Endocrinology Flashcards

Question

Actions of growth hormone?

Answer 1

Think burns fat, builds muscle: Metabolic effects (GH mediated) Cartilage and bone growth (IGF-1 mediated)

Answer 2

Constantly secreted UNLESS is inhibited by dopamine - therefore any disruption in the hypothalamus or pituitary leads to elevated prolactin levels

Answer 3

Central: many hormones from hypothalamus such as TRH, GnRH, VIP Peripheral: breastfeeding, stress and sleep

Answer 4

Initiation and maintenance of lactation Stimulates development of milk-secretory apparatus Note: oestrogen and progesterone inhibit lactation during pregnancy

Answer 5

Receptor binding activates cAMP and G protein second messenger system

Answer 6

TRH Cold (increases body temperature by increasing metabolic rate) Stress (SNS activation) Circadian rhythm (max 12am and 4am) Caloric intake

Answer 7

Thyrosine (negative feedback) Dopamine Somatostatin and glucocorticoids

Answer 8

Stimulates iodine pump Production of thyroglobulin Tyrosine iodination Hypertrophy of follicular cells Hyperplasia of follicular cells

Answer 9

Synthesised as POMC, broken down into lipotropin, MSH, beta endorphin and ACTH Secreted in diurnal pattern - cortisol levels highest when waking, low in late afternoon/evening, reach nadir 1-2 hours after sleep

Answer 10

CRH Vasopressin Oxytocin Angiotensin II CCK

Answer 11

ANP Opioids Cortisol

Answer 12

Adrenal cortex: cortisol synthesis and secretion

Answer 13

FSH - receptors on ovarian granuloma cells and Sertoli cells, stimulate follicular development and gametogenesis, FSH decreased by inhibin LH - promotes luteinisation of ovary and Leydig cell function, LH decreased by androgens/oestrogens

Answer 14

Testosterone from Leydig cells (LH) Inhibin from Sertoli cells (FSH)

Answer 15

1. Follicular phase of cycle - oestrogen from thecal/granulose cells inhibits FSH, inhibin from follicles inhibits LH 2. Ovulation - oestrogen provides positive feedback to stimulate LH and FSH release 3. Luteal phase - oestrogen, progesterone, inhibin from CL provide negative feedback for FSH/LH

Answer 16

V1 receptors: - arterial smooth muscle vasoconstriction and hepatic glycogenolysis - actions at corticotrophin to increase ACTH secretion V2 receptors: - increase water reabsorption via aquaporins in kidneys (located in collecting tubule, thick ascending LOH and periglomerular tubules) Other - mediates vWF and tPA

Answer 17

1. Increase in plasma osmolality (detected by osmoreceptors in hypothalamus) 2. Decrease in blood volume (detected by carotid arch baroreceptors) 3. Other - pain, stress, hyperthermia

Answer 18

1. ANP - produced by cardiac atrial muscles stimulates Na secretion/inhibition of Na reabsorption 2. Other - ethanol, alpha agonists, caffeine

Answer 19

Craniopharyngioma Can be caused by any lesion damaging the hypothalamus or pituitary

Answer 20

1. Abnormality of GH receptor 2. Abnormality of STAT5b gene 3. Severe GH deficiency in patients with antibodies to GH

Answer 21

GH, TSH, LH, ACTH

Answer 22

Mechanism: role in turning on POUF1 expression Anterior pituitary hormones not usually evident in neonatal period Median age at GH deficiency diagnosis is 6 years

Answer 23

GH, prolactin, TSH (variable)

Answer 24

Nuclear protein that binds to GH and prolactin promotors, necessary for function of somatotropes, lactotropes and thyrotropes Present with severe growth failure in first year of life With normal LH and FSH - puberty normal

Answer 25

HESX1 mutation - majority of patients with septo-optic dysplasia do not have HESX1 mutations

Answer 26

Condition combining incomplete development of the septum pellucid with optic nerve hypoplasia and other midline abnormalities Heterozygotes for loss of function mutations can lead to isolated GH deficiency and optic nerve hypoplasia, if homozygotic can have septo-optic dysplasia

Answer 27

Nystagmus and visual impairment in infancy May have GH deficiency

Answer 28

Phenotype resembles PROP1 mutation Deficiency in GH, prolactin, TSH, LH, FSH (not ACTH)

Answer 29

Can occur as an isolated phenomena or in association with other developmental abnormalities (anencephaly, holoprosencephaly) Associated with mid facial anomalies or a solitary maxillary central incisor Many genes implicated

Answer 30

High likelihood of GH or other anterior or posterior hormone deficiency

Answer 31

Growth hormone axis Common causes - radiotherapy, meningitis, histiocytosis, trauma

Answer 32

Failure to produce GH GH1 gene is one of a cluster of 5 genes on chromosome 17q22-24 Phenotype identical irrespective of whether GH1 alone lost or adjacent genes Most children respond well to recombinant GH

Answer 33

Optic nerve hypoplasia (from mild CNVI palsy to blindness) Midline defects (corpus callous, septum pellucid) Pituitary hypoplasia

Answer 34

HESX1 OTX2 SOX2 However: cases are usually sporadic, genetic cause found in <1%

Answer 35

Primary polydipsia (increased water intake) Osmotic diuresis Urinary tract cause (UTI, RTA) Post-obstructive diuresis Diabetes insipidus

Answer 36

Results from vasopressin deficiency (central) or insensitivity at the level of the kidney (nephrogenic)

Answer 37

Serum osmolality >300 mOsm/kg Urine osmolality <300 mOsm/kg

Answer 38

1. X linked - inactivating mutation of V2 receptor (most common) 2. AR - defects in aquaporin 2 gene 3. AD - processing mutation of aquaporin 2 gene

Answer 39

1. Hypercalcaemia/hypokalaemia - interferes with Na/Cl reabsorption which affects ADH's ability to increasing collecting tubule water permeability 2. Drugs - lithium, clozapine, rifampicin, amphotericin 3. Renal disease - obstruction, PCKD, Sjogren's

Answer 40

High-normal plasma sodium (>142) with urine osmolality lower than serum = DI

Answer 41

1. Rehydration (if Na >150, rehydration over 48 hours) 2. DDAVP (desmopressin): if Na >145 and specific gravity <1.005 and UO >4ml/kg/hr for 6 hours 3. Strict fluid balance 4. Regular monitoring of EUC

Answer 42

Involves water restriction followed by administration of DDAVP Not necessary if paired urine/serum/osmolality has made diagnosis

Answer 43

Increase in plasma osmolality -> ADH secretion -> increase in urine osmolality as more water is absorbed i.e. with synthetic ADH administration and limitation of water, would expect urine to become more concentrated

Answer 44

Water deprivation: serum osmolality will increase quickly as urine will not concentrate adequately DDAVP: will increase urine osmolality

Answer 45

Water deprivation: sub maximal rise in urine osmolality depending on whether there is partial vs complete resistance DDAVP: no effect in complete nephrogenic DI, small rise in partial DI

Answer 46

Central DI - will achieve urine osmolality >300 with water restriction Nephrogenic - persistently dilute urine that rises but remains suboptimal despite DDAVP

Answer 47

1. urine osmolality >600 (adequate concentrating by secretion/effect of ADH) 2. plasma osmolality >300 or plasma sodium >145 (inadequate response of ADH to water deprivation) 3. Urine specific gravity >1.02 4. 5% loss of body weight 5. Reaches time limit for study

Answer 48

Central DI - reduced UO Nephrogenic DI - no response

Answer 49

Usually present in first week, but may not become apparent until after weaning/with longer periods of night time sleep Many present with fever, vomiting, dehydration FTT may be secondary to large amounts of water loss, resulting in calorie malnutrition Can develop non-obstructive hydronephrosis, hyroureter and megabladder secondary to long term ingestion/excretion of large volumes of water

Answer 50

Congenital X linked NDI = vasopressin 2 mutation Congenital AR NDI = aquaporin 2 gene mutation AD NDI = processing mutation of aquaporin 2

Answer 51

Excess/inappropriate ADH secretion - usually excessive water intake = suppression of ADH release Too much ADH results in retaining water

Answer 52

Blood: - hyponatraemia +/- hypokalaemia - osmolality low, uric acid low Urine: - output normal or low - urine osmolality is inappropriately concentrated (>100mOsm/kg) - urine sodium is high (>40) Paired urine and blood shows elevated urinary vs plasma sodium and osmolality

Answer 53

Fluid restriction, fluid balance and daily weight High salt intake Monitor electrolytes 3% saline may be required + loop diuretic Demeclocycline (can inhibit ADH action at kidney)

