Endocrinology

Question 1

Name commonly used steriods and their relative glucocorticoid vs mineralocorticoid activities

Answer 1

Fludrocortisone - V High mineralocorticoid
Hydrocortison - Glucocorticoid activity, High mineralocorticoid
Prednisilone - predominant glucocorticoid activity ( low min)

Dexamethasone - V high glucocorticoid and minimal mineralocorticoid
Betmethasone - V high glucocorticoid and minimal mineralocorticoid

Question 2

Name the common SE s of Steroids

Answer 2

Endocrine - impaired glucose regulation, increased appetite and weight gain. Hirsutism and high lipids.
Cushings - moon face, buffalo hump, striae
MSK - osteoporosis, proximal muscle weakness and AVN of femoral head.
Immunosuppression- increased risk of severe infection, reactivation of TB
Psychiatric - Insomnia/ mania/ depression & psychosis
GI - peptic ulceration, acute pancreatitis
Ophthalmic - Glaucoma and cataracts
Growth suppression in children
Intracranial HTN
Neutrophilia

Question 3

T2DM - diagnostic criteria?

Answer 3

T2DM can be diagnosed either by plasma glucose or HbA1C and whether the pt is symptomatic or asymptomatic.

If symptomatic:
Fasting glucose >= to 7.00 mmol / L
Random glucosee >= 11.1 mmol / L ( or after oral GTT)

If pt is symptomatic above criteria must be demonstrated on two occasions:
HbA1C > = 48 mmol/mol is diagnostic
Less than 48 mmol does not exclude DB’s - not as sensitive as fasting samples for detecting db.
In pts w/out sx the test must be repeated to confirm the diagnosis.

Question 4

What conditions can HbA1c not be used to diagnosis Diabetes?

Answer 4

Any condition where there is increased RBC turnover:

Haemoglobinopathies
Haemolytic anaemia
Untreated IDA
Suspected gestational DB
Children
HIV
CKD
People on medications that falsely increases blood glucose- steroids

Question 5

What glucose levels implies impaired fasting glucose?
What glucose levels imply impaired glucose tolerance?

Answer 5

Fasting glucose greater than or equal to 6.1 but less than 7.0 implies impaired fasting glucose.

IGT is defined as fasting plasma glucose < 7.0 and an OGTT 2 hr value greater than or equal to 7.8 mmol but less than 11.1 mmol/L.

A patient with impaired fasting glucose should be offered an oral glucose tolerance test to rule out a diagnosis of diabetes. Result below 11.1 but above 7.8 mmol indicates a person does not have diabetes but does have IGT.

Question 6

Management of subclinical hypothyroidism

Answer 6

Depending on the level of TSH on initial presentation.
TSH > 10 mU/L and free T4 level within normal range:
- Consider oral levothyroxine if TSH level greater than 10 on 2 separate occasions 3 months apart

If TSH level is between 5.5 - 10 mU/L and free T4 normal:
If under 65 consider 6 m trial of levothyroxine if TSH is 5.5-10 on two separate occasions and the pt is symptomatic.

In older pts > 80 yrs the watch and wait strategy is used.
If asymptomatic, observe and repeat TFT in 6 months time.

Question 7

What is euthyroid sick syndrome (ESS)?

Answer 7

State of dysregulation of thyrotropic feedback control where levels of T4 and/or T3 are abnormal, but the thyroid gland does not appear dysfunctional.
In sick euthyroid syndrome (now referred to as non-thyroidal illness) it is often said that 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).
It is most commonly seen in critical illness and in intensive care. Changes are typically reversed upon recovery from the illness in question and so no treatment is needed - therefore, the correct answer is to simply continue monitoring.

Question 8

Management of addison’s disease?

Answer 8

Glucocorticoid and mineralocorticoid replacement therapy
1) hydrocortisone usualyl given in 2-3 daily divided doses. Usually 20-30 mg per day, with the majority given in the 1st half of the day.
2) Fludrocortisone ( replacement of aldosterone).

Patient education is important:
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 (see below)

Management of intercurrent illness
in simple terms the glucocorticoid dose should be doubled, with the fludrocortisone dose staying the same

Question 9

MX of diabetic neuropathy

Answer 9

Now managed in the same way as other types of neuropathic pain:
1st line :
Amitryptiline ( TCA)
Duloxetine (SNRI) (-It works by inhibiting the reuptake of serotonin and norepinephrine in the central nervous system, thereby increasing their concentration and enhancing pain suppression.)
Gabapentin
Pregabalin

( Pregabalin and gabapentin share a similar mechanism of action, inhibiting calcium influx and subsequent release of excitatory neurotransmitters)

If 1st line treatment drug does not work, try one of the three others.
Tramadol may be useds as “ rescue therapy” for exacerbations of neuropathic pain
Topical capsaicin for localised neuropathic pain
Pain mx clinic useful for pts with resistant problems.

