Endocrine Flashcards
What is adrenal cortical ca?
cancer cells form in outer layer (cortex) of adrenal gland
Rare, usually functional, XS hormone secretion
GC: Cushing’s
Androgens: virilisation/ feminisation
Aldosterone: ↑K
RF: F, 0-5, 40-50, more aggressive in adults, MEN1, Li-Fraumeni, CAH,
Sx of adrenal cortical ca?
Rapidly progressing hypercortisolism: ↑weight, muscle wasting, fat redistribution, skin atrophy
Hyperaldosterone - raised blood pressure, thirst, passing urine frequently, muscle cramps
Hyperandrogenism: female (hirsutism, male pattern baldness, oligomenorrhoea), male (gynecomastia, testicular atrophy, ED).
Mass effect: abdo/ flank pain, N/V
Complications:
Mets
DM
Diagnosis and Tx of adrenal cortical ca?
CT: unilat, irregular shape, heterogenous, necrosis, calcification
Fasting BG, K, basal cortisol, corticotropin, 24 hr urinary free cortisol, sex hormones
Chemo
Surgery
Radiation
Symptoms of pituitary adenoma?
excess of a hormone (e.g. Cushing’s disease due to excess ACTH, acromegaly due to excess GH or amenorrhea and galactorrhea due to excess prolactin)
depletion of a hormone(s) (due to compression of the normal functioning pituitary gland)
non-functioning tumours, therefore, present with generalised hypopituitarism
stretching of the dura within/around pituitary fossa (causing headaches)
compression of the optic chiasm (causing a bitemporal hemianopia due to crossing nasal fibers)
Go look for that adenoma please: G: GH, L: LH, F: FSH, T: TSH, A: ACTH, P: prolactin function. Order of loss of hormones due to mass effect.
Symptoms of pituitary adenoma?
excess of a hormone (e.g. Cushing’s disease due to excess ACTH, acromegaly due to excess GH or amenorrhea and galactorrhea due to excess prolactin)
depletion of a hormone(s) (due to compression of the normal functioning pituitary gland)
non-functioning tumours, therefore, present with generalised hypopituitarism
stretching of the dura within/around pituitary fossa (causing headaches)
compression of the optic chiasm (causing a bitemporal hemianopia due to crossing nasal fibers)
Pressure: CN 3, 4, 5 palsy (pressure/ invasion of cavernous sinus), DI, disturbance of temp, sleep, appetite
Go look for that adenoma please: G: GH, L: LH, F: FSH, T: TSH, A: ACTH, P: prolactin function. Order of loss of hormones due to mass effect.
Investigations for pituitary adenoma?
a pituitary blood profile (including: GH, prolactin, ACTH, FH, LSH and TFTs)
formal visual field testing
MRI brain with contrast (Gadolinium)
Treatment of pituitary adenoma?
hormonal therapy (e.g. bromocriptine is the first line treatment for prolactinomas)
surgery (e.g. transsphenoidal transnasal hypophysectomy)
e.g. if progression in size
radiotherapy
Treatment of pituitary adenoma?
hormonal therapy (e.g. bromocriptine is the first line treatment for prolactinomas)
Replacement hormones eg hydrocortisone for hypopit
Hormone suppression: somatostatin analogue for GH, bromocriptine/ cabergoline for prolactinomas.
Steroids given before levothyroxine as may precipitate adrenal crisis.
surgery (e.g. transsphenoidal transnasal hypophysectomy)
e.g. if progression in size
radiotherapy
Complications of pituitary adenoma?
Mass effect
Pit apoplexy > haem into pit
Sella turcica erosion
Panhypopituitarism
What is pituitary apoplexy?
Sudden enlargement of a pituitary tumour (usually non-functioning macroadenoma) secondary to haemorrhage or infarction.
Precipitating factors:
HTN, pregnancy, trauma, anticoagulation
Features:
- sudden onset headache similar to SAH
- vomiting
- neck stiffness
- visual field defects - classically bitemporal superior quadrantic defect
- extraocular nerve palsies
- features of pituitary insufficiency
e. g. hypotension/hyponatraemia secondary to hypoadrenalism
Investigation
- MRI is diagnostic
Management
- urgent steroid replacement due to loss of ACTH
- careful fluid balance
- surgery
Types of thyroid cancer?
Papillary: differentiated, 60%. Least aggressive. RET/BRAF mutations, ionising radiation as kid. Cowden/ Gardner syndrome. Multiple small projections from follicular cells, growing towards BVs, lymphatic. Seldon encapsulated. LN mets predominate
Follicular: <25%, differentiated. Adenocarcinoma. Grows until breaks through fibrous capsule, invade nearby BV + spread. Well circumscribed single nodules, with colloid filled follicles, may be calcified/ central necrosis. Low dietary iodine, RAS, PTEN vascular invasion.
Medullary: 5%, parafollicular C cells, upper 1/3 or gland/ medulla. C cells make XS calcitonin, deposits between C cells. Release serotonin + VIP ↑GI motility. 1/3 familial, 1/3 sporadic 1/3 MEN 2A, 2B. RET mutation (single Ca in 1 lobe), familial multiple across both lobes.
Symptoms of thyroid cancer?
Large, solitary, painless, thyroid nodule, hard consistency, fixed
Hypothyroid
Mass effect: hoarseness, dysphagia, tracheal deviation
Cervical lymphadenopathy: neck mets
Medullary: release of VIP, diarrhoea, ↑serotonin, flushing of skin.
Complications of thyroid cancer?
Lymphoma, rare, associated with Hashimoto’s thyroiditis
Anaplastic: rare, most aggressive, undiff, grow beyond fibrous capsule, invade nearby structures, may derive from existing papillary/ follicular Ca where cells mutate more. Elderly females.
Investigation of thyroid cancer?
Papillary: cells with empty nuclei, Orphan Annie eyes. Psammoma bodies (Ca deposit in papillae)
Follicular: eosinophilic cells, granula cytoplasm > Hurthle cells stains pink.
Medullary: spindle shaped cells, amyloid deposits
Anaplastic: spindle shaped, pleomorphic giant cells.
USS thyroid
TFTs
Fine needle aspiration
Calcitonin levels
Radioiodine scan: usually thyroid tumours don’t make thyroid hormones so cold nodules.
Treatment of thyroid cancer?
Surgical resection
Levothyroxine
Radioactive iodine ablation
Yearly thyroglobulin levels to detect early recurrent disease.
Metastatic: sorafenib, Lenvatinib, vandetanib
Papillary: excellent prognosis
Anaplastic: not responsive to Tx/ chemo , can cause pressure Sx
What is hyperaldosteronism?
condition in which one or both adrenal glands produce too much of the hormone aldosterone
can lower K+ levels > weakness and muscle spasms
XS reabsorption of Na within distal nephron, HTN, RAAS suppression. Urinary loss of H + K.
RF: F, 20-60, FH
Causes of primary hyperaldosteronism?
genetic
random
benign cortical adenoma (Conn’s synd)
bilat idiopathic adrenal hyperplasia (70%)
familial hyperaldosteronism
Causes of primary hyperaldosteronism?
genetic
random
benign cortical adenoma (Conn’s synd)
bilat idiopathic adrenal hyperplasia (70%)
familial hyperaldosteronism
adrenal carcinoma - rare cause
Features of hyperaldosteronism?
Headache, facial flushing (HTN)
Constipation, muscle weakness, arrhythmias (↓K)
HTN unresponsive to Tx
Cramps, paraesthesia, polyuria, polydipsia, nocturia, lethargy, mood disturbance, difficulty concentrating, muscle cramps, palpitations.
Alkalosis
Complications of hyperaldosteronism?
↓K, HCO3, ↑Na, met alkalosis.
Heart disease, vascular disease, renal disease, stroke
Investigations for hyperaldosteronism?
1st Plasma aldosterone: renin, >20. 1° ↑aldosterone, ↓ renin. (-ve feedback due to Na retention form aldosterone)
CT abdo: tumour or idiopathic hyperaldosteronism
Adrenal vein sampling: if Ct normal, CT doesn’t detect lesions <1cm, aldosterone production lateralises to 1 adrenal in unilat, bilat in bilat forms. Distinguish between unilat adenoma + bilat hyperplasia.
No suppression of aldosterone to fludrocortisone or salt loading.
2°: ↑renin, ↑aldosterone
Management of hyperaldosteronism?
Adenoma: surgery
Bilat hyperplasia: aldosterone antagonist, spironolactone
Control HTN: thiazide, ACEi, CCB, Ang II blockers
What is Cushing’s syndrome?
too much cortisol
Causes of Cushing’s syndrome?
1°: adenoma/ adenocarcinoma in zona fasciculata of adrenal secretes cortisol, hyperplastic adrenal gland/ nodular adrenal hyperplasia.
2°: iatrogenic (GCs) pit adenoma (Cushing’s disease), ectopic ACTH (benign bronchial carcinoid, malig oat cell Ca/ small cell lung ca.
