Revise Notes Endo

Question 1

Adrenal Gland Disorders

Answer 1

The Adrenal Glands

The adrenal cortex is the outermost region of the adrenal glands, surrounding the adrenal medulla.

The cortex consists of three main zones.

Zones - GFR = ACD

Zona Glomerulosa - Aldosterone
Zona Fasciculata - Cortisol
Zona Reticularis - DHEA

Question 2

Zona Glomerulosa

Function

Production of mineralocorticoids - Aldosterone
Physiology

Answer 2

Hypovolaemia/hypotension leads to reduced renal perfusion. This is detected by the juxtaglomerular apparatus (JGA) which secretes renin.

Renin converts angiotensin (produced in the liver) into angiotensin 1 (AT1).

AT1 is converted by ACE (produced by the lungs) into AT2.

AT2 increases the effective circulating volume/BP by:

SNS activation & vasoconstriction
ADH secretion
Aldosterone secretion

Aldosterone acts on the distal tubule and collecting ducts, facilitating:

Reabsorption of Na+ and H2O
Excretion of K+ and H+ ions

Question 3

Zona fasciculata

Answer 3

Zona Fasiculata

Function

Production of glucocorticoids - Cortisol
Physiology

Hypoglycaemia & stress results in cortisol release (via HPA axis)

Hypothalamus releases corticotrophin-releasing hormone (CRH)

CRH stimulates the secretion of ACTH from the anterior pituitary

ACTH stimulates the zona fasiculata to produce cortisol

Cortisol has several actions including gluconeogenesis, immunosuppression, metabolism of fats/proteins/carbohydrates

Question 5

Zona Reticularis

Function

Production of androgens -

Answer 5

Zona Reticularis

Function

Production of androgens - DHEA

Question 6

Cushing’s Syndrome

Causes of Cushing’s Syndrome
Pathophysiology

Excess exposure to glucocorticoids which can be ACTH-dependent or ACTH-independent.

Answer 6

Pseudo-Cushing’s

Causes: Alcohol excess, severe depression

Investigations:
False positive dexamethasone suppression test
Diagnosis: Insulin stress test

Question 7

ACTH-Dependent

Cushing’s disease - ACTH secreting pituitary tumour - 80% of cases of Cushing’s syndrome

Ectopic ACTH production - small cell lung cancer (10% cases)

Answer 7

ACTH-Independent

Iatrogenic Cushing’s syndrome - exogenous steroids

Adrenal adenoma or adrenal carcinoma

Carney complex syndrome - features include cardiac myxoma & skin myxomas, hyperpigmentation of skin, endocrine overactivity & tumours (including adrenal, thyroid etc.)

Question 8

Phaeochromocytoma

Pathology

A catecholamine secreting tumour of the chromaffin cells of the adrenal medulla
10% Rule

10% are familial (e.g. Von Hippel Lindau, Men 2a/2b)
10% are bilateral
10% are malignant

10% are extra-adrenal - paragangliomas
Commonly of the organ of zuckerandl - a small mass of chromaffin cells located along the aorta)

Answer 8

Clinical features

Episodic sweating, palpitations, headache, anxiety
Hypertension and tachycardia
Diagnosis

24 hour urinary metanephrines /catecholamines
Platelet norepinephrine
Management

Surgery
Pre-op - adrenergic blockade - alpha-blocker first, then beta-blocker

Question 9

Addisonian Crisis

Clinical features

Abdominal pain
Vomiting
Syncope
Hypotension
Hypoglycaemia

Answer 9

Management

IV Hydrocortisone 100 mg (or IM if no access)
IV fluid resuscitation

Question 11

Other causes of hypoadrenalism

Primary hypoadrenalism

Answer 11

Tuberculosis
Adrenal metastasis

Meningococcal sepsis (Friedrichsen-Waterhouse syndrome) - bleeding into the adrenals secondary to severe bacterial infection

HIV

Question 12

Secondary hypoadrenalism

Answer 12

Disorder of the HPA axis

Exogenous glucocorticoid use - adrenal suppression

Question 13

Management of hypoadrenalism

Answer 13

Mineralocorticoid/glucocorticoid replacement dependent on cause

Addisons - Prednisolone + Fludrocortisone

Question 14

Addison’s disease

Pathophysiology

Autoimmune destruction of the adrenal glands results in loss of production of aldosterone and cortisol

Answer 14

Clinical features

Low aldosterone results in

Hyponatraemia, hypotension

Hyperkalaemia and acidosis

Low cortisol - hypoglycaemia etc

High ACTH levels..
Stimulate melanocytes to produce melanin (hyperpigmentation) and loss of pubic hair (low androgens)

Question 15

Addison disease

Answer 15

Diagnosis

Diagnostic investigation of choice - ACTH stimulation test (short synacthen test)

Synthetic ACTH administration to assess adrenal response

Cortisol measurements - taken 30 minutes, 1 hour post administration
Other tests

Random cortisol/9am cortisol - may be used as a screening investigation
21-OH antibodies

Question 16

Hyperaldosteronism

Excess mineralocorticoid (aldosterone) exposure

Aetiology

1.Primary hyperaldosteronism

Bilateral adrenal hyperplasia - most common cause - 70% cases
Conn’s syndrome - adrenal adenoma

2. Secondary hyperaldosteronism - due to excessive activation of the renin-angiotensin-aldosterone system (RAAS)

Renal artery stenosis
Renin producing tumour

Answer 16

Clinical features

Aldosterone..
Increases Na+ and H20 retention
Hypernatraemia
Hypertension

Increased K+ and H+ excretion
Hypokalaemia - ‘muscle weakness’
Metabolic alkalosis

Investigations

1st Line: Plasma Aldosterone/Renin ratio
Low renin & high aldosterone suggests primary hyperaldosteronism
High renin & high aldosterone suggests secondary hyperaldosteronism

Primary hyperaldosteronism:
CT adrenal glands + adrenal venous sampling (identify site of autonomous aldosterone secretion, unilateral or bilateral - adenoma vs BAH)

Secondary hyperaldosteronism:
USKUB, MR angiogram etc.

Management

Bilateral adrenal adenoma - 1st line: Aldosterone antagonist (spironolactone)

Conn’s - 1st line: Adrenal surgery

Question 18

Cushing syndrome
Cf

Answer 18

Clinical Features

Symptoms/signs include:

Weight gain
Buffalo hump - faton back of neck
‘Moon face’, plethoric

Purple striae
Easy bruising

Proximal weakness
Difficult to control hypertension
Hyperglycaemia/diabetes

Question 19

Investigations

Bloods suggestive of Cushing’s include:

Hypokalaemic Metabolic Alkalosis (corticosteroids have mineralocorticoid activity)

Remember, mineralocorticoids (aldosterone) cause a decrease in K+ and H+

Hyperglycaemia/ impaired glucose tolerance

Answer 19

Diagnosis of Cushing’s includes the following

Confirmation of glucocorticod excess
Localisation/identification of the cause

Question 20

1) Confirmation of excess glucocorticoid

Answer 20

Overnight dexamethasone suppression test (alternative - 24hr urinary free cortisol)

Patient takes 1mg dexamethasone at approx. 23:00h

Check serum cortisol levels at 09:00h next morning

A normal response is suppression of serum cortisol to < 50 nmol/L

If > 50nmol/L, this suggests excess glucocorticoid production

Question 22

2) Localisation

Answer 22

2) Localisation

1st: Midnight + 9am ACTH levels

If ACTH is LOW this suggests a non-ACTH dependent cause
Iatrogenic,
adrenal adenoma or carcinoma,
Carney

If ACTH is HIGH this suggests an ACTH-dependent cause
Cushing’s disease,
ectopic ACTH production (SCLC)

2nd: High dose dexamethasone suppression test
Low dose dexamethasone test - suppresses cortisol levels = NAD

High dose dexamethasone test
Suppresses cortisol levels in Cushing’s Disease (pituitary tumour)

Does NOT suppress cortisol levels in ectopic ACTH production (small cell lung cancer

Question 24

Diabetes Insipidus

Answer 24

Pathophysiology

Diabetes insipidus results from insufficient production or action of antidiuretic hormone (ADH), leading to impaired water reabsorption in the kidneys and excessive urination.