Question 10

Management for diabetic gastroparesis

Answer 10

Symptoms of diabetic gastroparesis - erratic blood glucose control, bloating , vomiting.
MX - metoclopramide, domperidone and erythromycin ( prokinetic agents).

Question 11

What is the presentation of Thyroid storm?
What are the precipitating causes?

Answer 11

Thyrotoxic crisis/storm is a rare but life threatening complication of thyrotoxicosis, it is seen in patients with estbalished thyrotoxicosis but is rarely the presenting feature.

Presentation:
Confusion / agitation
tachycardia ( often > 140 bpm) & hf
hypertension
fever
dehydration
abdominal pain/ N/ V/ Diarrhoea
Deranged LFTs and clinically jaundiced.

Precipitating events:
Infection
thyroid surgery
Trauma / MI/ Stroke
Suddenly stopping thryoid replacement therapy
Acute iodine load - CT contrast media

Question 12

Management of thyroid storm:

Answer 12

1) Antithyroid treatment - propylthiouracil. After 4 hours oral iodine solution to prevent new stimulation of hormone synthesis.
2) IV propanolol ( if not asthmatic)
3) Hydrocortisone IV 100 mg ( prevents T4–>T3 conversion)
If failure of above then therapeutic plasma exchange or thyroidectomy

Supportive:
paracetamol, keeping cool w tepid sponging, IVI, NG tube for vomiting.

Question 13

Mx of hypothyroidism:
Dosing of thyroid replacement therapy in different patient cohorts ( old vs young vs pregnant) and monitoring requirements?

Answer 13

Initial dose of levothyroxine should be lower in the elderly ( > 50 yrs) , those with cardiac disease or with severe hypothyroidism. Starting dose should be 25 mcg with dose slowly up titrated.
Other patients should be started on 50-100 mcg.

Women with established hypothyroidism that fall pregannt should have their dose increased by 25-50 mcg due to increased demands of pregnancy.

Following initiation/ change in levothyroxine dose TFTs should be rechecked in 8-12 weeks.

Goal of therapy is to “normalise” TSH level, aiming 0.5-2.5 mU/l.

Question 14

Important interactions with levothyroxine?

Answer 14

Levothyroxine absorption is reduced with iron and calcium carbonate. They should be given at least 4 hours apart.

Question 15

What is myxoedema coma and how does it present?

what are the precipitants?

Complications?

Answer 15

Potentially fatal complication of long standing undertreated hypothyroidism. Often elderly female patient.
May be preciptated by:

Infection/ influenza
Hypothermia or cold exposure
Surgery/ trauma
Medication - amiodarone.

Symptoms:
Long standing hypothyroid - overweight, thinning hair, goitre, myxoedema ( non pitting leg oedema). Confusion/ psychosis and apathy.
Constipation and faecal impaction.

Signs:
Bradycardia
Hypotension
Hypothermia ( often 35.5)
Non pittting periorbital and leg oedema ( myxoedematous face)
Reduced RR / hypoventilation ( Hypoxia and resp acidosis on ABG)

Complications - pericardial effusion, anaemia, seizure.

Question 16

mx of myxoedema crisis/ coma?

Answer 16

Medical mx:
IV thyroid hormone replacement - Often levothyroxine alone.
IVI & electrolyte correction
Slow rewarming
IV hydrocortisone 100 mg - given until exclusion of addisonian crisis.

ITU assessment and NIV / mechanical ventilation may be required

Question 17

MOA of sulfonylureas?
SE’s?

Answer 17

Sulfonylureas are oral hypoglycaemic agents used in the mx of T2DM. Work by increasing pancreatic beta cell insulin rlease and therefore only effective if there are some functional beta cells present. Bind to ATP K channel on beta cell.

SE:
WG
Hypoglycaemia

Rare SE
Bone marrow suppression
Hepatotoxicity
Hyponatraemia due to SIADH
Peripheral neuropathy

AVOID in pregnancy and breastfeeding

Question 18

Diagnostic criteria of DKA

Answer 18

Glucose. > 11 mmol /l or known diabetes mellitus
pH < 7.3
Biacrb < 15 mmol /l
Ketones > 3 mmol or urine ketones ++ on dipstick

Question 19

Main principles of immediate mx of DKA

Answer 19

1) IVI - most pts deplete 5-8 L. Isotonic saline used initially, even if pt severely acidotic.
SBP < 90 2x 500 ml bolus stat
SBP > 90 - 1L over 1 hr
2) FRII -Fixed rate insulin infusion started at 0.1 unit/ kg / hr of ACTRAPID. 6 units if no weight, max 15 units. If patient normally takes a long acting insulin analogue then continue as normal , stop short acting insulin. Once BM < 14 mmol an infusion of 10% dextrose should be started ( 8 hrly bag) in addition to sodium chloride
3) K replacement - Often high on admission despite total body potassium being low, often falls quickly following treatment and therefore potassium may need to be added to replacement fluids. If rate of K infusion > 20 mmol/ hour then cardiac monitoring is required.