Carney complex: syndrome incl cardiac myxoma.
Pseudo Cushing’s: oestrogen contraceptives ↑ cortisol binding globulin ↑cortisol. Alcohol XS or severe depression.
Causes of Cushing’s syndrome?
1°: adenoma/ adenocarcinoma in zona fasciculata of adrenal secretes cortisol, hyperplastic adrenal gland/ nodular adrenal hyperplasia.
2°: iatrogenic (GCs) pit adenoma (Cushing’s disease), ectopic ACTH (benign bronchial carcinoid, malig oat cell Ca/ small cell lung ca.
Carney complex: syndrome incl cardiac myxoma.
Pseudo Cushing’s: mimics Cushing’s, often due to alcohol excess or severe depression, cause false positive dexamethasone suppression test or 24hr urinary free cortisol, oestrogen contraceptives ↑ cortisol binding globulin ↑cortisol.
ACTH dependent
- Cushing’s disease - pituitary tumour secreting ACTH producing adrenal hyperplasia
- ectopic ACTH production - SCLC
ACTH independent
- iatrogenic - steroids
- adrenal adenoma
- adrenal carcinoma
- Carney complex
- micro nodular adrenal dysplasia (rare)
Complications of Cushing’s syndrome?
Metabolic syndrome
DM
Infection due to IS
Fragility # due to osteoporosis
Renal stones
Venothrombolic event: hypercoag
Necrosis of femoral head
Glaucoma
Poor libido, ED
Amenorrhoea
Hypokalaemia metabolic alkalosis
↓K common with ectopic ACTH
Investigations for Cushing’s syndrome?
Overnight dexa suppression test: ↑ cortisol
High dose dexa: ↓cortisol Cushing’s disease,
↑cortisol ↓ACTH adrenal cushing
↑cortisol ↑ACTH ectopic ACTH
↑24hr urinary free cortisol
9am + midnight ACTH if ACTH supressed then non-ACTH dependent cause likely: adrenal adenoma. If >4 ACTH dependend eg Cushing’s disease/ ectopic ACTH.
CRH stimulation: if pit source, cortisol ↑, ectopic/adrenal, no change in cortisol.
Psuedo: false pos dexamethasone suppression test or 24 urinary cortisol. Insulin test to differentiate
Management of Cushing’s syndrome?
Wean steroid meds for iatrogenic Cushing;s
Surgery: for adenoma or ectopic ACTH
Pasierotide (somatostatin analogue), cabergoline (dopamine agonist), osilodrostat, ketoconazole, metyrapone, mitotane, etomidate (steroidogenesis inhibitor), mifepristone (glucocorticoid antagonist)
Pituitary radiotherapy
What is Addison’s disease?
hypoadrenalism
reduced cortisol and aldosterone
AI destruction of adrenal glands is commonest cause
What is Addison’s disease?
hypoadrenalism
reduced cortisol and aldosterone
AI destruction of adrenal glands is commonest cause
RF: F>M, adrenocortical IG, use of anticoags.
Causes of hypoadrenalism?
Primary causes
- Addison’s
- tuberculosis
- metastases (e.g. bronchial carcinoma)
- meningococcal septicaemia (Waterhouse-Friderichsen syndrome)
- HIV
- antiphospholipid syndrome
- Drugs that inhibit cortisol synthesis eg ketoconazole, suramin.
Secondary causes
- pituitary disorders (e.g. tumours, irradiation, infiltration)
Exogenous glucocorticoid therapy
Features hypoadrenalism/ Addison’s?
Lean, tanned, tired + tearful, weakness.
lethargy, weakness, anorexia, nausea & vomiting, weight loss, ‘salt-craving’
hyperpigmentation (especially palmar creases)*, vitiligo, loss of pubic hair in women, hypotension, hypoglycaemia
GI: abdo pain, anorexia, N/V, weight loss
Vitiligo: AI destruction of melanocytes.
hyponatraemia and hyperkalaemia may be seen
crisis: collapse, shock, pyrexia
* Primary Addison’s is associated with hyperpigmentation whereas secondary adrenal insufficiency is not
Investigations for Addison’s disease?
ACTH stimulation test (short Synacthen test). Plasma cortisol is measured before and 30 minutes after giving Synacthen 250ug IM. insuff/ no cortisol produced. Addison’s excluded if 30 min cortisol >550nmol/L.
Adrenal autoantibodies such as anti-21-hydroxylase may also be demonstrated.
9am serum cortisol:
> 500 nmol/l makes Addison’s very unlikely
< 100 nmol/l is definitely abnormal
100-500 nmol/l should prompt a ACTH stimulation test to be performed
Electrolyte abnormalities: hyperkalaemia hyponatraemia hypoglycaemia metabolic hyperchloraemic acidosis
↑renin compensatory to ↓aldosterone
Plasma dehydroepiandrosterone + DHEA sulphate suppressed.
Abdo CT: enlarged adrenal glands with TB/malig, small if AI/ advanced TB. If infectious > calcifications
Management of Addison’s disease?
GC and MC replacement therapy
> hydrocortisone: usually given in 2 or 3 divided doses. Patients typically require 20-30 mg per day, with the majority given in the first half of the day
fludrocortisone
Pt. education
- emphasise the importance of not missing glucocorticoid doses
- consider MedicAlert bracelets and steroid cards
- patients should be provided with hydrocortisone for injection with needles and syringes to treat an adrenal crisis
- discuss how to adjust the glucocorticoid dose during an intercurrent illness
Management of intercurrent illness?
- in simple terms the glucocorticoid dose should be doubled, with the fludrocortisone dose staying the same
What is Addisonian crisis?
life-threatening situation that results in low blood pressure, low blood levels of sugar and high blood levels of potassium, precipitated by physiological stress where sudden need for aldosterone + cortisol but body can’t deliver
Features = hypoglycaemia, circ collapse, shock fatal. Pain in back, abdo legs, severe N/V, pyrexia
Causes
- sepsis or surgery causing an acute exacerbation of chronic insufficiency (Addison’s, Hypopituitarism)
- adrenal haemorrhage eg Waterhouse-Friderichsen syndrome (fulminant meningococcemia)
- steroid withdrawal
Management
- hydrocortisone 100 mg im or iv
- 1 litre normal saline infused over 30-60 mins or with dextrose if hypoglycaemic
- continue hydrocortisone 6 hourly until the patient is stable. No fludrocortisone is required because high cortisol exerts weak mineralocorticoid action
- oral replacement may begin after 24 hours and be reduced to maintenance over 3-4 days
What is Waterhouse-Friderichsen syndrome?
Severe, adrenal failure due to overwhelming infection, adrenal gland haem. Necrosis, adrenal crisis.
Sx:
Initial: fever, malaise, chills, headache, vomiting
Shock: ↓BP ↑HR, tachypnoea
Cyanosis
Ix:
CT: blood in adrenals
Blood culture
DIC: ↑fibrinogen degradation products, d dimer, prolonged PT, aPTT ↓plts, fibrinogen.
Tx:
IV GC
Abx
IV fluids, vasopressors
What is diabetes mellitus?
defined as a chronic condition characterised by abnormally raised levels of blood glucose
What is type 1 diabetes mellitus?
Autoimmune disorder where the insulin-producing beta cells of the islets of Langerhans in the pancreas are destroyed by the immune system
This results in an absolute deficiency of insulin resulting in raised glucose levels
Patients tend to develop T1DM in childhood/early adult life and typically present unwell, possibly in diabetic ketoacidosis
Genes (HLA-DR3/4, PTPN22, CD25) + environmental trigger (childhood enterovirus, bystander activation, molecular mimcry)
What is type 2 diabetes mellitus?
the most common cause of diabetes in the developed world.
It is caused by a relative deficiency of insulin due to an excess of adipose tissue. In simple terms there isn’t enough insulin to ‘go around’ all the excess fatty tissue, leading to blood glucose creeping up.
What is prediabetes?
This term is used for patients who don’t yet meet the criteria for a formal diagnosis of T2DM to be made but are likely to develop the condition over the next few years. They, therefore, require closer monitoring and lifestyle interventions such as weight loss
What is Gestational diabetes?
Some pregnant develop raised glucose levels during pregnancy. This is important to detect as untreated it may lead to adverse outcomes for the mother and baby
What is Maturity onset diabetes of the young (MODY)?
A group of inherited genetic disorders affecting the production of insulin.
Results in younger patients developing symptoms similar to those with T2DM, i.e. asymptomatic hyperglycaemia with progression to more severe complications such as diabetic ketoacidosis
What is Latent autoimmune diabetes of adults (LADA)?
The majority of patients with autoimmune-related diabetes present younger in life. There are however a small group of patients who develop such problems later in life. These patients are often misdiagnosed as having T2DM
Other causes of DM?
Any pathological process which damages the insulin-producing cells of the pancreas may cause diabetes to develop. Examples include chronic pancreatitis and haemochromatosis.
