Endocrine Flashcards
(233 cards)
1
Q
Peripheral endocrine glands (thyroid, pancreas, adrenals and gonads) when and from where it developed?
A
form early in the second month from epithelial/mesenchyme interactions
2
Q
What Amine hormones?
A
🔺catecholamines
🔺serotonin (5-hydroxytryptamine, 5HT)
3
Q
What are the Peptide hormones?
A
🔺growth hormone (GH)
🔺 insulin
🔺thyroxine
4
Q
what are the Steroid hormones?
A
🔺cortisol, aldosterone 🔺androgens🔺oestrogen, progesterone
5
Q
What are the functions of These binding proteins?
A
🔺buffer against very rapid changes
🔺 act as a reservoir for the hormones.
6
Q
administration of intermittent gonadotrophin-releasing hormone (GnRH)
A
induces priming and facilitates a large output of gonadotrophins,
7
Q
continuous GnRH?
A
leads to a downregulation of receptors and hence has a protective effect
8
Q
What are the different patterns of hormone secretion??
A
🥑Continuous, e.g. thyroxine
🥑Pulsatile, e.g. follicle-stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH)
🥑Circadian, e.g. cortisol
🥑 Stress related, e.g. ACTH
🥑Sleep related, e.g. GH, prolactin
9
Q
What are the main types of receptor?
A
- Cell surface membrane receptors:
**Amine and peptide hormones **
• G-protein-coupled receptors (GPCRs)
Gi ( somatostatin)
Gs (all hormones)
• Tyosine kinase receptors (TKRs) - Intracellular receptors (for fat-soluble hormones)
Steroid (cytoplasmic)
Thyroxine (nucleus)
10
Q
Amine and peptide hormones what are their mechanism of action?
A
Via intracellular second messenger (e.g. adenosine cyclic monophosphate or cAMP, calcium).
11
Q
Steroid hormones what is their mechanism of action?
A
They act on DNA to alter gene transcription and protein synthesis.
12
Q
Give example of receptor abnormalitllty causing endocrine disease
A
🧶Syndromes of G-protein abnormalities, e.g. McCune–Albright syndrome
🧶Syndromes of receptor resistance: these mutations in nuclear receptors result in end-organ unresponsiveness, e.g. vitamin D-resistant rickets.
🧶Mutations of nuclear receptors, e.g. pseudohypoparathyroidism
13
Q
What is the location of hypothalamus?
A
between the preoptic area and the mamillary bodies
14
Q
Where is the pituitary gland?
A
a midline structure situated inferior to the hypothalamus within the pituitary fossa.
15
Q
What is the transcription factor that is essential for development of the normal pituitary gland relies on?
A
homeobox genes
♂️ HESX1 is a homeobox gene implicated in some forms of septo-optic dysplasia.
16
Q
What are the function of hypothalamus?
A
🔺appetite suppression
🔺temperature control.
🔺Thirst regulation
17
Q
Leptin, what it is function??
A
💤 provides the body with information about nutritional status.
🚀 The hypothalamus contains large numbers of leptin receptors and plays an important role in controlling feeding behaviour and hunger.
🚀Leptin also plays a significant role in the regulation of reproduction.
18
Q
Function of GH??
A
carbohydrate and lipid metabolism
19
Q
What is the time for GH release??
A
Nocturnal release occurs during nondreaming or slow-wave sleep, shortly after the onset of deep sleep.
20
Q
What are the Three peptides that are critical to the control of GH secretion:
A
• Growth hormone-releasing hormone (GHRH)
• Growth hormone-releasing peptide (GHRP) – ghrelin
• Somatostatin
factors that influence the secretion of GH, which include sex steroids, environmental inputs and genetic determinants.
21
Q
Why ghrelin is released??
A
response to acute and chronic changes in nutritional state.
22
Q
How many lobes does the pituitary gland has and what is the origin of each lobe??
A
💜The anterior and intermediate lobes are derived from the buccal mucosa
💜 the posterior lobe is derived from neural ectoderm.
23
Q
Ghrelin??
A
is a gastric peptide that stimulates GH secretion and increases adiposity.
🔺 It acts at the GH secretagogue receptors located in the hypothalamus and pituitary gland.
24
Q
How ghrelin hormone are released??
A
The concentrations of ghrelin
⬆️ rise during fasting, after weight loss or gastrectomy, and in anorexia nervosa.
⬇️fall postprandially and in obesity,
25
What is the function of LH??
🔶🔶male➡️ Leydig cells ➡️ stimulates the first step in testosterone production.
🔶🔶 female➡️ binds to ovarian cells➡️ and stimulates steroidogenesis.
26
What is indication of growth hormone replacement??
• Documented GH deficiency – congenital or acquired
• Turner syndrome
• Chronic renal failure
• Prader–Willi syndrome
• Small for gestational age
27
What are the cells that produce testosterone??
Testosterone is produced by the Leydig cells of the testes.
28
Testosterone is produced by the Leydig cells of the testes. It is present in the circulation bound to sex hormone-binding globulin (SHBG). Free testosterone is the active moiety at the level of target cells. Testosterone is then converted either to dihydrotestosterone (DHT) by 5α-reductase or to oestrogen by aromatase. Both DHT and testosterone attach to nuclear receptors, which then bind to steroidresponsive regions of genomic DNA to influence transcription and translation.
29
What is the inhibin hormone?
Inhibin is a glycoprotein produced by Sertoli cells in males and granulosa cells in females.
30
Inhibin Inhibin is a glycoprotein produced by Sertoli cells in males and granulosa cells in females.
SHBG Androgens reduce SHBG formation, and oestrogens stimulate its formation. Therefore increased free testosterone levels magnify androgen effects.
31
Hormonal regulation
In the presence of GnRH the gonadotrophins are controlled by the sex steroids and inhibin. LH and FSH levels are under the influence of negative feedback mechanisms in both the hypothalamus and the pituitary. Inhibin inhibits only FSH and acts at the level of the pituitary.
Positive feedback also occurs during mid-puberty in females. Increased oestrogen primes gonadotrophins to produce LH until, at a critical stage at the middle of the menstrual cycle, a large surge occurs causing ovulation.
32
What are the stages of male genitalia development??
🔺Stage 1: pre-adolescent
🔺Stage 2: enlargement of scrotum and testes and changes in scrotal skin
🔺Stage 3: further growth of testes and scrotum; enlargement of penisStage
🔺4: increase in breadth of penis and development of glans; further growth of scrotum and testes Stage 🔺5: adult genitalia in shape and size
33
What are the stages of Female breast development??
🔺Stage 1: pre-adolescent
🔺Stage 2: breast-bud formation 🔺Stage 3: further enlargement and elevation of breast and papilla with no separation of their contours
🔺Stage 4: projection of areola and papilla to form a secondary mound above the level of the breast
🔺Stage 5: mature stage with projection of papilla only
34
Pubic hair
Stage 1: pre-adolescent Stage 2: sparse growth of long, slightly pigmented, downy hair Stage 3: hair spread over junction of the pubes, darker and coarser Stage 4: adult-type hair, but area covered is smaller Stage 5: adult in quantity and type
Axillary hair
Stage 1: no axillary hair Stage 2: scanty growth Stage 3: adult in quantity and type
35
Peak height velocity occurs with testicular volumes of 10–12 ml.
In the female, the appearance of the breast bud and breast development are the first sign of puberty. It is due to production of oestrogen from the ovaries. This is followed by the development of pubic and axillary hair, which is controlled by the adrenal gland. Peak height velocity coincides with breast stage 2–3. Menarche occurs late at breast stage 4, by which stage growth is slowing down. Most girls have attained menarche by age 13 years.
36
When is Peak height velocity for male??
occurs with testicular volumes of 10–12 ml.
37
What are the Causes of gynaecomastia??
• Normal puberty (common)
• Obesity (common)
• Klinefelter syndrome
• Partial androgen insensitivity
38
What is the function of FSH??
🔶🔶In males ➡️binds to Sertoli cells ➡️ it increases the mass of the seminiferous tubules and supports the development of sperm.
