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Written exam > Endocrinology > Flashcards

Endocrinology Flashcards

1
Q

Clinical parameters in SIADH?

A

Serum sodium: low
Urine output: normal or low
Urine sodium: high
Intravascular volume status: normal or high
Vasopressin level: high

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2
Q

Clinical parameters in cerebral salt wasting?

A

Serum sodium: low
Urine output: high
Urine sodium: very high
Intravascular volume status: low
Vasopressin level: low

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3
Q

Clinical parameters in central DI?

A

Serum sodium: high
Urine output: high
Urine sodium: low
Intravascular volume status: low
Vasopressin level: low

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4
Q

Hormones of the anterior pituitary

A

Growth hormone
Prolactin
Thyroid stimulating hormone
Adrenocorticotropin
Follicle-stimulating hormone
Luteinizing hormone

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5
Q

Hormones of the hypothalamus

A

Thyrotropin releasing hormone (TRH)
Corticotropin releasing hormone (CRH)
Growth hormone releasing hormone (GHRH)
Gonadotropin releasing hormone (GnRH)
Dopamine

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6
Q

Action of thyrotropin releasing hormone?

A

Controls release of TSH

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7
Q

Action of corticotropin releasing hormone?

A

Controls release of ACTH

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8
Q

Action of growth hormone releasing hormone?

A

Releases GH and SS (which inhibits release of GH)

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9
Q

Action of gonadotropin releasing hormone (GnRH)?

A

Releases LH and FSH

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10
Q

Action of dopamine?

A

Inhibits prolactin secretion

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11
Q

Role of hypothalamus

A

Autonomic nervous system regulation
Temperature regulation
Water balance
Food intake and energy balance
Emotions and behaviours
Endocrine secretions from the pituitary gland

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12
Q

Embryological origins of the pituitary?

A

Anterior pituitary: pharyngeal arches (specifically, derived from Rathke’s pouch - invagination of the oral ectoderm)
Posterior pituitary: outpouching of the brain

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13
Q

Blood supply of the pituitary?

A

Arterial blood supply originates from the internal carotid via the inferior, middle and superior hypophyseal arteries

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14
Q

Target cells and major function of growth hormone?

A

Target cells: bone, soft tissue
Major function: stimulate growth of bones and soft tissue, have metabolic effects (protein anabolism, fat mobilisation and glucose conservation)

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15
Q

Target cells and major function of prolactin?

A

Target cells: mammary glands (females)
Major function: promote breast development and stimulate milk secretion

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16
Q

Target cells and major function of TSH?

A

Target cells: thyroid follicular cells
Major function: stimulates T3 and T4 secretion

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17
Q

Target cells and major function of ACTH?

A

Target cells: zona fasciulata and zona reticularis of adrenal cortex
Major function: stimulates cortisol secretion

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18
Q

Target cells and major function of FSH?

A

Target cells: ovarian follicles (female), seminiferous tubules in testes (male)
Major function: promotes follicular growth and development and stimulates oestrogen secretion (female), stimulates sperm production (male)

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19
Q

Target cells and major function of LH?

A

Target cells: ovarian follicle and corpus luteum (female), interstitial cells of Leydig cells (male)
Major function: stimulates ovulation, corpus luteum development, and oestrogen and progesterone secretion (female), stimulates testosterone secretion (male)

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20
Q

Gene responsible for growth hormone?

A

GH1 on chromosome 17

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21
Q

GH secretion pattern?

A

Pulsatile - most intense period of GH release is shortly after onset of deep sleep

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22
Q

Factors stimulating release of GH?

A

GHRH
Ghrelin
Hypoglycaemia
Sleep, exercise, stress, nutritional deficiency, oestrogen or testosterone

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23
Q

Factors inhibiting GH release?

A

Somatostatin
Hyperglycaemia
Steroids
Hypothyroidism
GH and IGF1 (acts at hypothalamus and pituitary as negative feedback)

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24
Q

Mechanism of GH release?

A

Binds to GH receptor which activates Jak2-stat transcription pathway
Primarily acts through synthesis of somatomedins, particularly IGF-1, at the liver
Largely protein bound to IGF-BP3 (this is decreased in GH deficient children

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25
Q

Actions of growth hormone?