Drugs may also cause raised glucose levels. A common example is glucocorticoids which commonly result in raised blood glucose levels
Sx of DM?
Polyuria, polydipsia, polyphagia.
Glycosuria
Dehydration
Hypotension
Blurred vision
Gastroparesis
Paraesthesia
Unexplained weight loss
↓sensation, glove + stocking distribution
Autonomic NS malfunction: sweating, passing gas
Complications of T1DM?
DKA: abdo pain, vomiting, ↓consciousness
Infection
Delayed wound healing
Amputations
Microvascular: retinopathy, nephropathy, ED
Macrovascular: CV, cerebrovascular, peripheral vascular disease
Hypoglycaemia
Lipodystrophy
Investigations for T1DM?
Random glucose/ 2hr GTT >11
Fasting: >7
HbA1c: >48. Not as useful in T1, as not accurately reflect rapid ↑
Urinalysis: albuminemia, glycosuria, ketones
C peptide: byproduct of insulin production, if ↓ pancreas no longer producing enough insulin
Autoantibodies against β cells: glutamic acid decarboxylase (GAD), insulinoma-associated-2 autoantibodies (IA-2A), islet cell autoantibodies, insulin autoantibodies (IAA), zinc transporter 8 (ZnT8Ab), tyrosine-phosphate like molecule – islet auto-antigen-2.
Consider C-peptide and/or diabetes-specific autoantibodiesif T1DM suspected but clinical presentation includes atypical features (>50, BMI >25m slow evolution of hypoglycaemia or long prodrome)
Management of T1DM?
Life long insulin
Illness: maintain calorie intake, monitor glucose, ↑insulin if glucose rising.
HbA1c: monitor 3-6 mnths, target 48
Self-monitoring - at least 4 times a day (before meals and bed), more frequent monitoring if frequent hypoglycaemic episodes, periods of illness, before, during and after sport, planning pregnancy and during, and while breastfeeding
BG targets: 5-7 on waking, 4-7 before meals + other times.
Metformin: BMI>25
Basal bolus: basal glargine + degludec, determir, bolus lispro (humalog), aspart (novorapid)
Bipashic: Humalog mix 25: 25% quick acting, 75% intermediate acting.
Insulin pumps
Summary of ultra-short acting insulin analogues?
Lispro, aspart, glulisine
12-30 min onset
Take prior to meal
Peak 0.5-3 hours
Duration 3-5 hours
Summary of short-acting soluble/ neutral insulin?
Humulin S, Hypurin Porcine, Neutral
Humulin S - 30mins
Hypurin Porcine - 60 mins
Taken 30 mins prior to eating a meal
Humulin S - 2-3 hrs onset
Hypurin Porcine - 2-5 hrs onset
6-8 hours duration
Summary of intermediate acting insulin?
Insulin NPH
1.5-4 hour onset
Taken twice daily in combination with rapid acting insulin
Peak 4-12 hours
Duration 14-24 hours
Summary of long-acting insulin?
glargine/Lantus, detemir/Levemir
3-4 hour onset
Used when rapid-acting insulin stops working
Peak minimal, non-defined peak
Duration >24 hours
RFs for T2DM?
FH
physical inactivity
poor diet
obesity
HTN
hypertriglyceridemia
> 45
gestational DM
prediabetes
PCOS
↑BG level (GC, atypical antipsychotics, thiazide diuretics)
LBW
Sx of T2DM?
Polyuria, polydipsia, polyphagia
Glycosuria
Weakness
Blurred vision
Acanthosis nigricans: hyperpigmented
Candida infections
Skin abscesses: cellulitis/ abscess
UTIs
Fatigue
Complications of T2DM?
↑risk CV, PAD.
Hyperosmolar hyperglycaemic state.
HTN: <80 clinic 140/90, HBPM 135/85. >80 150/90, HBPM 145/85
Neuropathy
Diabetic food
Retinopathy
How does metformin work?
↑insulin sensitivity, ↓hepatic gluconeogenesis, GI upsets, ↓B12 absorption, lactic acidosis (liver/ renal failure, MI, sepsis, dehydration), CI GFR <30
SE - Gastrointestinal side-effects
Lactic acidosis
How do sulfonylureas work?
stimulate pancreatic β cells to secrete insulin, gliclazide, hypoglycaemia, hypersensitivity, ↓Na, weight gain. ↑appetite, weight gain, SiADH, liver dysfunction (cholestatic)
SE - Hypoglycaemic episodes
Increased appetite and weight gain
Syndrome of inappropriate ADH secretion
Liver dysfunction (cholestatic)
How do thiazolinediones work?
pioglitazone. Activate PPAR gamma receptor in adiopocytes, promote adipogenesis + fatty acid uptake. Weight gain, fluid retention, liver dysfunction, #. CI in HF.
SE - Weight gain
Fluid retention
Liver dysfunction
Fractures
How to DDP-4 inhibitors work?
gliptin, ↑incretin by ↓periph breakdown, inhibit glucagon secretion. Well tolerated, ↑ risk of pancreatitis. Don’t cause WL.
SE - pancreatitis
How do SGLT-2 inhibitors work?
gliflozins, inhib reabsorption of glucose in PCT. SE: UTIs. Gangrenous infection of peritoneum. DKA.
How do GLP-1 inhibitors work?
exenatide. Injection. Inhibits glucagon secretion. SE: N/V, pancreatitis
Diagnosis of T2DM?
Non-fasting: >11.1, impaired gluc tol if >7.8
Fasting: prediabetes 6-7, DM >7
If asymptomatic above must be demonstrated on 2 occasions.
HbA1c: >48. ↓than normal sickle cell, GP6D def, hereditary spherocytosis ↑than normal: vit B12/ folic acid def, Fe def anaemia, splenectomy.
Features of DKA?
abdominal pain
polyuria, polydipsia, dehydration
Kussmaul respiration (deep hyperventilation)
acetone-smelling breath (‘pear drops’ smell)
Main differences between T1DM and T2DM?
T1 - typically <20, more acute (hours-days), recent weight loss typical, features of DKA how present, ketonuria is common
T2 - typically >40, slower onset of weeks to months, obesity strong RF (WL rare), milder Sx (polydipsia/polyuria), ketonuria is rare
When can HbA1c not be used for diagnosis of T2DM?
haemoglobinopathies
haemolytic anaemia
untreated iron deficiency
anaemia
suspected gestational diabetes
children
HIV
chronic kidney disease
people taking medication that may cause hyperglycaemia (for example corticosteroids)
What is impaired fasting glucose?
A fasting glucose greater than or equal to 6.1 but less than 7.0 mmol/l
People with IFG should then be offered an oral glucose tolerance test to rule out a diagnosis of diabetes. A result below 11.1 mmol/l but above 7.8 mmol/l indicates that the person doesn’t have diabetes but does have IGT.
What is impaired glucose tolerance?
defined as fasting plasma glucose less than 7.0 mmol/l and OGTT 2-hour value greater than or equal to 7.8 mmol/l but less than 11.1 mmol/l
Management of T2DM?
Lifestyle - high fibre, low glycemic index source of carbs, low-fat airy and oily fish, control sat fats and trans fatty acids, initial target weight loss in overweight person is 5-10%
Metformin: titrated up slowly. If SE modified release
Target HbA1c 48. If on gliclazide (or any drug causing hypoglycaemia, eg sulfonylurea) aim for 53.
If HbA1c 58 add: sulfonylurea (gliclazide), gliptin (DDP-4), pioglitazone, SGLT-2 inhib (empagliflozin)
If stays 58: metformin + gliptin + SU OR, metformin + SU + pioglitazone, OR metformin + SU + SGLT-2 inhib OR metformin, pioglitazone, SGLT-2.
Insulin
GLP-1 mimetic: exenatide, after triple therapy. Metformin + SU + GLP-1.
RF modification - BP targets same as person without T2D
Diabetes sick day rules?
Increase frequency of blood glucose monitoring to four hourly or more frequently
Encourage fluid intake aiming for at least 3 litres in 24hrs
If unable to take struggling to eat may need sugary drinks to maintain carbohydrate intake
It is useful to educate patients so that they have a box of ‘sick day supplies’ that they can access if they become unwell
Access to a mobile phone has been shown to reduce progression of ketosis to diabetic ketoacidosis
If a patient is taking oral hypoglycaemic medication, they should be advised to continue taking their medication even if they are not eating much
If a patient is on insulin, they must not stop it due to the risk of diabetic ketoacidosis.