Answer 54

Susceptibility noted with allele variation in HLA class II region on chromosome 6 Strong association with HLA DR3-DQ2 and DR4-DQ8 Monozygotic twins have a concordance rate of 30-65%, dizygotic twins have a concordance of 6-10%

Answer 55

HbA1c >6.5% Fasting glucose >12 OGTT reading >20 Random glucose >20 with symptoms of hyperglycaemia

Answer 56

Autoimmune pathology: destruction of pancreatic insulin-producing beta cells in islets of Langerhans, leads to progressive loss of insulin production and consequential hyperglycaemia

Answer 57

Age <2 Ethnic minority Lower SES Lower BMI

Answer 58

Celiac disease (10%) Autoimmune hypothyroidism Vitiligo Autoimmune adrenalitis Pernicious anaemia

Answer 59

Hyperglycaemia and dehydration: sunken eyes, dry mucous membranes Ketoacidosis: - neurological symptoms (lethargy and confusion) - GI symptoms (nausea, emesis, abdominal pain) - tachypnoea, with severe cases developing Kussmaul breathing

Answer 60

Hyperglycaemia (BSL >20) Metabolic acidosis (pH <7.3 or bicarb <15) Ketosis: positive in blood or urine

Answer 61

Patients are often total body potassium deplete on presentation, and with administration of insulin and the correction of acidosis will shift potassium intracellularly

Answer 62

Altered mental status Abnormal response to pain Decorticate or decerebrate posture Cranial nerve palsy Persistent bradycardia Abnormal neurogenic breathing

Answer 63

Same as for intracranial hypertension: Hyperosmolar therapy with mannitol or 3% hypertonic saline

Answer 64

Rare but significant complication of DKA Usually occurs 4-12 hours after starting treatment for DKA Can lead to mortality or permanent neurological impairments

Answer 65

Impairment of insulin secretion and insulin resistance, leading to hyperglycaemia

Answer 66

Genetics Environmental factors Obesity Females Ethnic minority groups

Answer 67

1. Symptomatic (subacute polyuria and polydipsia, weight loss) 2. DKA 3. Asymptomatic (incidental finding)

Answer 68

Microvascular and macrovascular disease Nephropathy - monitor for microalbuminuria with albumin:creatinine ratio in urine (positive if ratio 30-299), screen from 10 years of age Retinopathy - screen from 10 years of age Lipid screening from 10 years of age

Answer 69

Severe complication of T2DM characterised by severe hyperglycaemia, hyperosmolarity (serum osmolality >330) and dehydration, but no ketonuria or acidosis

Answer 70

The decreased activity of insulin leads to hyperglycaemia and increased renal osmotic diuresis with sodium, glucose and potassium loss, hypernatraemia occurs along with dehydration

Answer 71

Glucose production

Answer 72

Glycogen breakdown

Answer 73

1. Decreased insulin secretion 2. Glucagon and epinephrine are secreted, stimulating the liver to undergo glycolysis (breakdown glycogen to glucose) 3. By 24-48 hours, gluconeogenesis occurs to make an endogenous glucose supply form amino acids, lactate and fats 4. With prolonged starvation, the body breaks down fatty acids to produce ketone bodies to be used as alternative fuel sources

Answer 74

SGA Prematurity IUGR Perinatal stress (birth asphyxia, pre-eclampsia, sepsis) Polycythemia (more RBCs means more glucose utilised) Infant of a diabetic mother Maternal drug exposure

Answer 75

Genetic mutations involving enzymes and transport channels in the insulin secretion pathway (e.g. ABCC8, KCNJ11) Usually AR inheritance Most common cause of persistent hypoglycaemia in infants

Answer 76

Decreased mobilisation of precursors for gluconeogenesis (amino acids and fatty acids) or an imbalance of suppression of glucose utilisation by ketone bodies and limited rate of glucose production in the liver

Answer 77

Fasting hypoglycaemia 9typically during illnesses) at 2-5 years of age Diagnosis of exclusion Usually spontaneously remits by 10 years

Answer 78

Elevated GH, cortisol, free fatty acids, ketones Decreased insulin level Normal carnitine, lactate and pyruvate No response to glucagon

Answer 79

Prevention of hypoglycaemia with a high protein and high carbohydrate diet, and home monitoring for urinary ketones

Answer 80

Bipotential gonad initially If SRY gene present (sex determining region on Y chromosome), the fetal gonad develops into a testis If no SRY gene present, the ovary spontaneously develops

Answer 81

- Leydig cells secrete testosterone, stimulates development of wolffish ducts and is converted by 5a-reductase into dihydrotestosterone (DHT) - DHT leads to external virilisation (formation of scrotum, penis and enlargement of the phallus) - Sertoli cells secrete Mullerian-inhibitory substance (MIS) which leads to regression and disappearance of the mullerian ducts - testosterone promotes wolffish ducts to develop into vas deferent, seminiferous tubules and prostate

Answer 82

Breast development

Answer 83

Pubic hair, oily hair and skin, axillary hair and body odour Results from adrenal maturation

Answer 84

Maturation of the hypothalamic-pituitary axis leading to increased secretion of gonadal sex steroids M: testosterone from testes F: Oestradiol and progesterone from the ovaries

Answer 85

GnRH is secreted into the pituitary portal system Stimulates release of LH and FSH GnRH is released in episodic pulses that ensure that LH and FSH are also released in a pulsatile manner

Answer 86

M: LH stimulates testosterone production from Leydig cells, FSH stimulates the development of the seminiferous tubules F: FSH stimulates ovarian production of oestrogen

Answer 87

Dehydroepiandrosterone (DHEA) or androstenedione

Answer 88

Secondary sexual development occurring before the age of 9 years in boys, and 8 years in girls

Answer 89

Isolated breast development, usually benign Can regress over time Associated with higher baseline FSH Need monitoring as 10% can develop sexual precocity

Answer 90

Caused by elevated adrenal androgens causing pubic or axillary hair growth NO breast development Bone age often mildly advanced Androgens in early pubertal range Usually normal onset of gonadarche and normal adult final height

Answer 91

Results from gonadarche initiated by premature activation of the hypothalamic-pituitary-gonadal (HPG) axis, i.e. GnRH dependent Usual process occurs but is too early Tall stature, advanced bone age, increase sex steroid production, and pulsatile gonadotropin secretion

Answer 92

Results from gonadarche or adrenarche that does not involve the HPG axis, i.e. GnRH independent

Answer 93

McCune-Albright syndrome

Answer 94

Polyostotic fibrous dysplasia (FD) - most common feature Precocious gonadarche - results from ovarian hyperfunctioning and erratic oestrogen secretion Hyperpigmented macule (cafe-au-lait spots)

Answer 95

Hyperfunctioning endocrinopathy: - hyperthyroidism - hyperadrenalism (Cushing syndrome) - acromegaly - renal phosphate wasting

Answer 96

Results from mutation in the G protein intracellular signalling system and leads to constitutive activation of adenylate cyclase and of c-AMP

Answer 97

Irregular vaginal bleeding Recurrent ovarian cysts

Answer 98

Constitutive activation of an LH receptor that leads to continuous production and secretion of testosterone Also known as "testotoxicosis"

Answer 99

Determine if sex steroid levels are in pubertal range (estradiol, testosterone, DHEAS or androstenedione) FSH and LH - if these are elevated, suggests central precocious puberty. LH >0.3 is diagnostic for CPP

Answer 100

Done if FSH/LH are low (as this is difficult to interpret due to pulsatile secretion) Dose of GnRH is given and then FSH/LH checked FSH is dominant during prepuberty, LH is dominant during puberty Stimulated LH >5 is diagnostic for CPP

Answer 101

Isolated gonadotropin deficiency with disorder of olfaction Mutations of KAL1 genes of X chromosome Mutation causes GnRH neurons to remain in primitive nasal area, and prevent migration to the hypothalamus

Answer 102

Elevated gonadotropins and low sex steroid levels due to primary gonadal failure

Answer 103

No spontaneous entry into gonadarche (may be some degree of adrenarche) Result in eunuchoid proportions in adulthood (normal growth/size in childhood)

Answer 104

Elevated gonadotropins (LH, FSH) In Turner: gonadal dysgenesis is the common cause of ovarian failure and short stature Risk of ovarian failure following chemo/radiotherapy Autoimmune ovarian failure is less common but can occur

Answer 105

Most common cause of testicular failure Due to seminiferous tubule dysgenesis Testosterone level may be close to normal because Leydig cell function may be retained Seminiferous tubules are lost and lead to infertility LH levels are normal/elevated, FSH levels are characteristically high