🔶🔶 female ➡️FSH binds to the glomerulosa cells ➡️stimulates the conversion of testosterone tooestrogen.
39
What is the mechanism of action of testosterone
🔶It is present in the circulation bound to sex hormone-binding globulin (SHBG).
🔶Free testosterone is the active moiety at the level of target cells. 🔶Testosterone is then converted either to dihydrotestosterone (DHT) by 5α-reductase or to oestrogen by aromatase.
🔶Both DHT and testosterone attach to nuclear receptors, which then bind to steroidresponsive regions of genomic DNA to influence transcription and translation.
40
How to monitor the recovery of the HPA recovery after discontinuation of steroid?
This may be achieved by the short synacthen (ACTH) test, which may be performed after a steroid weaning
programme is completed.
41
What is the benefit of standard vs physiological dose of ACTH?
📶The standard dose of ACTH is 250 micrograms, a supraphysiological dose.
🎦The use of physiological doses (e.g. 1 microgram)) may prove useful in identifying those patients with partial
adrenal insufficiency, such as may occur with chronic steroid treatment ↪️↪️↪️as adrenal glands which are only
partially suppressed may still show a response to the supraphysiological, but not to the physiological
dose
42
Congenital adrenal hyperplasia (CAH) what is the mood of inheritance??
🔹autosomal recessive disorders🔹
43
What is the cause of congenital adrenal hyperplasia??
deficiency in **one of the five enzymes **needed for
steroidogenesis
❤️ (>90%) this is 21-hydroxylase deficiency.
44
What is the function of 21-hydroxylase?.
converts progesterone to deoxvcorticosterone
17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol.
45
what are the substances that accumulate
21-hydroxylase deficiency??
17-OHP and related metabolites (17 hydroxyprogesteron )
46
What are the main important differential diagnoses for CAH??
▪️▪️other cause of adrenal insufficiency.
▪️▪️sepsis.
▪️▪️secondary hypoaldosteronism (pseudohypoaldosteronism).
47
What is the cause of Secondary hypoaldosteronism in infancy??
🔹may occur as a result of urinary tract infection with aldosterone resistance ➡️endotoxin damage to the aldosterone receptors.
This results in hyponatraemia, hyperkalaemia and metabolic acidosis but most frequently with** normoglycaemia**
48
In phenotypicaly male. Palpationof of goad is the important part of the examination why??
To exclude virrilized female
49
When 17-OHP levels should only be taken in suspicion of CAH?? And why??
🕰️after 72 hours of age
✔️fetal adrenal is very metabolically active, 17-OHP and other adrenal metabolites are normally high in
the fetus and the first few days of life and so the results can be difficult to interpret in the newborn
period particularly in prematurity
50
Beckwith–Wiedemann syndrome
What is the genetic cause??
• Usually occurs where there is abnormal regulation of genes in a particular region of chromosome 11.
❤️Up to 20% cases are due to paternal uniparental disomy
51
What are the features of Prader–Willi syndrome??
• Neonatal hypotonia
• Feeding difficulties in the newborn period
• Obesity (food-seeking behaviour)
• Tendency to diabetes mellitus
• Hypogonadism
• Strabismus
❤️Facial features:
• Narrow forehead
• Olive-shaped eyes
• Anti-mongoloid slant
• Carp mouth
• Abnormal ear lobes
❤️ Orthopaedic:
• Small, tapering fingers
• Congenital dislocation of the hips
• Retarded bone age
❤️ IQ: reduced, usually 40–70
52
What is genetic cause ot prader- willi syndrom??
• Genetics: deletion from paternally derived long arm of chromosome 15q
53
What are the Clinical features beckwith-wiedmann syndrom ??
▪️Large birthweight
▪️ Transient hyperinsulinism
▪️ Macrosomia
▪️**Linear fissures on ear lobes**
▪️Umbilical hernia/exomphalos
▪️Hemihypertrophy
❤️Associations: • Wilms tumour
54
Bardet–Biedl syndrome what is the genetic cause?
Mutations in at least 14 different ➡️ BBS genes, which are involved in the structure and function of cilia
55
What are the Clinical features of bardet-Biedl syndrom??
• Learning disability
• Obesity – marked by 4 years of age
• Moderate short stature
• Hypogonadism
• Retinitis pigmentosa/strabismus
• Polydactyly/clinodactyly
❤️Associations:
• Renal abnormalities
• Diabetes insipidus
56
What are the mode of inheritance of Multiple endocrine neoplasia syndromes??
Autosomal dominant syndromes:
• Type I (Wermer syndrome): pancreatic (gastrinoma, insulinoma)/pituitary/parathyroid. This is caused by mutations in the MEN1 gene which provides instructions for producing a protein called menin; this acts as a tumour suppressor
57
What the features of Type 1 Autoimmune polyglandular syndrome??
🔹Addison disease
🔹chronic mucocutaneous candidiasis
🔹hypoparathyroidism
58
what are the features of Type 2 Autoimmune polyglandular syndrome?? :
▪️primary hypothyroidism
▪️primary hypogonadism
▪️type 1 diabetes
▪️pernicious anaemia
▪️Addison disease
▪️vitiligo
59
What is the genetic cause Type II (Sipple syndrome) MEN1 and what are clinical features??
RET gene mutation ➡️ which provides instructions for a protein involved with signalling within cells.
MEN2
🔹medullary thyroid cancer
🔹parathyroid
🔹phaeochromocytoma.
MEN IIb have additional phenotypic features
🔹marfanoid habitus
🔹skeletal abnormalities
🔹abnormal dental enamel
🔹multiple mucosal neuromas.
60
What are Disorders of sexual development?
Virilized female
Inadequately virilized male
True hermaphrodite
61
What are the Causes of a virilized female??
• Androgens of fetal origin
• CAH
• Androgens of maternal origin
• Drugs/maternal CAH
• Tumours of ovary or adrenal gland
• Idiopathic
62
What are the Causes of an inadequately virilized male??
• XY gonadal dysgenesis
• LH deficiency: Leydig cell hypoplasia
• Inborn errors of testosterone synthesis
• 5α-Reductase deficiency
• Androgen insensitivity
63
What Useful investigations for sex development disorder s??
• Karyotype
• Urine steroid profile
• Pelvic ultrasonography
• 17-Hydroxyprogesterone (day 3)
• LH/FSH or testosterone/dihydrotestosterone
• Human chorionic gonadotrophin (hCG) test
64
What are the Causes of obesity??
• Nutritional:
Simple obesity/constitutional obesity
• Monogenic : Leptin gene/receptor _ melanocortin receptor (MC4R)
• Associated with genetic syndromes:
Down syndrome
Laurence–Moon–Biedl syndrome
Prader–Willi syndrome
• Endocrine:
Hypothalamic damage
Hypopituitarism, GH deficiency
Hypogonadism
Hypothyroidism
Cushing syndrome
Pseudohypoparathyroidism
• Hyperinsulinism
• Iatrogenic
Glucocorticoids
Oestrogens
• Inactivity
• Psychological disturbances
65
What is the sequence of puberty in female??
🔹Breast bud development ➡️ estrogen
🔹the development of pubic and axillary hair, which is controlled by the adrenal gland.
🕳️Peak height velocity coincides with breast stage 2–3.
🔹Menarche occurs late at breast stage 4, by which stage growth is slowing down. Most girls have attained menarche by age 13 years.
66
What are the Factors that influencing intrauterine growth??
• Nutrition
• Genetic
• Maternal factors (smoking, blood pressure)
• Placental function
• Intrauterine infections
• Endocrine factors, e.g. IGF-2
67
What is the Average growth during the pubertal phase ❓
30 cm (12 inches).
68
What factors influence the Phases of postnatal growth ❓
• Nutrition
• Infancy: nutrition
• Childhood: GH (thyroxine)
• Puberty: sex hormones (GH)
69
How to calculate Mid-parental height??
