Obesity and Endocrine Management of the Patient With Duchenne Muscular Dystrophy

Obesity Prevention

Obesity prevention strategies should be introduced at 3 key time points: (1) diagnosis, (2) time of glucocorticoid initiation, and (3) time of loss of mobility. Particular attention should be given to patients who have a family history of obesity, given the highly hereditary nature of obesity.¹⁰ An increase in weight or BMI z score of ≥0.5 also should trigger intervention.¹¹

Obesity prevention strategies should aim to facilitate a healthy home food environment of mostly whole foods, regular and predictable times for meals and snacks that are mostly home prepared, family meals, limits on sugar-sweetened beverage consumption and restaurant meals, and encouragement of screen-free meals and snacks at the table. This should be done in consultation with a dietitian. Obesity prevention strategies also should include counseling around appropriate sleep hygiene and duration, limitations on screen time, and psychosocial assessments and support for both the patients and their caregivers.^12,13

Although physical activity is a mainstay of obesity prevention strategies, the approach to physical activity recommendations in patients with DMD is more measured, and the role of physical activity in DMD remains controversial.¹⁴ To avoid disuse atrophy and other secondary complications of inactivity, it is necessary that those who are ambulatory or in the early nonambulatory stage participate in gentle functional strengthening activity, including a combination of swimming pool exercises and recreation-based exercises in the community. Swimming is highly recommended from the early ambulatory to early nonambulatory phase and could be continued in the nonambulatory phase as long as it is medically safe. Additional benefits might be provided by low-resistance strength training and optimization of upper body function. Significant muscle pain or myoglobulinuria in the 24-hour period after a specific activity is a sign of overexertion and that the activity should be modified.¹⁵

Monitoring of Weight Status

Monitoring weight status should include measuring body weight and linear height in ambulatory patients or arm span and segmental length in nonambulatory patients at least every 6 months. Both BMI and weight should be plotted on the appropriate curve to determine the percentile for age. Optimal weight status is defined as BMI between the 10th and 85th percentiles. If height is unavailable or there are significant concerns about its accuracy, weight for age can be used, and an appropriate weight gain trajectory as per the growth curve can be another indicator of optimal weight gain. An increase in weight for age or BMI z scores by >0.5 between visits should raise concern and prompt intervention.¹¹

Although body composition is altered in individuals with DMD (lower lean body mass and higher fat mass), the role of direct measurement of body composition remains unclear and is not routinely recommended. Direct measures of adiposity have limited accessibility in most clinical settings and are not sufficiently accurate.¹⁶ Although reference data for a number of pediatric dual-energy x-ray absorptiometry body composition measures have been published,^17–19 it remains unclear what their clinical applicability will be both within and outside of the population with DMD. Longitudinal data on the relation of adiposity in children to future disease risk in adults also is lacking; therefore, no agreement exists about cut-points for excess adiposity that would constitute obesity.²⁰

Weight Management

More intensive weight management strategies should be introduced if weight for age or BMI z score is increased by >0.5 between visits and/or if BMI is >85th percentile. A referral to an intensive interdisciplinary weight management program or to a clinician with expertise in pediatric weight management should be made if BMI is >85th percentile with associated weight-related health complications and/or if BMI is >95th percentile.

Evidence-based guidelines for managing obesity in individuals with DMD or children with physical and developmental disabilities do not currently exist⁴; therefore, an adaptation of current clinical practice guidelines for managing pediatric obesity, with the exception of physical activity recommendations, should be applied. The principles of weight management are in essence a more intensive application of obesity prevention strategies (as above). Family participation in lifestyle change is essential, and interventions must include nutritional and psychosocial reassessment and support, with frequent follow-up.⁶ High-intensity programs (>25 hours of contact with the child and/or family over a 6-month period) were able to demonstrate improvement in weight status 12 months after beginning the intervention.⁶ These interventions were focused on counseling and behavioral management techniques to assist with implementation of lifestyle change. Interventions may incorporate a structured daily eating plan with the addition of some self-monitoring (through the use of logs) under the supervision of a dietitian who has training in weight management, with careful attention paid to avoid overly restrictive dieting practices. Personnel should include a registered dietitian, physical activity expert, and mental health professional (social worker, counselor, and/or psychologist) who have training in motivational interviewing, goal setting, monitoring, and positive reinforcement techniques. Interventions must be mindful of, and adapted to, the unique needs of the patient and family. More specific recommendations can be found within the “Recommendations for Treatment of Child and Adolescent Overweight and Obesity.”²¹ Practical clinical resources include The 5As of Pediatric Obesity Management²² and the Healthy Active Living for Families Program.²²

Monitoring Weight-Related Health Complications

Metabolic complications of obesity include glucose dysregulation, type 2 diabetes, dyslipidemia, and hypertension. The metabolic complications of obesity are often silent and need to be screened to identify and manage them. Table 1 lists comorbidities for which regular monitoring and possible intervention are recommended. Metabolic complications also are highly heritable, and a family history should result in increased vigilance around screening.²³ Glucocorticoid use increases the risk of both obesity and its metabolic complications.