A

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

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26
Q

Regulation of prolactin secretion?

A

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

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27
Q

Factors stimulating prolactin release?

A

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

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28
Q

Factors inhibiting prolactin release?

A

Dopamine

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29
Q

Actions of prolactin?

A

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

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30
Q

Mechanism of TSH binding?

A

Receptor binding activates cAMP and G protein second messenger system

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31
Q

Factors stimulating TSH release?

A

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

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32
Q

Factors inhibiting TSH release?

A

Thyrosine (negative feedback)
Dopamine
Somatostatin and glucocorticoids

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33
Q

Actions of TSH

A

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

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34
Q

Process of ACTH secretion?

A

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

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35
Q

Factors stimulating ACTH release?

A

CRH
Vasopressin
Oxytocin
Angiotensin II
CCK

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36
Q

Factors inhibiting ACTH release?

A

ANP
Opioids
Cortisol

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37
Q

Action of ACTH

A

Adrenal cortex: cortisol synthesis and secretion

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38
Q

Actions of LH and FSH?

A

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

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39
Q

Factor stimulating LH/FSH release?

A

GnRH

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40
Q

Inhibition of LH/FSH release in males?

A

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

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41
Q

Inhibition of LH/FSH release in females?

A
  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
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42
Q

Actions of ADH?

A

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

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43
Q

Factors stimulating ADH release?

A
  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
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44
Q

Factors inhibiting ADH release?

A
  1. ANP - produced by cardiac atrial muscles stimulates Na secretion/inhibition of Na reabsorption
  2. Other - ethanol, alpha agonists, caffeine
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45
Q

Most common lesion causing hypopituitarism?

A

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

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46
Q

Situations where treatment with IGF-1 is most helpful?

A
  1. Abnormality of GH receptor
  2. Abnormality of STAT5b gene
  3. Severe GH deficiency in patients with antibodies to GH
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47
Q

Hormone deficiencies seen in PROP1?

A

GH, TSH, LH, ACTH

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48
Q

Mechanism and presentation with PROP1?

A

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

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49
Q

Hormone deficiency in POUF1?

A

GH, prolactin, TSH (variable)

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50
Q

Mechanism and presentation of POUF1?

A

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

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51
Q

Mutation associated with septo-optic dysplasia?

A

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

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52
Q

Overview of HESX1 mutation?

A

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

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53
Q

Clinical manifestations of HESX1 mutation?

A

Nystagmus and visual impairment in infancy
May have GH deficiency

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54
Q

Hormone deficiency seen in LHX3 and LHX4?

A

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

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55
Q

Overview of pituitary hypoplasia

A

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

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56
Q

Solitary maxillary central incisor raises suspicion of?

A

High likelihood of GH or other anterior or posterior hormone deficiency

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57
Q

Which hormone is most susceptible to disruption by acquired conditions?

A

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

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58
Q

Overview of GH1 gene mutation?

A

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

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59
Q

Features of septo-optic dysplasia?

A

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

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60
Q

Genes associated with septo-optic dysplasia?

A

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

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61
Q

Polyuria DDx?

A

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

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62
Q

Causes of diabetes insipidus?

A

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

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63
Q

Definition of diabetes insipidus?

A

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

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64
Q

Genetic causes of nephrogenic DI?

A
  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
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65
Q

Acquired causes of nephrogenic DI?

A
  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
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66
Q

Paired urine and serum sodium and osmolality results in DI?

A

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

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67
Q

Acute management of DI

A
  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
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68
Q

Overview of water deprivation test?

A

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

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69
Q

Normal response to water deprivation test?

A

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

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70
Q

Response to water deprivation test seen in central DI?

A

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

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71
Q

Response to water deprivation test seen in nephrogenic DI?

A

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

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72
Q

Partial central vs partial nephrogenic DI?

A

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

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73
Q

When to cease water deprivation during study?

A
  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
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74
Q

Overview of response to DDAVP in DI?

