Endocrine   diseases,  congenital   and   acquired   hypothalamic defects,  genetic syndromes,  and use of drugs affecting   appetite   should   be   considered   during assessment of paediatric patients with obesity (figure 2).

Clinical history and examination should guide differential diagnosis.  Onset of obesity during early infancy raises suspicion   of   function-changing   genetic   mutations affecting   the   leptin   signalling   pathway,  but   these disorders   are   very   rare,  with   the   most   common, melanocortin-4-receptor   defects,  affecting   less   than 5%  of   children   with   early-onset   obesity.⁵⁶ 

During assessment of new-onset excessive weight gain, potential side-effects from a recently initiated drug should be taken into consideration,  because weight gain can be associated with administration of insulin or insulin secretagogues, glucocorticoids, hormonal contraceptives (eg,  depot medroxyprogesterone acetate),  psychotropic drugs (including atypical antipsychotics [eg,  clozapine, olanzapine, risperidone], mood stabilisers [eg, lithium], tricyclic antidepressants [eg, amitriptyline, imipramine, and nortriptyline], and anticonvulsants [eg, valproic acid, gabapentin,  and   carbamazepine]),  antihypertensive drugs   (eg,  propranolol   and   clonidine),  and   antihistamines.⁶⁵ In patients with decreased growth velocity despite   continued   weight   gain,  an   endocrinopathy should   be   considered;  measurement   of   thyroidstimulating hormone and free thyroxine and referral to a paediatric endocrinologist are recommended.

Almost all patients, however, do not have any of these identifiable disorders. All patients, irrespective of cause of obesity,  should be assessed for modifiable lifestyle factors, including physical activity and diet, and screened for complications of obesity, including measurement of lipid and glucose concentrations after overnight fasting, and   alanine   aminotransferase.  If   fasting   glucose concentration   is   5.6 - 6.9   mmol/L,  an   oral   glucose tolerance test is recommended. Screening for vitamin D and iron deficiency should also be considered.

Figure 1A simplified model of the leptin signalling pathway
Lines with arrowheads show stimulatory action. Lines with perpendicular endblocks show inhibitory action. AgRP=agouti-related protein. BDNF=brain-derived neurotrophic factor. CART=cocaine-amphetamine related transcript. CPE=carboxypeptidase E. CRH=corticotropin-releasing hormone. GABA=gamma amino butyric acid.

GI=gastrointestinal. IR=insulin receptor. LR=leptin receptor. MCH=melanin-concentrating hormone. MSH=melanocyte-stimulating hormone. NPY=neuropeptide Y.
PC1=prohormone convertase 1. POMC=pro-opiomelanocortin. PYY=peptide YY. TRH=thyrotropin-releasing hormone. TrkB=tropomyosin receptor kinase B.

Childhood obesity can adversely affect almost every organ   system   (figure 3)  and   often   has   serious consequences,  including hypertension,  dyslipidaemia, insulin resistance or diabetes,  fatty liver disease,  and psychosocial   complications.⁶⁶  Results   of   one   study showed that being overweight or obese between ages 14 and 19 years was associated with increased adult mortality (from age 30 years)  from various systemic diseases.⁶⁷  The atherosclerotic process⁶⁸  seems to be accelerated in obese children and almost half of children with BMI higher than the 97th percentile have one or more of the disorders that make up the metabolic syndrome.⁶⁹  High childhood and adolescent BMI is associated with increased risk of cardiovascular disease in   adulthood.⁷⁰    Pulmonary   disorders,    including obstructive sleep apnoea and reactive airway disease,⁷¹ are reported more frequently in obese children than in their normal-weight counterparts.  Asthma severity,  however, does not seem to be affected by obesity;⁷² weight-related but non-asthmatic airflow limitations are perhaps being misdiagnosed as asthma in some obese children.⁷³ Specific   nutritional   deficiencies   often   accompany childhood obesity.  High BMI and adiposity have been associated with low vitamin D concentrations in children.⁷⁴

The mechanism underlying low vitamin D concentrations in obesity is unclear, but increased storage of vitamin D in adipose tissue has been proposed.⁷⁵ Overweight or obese children are also at least twice as likely to be iron-deficient than children of normal weight.⁷⁶ Obesity leads to increased production of proinflammatory cytokines that in turn promote release of hepcidin, which is a peptide hormone produced by the liver and adipocytes that decreases iron absorption from the gut.⁷⁷

Complications of childhood obesity include acceleration in timing of thelarche and menarche in girls,^78,79 pubertal advancement in boys⁸⁰ and adverse effects on maturation⁸¹ and alignment⁸²  of developing bones in both sexes.

Advanced skeletal maturation has been attributed to increased adipose tissue aromatisation of weak androgens into more potent oestrogens.  Obesity might also affect pubertal timing through nutrition-related signals (eg,  insulin   and   leptin)  on   the   reproductive   axis.⁸³

Orthopaedic complaints,  including fractures,  musculoskeletal discomfort,  impaired mobility,  and lower-limb mal alignment seem to be more common in obese children than in those who are not overweight.⁸² Serious orthopaedic complications of childhood obesity are tibia vara (Blount’s disease or adolescent bowing of the legs)⁸⁴  and slipped capital femoral epiphyses.⁸⁵ By contrast, however, obesity might have some beneficial effect on bone mineral density.

Results of a recent study, using variation in the FTO gene as an instrumental variable, suggested that high fat mass in children was causally associated with increased total, spinal, and limb bone mineral content.⁸⁶

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Joan C Han, Debbie A Lawlor, Sue Y S Kimm

Lancet 2010; 375 - 1737-48
Published Online May 6, 2010 DOI - 10.1016/ S0140- 6736(10)60171-7

Unit on Growth and Obesity, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, Bethesda, MD, USA (J C Han MD); MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol, UK (Prof D A Lawlor PhD); and Department of Internal Medicine/Epidemiology, University of New Mexico School of Medicine, Albuquerque, NM, USA (S Y S Kimm MD)

Correspondence to - Dr Sue Y S Kimm, University of New Mexico Health Sciences Center, Department of Internal Medicine/Epidemiology, University of New Mexico, MSC 10 5550 Albuquerque, NM 87131-0001, USA .(JavaScript must be enabled to view this email address)

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