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Endocrine Pathology Pituitary, thyroid, adrenals, pancreas and metabolic disorders Jared Bhaskar Academic Foundation Doctor Guy’s and St Thomas’ Hospitals NHS Foundation Trust Slides adapted from Dr Vlad MakeevThe purpose of this talk 1. Give you an overview of the important topics regarding to some (not all) of chemical pathology 2. Revise some basic physiology relevant to the above 3. Emphasise the concept of a structured approach to examination answers 4. Hopefully make you feel more comfortable with pathology in general This talk will not: ● Provide intense details on all pathology pertaining to a particular topic ● Provide you with every bit of information you need to get a distinction ● Cover the minutiaeOutline 2 sections with questions at the end of each section Section 1 • Thyroid • Pituitary Section 2 • Adrenals • Pancreas • PorphyriasLearning objectives • Anterior pituitary hormones: recall the six anterior pituitary hormones and explain the hypothalamic factors responsible for their control • Plasma protein function: summarise the functions of commonly measured plasma proteins and explain factors that contribute to their concentration • Cori cycle: explain the Cori cycle • Insulin: explain the synthesis, storage, secretion and physiological actions of insulin incl. the role of c-peptide, and homeostatic mechanisms of control • Glucose homeostasis: explain the factors regulating blood glucose incl. counter-regulatory mechanisms • Porphyrine metabolism: summarise the principles of porphyrine metabolism • Adrenal physiology: summarise adrenal function, histology, microanatomy and zonation • Cholesterol and lipoprotein metabolism: summarise cholesterol and lipoprotein metabolism and explain the link between lipid disturbance and cardiovascular disease • Renal physiology: define glomerular filtration rate (GFR) and compare different methods of GFR assessment • Renal physiology: explain why serum creatinine alone is a poor marker of absolute kidney function, and why a normal serum creatinine does not mean that renal function is normal • Thyroid physiology: summarise thyroid physiology • Energy metabolism: summarise energy metabolism incl. protein, lipid and carbohydrate metabolism • Purine metabolism: summarise the basics of purine metabolism • Enzymes: summarise the roles of enzymes in body metabolism and recognise the effect of organ-specific/biochemical disease on plasma levels of enzymes and subsequent outcomes • Therapeutic drug monitoring: interpret the factors affecting serum levels for a given dose (pharmacokinetics) and those factors affecting response to a drug at its active site (pharmacodynamics) • Therapeutic drug monitoring: explain the concept of a therapeutic range and demonstrate awareness of its limitations • Therapeutic drug monitoring: list examples of drugs which require measurement of levels, for therapeutic and toxic reasons e.g. anticonvulsants, lithium, digoxin and theophylline • Metabolic disorders and screening: recognise how prevalence, predictive values, sensitivity and specificity relate to disease and diagnostic tests of disease • Metabolic disorders and Screening: demonstrate awareness of current UK screening for inherited metabolic disorders and future prospects incl. Phenylketonuria (PKU)The concept of negative feedback Hypothalamus External Factors Pituitary End organThyroidThyroid – Anatomy and Physiology Free thyroxine: ● Intranuclear receptor: ● Regulating basal metabolic rate ● Potentiating responses to catecholaminesClinical Features Aetiology Hyper: Hypo: • Autoimmune - Graves’ • Congenital/cretinism • De Quervain’s (subacute) • Primary atrophic • Hashimoto’s thyroiditis thyroiditis • Iodine deficiency • Neoplasm - Thyroid • Surgery/radioactive adenoma/ectopic ablation • Drug induced - Amiodarone • Hypopituitarism • Toxic multinodular goitre • Drugs: amiodarone, • Postpartum lithium, carbimazole • Wolff Chaikoff effect • Iodine/Jon Basedow reaction Investigations • Bedside • ECG, examination • Bloods • FBC, U+Es, TFTs, antibodies, lipid profile, BM. LFTs • Basic imaging • USS • Thyroid uptake/isotope scan • CT/MRIA quick guide to TFT interpretation Thyroid state TSH Free T4 T3 Hyperthyroid Hypothyroid Sick euthyroid Subacute thyroid Subclinical hypothyroid Subclinical hyperthyroid Management Hyper: Hypo: • Propranolol – Sx control ● Oral levothyroxine • Thioamides – inhibit TPO ○ Titrate to normal TSH with 6 • Titration according to weekly check ups until stable TFTs ○ Ensure no signs of over- • Blocking-replacement replacement - palpitations ○ Higher doses may be needed regimen • Radioiodine in pregnancy, nephrotic • Surgical resection syndrome ● I.V Liothyronine ○ Only for Myxoedema coma Additional thyroid states Sick euthyroid Subclinical hypothyroidism • Severe illness • Pre-hypothyroid – Body tries to shut down metabolism – Pituitary gland can compensate – To conserve energy • High TSH, normal T3/4 • Low T3 and T4 • If positive anti TPO Ig then higher risk of • Initially high TSH, then low TSH hypothyroidism later Have similar TFTs Only way to differentiate is based on clinical picture Thyroid tumours • 70% Papillary – Psammoma bodies, Orphan Annie nuclei, lymphatic invasion • Papillary & Follicular – Best prognosis • 20% Follicular – Surgery +/- radio-iodine – Replace thyroxine to completely – Encapsulated, vascular invasion suppress TSH – Good prognosis • 5% Medullary – Monitor thyroglobulin/calcitonin – C-cells that produce calcitonin – Linked to MEN2 • Lymphoma – Risk in Hashimoto’s – DLBCL, CD20 • Anaplastic – Elderly, undifferentiated – Rapid growth, giant and spindle shaped cells Psammoma body 1 – Poor prognosis 516/03/2023 Question 1 A 50 year old woman presents with diarrhoea, sweating, fever and palpitations for the last week. She has also had recent coryzal symptoms. There is diffuse neck tenderness with no obvious swelling. Bloods show low TSH and high thyroxine. She does not have good uptake on technetium scan. What is the most likely diagnosis? • Sick Euthyroid • Subacute (De Quervain’s) Thyroiditis • Multinodular goitre • Toxic adenoma • Viral gastroenteritis17/03/2023 Question 2 Which blood marker is used to monitor for recurrence of medullar thyroid carcinoma post resection? • Thyroid Peroxidase enzyme • Thyroglobulin • TSH receptor antibodies • Serum calcium • Calcitonin08/03/2023 Question 3 You are called to see a 45 year old female patient who is 12 hours post-operative hemi- mandibulectomy. On examination she is noted to be in fast atrial fibrillation, tachypneoic, hypertensive and confused. She is warm peripherally and diffusely sweating. You note myxoedematous changes in her shins. What is the appropriate management plan? • IV fluids and beta-blocker • Beta blocker and steroid • Beta-blocker, thioamide • Thioamide, steroid and IV fluids • Beta-blocker, steroid and thioamide09/03/2023 Pituitary gland Anatomy & PhysiologyThe (anterior) Pituitary Laycock and Meeran 2012Pituitary mass Pituitary adenoma Symptoms: ● Macroadenoma >1cm ● Bitemporal hemianopia ○ Usually non-functional ● Superior quadrantanopia ■ Occasionally can be associ●teHeadache with hyperprolactinaemia ● Microadenoma ● Hormone related – mainly ○ <1cm prolactin ○ More likely to be functional ○ Sx related to hormone secretionAcromegaly/Gigantinism Clinical features Investigation: • Somatotrophin related • Glucose tolerance test • Acromegaly - Soft tissue • Measurement of GH growth (Hands, feet, tongue) • Plasma IGF-1 (first line) • MRI pituitary • Organomegaly • Symptoms of heart failure hypertension Management: • Diabetes • Trans-sphenoidal surgical • Carpal tunnel resection • Somatostatin analogue • Modify CV risk factors • Monitor serum GH • Colonoscopy surveillanceProlactinoma Clinical features: Investigations: • Galactorrhoea • Serum prolactin levels (>6000) • MRI Pituitary • Gynaecomastia • Oligo/amenorrhoea • Loss of libido Management: • Dopamine agonist • Impotence • Trans-sphenoidal resection • Serum PRL for monitoringHypopituitarism Aetiology: Symptoms/signs: ● Malignancy ● Generic ○ Pituitary adenoma* ○ Lethargy ○ Craniopharyngioma ○ Weight gain ● Infection ○ Hypotension ○ TB ○ Hair loss ○ Syphilis ○ Myalgia ● Infiltration ● Sex hormones ○ Sarcoid ○ Impotence (men) ○ Lymphoma ○ Loss of libido ● Iatrogenic ○ Oligo/amenorrhoea ○ Surgical / Traumatic / ● ACTH radiation ○ Addisonian crisis ● Infarct ● TSH ○ Sheehan’s or Apoplexy ○ Myxoedema coma ● Tertiary o Kallman’s syndrome Hypopituitarism Investigation Management ● Screening ● Replacement of end hormones ○ 9am cortisol / urinary - much cheaper and easier to cortisol control ○ TFTs ○ Hydrocortisone ○ Serum ○ No need for fludrocortisone testosterone/oestrogen ○ Thyroxine ○ Oestrogen / Testosterone ● Combined pituitary function test ● Cause specific ○ Administer LHRH + TRH + Induce hypoglycaemia ○ Adenoma ○ Measure LH, FSH, TSH, ■ Next section ○ Infiltration ACTH and growth hormone ■ Steroids for 2 hours at half hourly ○ Infection increments ■ Antibiotics as needed ● Imaging ○ CT/MRI26 CPFT : combined pituitary function test • Give a patient GnRH, TRH and insulin • Measure levels of pituitary hormones every 30 mins for 2h • Check to see if an adequate response • FSH/LH only applicable after puberty – GH – Cortisol • Poor response can indicate – TSH hypopituitarism – LH – FSH – Prolactin • NB: Acromegaly needs an oral glucose tolerance test to diagnose • Measurement of IGF-1 is sensitive • Various normal ranges but not specific27/03/2023 Question 4 A 30 year old lady presents with a headache and notable changes to her vision. Blood tests below reveal the following. She has no other symptoms. What is the most likely diagnosis? • Hypopituitarism • Non-functioning macroadenoma • Prolactinoma • Optic neuritis • Migraine28/03/2023 Question 5 A patient is diagnosed with a non-functioning macroadenoma of the pituitary gland. What is the most likely visual defect given the location of the pathology? • Homonymous hemianopia • Bitemporal superior quandrantanopia • Bitemporal inferior quandrantanopia • Complete visual field loss • Central visual field defect09/03/2023 Halfway questions and break00/03/2023 Adrenal gland anatomyAdrenal gland physiology The adrenal gland is divided into zones which provide different steroid hormones: ● Glomerulosa - Mineralocorticoids (Aldosterone) ● Fasciculata - Glucocorticoids (Cortisol) ● Reticularis - Sex hormones ● Medulla – CatecholaminesSteroid synthesis pathway Adrenal Insufficiency Aetiology: Clinical Features: ● Primary ○ Iatrogenic • Postural symptoms ○ Autoimmune – Addison’s • Weight loss, anorexia ○ TB • Abdominal pain, N&V ○ Waterhouse Friderichson • Fatigue syndrome • Vomiting, salt craving ○ Infarct • Skin/Mucosal pigmentation ○ Malignancy • Decreased arm and pubic hair ○ AIPE syndromes 1&2 ● Secondary • Addisonian Crisis o Hypopituitarism34 Adrenal Insufficiency Investigations: Management ● 9am Cortisol (>350 excludes ● Hydrocortisone ○ Sick day rules Addisons) ● Electrolytes (Hyponatraemia, ● Fludrocortisone Hyperkalaemia). Serum ACTH ● Check glucose ● CT abdomen ● Synacthen test ○ Synthetic ACTH administered IV/IM ○ Cortisol readings at 0, 30, 60 ■ Only rises in secondary disease Hyperaldosteronism Aetiology Symptoms/Signs ● Primary • Treatment resistant ● Bilateral idiopathic hypertension hyperplasia • Hypokalaemia ● Adrenal adenoma • Hypernatraemia ● Familial GRA • Polyuria ● Secondary: ● RAS • Polydipsia ● FMD ● CCF Hyperaldosteronism Investigations Management • Bloods - electrolytes, plasma • Aldosterone antagonists • Surgical resection aldosterone:renin ratio (raised) • CT Abdomen • Adrenal vein sampling Cushing’s syndrome Aetiology ● Primary ○ Adrenal secreting tumour ● Secondary ○ Pituitary adenoma ○ Ectopic/Paraneoplastic ACTH (SCC Lung Ca) ● Iatrogenic ● Exogenous steroids ● McCune-Albright syndrome Cushing’s Syndrome Investigations Management: • 24hr urinary cortisol/9am – • Exogenous steroids: gradual confirms raised cortisol tapering • Low dose dexamethasone- • Cushing’s disease: Trans- confirms true Cushing’s sphenoidal resection • Adrenal tumour: Monitoring, syndrome resection, radiotherapy • High dose dexamethasone- • Ectopic tumour: radiotherapy, Helps to determine Cushing’s disease resection, Ketoconazole / Metyrapone / Mifepristone • Steroid replacement Imaging/localisation tests: • CT CAP / Adrenals • Nelson Syndrome • MRI pituitary Phaeochromocytoma Associated with: Investigations ● MEN-2(A/B) • BP, ECG ● NF-1 • Urinary metanephrines ● VHL • False positives - TCAs, CCBs, Beta-blockers Clinical features: • Electrolytes, LFTs, ● 10% rule catecholamines ● Malignant, extra-adrenal, • CT abdomen, MIBG scan bilateral, normotensive ● Episodes of “impending Management doom”/Panic ● Alpha blockade ● Resistant hypertension ○ Phenoxybenzamine ● Triad: throbbing headache, ● Beta blockade palpitations, sweating ● Surgery ● Chemotherapy, labelled MIBG40 Conn’s and Phaeos Conn’s syndrome Phaeochromocytoma • Adrenal hyperplasia or tumour • Pulses of hypertension, arrhythmias, • Hypertension sweats • High sodium, low potassium • Measure 24h urine catecholamines – Formerly vanillylmandelic acid • Measure aldosterone:renin ratio (VMA) – High in Conn’s syndrome • Adrenal medulla tumour : adrenaline • Treat with spironolactone and possibly adrenalectomy • Peripheral neural tumour : noradrenaline 2 x P 1 x M 3 x P 1 x P 3 x M Wikipedia42/03/2023 Question 6 A 55 year old Caucasian male presents with low blood pressure, increased pigmentation of skin creases, low glucose, low sodium and high potassium. What is the best investigation to order to confirm the likely diagnosis? • Serum catecholamines • Serum renin:aldosterone • Short SynATCHen test • Oral glucose tolerance test • Renal ultrasound43 Question 7 A 25 year old male presents with refractory hypertension despite triple anti- hypertensive therapy. He is noted to be hypokalaemic on blood tests. What is the first line investigation for this patient? • Serum aldosterone only • Serum renin:aldosterone • Renal ultrasound • CT AP • Urinary VMA04/03/2023 Question 8 • A young male is 12 hours post-operative. He is noted to be drowsy and significantly hypotensive. You note he is tanned skin. A blood gas reveals hyponatraemia and hyperkalaemia. What is the most appropriate treatment? • IV fludrocortisone • IV dexamethasone • IV fluids • IV noradrenaline • IV Hydrocortisone05/03/2023 