A

Central DI - reduced UO
Nephrogenic DI - no response

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75
Q

Clinical manifestations of nephrogenic DI?

A

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

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76
Q

Mutations seen in nephrogenic DI?

A

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

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77
Q

Pathophysiology of SIADH?

A

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

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78
Q

Clinical manifestations/investigations in SIADH

A

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

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79
Q

Management of SIADH

A

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)

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80
Q

Genetic influence in T1DM?

A

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%

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81
Q

Criteria for diagnosis of diabetes?

A

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

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82
Q

Pathophysiology of T1DM

A

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

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83
Q

Risk factors for presenting in DKA?

A

Age <2
Ethnic minority
Lower SES
Lower BMI

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84
Q

Associations with T1DM?

A

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

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85
Q

Clinical features of DKA

A

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

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86
Q

Criteria for DKA

A

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

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87
Q

Rationale for including potassium in maintenance fluids for treatment of DKA?

A

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

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88
Q

Diagnostic criteria for cerebral oedema as a complication of DKA?

A

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

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89
Q

Treatment for cerebral oedema secondary to DKA treatment?

A

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

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90
Q

Overview of cerebral oedema as a DKA complication?

A

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

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91
Q

Pathophysiology of T2DM?

A

Impairment of insulin secretion and insulin resistance, leading to hyperglycaemia

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92
Q

Risk factors for T2DM?

A

Genetics
Environmental factors
Obesity
Females
Ethnic minority groups

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93
Q

Forms of presentation of T1DM?

A
  1. Symptomatic (subacute polyuria and polydipsia, weight loss)
  2. DKA
  3. Asymptomatic (incidental finding)
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94
Q

Complications of T1DM?

A

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

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95
Q

Overview of hyperosmolar hyperglycaemic non-ketotic syndrome

A

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

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96
Q

Pathogenesis of hyperosmolar hyperglycaemia non-ketotic syndrome

A

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

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97
Q

Gluconeogenesis

A

Glucose production

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98
Q

Glycogenolysis

A

Glycogen breakdown

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99
Q

Physiological response to fasting

A
  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
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100
Q

Risk factors for transient hypoglycaemia in neonates?

A

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

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101
Q

Causes of persistent congenital hyperinsulinism?

A

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

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102
Q

Cause of ketotic hypoglycaemia of childhood?

A

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

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103
Q

Presentation of ketotic hypoglycaemia of childhood

A

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

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104
Q

Investigations in ketotic hypoglycaemia of childhood?

A

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

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105
Q

Treatment of ketotic hypoglycaemia of childhood?

A

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

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106
Q

Overview of normal sexual development

A

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

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107
Q

Development of testes from bipotential gonads

A
  • 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
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108
Q

Thelarche

A

Breast development

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109
Q

Adrenarche

A

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

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110
Q

Gonadarche

A

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

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111
Q

Development of hypothalamic-pituitary axis to stimulate puberty?

A

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

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112
Q

Effect of LH and FSH?

A

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

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113
Q

What simulates adrenarche?

A

Dehydroepiandrosterone (DHEA) or androstenedione

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114
Q

Definition of precocious puberty

A

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

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115
Q

Premature thelarche

A

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

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116
Q

Premature adrenarche/pubarche

A

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

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117
Q

Central precocious puberty

A

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

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118
Q

Peripheral precocious puberty

A

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

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119
Q

Most common cause of peripheral precocious puberty?

A

McCune-Albright syndrome

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120
Q

Classic triad seen in McCune-Albright syndrome?

A

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

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121
Q

Associations with McCune-Albright syndrome?

A

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

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122
Q

Physiology of McCune-Albright syndrome?

A

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

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123
Q

Common presentation with McCune-Albright (not classic triad)

A

Irregular vaginal bleeding
Recurrent ovarian cysts

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124
Q

Mechanism of familial GnRH independent sexual precocity?

A

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

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125
Q

Investigating precocious puberty

A

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

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126
Q

GnRH stimulation test to investigate precocious puberty

A

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

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127
Q

Overview of Kallman syndrome

A

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

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128
Q

Classification of hypergonadotropic hypogonadism?

