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Endocrine and Metabolic Disease Dr Judy Tabbakh and Dr Masooma AliWhy is this relevant to the UKMLA?Why is this relevant to the UKMLA? Addisons Disease •Addison's disease is a form of primary adrenal insufficiency that results from the autoimmune destruction of the adrenal cortex. This leads to a deficiency of cortisol and aldosterone, two vital hormones produced by the adrenal glands. •Cortisol à maintaining glucose metabolism, immune function, and response to stress. •Aldosterone à regulating sodium, potassium, and water balance, impacting blood pressure and fluid status. Deficiency in aldosterone results in hypotension, salt cravings, and electrolyte disturbances (e.g., hyperkalemia). •Results in: 1) Impaired glucocorticoid and mineralocorticoid production. 2) Increased ACTH secretion due to lack of negative feedback from cortisol. 3) Elevated plasma renin levels due to aldosterone deficiency. Addison’s Disease - signs and symptoms •Fatigue and weakness •Hyperpigmentation (darkening of the skin, especially in creases and scars) due to elevated ACTH. •Postural hypotension (due to aldosterone deficiency and reduced sodium retention). •Salt craving (due to low aldosterone levels). •Nausea, vomiting, and abdominal pain. •Weight loss and anorexia. •Hypoglycaemia (due to cortisol deficiency). •Menstrual irregularities (in women). •Dehydration and dizziness. Addison’s Disease – investigations •Short Synacthen Test (ACTH Stimulation Test): • Gold standard test for diagnosing Addison’s disease. • Procedure: Measure baseline cortisol, then administer a synthetic ACTH (Synacthen). Measure cortisol at 30 and 60 minutes after injection. • Diagnosis: If cortisol fails to rise above 500 nmol/L, it confirms primary adrenal insufficiency (Addison's disease). •Anti-Adrenal Antibody Test: •Adrenal cortex antibodies •21-hydroxylase antibodies Addison’s Disease - Management 1) Hormone replacement therapy: •Glucocorticoids: e.g., Hydrocortisone or Prednisolone to replace cortisol. •Mineralocorticoids: e.g., Fludrocortisone to replace aldosterone. 2) Patient education: •Teach patients to adjust glucocorticoid doses during illness or stress (e.g., "Sick Day Rules") and the importance of compliance. 3) Crisis management (Addisonian crisis): •IV hydrocortisone and IV fluids (saline with glucose) in emergencies. •Treat underlying causes (e.g., infections) promptly. 4) Electrolyte management: •Monitor for hyponatraemia and hyperkalaemia, adjust therapy accordingly. Cushing’s Syndrome = prolonged high levels of glucocorticoids, most commonly cortisol Cushing’s syndrome = high cortisol levels as a result of any cause/pathology, including both exogenous and endogenous causes Cushing’s disease = Cushing’s syndrome specifically as a result of a pituitary adenoma Aetiology Endogenous Cushing’s: • Pituitary adenoma secreting excess levels of ACTH, stimulating excessive cortisol release from the adrenal glands • Ectopic ACTH production from tumours – e.g., lung cancer • Adrenal adenoma resulting in excessive cortisol secretion Exogenous Cushing’s • Prolonged use of corticosteroids – often iatrogenic Cushing’s Syndrome Presentation • Weight gain o Central obesity o Round, ‘moon-like’ face o Fat pad on upper back – ‘buffalo hump’ • Abdominal striae • Proximal myopathy • Psychiatric symptoms – depression, sleep disturbance • Hirsutism • Easy bruising • Skin thinning • Hyperpigmentation Cushing’s Syndrome Investigations Bedside • BM monitoring – likely hyperglycaemia Cortisol - Cortisol – ACTH • BP – hypertension common low dose high dose DST DST Bloods Normal Low Low Normal • 9am cortisol level – ++ Adrenal Not Not Low • ACTH levels – will depend on cause