Insulin tolerance test: mild hypoglycaemia is used to assess the integrity of the entire hy pothalamic \200\223pituitary \200\223adrenal axis. Serum cortisol response to hypoglycaemia (>550nmol/L) is normal. ACTH stimulation (synacthen) test: baseline and at +30 and +60min after IV/IM of synthetic ACTH (short synacthen test). Serum cortisol response >550nmol/L at 60min is considered normal. Recent onset secondary adrenal insuf \201 ciency may produce a normal response to a short synacthen test. considered the gold standard test. Insulin-induced serum cortisol is measured at Other investigations \200 Serum electrolytes: \200 Adrenal antibody titres (Addison \200\231s disease). \200 Adrenal imaging: US; CT scan. \200 Adrenal androgen pro \201 le: serum/urine. \200 Molecular genetic studies. \200 Pituitary imaging: serum sodium (low); serum potassium (high). CT or MRI scan. 12_McClure_12.indd 431 11/14/2012 3:27:04 PM CHAPTER 12 Endocrinology and diabetes 432 Adrenal insuf \201 ciency: treatment Primary adrenal insuf \201 ciency requires both gluc ocorticoid and mineralo- corticoid replacement therapy. s adrenal insuf \201 ciency requir es glucocor- ticoid therapy only. \200 Glucocorticoid therapy: \200 \200\224oral 12 \200\22315mg/m2/day in 2 \200\2233 divided doses per day. hydrocortisone U sually about two-thirds of the dose is given in the morning, in an attempt to mimic normal diurnal variation in cortisol secretion. During times of illness and stress (e.g. infection , trauma, surgery) patients are advised to increase their normal daily maintenance dose of hydrocortisone by 2 to 3 times. Mineralocorticoid therapy: day. Monitor BP and plasma renin levels. \202 udrocortisone \200\224oral 50 \200\223150micrograms/ Adrenal crises An adrenal (or Addisonian) crisis is an acute exacerbation of an underlying adrenal insuf \201 ciency brought on by \200\230stresses \200\231 that necessitate increa sed production and secretion of cortisol from the adrenal gland. This is a life- threatenin g emergency and should be treated if there is a strong clinical suspicion rather than waiti ng for con \201 rmatory test results. Typical causes include infection, trauma, and surger y. Symptoms include: \200 \200 \200 \200 nausea/vomiting; abdominal pain; lethargy/somnolence; hypotension. Treatment \200 Immediate IV bolus of hydrocortisone followed by 6-hourly repeat injections. IVI \202 uid s/glucose. 12_McClure_12.indd 432 11/14/2012 3:27:04 PM ADRENAL INSUFFICIENCY: TREATMENT 433 12_McClure_12.indd 433 11/14/2012 3:27:04 PM CHAPTER 12 Endocrinology and diabetes 434 Adrenal excess A state of glucocorticoid (cortisol) excess. The commonest cause of hy- perc ortisolaemia is iatrogenic, due to exogenous steroids. Hyperfunction of the adrenal cortex resulting in excess cortisol secretion may have p (adrenal or ACTH-independent) or s (ACTH- dependent) causes. The term Cushing \200\231s disease applies to an ACTH-secreting pituitar y tumor. All other causes of glucocorticoid excess are often referred to as Cushing \200 \231s syndrome. Causes of adrenal (cortisol) excess \200 p \200 \200 \200 \200 s \200 \200 \200 Iatrogenic. adrenal hyperfunction (ACTH-independent): adrenal tumor (carcinoma/adenoma); nodular adrena l hyperplasia; b p.441). McAS ( adrenal hyperfunction (ACTH-dependent): Cushing \200\231s d isease \200\224pituitary ademona/hyperplasia; ectopic ACTH secretion (tumor). In young children (<5yrs) adrenal disorders are the most common, non- iatrogenic, cause of hypercorticolism. In neonates and infants, McAS should be considered. In older children and adolescents Cushing \200\231s disease is most common. Clinical features All causes of hypercortisolaemia are characterized by the following pat- tern of clinical signs and symptoms. \200 \200 \200 Obesity: \200\230Moon \200\231 faecies. Buffalo hump: pads. Muscle wasting. Proximal muscl e weakness. Skin abnormalities: (abdomen/thighs). Hypertension. Growth impairment: Pubertal delay/amenorrhoea. Osteoporosis. central adiposity \200\224face, trunk, abdomen. prominent/enlarged posterior cervical/supraclavicular fat \200 \200 thinning (rare in children); easy bruising; striae \200 \200 \200 reduced growth velocity; short stature. Note: Other signs may be present depending on the underlying cause. Children with adrenal t umors may have signs of abnormal virilization and masculinization (early pubic hair, hirsui tism, acne, clitoromegaly) due to excess adrenal androgen secretion. 