Epidemiology

Relatively rare
Prevalence 1 in 25,000 people
Can occur at any age but often diagnosed in childhood or early adulthood

Causes

Central diabetes insipidus (CDI) results from deficient ADH production

Nephrogenic diabetes insipidus (NDI) occurs due to renal resistance to ADH

Question 26

DI

Answer 26

Clinical Features Polyuria Polydipsia Other symptoms may include: Nocturia Dehydration Fatigue. Investigations Hypernatraemic with dilute volume (high plasma osmolality with low urine osmolality) 24 hour urine volume = > 3L/day Fluid deprivation testing (distinguishes from psychogenic polydipsia): Plasma osmolality rises >305mOsm/kg and continue to produce large volumes of dilute volume despite fluid deprivation See table below to distinguish cranial vs nephrogenic DI Need to investigate cause i.e. MRI head for cranial DI

Question 27

Mng of DI

Answer 27

Management Maintain adequate fluid input and monitor sodium for hyper/hyponatramiae Cranial DI Managed with desmopressin (synthetic ADH) Nephrogenic DI Treatment depends on underlying cause- may require dietary modifications, discontinuation of offending medications, or treatment of underlying conditions. High dose desmopressin and thiazide diuretics can also be considered Complications Electrolyte imbalances Cognitive impairment Hypernatremic coma

Question 28

Aspect Central Diabetes Insipidus (CDI) Nephrogenic Diabetes Insipidus (NDI 3. Investigations Vasopressin challenge test - desmopressin results in increase in urine osmolality to > 800mOsm/kg - Vasopressin challenge test- desmopressin does not result in profound increase in urine osmolality 4. Management Replacement therapy with synthetic ADH (desmopressin) to supplement deficient hormone Treat underlying cause if identified (e.g., discontinue offending medications, manage renal disease)

Answer 28

) 1. Underlying Pathophysiology Deficiency of antidiuretic hormone (ADH) due to hypothalamic or pituitary dysfunction Renal resistance to ADH, resulting in impaired water reabsorption in the kidneys 2. Causes Idiopathic, tumors, trauma, infection, haemorrhage, haemochromatosis, autoimmune disorders affecting hypothalamus or pituitary Genetic mutations (e.g., in the AVPR2 or AQP2 genes), medications (e.g., lithium, demeclocycline), renal diseases (post-obstructive uropathy), hypercalcaemia

Question 29

DM

Answer 29

Diabetes Mellitus Background Diabetes is a metabolic disorder characterised by hyperglycaemia which occurs as a result of insulin resistance, insulin deficiency or a combination of the two. Type 1 diabetes Absolute insulin deficiency resulting from the autoimmune destruction of the beta cells of the pancreatic islets of langerhans, which are responsible for insulin production Type 2 diabetes Hyperglycaemia driven by insulin resistance, and a relative insulin deficiency. Often occurs as part of metabolic syndrome. Insulin resistance can develop as a result of by diet, a sedentary lifestyle and obesity.

Question 30

Note - HbA1c is not valid in certain patient groups, including:

Answer 30

Age < 18 Hemoglobinopathies HIV Pregnancy Regular medication which can induce hyperglycaemia (e.g. steroids) End-stage renal disease

Question 31

Making a diagnosis In the presence of symptoms, diabetes can be diagnosed with:

Answer 31

A single abnormal fasting BM A single abnormal HbA1c If the patient is asymptomatic, arrange repeat testing (with the same test) to ensure persistent hyperglycaemia, before making a diagnosis.

Question 32

It is also important to establish whether the patient is symptomatic of diabetes. Symptoms include

Answer 32

: Weight loss TATT Polyuria, polydipsia Blurred vision Recurrent infections (e.g. candidiasis, UTIs)

Question 34

Type 2 Diabetes Mellitus Diagnosis of diabetes mellitus Diabetes can be diagnosed with evidence of hyperglycaemia on capillary blood sugar monitoring or with a HbA1c blood test.

Answer 34

Hyperglycaemia is defined as: HbA1c >/= 48 mmol/mol (6.5%) Fasting BM >/= 7.0 mmol/L Random BM >/= 11.1 mmol/L (or post OGTT) in the presence of symptoms

Question 36

Diabetic Neuropathy Key learning

Answer 36

Common in poorly controlled or long-standing diabetics Painful sensory neuropathy Glove and stocking distribution No motor loss May have autonomic dysfunction - gastroparesis, orthostatic hypotension Management via: Optimising glycaemic control Neuropathic agents for analgesia (amitriptyline/gabapentin/pregbablin/duloxetine) Pathophysiology Nerve damage due to prolonged chronic hyperglyaemia causing microvascular damage, metabolic imbalances and inflammation Epidemiology Common- affecting up to 50% of patients with diabetes

Question 37

Dm risk factors History Neuropathy

Answer 37

Risk factors Poorly controlled diabetes Longer diabetes duration (Type 1 diabetics) Obesity Smoking History Peripheral neuropathy Numbness, tingling, burning pain, or loss of sensation in the extremities - commonly in the feet Autonomic neuropathy Altered gastric stasis (gastroparesis) Diarrhoae especially at night Urinary dysfunction or syncopal episodes (orthostatic hypotension)

Question 38

Examination findings Investigation

Answer 38

Examination Findings Sensory deficits often in the glove and stocking distribution in limb extremities Reduced or absent reflexes Muscle weakness Normal power in myotomes (no motor deficit!) Investigations HbA1c to assess glycaemic control Bloods including UEs, TFTs, B12/folate to exclude other causes of peripheral neuropathy Nerve conduction studies or electromyography may be required to assess the severity and type of neuropathy.

Question 40

Diabetic neuropathy mng Complication

Answer 40

Management Optimization of glycaemic control Analgesia - as per for neuropathic pain Amitriptyline Gabapentin Pregabalin Duloxetine If one does not work stop and try another Consider pain team or topical capsaicin if above measures fail Regular monitoring/screening Complications Diabetic foot ulcers Infections Charcot neuroarthropathy Autonomic dysfunction including erectile dysfunction, and orthostatic hypotension

Question 41

Diabetic Amyotrophy

Answer 41

Asymmetrical loss of proximal motor function Severe burning, neuropathic pain in the lower limbs Wasting and atrophy of the lower limbs muscles

Question 42

Management of Type 2 Diabetes Mellitus Education Refer for structured education - e.g. DESMOND

Answer 42

Monitoring - HbA1c Targets HbA1c should be monitored every 3-6 months until stable, and then every 6 months. Targets (L/S Measures or one drug) Lifestyle measures alone OR a single non-hypoglycemic drug (e.g. metformin) Target: 48 mmol/mol Treatment involving one or more hypoglycaemic drug (e.g. gliclazide) OR on two or more drugs: Target: 53 mmol/mol Intensifying treatment If HbA1c rises to 58 mmol/mol consider intensifying diabetic treatment

Question 43

Pharmacological management of T2DM Nb. If the patient is significantly hyperglycaemic, consider initial management with insulin/sulfonylurea until BMs are controlled and then review long-term pharmacological management

Answer 43

Step 1: (Metformin +/- SGLT2i) If HbA1c > 48 despite lifestyle measures 1st Line: Commence standard release metformin. Titrate dose over several weeks to reduce risk of SEs. Adverse effects - gastrointestinal upset (diarrhoea, urgency), B12 deficiency If not tolerated, trial modified release metformin Contraindications: CKD (eGFR < 30)

Question 44

Consider dual therapy

Answer 44

Determine if the patient would benefit from dual therapy with an SGLT-2 inhibitor (alongside metformin) as 1st line treatment. Indications include: Chronic heart failure Established cardiovascular disease High risk of developing cardiovascular disease (QRISK > 10%) T2DM with CKD and proteinuria (see later*)

Question 45

When treating a patient with metformin/SGLT-2i dual therapy:

Answer 45

First, introduce metformin, gradually titrate Once tolerating metformin, commence SGLT-2i

Question 46

Step 2: Add a second line drug

Answer 46

Figure 269: Management of T2DM Step 2: Add a second line drug If HbA1c rises to 58 mmol/mol despite metformin (+/- SGLT2i) Intensify antidiabetic treatment with one of the following second line options. Choose from: DPP-4 inhibitors - sitagliptin Thiazolidinediones – pioglitazone Sulfonylureas - gliclazide SGLT-2 inhibitor - dapagliflozin

Question 47

Step 3

Answer 47

Step 3: If HbA1c rises to 58 mmol/mol despite two drugs: Consider commencing triple therapy by adding a third drug from the above list or.. Consider insulin therapy Nb. Initiation/intensification of insulin therapy commonly results in weight gain

Question 48

Step 4: If triple therapy is ineffective, consider alternative triple therapy by switching one of the second line drugs for a GLP-1 mimetic (Liraglutide, Semaglutide etc) if:

Answer 48

BMI is > 35 OR BMI < 35 but.. insulin therapy would have significant occupational implications (e.g. HGV driver) Weight loss would benefit co-morbidities

Question 49

Monitoring the response to GLP-1 receptor agonists

Answer 49

Only continue the GLP-1 agonist after 6 months if there is BOTH a: Decrease in HbA1c of 11 mmol/mol (1%) and.. Weight loss of 3% Note - if commencing a GLP-1 agonist, discontinue any DPP-4 inhibitors.