of Cushing’s adenoma suppressed suppressed • U&Es: low K, high Na – especially if aldosterone is also high Pituitary Not Low High adenoma suppressed Special tests Ectopic Not Not High • 24-hour urinary free cortisol - ++ ACTH suppressed suppressed • Low and high dose dexamethasone suppression tests – for diagnosis and confirmation of cause Cushing’s Syndrome Imaging • MRI pituitary • CT adrenals • CXR/CT chest if suspecting SCLC Cushing’s Syndrome Management Cause dependent. • Iatrogenic: wean steroids • Pituitary adenoma: trans-sphenoidal adenectomy • SCLC & ectopic ACTH production: surgical removal of tumour/ cytotoxics/radiotherapy • Adrenal adenoma: adrenalectomy/removal of tumour If removing cause is not possible and patient remains very symptomatic, bilateral adrenalectomy can be considered, with lifelong steroid replacement Diabetes Inspidus Clinical Features: •Polyuria (excessive urination) – typically > 3 liters per day. •Polydipsia (excessive thirst) – patients often drink large amounts of water to compensate. •Urine characteristics: •Dilute urine (low specific gravity, typically <1.005) despite high fluid intake. •Nocturia (frequent urination during the night). Types of DI: •Central (Neurogenic) Diabetes Insipidus: Caused by deficiency of ADH (antidiuretic hormone) due to damage to the hypothalamus or pituitary. •Nephrogenic Diabetes Insipidus: Resistance to ADH in the kidneys due to renal tubular dysfunction, often due to genetic causes or chronic kidney disease. •Dipsogenic DI: Caused by damage to the thirst-regulating center, leading to excessive thirst. Diabetes Inspidus – Investigations Investigations: •Serum Osmolality: • High osmolality (>300 mOsm/kg) due to concentration of solutes in the blood as kidneys are unable to concentrate urine. •Urine Osmolality: • Low urine osmolality (typically <200 mOsm/kg), as the kidneys cannot concentrate urine despite high plasma osmolality. Urine Osmolality Urine Osmolality After Water Deprivation After Desmopressin Primary Polydipsia High Not required Cranial Diabetes Insipidus Low High Nephrogenic Diabetes InsipiduLow Low Diabetes Inspidus – Management Central Diabetes Insipidus (CDI): •Desmopressin (DDAVP): •Synthetic ADH that is typically administered intranasally or orally. •Controls polyuria and polydipsia by promoting water reabsorption in the kidneys. Nephrogenic Diabetes Insipidus (NDI): •Thiazide Diuretics •Ensuring access to plenty of water •High-dose desmopressin Type 1 Diabetes Mellitus = Persistent hyperglycaemia as a result of poor insulin production by the pancreas The cause is generally unclear – theories include genetic components and certain virus triggers e.g., enterovirus Pathophysiology 1. Following a meal or carbohydrate load, glucose levels increase, normally triggering release of insulin from the pancreatic beta cells 2. Insulin in turn stimulates the uptake of glucose from the blood into cells, and the process of glycogenesis In patients with T1DM, insulin production is insufficient, meaning glucose cannot move into cells following a meal, and instead remains in the blood, resulting in persistent hyperglycaemia. Type 1 Diabetes Mellitus Presentation Typically a triad of symptoms: • Polyuria • Polydipsia • Weight loss – generally secondary to dehydration Generally presents in younger patients (<30) as opposed to the slightly older population presenting for the first time with T2DM Some patients present for the first time with diabetic ketoacidosis (DKA) Type 1 Diabetes Mellitus Diabetic ketoacidosis (DKA) One of the main complications seen in T1DM, particularly in stress, illness, and non-compliance with insulin regime Pathophysiology: • In states of insulin deficiency, the body lacks the