A

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

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129
Q

Classification of hypogonadotropic hypogonadism?

A

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

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130
Q

Overview of ovarian failure

A

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

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131
Q

Overview of Klinefelter syndrome

A

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

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132
Q

Definition of primary amenorrhoea

A

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)

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133
Q

Definition of Mayer-Rokitansky-Kuster-Hauser syndrome?

A

Congenital absence of the uterus

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134
Q

Key investigation in primary gonadal failure?

A

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

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135
Q

Investigations for delayed puberty

A

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

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136
Q

46XX disorders of sexual development

A

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

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137
Q

Overview of CAH

A

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

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138
Q

46XY disorders of sexual development

A

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

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139
Q

Causes of reduced testosterone production

A
  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)
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140
Q

Most common type of CAH?

A

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

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141
Q

Significance of measuring AMH?

A

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

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142
Q

Overview of androgen insensitivity syndrome

A

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

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143
Q

Clinical presentation of androgen insensitivity syndrome

A

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)

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144
Q

Features of complete androgen insensitivity

A

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

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145
Q

Features of partial androgen insensitivity

A

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

146
Q

Causes of pathological gynaecomastia

A

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

147
Q

Signs of anabolic steroid use

A

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

148
Q

Long term side effects of anabolic steroid use

A

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

149
Q

Rules of thumb for growth in infancy

A

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

150
Q

Familial short stature

A

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

151
Q

Constitutional short stature

A

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

152
Q

Idiopathic short stature

A

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

153
Q

What is Laron syndrome?

A

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

154
Q

Overview of GH deficiency

A

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

155
Q

Clinical features of GH deficiency

A

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

156
Q

Genetic syndromes associated with short stature

A

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

157
Q

Indications for treatment with growth hormone

A

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

158
Q

Method of GH stimulation testing

A

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

159
Q

Side effects of GH therapy

A

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

160
Q

Contraindications for GH therapy?

A

Active malignancy

161
Q

Endocrine causes of accelerated linear growth

A

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

162
Q

Non-endocrine causes of accelerated linear growth

A

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

163
Q

What does high IGF-1 indicate?

A

GH excess

164
Q

Symptoms of craniopharyngioma?

A

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

165
Q

Symptoms of pituitary adenoma?

A

Overgrowth and hyperpituitarism

166
Q

Actions of PTH, vitamin D and calcitonin on calcium levels?

A

PTH and vitamin D - increase Ca
Calcitonin - decreases Ca

167
Q

Proportion of calcium absorbed via the GIT?

A

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

168
Q

Breakdown of calcium in serum?

A

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

169
Q

Most important influence on protein binding with calcium?

A

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

170
Q

Excretion of calcium?

A

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)

171
Q

Factors affecting calcium excretion?

A

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)

172
Q

Role of osteoblasts with relation to calcium?

A

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)

173
Q

Role of osteoclasts with relation to calcium?

A

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

174
Q

Location and role of calcium sensing receptors?

A

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

175
Q

William syndrome - high or low calcium?

A

Hypercalcaemia

176
Q

Parathyroid hormone - stimulated and inhibited by?

A

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

177
Q

Overview of PTH actions

A

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)

178
Q

PTH action on bone

A
  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
179
Q

PTH action on kidneys and gut

A

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

180
Q

Secretion and inhibition of calcitonin?

A

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

181
Q

Actions of calcitonin?

A

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

182
Q

Type of Vitamin D ingested orally?

A

Cholecalciferol (vitamin D3)

183
Q

Conversions of forms of vitamin D?

A

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

184
Q

Actions of Vitamin D

A

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

185
Q

Mechanism of gut effects of vitamin D?

A
  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
186
Q

Difference between 25-hydroxy-vitamin D and 1, 25-hydroxy-vitamin D?

A

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)

187
Q

Overview of PTH related peptide

A

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

188
Q

Causes of hypocalcaemia with low PTH

A
  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)
189
Q

Causes of hypocalcaemia with high PTH

A
  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
190
Q

Miscellaneous causes of hypocalcaemia

A

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

191
Q

Clinical features of hypocalcaemia

A

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

192
Q

Formula for corrected calcium?