Answer 106

Lack of menarche by 15 years of age - in the case of normal secondary sexual characteristics development, an anatomical variation should be considered (imperforate hymen, vaginal septum etc)

Answer 107

Congenital absence of the uterus

Answer 108

Strikingly elevated LH and FSH (trying to stimulate the failing gonads)

Answer 109

Serum gonadotropins (determine if patient has hypo or hypergonadotropic hypogonadism) Key tests include LH, FSH and total testosterone/oestradiol Delayed puberty: testosterone <40 (if testosterone >50, puberty is under way) LH >0.3 and oestradiol concentration greater than 20 suggest puberty onset If both constitutional delay in growth AND hypogonadotropic hypogonadism, may need GnRH or hCG stimulation test

Answer 110

Masculinisation of external genitalia of genotypic females is usually due to the presence of excessive androgens during the critical period of development (8-13 weeks of gestation) The degree can range from mild cliteromegaly to the appearance of a male phallus with penile urethra and fused scrotum CAH is the most common cause of female ambiguous genitalia

Answer 111

Due to enzyme deficiency that impairs glucocorticoids but does not affect androgen production Impairment in cortisol secretion leads to ACTH hyper secretion that induces hyperplasia of the adrenal cortex

Answer 112

Refers to underdevelopment of male external genitalia due to relative deficiency of testosterone production or action Small penis with various degrees of hypospadias as well as bilateral or unilateral cryptorchidism Testes should be palpable or able to find with ultrasound

Answer 113

1. Disorders of gonadal development - if MIS is reduced, a rudimentary uterus or fallopian tubes may be present 2. Disorders of androgen biosynthesis 3. Defects in the androgen action - complete androgen insensitivity syndrome is the most dramatic example - 5 alpha reductase deficiency (presents with female phenotype or ambiguous genitalia due to inability to convert testosterone to DHT which is critical in the development of male genitalia)

Answer 114

21-hydroxylase deficiency - results in significantly elevated 17-OH progesterone

Answer 115

M: released from Sertoli cells, low levels indicate testicular dysfunction and high levels can suggest CAIS F: released from granuloma cells and are a marker for ovarian reserve

Answer 116

Refers to insensitivity to androgens, and the most common cause of disorders of sexual differentiation X linked disorders, due to defects in the androgen receptor gene

Answer 117

Wide clinical spectrum ranging from complete phenotypic females, to males with various forms of atypical genitalia to males with normal genitalia but are infertile All have testes and normal/elevated testosterone levels (phenotype depends on degree of androgen insensitivity)

Answer 118

Infant is phenotypically female at birth Genital and somatic end organs do not respond to androgens in the foetus or at puberty External genitalia are female, vagina ends in blind pouch, there is no uterus +/- Fallopian tubes Testes are intra-abdominal At puberty: testosterone initiates feminisation of the body leading to breast development, but no menses and no pubic/axillary hair development

Answer 119

Due to a gene mutation that encodes for defective but partially functional androgen receptor Variable clinical spectrum: female appearance to those with ambiguous genitalia, or predominantly male phenotype Can present with micropenis, perineal hypospadias and cryptorchidism

Answer 120

Neoplasms - Leydig cell tumours secrete oestradiol, hCG-secreting tumours stimulate the testes to preferentially secrete oestradiol) Hyperthyroidism CAH Chronic liver/renal disease Obesity Medications

Answer 121

M: rapid increase in muscle strength and mass, gynaecomastia, acne, small testes, low sperm density F: irregular periods, hirsutism, acne, breast atrophy, temporal hair recession, deepening voice, cliteromegaly, increased muscle mass, decreased body fat May see high haemltocrit, low serum LH, and low sex hormone binding globulin

Answer 122

Brain remodelling in adolescents Premature growth plate closure, with reduced final adult height

Answer 123

Birth weight regained by day 10-14 of life Birth weight doubles by 4 months Birth weight triples by 12 months (approx 10kg)

Answer 124

Child with short parents, who is expected to reach lower than average height Bone age is equivalent to chronological age

Answer 125

Caused by delay in physiologic development A child who starts puberty later than others usually history of a family member with delayed puberty but achieved a normal final height Bone age DELAYED compared with chronological age Normal examination

Answer 126

Height >2SDs below the mean for age, sex and population No systemic, endocrine, nutritional or chromosomal abnormality Normal birth weight and GH sufficient Diagnosis of exclusion

Answer 127

GH resistance/insensitivity - rare cause of growth failure Occurs due to abnormal function or number of GH receptors

Answer 128

Infants with congenital GH deficiency are normal/near normal size at birth, growth slows after birth (more noticeable by 2-3 years, develop increased weight to height ratio) Usually normal intellect, unless severe hypoglycaemia or midline defect of the head

Answer 129

Short stature "Cherub" appearance: chubby, immature looking May have craniofacial midline abnormalities (think of single central incisor) Other features - hypoglycaemia, prolonged jaundice, microphallus, head trauma/CNS infection, cranial irradiation, family history of GH deficiency, other pituitary hormone deficiency

Answer 130

Turner syndrome Down syndrome Russell-Silver dwarfism Achondroplasia / hypochondroplasia / chondrodystrophy

Answer 131

Growth hormone deficiency Chronic renal failure with short stature Turner syndrome Noonan syndrome SHOX deficiency Prader-Willi syndrome Small for gestational age Idiopathic short stature

Answer 132

Used to determine adequacy of GH secretion Patients are given clonidine, arginine etc to induce GH secretion, measured every 30 minutes for 2 hours A peak serum GH greater than 7-10 is considered adequate Classic GH deficiency: no increase after stimulation

Answer 133

Oedema, joint pain, local bruising Worsening scoliosis Insulin resistance OSA due to tonsillar hyperplasia in Prader-Willi Long term cancer risk Rare - pseudotumour cerebri, SUFE, gynaecomastia

Answer 134

Active malignancy

Answer 135

Growth hormone excess Thyrotoxicosis Excess androgen hormones (CAH or virilising tumours) Sexual precocity

Answer 136

Obesity Marfan syndrome Homocystinuria Total lipodystrophy Neurofibromatosis Chromosomal abnormalities (Klinefelter)

Answer 137

Raised ICP (headaches) and pituitary dysfunction (usually as growth failure)

Answer 138

Overgrowth and hyperpituitarism

Answer 139

PTH and vitamin D - increase Ca Calcitonin - decreases Ca

Answer 140

Only 20-30% absorbed (poorly absorbed) 99% of calcium is in bone 1% in serum

Answer 141

50% ionised = physiologically active 40% bound = 80% to albumin, 20% to globulin 10% complex

Answer 142

Plasma pH - alkalosis encourages binding of calcium as more anionic sites (decreases ionised calcium)

Answer 143

10% excreted in urine, usually 99% reabsorbed - 90% at proximal tubule, loop of Henle and early distal tubules Final 10% reabsorbed in late tubules/CT (dependent on Ca ion concentration)

Answer 144

Loop diuretics - increase excretion of Na and Ca Thiazide diuretics - increase excretion of Na, but increase Ca reabsorption Acidosis - increases Ca excretion (alkalosis decreases Ca excretion)

Answer 145

Involved in mineralisation - lay down collagen to allow mineralisation to occur (process by which calcium and phosphate are absorbed from the blood and incorporated into bone)

Answer 146

Facilitate resorption, the process where calcium phosphate is dissolved from bone and released into the circulation

Answer 147

Located in parathyroid chief cells, renal tubular cells and C cells of the thyroid Regulated PTH and calcitonin secretion, and renal tubular calcium reabsorption CaSR: encoded by a gene on chromosome 3q13-q21

Answer 148

Hypercalcaemia

Answer 149

Stimulation - low ionised calcium cells (main stimulus, in SECONDS), or high phosphate levels (bind to calcium thereby stimulating PTH release) Inhibition - calcitriol, high ionised calcium levels, and 1, 25D suppresses PTH secretion by the parathyroid gland

Answer 150

Increases calcium, decreases phosphate - increased bone resorption (within minutes) - increased absorption of calcium via increased production of calcitriol (takes days) - decreased urinary Ca excretion due to stimulation of reabsorption in the distal tubule (within minutes)

Answer 151

1. Rapid phase (mins to hours) - activation of osteocytes to promote calcium and phosphate release 2. Slower phase - binds to osteoblasts stimulating RANKL to differentiate into mature osteoclasts that promote resorption, also inhibits osteoblasts