12_McClure_12.indd 434 11/14/2012 3:27:04 PM ADRENAL EXCESS 435 Investigations These are directed at establishing a diagnosis of hypercortisolism and there after at differentiating between ACTH-dependent and ACTH- independent causes (see Box 12.4) . Box 12.4 Investigations to determine the following Is hypercortisolism present or not? \200 Serum cortisol circadian rhythm: midnight serum cortisol. \200 sampling for test to be valid Loss of normal diurnal variation \200\224rai sed midnight value observed. Note: Patients must be asleep at time of Urinary free cortisol excretion: 24hr collection Dexamethasone suppression test: \200 \200 \200 \200 overnight test (1mg dexamethasone at midnight) low dose test (0.5mg every 6hr for 48hr) fai lure of suppression of plasma cortisol levels is observed Cause of hypercortisolism \200 \200 Plasma ACTH: high in ACTH-dependent causes Dexamethasone suppression test: \200 \200 high dose test (2mg every 6hr for 48hr) in Cushing \200\231s disease serum cortisol levels decrease by approximately 50%. Ectopic ACTH secretion: no suppression. \200 \200 \200 CoRF test CT scan of adrenal glands MRI scan of brain Bilateral inferior petrosal sinus sam pling Management Cushing \200\231s disease \200 Preoperative treatment in order to normalize blood cortisol levels: \200 \200 Pituitary surgery: transsphenoidal surgery. Pituitary radiotherapy. metyrapone; ketaconazole. \200 Adrenal disease/tumor \200 Surgery, i.e. adrenalectomy. 12_McClure_12.indd 435 11/14/2012 3:27:04 PM CHAPTER 12 Endocrinology and diabetes 436 Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a family of disorder s character- ized by enzyme defects in the steroidogenic pathways that lead to the bio- syn thesis of cortisol, aldosterone, and androgens. The relative decrease in cortisol productio n, acting via the classic negative feedback loop, results in increased secretion of ACTH fr om the anterior pituitary gland and to sub- sequent hyperplasia of the adrenals. All forms of CAH are inherited in an autosomal recessive manner, and their clinical manifestation is determined by the effects produced by the particular hormones that are de \201 cient and b y the excess production of steroids unaffected by the enzymatic block. The causes of CAH include de \201 ciencies in the following steroidogenic pathway enzymes: \200 A-hydroxylase (CYP21); \200 B-hydroxylase (CYP11); 3 \200 B-hydr oxysteroid dehydrogenase; \200 A-hydroxylase/17 \200\22320 lyase (CYP17); \200 21 11 17 side-chain cleavage (SCC/StAR). De \201 ciency of the 21-hydroxylase enzyme is the most common form of CAH, accounting for over 90% of cases. 21 -hydroxylase de \201 ciency CAH due to de \201 ciency of the 21A- hydroxylase enzyme arises as a result of deletions or deleterious mutations in the active g ene (CYP21) located on chromosome 6p. Many different mutations of the CYP21 gene have been identi \201 ed, causing varying degrees of impairment of 21A-hydroxylase ac- tivity that r esult in a spectrum of disease expression. CAH can be classi \201 ed according to symptoms and signs and to age of presentation. \200 Classic CAH: with acute adrenal crisis in early infancy (usually males at 7 \200\22310 days of life), and a \200\230simple virilizing \200\231 form in which patients demonstrate mas culinization of the external genitalia (females at birth) or signs of virilization in early life in males. Non-classic (late onset) CAH: symptoms of mild androgen excess at or around the time of puberty. The incidence of CAH due to 21A-hydroxylase de \201 ciency has been reported to be in the region of 1 in 10,000 \200\22317,000 in Western Europe and the USA, w ith an overall worldwide \201 gure of approximately 1/14,000 births. includes a severe \200\230salt wasting \200\231 form that usually presents this presents in females with signs and Diagnosis \200\230Classic \200\231 CAH is diagnosed by demonstrating characteristic bioche mical abnormalities, which are present regardless of severity, age, and sex of the infant: \200 \200 \200 elevated plasma 17-hydroxyprogesterone levels; elevated plasma 21-deoxycortisol levels; inc reased urinary adrenocorticosteroid metabolites. Note: It may be dif \201 cult to distinguish elevated androgen levels from the physiologic al hormonal surge that occurs in the \201 rst 2 days of life. These tests should be postp oned or repeated after 48hr of age. 12_McClure_12.indd 436 11/14/2012 3:27:04 PM CONGENITAL ADRENAL HYPERPLASIA 437 In the \200\230salt-wasting \200\231 form, the aldosterone de \201 ciency results in hypo nat- raemia, hyperkalaemia, and metabolic acidosis. However, these are not speci \201 c \201 ndings and can cause diagnostic confusion with children present- ing with more common causes of renal tubular dysfunction, such as acute pyleonephritis. Treatment Glucocorticoid replacement therapy Required in all patients. In addition to treat ing cortisol de \201 ciency, this therapy also suppresses the ACTH-dependent excess adrena l androgen production. Standard therapy usually consists of: hydrocortisone: oral 15mg/m2/d ay in 3 or 4 divided doses. As in other disorders associated with cortisol insuf \201 ciency, during peri- ods of stre ss and illness