K > 5.5 - nil added
K 3.5- 5.5 - 40 mmol /L
K < 3.5 - senior as additional will be required

Question 20

Monitoring during DKA treatment?

Answer 20

Hourly CBG and ketones
VBG done at 1 hour, then 2 hourly.
Formal U&Es at 4 hours.

Additional - urinary catheter and uo monitoring aiming o.5ml/kg/hr.
NGT if vomiting or reduced GCS .
Cardiac monitor if replacing K > 20mmol/ hr

Question 21

Mx of DKA 60- mins to 6 hours ( second stage)

Answer 21

Monitoring as prev - 1 hrly BM / ketones and 2 hrly VBG.
Aiming for ketones to fall 0.5 mmol /hr or HCO3 to rise 3 mmol/ hr.
Fluids : add 10% glucose at 125 ml /hr ( 8 hrly bag) if BM < 14 mmol.
Consider reducing rate of FRII to 0.05 units/ kg / hr if glucose falls < 14 mmol/ hr

Question 22

When should we be cautious about fluid replacement in DKA?

Signs of this complication?

Answer 22

Caution in children and young adults as they are at increased risk of cerebral oedema. Dehydration and raised glucose leads to shrinkage of brain neurons and fluid moves from IC to EC space. If this is corrected too rapidly, there is a rapid shift of water into IC space from EC and brain neurons swell and brain becomes oedematous. Leads to neuronal cell destruction and death.

Often need 1:1 nursing, neurobs to monitor for signs.
Signs of cerebral oedema:
Severe headache
confusion irritability
vomiting
hypertension ( Cushings reflex)
bradycardia ( cushings reflex)
Irregular/ reduced RR ( cushings reflex)
seizures

Question 23

HDU required when in DKA?

Answer 23

Age - young ( 18-25), elderly, pregnant.
HF/Renal F

Severe DKA:
Ketones > 6 mmol
HCO3 < 5 mmol
Venous pH < 7.1
hypokalaemia < 3.5
GCS. <12
o2 sats < 92%
HR < 60 or > 100
Increased anion gap > 16 mmol

Question 24

Mx of Graves disease

Answer 24

Tx options - antithyroid drugs (ATD), radioiodine tx & surgery.

ATD are 1st line. Especially in patients with severe sx of thyrotoxicosis and those with significant risk of hyperthyroid complications.

Tx to control symptoms - 1) Propanolol to block adrenergic effects
Referral to secondary care for ongoing tx.
Carbimazole considered in primary care if symptoms not controlled with propanolol.

ATD therapy - Carbimazole started at 40 mg and reduced gradually to maintain euthryroidism, usually 12-18 m.
Alternatively the block and replace regime - Carbimazole at 40 mg , and thyroxine added when pt is euthroid. 6-9m tx.

Radioiodine tx:
Often in those who relapse following ATD therapy or resistant to ATD tx.
-A proportion of pts become hypothyroid following tx , majority of pts will require thyroid replacement therapy after 5 yrs.
Contraindicated in - pregnancy ( should be avoided 4-6 following tx), < 16 yrs, and thyroid eye disease ( may worsen condition).

Question 25

What is Hyperosmolar hyperglycaemia state?

Answer 25

HHS is a medical emergency with high mortality and is a complication of T2DM.

Characterised by marked dehydration, raised plasma glucose conc ( > 30mmol), no acidosis ( normal pH and HCO3 > 15), and high serum osmolality ( > 340 mosmol/kg) with NO ketosis.

Question 26

Pathophysiology for HHS?
Precipitants for HHS?

Answer 26

Pathophysiology:
Hyperglycaemia –> osmotic diuresis & loss of electrolytes ( Na/K).
Severe volume depletion leading to sig raised serum osmolality –> hyperviscous blood.

Precipitants:
Illness
Sedative drugs
Dementia

Question 27

Clinical features of HHS?

Answer 27

HHS comes on slowly - days ( vs dka hours) therefore dehydration and metabolic disturbance are more extreme.
Clinical signs of dehydration - (dry mucus membranes, poor skin turgor, hypotension, tachycardia)
Polyuria
Thirst ( polydipsia)
Fatigue
WL
N&V
Reduced conscious level
Hyperviscosity - can result in MI/ Stroke/ Peripheral arterial thrombosis).

Question 28

MX of HHS?

Answer 28

Fluid replacement 1st line - 0.9% sodium chloride, typically at 0.5L-1L / hr. K levels monitored and added as required.
Insulin - not given unless Blood glucose stops falling whilst giving IVI.
VTE prophylaxis - higher risk of thrombosis ( Give LMWH).

Question 29

Important tests that distinguish between T1DM & T2DM?

Name those components of one of the tests?