Answer 152

Kidney - decreased calcium excretion by STIMULATING calcium reabsorption in the distal tubule, and increased phosphate excretion by INHIBITING phosphate reabsorption in the proximal tubule Gut - increase activity of 1-alpha hydroxylate (converts 25-hydroxy to 1, 25 dihydroxy) therefore increased intestinal absorption

Answer 153

Secreted by C cells of thyroid gland Release stimulated by increased Ca levels, INDEPENDENT of PTH and vitamin D Inhibited by low calcium levels and PTH

Answer 154

Decrease calcium, decrease phosphate Bone - stimulates calcium deposition in the bones (inhibits resorption): stimulates osteoblasts, inhibits osteoclasts Kidney - increases renal excretion of Ca

Answer 155

Cholecalciferol (vitamin D3)

Answer 156

Sunlight: 7-dehydrocholesterol to cholecalciferol Liver: cholecalciferol (D3) -> 25-hydroxy-vitamin D (calcidiol) via 25 hydroxylase Kidney: 25-hydroxy-vitamin D -> 1,25-dihydroxy-vitamin D (calcitriol) via 1 alpha hydroxylase

Answer 157

Increases calcium and phosphate Gut: promotes calcium and phosphate absorption (however most phosphate independent of Vit D) Kidney: increases Ca and PO4 reabsorption in PCT Bone: stimulates mineralisation (binds to osteoblasts which releases RANKL) Other: increases muscle strength, effect on RAAS, mood, immune system

Answer 158

1. Increases expression of transient receptor potential vanillin 6 (TRPV6) and basolateral efflux via increased expression of PMCA1b 2. Increases calbindin (calcium binding protein) in intestinal cells

Answer 159

25-hydroxy-vitamin D - stored form, test for stores 1, 25-hydroxy-vitamin D - active form, test in renal disease (short half life therefore not reflective of stores)

Answer 160

Similar to PTH (has same first 13 AAs) Gene on chromosome 12 Can activate PTH receptors on kidney and bone cells, to increase renal production of 1,25-hydroxy Often implicated in paraneoplastic phenomena

Answer 161

1. Genetic - diGeorge, mutations impairing PTH production, HDR syndrome, Sanjay-Sakati/Kenney-Caffey syndromes, mutation in CaSR, mutations interfering with parathyroid gland development, mitochondrial disorders 2. Autoimmune - APS1 3. Other - surgery, infiltration of gland (e.g. iron, copper)

Answer 162

1. Vitamin D deficiency/impaired metabolism - insufficient intake/sun exposure - decreased GI absorption - defects in Vit D metabolism or action (liver or renal disease, 25-hydroxylase deficiency) - Vitamin D dependent rickets (1-alpha hydroxylase deficiency, or hereditary resistance to Vitamin D) 2. Pseudohypoparathyroidism - Type 1 or 2

Answer 163

Hungry bone syndrome Osteopetrosis (marble bone disease) Sepsis Hyperphosphataemia Alkalosis IV products with citrate/lactate Pancreatitis Fluoride poisoning Hypomagnesaemia

Answer 164

Seizures, apnoea, weakness/tiredness Carpopedal spasm - Trousseau's (from inflated BP cuff), Chovstek's (facial spasm from tapping facial nerve) Stridor, irritability/behavioural issues Soft tissue and basal ganglia calcification Features of cardiac failure

Answer 165

Corrected calcium = Total Ca + (40 - albumin) x 0.02

Answer 166

Prolonged QT interval - calcium contributes to ECG positive charge that maintains resting membrane potential - ICF usually negatively charged, therefore presence of Ca in ECF results in potential increase - low calcium therefore results in decreasing potential and hyper-excitability

Answer 167

Treat cause Replace Vit D and magnesium Mild/moderate - oral supplementation (calcium carbonate 1-2mmol/kg/day) Severe (symptomatic) - IV calcium gluconate/calcium chloride, need telemetry for monitoring QT interval, can precipitate arrhythmias and cause calcium burns (need central access) Complications: nephrocalcinosis, pancreatitis

Answer 168

Early: in first 2-3 days, is exaggeration of the normal decline in calcium after birth Late: usually at the end of the first week, typically present with signs (neuromuscular excitability and seizures)

Answer 169

Transient hypoparathyroidism Transient PTH resistance High phosphorus intake (bovine milk) Low magnesium Maternal Vitamin D deficiency DiGeorge (hypoplastic or absent parathyroid glands)

Answer 170

= Low calcium and HIGH phosphate Impaired synthesis/secretion of PTH due to lack of PT gland tissue or a defect in the synthesis/release of PTH Defect in CaSR or related proteins

Answer 171

TBCE gene mutations (involved in tubules folding) Usually Arab families Features: congenital hypoparathyroidism, mental retardation, facial dysmorphism, severe growth failure

Answer 172

AR TBCE gene mutation Hypoparathyroidism, mental retardation, growth failure, osteosclerosis and immunodeficiency Thickened bone cortices -> medullary tubular stenosis, short stature and delayed bone age Eye abnormalities

Answer 173

60% have neonatal hypocalcaemia (often transitory) Can recur or have onset later in life

Answer 174

Absent parathyroid tissue due to defect in embryogenesis Variable transmission

Answer 175

Middle Eastern children, often consanguineous parentage Profound hypocalcaemia in neonates Dysmorphic (microcephaly, deep set eyes, beaked nose, micrognathia, large floppy ears IUGR and severe post natal growth restriction In some, mutations of PTH gene have been noted

Answer 176

Kearns Sayre syndromes and other mitochondrial disorders associated with hypoparathyroidism Present with ophthalmoplegia, sensorineural hearing loss, cardiac conduction disturbances

Answer 177

AD hypocalcaemia Activating mutation of the CaSR - gain of function and change in set point, PTH not released at serum Ca concentrations that normally trigger PTH release Renal calcium reabsorption is lower than expected due to absence of PTH

Answer 178

Often asymptomatic with mild to moderate hypocalcaemia Symptomatic with stress (febrile illness, tetany) Recurrent nephrolithiasis (particularly if treated with Vitamin D)

Answer 179

Hypocalcaemia Normal or low PTH, relative hypercalciuria High or high normal urinary calcium excretion (rather than expected low excretion)

Answer 180

No treatment required if asymptomatic Vitamin D results in nephrocalcinosis

Answer 181

ADH2 = activating mutation in the alpha subunit of GNA11 which mediates downstream CaSR signalling Other AD abnormalities: mutations of PTH and GCMB (glial cell missing gene B), transcription factor for PTH gland development)

Answer 182

Sanjad-Sakati syndrome Kenney-Caffey type 1 syndrome DiGeorge/velocardiofacial syndrome X linked recessive hypoparathyroidism AR hypoparathyroidism with dysmorphic features Mitochondrial disorders (Kearns Sayre) Familial hypocalcaemia

Answer 183

APECED/autoimmune polyglandular syndrome type 1 Triad of adrenal failure, chronic cutaneous candidiasis and hypoparathyroidism

Answer 184

Triad of adrenal failure, chronic cutaneous candidiasis and hypoparathyroidism AR, more common in Finnish/Iranian Jews AIRE gene mutation (not HLA associated) Other autoimmune problems: alopecia areata/totalis, malabsorption, pernicious anaemia, hepatitis, vitiligo, T1DM

Answer 185

Surgical - removal or damage of the parathyroid glands, symptoms of tetany can occur post operatively Iron deposition with chronic transfusions (e.g. beta thal major) Copper deposition in Wilson's disease Infection resulting in impaired PTH secretion

Answer 186

Vitamin D deficiency Abnormal Vitamin D metabolism End organ resistance to PTH = pseudohypoparathyroidism

Answer 187

Suspect in darker skinned infants, presenting 6-12 months Most common cause of hyperPTH RF: dark skin, maternal history, malabsorption Clinical features: rickets

Answer 188

Hepatic or renal dysfunction 1-alpha hydroxylase deficiency = VDDR type 1 Hereditary resistance to vitamin D (HRVD) = VDDR type 2

Answer 189

AR inheritance Inability to synthesise 1, 25 OHD Ix: Low/N Ca, low/N phosphate, high PTH 25 Vit D will be normal, but 1,25-Vit D will be low Rx: calcitriol - aim to keep Ca low normal, PTH high (excessive calcitriol can drive hypercalciuria and nephrocalcinosis)

Answer 190

Rare AR disorder Due to abnormal vitamin D receptor (in hormone binding or DNA binding domains) 50-75% also have alopecia Ix: Low/N Ca, low/N phosphate, high PTH, high 1,25-Vit D Rx: very high doses of vitamin D, 25D or calcitriol, may need long term IV calcium