Hosp admission - underlying illness needing hospital, inability to keep fluids down, persistent diarrhoea, significant ketosis, BG persistently >20 despite additional insulin, unable to manage adjusts to DM management, lack of support
What is DKA?
may be a complication of existing type 1 diabetes mellitus or be the first presentation, accounting for around 6% of cases. Rarely, under conditions of extreme stress, patients with type 2 diabetes mellitus may also develop DKA.
stress, body releases epinephrine, glucagon release, ↑glucose, loss of glucose in urine, loss of water, dehydration, need alternative energy
DKA is caused by uncontrolled lipolysis (not proteolysis) which results in an excess of free fatty acids that are ultimately converted to ketone bodies, increases blood acidity
most common precipitating factors of DKA are infection, missed insulin doses and myocardial infarction.
anion gap metabolic acidosis
Diagnostic criteria for DKA?
Key points
glucose > 11 mmol/l or known diabetes mellitus
pH < 7.3
bicarbonate < 15 mmol/l
ketones > 3 mmol/l or urine ketones ++ on dipstick
ECG: abnormal T/1 waves, K changes.
Management of DKA?
fluid replacement = isotonic saline is used initially, even if the patient is severely acidotic
insulin = an intravenous infusion should be started at 0.1 unit/kg/hour
once blood glucose is < 15 mmol/l an infusion of 5% dextrose should be started
correction of electrolyte disturbance = following Tx with insulin high serum potassium falls to hypokalaemia, so potassium may be needed to be added to replacement fluids, if the rate of potassium infusion is greater than 20 mmol/hour then cardiac monitoring may be required
potassium level 3.5-5.5 = give 40mmol/L replacement in solution
long-acting insulin should be continued, short-acting insulin should be stopped
Definition of DKA resolution?
pH >7.3 and
blood ketones < 0.6 mmol/L and
bicarbonate > 15.0mmol/L
both the ketonaemia and acidosis should have been resolved within 24 hours. If this hasn’t happened the patient requires senior review from an endocrinologist
if the above criteria are met and the patient is eating and drinking switch to subcutaneous insulin
the patient should be reviewed by the diabetes specialist nurse prior to discharge
Complications of DKA? (or Tx)
gastric stasis
thromboembolism
arrhythmias secondary to hyperkalaemia/iatrogenic hypokalaemia
iatrogenic due to incorrect fluid therapy: cerebral oedema*, hypokalaemia, hypoglycaemia
acute respiratory distress syndrome
acute kidney injury
What is hyperosmolar hyperglycaemic state?
medical emergency which is extremely difficult to manage and has a significant associated mortality
SE of T2DM (typically elderly with T2DM)
results in osmotic diuresis, severe dehydration, and electrolyte deficiencies
Systemic cellular dehydration as water leaves cell into blood following glucose
Pathophysiology of hyperosmolar hyperglycaemic state?
Hyperglycaemia results in osmotic diuresis with associated loss of sodium and potassium
Severe volume depletion results in a significant raised serum osmolarity (typically > than 320 mosmol/kg), resulting in hyperviscosity of blood.
Despite these severe electrolyte losses and total body volume depletion, the typical patient with HHS, may not look as dehydrated as they are, because hypertonicity leads to preservation of intravascular volume.
Features of hyperosmolar hyperglycaemic state?
General: fatigue, lethargy, nausea and vomiting, confusion
Neurological: altered level of consciousness, headaches, papilloedema, weakness, LOC
Haematological: hyperviscosity (may result in myocardial infarctions, stroke and peripheral arterial thrombosis)
Cardiovascular: dehydration, dry mucous membranes, poor skin turgor, hypotension, tachycardia, warm skin w/o sweat
Hallucinations
Polyuria
Diagnosis of hyperosmolar hyperglycaemic state?
- Hypovolaemia
- Marked Hyperglycaemia (>30 mmol/L) without significant ketonaemia or acidosis (Ketones <3mmol/L, pH >7.3)
- Significantly raised serum osmolarity (> 320 mosmol/kg)
Low Na + K
Management of hyperosmolar hyperglycaemic state?
- Normalise the osmolality (gradually)
> the serum osmolality is the key parameter to monitor
> if not available it can be estimated by 2 * Na+ + glucose + urea - Replace fluid and electrolyte losses
- Normalise blood glucose (gradually)
Intravenous (IV) 0.9% sodium chloride solution is the first line fluid for restoring total body fluid. Replace 50% of estimated fluid loss within 1st 12 hrs, + remainder in following 12 hrs
It is important to remember that isotonic 0.9% sodium chloride solution is already relatively hypotonic compared to the serum in someone with HHS. Therefore in most cases it is very effective at restoring normal serum osmolarity.
If the serum osmolarity is not declining despite positive balance with 0.9% sodium chloride, then the fluid should be switched to 0.45% sodium chloride solution which is more hypotonic relative to the HHS serum osmolarity
Keep BG 10-15 to avoid cerebral oedema
A rapid decline in serum glucose is potentially harmful therefore insulin should NOT be used in the first instance unless there is significant ketonaemia or acidosis
Measurement of ketones is essential for determining if insulin is required.
If significant ketonaemia is present (3β-hydroxy butyrate is more than 1 mmol/L) this indicates relative hypoinsulinaemia and insulin should be started at time zero (e.g. mixed DKA / HHS picture)
Potassium should be replaced or omitted as required with KCl
LWMH
RFs for hyperosmolar hyperglycaemic state?
infection
inadequate insulin or oral antidiabetic therapy
nursing home residents
post op
Cushing’s syndrome
hyperthyroid
acromegaly
Complications of hyperosmolar hyperglycaemic state?
High mortality
Seizures
Weakness down 1 side of body
Occlusive events due to hyper viscosity of blood
Central pontine myelinolysis
Summary of diabetic retinopathy?
Damage to microvasculature, ↓of pericytes around cap endothelium (help sustain BBB), leaky, microaneurysm formation, new vessel formation from growth factors in response to retinal ischaemia, vascular permeability causes exudates,
RF: poor diabetic control, co-existing HTN, smoking, pregnancy
Non-proliferative:
> mild - 1 or more microaneurysm
> moderate - micro aneurysms, blot haemorrhages, hard exudates, cotton wool spots (soft exudates), venous bleeding/looping and intraretinal microvascular abnormalities (IRMA)
> severe - blot haemorrhages and micro aneurysms in 4 quadrants, venous beading in at least 2 beading, IRMA in at least 1 quadrant
> refer
Proliferative:
> retinal neovascularisation - may lead to vitrous haemorrhage
> fibrous tissue forming anterior to retinal disc
> more common in Type I DM, need urgent referral, 50% blind in 5 years
Maculopathy
> based on location rather than severity, anything is potentially serious
> hard exudates and other ‘background’ changes on macula
> check visual acuity
> more common in Type II DM
Management:
> All patients
optimise glycaemic control, blood pressure and hyperlipidemia
> regular review by ophthalmology
Maculopathy
> if there is a change in visual acuity then intravitreal vascular endothelial growth factor (VEGF) inhibitors
Non-proliferative retinopathy
> regular observation
> if severe/very severe consider panretinal laser photocoagulation
Proliferative retinopathy
> panretinal laser photocoagulation
> intravitreal VEGF inhibitors
> if severe or vitreous haemorrhage: vitreoretinal surgery
Complications
> retinal detachment
> blindness
Virectomy if severe vitreous haem or retinal damage.
What is metabolic syndrome?
a cluster of conditions that occur together, increasing your risk of heart disease, stroke and type 2 diabetes.
Features: HTN Hyperglycaemia Obesity Hyperlipidaemia Hypertriglyceridemia
RF: poor diet sedentary life style age, genetics XS alcohol consumption stress
RFs for DKA?
stress/infection
poorly regulated glucose
surgery
MI
pancreatitis
chemo
antipsychotics
Complications of DKA?
Acute cerebral oedema: kids/ young adult particularly vulnerable. ↑K Aspiration pneumonia ↓K, Mg, P Thromboembolism Gastric stasis Arrhythmias ARDS AKI
What is Whipple’s triad?
may indicate pancreatic insulinoma
hypoglycaemia Sx, low BG + resolution of Sx after ↑BG
Symptoms of hypoglycaemia?
Sweating, anxiety, hunger
Tremor, palpitations
Dizziness, nausea
Generalised tingling
Confusion, irritability
Blurred vision
Drowsiness
Mutism
Personality change
Restlessness
Incoherence: misdiagnosis of
alcohol intoxication or psychosis
Unexplained weight gain: insulinoma
Unexplained WL: adrenal insuff
RFs for hypoglycaemia?
middle age, F, insulinoma, exogenous insulin, ethanol consumption, bariatric surgery, liver/renal failure intense exercise, fibromas, sarcomas, adrenal insuff (Addison’s disease), GH def, hypopituitarism, sepsis, glycogen storage disease, AN, malnutrition, ackee fruit ingestion, haloperidol, quine, fluroquinolone, SU, disopyramide, BB, salicylate, tramadol, PPI, alcohol (binge with no food), Addison’s.
Complications of hypoglycaemia?
Seizures
Comas
Diagnosis of hyopglycaemia?
BG <3
Insulin >21
Serum peptide >200
Management of hypoglycaemia?
Small high starch meals, if post-prandial slowly absorbed carbs (fibre).
