP6 increases hepcidin expression and reduces serum iron in mice. These data support a key role for BMP6 as a ligand for hemojuvelin and an endogenous regulator of hepcidin expression and iron metabolism in vivo.