Signs and symptoms of obesity-induced biomechanical complications can typically be elicited on routine history and physical examination. Effective management of biomechanical complications, especially sleep apnea and sleep-disordered breathing, may help improve success with weight management.²⁴

Children and youth with obesity are at increased risk of social isolation and stigmatization.²⁵ Childhood psychiatric disorders (depression, anxiety), school difficulties, body dissatisfaction, dysregulated eating behaviors, teasing, and bullying have all been linked with pediatric obesity.^26,27 Mental health disorders, as well as some of the pharmacotherapeutic agents that are used to manage them, can complicate weight management, promote weight gain, and affect prognosis and therefore should be routinely monitored through history at clinic visits.²⁸

Growth Failure Causing Short Stature

Short stature is common in individuals with DMD. Observational studies of glucocorticoid-naïve, ambulatory patients with DMD have described a growth pattern marked by (1) normal length at birth, (2) below-average growth velocity in early life, and (3) age-appropriate growth velocity at a below-average height percentile for the remainder of childhood.^28,29 A study of ambulatory patients with DMD revealed that participants were shorter than expected for age by an average of 4.3 cm compared with reference data.^30,31 The authors of a natural history study reported that the median height of participants at age 18 years was below the fifth percentile.³² The etiology of the impaired growth in individuals with DMD remains unclear because growth hormone secretion in response to provocative testing,³³ circulating growth factors,²⁸ and skeletal maturation²⁹ were normal in patients with DMD.

Growth impairment in DMD is exacerbated by glucocorticoid treatment.^34–36 Current recommendations support the initiation of glucocorticoid therapy before functional decline; therefore, patients are exposed to the deleterious effects of glucocorticoid for the majority of their growth.³⁷ Glucocorticoid treatment regimens vary and may affect growth differently. Growth impairment was observed irrespective of agent (prednisone, prednisolone, deflazacort) in a natural history study.³⁸ However, an RCT revealed that a weekend-only prednisone regimen resulted in greater growth compared with daily dosing.³⁹ The mechanisms underlying the growth inhibitory effects of glucocorticoids are complex. Glucocorticoid exposure appears to inhibit growth hormone release,⁴⁰ antagonize the peripheral action of growth hormone and IGF-1,^41–43 and induce chondrocyte apoptosis at the growth plate.⁴⁴

Growth should be verified every 6 months in all patients with DMD until puberty has finished and final adult height has been reached.³⁷ Standing height is acceptable for patients who are still walking, with the results compared with a standardized growth curve. A DMD-specific growth curve derived from glucocorticoid-naïve patients is available for patients ages 2 to 12 years, although its clinical usefulness is untested.³⁰ Growth is evaluated differently in nonambulatory patients, ideally starting before loss of ambulation to permit tracking of the growth rate during transition from walking to nonambulatory. Arm span, ulnar and tibia lengths, knee height, and segmental measurements of recumbent length have been proposed.⁴⁵ However, these methods have not been specifically validated in DMD. A finding of impaired growth (downward crossing of percentile for height, height velocity <4 cm/year, or height below the third percentile) should prompt consultation with an endocrinologist. A standard clinical evaluation should be performed in all patients with DMD with growth failure to identify treatable hormonal or other causes (Fig 1, Table 2).

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FIGURE 1

Assessments and interventions for impaired growth and delayed puberty in patients with DMD. (Reproduced with permission from Birnkrant DJ, Bushby K, Bann CM, et al; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, an update, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17[3]:258.)

The treatment of DMD-related short stature is controversial. Recombinant human growth hormone (rhGH) is commonly used to treat hypothalamic and/or pituitary growth hormone deficiency and a handful of other childhood conditions.⁴⁶ To date, no RCTs have been conducted to evaluate the efficacy and safety of rhGH to improve growth in individuals with DMD. The only RCT of rhGH conducted in this population was designed to investigate cardiac outcomes. The researchers found that rhGH was well tolerated and that left ventricular mass increased with treatment. However, no height outcomes were reported.⁴⁰ The largest report of clinical rhGH use in individuals with DMD included 39 boys and revealed that growth velocity increased from 1.3 to 5.2 cm/year over 12 months.⁴⁷ No detrimental musculoskeletal or pulmonary effects were observed, although 3 boys developed known rhGH-related adverse events (impaired fasting glucose, worsening of scoliosis, and benign intracranial hypertension). Adding to the controversy are theoretical concerns that increased growth may worsen muscle function in this context.^48,49 The relevance of this evidence to humans remains uncertain, however, and clinical trials investigating the use of mazindol, a postulated inhibitor of growth hormone release, yielded inconsistent effects on growth suppression and no benefits on muscle strength.^33,50–53 In light of limited data and the ongoing controversy, regular use of rhGH in the population with DMD is not recommended. The decision to use rhGH should be made on a case-by-case basis with biochemical evidence of growth hormone deficiency, and after a discussion of the benefits and known plus unknown risks. For example, it is unknown whether rhGH adversely affects muscle strength.

