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What is the epidemiology of Paget's disease?

- most common in UK and british ancestry
- men more than women
- prevalence doubles each decade after 40
- incidentally elevated ALP
- unknocn cause, often genetic component.


What is the pathophysiology of Paget's Disease?

High bone turnover and disorganised osteoid formation.

Unknown cause.


What are the clinical findings in Paget's disease?

- can be mild and asymptomatic
- one bone (monostotic) or multiple (polyostotic)
- skull, femur, tibia, pelvis and humerus
- bones involved immediately, additional bones don't get involved during it's course
- pain is first symptom, either in involved bone or adjacent joint featuring degenerative arthtitis
- bones can soften --> bowed tibias, kyphosis, chalkstick fractures with slight trauma
- skull involvement - headaches and increased hat size.  
- deafness
- vascular steal syndromes due to increase vascularity over involved bones (which are also warm to touch)


What are the lab findings of Paget's disease?

Markedly elevated ALP.
Serum bone specific ALP if normal, or to distinguish source of elevated ALP.
Serum C-telopeptide (CTx) is high
Urinary hydroxyproline is high in active disease
Elevated serum Ca esp if bed rested
Screen for OHD deficiency which can also present with elevated ALP and bone pain - correct before prescribing a bisphosphonate.


What is the evidence for calcium and vitamin D supplementation/

The strongest evidence for fracture benefits of supplements is observed when both calcium and vitamin D are used by institutionalised women with low vitamin D levels and low dietary intake of calcium


What are the imaging findings in Paget's disease?

- ostelytic with focal radiolucencies 'osteoporosis circumscripta' in the skull or advancing flame shaped lytic lesions in long bones
Bones subsequently become sclerotic or mixed scleoritc and lytic, then thickened and deformed
Technetium pyrophosphate bone scans can help show activity of bone lesions before radiologic changes are evident.


What is multisystem proteinopathy?

- constellation of Paget disease, inclusion body myopathy, and FTD
- caused by a mutation in gene that encodes valosin-containing protein.


What are the important differentials of Paget disease?

- osteogenic sarcoma
- multiple myeloma
- fibrous dysplasia
- secondary bone lesions: metastatic Ca and osteititis fibrosa cystica


What are the complications of Paget's disease?

Hypercalcaemia and renal calculi
Vertebral collapse and spinal cord or root compression - radiculopathy or paralysis
High output cardiac failure due to increased vascularity
Arthritis in adjacent joints
Cranial nerve palsies from impingement of the neural foramina
Petrous temporal bone involvement frequently causes mixed hearing loss
Vascular steal syndrome - in the skull this can cause somnolence, stroke or optic nerve involvement and loss of vision
Misaligned teeth if jaw involved
Osteosarcoma rarely in longstanding lesions - marked increase in bone pain, sudden rise in ALP and new lytic bone lesion


What is the treatment of Paget's disease?

Surveillance if asymptomatic unless extensive involvement of skull, long bones, or vertebrae

Bisphosphnates are treatment of choice - given until ALP normalised, then a break for about 3 months or until ALP rises again
May get paradoxical increase in pain - first dose effects and go away.
If given IV - Improvement lasts several months

May get asthma in aspirin sensitive patients.

IV zoledronic acid more effective than daily risedronate.

Nasal calcitonin-salmon is used but bisphosphonates better


What is the prognosis of Paget's disease?

Good unless sarcoma
Prognosis worse if it starts early in life

In severe forms: intractable pain, deformity and cardiac features.  Rare with prompt bisphosphonate tx.


What are the general symptoms of chronic adrenocortical insuffiency (Addison's disease)?

- weakness & fatigueability
- sparse axillary hair, crease & nipple pigmentation
- hypotension and small heart


What are the general biochemical features of Addison disease?

Eosinophilia and relative lymphocytosis


What happens to cortisol in chronic adrenocortical insufficiency? (Addison disease)

Low plasma cortisol levels that fail to rise after administration of corticotropin

Elevated ACTH


What is the difference between primary and secondary adrenal insufficiency?

Primary - dysfunction or absence of adrenal cortices

Secondary - deficient secretion of ACTH


What does 21-hydroxylase do?  What happens if you break it?

Catalyses conversion of progesterone to deoxycorticosterone which later becomes aldosterone.

Catalyses conversion of 17-alpha-hydroxyprogesterone to deoxycortisol which becomes cortisol.

Breaking it means cortisol and aldosterone insufficiency and sex steroid excess which is congenital adrenal hyperplasia


What is the most common cause of Addison disease?

Autoimmune destruction of the adrenals.


What is the mechanism of polyglandular autoimmune syndrome Type 1? (Type 1 PGA)

Defect in T-cell mediated immunity inherited as an autosomal recessive trait.


What are the non-autoimmune causes of Addison's disease?

- Tuberculosis
- Bilateral adrenal haemorrhage during sepsis, HITs, anticoagulation or antiphospholipid syndrome - presents at 1 week post
- Adrenoleukodystrophy


What is adrenoleukodystrophy?

X-linked peroxisomal disorder causing accumulation of very long chain fatty acids.

Accumulate in adrenals, testes, brain, and spinal cord.

Occurs at any age and accounts for 1/3 of Addison disease in boys.


What do peroxisomes do?

Break down very long chain fatty acids.


What does 17 hydroxylase do?

What does a deficiency cause?

Catalyses conversion of pregnenolone and progesterone to 17a-hydroxypregnenolone and 17a-hydroxyprogesterone respectively.
These get converted to DHEA (pregnenlonone) and androstenedione (progesterone) respectively.

Deficiency forces progesterone and pregnenlone down the mineralocorticoid pathway only.

This results in hypertension, hyperkalemia, and primary hypogonadism. 

It's a rare form of CAH.


What will a mild deficiency of 21 hydroxylase result in?

Women with hirstutism in adolescene but adequate cortisol.

Known as 'late onset' congenital adrenal hyperplasia


What nail changes are evident in Addison disease?

Longitudinal pigmented bands


What skin condition may be associated with Addison disease?



What effect does Addison disease have on blood pressure?

- hypotensive and orthostatic
- most have systolic BP less than 110


What do you screen for in young men with idiopathic Addison disease?



Very long chain fatty acid levels - they'll be really high


How is the diagnosis of primary adrenal insufficiency made?  (Addison's disease)

What is the role of doing a morning cortisol test?

A diagnosis of primary adrenal insufficiency is confirmed by the combination of:

1.  a positive short Synacthen test (ie an absent or severely blunted plasma cortisol response to tetracosactrin 30 to 60 minutes after injection)

2.  elevated adrenocorticotrophic hormone (ACTH)

3.  elevated plasma renin (measured by direct concentration or plasma renin activity).

Measuring diurnal (morning and afternoon) plasma or serum cortisol concentrations is not useful for evaluating adrenal insufficiency.


What does hypercalcaemia in Addison disease mean?

Heralds an Addisonian crises


What happens to the blood glucose in Addison disease?

Fasting blood glucose is low because there is no cortisol to help glycogenolysis