increased amounts (e.g. double or triple dose) of glucocorticoid therapy are required. Mineralocorticoid therapy For the salt-wasting form of CAH only: \202 udrocortisone: oral 50 \200\223300mi- crograms/day. Sodium chloride therapy Resistance to mineralocorticoid therapy is usually seen in infancy. Sodium chloride supplements are often required during this period of life to main- tain no rmal electrolyte balance. Once a normal solid diet is established salt supplements may be d iscontinued. Sodium chloride solution: oral, added to feed, 2 \200\22310mmol/kg/day in divided doses. Urogenital surgery Reconstructive surgery (clitoral reduction and vaginoplasty) is usually per- formed in infancy in females with signi \201 cant virilization of the external genita lia. Long-term management and monitoring Regular monitoring of patients by a specialist team is required in order to ensure the child \200\231s optimal growth and development. 12_McClure_12.indd 437 11/14/2012 3:27:04 PM CHAPTER 12 Endocrinology and diabetes 438 Mineralocorticoid excess The principal mineralocorticoid secreted by the adrenal gland is a ldoste- rone. Increased production may result from a primary defect of the adre- nal gland (primary hyperaldosteronism) or from factors that activate the renin \200\223angiotensin sy stem (secondary hyperaldosteronism). Hypokalaemia and hypertension are typical features. Primary hyperaldosteronism Characterized by hypokalaemia and hypertension. There is suppres sion of the renin \200\223angiotensin system with low plasma renin levels. Children may hav e no symptoms, the diagnosis being established after the incidental \201 nding of hyperte nsion. Chronic hypokalaemia may result in muscle weak- ness, fatigue, and poor growth. Causes of primary hyperaldosteronism \200 \200 \200 Bilateral adrenal hyperplasia Adrenal tumors Glucocorticoid-remediable hyperaldosteronism Secondary hyperaldosteronism This occurs when excess aldosterone production is secondary to elevated renin levels. Hypertension may or may not be present. Causes of secondary hyperaldosteronism Associated with hypertension \200 \200 \200 \200 \200 \200 \200 Renovascular malformations/stenosis Primary hyperreninaemia Juxtaglomerular tumor b p.668) Wilm \200\231s tumor ( Post-renal transplantation Urinary tract obstruction Phaeochromocyto ma No hypertension \200 \200 \200 \200 \200 \200 b p.344) Hepatic cirrhosis (see Congestive cardiac failure Nephrotic syndrome (see Bartter \200\231s syndrome (see Anorexia nervosa (see Syndrome of apparent mineralocorticoid excess: type 1 and type 2 variants b p.378) b p.386) b p.594) 12_McClure_12.indd 438 11/14/2012 3:27:04 PM MINERALOCORTICOID DEFICIENCY 439 Mineralocorticoid de \201 ciency Reduced aldosterone production or activity is rare and ma y be due to congenital or acquired causes. \200 Aldosterone synthase de \201 ciency: \200 \200 Pseudohypoaldosteronism: \200 \200 Hyporeninaemic hypoaldosteronism. Hyperreninaemic hypoaldosteronism. Transient hypoaldoster onism in infancy. Congenital adrenal hyperplasia: \200 -hydroxylase (CYP17) de \201 ci ency; \200 -hydroxylase (CYP11) de \201 ciency. Congenital adrenal hypoplasia. Primary adrenocortical insuf \201 ciency. Latrogenic hypoaldosteronism. type 1; type 2. type 1; type 2. \200 \200 \200 17 11 \200 \200 12_McClure_12.indd 439 11/14/2012 3:27:04 PM CHAPTER 12 Endocrinology and diabetes 440 Inherited endocrine syndromes Multiple endocrine neoplasia This is a family of endocrine ne oplasia syndromes that are inherited in an autosomal dominant manner: \200 \200 \200 multiple endocrine neoplasia (MEN) type 1; MEN type 2; Von Hippel \200\223Lindau (VHL) synd rome. The molecular genetic defects for these syndromes have been identi \201 ed and genetic scr eening is available. Patients with these conditions require close surveillance and screenin g (biochemistry, radiology, etc.). Multiple endocrine neoplasia (MEN) type 1 The condition is characterized by the following c linical features. \200 Hyperparathyroidism (90%). Due to parathyroid hyperplasia. Usually presents in second decad e of life. Pancreatic endocrine tumors (75%). Typically multifocal, pancreatic islet cell t umors. Include insulinoma (60%); gastrinoma (30%); VIPoma (rare); glucagonoma (rare). Prese nt in adulthood. Pituitary adenomas (10 \200\22365%). Prolactinoma (60%); GH-secreting (30% ). Other features: thyroid adenoma; thymic/bronchial carcinoid tumors; lipomas. \200 Multiple endocrine neoplasia type 2 MEN type 2 belongs to a family of three syndromes (MEN type 2A; MEN type 2B; familial medullary thyroid cancer) characterized by activating mu- ta tions in the RET proto-oncogene. Medullary thyroid cancer is a common feature in all the sy ndromes. MEN type 2A \200 \200 \200 Medullary thyroid cancer (90%). Phaeochromocytoma (50%). Parathyroid ademona (25%). MEN type 2B \200 \200 \200 \200 \200 Medullary thyroid cancer (90%). Phaeochromocytoma. Mucosal/intestinal ganglioneuromas. Marf anoid body habitus. Hirschsprung \200\231s disease. Familial medullary thyroid cancer Isolated medullary thyroid cancer. von Hippel \200\223Lindau syndrome (VHL) This condition is due to a mutation in the VHL gen e. This is a tumor re- pressor gene that is located on chromosome 3. The condition is characterized by the following features: Retinal haemangioblastomas (40%): \200 Uncommon before age 10yrs. \200 Bleeding and retinal detachment. 