Answer 29

C peptide - in T1DM were would expect a low or undetectable level of plasma C peptide due to absolute insulin deficiency. In T2DM C peptide levls will be normal as insulin production is still occuring, insulin sensitivity is reduced.

Diabetes specific autoantibodies:
Anti GAD ( 80% T1DM)
Anti islet cell ab ( ICA) - 80% T1DM)
Anti insulin autoantibodies ( IAA) - prescence in T1DM correlates w age , 90% in young children, only 60% older pts.

Question 30

HbA1C Targets in treatment of T2DM?

Answer 30

Lifestyle only - 48 mmol
Lifestyle + metformin - 48 mmol
Lifestyle + sulfonylurea ( or a drug that causes hypoglycaemia) - 53 mmol
On one drug but HbA1c risen to 58 mmol/mol - 53 mmol

E.g. pt on metformin, titrated up to max, HbA1C rises above 58 mmol - add second drug and titrate target to 53)

Question 31

1st step managment of T2DM

Answer 31

Metformin is 1st line , titrated up slowly to avoid GI upset. MR metformin can be trialled if this occurs.

SGLT2 inhibitors - Given in addition to metformin if there are CV risk factors. (QRISK > 10%, established CVD, Chronic HF). Metformin is first established then titrated before the addition of SGLT2 inhibitor.
SGLT2 inihbitor also started if at any point pt develops CVD, QRISK > 10% or chronic HF.

If Metformin is CI:
- if pt has CV RF - SGLT2 monotherapy
- if pt does not have CV RF then : DPP4 inhibitor, pioglitazone, or sulfonylurea. SGLT2 if certain criteria are met.

Question 32

Further mx of T2DM if Hba1c targets not being met?

Answer 32

If HbA1C risen to 58 mmol then additional tx required.

2nd line therapy - add one of to metformin:
DPP4 inhibitor “ Gliptins”
Pioglitazone
Sulfonylurea
SGLT2 i - if sulfonylurea contraindicated or not tolerated. Or if CVD.

3rd line - e.g on metformin plus DPP4 i - add another drug from list above. OR start insulin based treatment.

Further therapy - If Triple therapy inffective/ not tolerated then consider switching one of the drugs for GLP1 mimetic ( exenatide). If:
BMI > 35 kg or < 35 kg but insulin therapy has occupational implications or WL would benefit other obesity related comorbidities.
Exenatide only continued if Reduction 11 mmol Hba1c and WL of 3%.

Question 33

Staring insulin for T2DM practicalities

Answer 33

Metformin should be continued. Review the need for other antidiabetic medications.
NICE recommend starting Human NPH insulin ( isophane, intermediate insukin) taken at bed time or BD.

Question 34

RF modification in pts w T2DM?

Answer 34

1) HTN - BP targets are the same as for pts without T2DM. ACEi/ ARB 1st line. Targets - under 80 < 140/90 Clinic BP or < 135/85 ABPM. Target > 80 < 150/90 clinic BO and < 145/84 ABPM.

2) Antiplatelet only if CV disease

3) Lipids - only in patients w QRISK > 10% should be offered statin. Primary prevention 20 mg atorvastatin, secondary prevention 80 mg

Question 35

Drug causes of gynaecomastia

Answer 35

Spironolactone
Digoxin
Cannabis
Finasteride
GnRH agonists - goserelin, buserelin
Oestrogen
Steroids

Question 36

Physiology of Calcium and phosphate homeostasis?

Answer 36

Parathyroid glands detect the concentration of plasma Ca2+ and PO4-. Also produce and secrete PTH via chief cells.

When Ca2+ low, PT glands release PTH.
PTH acts in bone, kidney and gut to increase Ca2+ absorption.
PTH increases osteoclast bone resorption ( releasing ca) and activates vitamin D. Active vitamin D increases Ca2+ absorption in both Kidney and gut. Vitamin D also increases phosphate reabsorption in kidney and stimulates bone resorption and release of Ca.

When Ca2+ is high the C cells of thyroid gland produce calcitonin. Calcitonin inhibits Ca2+ reabsoprtion via the kidneys, inhibits phosphate reabsorption and inhibits bone resorption.

Phosphate regulation - low phosphate stimulates activation of vitamin D which increases its reabsorption in kidney and gut & bone reabsorption. Also at same time activates negative feedback loop , increased vitamin D activates FGF23. FGF23 binds klotho, complex inhibits 1aOHase and prevents further activation of vitamin D & also activates enzyme that breaks down vitamin D ( 24 hydroxylase).

Question 37

Normal levels of serum calcium?
Causes of hypercalceamia?

Answer 37

2.2-2.6 mmol. Most in bone and IC compartment, only 1% EC. Majority of circulating Ca bound to protein ( albumin) other half is ionised.

Causes:
Primary hyperparathyroidism ( non hosp) & malignancy (hosp pts) are the most common causes.