Pancreas – Anatomy & PhysiologyDiabetes Feature Type I Type II Habitus Lean Obese Plasma insulin Low Variable B cell function Absent Present B cell antibodies Present [ICA, IAA, GADA, Absent IA-2A] Family history Absent [usually] Present [usually] Ketosis prone Yes No Weight loss Yes No Prevalence 0.25% 4-7% HLA associations DR-3 or 4 None Ethnicities Europeans Asian, African Age Young / Adolescent (can Middle age (Can be and be old – LADA) is increasing in young) Onset Acute Gradual Diagnosis Pre-diabetes Diabetes Fasting blood 6.1-6.9 >7 glucose OGTT 7.8-11 >11.1 HbA1c 42-47 >48 (6.5%) Random BM 7.8 - 11 >11.1 Diagnosis = symptomatic + one of the above test being positive Be wary in using HbA1cManagement Type 1 Type 2 ● Conservative ● Conservative ○ Lifestyle advice (alcohol) ○ Diet + Lifestyle advice ○ Diabetes nurse review ○ Exercise ● Medical ○ Dietary advice ● Medical 1. Metformin ○ Insulin 2. Add one of: ■ Basal bolus a. Sulphonylurea ■ Insulin pump b. DPP-4 agonists ■ Biphasic OD/BD c. SGLT-2 inhibitors ○ Metformin if BMI >25 ● Surgical 3. Add GLP-1 antagonist or two of above ○ SPK (Single pancreas 4. Insulin kidney transplant) ● Surgical ○ Bariatric surgeryDKA ● Predominantly type I diabetics ● Signs / Symptoms ● A state of absolute insulin ○ Confusion deficiency regardless of ○ Abdominal pain whatever insulin is present in ○ Vomiting the body ○ Confusion / drowsiness ○ Body thinks it’s starving despite hyperglycaemia ○ Kussmaul breathing ○ Unregulated ketosis results ● Causes with subsequent acidosis ○ Infection ○ Results in polyuria, ○ Surgery ○ Alcohol dehdyration and circulatory ○ Missed insulin shock ○ TraumaDKA Investigations: Monitoring ● Ketones >3 ● pH <7.3 ● Catheter ● BM >15 ○ Accurate urine output needed ● Find the cause: ○ At least 0.5ml/kg/hr ○ FBC, blood Cultures, CXR, Urine● Hourly Ketones + BM culture/dip, ○ Ketones should drop by 0.5/h ● Find the damage ○ U/Es, A/VBG, ECG ● Hourly VBG Treatment: ○ K+ and bicarbonate 1. Fluids ○ Keep potassium >4 a. Deficit + Maintenance/24hr b. Rapid initial administration thenlution taper ● Ketones <3 c. Potassium (If K+ <5.5) 2. Intravenous Insulin (0.1u/kg) ● pH > 7.3 ● Stop FRII when back E+D and a. Continue normal s/c insulin! has had normal insulin 1h ago 3. 10% Dextrose a. When BM <15Hyperglycaemic hyperosmolar state (HHS) ● Predominantly type II diabetics Treatment: ● Insulin resistance causing 1. IV Fluids persistent hyperglycaemia a. Aim +3-6L/24h ○ Osmotic diuresis results b. NaCl +/- KCl ○ Takes days to fully develop 2. Monitoring ● Presents as: a. Electrolytes (Na, K) ○ Confusion i. Beware of rapidly over- correcting ○ Clinically very dehydrated hypernatraemia (Patients lose up 10-20% b. BMs + Ketones of body weight in water) ● Investigations: i. BMs should fall at around 5mM/h ○ Raised serum osmolality c. Neurological status (>320) 3. Insulin (0.05u/kg FRII) ○ Glucose >30 a. Only needed if Ketones rising ○ NO ketones / acidosis or if BMs no longer falling with just fluids Question 9 A 24-year-old female is brought into the emergency department with a 3-day history of abdominal pain, vomiting, polyuria and reduced eating and drinking. She has T1DM and usually takes both long and short acting insulin. She has pH 7.32, Ketones 5, BM 20. What is the most appropriate initial management? • IV fluids • IV lantus • IM novorapid • IV novorapid • Call Medical SpR Question 10 Which of the following anti-diabetic medications is most effective in a T2DM patient with a concurrent diagnosis of heart failure? • Metformin • Insulin • Sitagliptin • Pioglitazone • DapagliflozinPorphyriaThank you!