Question 50

Stepwise management when metformin is not tolerated/ CId

Answer 50

Step 1: Commence one of: SGLT2 inhibitor (empagliflozin) (1st line if HF/CVD/QRISK>10%) DPP-4 inhibitor (gliptins) Thiazolidinedione (pioglitazone) Sulfonylurea (gliclazide)

Question 51

Stepwise management when metformin is not tolerated/ CId

Answer 51

Step 2: If HbA1c rises to 58 despite one drug, commence another from the above list: sulfonylurea + DPP-4 inhibitor sulfonylurea + thiazolidinedione DPP-4 inhibitor + thiazolidinedione

Question 52

Stepwise management when metformin is not tolerated/ CId

Answer 52

Step 3: Consider insulin therapy

Question 53

Stepwise management when metformin is not tolerated/ CId

Question 54

SGLT-2 inhibitors - further information In addition to the above guideline, NICE states that we should add an SGLT2 inhibitor (or switch for one of the current treatments), if at any point a patient: Develops HF Established CVD Develops increased risk of CVD (QRISK >10%) CKD as below

Answer 54

SGLT2-inhibitors in CKD NICE recommend dapagliflozin in patients with CKD with an eGFR of 25-75 when commencing treatment and have either: Type 2 diabetes mellitus Or urine ACR > 22.6 mg/mmol It must be used as an add-on to highest tolerated dose of ACEi/ARB

Question 55

Pharmacology - Antidiabetic Drugs Biguanides - Metformin Mechanism of action Increases peripheral insulin sensitivity - enhanced peripheral glucose uptake/glycolysis Decreases hepatic gluconeogenesis Benefits: Weight loss Adverse effects Gastrointestinal upset/diarrhoea Lactic acidosis Contraindications eGFR < 30/ Cr > 150 (review dose if eGFR < 45) Tissue hypoxia (increased risk of lactic acidosis) Acute metabolic acidosis

Answer 55

Sulfonylureas - Gliclazide, glimepiride Mechanism of action Stimulate pancreatic B cells - increases insulin secretion Side effects Hypoglycaemia Weight gain Less common: Hepatotoxicity, SIADH

Question 62

Thiazolidinediones - Pioglitazone Mechanism of action Reduce insulin resistance Side effects Increased risk of fractures Bladder cancer Weight gain Liver impairment (LFTs should be monitored) Fluid retention (contraindicated in history of CCF) Contraindications: Heart failure Active/previous bladder cancer or uninvestigated macroscopic haematuria Hepatic impairment

Answer 62

DPP-4 Inhibitors - Sitagliptin, linagliptin Mechanism of action Increase function of incretins (GLP-1 & GIP) by decreasing peripheral breakdown by DPP-4 enzymes - increases the ‘incretin effect’ (see below) - increased insulin secretion Delayed gastric emptying Do NOT cause weight gain - may be preferred in obese patients Complications Pancreatitis

Question 63

SGLT-2 inhibitors – Dapagliflozin, empagliflozin Mechanism of action Inhibit Na+/Glucose co-transporters in the proximal convoluted tubule, resulting in decreased glucose reabsorption → glycosuria and weight loss Side effects Glycosuria results in.. Increased risk of UTI Genital infections - balanitis/vulvovaginal candidiasis Complications Diabetic ketoacidosis (can be euglycaemic) Fournier's gangrene

Answer 63

GLP-1 Mimetics - Exenatide/Liraglutide Mechanism of action GLP-1 mimetics increase insulin secretion and decrease glucagon secretion (see below - incretin effect) Benefits: Weight loss Side effects Nausea and vomiting Renal impairment Complications Severe pancreatitis Contraindications Chronic pancreatitis

Question 64

Incretin effect

Answer 64

The Incretin effect Oral glucose loads cause a greater insulin response than IV loads due to the incretin effect. This is because incretins (GLP-1 & GIP) are released from the small intestine after ingestion of oral glucose. GLP-1/GIP: Stimulates insulin secretion by the pancreatic B cells Reduce glucagon secretion Delay gastric emptying - causing earlier satiety

Question 65

Patients at risk of type 2 diabetes Pre-diabetes Diagnosis: HbA1c 42-47 (6-6.4%) Management: Monitoring: Yearly HbA1c Lifestyle changes Consider offering metformin in addition to lifestyle changes, if: HbA1c/fasting BM worsens despite lifestyle changes

Answer 65

Impaired glucose regulation Impaired fasting glucose Fasting BM of 6.1-6.9 Impaired glucose tolerance Fasting BM < 7 and.. BM 7.8-11.1 2 hours following OGTT

Question 66

Type 1 diabetes mellitus Pathophysiology A chronic autoimmune condition, caused by the destruction of the Beta cells of the islets of langerhans by autoantibodies (including GAD, ICA+ IAA antibodies) Management of T1DM Monitoring HbA1c should be checked every 3-6 months with a target of < 48mmol/mol BMs should be checked QDS with the following targets: Waking 5-7 Pre-meal 4-7

Answer 66

Insulin A basal-bolus regimen is 1st line Basal insulin of choice = BD detemir (brand: levemir), (preferred vs lantus) Bolus x 3 (actrapid/novorapid etc) injected before each meal Metformin Consider adding metformin if BMI >/= 25 Hypertension in T1DM Aim for clinic BP < 140/90mmHg (> 80yrs - 150/80) If urine ACR is > 70 mg/mmol - aim for < 130/80 mmHg 1st Line: ACEi/ARB (renoprotection)

Question 67

Monogenic diabetes A group of hereditary forms of diabetes resulting from specific genetic mutations which disrupt insulin secretion. This includes the condition previously known as maturity-onset diabetes of the young (MODY) Inheritance: autosomal dominant Strong genetic link and family history of early onset diabetes mellitus is common Ketosis is normally absent Questions may describe 'skinny', young patients, with a 'strong family history of DM', with normal-ish ketones on investigations. MODY3 is the most common subtype - mutation of HNF-1 alpha gene

Answer 67

Management of MODY: 1st Line: Sulfonylurea - Gliclazide MODY --> reduced insulin secretion Sulfonylureas stimulate pancreatic insulin secretion - patients with MODY generally respond very well to this treatment.

Question 68

Other Management Considerations in Diabetes Lipid Modification in Diabetes Primary prevention - Type 2 DM: QRISK 10% or more - atorvastatin 20mg ON Secondary prevention - Type 2 DM + established CVD - atorvastatin 80mg ON Type 1 diabetes - do not use QRISK - commence treatment with atorvastatin if patient fulfils any of: > 40 years of age History of T1DM for > 10 yrs Diabetic nephropathy

Answer 68

Complications of chronic diabetes mellitus Diabetic Gastroparesis Metoclopramide, erythromycin or domperidone can be useful Erectile dysfunction 1st line: Sildenafil + refer to urology

Question 69

DVLA guidance for Diabetes Mellitus Group 1 A car driving licence (group 1) is attainable for patients with the following criteria: If on insulin - less than or equal to 1 hypoglycaemic event in the last 12 months & retains full hypo awareness If on sulfonylurea/ oral hypoglycaemics - equal to or less than 1 event but no need to inform DVLA

Answer 69

Group 2 A HGV (group 2) licence is attainable for patients who are on insulin/oral hypoglycaemics if: No severe hypos for 12 months Patient retains full hypo awareness Patient performs regular BM monitoring (at least twice daily + more when driving) Absence of debarring complication of DM (e.g. retinopathy) Patients must inform DVLA and complete a VDIAB1i form for insulin and oral hypoglycaemics

Question 70

Diabetic Complications DKA Pathophysiology Most common in T1DM Can also occur in T2DM, particularly if on SGLT-2 inhibitors (& be euglycaemic due to glycosuria) Unopposed lipolysis and oxidation of free fatty acids results in generation of ketone bodies. This results in a raised anion gap metabolic acidosis. Diagnostic criteria

Answer 70

Diagnostic criteria BM > 11 OR known diabetes mellitus pH < 7.3 or HCO3 < 15 Ketones > 3 mmol/L or ++ urinary ketones Management Fixed rate insulin infusion (0.1 units/kg/hr) Fluids with appropriate potassium replacement (insulin drives intracellular K+ uptake) - often 5-8 litres required Continue long acting insulin (suspend short acting whilst on IV insulin)

Question 71

Hyperosmolar Hyperglycaemic State (prev. HONK) Pathology Persistent severe hyperglycaemia results in osmotic diuresis and polyuria with resultant severe dehydration and electrolyte derangement. Clinical features Typically an elderly patient with type 2 diabetes mellitus Initial presentation may be with a complication of hyperviscosity - MI, stroke, arterial thrombosis Reduced GCS

Answer 71

Diagnostic criteria Hypovolaemia Hyperglycaemia (>30mmol/L) without significant ketosis Serum osmolality > 320mosmol/kg Osmolality can be calculated by (2 x [Na+]) + [glucose] + [urea] Management Fluids are the mainstay of management - patients are significantly hypovolaemic and often require 10-20+ litres. 1st line: IV NaCl 0.9% If BMs do not improve adequately with IV fluid, consider commencing fixed rate insulin (0.05 units/kg/hr)

Question 72

Hypoglycaemia Investigating of Hypoglycaemia Raised insulin, low C-peptide = insulin abuse Raised insulin, high C-peptide = sulfonylurea abuse/insulinoma Increased ratio of proinsulin to insulin = insulinoma

Answer 72

Insulinoma A neuroendocrine tumour of the pancreatic islets of Langerhans cells 50% of patients with insulinomas have MEN-1 (3 Ps: hyperParathyroidism, Pancreatic tumour, Pituitary adenoma) Clinical features Rapid weight gain Hypoglycaemic episodes Bloods: Raised C-peptide, Raised insulin, Increased pro-insulin to insulin ratio Diagnosis: Supervised prolonged fast (+/- CT pancreas) Determines if excess insulin production in the absence of food/sugar intake

