Endocrinology Flashcards
What are the features + pathophysiology of Pendred syndrome?
Pathophysiology
- SLC26A4 gene
- Mutant anion transporter: pendrin
- Pendrin usually transports iodide across the apical membrane of the thyrocte into the colloid space where it undergoes organification and incorporation into the tyrosine residues on thyroglobulin.
Features
- Sensorineural hearing loss + goitre
- MRI: enlarged vestibular aqueduct
- Clinically euthyroid
- Autosomal recessive
- Goitre usually 75% in 2nd decade of life
- Goitre worsens with iodine deficiency
- Learning difficulties
What are the x-ray features in vitamin D deficiency?
- Earliest sign is usually osteopenia
- Widening of the growth plate (physis); due to proliferation of uncalcified cartilage and osteoid
- Metaphyseal widening, splaying, cupping + fraying
- Coarse metaphyseal trabecular pattern
What is hypophosphatasia?
- Hypophosphatasia is due to a deficiency of tissue nonspecific alkaline phosphatase.
- ALP level = LOW
- Does NOT respond to vitamin D
- Perinatal form is universally lethal
- Presentation
- Marked hypomineralization of the bones, multiple fractures, and dysplasticvertebral bodies, which may be flattened, round, rectangular, or butterfly.
- On prenatal ultrasound, characteristic findings include decreased skull echogenicity; short, bowed limbs; small thorax; and polyhydramnios.
- The infantile form, which hasa slightly better prognosis than the perinatal form, has skeletal changes similar to rickets.
- Multiple fractures, premature loss of childhood teeth, and short stature.
What regulates the release of GH + somatostatin?
GnRH
Somatostatin= growth hormone inhibiting hormone
Is the pituitary extra-dural or intra-dural?
EXTRADURAL
Not in contact with the CSF
Pituitary divided into: anterior (adenohypophysis) + posterior (neurohypophysis)
What is the origin of the anterior pituitary + posterior pituitary?
Anterior pituitary: derived from pharyngeal arches (Rathke’s pouch)
- Craniopharyngiomas = permanent remnant between the connection between the Rathke pouch + the oral cavity
Posterior pituitary: outpouching of the brain
What do the following cell types release?
- Somatotrophs (50% cells)
- Lactotrophs (10-25% cells)
- Thyrotrophs (10% cells)
- Gonadotrophs (10-15% cells)
- Corticotrophs (10-15% cells)
- Somatotrophs (50% cells) = release human growth hormone
- MOST sensitive cells in the pituitary therefore first to get destroyed
- Lactotrophs (10-25% cells) = release prolactin
- Thyrotrophs (10% cells) = release thyroid stimulating hormone
- Gonadotrophs (10-15% cells) = release follicle stimulating hormone and lutenizing hormone
- Corticotrophs (10-15% cells) = release of POMC (precursors of ACTH)
What is the most common cause of a goiter?
When is the most intense release of GH in children?
GH is released in a pulsatile fashion
Most intense period of GH release = within 1hr after the onset of deep sleep
GH secretion is lower in obese individuals
GH secretion is higher in females
Is GH produced anywhere else in the body?
What factors stimulate + inhibit the release of growth hormone?
Stimulation
- GHRH
- Ghrelin (produced in the stomach + hypothalamus)= hunger hormone
- Hypoglycaemia
- Deep sleep, exercise, stress, nutritional deficiency, estrogen or testosterone
- Dopamine
- Amino acids
- High protein meals
Inhibition
- Somatostatin
- Hyperglycaemia
- Leptin (released from fat)
- Steroids
- Hypothyroidism
- GH and IGF1 (produced by the liver)– acts at the hypothalamus and pituitary as negative feedback
What does GH do?
- Predominant action is to stimulate hepatic synthesis + secretion of IGF-1
- Metabolic effects = opposes insulin action
- Stimulates protein synthesis
- Stimulates lipolysis
- Antagonism of insulin
- Phosphate, water + sodium retention
- Anabolic effect= cartilage + bone growth
- Stimulates linear growth (via synthesis of IGF-1)
Where does FSH + LH act?
FSH: reduced by inhibin
- Ovarian granulosa cells
- Sertoli cells in testicles
LH: reduced by androgrens/oestrogens
- Luteinisation of ovary
- Leydig cells in testicles
What is Pallister Hall syndrome?
- Autosomal dominant
- GL13 mutation = loss of function
- Absence of pituitary gland
- Hypothalaemic harmatoma
- Polydactyly
- Bifid uvula
- Imperforate anus
- Renal + heart abnormalities
What is the best test of iodine deficiency?
Urinary iodine excretion
What does iodine deficiency + iodine excess cause?
Iodine deficiency
- Causes hypothyroidism
Iodine excess
- Causes hyperthyroidism OR hypothyroidism (Wolff-Chaikoff effect)
What is the commonest causes of congenital hypothroidism
WORLDWIDE
DEVELOPED COUNTRIES
WORLDWIDE = iodine deficiency
DEVELOPED COUNTRIES
- Thyroid dysgenesis (agenesis, ectopic/lingual, hypoplasia)
How does the NST test for thyroid disease?
