Learning Objectives 4/17/2013. Toni Eimicke has no conflicts of interest or disclosures Heather Shanholtz has no conflicts of interest or disclosures

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1 OVERVIEW OF CONGENITAL ADRENAL HYPERPLASIA PATHOPHYSIOLOGY, LAB INTERPRETATION & MANAGEMENT Presented by: Toni Eimicke, MS, CPNP & Heather J Shanholtz, RN Pediatric Endocrinology Barbara Bush Children s Hospital at Maine Medical Center in Portland, ME Disclosures/Conflicts of Interest Toni Eimicke has no conflicts of interest or disclosures Heather Shanholtz has no conflicts of interest or disclosures Learning Objectives Explain the pathophysiology of CAH Describe how CAH presents in the neonate Describe the effects on growth and pubertal development Interpret lab results and other clinical data Propose treatment plan for optimal managment of CAH patients 1

2 CAH Definition Congenital Adrenal Hyperplasia (CAH) refers to a group of autosomal recessive disorders in which there is a defect in one of the enzymes responsible for the production of steroids by the adrenal cortex. From: Adrenal gland structure and steroidogenesis Medulla (inner): produces catecholamines - Epinephrine and norephinephrine Cortex (outer): 3 zones 1. Zona glomerulosa: Mineralocorticoids aldosterone 2. Zona fasciculata: Glucocorticoids cortisol 3. Zona reticularis: Sex hormones Dehydroepiandrosterone (DHEA) & Androstenedione, which are precursors to testosterone Testosterone is aromatized to estradiol Via aromatase (CYP19) Androstenedione is aromatized to estrone H-P-A Axis & Negative Feedback If Cortisol production is low ACTH rises Cortisol ACTH ACTH stimulation on adrenal glands = hyperplasia of adrenal cortex 2

3 Etiology Most common cause of CAH: 21 hydroxylase (21OHD) deficiency Incidence for classic 21OHD is 1 in 16,000 births 21 hydroxylase is a cytrochrome P-450 (CYP) enzyme 21 hydroxylase is also referred to as CYP21, CYP21A2 and P450c21 21OHD is caused by mutations in the CYP21 gene Less common causes of CAH: 11ß-hydroxylase 3ß-hydroxysteroid dehydrogenase 17α-hydroxylase/17,20-lyase Steroidogenic acute regulatory (StAR) protein (lipoid hyperplasia) P450 Oxidoreductase defect (newly described) Pathways of steroid biosynthesis. White P C, and Speiser P W Endocrine Reviews 2000;21: by Endocrine Society Simplified Pathway 3

4 Cortisol and Aldosterone Cortisol Necessary for survival! Maintains BP Stimulates gluconeogenisis Maintains adequate cardiac function Increases 5-10 fold during times of physiologic stress When deficient can lead to shock Aldosterone Regulates sodium homeostasis Untreated pts have excessive renal Na+ secretion leading to hypovolemia and dehydration Pts with aldosterone deficiency can t excrete K+ efficiently, so also prone to hyperkalemia. 21 Hydroxylase Deficient CAH 21 OHD CAH Classical +prenatal virilization in females +postnatal virilization in both males and females ~75% are salt wasting ~100% are cortisol deficient Nonclassical 1 in 1000 Caucasians more common among : Eastern European Jews, Hispanics & Yugoslavs No prenatal virilization Variable postnatal virilization No salt wasting Cortisol deficiency is rare SIMPLE VIRILIZING ~25% SALT WASTING >/= 75% Newborns are at risk for life-threatening salt wasting crisis CAH newborn screening results CAH is one of the 31 core tests screened As of 2009, all 50 states in the US screen for CAH at birth A positive newborn screening result reveals elevated 17-OHP 17-OHP levels are normally high at birth and decrease rapidly during the first few days of life - an early newborn screening could yield a false positive result Premature, sick or stressed infants can have high levels of 17-OHP, resulting in false positive. Most U.S. labs use birth wt adjusted reference range, but 17OPH levels correlate better with GA. Screening accuracy may be improved by using GA. If level is elevated, a second 17-OHP is done. If this is still elevated a cosyntropin (Cortrosyn) stimulation test is the gold standard. If infant is symptomatic, electrolytes must be obtained. 4

