Week 9 Flashcards
Define diabete mellitus:
A metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, protein and fat metabolism resulting from defects in insulin secretion, insulin action, or both
What are the WHO diagnostic criteria for DM?
WHO Criteria
- Fasting plasma glucose of >7.0 mmol/L
- Random plasma glucose of >11.1 mmol/L
- One abnormal values diagnostic if symptomatic
- Two abnormal values if diagnostic if asymptomatic
- HbA1c 6.5% or 48 mmol/mol
- Diabetes should not be diagnosed on the basis of glycosuria or a BM stick
- OGTT only required for diagnosis if IFG or GDM
Describe the pathogenesis and epidemiology of T1DM:
5% of DM.
Chronic, progressive metabolic disorder characterised by hyperglycaemia and the absence of insulin secretion.
Type 1 diabetes results from autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans.
Occurs in genetically susceptible subjects and is probably triggered by one or more environmental agents.
Lifetime risk of developing T1DM:
No family history – 0.4 percent
Offspring of an affected mother – 1 to 4 percent
Offspring of an affected father – 3 to 8 percent
Offspring with both parents affected – reported as high as 30 percent
Non-twin sibling of affected patient – 3 to 6 percent
Dizygotic twin – 8 percent
Monozygotic twin – 30 percent within 10 years of diagnosis of the first twin, and 65 percent concordance by age 60 years 5% of DM.
Describe the pathogenesis and epidemiology of T2DM:
90% of DM.
Chronic, progressive metabolic disorder characterised by hyperglycaemia, insulin resistance and relative impairment of insulin deficiency
Common with a prevalence that rises markedly with increasing levels of obesity
Most likely arises through a complex interaction among many genes and environmental factors
39% have at least one parent with T2DM
Lifetime risk for a first-degree relative of a is 5 -10 times higher than that of age- and weight-matched without family history of diabetes.
Describe the pathogenesis and epidemiology of GDM:
1-2% of DM (often unrecognised)
Caused by change in a single gene (monogenic). Autosomal dominant (50% chance of inheriting)
6 genes have been identified accounting for 87% of UK MODY (HNF1-A around 70%)
3 main features:
Often <25yrs onset
Runs in families from one generation to next
Managed by diet, OHAs, insulin (not always)
Describe the pathogenesis and epidemiology of MODY:
Carbohydrate intolerance with onset, or diagnosis, during pregnancy
Studies show that appropriate interventions reduce adverse outcomes in pregnancy
Risk factors include high body mass index, previous macrosomic baby or gestational diabetes, or family history of, or ethnic prevalence of, diabetes
Compare and contrast T1 and T2DM
Learn grid in summary sheets
What are the causes of 2ndry diabetes?
Secondary Diabetes
Genetic Defects of beta-cell function Genetic defects in insulin action Disease of exocrine pancreas Pancreatitis/Carcinoma/CF/Haemochromatosis Endocrinopathies Acromegaly/Cushings/Phaeochromocytoma Immunosuppressive agents Glucocorticoids/Tacrolimus/Ciclosporin Anti Psychotics – Cloazpine/Olanzipine Genetic syndromes associated with DM Down’s Syndrome Friedreich’s Ataxia, Turner’s Myotonic Dystrophy, Kleinfelter’s Syndrome.
What are the diagnostic criteria for GDM?
All women with risk factors should have an OGTT at
24 to 28 weeks. Internationally agreed criteria for gestational diabetes using 75 g OGTT:
Fasting venous plasma glucose ≥ 5.1 mmol/l, or
One hour value ≥ 10 mmol/l, or
Two hours after OGTT ≥ 8.5 mmol/l
How is micro and microvascular disease managed in diabetes?