Conscious: 10-20g of quick acting carb snack, orange juice (repeat up to 3X)
Conscious, uncooperative: glucose gel
Unconscious: IV 20% glucose or SC/im glucagon
Hypokit: IM/SC glucagon
Causes of hypoglycaemia?
insulinoma - increased ratio of proinsulin to insulin
self-administration of insulin/sulphonylureas
liver failure
Addison’s disease
alcohol
nesidioblastosis - beta cell hyperplasia
What is diabetes insipidus?
condition characterised by either a decreased secretion of antidiuretic hormone (ADH) from the pituitary (cranial DI) or an insensitivity to antidiuretic hormone (nephrogenic DI).
Causes of cranial DI?
idiopathic
post head injury
pituitary surgery
craniopharyngiomas
infiltrative
>histiocytosis X
>sarcoidosis
DIDMOAD is the association of cranial Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness (also known as Wolfram’s syndrome)
haemochromatosis
Causes of nephrogenic DI?
genetic: the more common form affects the vasopression (ADH) receptor, the less common form results from a mutation in the gene that encodes the aquaporin 2 channel
electrolytes: hypercalcaemia, hypokalaemia
lithium
>lithium desensitizes the kidney’s ability to respond to ADH in the collecting ducts
demeclocycline
tubulo-interstitial disease: obstruction, sickle-cell, pyelonephritis
Features of DI?
polyuria - even with restricted fluid intake
polydipsia
nocturne
dehydration
hypotension
fatigue, nausea, poor concentration, confusion
↑Na: irritability, restlessness, lethargy, spasticity, hyperreflexia
Investigations for DI?
high plasma osmolality, low urine osmolality
> a urine osmolality of >700 mOsm/kg excludes diabetes insipidus
water deprivation test - fluid deprivation 8 hrs. Urine osmolarity <300 despite no fluid, normally would rise >700. ADH analogue SC, ↑urine osmolality > central DI. If no change > nephrogenic.
Cranial MRI
↓ ADH (neurogenic), urine osmolarity <300mmol/kg
↑ plasma osmolarity: >295mOsm/Kg for central, gestational + nephrogenic DI. If normal but still has polyuria + polydipsia could be dipsogenic.
Management of DI?
nephrogenic diabetes insipidus: thiazides (increase urine excretion of Na, decrease blood osmolarity, and stops thirst, decrease polyuria), low salt/protein diet, NSAIDs/indomethacin (inhibit action of ADH), high dose desmopresin
central diabetes insipidus can be treated with desmopressin, excision of tumour, chlorpropamide (enhance renal response to low ADH)
Other causes of DI?
Gestational: placenta releases vasopressinase, breaks down ADH, gets worse until birth, can last 2 mnth after birth.
Dipsogenic/psychogenic: drinking too much, schizophrenia, ↓blood osmolality, hypothalamus ↓ADH as normal physiological response
Complications of DI?
↑Na Thrombosis Dehydration Bladder + renal dysfunction Iatrogenic ↓Na: desmopressin
Wolfram’s syndrome: cranial DI, optic atrophy, deafness
What is acromegaly?
excess growth hormone in adulthood
causes:
> pituitary adenoma in over 95% of cases
> ectopic GHRH or GH production by tumours e.g. pancreatic.
Features of acromegaly?
coarse facial appearance,
spade-like hands, increase in shoe size
large tongue, prognathism, interdental spaces
excessive sweating and oily skin: caused by sweat gland hypertrophy
features of pituitary tumour: hypopituitarism, headaches, bitemporal hemianopia
raised prolactin in 1/3 of cases → galactorrhoea
6% of patients have MEN-1
Complications of acromegaly?
hypertension diabetes (>10%) cardiomyopathy colorectal cancer due to polyps CTS OSA arrhythmia
Investigations for acromegaly?
Growth hormone (GH) levels vary during the day and are therefore not diagnostic.
Serum IGF-1 levels - first-line test, also used to monitor disease
Then OGTT test (no suppression, normally suppressed to <2 mu/L) with serial GH measurement
pituitary MRI of sella turcica with gadolinium
CT scan chest/abdo: ectopic tumours
↑Ca, P
Often: cortisol ↓, PRL↑
Management of acromegaly?
Trans-sphenoidal resection
Somastostatin agonists: inhibit GH release, octreotide or lanreotide
Dopamine agonists: bromocriptine, cabergoline.
GHr antagonists: pegvisomant
Radiation
What is gigantism?
GH hypersecretion in childhood.
XS GH, GHRH, IGF-1
Pit gland Ca, pit adenoma, hypothalamic tumour, ectopic GH secretion, hereditary (McCune Albright syndrome, MEN1)
Features of gigantism?
Linear growth of long bone
Height sig above SD, XS fast growth in height
Obesity: rapid weight gain due to XS IGF-1
Overgrowth of face/ extremities
Headache/ compression of optic nerve
Maxilla/ mandible protrusion
Enlargement of skull bones
Soft tissue swelling (hands + feet)
Complications of gigantism?
HTN
Osteoarthritis
Insulin resistance: DM
CTS
Organomegaly
↑PRL: ↓menstruation, breast enlargement in boys
Investigations for gigantism?
MRI: pit tumours
CT: tumours in other organs
OGTT: hyperglycaemia, elevated IGF-1
Elevated GH + IGF-1
Summary of constitutional growth delay?
Normal variation in growth, temp delay, eventual adult height within normal range.
RF: FH of delayed growth
Transient GH or pit doesn’t start producing hormones on time
Sx: Normal size at birth Short preadolescent stature, growth rate falls, picks up again, matches to peers around age 4. (Height still lags behind) typically have growth spurt later + catches up Psychosocial stress Delayed pubertal development
Ix:
XR: delayed bone development, hand XR for bone age, normally at least 1 yr less than actual age
Management:
Provide reassurance regarding eventual normal growth + development
Summary of GH deficiency?
Hypothalamic/ pit dysfunction, tumours, radiation, traumatic injury, AI disease, genetic (PROP1 mutation in GHRH receptor), Prader-Willi, Turner’s. idiopathic
Sx:
Newborn: hypoglycaemia, micropenis, XS jaundice
Children: stunted growth/ short stature, delayed puberty, dwarfism, growth plates don’t fully fuse, delayed bone age, nystagmus, hypoglycaemia, retinal defects, cleft lip, delayed motor skills (↓ muscle development)
Adults: ↓muscle mass, ↓bone mineral density, baldness
Complications: Psychosocial stress Delayed pubertal development Overweight # Cardiac conditions Psychological issues: memory problems, social issues, depression
Ix:
> Serum GH levels <1ng/mL. Nonspecific affected by circadian rhythms, food, stress.
> Serum IGF-1: more accurate, not affected by external factors.
> Insulin tolerance test: regular insulin administered via IV > measure blood at 30 min intervals. Subnormal ↑ in serum GH
Tx:
Injection with recombinant GH, childhood > daily, adulthood 25% Tx for children
What is hyperprolactinaemia?
High prolactin
Damage to hypothalamic-pit stalk (trauma, tumour, surgery, dopamine can’t reach lacotrophs to inhib)
Prolactinoma/ lacotroph adenoma,
Preg + BF, stress, exercise, sleep, PCOS
Hypothalamus dys,
Heavy metal poisoning, dopamine antagonists, oestrogen meds (stimulate more PRL), metoclopramide, haloperidol, methyldopa oestrogens, ecstasy, phenothiazines, SSRIs
Renal failure
1° hyperthyroid (hypothalamus tries to ↑ thyroxine, release TRH)
Features of hyperprolactinoma?
Visual impairment (bitemporal hemianopia (lateral visual fields) or upper temporal quadrantanopia), headaches, S+S of hypopituitarism
Males: infertility, ED, impotence, ↓libido, gynecomastia, galactorrhoea
Females: irregular menstrual cycles, infertility, dry vagina, galactorrhoea, painful breasts
Osteoporosis
Investigations for hyperprolactinaemia?
Head MRI/CT: tumours/ lesions in hypothalamic-pit area, if none + high serum levels, idiopathic hyperprolactinaemia
High serum prolactin levels
Lower bone density
Management of hyperprolactinaemia?
Dopamine agonist: bromocriptine/ cabergoline - inhibit release of prolactin
Surgical removal of tumour
If hypothyroid > replacement thyroid hormones
What is hypopituitarism?
escribes the inadequate production of one or more of the hormones secreted by the pituitary gland.
Ant pit: GH, ACTH, PRL, TSH, LH, FSH
Post: ADH, oxytocin
Causes of hypopituitarism?
compression of the pituitary gland by non-secretory pituitary macroadenoma (most common)
pituitary apoplexy
Sheehan’s syndrome: postpartum pituitary necrosis secondary to a postpartum haemorrhage
hypothalamic tumours e.g. craniopharyngioma
trauma
iatrogenic irradiation
infiltrative e.g. hemochromatosis, sarcoidosis
Features of hypopituitarism?