1) Hyperparathyroidism
2) Malignancy - bone mets, myeloma ( increased bone resorption) and ectopic PTHrP e.g. from Squamous cell lung cancer.
3) Excess vitamin D
4) Endocrine - thyrotoxicosis or addisons or acromegaly
5) sarcoidosis
6) Excessive Ca intake - milk alkali syndrome ( excess dietary Ca / supplementation or use of alkali for dyspepsia)
7) Drugs - thiazide, lithium, vitamin A, vit D analogues

Question 38

Types of hyperparathyroidism and levels of PTH

Answer 38

Primary hyperparathyroidism - Uncontrolled PTH by a tumour of the parathyroid gland:
-Parathyroid adenoma most common 80%
-Parathyroid hyperplasia 15%
-Multiple adenoma 4%
-Carcinoma 1%

Secondary hyperparathyroidism:
Disease causing chronically low calcium leads to increase in PTH release and parathyroid gland hyperplasia. Caused by renal F ( reduced Ca absorption) or vitamin D deficiency. Serum calcium will be low or normal, and PTH will be high.

Tertiary hyperparathyroidism:
When secondary hyperparathyroidism occurs over a long time there is hyperplasia of the glands and inapp. high PTH. Leads to high calcium, high phosphate and high pTH. Treatment with parathyroidectomy.
Tertiary hyperparathyroidism

Question 39

Symptoms of hypercalcaemia

Answer 39

” Bones, stones , groans and psychiatric moans.”

BONES - Chronic bone pain, bone loss , ectopic calcification and fractures.
STONES - Renal stones ( renal colic), polyuria, polydipsia, nocturia, hypertension.
Abdominal GROANS - abdo pain, N& V, constipation. Peptic ulceration and pancreatitis.
Psychiatric MOANs - fatigue, confusion, depression, psychosis.

Short QT interval & arrhythmias
Muscle weakness

Question 40

PTH/ Ca/PO4 levels in:

Primary hyperparathyroidism

Secondary hyperparathyroidism

Tertiary hyperparathyroidism

Answer 40

1 hyperparathyroidism - Serum PTH high or normal, Serum Ca high, PO4 low.

PTH HIGH/ Normal , Ca HIGH, PO4 LOW

2 hyperparathyroidism - Increased PTH ( hyperplasia of PT Gland) yet Ca2+ low due to disease ( Vit D def, renal disease, liver or bowel disease). Phosphate levels are LOW in vit D deficiency, Phosphate levels are HIGH in renal cause.

PTH HIGH, Ca LOW, PO4 High ( Renal) / Low ( Vit D def)

3 hyperparathyroidism - PTH high, Ca2+ high, PO4 high

PTH HIGH, Ca HIGH, PO4 HIGH

Question 41

mx of acute hypercalcaemia

Answer 41

In acute hypercalcaemia Rehydration with IVI mainstay of treatment ( aim 4-6 L over day 1, then 3-4L day after).
IV bisphosphonates - zolendronate and pamidronate can be used.
Prednisilone - myeloma, sarcoidosis/ vit D excess

Calcitonin may be given to inhibit osteoclast activity & enhance urinary excretion of Ca under specialist advice if poor response to above measures.

Question 42

How is Carbimazole usually given?
MOA?
Important SEs

Answer 42

Carbimazole given in hyperthyroidism in high doses for 6 weeks until patient becomes euthyroid before having dose reduced.

MOA - blocks thyroid peroxidase from coupling and iodinating tyrosine residues on thyroglobulin, reduced thyroid hormone production.

SE - agranulocytosis - always safety net pt that they need to attend for medical review if they develop symptoms of infection, sore throat, fever. FBC must be performed to check neutrophil count

Question 43

MOA of thiazolidinediones
Name of drug
Common SE / Cautions/ CI ‘s

Answer 43

Thiazolidinediones - (agonist to PPAR gamma receptor) and reduces peripheral insulin resistance. (PPAR gamma receptor is an intracellular nuclear receptor whose natural ligand is free fatty acid and controls adipocyte differentiation. )

Adverse effects:
WG
Liver impairment
Fluid retention - ( reduced insulin resistance therefore increased glucose uptake in tissues and peripheral oedema) - CI in heart failure.
Increased fractures
Bladder cancer - increased risk

Question 44

Management of primary hyperparathyroidism

Answer 44

Definitive tx is a total parathyroidectomy. Conservative mx may be offered if Ca level less than 0.25 mmol/L above upper limit and patient > 50 yrs and no evidence of end organ damage.
Pts not suitable for surgery may be treated with cinacalcet ( calcimimetic that mimics action of ca on calcium sensing receptor).

Question 45

Galactorrhoea - pathophysiology?
Clinical features?

Causes of galactorrhoea?
Drugs causes?