Retinopathy: annual photographic retinal screening with triggers for ophthalmology referral
Nephropathy: annual monitoring of renal function and urinary albumin excretion, referral to renal team if nephropathy progresses e.g. CKD4, macroalbuminuria
Neuropathy/foot disease: annual foot-screening (minimum) with risk stratification and referral to podiatry/vascular as appropriate e.g. progressive neuropathy, structural change, ischaemia
CVS disease: keep BP <130/80, lower nephropathy. Statin therapy if T2DM and age >40 regardless of DM duration and baseline cholesterol. Consider in T1DM especially if complications
Describe hypoglycaemia, and driving and diabetes:
5 to drive
Describe insulin secretion:
- Raised glucose blood concentration
- Increased uptake of glucose into beta cells by GLUT2
- Increased ATP:ADP ratio closing ATP-gated K+ channels
- K+ ions no longer shunted across cell membrane, leading to rise of positive charge inside cell and depolarisation of cell
- Net effect is activation of voltage gated calcium channels, increasing intracellular calcium concentration
- Increased calcium triggers export of insulin by exocytosis and diffusion into nearby blood vessels
Describe hypoglycaemia, and driving and diabetes:
4.6 mmol/l - inhibition of insulin release - general malaise: headache, nausea
3.8 mmol/l - release of counterrgulatory hormones glucagon and adrenaline – onset of autonomic symptoms (most occur ~3 mmol/l) - sweating, palpitations, shaking, nausea, anxiety, hunger
BUT 70-80% of readings at this level no symptoms
2.5 -2.8 mmol/l - impairment of cognitive function and concentration, inability to perform complex tasks - confusion, drowsiness, odd behaviour, speech difficulty, incoordination, weakness, visual change, dizziness, tiredness
<2mmol/l – EEG changes, seizures
<1.5 mmol/l - coma, convulsions
5 TO DRIVE
Compare and contrast DKA and HHS:
DKA: absolute or relative insulin deficiency + increase in stress hormones leading to lipolysis (FFA: ketogenesis), gluconeogenesis (severe hyperglycaemia) and osmotic diuresis + acidosis leading to dehydration
Treat with fluid rehydration, electrolyte replacement (potassium) and insulin
HHS: hypovolaemia from hyperglycaemia, bicarbonate > 15mmol/l, absence of significant ketones
Treat with fluid, insulin and electrolyte replacement (sodium)
Describe the pharmacology of T2DM treatments:
Suplhonylureas: found to inhibit ATP-sensitive K+ channels in beta cells
Biguanides (metformin): mimics insulin by inhibiting hepatic gluconeogenesis, MoA uncertain but all involve inhibition of liver mitochondrial function
Pioglitazone: stops inappropriate deposition of lipid in non-adipose tissues (which leads to insulin resistance), therefore improves insulin sensitivity
DPP4 inhibitors: inhibit DPP4 which inactivates gastrointestinal hormones that potentiate insulin secretion, increasing endogenous incretin-mediated increase in insulin secretion
GLP1 receptor agonists: mimic incretins and are not cleaved by DPP-4, improving insulin secretion
SGLT2 inhibitors: inhibit renal re-uptake of glucose from filtrate by SGLT2, reducing hyperglycaemia. Also reduce blood pressure
Describe the pathophysiology, investigations and treatment of cushing’s syndrome and disease:
Pituitary tumour releasing ACTH
One of the causes of Cushing’s syndrome
wt gain / thin skin / easy bruising / increased BP / osteoporosis
Diagnosis- try to suppress it
- dexamethasone suppression testing
Treatment:
Surgery first line
If surgery fails / inappropriate / refused Bilateral adrenalectomy Medical therapy Ketoconazole / metyrapone Radiotherapy
Describe Whipples triad:
- Symptoms consistent with hypoglycaemia
- Low plasma glucose concentration
- Relief of those symptoms after the plasma glucose is raised
What are the different causes of non-diabetic hypoglycaemia?
- Pancreatic: insulinoma
- Non-islet cell tumour hypoglycaemia
- Autoimmune hypoglycaemia
- Reactive hypoglycaemia
- Drug induced
- Dietary toxins
- Organ failure
- Endocrine disease
- Inborn errors of metabolism
- Misc
How is NDHG investigated?
- Glucose (72 hour fast)
- Insulin, C petite
- SU screen,
- Beta hydroxybutyrate, low in insulinoma
- Pro insulin low with exogenous insulin
- Insulin antibodies
Describe the pathophysiology, investigations and treatment of hypoadrenalism:
Inadequate adrenocortical function
Primary insufficiency:
- Addison’s disease
- Autoimmune destruction
Clinical features:
Anorexia, weight loss Fatigue/lethargy Dizziness and low BP Abdominal pain, vomiting, diarrhoea Skin pigmentation
Diagnosis:
- suspicious biochemistry: decreased Na, raised K and hypoglycaemia
- SHORT SYNACTHEN TEST: measure plasma cortisol before and 30 minutes after IV ACTH injection
- ACTH should be greatly increased, causing skin pigmentation
- increased renin, decreased aldosterone
- Adrenal antibodies
Treatment:
- replacement corticosteroids and mineralocorticoids
Describe the pathophysiology, investigations and treatment of CAH:
Autosomal recessive disorder
Range of genetic disorders relating to defects in steroidogenic genes
Most common
CYP21 (21α hydroxylase)
Female- ambiguous genitalia
Boys- adrenal crisis (Hypotension, hyponatraemia)
Early virilisation
Treated with mineralocorticoid and glucocorticoid replacement
Describe the pathophysiology, investigations and treatment of phaeochromocytoma:
Pathophysiology:
Rare catecholamine-producing tumours arising from sympathetic paraganglia cells, which are collections of chromatin cells. Usually found within the adrenal medulla
Symptoms: episodic headache, sweating and tachycardia
Investigations:
Abdominal CT/MRI or MIBG-chromaffin seeking isotope scan
Treatment:
Surgery Pharmaceutical: - alpha-blockade initially - then beta-blocker if tachycardia - encourage salt intake
Describe the pathophysiology, investigations and treatment of primary hyperaldosteronism:
Pathophysiology:
Excess production aldosterone, independent of RAS system causing increased sodium and water retention and decreased renin release.