▪️Add 13 cm to mother’s height to plot on a boy’s chart
▪️Subtract 13 cm if plotting a father’s height on a girl’s chart
▪️Mid-parental height is half-way between the plotted corrected parental heights
70
What are the Causes of short stature
❤️ Familial
❤️Constitutional short stature, constitutional delay of growth and puberty
❤️Chronic illness:
• Congenital heart disease
• Respiratory disorders, e.g. cystic fibrosis
• Renal failure
• Gastrointestinal (GI) disorders: malabsorption, e.g. coeliac disease, Crohn disease
• Neurological, e.g. intracranial tumours
❤️ Endocrine:
• GH insufficiency
• Hypothyroidism
• Cushing syndrome
❤️Dysmorphic syndromes:
• Turner syndrome
• Down syndrome
• Low birthweight, e.g. Russell–Silver syndrome • Prader–Willi syndrome
❤️Skeletal dysplasia: • Achondroplasia • Hypochondroplasia • Mucopolysaccharidoses • Spondyloepiphyseal dysplasia
❤️Psychosocial/emotional deprivation
71
What are the characteristics of Constitutional short stature ❓
▪️delay in growth and delay in puberty.
▪️There is often a history of a similar pattern of growth in male members of the family.
▪️Bone-age assessment shows a delay.
72
What is the genetic defect in Achondroplasia??
▪️ Caused by mutations in the FGFR3, gene which provides the instructions for making a protein involved in the maintenance and development of brain and bone tissue.
▪️The inheritance is autosomal dominant but there are new mutations in 80%
73
What is the genetic abnormality in Hypochondroplasia❓
• Definition: • Rhizomelic short stature distinct from achondroplasia
• Inheritance: • About 70% affected individuals have mutations in the FGFR3 gene
74
What are the genetic cause and the mode of inheritance of Mucopolysaccharidoses❓
• This can be autosomal recessive or X-linked recessive
🔅 enzyme deficiencies that break down the complex carbohydrates called glycosaminoglycans
75
What is mode of inheritance and the genetic cause of Russell–Silver syndrome❓
• Sporadic: the genetic causes are complex but research has focused on genes located in particular regions of chromosomes 7 and 11. Parent-specific gene expression is also thought to play a role
76
What is the genetic cause of Turner syndrome and what are the Clinical features ❓❓
• Definition: a syndrome with a 45XO (or XO/XX or rarely XO/XY)
• Inheritance: sporadic
📍📍Clinical features:
• Neonatal lymphoedema of hands and feet
• Skeletal: short stature (mean adult height is 142 cm); widely spaced nipples, shield-shaped chest; wide carrying angle; short fourth metacarpal; hyperconvex nails
• Facial: prominent, backward-rotated ears; squint, ptosis; high arched palate; low posterior hairline, webbed neck
• Neurological: specific space–form perception defect
• Endocrine: autoimmune diseases (hypothyroidism); type 2 diabetes; infertility and pubertal failure
• Associations: horse-shoe kidneys; coarctation of the aorta; excessive pigmented naevi
***Turner syndrome needs to be excluded in all girls whose height is below that expected for the midparental centile because not all girls with Turner syndrome show the classic phenotype.
77
What are the Investigation of short stature❓❓
• Full blood count
• Urea and electrolytes, C-reactive protein (CRP)
• Coeliac antibodies screen
• Thyroid function tests
• Karyotyping in females
• IGF-1 and IGF-BP3 levels
• Bone age
• GH provocation tests
78
What is the Bone age❓❓
This is a measure of the maturation of the epiphyseal ossification centres in the skeleton.
79
What are the Causes of delayed and advanced bone age ❓❓
A delayed bone age :
🔺 constitutional delay of growth and puberty,
🔺GH deficiency
🔺hypothyroidism.
An advanced bone age:
🔺precocious puberty
🔺androgen excess (e.g. congenital adrenal hypoplasia, CAH)
🔺GH excess.
80
What are the features of achondroplasia ❓❓
Clinical features:
• Megalocephaly
• Short limbs
• Prominent forehead
• Thoracolumbar kyphosis
• Midfacial hypoplasia
• Disproportionate short stature
😐 Complications:
• Dental malocclusion
• Hydrocephalus
• Repeated otitis media
81
What is radiological finding of achondroplasia??
• Diminishing interpeduncular distances between L1 and L5
82
What are the Causes of short stature??
❤️ Familial
❤️Constitutional short stature, constitutional delay of growth and puberty
❤️Chronic illness:
• Congenital heart disease
• Respiratory disorders, e.g. cystic fibrosis
• Renal failure
• Gastrointestinal (GI) disorders: malabsorption, e.g. coeliac disease, Crohn disease
• Neurological, e.g. intracranial tumours
❤️ Endocrine:
• GH insufficiency
• Hypothyroidism
• Cushing syndrome
❤️Dysmorphic syndromes:
• Turner s unusualyndrome
• Down syndrome
• Low birthweight, e.g. Russell–Silver syndrome • Prader–Willi syndrome
❤️Skeletal dysplasia: • Achondroplasia • Hypochondroplasia • Mucopolysaccharidoses • Spondyloepiphyseal dysplasia
❤️Psychosocial/emotional deprivation
83
What I the genetic cause of Marfan syndrome?
🔹Autosomal dominant.
🔹Caused by mutations in the FBN1 gene which codes for fibrillin – 1. 25% of affected individuals have a new mutation
84
What are the cardiac and pulmonary complication in marfan syndrom ❓❓
Cardiovascular system:
• Aortic dissection
• Mitral valve prolapse
Respiratory:
• Pneumothorax
85
What are the genetic causes and clinical features of Klinefelter syndrome ❓❓
®️ Karyotype 47XXY
®️ Inheritance: • Sporadic
®️ Clinical features:
• Tall and slim
• Cryptorchidism
• Gynaecomastia
• Learning disability
• Azoospermia and infertility
• Immature behaviour
86
What is the cause of Sotos syndrome (cerebral gigantism) and the Clinical features ❓❓
💛 Inheritance: • Sporadic caused by mutations in the NSD1 gene
💛Clinical features:
• Birthweight and length >90th centile
• Excessive linear growth during the first few years (which characteristically falls back)
• Head circumference is proportional to length
• Large hands and feet
• Large ears and nose
• Intellectual retardation
• Clumsiness
87
What are the Investigation of tall stature❓
• Thyroid function
• Bone age
• Skeletal survey
• Karyotype
88
What are the Causes of tall stature in childhood ❓
🔅 Familial tall stature
🔅 Constitutional obesity
🔅Precocious puberty
🔅Androgen excess: • Congenital adrenal hyperplasia
🔅GH excess
🔅Thyrotoxicosis
🔅 Syndromes:
📍Cerebral gigantism (Sotos syndrome)
📍 Marfan syndrome
📍 Klinefelter syndrome
89
How are the growth-promoting effects of GH mediated ❓❓
by somatomedin C (otherwise known as IGF-1), which is produced in the liver cells after GH binding to cell-surface receptors and results in gene transcription.
90
How production of FSH / LH regulated ❓❓
GnRH released in a pulsatile fashion, which stimulates the synthesis and secretion of LH and FSH.
Expression and excretion of FSH are inhibited by inhibin, a gonadal glycoprotein. This has no effect on LH.
91
What is the TSH structure ❓❓
is a glycoprotein containing the same α subunit as LH and FSH but a specific β subunit.
92
What is ACTH and from where it is produced❓❓
is a 39-amino acid peptide cleaved from a large glycosylated precursor (proopiomelanocortin or POMC) which also gives rise to melanocyte-stimulating hormone (MSH) and βendorphin.
93
How ACTH release is stimulated ❓❓
🔺Corticotrophin-releasing hormone (CRH) stimulates ACTH release via increasing cAMP levels.
🔺 Arginine vasopressin (AVP) also stimulates ACTH release and potentiates the response to CRH.
94
What is the Function Prolactin and what is the level in neonates ❓❓
is responsible for the induction of lactation and cessation of menses during the puerperium.
During the neonatal period, prolactin levels are high secondary to fetoplacental oestrogen. It then falls and remains consistent during childhood but there is a slight rise at puberty.