Answer 45

Prolactin is secreted by the anterior pituitary gland and dopamine acts as the main inhibiting factor on its release. Bromocriptine ( dopamine agonist) may be used to control galactorrhoea.

Features in men –> impotence, loss of libido and galactorrhoea.
Features in women –> amenorrhoea, loss of libido, galactorrhoea.

Causes of raised prolactin: 5 P’S OA
Prolactinoma
Pregnancy
Physiological - sleep disturbance/ stress/ exercise
PCOS
Primary hypothyroidism ( due to thyrotrophin releasing hormone TRH stimulating prolactin release)
Oestrogens
Acromegaly ( 1/3rd of patients)

Drug causes:
Dopamine antagonists:
Metoclopramide and domperidone ( antiemetics and prokinetics)

Antipsychotics - all 1st generation AP’s, chlorpromazine, haloperidol.
Rarely SSRI and opiods

Question 46

Pathophysiology of addisons disease? ( physiology of adrenal gland / HPA Axis)

Answer 46

Adrenal fland / suprarenal gland divided into outer cortex and inner medulla.

Cortex has three layers : GFR
Glomerulosa releases mineralocorticoids - aldosterone.
Fasciculata - releases glucocorticoids ( cortisol) under control of HPA axis.
Reticularis - releases androgens as part of gonadal - hypothalamic - pituitary axis. Note in male pts testes produces majority of androgens, hence why in addisons androgen loss affects women.
Medulla - releases adrenaline, noradrenaline and dopamine.

Cortisol released as part of hypothalamic - pituitary - adrenal axis.
Hypothalamus releases CRH which acts on anterior pituitary to release ACTH. ACTH acts on adrenal gland ( zona fasciculata) to release cortisol. Negative feedback of cortisol on further release of CRH/ACTH.

Cortisol naturally exhibits diurnal variation , peaking at 8am ( zenith) and nadir at 12 aM-1AM.

ACTH also acts to stimulate melanocytes, hence pts with addisons disease develop hyperpigmentation in their oral mucosa and palmar creases.

Question 47

Physiology of RAAS system

Answer 47

Renin is released by the granular cells of the JGA in response to 1) SNS 2) Renal art hypotension 3) reduced Na at distal tubule.

Renin released from Kidneys converts angiotensinogen from the liver into angiotensin 1. This is converted via ACE in the pulmonary vasculature to Angiotensin 2. Angiotensin 2 leads to release of aldosterone from the adrenal cortex, increases Na/H20 reabsorption ( both via aldosterone and independently).
It causes efferent arteriole vasoconstriction increasing filtration pressure, causes general arteriolar constriction ( increasing BP) and increases ADH secretion ( increased Blood volume by increased h20 reabsorption). Also +ve feedback on SNS stimulation.

Aldosterone is released in response to 1) AGtii 2) ACTH 3) High K levels

Question 48

Pathophysiology / causes of hypocortisolism

Answer 48

Hypocortisolism can be caused by:
1) lack of CRH from the hypothalamus ( tertiary adrenal insufficiency)
2) Lack of ACTH from the anterior pituitary gland ( secondary adrenal insufficiency)
3) Adrenal insufficiency ( Addison’s disease/ primary adrenal insufficiency).

Question 49

Causes of primary hypocortisolism

Answer 49

Primary adrenal insufficiency - specific condition where the adrenal glands have become damaged and unable to release glucocorticoid/ mineralocorticoid.
Causes:
1) Most common - ADDISONS- autoimmune destruction of adrenal glands.
2) Infective - TB/HIV/Syphilis or meningococcal septicaemia (waterhouse friderichesen syndrome - adrenal haemorrhage secondary to sepsis).
3) Metastases to adrenal gland
4) Iatrogenic - BL adrenalectomy
5) Infiltrative - amyloid disease

Question 50

Causes of Secondary adrenal insufficiency

Answer 50

Result of insufficient ACTH from anterior pituitary:

1) Pituitary resection of tumour
2) Pituitary apoplexy ( loss of blood flow/ bleeding into organ often due to tumour)
3) Sheehan’s syndrome - massive blood loss at childbirth leads to pit gland necrosis.

Question 51

Causes of tertiary adrenal insufficiency

Answer 51

Damage to hypothalamus / inadequate release of CRH.
Most often due to sudden withdrawal of long term oral steroids ( > 3 week course) causing suppression of the hypothalamus. If suddenly withdrawn hypothalamus does not respond fast enough to produce endogenous steroid.