12_McClure_12.indd 440 11/14/2012 3:27:05 PM INHERITED ENDOCRINE SYNDROMES 441 \200 \200 CNS haemangioblastomas: Phaeochromocytomas (20%): Renal cysts and carcinomas: \200 \200 Pancreatic neuroendocrine tumors: are non-functioning tumors, but may be secreting (insuli n, glucagons, VIP). Simple adenomas/cysts: \200 \200 75% occur in cerebellum. bilateral in 40%. Late feature: from 4th decade. Occur in 70% by age 60yrs. uncommon. 50% malignant. Most uncommon. Pancreas; liver; epididymis; lung. Meningioma. McCune \200\223Albright Syndrome Characterized by the following triad of clinical features: \200 Skin: \200 classically, irregular edge (so-called \200\230coast of Maine \200\231 appear ance); \200 do not cross midline. Polyostic \201 brous dysplasia: \200 \200 hyperpigmented (caf au lait) macules. slowly progressive bone lesion; any bones, although facial/base of skull bones most commonl y affected. Autonomous endocrine gland hyperfunction: \200 \200 \200 \200 \200 \200 ovary most commonly affected; precocious puberty (gonadotrophin-indepdent); thyroid (hypert hyroidism); adrenal (Cushing \200\231s syndrome); pituitary (adenoma \200\224gigantism); pa rathyroid (hyperparathyroidism). Neuro \201 bromatosis See also b pp.531, 662, 946. Two types of neuro \201 bromatosis (NF ) are recognized. Type 1 (NF-1; also known as von Recklinghausen \200\231s disease) is an a utosomal dominant condition due to a mutation of the NF-1 gene (b Chapter 25). NF-1 may be associated with endocrine abnormalities: Hypothalamic/pituitary tumors: optic g lioma (15%). GH de \201 ciency. Precocious puberty. Delayed puberty. \200 \200 \200 12_McClure_12.indd 441 11/14/2012 3:27:05 PM CHAPTER 12 Endocrinology and diabetes 442 Hypocalcaemia Most causes of low calcium (hypocalcaemia) can be explained by abnor- malitie s of vitamin D or PTH metabolism or by disordered kidney func- tion. The principal manifest ations of hypocalcaemia are related to neuro- muscular irritability and include tetany and paraesthesiae. \200 Hypocalcaemic seizures (grand-mal type) or laryngeal spasm may occur acutely. Cardiac condu ction abnormalities (prolonged QT interval, QRS and ST changes, and ventricular arrhythmias ) may be seen. Chronic hypocalcaemia may be asymptomatic. The child \200\231s age is helpful in determinin g the differential diagnosis of hypocalcaemia. Causes of hypocalcaemia Early neonatal causes \200 \200 \200 \200 Prematurity Maternal diabetes Maternal pre-eclampsia RDS Late neonatal causes \200 \200 \200 Cow \200\231s milk hyperphosphataemia Maternal hypercalcaemia Congenital hypoparathyroidism Causes in infancy \200 \200 Nutritional rickets Pseudohypoparathroidism type 1a Childhood causes \200 \200 Pseudohypoparathyroidism type 1b Hypoparathyroidism Iatrogenic causes \200 \200 Chemotherapy agents, e.g. cisplatin Anticonvulsant agents, e.g. phenytoin Investigations \200 Plasma calcium. \200 Plasma phosphate. \200 Serum PTH. failure of PTH secretion. Plasma vitamin D. Plasma magnesium. X-ray of skull. Chronic hypocalcaemia: basal ganglia calci \201 cation may be seen. Note: Low or even normal PTH concentration implies \200 \200 Treatment Acute treatment See b p.93. 12_McClure_12.indd 442 11/14/2012 3:27:05 PM HYPOCALCAEMIA 443 Chronic treatment \200 \200 Should be directed at the underlying cause. Oral calcium supplements, together with oral vi tamin D therapy in the form of calcitriol (1-A calcidiol) are often required to maintain pl asma calcium levels within the normal range. Hypoparathyroidism Low serum parathyroid hormone levels in childhood may be due to the foll owing: \200 Failure in parathyroid development (agenesis/dysgenesis): \200 \200 isolated defect: X-linked recessive; associated with other abnormalities, e.g. DiGeorge syn drome, Kearnes \200\223Sayre syndrome. Destruction of parathyroid glands: \200 \200 \200 Failure in PTH secretion: magnesium de \201 ciency. Failure in PTH action: pseudohyp oparathyrodism. autoimmune surgery (post-thyroidectomy); radiotherapy. \200\224type 1 autoimmune polyendocrinopathy; \200 Investigations \200 \200 \200 low. Plasma calcium: Plasma phosphate: Serum PTH: high. low. Pseudohypoparathyroidism (PHP) Characterized by end-organ resistance to the actions of PTH. It is a genet- A-adenylate cyclase signaling system ic disorder due to a defect in the Gs common to the PTH receptor and other endocrine receptors belonging to the G protein-recepto r family (e.g. TSH, LH, FSH). See Table 12.2. Table 12.2 Classi \201 cation of pseudohypoparathyroidism (PHP) Classi \201 cation Pathophysiology AHO* Other hormone resistance Urinary cAMP response to PTH PHP Ia GNAS1 mutation Yes Yes Decreased Pseudo PHP GNAS1 mutation Yes A-related protein No Yes No Normal PHP Ib Gs ? Receptor signal transduction No Decreased PHP Ic Yes Decreased PHP II cAMP dependent protein No No Normal AHO, Albright hereditary osteodystrophy (short stature and short metacarpels). 