Question 73

Endocrine Syndromes Autoimmune Polyendocrine Syndrome (APS) APS are rare conditions characterised by autoimmune disease against multiple endocrine systems. APS 1 Genetics: Mutation of AIRE1 gene Clinical features: Oral candidiasis Addison's disease Primary hypOthyroidism +/- vitiligo

Answer 73

APS 2 Genetics: associated with HLA-DR3/4 Clinical features: Addison's disease Type 1 diabetes mellitus OR Hashimoto's hypothyroidism +/- vitiligo

Question 75

Multiple Endocrine Neoplasia MEN is an autosomal dominant condition which results in the development of multiple endocrine tumours. MEN1 Genetics: MEN1 gene mutation Clinical features: 3 Ps HyperParathyroidism (hypercalcaemia) Pituitary tumour (with release of PRL or GH) Pancreatic tumours Insulinomas - rapid weight gain, symptoms of hypoglycaemia Gastrinomas - reflux, epigastric pain, recurrent PUD

Answer 75

MEN2 Genetics: RET oncogene mutation MEN2a Features: 2Ps + 1M Phaeochromocytoma HyperParathyroidism (hypercalcaemia) Medullary Thyroid cancer MEN2b Features: 1P + 2Ms Phaeochromocytoma Medullary Thyroid cancer Marfanoid body habitus & mucosal neuromas

Question 76

Androgen Insensitivity Syndrome Pathophysiology Inheritance: X-Linked Recessive Karyotype: 46 XY Insensitivity to androgens results in development of female phenotype in people with 46XY karyotype

Answer 76

Clinical features Primary amenorrhoea Bilateral groin swellings - undescended testis Investigations Diagnosis via chromosomal analysis Management Patients are raised as female, oestrogen therapy B/L orchidectomy (higher risk of testicular ca.)

Question 77

Carcinoid syndrome Pathophysiology Most commonly caused by neuroendocrine tumours of the midgut which metastasise to the liver (or lung cancer carcinoid rarely). Tumours secrete SEROTONIN into the systemic circulation Clinical features Flushing Diarrhoea Bronchospasm and wheeze Tricuspid stenosis – mid diastolic murmur at LLSE

Answer 77

Investigations 1st line: Urinary 5-HIAA increased (this is the primary metabolite of serotonin) Serum Plasma chromogranin AY are elevated Management 1st line: Octreotide - somatostatin analogue Cyproheptadine can improve diarrhoea (serotonin receptor antagonist)

Question 78

Hypercalcaemia Hypercalcaemia is defined as a serum calcium concentration of 2.6 mmol/L or higher after adjusting for serum albumin levels. Severity is classified as follows: Mild: 2.6–3.00 mmol/L Moderate: 3.01–3.40 mmol/L Severe: > 3.40 mmol/L Causes Primary hyperparathyroidism - the commonest cause Hypercalcaemia of malignancy - second commonest cause Other causes: Medications - thiazides, thiazide-like diuretics (indapamide), lithium Granulomatous disease - sarcoidosis, TB CKD - Tertiary hyperparathyroidism

Answer 78

Clinical features Painful bones, renal stones, abdominal groans, thrones and psychic moans Bone pain Symptoms of renal/ureteric stones Abdominal pain, constipation Confusion, psychosis, depression Thirst, polydipsia, polyuria ECG findings Short QTc Management Admission criteria: severe symptoms OR severe hypercalcaemia (>3.4) Severe hypercalcaemia (>3.4) or severe symptoms Emergency admission Establish cause and correct where possible IV fluids - often require 4-6L of sodium chloride 0.9% over 24 hours if dehydrated Monitor for fluid overload if renal impairment/frail/HF IV bisphosphonates - if remains hypercalcaemic despite IVI, consider IV bisphosphonates Pamidronate OR Zolendronic acid If mild or moderate (2.6-3.4) and asymptomatic / minimal symptoms, can be managed in community: Treat cause / refer as appropriate / review medications

Question 80

Hyperkalaemia Key Learning Points Definition: Serum potassium >5.5mmol/L. Clinical Features: Often asymptomatic; symptoms may include weakness, palpitations, and arrhythmias . ECG changes: Peaked T waves, flattened P waves, prolonged PR, wide QRS Management: Treat acute hyperkalaemia promptly with IV calcium gluconate to stabilise the heart (risk if severe of VF and asystole) as well as insulin/ glucose regime and saline nebulisers; consider underlying cause. Definition Serum potassium level above 5.5mmol/L Normal serum potassium range is 3.5 - 5.4mmol/L Pathophysiology Excessive potassium intake, decreased excretion (renal failure), or transcellular shift (acidosis) can lead to hyperkalaemia. Causes Decreased Renal Excretion: Acute kidney injury (AKI). Chronic kidney disease (CKD). Renin-angiotensin-aldosterone system inhibitors (RAASi). Increased Intake or Redistribution: Excessive dietary intake. Potassium-sparing diuretics (e.g., spironolactone). Tissue breakdown (e.g., rhabdomyolysis). Others: Metabolic acidosis. Adrenal insufficiency (Addison's disease). Pseudohyperkalaemia (due to hemolysis during blood sampling).

Answer 80

Clinical Features Often asymptomatic Muscle weakness Palpitations Cardiac arrhythmias (e.g., bradycardia, ventricular fibrillation). Examination Findings Look for signs of muscle weakness ECG Changes Mild - Peaked T waves. Moderate - Prolonged PR interval, flattened P waves, widened QRS complex. Severe - Sine wave pattern, ventricular fibrillation, asystole.

Question 81

Hyperkalaemia Key Learning Points Definition: Serum potassium >5.5mmol/L. Clinical Features: Often asymptomatic; symptoms may include weakness, palpitations, and arrhythmias. ECG changes: Peaked T waves, flattened P waves, prolonged PR, wide QRS Management: Treat acute hyperkalaemia promptly with IV calcium gluconate to stabilise the heart (risk if severe of VF and asystole) as well as insulin/ glucose regime and saline nebulisers; consider underlying cause.

Answer 81

Investigations Bloods: Electrolytes- serum potassium/calcium/magnesium/phosphate Renal function- urea, creatinine Glucose ECG: See above Further Evaluation: Investigate underlying causes (e.g., renal ultrasound if indicated). Management Mild Hyperkalaemia (5.5 - 6.0mmol/L): Discontinue potassium supplements. Review medications (e.g., RAASi). Monitor closely with repeat potassium checks. Moderate Hyperkalaemia (6.0 - 6.5mmol/L): Stabilize the myocardium with IV calcium gluconate. Consider IV insulin and glucose or nebulized salbutamol to shift potassium intracellularly. Severe Hyperkalaemia (>6.5mmol/L or ECG changes): Treat as a medical emergency. Administer IV calcium gluconate to stabilize cardiac membranes. Give IV insulin and glucose and/or nebulized salbutamol to shift potassium intracellularly. Consider IV sodium bicarbonate or dialysis for rapid potassium reduction.

Question 83

Hypernatraemia Key Learning Definition: Mild (145 - 149 mmol/L), Moderate (150 - 154 mmol/L), Severe (>155 mmol/L or symptomatic). Clinical Features: Thirst, restlessness, confusion, seizures, coma. Examination Findings: Assess volume status (dry mucous membranes, skin turgor). Investigations: Urine osmolality < plasma osmolality – think diabetes insipidus Urine osmolality > plasma osmolality – think osmotic diuresis / heatstroke Management: Correct with appropriate fluids based on volume status.

Answer 83

Pathophysiology Results from a deficit of water relative to sodium, leading to elevated serum sodium levels. Causes Hypovolaemic: Fluid loss (e.g., diarrhoea, vomiting), heatstroke Euvolaemic: Diabetes insipidus (central or nephrogenic), excessive sweating, inadequate water intake. Hypervolaemic: Excessive sodium intake, renal failure, heart failure. Clinical Features Mild to Moderate: Thirst, dry mucous membranes, restlessness. Severe: Confusion, seizures, coma, hyperthermia. Examination Findings Assess for signs of dehydration (e.g., dry mucous membranes, reduced skin turgor). Neurological assessment for signs of cerebral oedema (e.g., altered mental status, focal neurological deficits). Investigations Serum Sodium: Confirm hypernatraemia and severity. Serum / Urine Osmolality: Differentiate between diabetes insipidus types (central vs. nephrogenic). Urine osmolality < plasma osmolality – think diabetes insipidus Urine osmolality > plasma osmolality – think osmotic diuresis / heatstroke Volume Status: Assess fluid balance (hypovolaemia, euvolaemia, hypervolaemia).

Question 84

Hypernatraemia Key Learning Definition: Mild (145 - 149 mmol/L), Moderate (150 - 154 mmol/L), Severe (>155 mmol/L or symptomatic). Clinical Features: Thirst, restlessness, confusion, seizures, coma. Examination Findings: Assess volume status (dry mucous membranes, skin turgor). Investigations: Urine osmolality < plasma osmolality – think diabetes insipidus Urine osmolality > plasma osmolality – think osmotic diuresis / heatstroke Management: Correct with appropriate fluids based on volume status.

