Endocrinology

Question 1

What are the most common causes of neonatal hypothyroidism?

Answer 1

• Thyroid dysgenesis (Agenesis, Hypoplasia, Ectopia)
• Thyroid Hormone Synthesis Defect (TPO defect)
• Hypopituitarism
• Maternal Thyroid Disease (Grave’s, Hashimoto’s)
• Iodine Deficiency

Question 2

What other autoimmune conditions are associated with TIDM?

Answer 2

1) Hashimoto’s / Lymphocytic Thyroiditis (TPO antibodies, TFTs)
2) Coeliac Disease (TTG antibodies, total IgA)
3) Addison’s (<1%)
4) also pernicious anaemia, alopecia, JIA, vitiligo

Question 3

What are the causes of ambiguous genitalia?

Answer 3

1) undervirilised male (gonadal dysgenesis, androgen insensitivity, 5a reductase deficiency)
2) over-virilised female (CAH (21 hydroxylase) most importantly)
3) ovotesticular gonads
4) severe hypospadias

Question 4

What is the most common cause of hypothyroidism in children?

Answer 4

Hashimoto’s Thyroiditis / Lymphocytic Thyroiditis

Autoimmune condition - antibodies to TPO and Thyroglobulin Girls>Boys, can present with atrophy or goitre, treat with thyroxin

Associations - Downs, Turners, Klinefelters, Coeliac, TIDM

Question 5

2008A Q13

Thyroid dysfunction due to which of the following is most likely to be missed on newborn screening?
A. Dyshormonogenesis.
B. Ectopic thyroid gland.
C. Panhypopituitarism.
D. Thyroid agenesis.
E. Transient hyperthyrotropinemia.

Answer 5

C. Panhypopituitarism.

Question 6

2008A Q20

A three-year-old girl presents following a hypoglycaemic seizure and has some investigations. Urinary metabolic screen confirms the diagnosis of Medium-Chain Acyl-CoA dehydrogenase deficiency (MCAD). The defect in this condition is most likely to cause hypoglycaemia by which of the following mechanisms?
A. Hyperinsulinism.
B. Impaired gluconeogenesis.
C. Impaired glycogenolysis.
D. Increased glycogen synthesis.
E. Increased ketone production.

Answer 6

B. Impaired gluconeogenesis.

Question 7

2008A Q24

Centre for Disease Control (CDC) body mass index (BMI) charts have been recommended as a screening tool to identify individuals who are overweight.
Which of the following BMI’s define a child likely to be obese?
A. >25 kg/m2.
B. >30 kg/m2.
C. >85th percentile for age.
D. >85th <95th percentile for age.
E. ≥95th percentile for age.

Answer 7

E. ≥95th percentile for age.

Question 8

Discuss the peaks and role of each of the following hormones in the phases of the menstrual cycle.

• FSH
• LH
• Oestrodiol
• Progesterone
• Inhibin A & B
• GnRH

Answer 8

Follicular Phase

GnRH released from Hypothalamus - stimulates release of FSH and LH from Ant Pit.

FSH and LH stimulate follicular maturation in ovaries.

Granulosa cells in the maturing Antral Follicle secrete oestrogen with levels progressively increasing prior to ovulation.

LH and FSH surge cause ovulation. LH 2/7 prior and FSH approx 16 hrs prior to ovulation.

Inhibin secretion from granulosa cells is stimulated by FSH. Inhibin suppresses FSH and is diminished by GnRH. Inhibin A peaks in luteal phase and inhibin B has bimodal peaks at early to mid follicular and at ovulation.

Luteal Phase

FSH and LH are low.

Progesterone increasing markedly and oestrogen, less so than progesterone.

Question 9

McCune-Albright Syndrome

Answer 9

Triad of:

1. precocious puberty
2. cafe-au-lait skin pigmentation
3. fibrous dysplasia of bone

Cafe-au-lait

• classic “coast of maine” (jagged edges)
• Do not cross over the mid line

Question 10

Classic triad of phaeochromocytoma

Initial test

Treatment

Answer 10

1. Episodic headache
2. Sweating
3. Tachycardia

Plasma free metanephrines is initial diagnostic test, 24 hour catacholamine test usually recommended but not always possible.

Treatment is adrenalectomy. Prior to surgery, patients should be prepared first with alpha adrenergic blockade, followed by beta adrenergic blockade.