Go Look For That Adenoma sequence of loss, GH, LH, FSH, TSH, ACTH.
low ACTH > tiredness > postural hypotension > weight loss > delayed puberty > low BG + Na > decreased skin pigmentation
low FSH/LH
> amenorrhoea
> infertility
> loss of libido
low TSH
> feeling cold
> constipation
low GH
> if occurs during childhood then short stature
low prolactin
> problems with lactation
there may also be features suggestive of the underlying causes
> pituitary macroadenoma → bitemporal hemianopia
> pituitary apoplexy → sudden, severe headache
Investigations of hypopituitarism?
hormone profile testing
Insulin stimulation: should ↓ blood sugar which stim GH + ACTH, if levels remain low = hypopit
imaging - MRI scan, Sheehans pit ring sign (halo round empty sella)
IGF ↓
Water deprivation + desmopressin response test
Management of hypopituitarism?
treatment of any underlying cause (e.g. surgical removal of pituitary macroadenoma)
replacement of deficient hormones
surgical excision of tumours
Dopamine antagonist if PRL def + want to BF
Complications of hypopituitarism?
Bitemporal adenoma
↓bone mass
DI
What is SIADH?
is characterised by hyponatraemia secondary to the dilutional effects of excessive water retention
ADH, water retention, dilutes plasma, ↓Na, extra fluid takes up more space in BV, inhibs aldosterone release, body dumps Na into urine, water follows Na, XS urine
TA: erratic, independent of plasma osmolarity, ADH very high, lot of fluid retained, urine osmolality very high.
TB: constant release of moderate ADH
TC: baseline plasma Na set lower than normal, plasma Na stable, other types it falls.
T4: ADH secretion normal but osmolality high.
Causes of SIADH?
CNS disorders enhance ADH production, trauma, stroke, haem, infection, SAH, subdural haemorrhage, mental illness through carbamazepine effects
Ectopic ADH: lung malig (small cell), pancreas ca, prostate ca, TB, CF, pneumonia.
Infection - TB, pneumonia
Anticonvulsants, opioids, SU, SSRIs, TCAs, vincristine, cyclophosphamide
Injury/ removal of pit
Positive end expiratory pressure (PEEP)
porphyria
Management of SIADH?
correction must be done slowly to avoid precipitating central pontine myelinolysis
fluid restriction - <800mL, if associated with subarach haem fluid restriction not recommended
demeclocycline: Abx, reduces the responsiveness of the collecting tubule cells to ADH
ADH (vasopressin) receptor antagonists (tolvaptan) have been developed
IV saline for severe
Furosemide
High salt + protein diet
Features of SIADH?
Body weakness
Fatigue, lethargy
Dizziness
Confusion
Nausea, anorexia, vomiting
Headaches
Muscle cramps, myoclonus, tremors
Complications of SIADH?
Cerebral oedema: confusion, mood swings, hallucinations, coma, death, seizures
Investigations for SIADH?
Urinalysis: highly concentrated urine >100, high urine na >30
Serum: ↓Na, ↓osmolarity (<275mmol/kg), urea (<3.6mmol/L, due to mild volume expansion)
Absence of hypo/hypervolaemia
Fractional excretion of Na: >1%.
Fractional excretion of urea: >55%
Causes of primary hyperparathyroidism?
parathyroid secretes PTH independently of Ca. parathyroid adenoma, mutation, MEN. Parathyroid hyperplasia.
Features of hyperparathyroidism?
PTH stimulates osteoclasts, kidneys hold onto Ca + get rid of P
Slower muscle contraction
Stones, thrones, bones, groans, psychiatric overtones
Poor sleep, fatigue, anxiety, memory loss, myalgias, paraesthesia, muscle cramps, constipation, abdo pain.
1°/3°: slower muscle contractions, less excitable neurons
2°: Sx CKD, ↓Ca Sx.
Polyuria, polydipsia
Complications of hyperparathyroidism?
1°: brown tumours, large bone cysts (high osteoclast activity), osteitis fibrosa cystica, soft tissue calcifications Peptic ulceration Pancreatitis Bone pain/# HTN
Investigation results for primary hyperparathyroidism?
1°: ↑Ca, ↓P, hypercalciuria, ↑PTH, vit D def, ↑ALP (high bone turn over)
Pepper pot skull on XR
Investigation results for secondary hyperparathyroidism?
↓Ca ↑P ↓vit D, Ur+Cr ↑
Investigation results for tertiary hyperparathyroidism?
↑PTH, ↑Ca, if person still has CKD ↑P, if had kidney transplant ↓K.
Management of hyperparathyroidism?
1/3°: calcimimetics (imitate Ca on PT cells), remove abnormal parathyroid glands. Vit supplements: ergocalciferol. Bisphosphonate.
2°: phosphate binders (sevelamer), vit D supplements, calcitriol (suppress PTH)
Causes of secondary hyperparathyroidism?
gland normal, XS PTH in response to chronic ↓Ca, impaired kidney function (↑P ↓calcitriol, ↓Ca intestine absorption) chronic lack of calcitriol (lack of sunlight, poor vit D intake.)
Causes of tertiary hyperparathyroidism?
2° hyperparathyroid for many years develop 1° due to hyperplasia of PT glands.
RFs for hyperparathyroidism?
genes F>M
lithium
Causes of hypoparathyroidism?
AI destruction
Mg def, chronic alcoholism, malnutrition, malabsorption, diarrhoea
Iatrogenic: parathyroid/ thyroid surgery/ radiation
DiGeorge synd, AD hypoparathyroidism, Albright hereditary osteodystrophy (pseudo, kidneys/ bones resistant to PTH), haemochromatosis, tumours, Wilson’s
Features of hypoparathyroidism?
Muscle spasms/ cramps
Tetany
Chvosteks/trousseau
Perioral numbness, paraesthesia
Poor memory/ slowed thinking
Chronic: BG calcifications dystonia, parkinsonism, athetosis, hemiballismus, oculogyric crisis, cataracts, dry coarse skin, brittle nails, patchy alopecia.
Complications of hypoparathyroidism?
Seizures
Resp paralysis
Death
Investigations of hypoparathyroidism?
↓Ca, ↓PTH
ECG: prolonged QT, ST, TdP, AF
Management of hypoparathyroidism?
IV calcium gluconate: if severe
Oral Ca: carbonate/ citrate
Vit D: calcitriol
Synthetic PTH
Mg sulphate
Thiazide diuretic
Summary of Zollinger-Ellison syndrome?
Condition characterised by excessive levels of gastrin, usually from a gastrin secreting tumour usually of the duodenum or pancreas. Around 30% occur as part of MEN type I syndrome.
Gastrinoma, ↑acid secrtion + peptic ulcers. Usually malig
Features
- multiple gastroduodenal ulcers
- diarrhoea, steatorrhoea
- malabsorption
- GORD
- Abdo pain
- N/V, bloating, belching
- dysphagia, weight loss
- GI bleed
- oesophageal strictures
- pancreatitis
Diagnosis
- fasting gastrin levels: the single best screen test - ^ gastrin
- secretin stimulation test - ^ gastrin
- endoscopy - ulcer, enlarged rugal folds, oesophagitis
- endoscopic US - hypo echoic, homogenous mass
Management
- surgery
- chemo
- PPIs
- Somatostatin analogue:↓gastrin levels.
What is phaeochromocytoma?
a rare catecholamine secreting tumour. Cells darken. Arise from chromaffin cells in adrenal medulla.
About 10% are familial and may be associated with MEN type II, neurofibromatosis and von Hippel-Lindau syndrome
Rule of 10: 10% bilat, 10% kids, 10% metastasise, 10% calcify, 10% extra-adrenal.
bilateral in 10%
malignant in 10%
extra-adrenal in 10% (most common site = organ of Zuckerkandl, adjacent to the bifurcation of the aorta)
Features of phaeochromocytoma?
typically episodic
Ps: perspiration, palpitation, pallor, ↑BP, pain (headache).
Tachycardia
hypertension (around 90% of cases, may be sustained)
headaches
palpitations
sweating
anxiety
Investigations for phaeochromocytoma?
24 hr urinary collection of metanephrines (sensitivity 97%*)
this has replaced a 24 hr urinary collection of catecholamines (sensitivity 86%)
CT/MRI
Management of phaeochromocytoma?
Surgery definitive management
First stabilised with medical management:
alpha-blocker (e.g. phenoxybenzamine), given before a
beta-blocker (e.g. propranolol)
Complications of phaeochromocytoma?
↑180/120 emergency: stroke, retinal haemorrhage, ischaemia, kidney failure, burst vessels
Polycythaemia.
What is MEN 2A?
Multiple Endocrine Neoplasia
2P’s and M:
Medullary thyroid cancer (70%)
Parathyroid (60%)
Phaeochromocytoma
Hirschsprungs, cutaneous lichen amyloidosis
RET oncogene
What is MEN 2B?