Answer 84

Pathophysiology Results from a deficit of water relative to sodium, leading to elevated serum sodium levels. Causes Hypovolaemic: Fluid loss (e.g., diarrhoea, vomiting), heatstroke Euvolaemic: Diabetes insipidus (central or nephrogenic), excessive sweating, inadequate water intake. Hypervolaemic: Excessive sodium intake, renal failure, heart failure. Clinical Features Mild to Moderate: Thirst, dry mucous membranes, restlessness. Severe: Confusion, seizures, coma, hyperthermia.

Question 85

Examination Findings Assess for signs of dehydration (e.g., dry mucous membranes, reduced skin turgor). Neurological assessment for signs of cerebral oedema (e.g., altered mental status, focal neurological deficits). Investigations Serum Sodium: Confirm hypernatraemia and severity. Serum / Urine Osmolality: Differentiate between diabetes insipidus types (central vs. nephrogenic). Urine osmolality < plasma osmolality – think diabetes insipidus Urine osmolality > plasma osmolality – think osmotic diuresis / heatstroke Volume Status: Assess fluid balance (hypovolaemia, euvolaemia, hypervolaemia).

Answer 85

Management If hypovolaemic: Mild Hypernatraemia (145 - 149 mmol/L): Correct slowly with oral rehydration solutions or hypotonic fluids. Moderate Hypernatraemia (150 - 154 mmol/L): Correct with isotonic saline followed by hypotonic fluids. Severe Hypernatraemia (>155 mmol/L or symptomatic): Correct rapidly - usually with isotonic saline, followed by hypotonic fluids under specialist guidance. If euvolaemic / hypervolaemic- Consider IV dextrose and diuretics under specialist guidance Monitor: Serial sodium levels, fluid balance, and neurological status closely during correction. Complications Avoid rapid correction to prevent cerebral oedema and neurological complications. Monitor for signs of overcorrection (e.g., seizures, cerebral oedema). Specialist Involvement Consult nephrology or endocrinology for refractory cases or complex underlying conditions.

Question 86

Hyperthyroidism Causes of hyperthyroidism Graves disease - the most common cause of thyrotoxicosis Toxic multinodular goitre (TMN) Amiodarone induced thyrotoxicosis De Quervain’s thyroiditis (phase 1) Clinical features Sweating, intolerance of heat Anxiety and irritability Palpitations, tachycardia Weight loss Diarrhoea Tremor, brisk reflexes

Answer 86

Investigations TFTs Suppressed TSH High T3/T4 Management Propranolol – used for symptomatic relief Carbimazole Blocks thyroid perioxidase (TPO) – prevents the iodination of thyroglobulin tyrosine residues Adverse effects: Agranulocytosis - Red flag: Sore throat - urgent FBC Pancreatitis Propylthiouracil Adverse effects: Agranulocytosis Hepatotoxicity Radio-iodine 131

Question 87

Graves Disease Grave’s disease is the commonest cause of hyperthyroidism Pathophysiology An autoimmune process in which thyroid stimulating immunoglobulins bind to TSH receptors, stimulating the production of excess T3/T4 by the thyroid gland. Antibodies IgG antibodies vs TSH R (90% of patients) Anti-TPO antibodies (70% patients)

Answer 87

Clinical features Epidemiology: Grave’s most commonly affects females aged between 25-50 years Symptoms of generalised thyrotoxicosis as above Features specific to graves include: Diffuse goitre (without nodules) Thyroid eye disease ( exophthalmos, ophthalmoplegia) Pretibial myxoedema Thyroid acropachy - clubbing, swelling of hands & feet, periosteal new bone formation

Question 88

Graves’ disease mng

Answer 88

Management Symptomatic relief - propranolol Pharmacological management Antithyroid drugs include carbimazole (1st line) and propylthiouracil. They can be gradually titrated to achieve euthyroidism, or alternatively a block and replace regimen can be used. Antithyroid drug titration 1st Line: Carbimazole - dose titrated to maintain a euthyroid state Adverse effects: Teratogenic. Pancreatitis. Alternative: Propylthiouracil Adverse effects: Severe liver damage. Vasculitis. Skin rash. Typical duration: 12-18 months Block + Replace regimen A higher dose of carbimazole is used to block production of T3/4 Levothyroxine is given alongside Typical duration: 6-9 months

Question 89

Graves’ disease mng

Answer 89

Radio-iodine 131 RI131 may be used in Grave’s, though it is important to be aware of complications and contraindications Complications: Hypothyroidism – the vast majority of patients develop hypothyroidism, and therefore require lifelong levothyroxine Contra-indications: PREGNANCY (plus, pregnancy should be avoided for 6 months following treatment) Age < 16 years Relative CI: thyroid eye disease – symptoms are worsened by RI131 Thyroid eye disease Physiology: autoimmune response results in retro-orbital inflammation Affects approximately 1 in 3 patients with Graves’ disease Prevention: Smoking Cessation – very important Management of flare: Steroids

Question 92

Toxic Multinodular Goitre Pathophysiology: The presence of autonomously functioning thyroid nodules, which produce excess T3/T4 causing thyrotoxicosis. Investigations: Thyroid nuclear scintigraphy demonstrates patchy uptake Management: 1st Line: Radio-iodine 131 is the management option of choice

Answer 92

Toxic thyroid adenoma Pathophysiology: A single autonomously functioning thyroid nodules (usually benign), which produces excess T3/T4 causing thyrotoxicosis. Investigations: Thyroid nuclear scintigraphy– well defined area of uptake, with suppression of extranodular thyroid tissue Management: Surgery or Radio-iodine 131 are commonly used

Question 93

Amiodarone induced Thyrotoxicosis Amiodarone is associated with both drug-induced hypothyroidism and hyperthyroidism ( amiodarone induced thyrotoxicosis (AIT)).

Answer 93

De Quervain’s / subacute thyroiditis Cause: Most commonly triggered by a viral infection Disease course - Subacute thyroiditis follows a course of 3 distinct phases: Phase 1: HypERthyroidism (approx.. 1 month) with a PAINFUL GOITRE. Phase 2: Euthyroid (approx. 2 weeks) Phase 3: HypOthyroidism - may last several weeks to several months. Most often, thyroid function will gradually return to normal. Thyroid Scintigraphy: Globally reduced uptake of Iodine 131 Management: Observe most cases, NSAIDS can be used, if severe steroids are effective.

Question 94

Subclinical hyperthyroidism Investigations Low TSH in the context of Normal T3/T4 Complications Atrial fibrillation Osteoporosis

Answer 94

Management Arrange referral to endocrinology for investigations/management if: Two TSH readings < 0.1 at least 3 months apart And evidence of thyrotoxicosis - e.g. symptoms/antibodies/goitre Treatment of subclinical hyperthyroidism with carbimazole may be considered in some patients due to the risk of atrial fibrillation, osteoporosis and fractures.

Question 95

Thyroid storm Causes Infection Trauma Thyroid surgery Clinical features A history of hyperthyroidism Fever, tachycardia, hypertension Confusion & agitation Heart failure

Answer 95

Management IV Propanolol Anti-thyroid drugs: Propylthiouracil / Methimazole IV Dexamethasone – 4mg QDS – blocks the conversion of T4 --> T3 (which is more metabolically active)

Question 96

Hyperthyroidism in pregnancy Complications Hyperthyroidism in pregnancy is associated with increased risk of: Foetal loss or prematurity Maternal heart failure Aetiology Grave’s is the most common cause of thyrotoxicosis in pregnancy hCG can also stimulate the TSH receptor resulting in transient gestational hyperthyroidism

Answer 96

Risks of antithyroid drugs during pregnancy Propylthiouracil – increased risk of severe hepatic injury Carbimazole – Teratogenic in the first trimester Management - NICE guidelines: First trimester: Use propylthiouracil Second and third trimester: Switch to carbimazole Monitoring: Target T3 levels at upper 1/3rd of normal range Check thyrotrophin receptor antibodies at 30-36 weeks Radio-iodine 131 and B&R regimens are contraindicated

Question 97

Hypocalcaemia Key Learning Points Definition: Serum adjusted calcium <2.2mmol/L. Clinical Features: Muscle cramps, paraesthesia, tetany, carpopedal spasm. Investigations: Serum calcium, phosphate, PTH, electrolytes, magnesium, vitamin D. Management: Oral calcium for mild cases; IV calcium gluconate for severe cases.

Answer 97

Clinical Features Muscle cramps Paraesthesia Tetany Carpopedal spasm Severe cases: Seizures Cardiac arrhythmias Examination Findings Trousseau's sign (carpal spasm with inflating a blood pressure cuff) Chvostek's sign (facial muscle spasm with tapping the facial nerve). Investigations Bloods: Serum adjusted calcium Phosphate PTH Renal function Potassium Magnesium Vitamin D levels. ECG: Risk of QT prolongation.

Question 98

Hypocalcaemia Key Learning Points Definition: Serum adjusted calcium <2.2mmol/L. Clinical Features: Muscle cramps, paraesthesia, tetany, carpopedal spasm. Investigations: Serum calcium, phosphate, PTH, electrolytes, magnesium, vitamin D. Management: Oral calcium for mild cases; IV calcium gluconate for severe cases.