Question 11

Craniopharyngioma

Answer 11

• Arises from Rathke’s pouch.
• Dx by calcified mass on CT/MRI and sometimes xray.
• Slow growing, sx over a year or so
• Visual disturbance, endocrine abnormalities and headache frequent clinical picture

Question 12

An infant diagnosed with DM before 6 months of age may have a defect in the kir6.2. What should these infants be treated with?

Answer 12

Sulfonylurea

Question 13

Describe Vitamin D synthesis

Answer 13

1. Skin - conversion of 7-dehydrochlesterol to vitamin D3 (3- cholecalciferol) by ultraviolet B radiation from the sun
2. Liver - cholecalciferal is hydroxylated to 25-hydroxycholecalciferol by the enzyme 25-hydroxylase.
3. Kidney - 25-hydroxycholecalciferol serves as a substrate for 1-alpha-hydroxylase, yielding 1,25-dihydroxycholecalciferol, the biologically active form.

Question 14

What test is appropriate to dx a pt suspected of having Cushings?

Answer 14

24-hour urinary free cortisol level

In Cushing Syndrome there is elevated urinary free cortisol which is best measured with a 24 hour collect. A dexamethasone suppression test may be helpful and glucose tolerance testing is often abnormal.
Serum electrolytes are generally normal but a decrease in potassium may occur, especially in patients with ACTH secreting tumours.


Question 15

What is the action of glucokinase in the beta cell of pancreas?

Answer 15

Phosphorylation of glucose to glucose-6-
phosphate.

Question 16

What does an activating mutation of glucokinase gene cause?

Answer 16

Activating mutations in glucokinase gene cause hyperinsulinism due to closure of the potassium channel through overproduction of ATP

Question 17

What does an inactivating mutation in glucokinase gene cause?

Answer 17

Inactivating mutations of glucokinase gene results in inadequate insulin secretion and form the basis of maturity-onset diabetes of youth

Question 18

Tanner stages

Answer 18

Tanner stages of development of secondary sexual characteristics
Boys - development of external genitalia
Stage 1: Prepubertal
Stage 2: Enlargement of scrotum and testes; scrotum skin reddens and changes in texture
Stage 3: Enlargement of penis (length at first); further growth of testes
Stage 4: Increased size of penis with growth in breadth and development of glans; testes and scrotum larger, scrotum skin darker
Stage 5: Adult genitalia
Girls - breast development
Stage 1: Prepubertal
Stage 2: Breast bud stage with elevation of breast and papilla; enlargement of areola
Stage 3: Further enlargement of breast and areola; no separation of their contour
Stage 4: Areola and papilla form a secondary mound above level of breast
Stage 5: Mature stage: projection of papilla only, related to recession of areola
Boys and girls - pubic hair
Stage 1: Prepubertal (can see velus hair similar to abdominal wall)
Stage 2: Sparse growth of long, slightly pigmented hair, straight or curled, at base of penis or along labia
Stage 3: Darker, coarser and more curled hair, spreading sparsely over junction of pubes
Stage 4: Hair adult in type, but covering smaller area than in adult; no spread to medial surface of thighs
Stage 5: Adult in type and quantity, with horizontal distribution (“feminine”)

Question 19

testicular volume by age

Answer 19

• Tanner I < 1.5 ml [<9 yrs]
• Tanner II - 1.6 - 6 ml [9-11yrs]
• Tanner III - 6 - 12 ml [11-12.5]
• Tanner IV - 12 - 20 ml [12.5-14 yrs]
• Tanner V > 20 ml [14+]

Question 20

Steroidogenesis

Answer 20

Question 21

Precocious puberty

Answer 21

onset of secondary sexual development before the age of eight years in girls and nine years in boys.

mean age of onset of puberty is about 10.5 years of age in girls and 11.5 years in boys

Question 22

The lifetime risk of developing T1DM is

Answer 22

■No family history – 0.4 percent
■Offspring of an affected mother – 1 to 4 percent
■Offspring of an affected father – 3 to 8 percent
■Offspring with both parents affected – reported as high as 30 percent
■Non-twin sibling of affected patient – 3 to 6 percent
■Dizygotic twin – 8 percent
■Monozygotic twin – 30 percent within 10 years of diagnosis of the first twin, and 65 percent concordance by age 60 years

UPTODATE

Question 23

Diabetes Insipidus

Plasma sodium and urine osmolality in

primary polydipsia,

Answer 23

Primary polydipsia low plasma sodium concentration (less than 137 meq/L) with a low urine osmolality (eg, less than one-half the plasma osmolality)

1. primary polydipsia -excessive water intake
2. Central - deficient secretion of ADH
3. Nephrogenic - normal ADH secretion but varying degrees of renal resistance to its water-retaining effect

Question 24

Treatment of Central Diabetes Inspidus?