Medullary thyroid cancer
1P and M:
Phaeochromocytoma
Marfanoid body habitus
Neuromas
RET oncogene
What is MEN 1?
3 P’s:
Parathyroid (95%): hyperparathyroidism due to parathyroid hyperplasia
Pituitary (70%)
Pancreas (50%): e.g. insulinoma, gastrinoma (leading to recurrent peptic ulceration)
Also: adrenal and thyroid
AD, MEN1 gene Chr11, encodes menin > inactive > endocrine neoplasia
Most common presentation = hypercalcaemia
↓BMD, nephrolithiasis
Bitemporal hemianopia
Investigation and management of MEN 2?
CT/MRI: tumours Thyroid USS MTC: ↑CEA, calcitonin Parathyroid: ↑Ca, PTH Pheochromocytoma: ↑plasma fractionated metanephrines + 24hr urine metanephrine.
Tyrosine kinase inhibs
Bisphosphonates
CLA: intralesional steroids, antihistamines, UV light/ laser therapy
Tumour resection
Investigations and management of MEN 2?
MRI/CT: tumour/mets
Endoscopy: biopsy
Endoscopic USS, somatostatin receptor scintigraphy: pancreatic neuroendocrine neoplasms.
Parathyroid: ↑Ca, PTH
PaNETs: ↑gastrin, insulin, VIP, ↓glucose
MEN 1 gene mutation
Treat tumour > see in other notes how to
Surgical resection
Radiation
What is carcinoid syndrome?
Neuroendocrine tumours secrete: serotonin, histamine, bradykinin + prostaglandins.
Appendix most common GIT site
usually occurs when metastases are present in the liver and release serotonin into the systemic circulation
may also occur with lung carcinoid as mediators are not ‘cleared’ by the liver
Features of carcinoid syndrome?
GIT tumour: hormone secretion inactivated by liver > no Sx. When liver mets > hormones released into circ > Sx
flushing (often earliest symptom)
diarrhoea
bronchospasm
hypotension
Plt take up serotonin + use it to constrict BVs
right heart valvular stenosis (left heart can be affected in bronchial carcinoid)
other molecules such as ACTH and GHRH may also be secreted resulting in, for example, Cushing’s syndrome
pellagra (dermatitis, diarrhoea, mental Disturbance) can rarely develop as dietary tryptophan is diverted to serotonin by the tumour
Investigations for carcinoid syndrome?
urinary 5-HIAA
plasma chromogranin A y
Sx worsened by alcohol or emotional stress
CT: locate tumours
Octreoscan: inject radiolabelled somatostatin analogue, octreotride which binds to increased somatostatin receptors on tumour cells
Niacin deficiency
Management of carcinoid syndrome?
somatostatin analogues e.g. octreotide
diarrhoea: cyproheptadine may help
Complications of carcinoid syndrome?
1/3 metastasise
1/3 associated with secondary malig
1/3 multiple tumours
Collagen fibre thickening, fibrosis, heart valve dysfunction > TR, PS
Summary of euthyroid sick syndrome?
Transient central hypothyroid in severely sick. Thyroid gland functioning normal but thyroid hormone levels abnormal
Less deiodinase in catabolic state, less T4> T3 conversion.
everything (TSH, thyroxine and T3) is low. In the majority of cases however the TSH level is within the >normal range (inappropriately normal given the low thyroxine and T3).
Changes are reversible upon recovery from the systemic illness and hence no treatment is usually needed.
Sx: Fatigue Cold intolerance Weight loss/ gain Constipation Muscle cramps Headache Hair loss/ brittleness Menstrual irregularities
Complication:
Myxedema coma
Investigations:
Serum TSH: normal/ low
Normal/low T4
Low T3
Management: Levothyroxine Treat underlying cause when starts eating again/ recovers from illness thyroid hormones return to normal NO TX NEEDED
What is Graves disease?
AI disease, TSH receptor antibodies, mimics TSH, can lead to thyroid hypertrophy + hyperplasia.
RF: CTLA4, PTPN22, HLA-DR3, 20-40, F>M, tobacco RF for orbitopathy.
Most common cause thyrotoxicosis
Features of Graves disease?
typical features of thyrotoxicosis
goitre
thyroid bruit
eye signs (30% of patients)
> exophthalmos
> ophthalmoplegia
pretibial myxoedema
thyroid acropachy, a triad of:
> digital clubbing
> soft tissue swelling of the hands and feet
> periosteal new bone formation
Investigations of Graves disease?
↓ TSH, ↑ T3, ↑ T4, ↑ TSI
Autoantibodies
> TSH receptor stimulating antibodies (90%)
> anti-thyroid peroxidase antibodies (75%)
Thyroid USS: diffuse enlargement, highly vascular
Thyroid scintigraphy
> diffuse, homogenous, increased uptake of radioactive iodine
Management of Graves disease?
BB: propranolol
Refer to 2° care
Carbimazole (complication, agranulocytosis)
Radioiodine: CI in pregnancy (avoid 4-6 mnth after Tx) + <16 y/o, thyroid eye disease.
Thyroidectomy
Optic: steroids (pred),
Causes of hyperthyroidism?
AI: graves
TSH disease: TSH secreting adenomas, TSH receptor stimulation with XS hCG (trophoblastic disease, hyperemesis gravidarum)
Solitary autonomous adenoma
XS iodine ingestion
Toxic nodular goitre
Job-Basedow syndrome: iodine induced
Neonatal hyperthyroid: newborn mothers who have
Graves.
Amiodarone
RF: F>M, smoking, genes
Features of hyperthyroidism?
Thyroid: normal/ enlarged, goitre, palpable nodules.
CV: bounding, rapid pulse, HTN, palpitations.
GI: ↑appetite/ ↓weight, V/D, hyperdefecation
Warm, flushed, moist skin, patchy hair loss, thyroid acropachy (clubbing), pretibial myxedema, XS sweating, red palms.
Heat intolerance, fine tremor, agitation, insomnia
Menstrual irregularities, ↓libido, infertility
Complications of hyperthyroidism?
Thyroid storm
Congestive heart failure
Osteoporosis
Skeletal muscle atrophy
AF
Investigations for hyperthyroidism?
RAIU: ↑123I uptake confirms hyperthyroidism
USS: benign/ malig nodules, microcalcifications, hypoechogenicity in malig nodules.
1°: ↓ TSH, ↑T4 + T3
↑TSH, T3/4, TSH induced
Management of hyperthyroidism?
Carbimazole, propylthiouracil
Thyroidectomy
Radioactive thyroid ablation
BB: propranolol
What is thyroid storm?
rare but life-threatening complication of thyrotoxicosis. It is typically seen in patients with established thyrotoxicosis and is rarely seen as the presenting feature. Iatrogenic thyroxine excess does not usually result in thyroid storm.
More unbound thyroid hormones or tissue more sensitive to thyroid hormones or catecholamines
Precipitating events:
- thyroid or non-thyroidal surgery
- trauma
- infection
- acute iodine load e.g. CT contrast media
Features of thyroid storm?
fever > 38.5ºC tachycardia confusion and agitation nausea and vomiting hypertension heart failure abnormal liver function test - jaundice may be seen clinically
Can result in: MI, death
Management of thyroid storm?
symptomatic treatment e.g. paracetamol
treatment of underlying precipitating event
beta-blockers: typically IV propranolol
anti-thyroid drugs: e.g. methimazole or propylthiouracil
Thioamides: block thyroid hormone production, iodine preparations, GC (dexamethasone), bile acid sequestrants, methimazole or propylthiouracil
Plasmapheresis: blood plasma removed
Intensive supportive care
Lugol’s iodine
dexamethasone - e.g. 4mg IV qds - blocks the conversion of T4 to T3
Summary of toxic multinodular goitre?
describes a thyroid gland that contains a number of autonomously functioning thyroid nodules resulting in hyperthyroidism.
Lack of iodine > ↓T3/4 > ant pit release TSH > thyroid hypertrophy/ hyperplasia. Some part of thyroid gland more responsive to TSH than others, uneven growth > multiple nodules > mutation in TSH receptor in 1 of follicles > cell active without TSH > ↑ thyroid hormone.
Goitre
Nuclear scintigraphy reveals patchy uptake.
The treatment of choice is radioiodine therapy. Also surgery
Causes of hypothyroidism?
1°: thyroid gland problem iodine def, AI (Hashimoto) congen (inborn errors, thyroid agenesis/ hypoplasia), iatrogenic (Tx of hyperthyroid/ neoplasm), 1° atrophic hypothyroid (diffuse lymphocytic infiltration leading to atrophy), post-partum thyroiditis, sarcoidosis, haemochromatosis. ↓T4 absorption (iron salts, cholestyramine), ↓T4>T3 (amiodarone), ↓clearance T4 (phenytoin, carbamazepine), lithium, IFNα, IL2, TK inhib, P-amino salicylic acid.