Due to either aldosterone-producing adenoma (Conn’s syndrome) or bilateral adrenocortical hyperplasia
Investigations:
U&Es, renin and aldosterone (preferably not on medications, especially beta blockers and MR antagonists)
Saline suppression test:
- 2L saline over 4 hours
- 4H aldosterone >270 highly suspicious
Treatment:
Surgery: only if adrenal adenoma
Medical: use MR antagonists (spironolactone or eplerenone)
What is an adrenal insulinoma?
a
Describe the pathophysiology and management of PCOS:
Pathophysiology is a combination of inappropriate secretion of gonadotrophins (increased LH, decreased FSH), androgens (increased, androstenedione heavily increased) and insulin resistance (overweight women more symptomatic)
Management:
Weight loss and insulin sensitisers (metformin)
Can also use ovarian androgen suppression, adrenal androgen suppression. androgen receptor antagonist, 5 alpha reductase inhibition, insulin sensitisers, topical inhibitors
Describe Kallman’s syndrome:
Pathophysiology- failure of cell migration of GnRH cells to hypothalamus from Olfactory placode, associated with aplasia/hypoplasia of olfactory lobes giving anosmia or hyposmia
Isolated gonadotrophin deficiency
May also be associated with deafness, renal genesis, cleft lip/palate or micropenis ± cryptorchidism
Describe the pathophysiology, investigations and treatment of primary gonadal disease:
Pathophysiology: complex genetic syndromes, Klinefelter’s syndrome
Characterised by cryptorchidism, adult Leydig cell failure, seminiferous tubule failure
Treatment: androgen replacement therapy (oral, IM, topical), fertility treatment (hCG, recombinant LH & FSH, GnRH pumps)
Describe Kleinfelters:
XXY
Clinically manifests at puberty
Increased LH and FSH- but seminiferous tubules regress and Leydig cells do not function normally
Wide clinical variation in phenotype due to hormonal response to LH surges
- delayed puberty
- suboptimal secondary male sexual characteristics
- persistent gynaecomastia
- azospermia
- behavioural issues/learning difficulties
Androgen replacement ± psychological support ± fertility counselling
Describe investigations for hypogonadism:
Sex steroid deficiency?
- Testosterone
- early morning
- free test >200
- total test >16
- SHBG
- LH&FSH
- help determine possible pituitary cause
Fertility?
- Semen analysis
- 1-3 days after last ejaculation
- 2-5 ml volume
- 20 x 106 sperm/ml
- 50% progressive motility
- ≥ 30% normal morphology
Describe SEs of testosterone replacement:
Side Effects
- Mood issues (aggression/behaviour change)
- Libido issues
- Increased haematocrit
- Possible prostate effects
- Acne, sweating
- Gynaecomastia
Describe the normal regulation of calcium:
Regulated by parathyroid hormone and vitamin D
PTH raises serum calcium at kidney, bone and GI
Kidney: reabsorption of calcium at distal tubule
Bone: increased number and activity of osteoclasts in continuous PTH exposure
GI: stimulates synthesis of active for of VIt D in kidney, thereby increases calcium absorption from the gut
Vitamin D also acts to increase serum calcium levels
What are the signs and symptoms of hypercalcaemia?
- If mild often asymptomatic
- Once calcium >3mmol/L symptoms are common
- Muscle weakness, bone pain, osteoporosis
- Anorexia, nausea, constipation, pancreatitis
- Confusion, depression, fatigue, coma
- Shortening of QTc, bradycardia, hypertension
- Polyuria, nephrogenic DI, stones, nephrocaclinosis
How is hypercalcaemia investigated and treated?
Investigations:
History and exam, CXR, FBC/ESR, TFTs, myeloma screen, synacthen test, vit D
Treatment:
- Treat underlying cause
- Stop offending/contributing medications
- Rehydration
- ± loop diuretic to promote calciuria
- Bisphosphonates to inhibit bone resorption
- Steroids
Describe vitamin D deficiency and treatment:
Caused by poor sunlight exposure, malabsorption, gastrectomy, enzyme inducing drugs, renal disease
Can cause osteomalacia- failure to ossify bones in adulthood as a result of vitamin D deficiency
Treatment with cholecalciferol (D3) or alfacalcifol (active bit D)
What is potential aetiology of hypercalcaemia?
PTH-mediated
- Primary hyperparathyroidism
- Familial syndromes e.g. MEN-1 and MEN-
- Familial hypocalciuric hypercalcaemia
PTH-independent
- Malignancy
- Granulomatous disorders
- Vitamin D toxicity
- Drugs: thiazides, lithium, calcium supplements
- Adrenal insufficiency
- Milk-alkali syndrome
- Immobolisation
• understand the clinical presentation of Conn’s Syndrome, Addison’s Disease and
Acromegaly highlight biochemical assessment of endocrine hypertension, adrenal
function and growth
• hormone excess
• understand the pathological basis of Conn’s Syndrome, Addison’s Disease and
acromegaly review the anatomy and radiology of the pituitary and the adrenal gland
a