Question 52

Symptoms of addisons disease

Answer 52

Loss of normal glucocorticoid function leads to:

Dehydration ( loss of Na reabsorption)
WL
N & V
Abdominal pain
Change BH - diarrhoea
Androgen deficiency symptoms in women ( loss of libido and loss of pubic hair / axillary hair) ( not in men as testes primary site)
Muscle cramps/ weakness / wasting
Fatigue

Signs:
Hyperpigmentation in oral mucosa and palmar creases ( only in primary adrenal insufficiency where there is an increase in ACTH).
Loss of pubic & axillary hair
Hypotension
Hypoglycaemia

Question 53

Investigation of Addison’s disease

Answer 53

Bedside - hypoglycaemia common
Bloods - U&E derangement - Metabolic acidosis with hyponatraemia and hyperkalaemia

Definitive - ACTH stimulation / Short synacthen test is the gold standard test. Plasma cortisol is measured before and 30 mins after giving IM synacthen. In healthy person, ACTH will stimulate the adrenals to produce cortisol and levels should at least double.

If ACTH stimulation test unavailable e.g. in primary care then sending 9am serum cortisol can be useful:
< 100 nmol - definitely abnormal
100- 500 - should prompt ACTH stimulation test
> 500 nmol - makes Addison’s disease very unlikely.

Other tests:
Plasma ACTH - in primary adrenal insufficiency it will be raised with low morning cortisol. In Secondary / tertiary it will be low.

Adrenal antibody screen - Anti 21 hydroxylase ab or adrenal cortex ab’s

Imaging:
CT/MRI adrenals - if suspecting an adrenal tumour/ haemorrhage/ structural pathology

MRI pituitary - for secondary adrenal insufficiency.

Question 54

Management of Addison’s disease

Answer 54

Lifelong corticosteroids/ mineralocorticoid replacement:

Hydrocortisone - typically 20-30 mg per day in split doses with the majority given in the first half of the day.
Fludrocortisone 50-300 mcg / day to replace aldosterone.

Patients are counselled and given a steroid alert card. Emphasise importance of not missing a glucocorticoid dose, sick day rules to double glucocorticoid dose but keep mineralocorticoid dose the same, and provide adrenal crisis box with hydrocortisone for injection.

Question 55

Management of vomiting patient with Addison’s disease

Answer 55

Pt with Addisons who is vomiting and unable to take oral hydrocortisone should have IM hydrocortisone until the vomiting stops.

Question 56

What are normal:
TSH levels in mU/L
T4 levels in pmol/L
Free T3 in pmol /L

Answer 56

TSH normal range - 0.5 -5.5 mU/L

T4 9.0-18 pmol/L

Free T3 4-7.4 pmol/L

Question 57

Causes of thyrotoxicosis

Answer 57

Graves disease - 50/60% of cases - Thyroid stimulating hormone receptor antibody
Toxic multinodular goitre -multiple nodules independent of -ve feedback
Solitary toxic adenoma - single adenoma producing excess
Acute phase of de Quervains thyroiditis
Acute phase of post partum thyroiditis
Acute phase of hashimotos thyroiditis ( later hypothyroid)
Amiodarone therapy ( excess iodine)
contrast load - rare, in elderly pts with pre existing thyroid disease
Follicular thyroid cancer

Secondary causes:
Struma ovarii - ectopic thyroid tissue from ovarian tumour or dermoid tumour
B HCG - mimics action of TSH , pregnancy / testicular germ cell tumour / choriocarcinoma or hyatidiform mole
Pituitary adenoma producing excess TSH

Question 58

Common symptoms for thyrotoxicosis?

Answer 58

Restlessness / manic-ness/ irritability / anxiety
Heat intolerance
Weight loss
Palpitations
Diarrhoea
Oligomenorrhoea
ED
Muscle weakness and tremor, hyper-reflexia

Specific to Graves disease - Vertical diplopia ( thyroid eye disease, swelling of periorbital muscles usually inferior rectus), waxy calf skin ( pretibial myxoedema)

Question 59

Graves specific examination findings

Answer 59

Grave specific eye disease:
Exopthalmos
Lid lag / lid retraction
Opthalmoplegia - often inferior rectus leading to vertical diplopia

Pretibial mxyodema ( waxy discolouration of shin area)

Thyroid acropachy : Triad of:
Clubbing
Soft tissue swelling of hands and feet
Periosteal new bone formation

Diffuse Goitre - normally diffusely and symmetrically enlarged without nodules, may be bruit from increased vascularity .

Question 60

Investigations Graves D

Answer 60

TFT - High T3/T4, Low TSH
+ve for autoantibodies:
Thyroid stimulating receptor autoantibody ( Anti TSH receptor Ab) in 90%
Thyroid peroxidase ab ( Anti TPO) in 75%

Could consider:
thyroid USS if nodule palpated
Radionucleotide scan - performed if Abs negative. Diffuse, homogenous increased uptake of radioactive iodine.

Question 61

Mx of Graves disease

Drug management 1st line / 2nd line - important considerations
Further mx options pros/ cons

Answer 61

Refer all pts with new onset hyperthyroidism to endocrinology.

Carbimazole is 1st line. 40 mg for 6 weeks until euthyroid. Then two options - titrate to a maintenance dose or block and replace regime.
MOA - Blocks Thyroid peroxidase from coupling and iodinating tyrosine on thyroglobulin.