Answer 24

Intranasal desmopressin (DDAVP)

Anti-diuretic hormone analogue.

Question 25

Diabetes Insipidus

Plasma sodium and urine osmolality in Central and nephrogenic DI

Answer 25

Central and nephrogenic DI - high-normal plasma sodium concentration (greater than 142 meq/L, due to water loss) points toward DI, particularly if the urine osmolality is less than the plasma osmolality

1. primary polydipsia -excessive water intake
2. Central - deficient secretion of ADH
3. Nephrogenic - normal ADH secretion but varying degrees of renal resistance to its water-retaining effect

Look for urine more dilute than plasma….in DI patients are not concentrating urine.

Question 26

Diabetes Insipidus

Plasma sodium and urine osmolality in

1. primary polydipsia,
2. Central DI
3. Nephrogenic DI

Answer 26

1. primary polydipsia low plasma sodium concentration (less than 137 meq/L) with a low urine osmolality (eg, less than one-half the plasma osmolality)
2. Central and Nephrogenic DI - high-normal plasma sodium concentration (greater than 142 meq/L, due to water loss) points toward DI, particularly if the urine osmolality is less than the plasma osmolality
3. primary polydipsia -excessive water intake
4. Central - deficient secretion of ADH
5. Nephrogenic - normal ADH secretion but varying degrees of renal resistance to its water-retaining effect

Question 27

What is the normal physiologic response to a water restriction test, and what is the response in diabetes insipidus?

Answer 27

• Raising the plasma osmolality leads to a progressive elevation in ADH release and an increase in urine osmolality in normal individuals.
• Once the plasma osmolality reaches 295 to 300 mosmol/kg (normal 275 to 290 mosmol/kg) or the plasma sodium is 145 meq/L or higher, the effect of endogenous ADH on the kidney is maximal. At this point, administering desmopressin will not further elevate the urine osmolality unless endogenous ADH release is impaired (ie, unless the patient has central DI).

Question 28

What is the chromosome and gene affected in MODY 1?

Answer 28

Chromosome: 20

Gene: HNF-4a

5-10% of cases

Question 29

What is the chromosome and gene affected in MODY 2?

Answer 29

Chromosome: 7

Gene: Glucokinase

30-70% of cases (MODY 2 and MODY 3 most common).

Mild fasting hyperglycaemia throughout life.

Question 30

What is the chromosome and gene affected in MODY 3?

Answer 30

Chromosome: 12

Gene: HNF-1a

30-70% of cases (MODY 2 and MODY 3 most common)

Responds well to sulfonylureas

Question 31

What is the chromosome and gene in MODY 4?

Answer 31

Chromosome: 13

Gene: PDX-1 (IPF-1)

Associated with pancreatic agenesis in homozygotes and sometime in heterozygotes.

<1% of cases

Question 32

What is the chromosome and gene affected in MODY 5?

Answer 32

Chromosome: 17

Gene: HNF-1ß

5-10% of cases

Assoc. with pancreatic atrophy and several forms of renal disease.

Question 33

What is the gene affected in MODY 6?

Answer 33

Neuro D-1

Question 34

What is the action of Aldosterone on Na+ and K+ in the kidneys?

Answer 34

Sodium in, potassium out

• Acts on nuclear mineralocorticoid receptors (MR) within the principal cells of the distal tubule and the collecting duct.
• Upregulates and activates the basolateral Na+/K+ pumps
  
  • 3x Na⁺ out of the cell, into the interstitial fluid
  • 2x K⁺ ions into the cell from the interstitial fluid.
• ⇒ concentration gradient ⇒ reabsorption of Na+ and water (which follows sodium) into the blood, and secreting (K+) into the urine (lumen of collecting duct).