What are the problems?
- NST ONLY detects HIGH TSH
- Problems
- 33% neonatal T4 is from mother therefore hypothyroidism may be missed
- Only TSH elevation detected therefore wont detect;
- Hyperthyroidism
- Secondary / tertiary hypothyroidism
- Premature babies have lower surge in TSH therefore can be false negative
- Need to repeat test at 2-4 weeks of life
What do you see on bone age x-ray post birth in athyreosis?
No or small epiphyses seen at lower femoral or upper tibial areas on bilateral knee x-ray
Where is the most common site of ectopic thyroid tissue?
Lingual
Congenital hypothyroidism: dose adjustment problems
- Potential problems with TSH setpoint
- Children with athyreosis:
- T4 can go into the hyperthyroid range even though TSH has not normalised
- Adjust dose based on TSH levels even if T4 is “normal”
- Overtreatment can potentially cause premature closure of the sutures (craniosynostosis); major complication of neonatal thyrotoxicosis
What is the most common cause of hyperthyroidism in children + adolescents?
Grave’s disease
Most common autoantibody: TSHrAB
What levels of the following do you get in sick euthyroid?
TSH
T4
T3
rT3
TSH: low, normal or high
T4: normal or low
T3: LOW (due to reduced thyrozine-5’ deiodinase levels being reduced in illness which reduces the conversion of T4–> T3
rT3: HIGH
Why do we avoid propylthiouracil in children?
Can cause liver failure
What are the side effects of carbimazole?
- Rash (15%)
- GI disturbance
- Cutis aplasia of scalp in neonates
- Agranulocytosis
- Neutropenia- dose related
- Abnormal LFT’s
What are the thyroi cancer syndromes?
FMTC
Familial MEN2a
- AD RET gene
- MTC, pheo, prim hyperparathyroidism, hirschprungs
Familial MEN2b
- AD RET gene
- MTC, pheo, mucosal neuromas, marfanoid
Gardner
- Familial adenomatous polyps in the GIT + papillar thyroid cancer
Cowden / Proteus / Bannayan Riley Ruvalcaba (PTEN mutation)
- AD harmatomas
- Increased risk breast / endometrial / thyroid cancer
Werner: connective tissue disease
What is the triad of hypopituitarism?
- Hypoglycaemia
- Loss of anti-insulin counter regulatory hormones
- Delayed maturation of liver enzymes
- GH, ACTH + TSH deficiency
- Prolonged jaundice
- Delayed maturation of liver enzymes
- Giant cell hepatitis
- TSH, GH, ACTH deficiency
- Males- micropenis (<1.9cm in neonate) + underscended testes
- GH + GnRH defiency
What is septo-optic dysplasia (de Morsier’s syndrome)?
Midline defects
Septo- septum pellucidum may be absent
Optic- optic nerve hypoplasia
Hypopituituirism
Usually sporadic, 3 genes associated HESX1, PTX2, SOX2
What are the heart defects associated with congenital hypothyroidism?
ASD, VSD, pulmonary stenosis
What is growth hormone deficiency defined as on the stimulation test?
Patient must have evidence of biochemical growth hormone deficiency, with a peak serum growth hormone concentration less than 10 mU/L or less than or equal to 3.3 micrograms per litre in response to 2 pharmacological growth hormone stimulation tests (e.g. arginine, clonidine, glucagon, insulin)
How do you investigate ACTH-Cortisol?
- Morning cortisol
- Low < 300 = hypopituitarism
- Highest cortisol in the morning
- ACTH level
- Low or normal in hypopituitarism
- Synacthen stimulation test
- Low dose more sensitive if short synacten normal
How do you adjust thyroxine dosing?
Aim to have the T4 in the upper limit of normal AND the TSH within normal range
When should you cease thyroxine in neonates with suspected transient congenital hypothyroidism?
NOT until 3 years of age
Why do you need to perform hearing tests in neonates with dyshormonogenesis
Why do you perform a knee x-ray in neonates with congenital hypothyroidism?
Looking for absence of epiphyses which is suggestive of intrauterine hypothyroidism
What are the genetic syndromes associated with Hashimoto’s?
- Turner’s
- T21
- Klinefelter
- IPEX
- APS1 + APS2
What is the most common cause of hyperthyroidisim in children?
Grave’s
What are the common antibodies in Hashimoto’s?
TPO Ab + Anti Tg Abs 90% have one or both
Thyrotropin receptor blocking antibodies only ~ 10%
Why can you get galactorrhoea + pseudoprecocious puberty in hypothyroidism?
In hypothyroidism you will have HIGH levels of TSH which can bind to the FSH receptor = stimulation
What causes stare + lid lag in hyperthyroidism?
Sympathetic overactivity
Is age of puberty + pubertal growth stages affecter by hyperthyroidism?