Answer 191

= end organ resistance to PTH 1. Hypocalcaemia 2. Hyperphosphataemia 3. Elevated PTH

Answer 192

Type 1A - Albrights hereditary osteodystrophy and biochemical and resistance to other hormones Type 1b - biochemical, normal phenotype, post receptor defect Type 1c - different receptor mutation, phenotypically the same as 1a, distal defect Type 2 - no features of AHO, post receptor defect

Answer 193

= Albright hereditary osteodystrophy Inactivating mutation in GNAS1 gene (chromosome 20q13.2), usually sporadic AD - paucity of father to son transmission due to reduced male fertility Maternal GNAS affected = pseudohypoPTH type 1a, 1b or 1c Paternal GNAS affected = pseudopseudohypoPTH or progressive osseous heteroplasia/osteoma cutis Expression varies across tissues (imprinting condition)

Answer 194

Mutation in GNAS1 gene encoding alpha subunit of the stimulatory guanine nucleotide-binding protein (Gas): inhibits PTH receptor coupling to activate cAMP Obese, short stature, round face, subcutaneous ossification, brachydactyly type E (short 4th/5th metacarpals and metatarsals), IUGR Developmental delay, osteitis fibrosis, tetany

Answer 195

PTH: elevated PTH, hyperphosphataemia, hypocalcaemia TSH (second most common!): hypothyroid, elevated TSH without goitre LH/FSH - reduced fertility, menstrual disorders, bilateral cryptorchidism, elevated LH/FSH GHRH - poor growth Calcitonin - asymptomatic hypercalcitonaemia

Answer 196

Anatomic stigmata of pseudohypoparathyroidism - but serum levels of calcium and phosphorus are normal despite reduced Gsa activity (PTH may be slightly elevated) Possibly related to paternal transmission (compared with maternal transmission in pseudohypoparathyroidism)

Answer 197

Affected patients have normal G protein activity and a normal phenotypic appearance Tissue specific resistance to PTH only Serum Ca, phosphate and PTH are the same as Type 1A PHP Due to abnormal Gna methylation = PTH resistance Usually sporadic

Answer 198

Normal/elevated urinary cAMP responses (demonstrating Ca reabsorption) but do NOT have concomitant phosphate excretion Normal phenotype, hypocalcaemia Probably due to a defect distal to cAMP, dose not respond to signal for some reason

Answer 199

Phase of avid bone mineralisation with hypocalcaemia due to rapid movement of calcium from bone to skeletal compartment Occurs during early phases of recovery from severe mineralisation defect or after a prolonged period of calcium resorption from bone

Answer 200

1. Reduced responsiveness to PTH 2. Impaired PTH release 3. Impaired formation of 1,25 Vit D Features: carpopedal spasm, tetany/seizures, anorexia, hypokalaemia, tachycardia

Answer 201

Leads to decreased 1-alpha hydroxylase (essential for conversion of 25-OH-Vit D to 1,25-Vit D) which assists with intestinal calcium absorption Can ultimately results in secondary and tertiary hyperPTH

Answer 202

A constellation of findings associated with hypocalcaemia and/or hypophosphatemia If a patient has closed growth plates = osteomalacia (rickets requires open growth plates)

Answer 203

Short stature, poor growth, bone pain/deformities, pseudo fractures and fractures Bone abnormalities: - delayed fontanelle closure, frontal bossing - Rachitic rosary (enlarged costochondral junctions) - Leg bowing - Dental abscesses - Widening of wrist/ankle joints Enthesopathy (disorders of muscle/ligament attachment) caused by calcification of tendons/ligaments Harrison's grooves in the thorax Infantile seizures

Answer 204

Plain films of wrists, ankles and legs tend to show generalised demineralisation, bowing deformities, widening of the physes with metaphyseal fraying, cupping and irregularity

Answer 205

Vitamin D deficiency rickets Vitamin D dependent rickets Hypophosphatemic rickets

Answer 206

Inadequate Vitamin D intake Inadequate UV exposure Malabsorption Nephrotic syndrome Renal/liver dysfunction Phenytoin/phenobarbital use

Answer 207

Mutations affecting 25-hydroxylase, 1-alpha-hydroxylase, vitamin D receptor

Answer 208

Inadequate intake Malabsorption or ingestion of phosphate binders Mutations affecting FGF23 signalling Fanconi syndrome

Answer 209

ALPL gene mutation

Answer 210

Low Vit D bioavailability, leads to low Ca and phosphate, to compensate PTH is increased which may improve hypocalcaemia but exacerbates hypophosphataemia Low 25-Vit D (but 1,25-Vit D will be normal), elevated PTH, ALP elevated due to increased bone turnover Rx: calcium and high doses of vitamin D3 or D2

Answer 211

Caused by inherited defects in vitamin D processing or downstream signalling - presentation resembles Vit D deficiency rickets, with timing in the neonatal/infantile period Types include 1-alpha hydroxylase deficiency, 25-hydroxylase deficiency, and hereditary resistance to vitamin D

Answer 212

Inherited AR disorder, resulting in impaired conversion of 25-OH-vit D into 1,25-Vit D Presents in first year of life with skeletal disease and severe hypocalcaemia, and secondary hyperparathyroidism with moderate hypophosphataemia Elevated 25-OH-Vit D and low 1,25-Vit D Rx: daily 1,25 Vit D (alcitriol) and calcium supplements

Answer 213

Caused by mutations in the gene encoding the enzyme responsible for 25-hydroxylation of vitamin D Rx: heterozygotes respond to calcium supplementation, homozygotes respond to either vitamin D or calcium supplementation

Answer 214

Very rare AR disorder Mutations in gene encoding Vit D receptor leading to end organ resistance to Vitamin D Normal at birth, develops rickets within first 2 years of life Associated with alopecia in 2/3 (due to lack of vitamin D receptor activity within keratinocytes) Elevated 25-OH-Vit D and 1,25-Vit D levels Rx: high dose calcitriol and calcium supplementation (may need IV calcium if not responding)

Answer 215

Can be due to acquired phosphate deficiency, but there are also inherited forms of hypophosphatemic rickets FGF23 is the major phosphate regulator that simulates phosphaturia (renal phosphate wasting) and therefore causes are classified as FGF23 dependent or FGF23 independent Presentation is similar to Vit D deficient rickets, with a propensity towards dental abscesses, craniosynostosis and enthesopathy, bone pain is classic and also family history of rickets is typical Rx: phosphate and calcitriol supplementation - heal rickets and may be able to restore linear growth

Answer 216

X linked hypophosphatemic rickets (PHEX) AD hypophosphatemic rickets (FGF23) AR hypophosphatemic rickets (DMP and ENPP1 mutations) Ectopic FGF23 production (e.g. McCune-Albright syndrome, tumour-induced osteomalacia)

Answer 217

Fanconi syndrome/renal tubular acidosis Hereditary hypophosphatemic rickets with hypercalciuria

Answer 218

Most common cause of inherited rickets Caused by mutations in phosphate regulating zone on the PHEX gene, which leads to elevated FGF23 and hypophosphatemia FGF23 inhibits 1-alpha-hydroxylase (decreased conversion of 25-OH-Vit D to 1,25-Vit D), therefore decreased intestinal phosphate absorption FGF23 decreases renal phosphate absorption therefore more excretion of phosphate Key biochemical finding: low phosphate level and evidence of renal phosphate wasting, serum Ca usually normal, PTH usually normal or only slightly elevated

Answer 219

Burosumab (monoclonal antibody) - against FGF23, approved for treatment for children over 12 months Improved outcomes with regards to phosphorus levels, pain, healing of rickets, and stature Also better side effect profie compared with phosphate and calcitriol

Answer 220

ALPL gene mutations result in decreased ALP activity with varying severity 6 clinical phenotypes (range from mild to severe) with pyridoxine (vitamin B6) responsive seizure in severely affected infants Rx: asfotase alfa, bone targeted infusion of ALP replacement therapy

Answer 221

Neonates: irritability, FTT, lethargy, constipation, fractures Muscle weakness, fatigue headache Abdo pain, nausea vomiting, weight loss Polydipsia/polyuria Fevers, pancreatitis, stupor

Answer 222

Renal failure, nephrolithiasis, nephrocalcinosis Soft tissue calcifications, brain microcalcifications, skeletal abnormalities Emotional lability, depression, psychosis Cognitive impairment, convulsions Blindness Hypercalcaemic crisis (oliguria, azotemia and coma)