A

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

193
Q

ECG findings in hypocalcaemia?

A

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

194
Q

Treatment of hypocalcaemia?

A

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

195
Q

Early vs late neonatal hypocalcaemia

A

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)

196
Q

Causes of late neonatal hypocalcaemia

A

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

197
Q

Hypoparathyroidism

A

= 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

198
Q

Sanjad-Sakati syndrome?

A

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

199
Q

Kenney-Caffey type 1 syndrome

A

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

200
Q

DiGeorge/velocardiofacial syndrome: hyper or hypocalcaemia?

A

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

201
Q

X linked recessive hypoparathyroidism

A

Absent parathyroid tissue due to defect in embryogenesis
Variable transmission

202
Q

AR hypoparathyroidism with dysmorphic features

A

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

203
Q

Hypoparathyroidism associated with mitochondrial disorders?

A

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

204
Q

Familial hypocalcaemia

A

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

205
Q

Clinical features of familial hypocalcaemia

A

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

206
Q

Investigations for familial hypocalcaemia

A

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

207
Q

Treatment for familial hypocalcaemia

A

No treatment required if asymptomatic
Vitamin D results in nephrocalcinosis

208
Q

Variants of familial hypocalcaemia

A

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)

209
Q

Congenital causes of hypoparathyroidism

A

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

210
Q

Autoimmune causes of hypoparathyroidism

A

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

211
Q

APECED/autoimmune polyglandular syndrome type 1

A

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

212
Q

Acquired causes of hypoparathyroidism

A

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

213
Q

Causes of hyperparathyroidism

A

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

214
Q

Vitamin D deficiency

A

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

215
Q

Abnormal Vitamin D metabolism

A

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

216
Q

VDDR type 1 (1-alpha hydroxylase deficiency)

A

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)

217
Q

VDDR type 2 (hereditary resistance to Vitamin D)

A

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

218
Q

Key features of pseudohypoparathyroidism

A

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

219
Q

Types of pseudohypoparathyroidism

A

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

220
Q

Genetics of type 1A pseudohypoparathyroidism

A

= 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)

221
Q

Pathogenesis and clinical findings of Albright hereditary osteodystrophy?

A

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

222
Q

Hormonal abnormalities seen in Albright Hereditary Osteodystrophy?

A

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

223
Q

Pseudopseudohypoparathyroidism?

A

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)

224
Q

Type 1b pseudohypoparathyroidism

A

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

225
Q

Type 2 pseudohypoparathyroidism

A

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

226
Q

Hungry bone syndrome

A

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

227
Q

Mechanisms of hypocalcaemia seen in hypoMg?

A
  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
228
Q

Mechanism of renal failure leading to hypocalcaemia

A

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

229
Q

Rickets vs osteomalacia

A

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

230
Q

Clinical presentation of rickets/osteomalacia

A

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

231
Q

XR findings in rickets/osteomalacia

A

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

232
Q

Types of rickets

A

Vitamin D deficiency rickets
Vitamin D dependent rickets
Hypophosphatemic rickets

233
Q

Causes of Vitamin D deficient rickets

A

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

234
Q

Cause of Vitamin D dependent rickets

A

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

235
Q

Causes of hypophosphatemic rickets

A

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

236
Q

Cause of hypophosphatasia?

A

ALPL gene mutation

237
Q

Overview of Vitamin D deficiency rickets

A

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

238
Q

Overview of Vitamin D dependent rickets

A

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

239
Q

1-alpha hydroxylase deficiency

A

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

240
Q

25-hydroxylase deficiency

A

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

241
Q

Hereditary resistance to Vitamin D

A

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)

242
Q

Hypophosphatemic rickets

A

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

243
Q

FGF23 dependent causes of hypophosphatemic rickets

A

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)

244
Q

FGF23 independent causes hypophosphatemic rickets

A

Fanconi syndrome/renal tubular acidosis
Hereditary hypophosphatemic rickets with hypercalciuria

245
Q

Overview of X linked hypophosphatemic rickets (XLH)

A

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

246
Q

Treatment for X linked hypophosphatemic rickets?