95
How is dopamine level completed ❓❓
Dopamine inhibition from the hypothalamus.
96
What is the management for constitutional short stature ❓
Management consists primarily of reassurance and, in certain circumstances, the use of a short (<6-month) course of androgens to ‘kick start’ puberty
97
What are the Clinical features of Hypochondroplasia ❓
• Affected individuals appear stocky or muscular
• Usually recognized from age 2–3 years
• Wide variability in severity
• Radiology: • No change in interpeduncular distances between L1 and L5
98
What is the Clinical features of Russell-silver ❓
• Normal intelligence
• Short stature of prenatal onset
• Limb asymmetry
• Short incurved fifth finger
• Small triangular face
• Bluish sclerae in early infancy
• Café-au-lait spots
99
What are the Clinical features ❓
depend on type of MPS:
• Short spine and limbs
• Coarse facial features
• Reduced intelligence and abnormal behaviour in some forms • Hurler syndrome – shortened lifespan
• Marked skeletal abnormalities and severe short stature in Morquio syndrome
100
What is the Embryological origin of pituitary ❓❓
The anterior and intermediate lobes are derived from the buccal mucosa whereas the posterior lobe is derived from neural ectoderm
101
The development of the normal pituitary gland relies on a number of transcription factors what are these❓❓l
called homeobox genes
🔹Prop-1 (prophet of Pit-1) is a homeobox gene necessary for the development of ➡️➡️GH-, PRL- and thyrotrophin-producing cells.
🔹HESX1 is a homeobox gene ➡️➡️implicated in some forms of septo-optic dysplasia.
102
What are the normal serum osmolality and how the input and output maintained ❓❓
osmolality between 280 and 295 mosmol/l.
Output Controlled by:
• Hypothalamic osmoreceptors and neighbouring neurons that secrete AVP
• Concentrating effect of the kidney
Input Controlled by:
• Hypothalamic thirst centre
103
Where AVP is produced ❓❓
as a pro-hormone in the supraoptic and paraventricular nuclei. Action potentials from the hypothalamus cause its release from the posterior pituitary gland into the circulation.
104
What is the function of AVP❓❓
regulates the permeability of the luminal membrane of the collecting ducts. Low permeability in the presence of a low AVP concentration leads to dilute urine.
105
What are pituitary disorders ❓❓
💙Congenital:
• Agenesis of the corpus callosum
💙Structural abnormalities:
• Septo-optic dysplasia
• Pituitary hypoplasia
💙 Idiopathic hormonal abnormalities:
• Isolated GH deficiency
• Idiopathic precocious puberty
💙 Acquired:
• Excess: • Intracranial tumours • Cushing disease – pituitary adenoma
• Deficiency: • Pituitary damage • Tumours • Surgery • Radiotherapy • Trauma
106
What is Septo-optic dysplasia (De Morsier syndrome) and what are it is features ❓❓
A developmental anomaly of the midline structures of the brain.
Classically characterized by:
• Absence of septum pellucidum and/or corpus callosum
• Optic nerve hypoplasia
• Pituitary hypoplasia with variable pituitary hormone deficiencies (most commonly this is GH deficiency which may either be isolated or progress to an evolving endocrinopathy)
Treatment is by hormone replacement and management of visual difficulties
107
What is Craniopharyngioma ❓❓
🔺This is one of the most common supratentorial tumours in children.
🔺 It commonly presents with headaches and visual field defects. On imaging, the tumour is frequently large and cystic.
108
What are the treatment of Craniopharyngioma and what are the complications of it ❓❓
🔺Treatment is by resection plus radiotherapy if initial resection is incomplete or recurrence occurs.
🔺Postoperative hormonal deficiencies are common, involving both anterior and posterior pituitary hormones.
Treatment is by hormonal supplementation
109
What is the diabetes insipidus and what is the importance of hypothalmic normal functioning ❓❓
Defined as insufficient AVP causing a syndrome of polyuria and polydipsia.
With an intact thirst mechanism copious water drinking maintains normal osmolalities. However, problems with the thirst mechanism or insufficient water intake lead to hypernatraemic dehydration
110
cortisol is required for water excretion. Therefore in children with combined anterior and posterior pituitary dysfunction, there is a risk of dilutional hyponatraemia if they are cortisol deficient and receiving DDAVP (1-deamino-8-D-arginine vasopressin) treatment. Hence the emergency management of the unwell child is to increase the hydrocortisone treatment and to stop the DDAVP.
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What are the Causes of diabetes insipidus ❓❓
✔️ Central:
• Craniopharyngioma
• Germinoma
• Langerhans cell histiocytosis (LCH)
• Idiopathic
• Trauma
✔️Nephrogenic:
• X-linked nephrogenic diabetes insipidus
• Secondary to renal damage
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What are the criteria of Syndrome of inappropriate ADH (SIADH) ❓❓
• Water retention with hypo-osmolality
• Normal or slightly raised blood volumes
• Less than maximally dilute urine
• Urinary sodium > sodium intake
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What are the Causes of SIADH ❓❓
• CNS disorders: meningitis, abscess; trauma; hypoxic–ischaemic insult
• Respiratory tract disease: pneumonia; cavitation
• Reduced left atrial filling: drugs
• Malignancies: lymphoma; bronchogenic carcinoma; idiopathic
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Why we need Anterior pituitary stimulation tests❓❓ what are the tests used ❓❓
➡️Many hormones (e.g. GH, LH and FSH) are secreted in a pulsatile fashion, and therefore a random measurement of the concentration of the circulating hormone is often inadequate for diagnosing a deficiency disorder.
Hormone measurement tests include:
♀️♀️GH release/ACTH (via cortisol response): insulin tolerance test /glucagon stimulation test
♀️♀️TSH/prolactin response: TRH test
♀️♀️ FSH/LH response: LHRH test
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What is GH provocation test ❓❓
Provocation tests of GH are potentially hazardous.
✔️ Insulin tolerance tests should be performed only in specialist centres because of the risk of severe hypoglycaemia.
✔️Other GH provocation tests include the use of glucagon, arginine and clonidine.
▪️▪️Physiological tests of GH secretion include a 24-h GH profile and measurement of GH after exercise or during sleep
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Combined pituitary function test
The standard test involves the intravenous injection of either insulin or glucagon in combination with TRH and LHRH (in the pubertal child). Blood samples are taken at 0 min (before stimulation), 20, 30, 60, 90 and 120 min.
After insulin administration, a profound hypoglycaemia results in 20 min which needs to be corrected by the use of an oral glucose solution or the judicious use of intravenous 10% dextrose. (Remember: the rapid correction of hypoglycaemia with a hypertonic glucose solution can result in cerebral oedema.)
GH concentrations rise at 30 min after insulin, or 60–90 min after glucagon injection. A rise to over 6 mg/l rules out GH deficiency.
A normal TSH response to TRH is a rise at 20 min post-dose and then a fall by 60 min. A continued rise of TSH at 60 min implies hypothalamic damage. Secondary hypothyroidism is demonstrated by a low baseline TSH level, whereas primary hypothyroidism is associated with a raised TSH.
A raised baseline prolactin level suggests a lack of hypothalamic inhibition of its release. Under normal circumstances, after the administration of TRH, prolactin would be expected to rise at 20 min and then to be falling by 60 min.
In the absence of precocious puberty, the LHRH test will demonstrate only a rise in FSH and LH at 20 and 60 min during the first 6 months of life and in the peripubertal period. Raised baseline gonadotrophin levels reflect gonadal failure.
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Posterior pituitary function tests
• Paired urine and serum osmolalities • Water deprivation test
The child is weighed in the morning and is then deprived of water for a maximum of 7 h, during which time the child’s weight, pulse rate and blood pressure, and urine osmolality are measured hourly.
Plasma sodium levels and osmolality are measured every 2 h.
The test is terminated if the patient’s weight falls by 5% from the starting weight, serum osmolality rises (>295 mosmol/kg of water) in the face of an inappropriately dilute urine (<300 mosmol/kg) or if the patient becomes significantly clinically dehydrated/clinically unwell.