ability to take up glucose into its cells and even recognise the presence of glucose in the blood • As a result, the liver breaks down fats and produces ketones as a fuel source • Although this is initially buffered by the kidneys’ production of bicarbonate, overtime this is used up, resulting in ketoacidosis • Osmotic diuresis also occurs, resulting in dehydration and thirst Presentation: • Polyuria • Abdominal pain • Polydipsia • Acetone/pear drop-smelling breath • Nausea and vomiting • Weight loss Type 1 Diabetes Mellitus Diagnosing DKA Requires all three of the following: 1. Hyperglycaemia (blood glucose >11mmol/L) or known diabetes 2. Ketosis (blood ketones >3mmol/L) 3. Acidosis (pH <7.3) Patients often also present with potassium disturbances – serum potassium often high on admission Management: 1. Fluid resuscitation – protocol usually 1L in 1h, followed by 1L in 2h… 2. Fixed rate insulin infusion – 0.1 units/kg/hour Actrapid 3. Strict CBG monitoring, with IV glucose commencing when CBG<14mmol/L 4. Potassium replacement – within IV fluids Close ketone and fluid balance monitoring is important FRIII can be stopped once pH>7.3 and ketones <0.6mmol/L, and patient is eating and drinking normally Type 1 Diabetes Mellitus Investigations Bedside • BM monitoring - >11.1mmol/L if random, >7mmol/L if fasting • ECG – especially if first presentation or DKA • Urine dip Bloods • Random and fasting glucose levels • HbA1c • VBG Special tests • If doubt regarding diabetes type: C-peptide, anti-GAD, anti-ICA, anti-insulin antibodies Type 1 Diabetes Mellitus Management Mainstay: life-long insulin replacement • Basal-bolus regimes • Twice daily mixed regimes • Lifestyle changes • Education surrounding diet and carbohydrate counting • Monitoring lifelong for complications Complications Hypoglycaemia - usually due to overtreatment, undereating or illness Long-term macrovascular: CHD, peripheral ischaemia and ulcers, stroke, hypertension Long-term microvascular: peripheral neuropathy, retinopathy, nephropathy Type 2 Diabetes Mellitus •Tiredness •Polyuria and polydipsia (frequent An HbA1c of 42 – 47 mmol/mol indicates pre-diabetes. urination and excessive thirst) •Unintentional weight loss NICE guidelines: •Opportunistic infections (e.g., oral thrush) 48 mmol/mol for new type 2 diabetics •Slow wound healing 53 mmol/mol for patients requiring more than one •Glucose in urine (on a dipstick) antidiabetic medication Acanthosis nigricansType 2 Diabetes MellitusType 2 Diabetes MellitusHyperosmolar hyperglycemic state High yield T2DM facts to commit to memory: ACE inhibitors= first line for hypertension in patients of any age with type 2 diabetes. ACE inhibitors for chronic kidney disease when the albumin-to-creatinine ratio (ACR) is above 3 mg/mmol (as opposed to 30 mg/mmol in patients without diabetes). SGLT-2 inhibitors are started in type 2 diabetics with chronic kidney disease when the albumin-to- creatinine ratio (ACR) is above 30 mg/mmol (in addition to the ACE inhibitor). Parathyroid disorders: Hyperparathyroidism = Raised levels of parathyroid hormone Primary hyperparathyroidism: benign or malignant tumor of the parathyroid gland(s) results in increased secretion of PTH Secondary hyperparathyroidism: increased secretion of PTH as a result of hypocalcaemia secondary to low vitamin D or chronic kidney disease Tertiary hyperparathyroidism: continuation of secondary hyperparathyroidism for a prolonged period of time, resulting in parathyroid hyperplasia. PTH levels remain high even when cause of secondary hyperparathyroidism is treated. Parathyroid disorders: Hyperparathyroidism Presentation Symptoms of hypercalcaemia as PTH increases serum calcium in three ways: 1. Increased bone osteoclast