Answer 98

Definition Hypocalcaemia is defined as a serum adjusted calcium level below 2.2mmol/L. Reference Range 2.2 - 2.6mmol/L. Causes Reduced Intake or Absorption: Inadequate dietary intake of calcium. Malabsorption syndromes (e.g., celiac disease, short bowel syndrome). Increased Losses: Renal losses (e.g., diuretics, renal tubular disorders). Gastrointestinal losses (e.g., diarrhea, pancreatitis). Hypoparathyroidism: Surgical removal or dysfunction of parathyroid glands. Autoimmune destruction (e.g., autoimmune polyendocrine syndrome). Vitamin D Deficiency: Lack of sunlight exposure. Malabsorption or inadequate dietary intake. Other Causes: Acute pancreatitis. Magnesium deficiency. Drugs (e.g., bisphosphonates, antiepileptics).

Question 99

Hypocalcemia

Answer 99

Management Mild Hypocalcaemia (1.9 - 2.2mmol/L, asymptomatic): Start oral calcium supplements (e.g., Calcichew Forte Chewable). Adjust dose based on response and recheck serum calcium within one week if post-thyroidectomy. Consider alfacalcidol if hypocalcaemia persists despite supplementation. Severe Hypocalcaemia (<1.9mmol/L, symptomatic): Immediate Treatment: Administer IV calcium gluconate 10%: Bolus dose over 10 minutes, repeated if necessary while monitoring ECG. Follow with continuous infusion adjusted to normalize calcium levels. Monitoring: Regularly monitor serum calcium to assess response and adjust treatment. Continue monitoring bone profile post-treatment and on discharge to GP. Note: Ensure to address underlying causes, such as vitamin D deficiency or hypomagnesaemia, to optimise management.

Question 100

Hypokalemia

Answer 100

Hypokalaemia Key Learning Points Definition: Serum potassium <3.5mmol/L. Clinical Features: Often asymptomatic; symptoms may include weakness, cramps, arrhythmias. Investigations: Serum potassium, ECG, renal function, magnesium. Management: Treat underlying cause; consider potassium replacement based on severity. Definition Hypokalaemia is defined as a serum potassium level below 3.5mmol/L. Normal serum potassium range is 3.5 - 5.0mmol/L. Pathophysiology Excessive potassium loss (e.g., renal, gastrointestinal) or transcellular shift (e.g., alkalosis) leads to hypokalaemia. Causes Increased Loss: Diuretics (especially loop and thiazide diuretics). Gastrointestinal losses (e.g., diarrhea, vomiting). Renal tubular disorders (e.g., renal tubular acidosis). Decreased Intake: Inadequate dietary intake of potassium. Shift into Cells: Alkalosis (metabolic or respiratory). Insulin administration.

Question 101

Hypokalemia Clinical Features Weakness Muscle cramps Palpitations Cardiac arrhythmias (e.g., ventricular ectopy, ST depression). Examination Findings Assess for signs of muscle weakness, including diminished reflexes ECG Changes Mild: Flattened T waves, U waves. Moderate: Prominent U waves, ST depression. Severe: Prolonged QT interval, arrhythmias (ventricular tachycardia, fibrillation).

Answer 101

Investigations Bloods: Serum potassium Renal function (urea, creatinine) Magnesium (always check and replace as potassium will not come up if magnesium remains low). ECG. Further Evaluation: Identify underlying causes (e.g., medication review, evaluation for renal or gastrointestinal losses). Management Mild Hypokalaemia (3.0 - 3.5mmol/L): Identify and correct reversible causes (e.g., diuretic adjustment). Oral potassium supplementation (e.g., potassium chloride tablets). Moderate Hypokalaemia (2.5 - 3.0mmol/L): Consider IV potassium supplementation if symptomatic or severe. Address underlying electrolyte abnormalities (e.g., magnesium deficiency). Severe Hypokalaemia (<2.5mmol/L): Treat as a medical emergency. Administer IV potassium chloride with continuous cardiac monitoring. Correct associated magnesium deficiency if present.

Question 102

Hypomagnesaemia Key Learning Points Definition: Serum magnesium <0.7mmol/L. Clinical Features: Often asymptomatic; may present with neuromuscular irritability, cardiac arrhythmias. Investigations: Serum magnesium, renal function, ECG. Management: Replace magnesium cautiously based on severity and symptoms. Definition Hypomagnesaemia is defined as a serum magnesium level below 0.7mmol/L (normal range 0.7-1.0mmol/L)

Answer 102

Pathophysiology Reduced intake or absorption, increased renal or gastrointestinal losses, or shifts into cells can lead to hypomagnesaemia. Causes Reduced Intake or Absorption: Inadequate dietary intake. Malabsorption syndromes (e.g., celiac disease). Increased Losses: Renal losses (e.g., diuretic use, renal tubular disorders). Gastrointestinal losses (e.g., diarrhea, vomiting). Shift into Cells: Alcoholism. Refeeding syndrome. Clinical Features Neuromuscular irritability (e.g., tremors, muscle cramps) Cardiac arrhythmias (e.g., prolonged QT interval, Torsades de Pointes) Seizures. Examination Findings Signs of neuromuscular irritability (e.g., muscle twitching, hyperreflexia)

Question 103

ECG Changes Mild: T-wave flattening. Moderate: Prolonged QT interval. Severe: Ventricular arrhythmias (e.g., Torsades de Pointes). Investigations Bloods: Serum magnesium Renal function (urea, creatinine) Other electrolytes (potassium calcium) ECG Further Evaluation: Identify underlying causes (e.g., medication review, evaluation for renal or gastrointestinal losses).

Answer 103

Management Mild Hypomagnesaemia (0.5 - 0.7mmol/L): Oral magnesium supplementation (e.g., magnesium oxide). Address underlying causes (e.g., adjust medications causing magnesium loss). Moderate Hypomagnesaemia (0.4 - 0.5mmol/L): Consider IV magnesium supplementation if symptomatic or severe. Monitor serum magnesium levels closely during treatment. Severe Hypomagnesaemia (<0.4mmol/L): Administer IV magnesium sulfate with continuous cardiac monitoring. Correct associated electrolyte abnormalities (e.g., hypokalaemia).

Question 104

Metabolic Syndrome Background Metabolic syndrome describes a cluster of conditions, which often occur together, and are associated with an increased risk of cardiovascular disease. Significant association with insulin resistance Diagnosis SIGN diagnostic criteria - 3 of the following Increased waist circumference (M 102cm, W 88cm) Increased triglycerides (>1.7) Low HDLs (M < 1.03, W < 1.29) Hypertension Insulin resistance - T2DM or increased fasting BMs (> 5.6) Other features of metabolic syndrome can include: PCOS, NAFLD, Hyperuricaemia

Answer 104

Physiology of hunger Leptin Produced by adipose tissue - stimulates satiety (reduces appetite) Ghrelin Secreted by the P/D1 cells in the fundus of the stomach - Stimulates hunger Management of obesity Orlistat Mechanism: Orlistat is a pancreatic lipase inhibitor Side effects: GI upset - faecal incontinence, urgency, flatulence NICE criteria for orlistat BMI > 30 Or BMI > 28 with additional risk factors Target: To continue treatment, 5% weight loss should be achieved by 3 months

Question 105

Bariatric Surgery Indications BMI > 50 BMI 35-40 with risk factors (e.g. HTN/DM) or >40 and failure of medical measures Types of Bariatric Surgery Restrictive: Laproscopic adjustable gastric body (LAGB) or sleeve gastrectomy Achieve less weight loss but associated with fewer complications Malabsorptive: Biliopancreatic diversion with duodenal switch

Answer 105

Achieves greater weight loss but associated with more complications

Question 106

Dyslipidaemia Lipid modification - Primary Prevention Commence Atorvastatin 20mg ON as primary prevention, for the following patient cohorts. (1) QRISK > 10% Patient < 85 years + QRISK > 10% If age > 85 and QRISK > 10% - consider atorvastatin - reduces the risk of fatalMI/CVD

Answer 106

2) Diabetes Type 1 DM and age > 40 Diagnosis of DM > 10 yrs Diagnosis of diabetic nephropathy (3) CKD All patients with CKD

Question 107

Familial hyper cholesterolemia

Answer 107

Familial hypercholesterolaemia Inheritance: Autosomal dominant Pathophysiology Mutations in the LDL receptor gene - results in increased levels of LDL cholesterol Consider investigating patients for familial hypercholesterolaemia if: Total cholesterol (TC) > 7.5 and there if a family history of CVD < 60 yrs Total cholesterol > 9 Non-HDL cholesterol > 7.5 Management of FH: High dose statins

Question 108

Statins Mechanism: HMG-CoA reductase inhibitors - block LDL cholesterol Adverse effects: Deranged LFTs, myositis Contraindications include Pregnancy Breastfeeding Liver disease (LFTs > 3 x upper limit normal) Before initiation, measure Full lipid profile, LFTs, HbA1c , renal function, TSH CK is also required if: renal impairment, hypothyroid, unexplained muscle pain, history of liver disease

Answer 108

Targets Full lipid profile after 3 months of treatment If there is failure to achieve a reduction in non-HDL cholesterol of 40% - intensify treatment If still not achieved, despite max dose of statin, consider ezetimibe co-prescription Ezetimibe reduces cholesterol reabsorption in the small bowel Monitoring Lipid profile after 3 months, as above Repeat LFTs within 3 months, and again at 12 months (if stable, no further monitoring unless indicated) Check CK if muscle symptoms Repeat HbA1C after 3 months if high risk of DM

Question 109

Dyslipidemia

Answer 109

Secondary Prevention Following a cardiovascular event, patients should be commenced on Atorvastatin 80mg ON

Question 110

Remnant Hyperlipidaemia (dysbetalipoproteinaemia) Clinical features: Mixed dyslipidaemia with increased levels of both cholesterol and triglycerides

Answer 110

Genetics: Assoc. with APOE2 gene Clinical features Yellow palmar creases Palmar xanthomas Tuberous xanthomas Management: Fibrates PPAR-alpha receptor activators - increase lipoprotein lipase activity

Question 111

Other drugs used in the management of dyslipidaemia

Answer 111

Other drugs used in the management of dyslipidaemia Ezetimibe Mechanism: Reduces cholesterol absorption in the small intestine Side effect: Headaches Nicotinic acid Mechanism: Reduces VLDL secretion by liver Side effect: Flushing Cholestyramine Mechanism: Reduces reabsorption of bile acid in the SI which increases conversion of cholesterol into bile acid SE: GI upset - diarrhoea, flatulence etc.