A diagnosis of diabetes insipidus (DI) may be made in the presence of a plasma osmolality >290 mosmol/kg of water with an inappropriately low urine osmolality.The child is then given a dose of DDAVP and the urine and plasma osmolality are then measured. A rise in urine concentration confirms a diagnosis of central DI, whereas a child with nephrogenic DI will fail to concentrate urine after DDAVP.
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What is the management of Panhypopituitarism ❓❓
Panhypopituitarism is much less common than isolated hormone deficiency and may develop as an evolving endocrinopathy.
Management includes replacement with GH, thyroxine, cortisol during childhood with induction and maintenance of puberty with the appropriate sex hormone (testosteroneor estradiol)
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What is the treatment of Central diabetes insipidus❓❓
• Treatment with DDAVP (desmopressin) as either a nasal spray or tablets
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Oestrogen is produced by the follicle cells of the ovary. The main active form of oestrogen is estradiol. This circulates bound to SHBG and causes growth of the breasts and uterus, and the female distribution of adipose tissue, and increases bone mineralization
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Positive feedback also occurs during mid-puberty in females. Increased oestrogen primes gonadotrophins to produce LH until, at a critical stage at the middle of the menstrual cycle, a large surge occurs causing ovulation
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Adrenarche
Adrenal androgens, dehydroepiandrosterone sulphate (DHEAS) and androstenedione, rise approximately 2 years before gonadotrophins and sex steroids rise. Adrenarche begins at 6–8 years of age and continues until late puberty. Control of this is unknown. Adrenarche does not influence onset of puberty.
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Abnormal puberty
• Early (precocious): • <9 years in boys • <8 years in girls
• Discordant (abnormal pattern) • Delayed: • >14 years in boys • >13 years in girls
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What is the Precocious puberty and what is the cause ❓❓
Central precocious puberty is consonant with puberty (i.e. occurs in the usual physiological pattern of development but at an earlier age).
➿ It is due to premature activation of the GnRH pulse generator
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What are the Causes of true precocious puberty (gonadotrophin dependent)❓❓
• Idiopathic
• CNS tumour
• Neurofibromatosis
• Septo-optic dysplasia – in this rare condition precocious puberty may occur in the presence of deficiencies of other pituitary hormones.
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What are the Causes of gonadotrophin-independent precocious puberty❓❓
• McCune–Albright syndrome (usually due to ovarian hypersecretion) • Testicular/ovarian tumours
• Liver or adrenal tumours – may cause virilization
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What are the Useful tests for the investigation of precocious puberty❓❓
• Estradiol/Testosterone
• Adrenal androgens, including 17-hydroxyprogesterone
• LHRH stimulation test
• Bone age
• Pelvic ultrasound scan
• Brain magnetic resonance imaging (MRI)
• Abdominal computed tomography (CT) if adrenal/liver tumour suspected
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What is the Management of precocious puberty ❓❓
🔺A GnRH analogue (GnRHa) may be used to halt the progression of puberty.
🔺Children who enter puberty early are tall initially, but end up as short adults due to premature closure of epiphyses.
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What examples of Discordant puberty (abnormal pattern)❓❓
• Breast development only – gonadotrophin-independent precocious puberty, e.g. McCune–Albright syndrome
• Inadequate breast development, e.g. gonadal dysgenesis, Poland anomaly
• Androgen excess – pubic hair, acne, clitoral enlargement, e.g. CAH, Cushing disease, polycystic ovarian syndrome (PCO), adrenal neoplasm
• Inadequate pubic hair, e.g. androgen insensitivity, adrenal failure
• No menarche, e.g. polycystic ovaries/rarely absent, abnormal uterus, imperfect hymen
• No growth spurt, e.g. hypothalamic–pituitary disorders, skeletal dysplasias
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What is the Premature thelarche❓❓
• Usually in girls aged between 1 and 3 years
• Isolated breast development (never more than stage 3)
• No other signs of puberty • Normal growth velocity for age • Normal bone age
• Prepubertal gonadotrophin levels
• Progress to puberty at normal age
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What are the Causes of delayed puberty ❓❓
🔺 Constitutional delay of growth and puberty
🔺Hypothalamic or pituitary disorders:
• Hypogonadotrophic hypogonadism
• Idiopathic
• Pituitary tumours
• Post-central irradiation
• Post-intracranial surgery
• Post-chemotherapy
• Anorexia nervosa
🔺 Systemic disease
🔺 Kallman syndrome – hypogonadotrophic hypogonadism with anosmia
🔺Gonadal dysgenesis: • Turner syndrome
🔺Hypothyroidism
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Why there is an association between olfactory nerve and GnRH ❓
💛Several of these genes are involved in the development of the olfactory system and are frequently associated with the clinical features of Kallman syndrome.
💛The KAL1 gene codes for a protein called anosmin 1 which helps control the growth and migration of neurons that form the olfactory bulb and those that produce GnRH.
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What are the Investigations for delayed puberty ❓❓
Initially this requires no investigations apart from a bone age.
If after a trial of treatment there is no progression of puberty, further investigations may be needed including the following:
• In boys:• LH, FSH, testosterone • LHRH test • Karyotyping
• In girls, delayed puberty must always be investigated: • Karyotyping • LH, FSH, oestrogen • LHRH test • Pelvic ultrasonography
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How delay puberty is managed ❓❓
✔️Constitutional delay
• Reassurance
• Androgens: oxandrolone orally daily or depot testosterone injection monthly • Reassess at 4–6 months
✔️Other causes of delayed puberty
• Treat underlying cause
• Induce and maintain puberty with testosterone in boys, ethinylestradiol in girls
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What is the embryo logical origin of adrenal gland ❓❓
🔺adrenal gland is made up of cortex, arising from mesoderm at the cranial end of the mesonephros
🔺 medulla, which arises from neural crest cells.
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What are the 3 zones of the adrenal cortex ❓❓
• Zona glomerulosa: produces aldosterone
• Zona fasciculata: produces cortisol/androstenedione
• Zona reticularis: produces DHEAS
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ACTH has a circadian rhythm, being at its lowest at midnight and rising in the early morning.
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What are the main functions of cortisol ❓❓
✔️It plays a vital role in the body’s stress response
✔️ is an insulin counter-regulatory hormone increasing gluconeogenesis, hepatic glycogenolysis, ketogenesis necessary for the action of other hormones, e.g. noradrenaline, adrenaline, glucagons.
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What is the action of Aldosterone and how it is regulated ❓❓
♀️It increases sodium reabsorption from urine, sweat, saliva and gastric juices in exchange for potassium and hydrogen
💲💲💲 primarily regulated by the renin–angiotensin system, which is responsive to electrolyte balance and plasma volumes. 💲💲💲Hyponatraemia and hyperkalaemia can also have a direct aldosterone stimulatory effect.
💲💲💲 ACTH can produce a temporary rise in aldosterone butthis is not sustained.
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glycoprotein synthesized in the juxtaglomerular apparatus, and stored as an inactive proenzyme in cells of the macula densa of the distal convoluted tubule. Its release is stimulated by reduced renal perfusion, hyperkalaemia and hyponatraemia.
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What are Adrenal androgens ❓❓
✔️These include testosterone, androstenedione and DHEAS.
Secretion varies with age and, although responsive to ACTH, do not always parallel the cortisol response
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How renin angiotensin system activated ❓❓
Renin hydrolyses angiotensin to form angiotensin I (an α2-globulin synthesized in the liver).
This is converted to angiotensin II by angiotensin-converting enzyme (ACE).
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Phaeochromocytoma
Catecholamine-secreting tumour. Malignancy is uncommon, but 10% are bilateral.
Catecholamine excess leads to sustained hypertension
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What are conditions associated with Phaeochromocytomas ❓❓
♀️von Recklinghausen disease
♀️von Hippel–Landau disease
♀️syndromes of multiple endocrine neoplasia (MEN).