Answer 223

If severe, disappearance of p waves and tall peaking T waves

Answer 224

Excessive Vitamin D ingestion (maternal, neonatal) Maternal hypoPTH Subcutaneous fat necrosis Willliams-Beuren syndrome Various congenital disorders (e.g. CaSR mutation, hyperthyroidism-jaw tumour syndrome, Jansen-type metaphysical chondrodysplasia)

Answer 225

Parathyroid hyperplasia, adenoma, carcinoma MEN 1 and 2a (multiple endocrine neoplasia) McCune-Albright Post renal transplant Malignancy AKI and CKD due to hyperPTH

Answer 226

Milk-alkali syndrome Exogenous administration of calcium or vitamin D Granulomatous disease (e.g. sarcoidosis, TB, cat-scratch fever)

Answer 227

Immobilisation Drugs (vitamin A, thiazides, lithium) TPN Hypophosphatemia Other endocrinological disorders (hyperthyroidism, primary adrenal insufficiency, severe congenital hypothyroidism)

Answer 228

Telemetry Low-calcium formula Fluid administration Frusemide as needed for fluid administration Calcitonin Bisphosphonates

Answer 229

Increases renal clearance of both calcium and phosphate Reduces calcium release from bone by suppressing osteoclasts Tachyphylaxis prevents its use as a long term solution so only short term use provided

Answer 230

Acts at the osteoclasts as potent inhibitors of bone resorption Reserved for management of chronic hypercalcaemia (can cause hypocalcaemia if used in acute treatment), typically in the setting of malignancy related hypercalcaemia

Answer 231

Uncommon in childhood, usually due to single benign parathyroid adenomas (usually apparent >10 yo) AD inheritance Hypercalcaemia with elevated or inappropriately normal PTH Rx: surgical removal of adenoma

Answer 232

Uncommon, occurs in first few weeks of life Usually full term infants who experienced perinatal distress Firm subcutaneous nodules on cheeks, buttocks, back, arms and thighs; histology shows fat necrosis, abundant histiocytes and multinucleated giant cells with granuloma formation Mediated by granulomatous production of 1,25-Vit D Typically resolves over weeks to months

Answer 233

AD disorder Deletion in 7q11.23 Infantile hypercalcaemia occurs in 15%, usually in the first years of life with resollution by 4 years of age (possible recurrence in puberty) Cause of hypercalcemia is unknown and is usually mild and transient course, but some cases can be severe and life-threatening

Answer 234

AD disorder characterised by parathyroid adenomas and jaw tumours Other manifestations include polycystic kidneys, renal hamartomas and Wilms tumour

Answer 235

Associated with inadequately treated (or untreated) maternal hypoparathyroidism or pseudohypoparathyroidism which leads to hyperplasia of fetal parathyroid glands

Answer 236

Rare disorder with symptoms manifesting shortly after birth Caused by CaSR inactivating mutation and is biallelic

Answer 237

Zona glomerulosa: mineralocorticoid production (e.g. aldosterone) Zona fasciculata: cortisol production Zona reticularis: sex steroid production Medulla: synthesis of catecholamines

Answer 238

Hypothalamus secretes corticotropin releasing hormone (CRH), stimulates pituitary release of adrenocorticotropic hormone (ACTH) ACTH induces release of cortisol and adrenal androgens - glucocorticoids feedback to inhibit ACTH and CRH secretion

Answer 239

ACTH has little effect except in excess, otherwise aldosterone is regulated by the renin-angiotensin system and potassium concentration

Answer 240

Disorders characterised by insufficient production of cortisol and often aldosterone Includes acquired causes (Addison disease) and inherited causes Most common cause is CAH

Answer 241

Most common cause is CAH (60%) Others include autoimmune disease, APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy), adrenoleukodystrophy, and isolated glucocorticoid deficiency Infants tend to present after only a few days of symptoms with severe illness, whereas adolescents can develop subacute/chronic symptoms

Answer 242

General constitutional symptoms - anorexia, N/V, weight loss, lethargy, weakness, myalgia Hypoglycaemia (classically with ketosis) Decreased cardiac output and vascular tone, resulting in hypotension

Answer 243

May result in salt-wasting and electrolyte abnormalities: - Hypovolaemia (exacerbates glucocorticoid deficiency effects on CVS) - Hyponatraemia (due to aldosterone deficiency and attempt at BP compensation with arginine vasopressin) - Hyperkalaemia - May also cause hyperchloremic metabolic acidosis

Answer 244

Hyperpigmentation: fair skinned individuals may have "bronzing", gingival and buccal mucosa hyperpigmentation may be more sensitive signs on physical examination

Answer 245

Cortisol deficiency: hydrocortisone Aldosterone deficiency: fludrocortisone

Answer 246

Most commonly caused by autoimmune destruction of the adrenals May also occur as part of autoimmune polyendocrinopathy syndromes

Answer 247

Morning cortisol (best screening) - is low in the morning when would normally be high Short synacthen test (ACTH stimulation) Consider imaging to look at gland size Screen for associated autoimmune disorders - hypoparathyroidism, diabetes, hypothyroidism, premature ovarian failure

Answer 248

Inherited disorder (usually X linked) that results in impaired beta-oxidation of very long chain fatty acids in peroxisomes and subsequent accumulation in body tissues and fluids The result is an adrenocortical deficiency and CNS demyelination and neurodegeneration

Answer 249

Late childhood onset of subtle neurologic symptoms, and progressive deterioration (i.e. dementia, vision/hearing loss) associated with adrenal insufficiency (which may develop before, during or after neurological symptoms)

Answer 250

Disorder of adrenal development resulting in primary adrenal insufficiency X linked congenital adrenal hypoplasia - most common form, presents with salt wasting, glucocorticoid insufficiency and hypogonadotropic hypogonadism IMAGe syndrome: IUGR, metaphyseal dysplasia, adrenal hypoplasia, genitourinary anomalies

Answer 251

Infections - TB, meningococcal Drugs: - ketoconazole (direct steroidogenesis inhibition) - etomidate (direct steroidogenesis inhibition) - rifampin (increased liver metabolism of steroids) - phenytoin/phenobarb (increased liver metabolism of steroids)

Answer 252

Most common cause of primary adrenal insufficiency Family of AR disorders of adrenal steroidogenesis Clinical presentation is variable depending on the affected enzyme (e.g. 21-hydroxylase, 11-hydroxylase deficiencies)

Answer 253

Results from mutation in CYP21A2, leading to variable quantities/functionality of proteins necessary for production of cortisol and aldosterone

Answer 254

Hyperplasia of adrenal cortex Increased levels of precursor steroids (e.g. progesterone, 17-OH progesterone) A potential for shunting of 17-OH progesterone to increase androgen biosynthesis

Answer 255

"Classic" forms (salt-wasting and simple virilizing) present as neonate or infant "Non classic" forms present in childhood/adolescence The effects of prenatal androgen exposure on genital appearance is variable depending on male/female gender

Answer 256

No ambiguous genitalia at birth May have "excessive scrotal pigmentation" Patients are more likely to go undiagnosed until adrenal insufficiency develops

Answer 257

More likely to have ambiguous genitalia (cliteral hypertrophy, "rugated labia") - salt losing form has the most severe virilisation Internal genital organs (ovaries) are normal, no testes present

Answer 258

70-75% of "classic" presentations Presentation due to insufficient glucocorticoids and aldosterone (hyponatraemia, hyperkalaemia, non-gap metabolic acidosis, dehydration, shock) Usually presents with salt-losing crisis within the first 2 weeks of life

Answer 259

25-30% of "classic" presentations Able to produce adequate mineralocorticoid (therefore no salt-wasting) but are unable to synthesise glucocorticoids and still have androgen excess

Answer 260

May not be diagnosed until 3-7 years Accelerated linear growth with advanced skeletal maturation Premature pubarche Clitoral enlargement vs phallic enlargement with prepubertal testes Girls may have delayed breast development/amenorrhoea unless androgens are suppressed

Answer 261

Salt wasting CAH (insufficient glucocorticoids and aldosterone)

Answer 262

Least severe form as cortisol and aldosterone levels are normal Affected females usually have normal genitals at birth May present with precocious puberty and early pubarche Some may have hirsutism, acne and menstrual disorders, but many may be asymptomatic

Answer 263

Morning 17-OH progesterone is increased Electrolyte abnormalities ACTH increased, plasma renin increased, aldosterone decreased, serum androgens are increased)

Answer 264

Treat adrenal crisis Provide chronic mineralocorticoid (if salt-wasting) and corticosteroid (via hydrocortisone) - androgens will normalise because glucocorticoid treatment suppresses excessive production