Delayed Pubertal Development

Delayed or absent pubertal development in glucocorticoid-treated patients with DMD is due to hypogonadotropic hypogonadism⁵⁴ and may negatively affect physical health, psychosocial development, and self-esteem. Studies have revealed that pubertal delay in individuals with DMD is common, with a prevalence of 50% to 100% in glucocorticoid-treated boys.^55,56 No published RCTs have contained assessments of the safety and efficacy of testosterone to induce puberty in individuals with DMD. However, the authors of a retrospective study of 14 boys treated with testosterone reported patient satisfaction with treatment and increased growth velocity in the first year of therapy.⁵⁷ Testosterone is widely used in pediatrics to induce puberty and is specifically advised in treatment of adult men with glucocorticoid-induced hypogonadism.⁵⁸

All patients with DMD should undergo monitoring of pubertal development by physical examination every 6 months starting at age 9 years (Fig 1).³⁷ A finding of delayed puberty (absence of testicular enlargement ≥4 cm³ by age 14 years) should prompt referral to an endocrinologist. Testosterone is recommended starting by age 14 years (or by 12 years in those on glucocorticoids) at a low dose and should be increased gradually over 2 to 3 years until adult testosterone levels are achieved. Examples of commonly used testosterone regimens are provided in Table 3. Patients and families should be counseled about expected effects, including body odor, facial hair, acne, growth spurt, growth plate closure, and increased libido. Testosterone levels should be monitored to adjust dose. Annual monitoring of hemoglobin and/or hematocrit, lipids, and serum glucose should be considered.⁵⁸ An unexpected adverse effect on muscle or cardiac health may warrant discontinuation or dose reduction.

Currently, the expected benefit of restoring testosterone to normal physiologic levels is felt to outweigh potential risks of treatment. However, future studies are needed to identify the optimal timing and regimen for testosterone replacement in individuals with DMD.

Glucocorticoid Dependence and Adrenal Insufficiency

Chronic glucocorticoid therapy at the doses used on individuals with DMD leads to a suppressed hypothalamic-pituitary-adrenal (HPA) axis. Patients are therefore at risk for life-threatening adrenal crisis should glucocorticoid therapy be stopped suddenly and also during times of severe injury or illness.⁵⁹ All patients on glucocorticoids should be taught the symptoms, signs, and appropriate management of adrenal crisis at the time of initial glucocorticoid prescription, including intramuscular hydrocortisone administrative for home use in the event the patient cannot take his usual glucocorticoid therapy because of vomiting. Patient education should also include emergency administration of intramuscular hydrocortisone and instructions for stress dosing during times of illness, trauma, or surgical intervention (Table 4). The need for education around intramuscular hydrocortisone is testament to the potentially life-threatening nature of adrenal suppression in the face of illness and surgery. Glucocorticoid therapy is never discontinued abruptly, but rather tapered slowly to allow HPA recovery. A steroid taper should adhere to the following guidance: (1) gradual dose reduction; (2) monitoring for signs and/or symptoms of adrenal insufficiency (fatigue, headache, nausea and/or vomiting, hypoglycemia, hypotension); (3) dose increase and slowing of taper in response to signs or symptoms; and (4) continuation of stress steroid coverage until the taper is complete and the HPA axis has been proven normal by an adequate cortisol response to corticorelin or corticotropin stimulation (peak cortisol >20 μg/dL [550 nmol/L]).⁶⁰ HPA axis recovery can take months to years.^61,62 Periodic monitoring of 8:00 am cortisol levels for a return to a normal value (eg, >6 μg/dL [165 nmol/L])⁶³ can guide the decision around when to discontinue daily steroid therapy and to perform stimulation testing, recognizing that the precise threshold that is used to define a normal 8:00 am cortisol may vary depending on institution-specific practice standards. Irrespective of the specific threshold that is used to signal discontinuation of daily physiologic steroid therapy, an expert in adrenal suppression management should interpret the 8:00 am cortisol results in light of the child’s clinical status and in accordance with local practice standards. These decisions are typically made in collaboration with an endocrinologist. A protocol for the management of adrenal suppression has been developed previously⁶⁴ and endorsed by the DMD Care Considerations Working Group.