activity 2. Increased calcium reabsorption in the kidneys 3. Increased vitamin D activity and therefore increased Ca absorption in the intestines “Bones, stones, groans, thrones, psychic moans” • Bone pain • Recurrent kidney stones • Abdominal pain • Nausea/vomiting • Constipation • Polyuria • Confusion • Depression Parathyroid disorders: Hyperparathyroidism Investigations • ECG: hypercalcaemia changes – QT shortening, ST segment abnormalities • Bloods: • Parathyroid USS and biopsy if mass found on examination Management • Primary hyperparathyroidism: parathyroidectomy • Secondary hyperparathyroidism: treat underlying cause – i.e., replace vitamin D or renal replacement therapy • Tertiary hyperparathyroidism: parathyroidectomy Parathyroid disorders: Hypoparathyroidism Aetiology • Iatrogenic o Removal of parathyroid gland(s) o Damage to parathyroid glands during thyroid surgery o Radiotherapy • Autoimmune disorders • Hereditary disorders o DiGeorge syndrome o Autosomal dominant hypoparathyroidism o Hereditary pseudohypoparathyroidism – kidney resistance to PTH Presentation - hypocalcaemia • ECG changes – QT prolongation, torsades de pointes, atrial fibrillation • Muscle cramping • Peri-oral numbness/paraesthesia • Seizures • Carpopedal spasms • Trousseau and Chvostek’s signs Parathyroid disorders: Hypoparathyroidism Management Treatment of underlying cause Calcium replacement • Acute: IV calcium gluconate • Chronic: oral calcium supplementation Vitamin D supplementation Synthetic PTHHyperthyroidism The causes of hyperthyroidism can be remembered with the “GIST” mnemonic: •G – Graves’ disease •I – Inflammation (thyroiditis) •S – Solitary toxic thyroid nodule •T – Toxic multinodular goitre Hyperthyroidism •General Symptoms: •Neurological: • Weight loss despite increased appetite due • Nervousness and irritability. to increased metabolic rate. • Hyperreflexia (increased reflexes). • Heat intolerance (feeling hot despite normal • Anxiety and insomnia. temperature). • Tremors (fine tremor in hands, especially at •Gastrointestinal: rest). • Diarrhoea or increased bowel movements. • Fatigue or muscle weakness. •Other Clinical Features: •Cardiovascular: • Goitre (enlarged thyroid gland, often palpable and • Tachycardia (heart rate > 100 bpm). sometimes visible). • Palpitations. • Exophthalmos (protruding eyes, especially in Graves' • Atrial fibrillation (common in older adults). disease). • Pretibial myxedema (swelling of the lower legs in Graves' disease).Hyperthyroidism Hyperthyroidism •Primary Diagnosis of hyperthyroidism is confirmed with: •Low TSH and high T3/T4 levels on thyroid function tests. •Differentiating Causes: •Graves’ Disease: Clinical features (e.g., goitre, exophthalmos, pretibial myxedema) + elevated TSH receptor antibodies + increased radioactive iodine uptake. •Toxic Multinodular Goitre: No exophthalmos or skin changes, often seen in older patients with multinodular goitre, typically with increased iodine uptake but not as diffuse as Graves’. •Thyroiditis (e.g., Subacute De Quervain’s thyroiditis): Low iodine uptake, transient elevation in thyroid hormones, often following a viral infection. Hyperthyroidism •Medical Treatment: •Antithyroid Drugs: •Carbimazole (first-line) or Propylthiouracil (PTU): Inhibit thyroid hormone synthesis. •Side effects: Rash, agranulocytosis (low white blood cell count), and liver dysfunction (with PTU). •Beta-Blockers (e.g., Propranolol): •tachycardia, palpitations, and tremors. •Helpful in acute symptomatic management, especially before definitive treatment. •Iodine Therapy (Radioactive Iodine): •Radioactive iodine (RAI) is used to treat most cases of Graves’ disease and toxic multinodular goitre by ablating thyroid tissue. •Contraindicated