NO!
What is the effect of hyperthyroidism on bones?
Causes osteoporosis due to thyroid hormones stimulating bone resorption
Serum ALP high + osteocalcin high
High serum calcium
Who is at higher risk of Grave’s?
Females: males 5:1
Asians
HLAB8 + HLADR3
Addison’s
T1DM
Myasthenia Gravis
Celiac
Pernicious anaemia
Vitiligo
ITP
Psoriasis/ RA / alopecia
T21 + Turner’s
What is the pathophysiology of Grave’s?
T helper cells become sensitive to TSH antigen –> T helper cells diffentiate –> plasma cells develop which produce TSH stimulating Ab —> binds to TSH receptor —> Activation —-> overproduction of thyroid hormones + diffuse glandular growth
A TSH > 100 is usually due to…..
Athyreosis
OR
Defect in thyroid transcroption factor
Central vs primary hypothyroidism
Central hypothyroidism : usually XLR or AR
- Includes secondary (pituitary) + tertiary (hypothalamus) hypothyroidism
- TSH inappropriately low, normal or slightly increased
- FT4 low
Primary hypothyroidism
- TSH high
- FT4 low
How do haemangioma’s cause hypothyroidism?
- Haemangiomas can produce T4—> type 3 deiodinase (reverse T3) = inactive = clinical hypothyroidism
- Can require extremely large doses of L-thyroxine
- Condition resolves with regression of the haemangioma
What is Pendred syndrome?
- Autosomal recessive
- Chromosome 7q 31
- SLC26A4 gene which encodes an anion transported known as pendrin
- Pendrin: transports iodide across the apical membrane of the thyrocyte into the colloid space
- MRI: enlarged vestibular aqueduct syndrome
- Clinically euthyroid, goitre WORSENS with iodine deficiency
What are the signs and symptoms of a thyroid storm?
Use the Burch + Wartofsky criteria for the diagnosis of thyroid storm
- High temp
- CNS effects: seizures, coma, agitation, delirium, psychosis, lethargy
- GIT: N/V/D, abdominal pain, jaundice
- CVS: tachycardia/ heart failure/ AF
What does dopamine inhibit?
Prolactin secretion
TRH/TSH response
What is the pathophysiology of sick euthyroid syndrome?
- Cytokine mediated
- Reduced TRH release
- Reduced TSH response
- Reduced T4 production/ release
- Very low fT4 values have a poor prognosis
- Reduced T4 –>T3 production
- Reduced TBG
- Increased somatostatin secretion
What HLA’s increase the risk of T1DM
HLA DR3 + DR4
What is the pathophysiology of diabetes?
T cell mediated attack on target autoantigens in the islet beta cell
What are the BSL targets in T1DM?
Pre-prandial: 4-8
Post prandial < 10
HbA1c <7.5%
How do sulphonylureas work?
Sulphonylureas: gliclazide, glimepramide, glibenclamide
Increases insulin secretion by stimulating Beta cells
WIDELY used in MODY
DO NOT USE WITH INSULIN
What is the mechanism of DPP-IV inhibitors?
DPP-IV inhibitors: sitagliptin
Stimulates incretins + reduced gastric emptying
Most effective at post prandial BGL reduction
Results in weight loss
How do GLP-1 analogues work?
Stimulates incretins
Given via subcutaneous injection
Causes weight loss
Low risk of hypoglycaemia
NOT renally excreted
What is permanent neonatal diabetes?
- Heterozygous activating mutation in the KCNJ11 gene encoding Kir6.2 subunit of the pancreatic beta cell K ATP channel
- Can also be associated with developmental delay, muscle weakness + epilepsy
- Responsive to sulfonylureas
What is Wolfram syndrome (DIDMOAD)?
Diabetes Insidious Diabetes Melitis Optic Atrophy + Deafness
WFS1 gene
Diabetes in infancy
Optic atrophy in childhood
Definition of;
- Gluconeogenesis
- Glycogenolysis
- Glycogenesis
- Glycolysis
Definition of;
- Gluconeogenesis= metabolic pathway resulting in production of glucose from non CHO substrates
- 90% liver
- 10% kidney
- Glycogenolysis= breakdown of glycogen to glucose
- Glycogenesis= formation of glycogen
- Glycolysis= breakdown of glucose to generate ATP
Glucose transport
- Insulin INdependent
- Insulin dependent
- Insulin INdependent
- GLUT1= brain
- GLUT2= B islet cells, liver, kidney, small intestine
- GLUT3= neurons
- GLUT5= GIT
- Insulin dependent
- GLUT 4 = skeletal muscle + adipocytes
What is the action of insulin?
- Glucose transport in skeletal muscle + adipose tissue
- Glycogen synthesis + storage
- Triglyceride synthesis
- Na+ retention in the kidneys
- Protein synthesis
- Fat synthesis + storage
- Cellular uptake of K+ and amino acids
- REDUCED glucagon release