12_McClure_12.indd 443 11/14/2012 3:27:05 PM CHAPTER 12 Endocrinology and diabetes 444 Rickets A disorder of the growing skeleton due to inadequate mineralization of bone as it i s laid down at the epiphyseal growth plates. There is a char- acteristic widening of the en ds of long bones and characteristic radiology. Osteomalacia occurs when there is inadequate mineralization of mature bone. Both rickets and osteomalacia may be present at the same ti me. Causes Malnutrition and calcium de \201 ciency are common causes worldwide. Vitamin D de \201 ciency is rare in developed countries, although inadequate exposure to sunlight and ex clusive breastfeeding of 6 \200\22312mths during infan- cy are well recognized causes. Calcium de \201 ciency Dietary; malabsorption. Vitamin D \200 Vitamin D de \201 ciency: (drug-induced, e.g. phenytoin therapy). Defect in vitamin D meta bolism: (1A-hydroxylase de \201 ciency); liver disease; renal disease. Defect in vitamin D action: dietary; malabsorption; lack of sunlight; iatrogenic vitamin D-dependent rickets type I vitamin D-dependent rickets type II. Phosphate de \201 ciency \200 Renal tubular phosphate loss (isolated): hypophosphataemic rickets: \200 \200 \200 Ac quired hypophosphataemic rickets: \200 \200 \200 Reduced phosphate intake. b p.445); X-linked (see autosomal recessive; autosomal dominant. b pp.372, 384); Fanconi syndrome (see renal tubular acidosis; nephrotoxic drugs. Clinical features \200 \200 \200 \200 Growth delay or arrest. Bone pain and fracture. Muscle weakness. Skeletal deformities: \200 swelling of wrists; \200 swelling of costochondral junctions ( \200\230rickety rosa ry \200\231); \200 bowing of the long bones; \200 frontal cranial bossing; \200 crani otabes (softening of skull). Diagnosis \200 Laboratory (see Table 12.3): \200 \200 plasma calcium/phosphate/alkaline phosphatase/PTH; vitamin D metabolites (25-hydroxyvitamin -D3 (25 OHD)/1,25- dihydroxyvitamin-D3 (1,25 OHD)). Radiological: and fraying of metaphyses). X-ray of wrists (generalized osteopenia/widening, cupping 12_McClure_12.indd 444 11/14/2012 3:27:05 PM RICKETS 445 There are three characteristic stages in disease progression: \200 \200 Stage 1: Stage 2: hyperparathyroidism). Stage 3: low plasma calcium/normal plasma phosphate. normal plasma calcium (restored due to compensa tory low plasma calcium and phosphate \200\224advanced bone disease. Stages 1 and 2 are biochemically evident only. Stage 3 has clinical features. Table 12.3 Laboratory \201 ndings in different types of rickets Plasma Ca d Plasma PO4 d 25, OHD d 1,25 OHD d ALP i PTH i Vit. D de \201 ciency d d i n d i VDDR, type I d d i n i i n or i VDDR, type II n d i n n X-linked hypophos- phataemic d or n d i n n or i n Renal tubular acidosis Vitamin D-dependent rickets (VDDR) type I Autosomal recessive condition. Due to a de \201 ciency in renal 1A-hydroxylase, the enzyme responsible for the conversion of 25-hydroxyvita min-D3 to 1, 25 dihydroxyvitamin-D3. The condition is due to mutations in the 1A-hydroxylas e gene, P450c1A. Patients usually present with evidence of severe clinical rickets within the \201 rst 24mths of life. Treatment Requires replacement dose of 1, 25 dihydroxyvitami n-D3 (calcitriol). Vitamin D-dependent rickets type II Autosomal recessive condition. This disorder is due to mutations in the vitamin D receptor gene, leading to end-organ resistance to vitamin D. The condition is also referred to as vitamin D resistant rickets. Clinical, laboratory, and radiological features are similar to those seen in vitamin D de \201 ciency and VDDR type I. However, a striking feature observed in the majority of patien ts with VDDR-type II is sparse body hair development or total alopecia. This \201 nding i s usually present at birth or develops during the 1st year of life. Treatment with supraphysiological doses of 1, 25 dihydroxyvitamin-D3 (e.g. up to 60mcg/day of calcitriol) is often successful, although responses are highly variable. 