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Phaeochromocytomas are associated with von Recklinghausen disease, von Hippel–Landau disease and syndromes of multiple endocrine neoplasia (MEN).
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Management The management of phaeochromocytoma is by surgical excision. Preoperative management requires both α- and β-adrenoceptor blockade in order to prevent an acute hypertensive crisis or cardiac dysrhythmias.
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Adrenal insufficiency
Causes • Primary: • Idiopathic• Congenital adrenal hyperplasia • Adrenal haemorrhage • Addison disease
• TB • Autoimmune disease • Iatrogenic
• Secondary: • Pituitary hypoplasia • Isolated ACTH deficiency • Panhypopituitarism • Tumour, e.g. craniopharyngioma
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Addison disease
• Definition: • Adrenal hypofunction
• Aetiology: • Autoimmune • Secondary to TB • Associated with adrenal leukodystrophy
• Presentation: • Often with non-specific symptoms of tiredness and abdominal pain • May present with collapse related to a salt-losing crisis
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Investigation of adrenal cortical insufficiency • The Synacthen test, which assesses the ability of the stimulated adrenal glands to mount a hormone response. A dose of synthetic ACTH is given and the cortisol level measured after 30 and 60 min. A normal adrenal response would be a cortisol level >450–550 nmol/l at 30 min
• A 24-h blood cortisol profile
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What are the Investigations for Cushing syndrom ❓❓
• 24-h urine cortisol
• 24-h profile (loss of circadian rhythm, no suppression of midnight cortisol level)
• Dexamethasone suppression test
• MRI of the brain/CT of the adrenals
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How is the monitoring of CAH treatment ❓❓
🔺Growth is a good method of monitoring replacement therapy. Children who grow excessively fast with increased height velocity either are getting inadequate doses or may be non-compliant. 🔺17-OHP levels are also useful for monitoring treatment.
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What are the Genetics basis for 21 1hydroxylase enzyme ❓❓
🔹Two genes encoding 21-hydroxylase expression have been localized to the short arm of chromosome 6, namely CYP21B and CYP21A.
🔹Deletion of CYP21B is associated with severe salt wasting and HLA-B47, -DR7 haplotype.
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What are the presentation of congenital adrenal hyperplasia❓❓
• Ambiguous genitalia (in girls with 21-hydroxylase deficiency, and occasionally in boys with 3βhydroxy-steroid dehydrogenase deficiency)
• Salt-losing crisis and hypotension
• Hypertension may occur in 11β-hydroxylase deficiency
• Precocious puberty (in boys)
• Virilization
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What are the Investigations for CAH ❓❓
• Karyotype
• 17-Hydroxyprogesterone (17-OHP)
• Urine steroid profile (metabolite pattern will help in diagnosing specific enzyme block)
• Adrenal androgen levels
• Bone age in older children
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What are the treatment of CAH❓❓
🔺Hydrocortisone and fludrocortisone replace the deficient steroids and also suppress the ACTH drive to the adrenal androgens.
🔺It is important to teach parents to recognize signs of illness and to be able to administer emergency hydrocortisone
🔺Additional sodium chloride replacement is also required during the first year of life and electrolytes may need to be monitored over this period
🔺 Surgery may be required in girls with virilization
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What are the Causes of Adrenal steroid excess (Cushing syndrome)❓❓ :
of steroids
• Primary: adrenal tumour
• Secondary: pituitary ACTH-secreting tumour; ectopic ACTH production
• Iatrogenic: exogenous administration
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What are the complication of systemic steroid
▪️Gastritis
• Osteoporosis
• Raised blood glucose/altered glucose tolerance
• Increased appetite and weight gain
• Increased susceptibility to infection
• Poor healing
• Menstrual irregularities
• Unpredictable mood changes
• Sleep disturbances
• Increased risk of glaucoma and cataracts
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What are the Embryological origin of thyroid gland ❓❓
❗The thyroid gland is formed from a midline outpouching of ectoderm of the primitive buccal cavity, which then migrates caudally
❗Between the follicular cells are the parafollicular cells (C-cells), which are of neurogenic origin and secrete calcitonin.
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What are the functions of the thyroid gland ❓❓
✔️ to concentrate iodine from the blood and return it to peripheraltissues in the form of thyroid hormones (thyroxine or tetraiodothyronine [T4] and triiodothyronine [T3]).
✔️In blood, the hormones are linked with carrier proteins, e.g. thyroxine-binding globulin and pre-albumin.
➡️ T4 is metabolized in the periphery into T3 (more potent) and reverse T3 (less potent)
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What are the steps of thyroid Hormonogenesis ❓❓
1. Follicular cells actively uptake and tap iodine from the blood
2. Synthesis of thyroglobulin
3. Organification of trapped iodine as iodotyrosines (monoiodotyrosine [MIT] and diiodotyrosine [DIT])
4. Coupling of iodotyrosines to form iodothyronines and storage in the follicular colloid
5. Endocytosis of colloid droplets and hydrolysis of thyroglobulin to release T3, T4 and MIT and DIT
6. Deiodination of MIT and DIT with intrathyroid recycling of the iodine
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Regulation
Thyroid hormone release is regulated by TSH and iodine levels. TSH has both immediate and delayed actions on thyroid hormone secretion.
• Immediate actions: • Stimulates binding of iodide to protein • Stimulates thyroid hormone release • Stimulates pathways of intermediate metabolism
• Delayed action (several hours): • Stimulates trapping of iodide • Stimulates synthesis of thyroglobulin
Physiological variations in iodide modulate trapping by the thyroid membrane. Iodide inhibits the stimulation of cAMP by TSH and pharmacological doses block organification.
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Thyroid hormone has multiple physiological actions as follows:
• Growth and development (required for somatic and neuronal growth) • Thermogenesis• Catabolism (increased glycogenolysis, lipolysis and fee fatty acid oxidation) • It also potentiates the actions of catecholamines
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What are the Investigations for thyroid disease ❓❓
Baseline blood tests: free T4/T3/TSH measurements • Stimulation tests: TRH test • Thyroid ultrasound scan • Radionuclide scans
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Further investigation is with a TRH test.
secondary hypothyroidism, T4 will be low in association with a low TSH.
This involves the injection of TRH followed by measurement of TSH at 30 and 60 min post-dose. In an individual with normal thyroid function, TSH would rise at 30 min but fall by 60 min. However, in patients with hypothalamic dysfunction, TSH would continue to rise at 60 min postinjection.
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‘Sick thyroid syndrome’ refers to the scenario of a
variety of abnormalities on thyroid function testing in an unwell patient that spontaneously resolve as the illness improves. Usually there is a normal free T4 level with raised TSH.
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Functional assessment can be made using the technetium radionuclides.
Uptake is increased in thyrotoxicosis and reduced in thyroiditis.
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What are the Clinical features of Cushing syndrom ❓❓
• Obesity – central distribution of fat – buffalo hump
• Purple striae
• Hypertension
• Osteoporosis
• Hypogonadism
• Growth failure
• Muscle wasting/hypotonia
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However, the most common cause of thyroid dysfunction
is iodine deficiency disorder (IDD).
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Primary hypothyroidism
• Congenital: • Thyroid dysgenesis • Agenesis • Hypoplasia • Ectopic gland • Biosynthetic defects• Maternal thyroid disorder
• Acquired: • Autoimmune • Post-surgery • Post-cervical irradiation • Systemic disorders • Iodine deficiency • Iodine overload
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Secondary hypothyroidism
• Congenital: • Congenital pituitary abnormalities • Receptor resistance
• Acquired: • Post-cranial irradiation • Post-tumour • Post-surgery
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Congenital hypothyroidism has an incidence of 1/4000 live births. Most cases of thyroid dysgenesis are sporadic. The TSH receptor is critical for gland development and inactivating mutations may cause a range of severity of hypothyroidism. An activation mutation in GNAS1 causes McCune– Albright syndrome. Thyroid dyshormonogenesis has an autosomal recessive inheritance and mutations of SLC26A4 cause Pendred syndrome.