Answer 265

Can sometimes be diagnosed prenatally Can provide the mother with dexamethasone to suppress secretion of steroids by fetal adrenal glands, including adrenal androgens (which ameliorates virilisation of female fetuses)

Answer 266

Caused by mutation in CYP11B1 gene, second most common cause of CAH Leads to decreased cortisol and high levels of corticotropin (so may present with symptoms of glucocorticoid insufficiency) Patients may have normal or increased mineralocorticoid hormones (HTN, hypernatraemia, hypokalaemia) -> increased androgen production due to shunting of precursors (may have virilisation), will have elevated 11-deoxycortisol, DOC and DHEA before and after ACTH stimulation test

Answer 267

Results in decreased cortisol, aldosterone, and androstenedione, but increased DHEA - can result in salt-wasting crises - androstenedione and testosterone are not synthesised, therefore if XX will appear slightly masculine (due to elevated DHEA), and if XY there is no testosterone so appear incompletely virilised (small phallus)

Answer 268

Marked elevation of 17-OH pregnenolone and DHEA May also have 17-OH progesterone elevation, however at an INCREASED ratio of 17-OH pregnenolone:progesterone (vs decreased ratio in 21-OHase deficiency)

Answer 269

Most often due to insufficient pituitary release of ACTH - classically due to suppression of the HPA axis by chronic administration of high dose glucocorticoids with no or inadequate taper

Answer 270

Suppression of HPA axis by chronic glucocorticoids Pituitary lesions (craniopharyngioma) Congenital mmidline lesions (septo-optic dysplasia, anencephaly) Midline brain surgery Traumatic brain injury Autoimmune hypophysitis Other congenital diseases (e.g. Prader-Willi)

Answer 271

More likely to present with symptoms of glucocorticoid insufficiency Characterised by low ACTH, and adequate aldosterone (due to renin-angiotensin system is intact) therefore no hyperkalaemia, no hyponatraemia, no salt-wasting In presentations due to affected pituitary, there may be other hormonal deficiencies

Answer 272

Failure of the hypothalamic release of CRH (leading to low ACTH concentrations)

Answer 273

Syndrome characterised by an excess of glucocorticoid effects

Answer 274

Cushing disease (ACTH secreting pituitary adenoma) Exogenous ACTH use Ectopic ACTH syndrome CRH hypersecretion (rare in paeds)

Answer 275

Exogenous corticosteroid use (most common cause) Adrenocortical tumour (second most common cause) Bilateral primary adrenocortical hyperplasia PNAD or Carney complex Massive macronodular hyperplasia McCune-Albright syndrome

Answer 276

Weight gain with growth failure Hirsutism, acne, amenorrhoea, delayed puberty Centripetal obesity (buffalo hump, moon facies) Viloaceous striae (may have hyperpigmentation if ACTH is elevated) HTN Uncommon symptoms 0 headache, easy bruising, osteopenia, emotional lability, muscle weakness

Answer 277

24 hour urine collection or midnight salivary cortisol Midnight ACTH level - if excessive cortisol production would expect ACTH to be low, but if excessive ACTH production the level would be high Dexamethasone suppression test - would suppress 8am cortisol level but in Cushing syndrome would be elevated

Answer 278

Catecholamine-secreting tumours usually arising from chromaffin cells of the adrenal medulla (but can develop anywhere along the sympathetic chain) Children are more likely to have bilateral disease than adults, extrarenal disease, or multiple tumours Can be associated with genetic syndromes (e.g. VHL, MEN, NF1, TS)

Answer 279

Most often present with hypertension - children rarely present with the classic triad (tachycardia, headache, diaphoresis) May have vague symptoms such as back pain, abdominal pain, abdominal distention Rare presentations may mimic T1DM

Answer 280

24 hour urinary catecholamines Plasma measurements of free catecholamines and metanephrines may also be used for diagnosis Localisation of tumour with MRI (may need MIBG scans)

Answer 281

= also known as Autoimmune polyendocrine syndrome (APS type 1) - Autoimmune polyendocrinopathy (especially Addison diseae, hypoparathyroidism) - candidiasis 9chronic mucocutaneous, almost always precedes the other diseorders) - ectodermal dystrophy - other autoimmune diseases such as alopecia totalis, pernicious anaemia, vitiligo, T1DM

Answer 282

Multiple endocrine deficiencies causesd by an autoimmune aetiology - includ APS type 1, 2 or 3, and immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX)

Answer 283

Most common of immunoendocrinopathy syndromes Addison disease +/- Hashimoto thyroiditis +/- T1DM May have primary hypogonadism, myasthenia gravis, celiac Typically presents in early adulthood

Answer 284

Unlike type 1 and 2, does not involve the adrenal cortex but does involve autoimmune thyroiditis Additional coexisting autoimmune disorders include organ-specific diseases (T1DM, pernicious anaemia, vitiligo/alopecia, celiac, hypogonadism, myasthenia gravis) or systemic diseases (sarcoidosis, RA, Sjogren syndrome)

Answer 285

= immunodysregulation polyendocrinopathy enteropathy X linked Caused by mutation in FOXP3 resulting in loss of regulatory T cells Patients are immunocompromised

Answer 286

Autoimmune enteropathy (watery diarrhoea in <1 month) Eczema and early onset T1DM (in infancy) Thyroid dysfunction Severe allergies Variable lymphadenopathy/splenomegaly Cytopenias, eosinophilia

Answer 287

Immune modulation therapy with the goal of T cell inhibition Bone marrow transplant is only cure (untreated patients often die by 2 years of age)

Answer 288

Inherited disorders causing benign and/or malignant tumours in at least two endocrine glands Tumours can also develop in non-endocrine tissues

Answer 289

AD, MEN1 gene Hyperplasia/neoplasia of: - pancreas (may secrete gastrin, insulin, VIP, glucagon) - anterior pituitary (may secrete prolactin, GH0 - parathyroid (most common presenting symptom)

Answer 290

Carcinoid tumours Lipomas Adrenal tumours Thyroid adenomas Thymic neuroendocrine tumour

Answer 291

AD, RET (exon 10 or 11) Medullary thyroid carcinoma (almost 100%) Pheochromocytoma (up to 50%) Parathyroid hyperplasia (up to 20%, late manifestation)

Answer 292

RET (exon 16) Medullary thyroid carcinoma Pheochromocytomas Mucosal neuroma (tongue, buccal mucosa, lips and conjunctivae) Other: Marfan-like facies, may have peripheral neurofibromas or gangliomas (esp in GIT) and cafe au lait patches, "inability to cry tears)

Answer 293

Most common endocrinological disorder Leading preventable cause of intellectual disability

Answer 294

Iodine deficiency (most common cause globally) Thyroid gland dysgenesis (most common cause in iodine sufficient areas) - ectopic thyroid 2/3, aplastic/hypoplastic gland 1/3 Dyshormonogensis (15%) Iatrogenic Transient hypothyroidism

Answer 295

Nonspecific symptoms usually, well at birth Large posterior fontanelle (>1cm), macroglossia, goiter, coarse cry, prolonged jaundice, umbilical hernia, abdominal distension, constipation, hypotonia, hypothermia, lethargy Late findings: poor linear growth, developmental delay, delayed tooth development

Answer 296

NBST: high TSH is suspicious for hypothyroidism, normal TSH will not exclude it **Elevated serum TSH with low free T4 confirms congenital hypothyroidism**

Answer 297

Levothyroxine should be initiated - treatment within 2 weeks of life improves long term outcomes 10-15microg/kg/day (average term infant needs ~50microg daily) Goal is to maintain serum free T4 in the upper half of the normal range with therapy Monthly TSH and free T4 initially Trial off at 3-4 years of age if stable on treatment

Answer 298

= TSH deficiency (congenital or acquired) Congenital is relatively rare, usually associated with other pituitary hormone deficiencies, can be caused by mutational defects of the TSHR or TRH receptor gene'Acquired: can be due to cranial radiation or surgery involving the pituitary or hypothalamus

Answer 299

Signs of hypothyroidism May have signs of other pituitary hormone deficiencies (hypoglycaemia, polyuria, polydipsia, delayed/precocious puberty, galactorrhea, short stature, FTT)

Answer 300

Free T4 is low, and TSH is normal/low Not detected on NBST (as only detects elevated TSH) Should also screen for other pituitary deficiencies

Answer 301

Levothyroxine replacement therapy (aim for normalisation of free T4) Monitor TFTs 3 monthly for younger children