5 CAH Presentation in Neonate Varying degrees of ambiguous genitalia in female newborns. Newborn males may have subtle penile enlargement. Hyperpigmentation of skin creases and genitalia Poor feeding/weak suck Poor weight gain Metabolic acidosis Dry mucous membranes/dehydration Hyponatremia Hyperkalemia Hypoglycemia Clinical presentation/features Embryonic structures that develop into male/female reproductive organs indistinguishable until 6-7 weeks. In utero: adrenocorticol function begins about the 7 th week of gestation and the critical time for sexual differentiation is between 9 and 15 weeks gestation. Intrauterine exposure to androgens causes varying degrees of virilization in female infants. Normal internal female structures. Degree of virilization due to classical CAH varies from mild clitoral enlargement to a penile urethra (rare). Obstetrics and Gynecology Clinics of North America Volume 36, Issue 1, March 2009, Pediatric and Adolescent Gynecology Presentation of Nonclassical CAH Produce normal amounts of cortisol and aldosterone There is mild to moderate overproduction of sex steroid precursors Most are missed on newborn screening due to relatively low baseline levels of 17-OHP Some have advanced bone age, growth acceleration and premature adrenarche Women present with features similar to PCOS: hirsutism (60%), oligomenorrhea (54%) and acne (33%). Infertility presents in only 13%. Indication for glucocorticoid tx is infertility - HOWEVER, prevalence of infertility in NC CAH pts not greater than general population. 5

6 Effects on Growth and Puberty Poor management can lead to excessive androgen production causing clitoral or penile enlargement, clinical signs of premature adrenarche (pubarche, acne, axillary hair). Hyperandrogenism can lead to to growth acceleration, bone age advancement, premature epiphyseal closure and compromised adult height (Nimkarn, et al 2009). H-P-G axis: elevated androgens suppress gonadotropins through negative feedback. Long term androgen exposure advances bone age and once treated with glucocorticoids, patients can be at risk for CPP through early H-P-G activation. (Merke & Kabbani, 2001) Interventions Medications in Classic CAH: Goal of therapy is to reduce excessive androgen secretion by replacing deficient hormones Undertreatment of classic CAH can lead to adrenal crisis, adrenal androgen overproduction, accelerated bone age, loss of growth potential Overtreatment of classic CAH can lead to suppressing growth, increase blood pressure, Cushing s syndrome Delicate balance is needed CAH and Growth Study found that daily glucocorticoid doses have a significant negative effect on linear growth-especially in the first year of life, and between the age of 8-14 yrs. It is recommended that the daily glucocorticoid dose be sufficient to stop androgen excess, but as low as possible to allow optimum linear growth. Nike, M.M.L, Stikkelbrokeck 6

7 Managing Medications in CAH For classic CAH Glucocorticoids & Mineralocorticoids Medication Dose Schedule Glucocorticoids Hydrocortisone Tablets Mineralocorticoids Fludrocortisone tablets Sodium Chloride Supplements (used only in infants) mg/m2 x day 3 times/day mg/day 1-2 times/day 1-2 g/day Divided Medication Considerations Recommended to use Hydrocortisone tablets only in childhood Hydrocortisone suspension is not bioequivalent to tablets due to uneven distribution of drug in liquid Hydrocortisone is recommended over other glucocorticoids (like prednisone or dexamethasone) due to its short half life, which minimizes the adverse side effects (such as growth suppression) Aldosterone deficiency is present in all forms of 21-hydroxylase deficiencythere is a spectrum of salt loss, all patients with elevated renin or aldosterone to renin ratio can benefit from fludrocortisone therapy and adequate dietary sodium The maintenance of sodium reduces vasopression and ACTH levels which in turn leads to needing lower GC doses Glucocorticoid secretion Diurnal variation with peak level between 4AM and 8AM. Estimated normal cortisol secretion rate in the past was thought to be 12mg/m²/day More recently lower estimates have been reported and vary based on resource: 6-7 mg/m²/day 5-10 mg/m²/day These estimates are equivalent to about 20-30mg/d HC or 5-7mg/d of oral prednisone Due to short half life of HC and partial destruction by gastric acidity, daily oral replacement dose is 1.5 to 2 times normal daily secretion (ie mg/m2/24h) 7

