Endocrinology Flashcards
Features of T2DM pathogenesis
- Insulin resistance. Initially leading to an increase in insulin secretion. However, ultimately there is a significant reduction in insulin secretion in T1DM.
- Increased hepatic glucose production
- Decrease muscle / tissue glucose uptake
- Increased glucose re-absorption in kidneys
- Increased lipolysis
- Decreased incretin effect (GIP & GLP1 management 50% of post-prandial insulin secretion)
- Increased glucagon secretion
- Neurotransmitter dysfunction
What are the clinical stages of diabetic retinopathy?
Stage 1 - non-proliferative retinopathy
Hyperglycaemia causes changes in the blood vessels of the eye -> microaneurysm formation -> can burst to leak blood (haemorrhage)
Stage 2 - pre-proliferative retinopathy
Changes are increasingly severe and widespread, including bleeding into retino
Fundoscopy may show - microanuerysm or haemorrhage, cotton wool spots (obstruction of retinal arteriole -> ischaemia)
Stage 3 - proliferative retinopathy
New blood vessels and scar tissue form in the retina -> causing loss of vision
Fundoscopy -hard exudates (composed of lipid and proteinaceous material, such as fibrinogen and albumin that leak from the impaired blood–retinal barrier), new blood vessel formation at the optic disc
Diabetic macular oedema - vascular leakage & accumulation of plasma constituents in the macula
May not have symptoms in the non-proliferative & pre-proliferative stages -> therefore annual screening is essential
Contributing factors for diabetic foot ulcers
Which type of diabetic foot ulcer has the highest risk of amputation?
Ischaemic > neuroischaemic > purely neuropathic
What is the risk of diabetic foot ulcer recurrence? What are risk factors for ulcer recurrence?
Risk of diabetic foot ulcer recurrence is high
40% at 1 year, 60% at 3 years, 65% at 5 years.
- HbA1c < 7.5%
- Presence of osteomyelitis
- presence of previous ulcer at plantar hallux
- presence of peripheral artery disease
- smoking
- mobility
What is the Hba1C target in T2DM?
UKPDS trial established target of 7% (this trial compared 7% to 7.9%) - 25% reduction in microvascular complications, trend towards advantage for macrovacular complications, but non-significant
In this trial - patients were either on sulphonylureas or insulin
HbA1c target < 6.5% associated with increased mortality due to risk of hypoglycaemia and CV death
Personalised HbA1c target - factors to take into consideration
- disease duration
- life expectancy
- comorbidities
- important comorbidities
- established vascular complications
Side effects of GLP1 agonists
Acute pancreatitis
Hypoglycaemia - minimal risk as monotherapy (glucose dependent action), but slightly increased in combination with insulin
Renal impairment - dulaglutide eGFR >15, semaglutide eGFR > 30
Heart rate - small increment
Effects of insulin
What are the risks of proliferative diabetic retinopathy?
Vitreous haemorrhage
Retinal detachment
What is the pathogenesis of proliferative diabetic retinopathy?
Hypoxia -> VEGF -> neovascularisation
What are the features of severe and very severe non-proliferative diabetic retinopathy?
Severe NPDR 4-2-1 rule
- 4 quadrants of microaneurysms / haemorrhage
- 2 quadrants of venous bleeding
- 1 quadrant of intra-retinal microvascular abnormalities
- 15% progressive to proliferative retinopathy in 1 year
Very severe NPDR
- defined as 2 of the above criteria
- 50% progress to proliferative DR in 1 year
When should laser therapy be used for diabetic retinopathy?