12_McClure_12.indd 445 11/14/2012 3:27:05 PM CHAPTER 12 Endocrinology and diabetes 446 Hypercalcaemia There are a number of different causes of high plasma calcium levels: \200 \200 \200 \200 \200 \200 William \200\231s syndrome. Idiopathic infantile hypercalcaemia. Hyperparathyroidism. Hyper calcaemia of malignancy. Vitamin D intoxication. Familial hypocalciuric hypercalcaemia. Other uncommon causes include: sarcoidois and other granulomatous disease; chronic immobili zation; renal failure; hyperthyroidism; Addison \200\231s disease; iatrogenic, e.g. thiazid e diuretics. Clinical features Symptoms and signs of hypercalcaemia are non-speci \201 c. \200 GI: abdominal pain. Renal: CNS: anorexia; nausea and vomiting; failure to thrive; constipation; \200 polyuria and polydipsia. apathy; drowsiness; depression. Investigations Laboratory \200 \200 \200 \200 \200 \200 Plasma calcium (total and corrected for albumin). Serum PTH. Vitamin D metabolites. U&E/LFT s. TFT. Urinary calcium excretion (UCa:UCr ratio; 24hr UCa). Radiological Renal US scan (screen for nephrocalcinosis). Treatment Acute treatment See b p.447. Chronic treatment Directed at the underlying cause. 12_McClure_12.indd 446 11/14/2012 3:27:05 PM HYPERCALCAEMIA 447 Hyperparathyroidism Uncommon in children, excessive production of PTH may result from a pri mary defect of the parathyroid glands or may be secondary and com- pensatory to either hypo calcaemia or hyperphosphataemic states. p \200 \200 \200 hyperparathyroidism: parathyroid adenoma; parathyroid hyperplasia: MEN type 1; MEN type 2; neonatal severe form. hyperparathyroidism: hypocalcaemic states hyperphosphatemia s \200 \200 \200 Transient neonatal hyperparathyroidism: m \200\224rickets; \200\224chronic renal failure. aternal hypoparathyroidism. Primary hyperparathyroidism Rare in children. In the neonatal period it usually associated with general- ized parathyroid hyperplasia. In older children it is usually due to a para- thyroid adenoma and most often associated with MEN type 1. Transient neonatal hyperparathyroidism Observed in neonates born to mother with previously undetected and/ or untreated hypoparathyroidism or pseudohypoparathyroidism. Chronic intrau terine hypocalcaemia results in hyperplasia of the fetal parathyroid glands. Neonatal severe hyperparathyroidism See Familial hypocalciuric hyper- calcaemia. Hypercalcaemia of malignancy Rarely, in children with endocrine tumors (e.g. phaeochromocyt oma) or other tumors (e.g. lymphoma), production of humoral factors such as PTH-related pep tide (PTHrP) results in hypercalcaemia. Treatment requires resection and removal of the tumor to reverse the hypercalcaemic state. Interim control can be achieved with a single IV infusion of a bisphosphonate agent, e.g. p amidronate. The latter enhances calcium bone resorption. Familial hypocalciuric hypercalcaemia Autosomal dominant disorder caused by a mutation of t he calcium-sensing receptor (CaSR) gene. This is a benign, mostly asymptomatic disorder, wh ich is often an incidental \201 nding during routine biochemistry analysis. Plasma calciu m levels are raised (but usually <3mmol/L), and urinary calci- um excretion is low. PTH lev els are inappropriately normal for the degree of hypercalcaemia. Note: Those homozygous for the mutation have severe, life-threatening primary hyperparathyr oidism at birth. This form of neonatal severe hyper- parathyroidism requires immediate para thyroid surgery. 12_McClure_12.indd 447 11/14/2012 3:27:05 PM CHAPTER 12 Endocrinology and diabetes 448 Posterior pituitary: syndrome of inappropriate antidiuretic hormone secretion Heterogeneous disorder characterized by hypotonic hyponatraemia and impaired urinary dilution that canno t be accounted for by a recognized stimulus to ADH secretion. Plasma ADH is elevated or ina dequately sup- pressed. Several different types of pathogenic mechanisms are likely to be r esponsible for this. There are many causes of SIADH (Box 12.5). Box 12.5 Causes of SIADH \200 \200 Congenital: Acquired: \200 CNS \200\224 \200 Tumors \200\224 \200 Infection \200\224 \200 Neurological \200\224 \200 Respiratory \200\224 \200 Drugs \200\224 agenesis of corpus callosum traumatic brain injury, cerebrovascular bleeding brain, lung, thymus pneumonia, meningitis, encephalitis, TB Guillain \200\223Barr syndrome asthma, pneumothorax vincristine, cyclophosphamide Up to 15% of children presenting with brain trauma or infection develop SIADH. Clinical fea tures include development of: confusion; headache; lethargy; seizures and coma. Symptoms do not necessarily depend on the concentration of serum sodium, but on its rate of development. Slow, gradual development of hyponatraemia may be asymptomatic. SIADH diagnostic criteria \200 \200 \200 \200 \200 \200 + <135mmol/L) Hyponatraemia (serum Na Hypotonic plasma (osmolality <270mOsm/kg) Excessive renal sodium lo ss (>20mmol/L) No hypovolaemia or \202 uid overload Normal renal, adrenal, and thyroid fu nction Increased plasma ADH Management Treatment of the underlying cause is