in pregnancy and breastfeeding. •Requires close monitoring for hypothyroidism after treatment. •Surgical Treatment (Thyroidectomy) Hypothyroidism •General Symptoms: •Neurological: •Fatigue and lethargy. •Depression, memory problems, and •Weight gain despite normal or impaired concentration. reduced appetite. •Reflexes may be slowed (hyporeflexia). •Cold intolerance (feeling cold despite •Gastrointestinal: normal environmental temperatures). •Skin and Hair Changes: •Constipation and abdominal distension due to slowed gut motility. •Dry skin and coarse hair. •Reproductive: •Brittle hair and nails. •Menstrual irregularities, including heavy •Puffy face (myxedema). periods or oligomenorrhea (infrequent •Cardiovascular: periods). •Bradycardia (heart rate < 60 bpm). •Hyperlipidemia (elevated cholesterol and triglycerides). Hypothyroidism •Serum Thyroid Function Tests: • Elevated TSH (Thyroid Stimulating Hormone) – hallmark of hypothyroidism due to the pituitary gland trying to stimulate the thyroid. • Low Free T4 (Thyroxine) – low levels of thyroid hormone in the blood. • Low Free T3 (Triiodothyronine) may also be seen in more severe cases. •Thyroid Antibody Tests: • Anti-thyroid peroxidase (TPO) antibodies and Anti-thyroglobulin antibodies: Elevated in Hashimoto’s thyroiditis, an autoimmune cause of hypothyroidism. Hypothyroidism Management Levothyroxine (L-T4) Therapy: •First-line treatment for hypothyroidism. •Start with low doses in elderly or those with cardiac disease to avoid overstimulation of the heart. •Titration to normal TSH levels: Regular monitoring of TSH to adjust the dose (target is usually a TSH within the normal range). Emphasize the importance of daily medication at the same time, ideally on an empty stomach, to maximize absorption. Severe (Myxoedema Coma) TSH Result Levothyroxine Action •Altered mental state, hypothermia, and Dose hypoventilation. •Bradycardia, hypotension, and High Too low Increase the dose hypoglycaemia Low Too high Reduce the dose Mx: IV Levothyroxine Pituitary Tumours Types • Non-functioning tumour – usually leads to hormone hyposecretion • Functioning tumours: o Prolactinoma o ACTHoma o TSHoma o GH-secreting tumour o Can also be classified into microadenoma (<1cm) and macroadenoma (>1cm) Causes • Usually idiopathic/random • Genetic mutations – e.g., MEN1 Pituitary Tumours Presentation • Endocrine symptoms o Prolactinoma – galactorrhoea, hypogonadism (low libido, oligomenorrhoea in women, erectile dysfunction in men) o TSHoma – weight loss, heat intolerance, diarrhoea, anxiety, tachycardia o Somatotropic tumours – coarse facial features, acral enlargement o Corticotropic tumours - Cushingoid features • Visual disturbance – bitemporal hemianopia • Headaches Investigations • Bedside – visual fields testing • Bloods – endocrine profile (LH, FSH, prolactin, ACTH, IGF-1, thyroid profile) • Imaging – MRI pituitary with gadolinium contrast Pituitary Tumours Complications • Pituitary apoplexy – haemorrhage into pituitary as a result of rapid enlargement of tumour • Hormone-related disease development – e.g., thyrotoxicosis, Cushing’s • Panhypopituitarism Management Transsphenoidal tumour resection – first-line in all except prolactinomas Medical management: • First line in prolactinomas – dopamine agonists e.g. bromocriptine, somatostatin analogues • Hormone replacement in hypopituitarism – thyroxine, hydrocortisone etc. Radiotherapy • Trialled if surgery is not appropriate and medical treatment proves unsuccessful Resources • Zero to finals • Osmosis • Passmedicine textbook • Teach me Surgery • GMC UK – MLA content map Q&A Feedback form: (To get certificates for your portfolios!) 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