8 Stress dosing Stress dosing is needed in patients with CAH Synthesis of cortisol increases 5-10 fold during times of physiologic stress Increase GC dosage in times of febrile illness, severe illness, surgery or trauma Mental & emotional stress and minor illnesses do not warrant extra GC Patient age Infants, preschool children School-age children Adults Initial Parenteral HC dose 25 mg 50 mg 100 mg Clinical Management Patient needs regular monitoring of height, weight, growth velocity, physical examination (virilizing effects) Annual bone age 17-OHP, Androstenedione & Testosterone are the best indicators for adequate GC treatment Normalization of 17-OHP and other hormones is not a goal but actually indicative of over-treatment Any medication dose adjustments should be made with the overall clinical picture in mind and not made based on a single 17-OHP measurement Other measurements available include salivary & 24 hr urine no consensus on best method Surgical Interventions Severely virilized females will need feminizing surgery in infancy. Depending on degree of virilization a female could need vaginoplasty, perineal reconstruction, and/or clitoroplasty There is still a debate regarding whether surgery should be performed in infancy or later in childhood/adolescence The transient exposure to placental estrogens leads to more elasticity in the vaginal tissue in the neonate There is no evidence at this time that argues for or against early or late surgery better preserving sexual function, though the majority of women with CAH surveyed favored genital surgery before adolescence 8

9 Alternative Surgery Adrenalectomy Should only be considered in the most extreme cases, such as in those who have failed medical therapy Can lead to reduced virilization in females and lower GC doses, but risk of adrenal crisis is high Complications TART Reduced adult height Infertility (females) Obesity-insulin resistance Conversion from hydrocortisone to other preparations 1mg Hydrocortisone = 0.20mg Prednisone 0.20mg 0.25mg Prednisolone 0.04mg Dexamethasone Preparations Glucocorticoid Mineralocorticoid Time of Effect Effect biologic action (hr) Hydrocortisone Prednisone Prednisolone Dexamethasone Fludricortisone

10 Case Study 2 yr old female with Classic salt-wasting CAH Lab results: Androstenedione PREPUBERTAL CHILDREN: <10-17 Testosterone PREPUBERTAL FEMALES: < NG/DL 14.0 NG/DL 17-Hydroxyprogesterone PREPUBERTAL: < NG/DL Growth Velocity 1.3 cm/yr Bone Age 3 yrs for CA 2 yr 10 mos Should we increase or decrease dose of Hydrocortisone? References Speiser, PW, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(9): Speiser, PW & White, PC. Congenital adrenal hyperplasia. N Engl J Med. 2001;349(8): Clayton, PE. Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. J Clin Endocrinol Metab. 2002;87(9): Moran, C, et al. 21-Hydorxylase-deficient nonclassic adrenal hyperplasia is a progressive disorder: A multicenter study. Am J Obstet Gynecol Dauber, A, Kellogg, M & Majzoub, JA. Monitoring of therapy in congenital adrenal hyperplasia. Clinical Chemistry. 2010;56(8): Merke, DP & Bornstein, SR. Congenital adrenal hyperplasia. The Lancet. 2005;365: White, PC & Speiser, PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocrine Reviews. 2000;21(3): Nimkarn, S, Lin-Su, K, & New, MI. Steroid 21 hydroxylase deficiency congenital adrenal hyperplasia. Endorinol Metab Clin N Am. 2009;38: Merke, D, & Kabbani, M. Congenital adrenal hyperplasia. Pediatr Drugs. 2001;3(8): Antal, Z & Zhou, P. Congenital adrenal hyperplasia: Diagnosis, evaluation, and management. Pediatr Rev. 2009;30:e49-e57. Forest, MG. Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21- hydroxylase deficiency. Human reproduction update. 2004;10(6): Reisch, N, Arlt, W & Krone, N. Health problems in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Res Paediatr. 2011;76: Nike, MML. Growth inhibition by glucocorticoid treatment in salt wasting 21-hydroxylase deficiency: In early infancy and (pre)puberty. J Clin Endocrinol Metab. 2003; 88(8):