*Important - Contraindicated in Pregnancy as carbimazole can cross to the placenta inducing congenital hypothyroidism ( cretinism) & lack of brain development. * **Always warn of fever and risk of agranulocytosis **

2nd line - propylthiouracil 1st line for women wanting to become pregnant or those in 1st trimester. 2nd line due to increased risk of hepatic reactions.

Symptomatic mx - propanolol

3rd line radioactive iodine treatment:
Contraindicated in pregnancy and breastfeeding, children ( 16yrs) and those with thyroid eye disease ( may worsen).

Counselling: remission can take up to 6 months, patients can become hypothyroid ( majority within 5 yrs) and may require thyroid replacement therapy). After radioactive iodine must avoid close contact with women and children 3 weeks, avoid pregnancy 6 months. Men avoid fathering children for 4 months.

Thyroid surgery - Most pts become hypothyroid and require levoT after. Risk of recurrent laryngeal nerve injury, bleeding, larygneal swelling & airway compromise, damage to paraT gland leading to hypocalcaemia.

Question 62

Thyroid eye disease :
Cause
Most important modifiable RF?
Management
Urgent referral to opthalmologist?

Answer 62

Caused by TSH R Abs that leads to inflammation and accumulation of mucopolysaccharides behind the extraocular muscles.

Most important modifiable RF - Smoking

Management:
Smoking cessation
Topical lubricants / artificial tears
Steroids - prednisilone

Urgent referral to opthalmologist if:
Unexplained deterioration of vision
Change of colour vision
Corneal opacification
Disk swelling
Hx of eye popping - globe subluxation

Question 63

Causes of high aldosterone?

Answer 63

1) Primary hyperaldosteronism - where adrenal gland produces excess aldosterone.
Commonly caused by bilateral adrenal gland hyperplasia ( 60-70% of cases)
Adrenal adenoma ( 20-30%) ( Conns syndrome)
Unilateral hyperplasia
Familial hyperaldosteronism
Adrenal carcinoma ( rare)

2) Secondary hyperaldosteronism - where excess renin production leads to excess aldosterone from adrenal gland secondary to low cardiac output states.
Due to low BP in the renal arteries relative to systolic BP.
Causes:
Renal artery stenosis
Renal artery obstruction e.g. - Fibromuscular dysplasia
HF
Hepatic failure
Excessive diuretic use
Nephrotic syndrome

Question 64

Features of hyperaldosteronism?

Answer 64

Resistant HTN
High Na, low K, metabolic alkalosis.

High Na/ HTN: headaches, visual disturbance, increased thirst and polyuria/ nocturia.
Family Hx of early onset HTN or stroke.

Low K: Muscle cramps, weakness , fatigue.

Question 65

Investigations of hyperaldosteronism?

Answer 65

1) Aldosterone/ renin ratio 1st line ix in suspected primary hyperaldosteronism. Should show HIGH aldosterone levels and LOW renin levels. ( -ve feedback due to high Na retention)

2) HR CT Abdo / adrenal vein sampling to differentiate between BL/ unilateral sources of aldosterone excess.
If CT normal then adrenal venous sampling used to distinguish between unilateral adenoma vs BL hyperplasia.

3) If Aldo/Renin ratio shows renin HIGH then suspected secondary hyperaldosteronism. Further investigations with renal artery USS or CT angiogram.

Question 66

Management of hyperaldosteronism?

Answer 66

If primary hyperaldosteronism caused by adrenal adenoma then surgical removal or L/R adrenal gland if unilateral.
Adrenal hyperplasia - aldosterone antagonists - Spironolactone or eplerenone
Renal artery stenosis - renal art angioplasty

Question 67

Hba1c levels in T2DM when 1st/2nd line therapy recommended?
Hba1c levels in T2DM when 3rd/ 4th line recommended?

General rules of adding therapy in t2dm

Answer 67

1ST & 2ND LINE recommended when HbA1c > 6.5% (48 mmol/mol)
3rd & 4th line recommended when HbA1c > 53 mmol / mol or 7.0%.

Metformin tends to be 1st line due to beneficial effect on weight.
Sulphonylurea 2nd line unless not tolerated/ risk of hypoglycaemia unacceptable.
If Above CI then DPP4 inhibitors or thiazolidinedions may be considered.
When adding metformin plus a sulfonylurea, insulin remains next line, with alternatives such as DPP4 inhibitors being recommended when insulin is “ unacceptable or inapp”.

Question 68

What are the rules around metformin and renal function?

Answer 68

Metformin - recommended stopped when creatinine > 150 mmol or eGFR < 30 ml/min/1.73m2 due to risk of lactic acidosis.
Caution recommended between eGFRs of 30-45. If eGFR remaining stably lower e.g. 33 for 6 months then reasonable to continue. If dropping e.g. 50 - 38 then reasonable to stop.