Question 112

Parathyroid Disease Background Parathyroid hormone (PTH) is produced by the parathyroid glands, and is an important regulatory hormone of electrolytes including calcium and phosphate. Parathyroid Hormone - Increases calcium, decreases phosphate. Calcium: PTH INCREASES CALCIUM through.. Increased renal reabsorption Increased osteoclast activity Increased renal conversion of 25 🡪 1,25 OH vitamin D Phosphate: PTH DECREASES PHOSPHATE levels by.. Reducing renal reabsorption at the proximal convoluted tubule

Answer 112

Hyperparathyroidism Hyperparathyroidism is the condition resulting from excess production of PTH, and can be classified as primary, secondary or tertiary. Clinical Features Remembered by the mnemonic ‘stones, bones, abdominal groans, thrones, psychiatric moans’ which reflect hypercalcaemia Stones – nephrocalcinosis/renal stones Bones - bony pain - osteitis fibrosa cystica Abdominal groans - GI upset - N&V, constipation, abdominal pain Thrones - Polyuria Psychiatric moans - Depression / delirium

Question 113

Primary hyperparathyroidism

Answer 113

Primary Hyperparathyroidism Causes of Primary Hyperparathyroidism Solitary Adenoma - The most common cause of primary hyperparathyroidism is a solitary parathyroid adenoma, accounting for 80% of cases PTH hyperplasia – accounts for 15% of cases of primary hyperparathyroidism Multiple adenoma – 4% cases Parathyroid carcinoma – 1% of cases

Question 114

Primary hyperparathyroidism

Answer 114

Associations: Multiple endocrine neoplasia 1 & 2 MEN1 - 3 Ps: HyperParathyroidism, Pituitary tumour, Pancreatic tumours MEN2a - 2Ps + 1M: Phaeochromocytoma, hyperParathyroidism, Medullary thyroid ca. MEN 2b - 1P + 2Ms: Phaeochromocytoma, Medullary thyroid ca, Marfanoid/Mucosal neuromas Investigations Bloods High calcium Low phosphate PTH – high or inappropriately normal XRs Skull XR – may show a “pepper pot appearance” XRs show osteopenia – excess osteoclastic activity Preoperative localisation Parathyroid USS Parathyroid MIBI scan (nuclear medicine)

Question 115

Primary hyperparathyroidism

Answer 115

Management 1st line: Parathyroidectomy Commonly total parathyroidectomy. Subtotal may be performed alternatively. Conservative management can be considered if.. Calcium is < 0.25 > upper limit of normal and the patient is > 50 years of age with no end organ damage Alternative: If the patient is unsuitable for surgery cinacalcet can be considered Cinacalcet is a calcimimetic - it acts on the calcium-sensing receptors of the chief cells of the parathyroid gland, providing negative feedback for PTH secretion.

Question 116

Secondary Hyperparathyroidism Pathophysiology Secondary hyperparathyroidism describes excessive parathyroid hormone release in response to hypocalcaemia, in an attempt to normalise calcium levels. This can result in hyperplasia of the parathyroid glands. If left untreated, the disease will progress to irreversible tertiary hyperparathyroidism. CKD is the most common cause of secondary hyperparathyroidism CKD results in reduced 1,25-OH vitamin D production resulting in hypocalcaemia, and failure to excrete sufficient phosphate resulting in hyperphosphataemia Other causes include chronic vitamin D deficiency

Answer 116

Investigations Bloods: Calcium - LOW or normal Phosphate – HIGH PTH – HIGH Phosphate – HIGH Vitamin D – low Renal function - low Complications: Osteitis fibrosa cystica/ bone disease Management 1st Line: Medical treatment of underlying cause – for example replacement of calcium/vitamin D (e.g. adcal D3)

Question 117

Tertiary Hyperparathyroidism Pathophysiology Long-standing secondary hyperparathyroidism results in irreversible hyperplasia of the parathyroid gland (which persists even after the cause of secondary hyperparathyroidism has been corrected), which continue to produce excess PTH. Clinical features as per primary hyperparathyroidism (those of hypercalcaemia), ‘stones, bones, abdominal groans, thrones, psychiatric moans’.

Answer 117

Investigations Bloods Calcium - HIGH or normal PTH – inappropriately high Phosphate – high ALP – increased Management Observation may be appropriate (e.g. to see if resolves 12 months post-renal transplant) Definitive treatment is usually partial or total parathyroidectomy

Question 118

Hungry bone syndrome Background Hungry bone syndrome is a complication which can arise post-parathyroidectomy or thyroidectomy. It most commonly occurs in patients with severe primary hyperparathyroidism, with a high pre-operative bone turnover. Post-operatively, there is a sudden decrease in PTH levels, which leads to reduced osteoclastic activity, and a sudden shift towards osteoblastic activity, causing increased bone re-mineralisation = hungry bones. This can result in profound, prolonged hypocalcaemia, often associated with hypophosphataemia and hypomagnasaemia.

Answer 118

Clinical features Bone pain Symptoms of hypocalcaemia - paraesthesia, perioral numbness/tingling, seizures, tetany, spasms Management Calcium replacement IV calcium gluconate or chloride if severe (<1.9) or ECG changes (QTc prolongation) Oral supplementation when appropriate - calcium carbonate etc.

Question 119

Chronic kidney disease and mineral bone disease Pathophysiology CKD results in.. reduced 1-alpha hydroxylation of vitamin D - hypocalcaemia and secondary hyperparathyroidism Impaired phosphate excretion - hyperphosphataemia

Answer 119

This results in renal osteodystrophy. A term encompassing various biochemical/skeletal manifestations of CKD: Osteomalacia - due to low Vit D Osteitis fibrosa XRs: “brown tumours” Management Management is centred around control of phosphate, calcium, vit D levels. Phosphate: Reducing dietary phosphate is highly important Alternative: phosphate binders – sevelamer, vitamin D replacement Calcium / vit D replacement

Question 120

Hypoparathyroidism Primary hypoparathyroidism Causes Thyroidectomy is the most common cause Clinical Features Symptoms of hypocalcaemia Paraesthesia in fingertips/toes, lips/perioral Muscle cramps, twitching, tetany Trousseaus/ Chvostek’s signs

Answer 120

Bloods Low PTH with consequently low calcium and high phosphate Management 1st Line: Calcium and active vitamin D analogue therapy -to maintain serum calcium levels within normal range. Vitamin D - calcitriol or alfacalcidol Calcium carbonate

Question 121

Pseudohypoparathyroidism Pathophysiology A genetic disorder with Autosomal dominant inheritance Target cells are insensitive to parathyroid hormone Clinical features Low IQ Short 4th/5th metacarpals

Answer 121

Bloods High PTH Low calcium High phosphate

Question 122

Pituitary Disorders Background Hormones secreted by the anterior pituitary include.. TSH Prolactin GH FSH/LH ACTH Hormones secreted by the posterior pituitary include.. Oxytocin ADH (vasopressin)

Question 123

Primary Hypopituitarism Causes Primary Hypopituitarism Neoplasm - intra/parasellar tumours Sheehan’s syndrome Pituitary apoplexy Secondary Hypopituitarism - damage/compression of pituitary stalk, hypothalamus or CNS.

Answer 123

Investigation Dynamic Pituitary Function Tests Triple bolus test - insulin, TRH, LHRH are injected. Measurements are then taken of: Cortisol/GH levels which should rise in response to insulin induced hypoglycaemia Prolactin and TSH - should rise in response to TRH LH and FSH - should rise in response to GnRH

Question 124

Pituitary Adenoma Background Pathology: A benign tumour of the pituitary which can be functional or non-secretory Classification - size Microadenoma if < 1cm Macroadenoma if > 1cm. Classification - hormonal status

Answer 124

Prolactinomas - most common - accounting for 35% Key features: amenorrhoea & galactorrhoea Non-secretory pituitary adenoma Non-functioning, but can compress the pituitary leading to generalised hypopituitarism GH secreting adenomas Key features: acromegaly ACTH secreting account for 5-10%; LH/FSH are rare - < 1%

Question 125

Pituitary Adenoma Background Pathology: A benign tumour of the pituitary which can be functional or non-secretory Classification - size Microadenoma if < 1cm Macroadenoma if > 1cm.