necessary. Fluid restriction is the mainsta y of therapy. \200 Hypertonic (3%) saline solution may be used to correct severe hyponatraemia, or hyponatraem ia resistant to \202 uid restriction. Slow correction of hyponatraemia is essential to av oid rapid overcorrection with possible complication of central pontine demyelination. Longe r-term management/treatment with demeclocycline may be effective for \202 uid balance by inducing nephrogenic DI. 12_McClure_12.indd 448 11/14/2012 3:27:05 PM HYPOPITUITARISM 449 Hypopituitarism Hypopituitarism refers to either partial or complete de \201 ciency of the an- terior and/or posterior pituitary function. Hypopituitarism may be congen- ital or acq uired, secondary to pituitary disease or to hypothalamic pathol- ogy that interferes with p ituitary function. Clinical features depend on the type of hormone de \201 ciency, its sev erity, and rate of development. Congenital hypopituitarism Mutations in pituitary transcription factor genes (e.g. HESX-1, PIT-1, LHX-4) can result in isolated or multiple anterior pituitary hormone de \201 cienci es. A number of speci \201 c inherited genetic defects have been characterized. Abnormalities in the hypothalamic \200\223pituitary structures and other midline brain structures (e.g. s epto-optic dysplasia; optic nerve hypoplasia; absent corpus callosum) are often detected on imaging. Acquired hypopituitarism Potential causes of pituitary hormone de \201 ciency include the following: \200 \200 Intracranial (parapituitary) tumors. Cranial irradiation/radiotherapy: radiation damage, fo llowed by gonadotrophin, and adrenal axes, and \201 nally by thyroid axis. Traumatic brai n injury. In \202 ammatory/in \201 ltrative disease: sarcoidosis. Pituitary infarction (a poplexy). Intracranial infection. GH axis is the most sensitive to \200 Langerhan \200\231s cell histiocytosis; \200 Investigations \200 Basal hormone levels: IGF-I. Dynamic endocrine testing: the anterior pituitary gland. brain . MRI scan: e.g. LH/FSH; TSH, fT4; prolactin; cortisol (9 a.m.); speci \201 c tests to assess secretory capacity of Treatment involves adequate and appropriate hormone replacement therapy and, where applicab le, management of underlying cause. 12_McClure_12.indd 449 11/14/2012 3:27:05 PM CHAPTER 12 Endocrinology and diabetes 450 Posterior pituitary: diabetes insipidus The posterior pituitary gland secretes two hormones , arginine vasopressin (AVP) and oxytocin. Diabetes insipidus (DI) is de \201 ned as the inappropriate passage of large volumes of di lute urine (<300mOsm/L). Due to either de \201 ciency in AVP production (cranial DI) or re sistance to its actions at the kidney (neph- rogenic DI). The most common cause of DI is pr imary de \201 ciency of AVP production (i.e. cranial DI). This may be acquired or inherite d in origin. Classi \201 cation of diabetes insipidus Cranial DI Inherited/familial \200 Autosomal dominant \200 Autosomal recessive \200 X -linked recessive (Xq28) \200 Wolfram syndrome (4p WFS1) Congenital \200 Midline cranio facial defects \200 Holoprosencephaly Acquired \200 Intracranial tumors \200 Cranioph aryngioma \200 Germinoma Primary polydipsia \200 Psychogenic \200 Dipsogenic (abnormal thirst) Nephrogenic DI Inherited/familial \200 Autosomal dominant: Aquaporin-2 gene \200 Autoso mal recessive: Aquaporin-2 gene \200 X-linked recessive: ADH receptor-2 gene Acquired \200 Idiopathic \200 Drugs (lithium; cisplatin) \200 Metabolic (hypercalcaemia) Traumatic brain injury \200 In \201 ltrative/in \202 ammation: Langerhan \200\231s cell histiocytosis \200 CNS infection Children present with polydipsia, polyuria, and nocturia, which must be distinguished from more common causes. Infants may exhibit failure to thrive, fever, and constipation. Other s ymptoms may be related to the underlying cause, e.g. headache, visual acuity/visual \201 eld impairment. Diagnosis When suspected, assessment of 24hr urinary volume and osmolality under conditions of ad libitum \202 uid intake should be undertaken. Serum osmolali- ty, U&E (Na+), and b lood glucose should also be measured. Blood hypertonicity (serum osmolality >300mOsm) with inappropriate urine hypotonicity (urin e osmolality <300mOsm) should be demonstrated. Diabetes mellitus and renal failure should b e excluded. A water deprivation test (see Box 12.6) and assessment of responses to exogenously administ ered ADH is required to diagnose the type of DI. Other tests to determine the underlying ca use of DI will also be needed (e.g. cranial MRI imaging). 