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Transient congenital hypothyroidism may
be due to maternal anti-TSH antibodies or heterozygous DUOX2 mutations.
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Management of hypothyroidism Treatment is and
with L-thyroxine
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Screening for congenital hypothyroidism
TSH is measured as part of the newborn screening programme performed between days 5 and 7 of life. A blood spot from a heel prick is put on to a filter paper. Concentrations of TSH >10 mU/l are picked up by this test and abnormal results are immediately notified by the test centre to the relevant local hospital/specialist unit or the GP.
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What is the incidence and causes of thyrotoxicosis in children ❓❓
a female:male ratio of 8:1; 95% of young people with thyrotoxicosis have Graves disease which is caused by stimulatory antibodies to the TSH receptor.
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Causes of thyrotoxicosis
• Autoimmune thyroiditis, e.g. Graves disease • Diffuse toxic goitre • Nodular toxic goitre • TSH induced • Factitious
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Neonatal thyrotoxicosis .
is a rare condition caused by the transplacental passage of thyroidstimulating antibodies from mothers with either Graves disease (active or inactive) or Hashimoto thyroiditis
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The neonate usually presents with a .
rapidly developing tachycardia, dysrhythmia, hypertension and weight loss. A goitre may be present. There may also be associated jaundice and thrombocytopenia
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Management of neonatal hyperthyroidism?
The condition is usually self-limiting in 4–12 weeks but severely affected neonates will require treatment with propranolol, carbamazepine and Lugol’s iodine. A response is usually seen within 24–36 hours.
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Thyroid neoplasia
This usually presents as solitary nodules, of which 50% are benign adenomas or cystic lesions.
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Initial medical treatment: • Suppression of thyroid hormone secretion using specific antithyroid treatments, e.g. carbimazole,
propylthiouracil • Blunting the peripheral effects of the thyroid hormones using α blockade, e.g. propranolol
• Definitive treatment: • This is contemplated if there has been no remission in symptoms on medical treatment, and may involve subtotal thyroidectomy or radioactive iodine, which is becoming an increasingly popular choice for teenagers.
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The prevalence of malignancy in childhood is 30–40% and the risk increases following radiation to the neck during infancy or early childhood. Hyperfunctioning adenomas are rare and most (90%) are well-differentiated follicular carcinomas.
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How insulin release is regulated ❓❓
the fed state, insulin release is stimulated by a raised glucose and amino acid concentration. It is also stimulated by gut hormone release. In the fasting state, blood glucose concentrations fall and insulin production is turned off under the influence of somatostatin. A low glucose concentration is sensed by the hypothalamus, which regulates pancreatic secretion and stimulates the release of the counter-regulatory hormones glucagon, ACTH, GH, prolactin and catecholamines.
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Actions of insulin
• Liver: • Conversion of glucose to glycogen • Inhibits gluconeogenesis • nhibits glycogenolysis
• Peripheral: • Stimulates glucose and amino acid uptake by muscle • Stimulates glucose uptake by fat cells to form triglycerides
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What is the definition of diabetes ❓❓
>7 mmol/l or a blood glucose 2 h after a glucose load >11.1 mmol/. In 2011 an addendum to these diagnostic criteria was added as a glycated haemoglobin (HbA1c) of >6.5
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When is the peak incidence of DM ❓❓
Peaks occur at age 4–6 years and 10–14 years.
190
What is the risk for diabetes type 1 in siblings ❓❓
A person has a 10% risk of developing type 1 diabetes mellitus if they have an affected sibling
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What are the types and Aetiology of diabetes in children ❓
• Type 1 diabetes mellitus (95%): • Autoimmune destruction of the pancreatic islet cells
• Type 2 diabetes mellitus: • A combination of β-cell failure and insulin resistance
• Cystic fibrosis-related diabetes • Maturity-onset diabetes of the young (MODY) • Genetic syndromes (Down syndrome, Wolfram syndrome, DIDMOAD and neonatal diabetes)
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Risk factors for type 2 diabetes
• Family history of type 2 diabetes • High-risk ethnic groups (African, Caribbean, Asian, Hispanic) • Obesity • Female sex • Clinical signs of insulin resistance (acanthosis nigricans, POS) • Biochemical signs of insulin resistance (high insulin or C-peptide) • Pubertal • Absence of islet cell antibodies
193
What is the mechanism of glucoseurea ❓
As the blood glucose level increases, the glucose in the glomerular filtrate exceeds the ability of the proximal tubules to reabsorb it. This leads to glycosuria. Polyuria then occurs, as the loop of Henle is unable to concentrate the urine because the renal tubules are insufficiently hyperosmolar.
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Differential diagnosis of polyuria and polydipsia
• Diabetes mellitus • Diabetes insipidus: • Cranial – arginine vasopressin deficiency • Nephrogenic – AVP insensitivity
• Habitual water drinking • Drug induced
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What are the Clinical presentation of DM ❓❓.
Children usually present acutely with polyuria (including nocturia and incontinence), thirst, polydipsia. About 40% have diabetic ketoacidosis. Other symptoms are weight loss, fatigue, infections (e.g. abscess formation, urinary tract infections), muscle cramps and abdominal pain
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DKA is defined as:
• hyperglycaemia (glucose >11 mmol/l) • pH <7.3 • bicarbonate <15 mmol/l
197
and patients who are:
• 5% or more dehydrated • and/or vomiting • and/or drowsy • and/or clinically acidotic
198
How is fluid managed in DKA ❓
Initially use 0.9% saline with 20 mmol KCl in 500 ml, and continue this sodium concentration for at least 12 hours. Once the blood glucose has fallen to 14 mmol/l add glucose to the fluid. After 12 h, if the plasma sodium level is stable or increasing, change to 500 ml bags of 0.45% saline/5% glucose/20 mmol KCl. If the plasma sodium is falling, continue with 0.9% saline
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What do you do for children on long acting insulin presented
For children who are already on long-acting insulin you may want this to continue at the usual dose and time throughout the DKA treatment, in addition to the intravenous insulin infusion, in order to shorten length of stay after recovery from DKA.
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Cerebral oedema The signs and symptoms of cerebral oedema include:
• Headache and slowing of heart rate
• Change in neurological status (restlessness, irritability, increased drowsiness, incontinence)
• Specific neurological signs (e.g. cranial nerve palsies)
• Rising BP, decreased O2 saturation
• Abnormal posturing
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What is management of cerebral oedema while you are arranging transfer to the paediatric intensive care unit (PICU):
• Exclude hypoglycaemia as a possible cause of any behaviour change
• Give hypertonic (2.7%) saline (5 ml/kg over 5–10 min) or mannitol 0.5–1.0 g/kg stat (= 2.5–5 ml/kg mannitol 20% over 20 min)
• Restrict intravenous fluids to 1/2 maintenance and replace deficit over 72 rather than 48 h
• The child will need to be moved to PICU (if not there already)
• Discuss intubation with PICU consultant
203
What is target for long-term glycaemic control ❓❓
HbA1c level <7.5% (to minimize the risk of longterm complications) without frequent disabling hypoglycaemia
204
Children and young people with type 1 diabetes should be offered screening for the following❓❓
• Coeliac disease at diagnosis and at least every 3 years thereafter until transfer to adult services
• Thyroid disease at diagnosis and annually thereafter until transfer to adult services
• Retinopathy annually from the age of 12 years
• Microalbuminuria annually from the age of 12 years
• Blood pressure annually from the age of 12 years
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What are the insulin regimen ❓❓
💛One, two or three insulin injections per day
💛Multiple daily injection regimen
The person has injections of short-acting insulin or rapid-acting insulin analogue before meals, together with one or more separate daily injections of intermediate-acting insulin or long-acting insulin analogue.
💛Continuous subcutaneous insulin infusion
A programmable pump and insulin storage reservoir attached to a subcutaneous needle or cannula give a continuous amount of rapid-acting insulin analogue as basal insulin and via which bolus insulin may be given.
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Hypoglycaemia in a person on glucose-lowering treatment is
defined as a blood glucose <4 mmol/l.