A

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

247
Q

Hypophosphatasia

A

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

248
Q

Symptoms of hypercalcaemia

A

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

249
Q

Long term clinical features of hypercalcaemia

A

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)

250
Q

ECG findings in hypercalcaemia

A

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

251
Q

Neonatal causes of hypercalcaemia

A

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)

252
Q

Causes of hypercalcaemia due to hyperparathyroidism

A

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

253
Q

Causes of hypercalcaemia due to excessive calcium or vitamin D

A

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

254
Q

Other causes of hypercalcaemia

A

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

255
Q

Treatment of hypercalcaemia

A

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

256
Q

Mechanism of calcitonin in treating hypercalcaemia

A

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

257
Q

Mechanism of bisphosphonates in treatment of hypercalcaemia

A

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

258
Q

Primary hyperparathyroidism

A

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

259
Q

Subcutaneous fat necrosis of the newborn

A

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

260
Q

Williams-Beuren syndrome

A

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

261
Q

Hyperparathyroidism-jaw tumour syndrome

A

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

262
Q

Transient neonatal hyperparathyroidism

A

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

263
Q

Neonatal severe hyperparathyroidism

A

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

264
Q

Anatomy of adrenal gland

A

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

265
Q

Overview of hypothalamic-pituitary-adrenal (HPA) axis?

A

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

266
Q

Regulation of aldosterone production?

A

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

267
Q

Overview of primary adrenal insufficiency

A

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

268
Q

Causes of primary adrenal insufficiency?

A

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

269
Q

Clinical presentation of glucocorticoid deficiency

A

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

270
Q

Clinical presentation of aldosterone deficiency

A

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

271
Q

Skin findings associated with ACTH oversecretion?

A

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

272
Q

Long term treatment of adrenal insufficiency?

A

Cortisol deficiency: hydrocortisone
Aldosterone deficiency: fludrocortisone

273
Q

Overview of Addison disease

A

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

274
Q

Workup for suspected Addison disease

A

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

275
Q

Pathophysiology of adrenoleukodystrophy?

A

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

276
Q

Clinical presentation of adrenoleukodystrophy

A

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)

277
Q

Overview of congenital adrenal hypoplasia

A

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

278
Q

Acquired causes of primary adrenal insufficiency

A

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)

279
Q

Overview of congenital adrenal hyperplasia

A

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)

280
Q

Overview of 21-hydroxylase deficiency

A

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

281
Q

Pathophysiology of 21-hydroxylase deficiency

A

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

282
Q

Clinical presentation of 21-hydroxylase deficiency

A

“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

283
Q

Genital appearance of 21-hydroxylase deficiency in a genetic male?

A

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

284
Q

Genital appearance of 21-hydroxylase deficiency in a genetic female?

A

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

285
Q

Presentation of salt wasting CAH?

A

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

286
Q

Pathophysiology of simple virilising CAH?

A

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

287
Q

Presentation of simple virilising CAH?

A

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

288
Q

Hyponatraemia, hyperkalaemia, non-gap metabolic acidosis, dehydration?

A

Salt wasting CAH (insufficient glucocorticoids and aldosterone)

289
Q

“Non classic” CAH presentation?

A

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

290
Q

Investigation findings in 21-hydroxylase deficiency?

A

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

291
Q

Treatment of 21-hydroxylase deficiency?

A

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

292
Q

Prenatal treatment of 21-hydroxylase deficiency?

A

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)

293
Q

Overview of 11b-hydroxylase deficiency

A

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

294
Q

Pathophysiology and clinical features of 3b-hydroxysteroid dehydrogenase deficiency?

A

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)

295
Q

Investigation findings in 3b-hydroxysteroid dehydrogenase deficiency?