For high risk proliferative diabetic retinopathy
- neovascularisation of the disc > 1/4 to 1/3 disc area
- any neovascularisation of the disc with vitreous haemorrhage
- neovascularisation elsewhere >1/2 disc area with vitreous haemorrhage
Pathogenesis of diabetic kidney disease
3 major components
1. Glomerular hyperfiltration
2. Oxidative stress & inflammation
3. Interstitial fibrosis & tubular atrophy
Glomerular hyperfiltration
-hyperglycaemia -> advanced glycation end products & ROS. Diabetic products activate RAAS & other pathways -> kidney hypertrophy, reduced afferent arteriole resistance, increased efferent arteriole resistance
-upregulation of SGLT1 & 2 in proximal tubule -> increased Na reabsorption -> decreased sodium passing macula densa -> reduced afferent arteriole resistance
-imbalance in tone between afferent & efferent arterioles -> increased intraglomerular pressure
Oxidative stress & inflammation
Advanced glycation end products -> bind to ACE receptors (RAGE) on various kidney cells
Macrophage activation -> cytokine production
TGF beta -> mesangial cell hypertrophy & matrix accumulation
TNF alpha -> renal hypertrophy, podocyte & tubular cell injury
Interstitial fibrosis & tubular atrophy
TGF beta -> excess collagen & fibronectin deposition -> accumulation of mesangial matrix forms Kimmelstiel-Wilson nodules
Albuminuria ranges
- Microalbuminuria 30-300 mg/g or mg/day
- Macroalbuminuria >300 mg/g or mg/day
Nephrotic range >3.5g per 24 hours
- Macroalbuminuria >300 mg/g or mg/day
What are the renal biopsy changes seen in diabetic nephropathy?
Abnormalities in order of progression
- thickened glomerular basement membrane- can occur 2 years post diagnosis of T1DM
- mesangial cell proliferation
- mesangial matrix expansion - diffuse or nodular (Kimmelstiel - Wilson nodules)
- podocyte injury
- glomerular sclerosis
- tubulointerstitial fibrosis (occurs after initial glomerular lesions & is the final pathway mediating progression to advanced CKD and ESRF)
What are the autoantibodies associated with T1DM & what is their role in pathogenesis?
No role in pathogenesis. Pathogenesis of T1a diabetes - cell mediated destruction of pancreatic beta cells.
Abs may be positive for several years prior to clinical diabetes
Multiple positive Abs increase risk of clinical diabetes
Patients from normal population may have 2 or more positive Abs
Levels of autoantibodies decline following diagnosis, but anti-GAD persist
Glutamic acid decarboxylase (GAD65)
Zinc transporter 8 (Zn8)
Insulin autoantibodies (IAA)
Islet cell tyrosine phosphatase -2 (IA2)
Tetraspanin - 7
Genetic associations with T1DM
HLA DQA, HLA DQB
HLA-DR3, HLA-DR4 associated with increased risk
HLA-DR2 protective
if mother affected, 2-4% risk
if father affected, 5-8%
Siblings 8%
Dizygotic twins 10%
Monozygotci twins 50%
What are the risks associated with subclinical hyperthyroidism in people > 65 yrs?
Risk of sudden death in elderly
Bone loss, osteoporosis, fractures
AF (3 x fold increase), CCF, CAD
Dementia
Who should be treated for subclinical hypothyroidism?
Causes of hyperthyroidism
Adverse effects of antithyroid drugs
Antibodies in autoimmune thyroid disease
Criteria for thyroid storm
Degree of hyperthyroidism not a criteria for thyroid storm
Management of thyroid storm
Who to treat for subclinical hypothyroidism?
Vitamin D metabolism
Vitamin D / PTH metabolism
FGF-23 metabolism
Pros vs cons of CGM, CSCII with PLGS / HCL
Hypothalamus - pituitary - end organ axis
Characteristic features of thyroid eye disease
- proptosis
- periorbital oedema
- conjunctival inflammation
- extraocular muscle dysfunction (dysconjugate gaze)
Distinguish from lid lag / stare - non-specific signs of hyperthyroidism
Sonographic features of thyroid nodules - who should get an FNA?
Medications that interfere with RAAS testing
RAAS
Ion transport in collecting duct
Regulation of renin release
Plasma sodium & urine osmolality in diabetes insipidus vs primary polydipsia vs osmotic diuresis
Work up of polyuria / DI
Triggers for ADH release
Causes of amenorrhoea by breast development / FSH levels
Evaluation of amenorrhoea
Diagnosing menopause
Risks vs benefits of combined menopausal hormonal therapy