Answer 302

= autoimmune thyroiditis, chronic lymphocytic thyroiditis Most common cause of hypothyroidism in children F>M, increased prevalence in puberty RF: family history of autoimmune disease, may be part of autoimmune polyglandular syndrome Patients with Down syndrome, Turner syndrome and T1DM should be screened annually

Answer 303

Dry skin, dry hair Constipation Cold intolerance Fatigue, difficulty concentrating Slowed mentation (lethargy and poor academic performance) Delayed puberty, menstrual irregularity Growth delay Bradycardia Weight gain, dyslipidemia Delayed deep tendon reflexes

Answer 304

Usually insidious onset, may present only with goitre or firm thyroid gland (often described as rubbery or pebbly) Goitre present in 70% of children diagnosed with Hashimoto thyroiditis and is often the first manifestation ~80% of patients are often otherwise asymptomatic at time of diagnosis (may be euthyroid or only have mild hypothyroidism), yet some may have signs of moderate to severe hypothyroidism Few present with thyroxtoxicosis (tachycardia, anxiety)

Answer 305

Early: TSH may be normal with positive TPO antibodies and goitre Later: the TSH elevation becomes modest with a normal free T4 Presence of TGL and/or TPO antibodies (both >90% sensitivity, but 10-15% of normal population has anti-TPO antibodies) Diffuse lymphocytic infiltration with occasional germinal centres Ultrasound is recommended if palpable nodule, asymmetric gland or large goitre USS usually shows enlarged thyroid gland with heterogeneous echogenicity I-123 scan: decreased radioactive iodine uptake

Answer 306

Levothyrosine, goal is TSH between 1-3 Serum TSH and free T4 should be obtained 4-6 weeks after starting therapy Once euthyroid, monitor every 4-6 months

Answer 307

Dairy products Vitamin supplements including calcium and iron

Answer 308

Hashitoxicosis Hashimoto encephalopathy

Answer 309

Release of stored thyroid hormone resulting in Graves like presentation (difficult to distinguish other than this is a transient and self limited process) Radioactive iodine uptake is increased No opthalmologic findings of Graves May require beta blockers to control hyperthyroid symptoms

Answer 310

= steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT) Idiopathic encephalopathy (altered mental status, clonus, seizures) in the presence of positive thyroid autoantibodies (severity does not correlate to levels of antibodies) Diagnosis of exclusion, pathogenesis not well understood Responds to corticosteroids

Answer 311

Acute or chronic illnesses can result in abnormal thyroid hormone profile Secondary to changes in TSH secretion, thyroid hormone binding, transport of thyroid hormones, thyroid hormone receptor activity and TRH secretion Dopamine, dobutamine, high dose steroids and severe illnesses can result in a transient decrease in TSH secretion

Answer 312

Low T3, normal TSH and increased reverse triiodothyronine (rT3) levels Unclear clinical significance, no evidence to suggest treatment is beneficial

Answer 313

Neck radiation/surgery for Graves disease Medications: - thionamides (methimazole, carbimazole) - lithium - amiodarone (decrease in the formation and release of T4 and T3 = Wolff-Chaikoff effect), decreases conversion of T4 to T3 resulting in elevated TSH

Answer 314

X linked condition Low levels of T4 and T3, normal TSH, clinically euthyroid Normal FT4 and FT3 and/or low thyroid binding globulin (TBG) levels

Answer 315

AD in familial cases, 15-20% are sporadic Decreased activity of thyroid hormones on their receptors, leading to generalised resistance, pituitary resistance and peripheral resistance to thyroid hormone

Answer 316

Presentation depends on the location of resistance May vary from euthyroid/hyperthyroid/hypothyroid Deafness observed in 20%, ADHD reported in 50% Increased T4 and T3 with a normal or increased TSH

Answer 317

Important to detect in infants to address relative hypothyroidism and minimise brain dysfunction (ADHD) Indications for treatment (need 3-6x usual thyroxine replacement dose): - elevated TSH in the absence of clinical evidence for thyrotoxicosis - FTT - delayed developmental milestones - delayed bone maturation

Answer 318

Elevated TSH with normal T4 and T3, mostly asymptomatic TPO antibody positivity, presence of goitre, increasing TSH = increases risk of hypothyroidism Rx: consider levothyroxine if signs or symptoms of hypothyroidism with increasing TSH (>10) and positive antithyroid antibodies

Answer 319

Most common cause of hyperthyroidism in children Adolescent girls are more likely to be affected than boys IgG antibody against TSHR mimics the action of TSH

Answer 320

Goitre Tachycardia, palpitations Increased pulse pressure Weight loss Diarrhoea, polyuria Sleep disturbances, anxiety Heat intolerance Restlessness, tremor Headache, difficulty focusing Growth acceleration Bone maturation advancement Proximal muscle weakness Ophthalmopathy (lid lag)

Answer 321

Suppressed TSH and high free T4 Thyroid receptor antibody positivity - Thyrotropin receptor binding inhibitor immunoglobulins (TRAbs) - Thyroid stimulating immunoglobulin (TSI) Radioactive iodine uptake is increased

Answer 322

Initial trial of antithyroid drugs, then therapy with iodine ablation, or surgical thyroidectomy if remission is not achieved on medical therapy within 2 years - 40-60% relapse with medication withdrawal

Answer 323

Methimazole - inhibits thyroid hormone biosynthesis by decreasing oxidation of iodide and iodination of tyrosine SE = drug induced rash, granulocytoopenia (<1%, usually within 3 months), cholestasis PTU - inhibitor of type 1 deiodinase (T4 to T3 conversion), potential side effect of irreversible hepatotoxicity prohibits use in children Beta blockers used until euthyroid (alleviates CVS symptoms)

Answer 324

Beta emission induces initial radiation thyroiditis, causing thyroid follicular cell destruction and subsequent hypothyroidism Directed at the hyperthyroid gland, not the underlying autoimmune cause Extrathyroidal manifestations may appear/worsen due to ongoing immunological process Contraindicated in pregnancy, and pregnancy should be avoided for 6 months May take up to 2-6 months to achieve biochemically euthyroid or hypothyroid state, will need thyroxine after ablation once hypothyroidism develops

Answer 325

Indications: large thyroid gland, failed medical treatment, low uptake of RAI, severe eye disease, patient preference Common complications: scar, transient hypoparathyroidism, recurrent laryngeal nerve palsy Thyroxine replacement should be started immediately after surgery

Answer 326

= de Quervain syndrome (rare in paeds) Self-limited inflammation of the thyroid that usually follows an upper respiratory tract infection Presents with fever and jaw pain, thyroid gland may be tender to palpation Signs of hyperthyroidism present Suppressed TSH with high T4 and T3, decreased radioactive iodine uptake Self-limited, therefore only treat with analgesia/anti-inflammatories

Answer 327

Transplacental delivery of TSI antibodies from a mother with Graves disease Symptoms may be masked due to transplacental delivery of antithyroid medications

Answer 328

Symptoms may be masked due to transplacental delivery of maternal antithyroid medications Irritability Tachycardia, including SVT Polycythemia Craniosynostosis Bone age advancement Poor feeding, FTT

Answer 329

Ideally check maternal TSI levels at time of delivery Will have suppressed TSH and high T4 Self-limited disease, maternal antibodies will degrade over time (may take 6 months) May need methimazole and beta blockers to control transient hyperthyroidism and CVS symptoms Observe without treatment if minimal symptoms

Answer 330

2% of children develop solitary thyroid nodules, 70-80% are cystic in nature and benign (follicular adenoma, colloid cysts, thyroglossal duct cysts, chronic thyroiditis) Carcinoma of the thyroid is rare in children Papillary and follicular carcinomas represent 90% of childhood thyroid cancers Workup: TFTs, neck ultrasound, if low TSH consider scan, FNA is common diagnostic procedure (excisional biopsy may also be necessary)

Answer 331

- history of therapeutic head or neck irradiation - solid nodule on ultrasound - cold nodule on radioiodine scanning - solitary thyroid mass with consistency differing from the rest of the thyroid gland - nodule with rapid growth, hoarseness (recurrent laryngeal nerve involvement) - nodule with metastasis to local lymph nodes or lung

Answer 332

Seen with MEN 2a or 2b, possibly familial Arise from parafollicular C cells Presence of mutations of RET protooncogene is predictive - genetic screening is indicated after a proband is recognised Prophylactic thyroidectomy is indicated for family members with the same allele

Answer 333

Elevated calcitonin levels, basal or stimulated (pentagastrin stimulation) Treatment: resection of nodule vs subtotal/total thyroidectomy with or without lymph node dissection

Endocrinology Flashcards

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