A

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)

296
Q

Overview of secondary adrenal insufficiency

A

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

297
Q

Causes of secondary adrenal insufficiency

A

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)

298
Q

Presentation of secondary adrenal insufficiency

A

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

299
Q

Tertiary adrenal insufficiency

A

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

300
Q

Overview of Cushing syndrome

A

Syndrome characterised by an excess of glucocorticoid effects

301
Q

ACTH dependent causes of Cushing syndrome

A

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

302
Q

ACTH independent causes of Cushing syndrome

A

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

303
Q

Clinical presentation of Cushing syndrome

A

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

304
Q

Investigation of Cushing syndrome

A

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

305
Q

Overview of pheochromocytoma

A

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)

306
Q

Symptoms of pheochromocytoma

A

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

307
Q

Diagnosis of pheochromocytoma

A

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)

308
Q

Features of APECED

A

= 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

309
Q

Overview of autoimmune polyendocrine syndrome

A

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

310
Q

Overview of APS type 2

A

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

311
Q

Overview of APS type 3

A

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)

312
Q

Overview of IPEX

A

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

313
Q

Clinical features of IPEX

A

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

314
Q

Treatment of IPEX

A

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)

315
Q

Multiple endocrine neoplasia overview

A

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

316
Q

MEN type 1

A

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

317
Q

Other MEN 1 associated tumours?

A

Carcinoid tumours
Lipomas
Adrenal tumours
Thyroid adenomas
Thymic neuroendocrine tumour

318
Q

MEN type 2a

A

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

319
Q

MEN type 2b

A

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)

320
Q

Overview of congenital hypothyroidism

A

Most common endocrinological disorder
Leading preventable cause of intellectual disability

321
Q

Causes of congenital hypothyroidism

A

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

322
Q

Presentation of congenital hypothyroidism

A

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

323
Q

Investigation of congenital hypothyroidism

A

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

324
Q

Treatment of congenital hypothyroidism

A

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

325
Q

Overview of central hypothyroidism

A

= 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

326
Q

Features of central hypothyroidism

A

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

327
Q

Investigations in central hypothyroidism

A

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

328
Q

Treatment of central hypothyroidism

A

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

329
Q

Overview of Hashimoto thyroiditis

A

= 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

330
Q

Signs of moderate or severe hypothyroidism

A

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

331
Q

Clinical presentation of Hashimoto thyroiditis

A

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)

332
Q

Investigation findings in Hashimoto thyroiditis

A

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

333
Q

Treatment of Hashimoto’s thyroiditis

A

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

334
Q

Food/supplements which impact absorption of levothyroxine?

A

Dairy products
Vitamin supplements including calcium and iron

335
Q

Complications of Hashimoto’s thyroiditis

A

Hashitoxicosis
Hashimoto encephalopathy

336
Q

Hashitoxicosis

A

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

337
Q

Hashimoto encephalopathy

A

= 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

338
Q

Sick euthyroid syndrome overview

A

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

339
Q

Investigations and treatment of sick euthyroid syndrome

A

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

340
Q

Causes of iatrogenic hypothyroidism

A

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

341
Q

Overview of thyroid-binding globulin deficiency

A

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

342
Q

Overview of resistance to thyroid hormone

A

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

343
Q

Clinical presentation and investigation findings in thyroid hormone resistance

A

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

344
Q

Treatment of thyroid hormone resistance

A

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

345
Q

Overview of subclinical hypothyroidism

A

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

346
Q

Overview of Graves disease

A

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

347
Q

Clinical presentation of Graves disease

A

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)

348
Q

Investigation findings in Graves disease

A

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

349
Q

Overview of treatment of Graves disease

A

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

350
Q

Medical treatment of Graves

A

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)

351
Q

Radioactive iodine ablation in Graves

A

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

352
Q

Surgical management of Graves disease

A

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

353
Q

Overview of subacute thyroiditis

A

= 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

354
Q

Overview of neonatal thyrotoxicosis

A

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

355
Q

Presentation of neonatal thyrotoxicosis

A

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

356
Q

Investigations and treatment of neonatal thyrotoxicosis

A

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

357
Q

Overview of thyroid nodules

A

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)

358
Q

Scenarios that raise suspicion for thyroid carcinoma?

A
  • 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
359
Q

Overview of medullary thyroid cancer

A

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

360
Q

Diagnosis and treatment of medullary thyroid cancer

A

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

Written exam (21 decks)

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