2/3°: not enough TSH/ TRH, pit/ hypothalamus disorder
Features of hypothyroidism?
Fatigue, cold intolerance
Muscle weakness
Headache
↑weight ↓appetite
Brittle hair/ hair loss
Menstrual irregularities, menorrhagia
Goitre
Difficulty concentrating, poor memory
CTS, ↓reflexes, periph neuropathy.
Myxoedema: periorbital oedema, tongue, enlargement, puffy face, lower leg (pretibial), ascites, pericardial/ pleural effusion
Dry course skin
Voice: hoarser/ deeper
Ileus, constipation
Congen: prolonged neonatal jaundice, delayed mental/ physical milestone short stature, puffy face, macroglossia, hypotonia.
Complications of hypothyroidism?
Myxoedema coma: altered mental state, hypothermia, multi-organ failure, ↓BP, HR, Na, glucose, ventilation. Poorly managed hypothyroid, acute event eg trauma, infection, MI
Dyslipoproteinaemia
Dilated cardiomyopathy
Anaemia
Hyperprolactinaemia > galactorrhoea
↓clearance of drugs: antiepileptic, anticoag, ipiods, drug toxicity
Congen: FTT, intellectual disability
Investigations for hypothyroidism?
1°: ↑TSH ↓T4/3
Central: ↓TSH, T4/3
Antibodies: anti-TPO/ TSH receptor, antithyroid peroxidase antibodies
FBC: mild normocytic anaemia
Management of hypothyroidism?
Levothyroxine replacement, initial starting dose lower in elderly + ischaemic heart disease (25mcg), other pts (50-100mcg). TFTs 8-12 wks later. ↑dose in pregnancy. SE: hyperthyroid, ↓BMD worsening angina, AF. Fe/Ca carbonate ↓absorption
Subclinical hypothyroid: ↑TSH normal T3/4. TSH 4-10 (<65 with Sx trial thyroxine, older watch + wait, repeat TFT in 6mnth), TSH >10 (Tx with thyroxine <70, older watch + wait).
Poor compliance with thyroxine: ↑TSH, normal T3/T4 as pts take thyroxine in days before test.
2°: replacement steroid before thyroxine.
Summary of Hashimoto’s thyroiditis?
an autoimmune disorder of the thyroid gland.
It is typically associated with hypothyroidism although there may be a transient thyrotoxicosis in the acute phase.
It is 10 times more common in women
Features:
> features of hypothyroidism
> goitre: firm, non-tender
> anti-thyroid peroxidase (TPO) and also anti-thyroglobulin (Tg) antibodies
Associated with other AI conditions (coeliac, T1DM, vitiligo) and MALT lymphoma
Stridor > tracheal compression
Myxoedema: non pitting oedema, mucopolysaccharide deposition in upper skin layers, tibial area, may occur around eye + feet
↓T3 + T4
↑TSH + TRH
Tx:
Levothyroxine
Surgery
Summary of post partum thyroiditis?
Three stages
- Thyrotoxicosis - typically few mnths after delivery, last up to 8 wks
- Hypothyroidism - can last up to 6 mnth
- Normal thyroid function (but high recurrence rate in future pregnancies)
RF: prev PP thyroiditis, pre-existing hypothyroid, T1DM, FH
Thyroid peroxidase antibodies are found in 90% of patients
Management
the thyrotoxic phase is not usually treated with anti-thyroid drugs as the thyroid is not overactive. Propranolol is typically used for symptom control
the hypothyroid phase is usually treated with thyroxine
Summary of Riedel’s thyroiditis?
rare cause of hypothyroidism characterised by dense fibrous tissue replacing the normal thyroid parenchyma
associated with retroperitoneal fibrosis
Hardened wood like, fixed painless + enlarged goitre
Hypothyroidism
SOB/dyspnoea > trachea fibrosis
Voice hoarseness > recurrent laryngeal N
Dysphagia > oesophageal fibrosis
Parathyroid: ↓Ca
Anti-TPO ↓ T3 + T4 ↑ TSH + TRH Biopsy: predominant fibrous tissue, collagen + lymphocyte infiltration USS/CT/MRI: enlarged thyroid Middle aged women
Management: CS Tamoxifen Levothyroxine Surgery
Summary of Subacute (De Quervain’s) thyroiditis?
occur following viral infection and typically presents with hyperthyroidism.
There are typically 4 phases; phase 1 (lasts 3-6 weeks): hyperthyroidism, painful goitre, raised ESR phase 2 (1-3 weeks): euthyroid phase 3 (weeks - months): hypothyroidism phase 4: thyroid structure and function goes back to normal
Investigations
Initial ↑T3 + T4, ↓TSH low.
↑ESR + CRP
thyroid scintigraphy: globally reduced uptake of iodine-131
Management
usually self-limiting - most patients do not require treatment
thyroid pain may respond to aspirin or other NSAIDs
in more severe cases steroids are used, particularly if hypothyroidism develops
First line Tx of prolactinomas
Bromocriptine
Ix of phaeochromocytoma
24 hr urinary collection of metanephrines
Hormone profile of Kallmans
Low FSH/LH and low testosterone
Causes of hypoglycaemia
EXPLAIN
- Exogenous drugs (typically sulfonylureas or insulin)
- Pituitary insufficiency
- Liver failure
- Addison’s disease
- Islet cell tumours (insulinomas)
- Non-pancreatic neoplasms
MOA of acarbose
an inhibitor of intestinal alpha glucosidases which delays the digestion of starch and sucrose. It does not appear in NICE guidance due to significant gastrointestinal side-effects this medication causes.
MOA of canagliflozin
inhibits sodium-glucose co-transporter 2 in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion. It is contraindicated in active foot disease such as skin ulceration with a possible increased risk of toe amputation.
MOA of pioglitazone
a thiazolidinedione that reduces peripheral insulin resistance and is contraindicated in patients with active or previous bladder cancer
MOA of orlistat
works by inhibiting gastric and pancreatic lipase to reduce the digestion of fat
Features of De Quervain’s thyroiditis
initial hyperthyroidism, painful goitre and globally reduced uptake of iodine-131
Results of high-dose dexamethasone
Cortical - not suppressed, ACTH - suppressed, = Cushing’s syndrome (due to other causes adrenal adenomas)
Cortisol - suppressed, ACTH - suppressed, = Cushing’s disease (pituitary adenoma)
Cortisol - not suppressed, ACTH - not suppressed, = ectopic ACTH syndrome
Types of thyroid cancer
Papillary - 65%, generally young females. Metastasis to cervical lymph nodes. Thyroglobulin can be used as a tumour marker. Characteristic Orphan Annie eyes on light microscopy. Good prognosis
Follicular - 20%, generally women >50 years old. Metastasis to lung and bones. Thyroglobulin can be used as a tumour marker. Moderate prognosis
Medullary - 5%, sporadic or part of MEN2 syndrome. It originates from the parafollicular cells which produce calcitonin - can be used as a tumour marker.
Anaplastic - very rare. Elderly patient. Very poor prognosis
Lymphoma - 5%, might present with dysphagia or stridor
Results of water deprivation test for nephrogenic DI
- urine osmolality after fluid deprivation: low
* urine osmolality after desmopressin: low
Summary of hyperparathyroidism
Primary hyperparathyroidism - occur with a high calcium and high (or abnormally high within reference rang) PTH without any other factors.
Secondary - usually due to chronic renal failure so deranged U&Es, increase in PTH due to low calcium
Tertiary - history of hypocalcaemia that has been corrected, long-standing renal failure,
Summary of hyperosmolar hyperglycaemic state (HHS)
is a life-threatening complication of type 2 diabetes and will usually present with marked hyperglycaemia without ketoacidosis.
the diagnostic criteria for HHS include hypovolaemia, hyperglycaemia (blood sugar > 30mmol/L) and a serum osmolality > 320mosmol/kg.
Cause of adrenal insufficiency in HIV patients
commonly due to cytomegalovirus (CMV)-related necrotising adrenalitis.
Summary of Nelsons syndrome
Occurs due to rapid enlargement of a pituitary corticotroph adenoma (ACTH producing adenoma) that occurs after the removal of both adrenal glands (bilateral adrenalectomy) which is an operation used for Cushing’s syndrome.
Removal of both adrenal glands eliminates the production of cortisol, and the lack of cortisol’s negative feedback can allow any pre-existing pituitary adenoma to grow unchecked.
Continued growth can cause mass effects due to physical compression of brain tissue. Increased production of adrenocorticotrophic hormone (ACTH) can result in increased melanocyte stimulating hormone (MSH) which can result in hyperpigmentation.
Nelson’s syndrome is now rare because bilateral adrenalectomy is now only used in extreme circumstances. After bilateral adrenalectom follow-up should include awareness of Nelson’s syndrome. Monitoring of ACTH level and pituitary MRI are recommended 3-6 months after surgery and regularly thereafter.