12_McClure_12.indd 450 11/14/2012 3:27:05 PM POSTERIOR PITUITARY: DIABETES INSIPIDUS 451 Box 12.6 Water deprivation test Should be carried out in conditions of strict monitoring and in centers with experience wit h this test: \200 Allow \202 uids overnight. If primary polydipsia is suspected consider overnight \202 u id deprivation to avoid over hydration Commence \202 uid deprivation at 8 a.m. Serum osmo lality, serum Na sample voided Duration of water deprivation is seldom longer than 8 \200 \22312hr in children and 6 \200\2238hr in young infants. In any case, the water deprivation is terminated if there is either: \200 \200 \200 Serum osmolality: In those with ina dequate urinary concentration, desmopressin is administered: DDAVP 0.1mg/kg to maximum of 4 mg IM Interpretation of results: see table that follows \200 +, urine osmolalitiy. Each time urine \211 800mOsm/kg or urine osmolality concentrated: thirst becomes intolerable 5% dehydration (5% weight loss) or or \200 \211 300mOsm/L. Urine osmolality (mOsm/kg) After \202 uid deprivation After DDAVP Cranial DI (CDI) <300 >800 Nephrogenic <300 <300 Primary polydipsia >800 >800 Partial CDI/polydipsia >00 \200\223800 <800 Treatment Cranial DI Synthetic analog of ADH, DDAVP, which has a longer dura- tion of actio n, can be given intranasal or oral. Dose required varies con- siderably and must be titrate d for each patient. The dose and frequency of administration (1 \200\2233 times a day) is a djusted to maintain 24hr urine output volume within the normal range. Water retention shoul d be avoided. It is essential to educate all patients and families about the hazards of ex- cessive water intake. Patients with an intact thirst sensation mechanism should achieve th is. Nephrogenic DI Correction of underlying metabolic or iatrogenic causes, if possible. Mainte nance of an adequate \202 uid input is essential. Thiazide diuretics (e.g. hydrochlorthia zide), amiloride, and prostaglandin synthase inhibitors (e.g. indomethacin) can be effectiv e. Primary polydipsia Treatment is often dif \201 cult. Behavior modi \201 cation strategies usually required. 12_McClure_12.indd 451 11/14/2012 3:27:05 PM CHAPTER 12 Endocrinology and diabetes 452 Polycystic ovarian syndrome Polycystic ovarian syndrome (PCOS) is a common (5 to 10%) heter oge- neous condition, affecting females of reproductive age that is increasingly identi \201 ed in the adolescent population. It is a life-long condition charac- terised by chroni c anovulation, disordered gonadotrophin release, ovarian and adrenal hyperandrogenism, and insulin resistance. The pathogenesis of PCOS is uncertain, however, both genetic and envi- ronmental factors ar e thought to play a role. Risk factors include low birth weight for gestational age, premat ure adrenarche, atypical early pubertal development and obesity. A family history of PCOS i s often observed. The current diagnostic criteria for PCOS are de \201 ned as the presence of any two of the following three features: \200 \200 Oligo-and/or anovulation. Clinical or biochemical evidence of hyperandrogenism, provided ot her aetiologies of androgen excess (e.g. congenital adrenal hyperplasia, androgen-secreting tumors, Cushing \200\231s syndrome) have been excluded. Polycystic ovaries on US scan (i.e . the presence of 12 or more follicles in each ovary, measuring 2 \200\2239mm in diameter, and/or increased ovarian volume (>10mL)). The clinical and biochemical features of the syndrome are variable and the combination and degree of expression of these features vary between individuals. Typical signs and symptoms develop during or after puberty and may include any of the following: \200 \200 \200 \200 \200 oligo/amenorrhea; hirsuitism; acne; obesity; acanthosis nigricans. Laboratory \201 nding include: \200 Elevated androgen concentrations (e.g. testosterone; dehydroepiandrosterone sulfate (DHEAS) ). Elevated plasma LH:FSH ratio. Decreased sex hormone binding globulin (SHBG) concentratio ns. Hyperinsulinaemia (fasting, oral glucose tolerance test (OGTT), IVGT samples). Decrease d IGFBP-1 concentrations. \200 \200 PCOS is recognized to have important long-term health implications and is particularly asso ciated with a range of abnormalities that are characteris- tic of the metabolic syndrome. T hese include hyperinsulinaemia, impaired pancreatic -cell function, the development of ob esity, hyperlipidaemia, and an increased risk of T2DM and cardiovascular disease in later l ife. In addition, chronic anovulation is thought to carry an increased risk of endometrial cancer. 12_McClure_12.indd 452 11/14/2012 3:27:05 PM POLYCYSTIC OVARIAN SYNDROME 453 Treatment of PCOS is symptomatic and is directed at the presenting clinical problems. Lifes tyle modi \201 cations are an important \201 rst-line inter- vention particularly when o besity is evident. Other treatment approaches include the use of the following drugs: \200 \200 Metformin (insulin sensitizer). Combined oral contraceptive pill (suppress ovarian hyperand orgenism). Spironolactone (anti-androgen). Cyproterone acetate (synthetic progesterone \200 \224anti-androgen). Flutamide (anti-androgen).