The symptoms may be divided into neuroglycaemic and adrenergic, and include weakness, trembling, dizziness, poor concentration, hunger, sweating, pallor, aggressiveness, irritability and confusion.
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Causes of hypoglycaemia ❓❓
💛 Inadequate glucose production:
• Counter-regulatory hormone deficiencies
• Glycogen storage disease
• Enzyme deficiency, e.g. galactosaemia
💛Excessive glucose consumption, i.e. hyperinsulinism:
= Transient
• Infant of a mother with diabetes
• Beckwith–Wiedemann syndrome
= Persistent:
• Persistent hyperinsulinaemic hypoglycaemia of infancy
• Insulinoma
• Exogenous insulin
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diagnostic screen is useful only if taken when the patient is hypoglycaemic (glucose <2.6 mmol/l) and what should include ❓❓
• Blood:
• Glucose
• Insulin (C-peptide)
• Cortisol
• GH
• Lactate
• Free fatty acids
• Amino acids
• Ketone bodies (β-hydroxybutyrate and acetoacetate)
• Acylcarnitines
• Urine: • Organic acids
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How to deffrentiate hypoglycaemia based on urinary ketones ❓❓.
absence of ketones:
it is important to look at the free fatty acids (FFAs).
Normal FFAs suggest hyperinsulinism and raised FFAs a fatty-acid oxidation defect.
Urinary ketones :
either a counter-regulatory hormone deficiency or an enzyme defect in the glycogenolysis or gluconeogenesis pathways
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Actions of vitamin D
• Increases intestinal absorption of calcium • Increases osteoclastic bone resorption • Inhibits PTH secretion and hence increases 1α-hydroxylation
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Low calcium, cortisol, prolactin, phosphate and vitamin D all affect PTH secretion, but maximal PTH secretion occurs at a calcium concentration of <2 mmol/l
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Immediate effects of PTH
• Reduction in renal calcium excretion. It promotes calcium reabsorption in the distal tubule by stimulating the 1α-hydroxylation of vitamin D
• Promotion of phosphaturia by inhibiting phosphate and bicarbonate reabsorption in the proximal tubule
• Mobilization of calcium from bone – together with vitamin A, the osteoblasts are stimulated to produce a factor that activates osteoclasts to mobilize calcium
• Delayed effects of PTH • Promotion of calcium and phosphate absorption from gut
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Calcitonin
This is produced by the C-cells of the thyroid gland and synthesized as a large precursor molecule. Its primary functions:
• It inhibits bone resorption • It is thought to interact with GI hormones to prevent postprandial hypercalcaemia
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Causes of hypocalcaemia
• Transient neonatal hypocalcaemia • Dietary • Malabsorption • Vitamin D deficiency • Hypoparathyroidism • Pseudohypoparathyroidism
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Causes of hypoparathyroidism
• Parathyroid absence or aplasia • DiGeorge syndrome (thymic abnormalities/cardiac defects/facial appearances) • Autoimmune • Associated with multiple endocrinopathy • Iatrogenic – post-thyroid surgery
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the management of neonatal tetany consists of intravenous calcium gluconate and oral 1,25-dihydroxycholecalciferol.
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Pseudohypoparathyroidism Clinical features
• Learning disability • Short stature • Characteristic facies • Shortening of fourth and fifth metacarpal and metatarsal • Ectopic calcification
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PHP types 1a and 1c result from heterozygous inactivating mutations of the α subunit of the stimulatory G-protein (Gs). Both are associated with Albright hereditary osteodystrophy and, when the mutation is maternally derived, end-organ resistance to multiple hormones. Due to complex tissuespecific imprinting of Gsα, paternally derived mutations do not usually lead to hormone resistance resulting in the condition termed pseudo-pseudohypoparathyroidism.
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Hypercalcaemia
Clinical features are non-specific, often with anorexia, constipation, polyuria, nausea and vomiting in a child with failure to thrive.
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Causes of hypercalcaemia
• Low PTH: • Vitamin D intoxication • nfantile hypercalcaemia • Transient • Williams syndrome • Associated with tumours
• High PTH: • Primary hyperparathyroidism • Familial hypocalciuric hypercalcaemia
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Causes of rickets
• Hypocalcaemic: • Calcium deficiency: • Dietary • Malabsorption
• Vitamin D deficiency: • Dietary • Malabsorption • Lack of sunlight • Liver disease • Anticonvulsants • Biosynthetic defect of vitamin D • 1α-Hydroxylase deficiency
• Defective vitamin D action
• Phosphopenic: • Renal tubular loss • Isolated, e.g. X-linked hyphosphataemia • Mixed tubular, e.g. Fanconi anaemia
• Abnormal bones • Renal osteodystrophy
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Investigation of bone abnormalities
• Calcium, phosphate, alkaline phosphatase • Creatinine • 1,25-Hydroxy-vitamin D, 25-hydroxy-vitamin D, vitamin D concentrations • PTH • Urinary calcium, phosphate, creatinine and cAMP • X-rays • DXA (dual-energy X-ray absorptiometry)
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Consequences of obesity
Childhood
• Insulin resistance and abnormal glucose tolerance • Type 2 diabetes • Non-alcoholic steatohepatitis • Psychological problems • Obstructive sleep apnoea • Increased cardiac diameter
Adulthood
• Hyperlipidaemia • Hypertension • Diabetes • Increased risk of death from cardiovascular disease
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Assessment of the obese child
• Height, weight and pubertal assessment • Body mass index (BMI): BMI = weight (kg)/height (m)2; in children, the BMI should be compared with BMI centile charts for age as BMI varies during different phases of childhood.• Identification of an underlying cause: • Thyroid function tests • Cortisol measurements
• Evidence of complications: • Respiratory function • Liver function tests • Orthopaedic problems • Blood pressure • Fasting lipids • Oral glucose tolerance test
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Causes of amenorrhoea Ovarian
• Gonadal dysfunction • Secondary to irradiation/chemotherapy/surgery • Polycystic ovarian syndrome
Genital tract
• Müllerian dysgenesis • Hypothalamopituitary • Hypogonadotrophic hypogonadism • Secondary to tumours/irradiation/chemotherapy/surgery
Functional
• Weight loss • Exercise induced • Chronic illness • Psychogenic
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What is management of primary and 2dry amenorrhoea ❓❓
Primary amenorrhoea may require pubertal induction with exogenous oestrogen. In secondary amenorrhoea the underlying cause needs to be identified and addressed.
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What are the steps of steroidogenesis ❓❓
Cholesterol
➡️ pregnenolone➡️ 17 OH pregnenolone ➡️ DHEAS
4⬇️ 4 ⬇️ ⬇️
Progesterone ➡️17 OH Pregnenolone➡️androstenedione
5 ⬇️. 5 ⬇️. ⬇️
Deoxycorticosterone ➡️ deoxycortisol. ➡️ Testosterone
6 ⬇️ 6 ⬇️. 9 ⬇️
Corticosterone ➡️ cortisol. ➡️Estradiol
7 ⬇️
Aldosterone
4▪️ 3B hydroxysteroid dehydrogenase
5▪️21 @ hydroxylase
6▪️11 B hydroxylase
7▪️ aldosterone synthase
9▪️ Aromatase
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What are IGF-1 and IGF-2 and what are their functions ❓❓
IGF-1 and IGF-2 are 70-amino acid peptides, structurally related to insulin.
IGF-1 increases the synthesis of protein, RNA and DNA, increases the incorporation of protein into muscle and promotes lipogenesis.
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How IGFs transported in the plasma and why ❓❓
The IGFs are bound to a family of binding proteins (IGFBP-1 to -6), of which IGFBP-3 predominates.
These binding proteins not only act as transporters for the IGFs, but also increase their half-life and modulate their actions on peripheral tissues.
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How much the level of gonadotrophins and androgens in neonates and how is the level change till puperty ❓❓
In the neonate there are high levels of gonadotrophins and gonadal steroids. These decline progressively until a nocturnal increase occurs, leading up to the onset of puberty (amplification of low-amplitude pulses).
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