Answer 125

Clinical features Bitemporal hemianopsia - compression of the optic chiasm Headache Pituitary dysfunction – clinical features according to hormonal status as above Investigations Hormone profile MRI with contrast Formal visual fields assessment Management Depend on tumour – pharmacoloical, surgical (transsphenoidal) or RT

Question 126

Prolactin Physiology An anterior pituitary hormone Secretion is regulated by continuous secretion of dopamine from the hypothalamus, which inhibits prolactin secretion Hence dopamine inhibition results in disinhibition (increased) of prolactin secretion

Answer 126

Functions: Breast development, milk production Inhibts GnRH release - reducing the secretion of FSH/LH and their actions on gonads Causes of Hyperprolactinaemia Prolactinoma Pregnancy & breastfeeding PCOS Primary Hypothyroidism Drugs - Dopamine antagonists: Metoclopramide, domperidone, haloperidol, phenothiazines increase prolactin

Question 128

Causes of Hyperprolactinaemia Prolactinoma Pregnancy & breastfeeding PCOS Primary Hypothyroidism Drugs - Dopamine antagonists: Metoclopramide, domperidone, haloperidol, phenothiazines increase prolactin

Answer 128

Clinical features Male – erectile dysfunction/impotence, galactorrhoea, reduced libido, hypogonadism Female - amenorrhoea, galactorrhoea, reduced libido Management of Prolactinoma 1st Line: Medical treatment is often used 1st line - Dopamine agonists - bromocriptine, cabergoline, quinagolide Dopamine agonists normalise prolactin levels and restore normal function of the HPG axis AND can reduce the size of the tumour significantly Surgery - if the tumour is drug resistant or rapidly increasing in size causing posing a risk to visual acuity, surgery is considered. A transsphenoidal approach is commonly used.

Question 130

Growth Hormone Physiology GH is secreted by the somatotroph cells of the anterior pituitary and has the following functions: Stimulates secretion of insulin-like growth factor 1 (IGF-1) from the liver. IGF-1 acts as the major mediator of GH action, inducing growth and anabolic cellular responses. Post-natal growth & development, nutritional metabolism Secretion: There is pulsatile GHRH release from the hypothalamus in response to fasting, hypoglycaemia, sleep, exercise - which stimulates secretion of GH by the anterior pit. Inhibition: GH release is inhibited by somatostatin and hyperglycaemia

Answer 130

Disorders of Growth Hormone Excess - Acromegaly Deficiency - short stature

Question 131

Acromegaly

Answer 131

Acromegaly Causes Growth hormone secreting pituitary adenoma - vast majority Rare - GHRH secreting tumours (e.g. pancreatic cancer) Clinical features Excessive sweating (hypertrophy of sweat glands) Spade hands, increase in shoe size Facial changes - Prominent supraorbital bridge, enlargement of nose and jaw Increased spacing between teeth Complications Hypertension Hyperglycaemia / Diabetes (>10%) Cardiomyopathy Colorectal cancer Regular total colonoscopy is indicated (inc. of ascending colon) Galactorrhoea - 30% also have hyperprolactinaemia

Question 132

Acromegaly Causes Growth hormone secreting pituitary adenoma - vast majority Rare - GHRH secreting tumours (e.g. pancreatic cancer)

Answer 132

Clinical features Excessive sweating (hypertrophy of sweat glands) Spade hands, increase in shoe size Facial changes - Prominent supraorbital bridge, enlargement of nose and jaw Increased spacing between teeth Complications Hypertension Hyperglycaemia / Diabetes (>10%) Cardiomyopathy Colorectal cancer Regular total colonoscopy is indicated (inc. of ascending colon) Galactorrhoea - 30% also have hyperprolactinaemia

Question 133

Acromegaly Causes Growth hormone secreting pituitary adenoma - vast majority Rare - GHRH secreting tumours (e.g. pancreatic cancer)

Answer 133

Diagnosis Initial screening test - Serum IGF-1 levels If equivocal/elevated - perform OGTT with GH measurement Gold standard for diagnosis of acromegaly - oral glucose tolerance test (OGTT) - oral 75g glucose load fails to suppress GH levels to < 1 - suggests acromegaly If positive OGTT - MRI with contrast - to identify pituitary tumour Management 1st Line: Transsphenoidal resection of pituitary adenoma Medical therapy (e.g. inoperable/incomplete excision) - Octreotide (somatostatin analogue) Alternatives: PeGvisomANT (GH receptor ANTagonist) Bromocriptine - used as a last option If treatments fail radiotherapy can be considered

Question 134

GH Deficiency Causes Hypopituitarism - congenital, post-trauma, tumour or RT etc. Generalised hypopituitarism – chromophobe Clinical features Neonates – hypoglycaemia, small penis, neonatal jaundice Delayed puberty Short height Low muscle mass Truncal obesity, ‘chubby’ Delayed milestones Osteoporosis

Answer 134

Diagnosis Insulin tolerance test – IV insulin induces a state of hypoglycaemia which should stimulate GH release (failure of GH spike indicates GH deficiency) Management: Recombinant human growth hormone (rHGH)

Question 136

SIADH Pathophysiology The renal collecting ducts (CDs) are impermeable to water ADH stimulates the insertion of aquaporin-2 channels into the CDs, allowing reabsorption of water. Excess ADH release results in excess water reabsorption resulting in dilutional hyponatraemia. Diagnostic criteria Euvolaemic Hypotonic(plasma Osmolality < 270) hyponatraemia Urine Na+ > 20 and urine Osm > 100 (concentrated due to water resorption) Normal cortisol and TFTs

Answer 136

Aetiology Malignancy (small cell lung cancer) Neurological - stroke, SDH, SAH, meningitis (CT head must be performed) Infection - pneumonia, TB (CXR should be performed) Drugs - sulfonylureas / SSRIs/ Carbamazepine/ Antidepressants Management 1st line - Fluid restriction Pharmacological Demeclocycline - disrupts the renal functions of ADH Vaptans - ADH receptor antagonists Hypertonic saline - rapid correction in severe disease (e.g. seizures) Complications Correction of hyponatraemia must be cautious – increase Na+ by no more than 8-10 mmol/litre per day or risk of central pontine myelinolysis

Question 137

Thyroid Cancer Clinical features Neck lump/nodule Lymphadenopathy Changes in voice/ hoarseness due to recurrent laryngeal nerve involvement Most patients are euthyroid and TFTs are less commonly affected

Answer 137

Papillary thyroid cancer Papillary thyroid cancer is the most common, accounting for approximately 70% of cases Biopsy findings: Papillary + colloidal filled follicles with pale empty nuclei Management Total thyroidectomy followed by radio-iodine 131 Monitoring: yearly thyroglobulin levels Commonly every 3-6 months for first 2 years, and then every 6-12 months

Question 138

Follicular thyroid carcinoma Pathology: encapsulated with vascular invasion Management: thyroidectomy, followed by RI131

Answer 138

Medullary carcinoma Accounts for approximately 5% of thyroid cancers It is a cancer of the parafollicular c cells (neuroendocrine cells - secrete calcitonin) Important association: MEN-2 (suggested in question stems by symptoms/signs of mucosal neuromas, marfanoid habitus, hyperparathyroidism, phaeochromocytoma) Anaplastic thyroid cancer Typically affects elderly patients and causes local invasion Management – resection (chemotherapy is very ineffective)

Question 139

Anaplastic thyroid cancer Typically affects elderly patients and causes local invasion Management – resection (chemotherapy is very ineffective) Thyroid lymphoma Rare – but importantly associated with patients with Hashimoto’s thyroiditis.

Answer 139

Anaplastic thyroid cancer Typically affects elderly patients and causes local invasion Management – resection (chemotherapy is very ineffective) Thyroid lymphoma Rare – but importantly associated with patients with Hashimoto’s thyroiditis.

Question 145

Sulfonylureas - Gliclazide, glimepiride Mechanism of action Stimulate pancreatic B cells - increases insulin secretion

Answer 145

Side effects Hypoglycaemia Weight gain Less common: Hepatotoxicity, SIADH

Question 146

Thiazolidinediones - Pioglitazone Mechanism of action Reduce insulin resistance Side effects Increased risk of fractures Bladder cancer Weight gain Liver impairment (LFTs should be monitored) Fluid retention (contraindicated in history of CCF)

Answer 146

Contraindications: Heart failure Active/previous bladder cancer or uninvestigated macroscopic haematuria Hepatic impairment

Question 147

DPP-4 Inhibitors - Sitagliptin, linagliptin Mechanism of action Increase function of incretins (GLP-1 & GIP) by decreasing peripheral breakdown by DPP-4 enzymes - increases the ‘incretin effect’ (see below) - increased insulin secretion Delayed gastric emptying Do NOT cause weight gain - may be preferred in obese patients

Answer 147

Complications Pancreatitis