Endocrine Biochemistry

Dynamic investigations Excessive target organ hormone production SUPPRESSIVE TEST Diminished target organ hormone production STIMULATORY TEST

Thyroid Biochemistry
Front-line test usually TSH Should detect primary hypothyroidism May miss secondary hypothyroidism Hypothyroidism Clinical features Tiredness Weight gain Dry, puffy skin Hair loss, outer half of eyebrows Hoarse voice Causes of hormone deficiency PRIMARY Target organ (thyroid) destruction necrosis, ischaemia, inflammation etc SECONDARY Pituitary failure (lack of TSH) local destruction, tumour, inflammatory disease Hypothalamic disease (lack of TRH very rare) Investigations Primary Hypothyroidism Hypothalamus - High TRH Pituitary - High TSH Thyroid - Low T4 and T3 Secondary Hypotthyroidism Hypothalamus - High TRH Pituitary - Low TSH Thyroid - Low T4 and T3 TSH FT4 (0.35-5.1) IU/L (10.5-22) pmol/L Euthyroid Primary hypothyroidism 1.7 52.3 15.6 6.5 Ft3 (3.5-6.5) Pmol/L 4.5 2.5

Secondary hypothyroidism

4.3

8.3

2.3

Hyperthyroidism
Clinical Presentation Symptoms Weight loss, agitation, irritability, heat intolerance, sweating, itching, dyspnoea, palpatations Signs Tachycardia (AF), tremor, goitre, myopathy, lid lag

Graves Disease
Epidemiology Incidence estimated 0.4 % F:M = 10:1 Clinical features Goitre Diffuse thyroid enlargement Typically large, soft, non-tender goitre May extend into superior mediastinum Tracheal or major vessel obstruction possible Ophthalmopathy - autoimmune thyroid eye disease Lid retraction and lid lag found in any cause of hyperthyroidism Eye changes probably due to autoantibodies and associated with increased production of glycosaminoglycans and intraorbital fibroblasts Severity of eye signs can be independent of thyroid status Eye signs Proptosis - forward protrusion Lid retraction - sclera visible above/below iris Chemosis - oedema and injection of conjuntiva Periorbital oedema - oedema and herniation of orbital fat Positive autoantibody titre (thyroid peroxisomal Abs 70-80%, TSH-receptor Abs 70-100%) Less commonly skin involvement Pretibial myxoedema/localised dermopathy - indurated purple skin lesions, typically over the anterior tibia Large amount of glycosaminoglycans present in connective tissue Tends to be associated with high thyroid antibody titres Thyroid acropachy - similar to clubbing Aetiology stimulatory antibodies to TSH receptors Associations Addisons disease

Pernicious anaemia (B12 deficiency) Type 1 diabetes Vitiligo (skin depigmentation) Primary ovarian failure Coeliac disease

Laboratory Results TSH suppressed Thyroid hormones elevated Normochromic normocytic anaemia (longstanding) ESR increase (inflammation) Mild hypercalcaemia Abnormal liver enzymes Other Causes of Hyperthyroidism Toxic solitary adenoma/nodule Toxic multinodular goitre de Quervains thyroiditis subacute, viral, tender thyroid Hashimotos autoimmune thyroiditis painless goitre, lymphocytic infiltration, maybe normal, hypo or hyperthyroid Postpartum thyroiditis within 6/12 of delivery, chronic lymphocytic, transient hyper- or hypothyroidism

Case 1
22-year old female medical student Short history of itching and weight loss, some difficulty in rowing Medical student boyfriend diagnosed Hodgkins lymphoma One week later the boyfriend discovered her sleeping heart rate was 122 bpm

History Palpitations, diarrhoea, irritability, heat intolerance Examination Small symmetrical goitre Bilateral lid retraction Slight tremor DIAGNOSIS - Hyperthyroidism

Acromegaly
adult GH excess Clinical features Prognathism (prominent lower jaw), dental separation Sweaty, greasy thickened skin Enlarged hands, feet and neck

 Macroglossia, visceromegaly Arthropathy Increased risk of cardiovascular disease and colonic polyps Epidemiology Prevalence 40-60 cases/million population Annual UK incidence 4/million population M=F Most diagnosed 40-60 years Pituitary adenoma in > 99% cases < 1% GHRH secretion or ectopic GH secretion combin

Addisons disease
Destruction of the entire adrenal cortex No glucocorticoids No mineralocorticoids No adrenal androgens Female preponderance Autoimmune in 90% - similar associations to Graves disease (vitiligo, pernicious anaemia etc) Causes of Hypoadrenalism Common Exogenous steroid treatment 1o Autoimmune destruction Tuberculosis 2o pan-hypopituitarism HIV/AIDS Less common Adrenalectomy Metastatic deposits (breast, bronchus, Hodgkins, lymphoma) Amyloidosis, sarcoidosis Haemochromatosis

 Adrenal haemorrhage/infarction Adrenoleucodystrophy Clinical features Common Tiredness, weakness Anorexia, nausea, vomiting Weight loss Dizziness, postural hypotension Pigmentation Loss of body hair in women Uncommon Depression Hypoglycaemia Biochemical Features Hyponatraemia Na Feature of aldosterone deficiency hypovolaemia Elevated ADH - secondary to hypovolaemia Hyperkalaemia Elevated urea - dehydration and reduced cardiac output Mild hypercalcaemia elevated calcium binding proteins Investigations and Interpretation Random/9am cortisol NOT definitive Short synACTHen test - stimulation test for hormone deficiency Failure to respond to synthetic ACTH

Stimulatory test for deficiency: Synthetic ACTH Assess response at 0, 30, 60 mins Short Synacthen Test (SST) Primary adrenal cortical failure (Addisons disease) No/low cortisol output Elevated ACTH No response to synACTHen

Secondary adrenal failure (pituitary/hypothalamic failure) No/low cortisol No/low ACTH Response to synACTHen - increased cortisol Further investigations Primary adrenal failure Confirm with extended high dose synacthen stimulus (1 mg, monitor for 24 hours) Secondary failure (ACTH deficiency or exogenous steroid treatment) Other pituitary hormone deficiencies Visual field changes, headaches Treatment Glucocorticoid replacement e.g. hydrocortisone Assessed on clinical well-being and hydrocortisone day curve, urinary free cortisol Mineralocorticoid replacement e.g. fludrocortisone Assessed on plasma renin, BP, plasma potassium

Case 2
32-year old member of the department of Egyptology, recently returned from a dig Presented complaining of lethargy and generalised weakness since return stone weight loss Dizziness on standing Anorexia and early morning nausea O/E BP 90/60 standing Tanned appearance Palmar crease pigmentation, also in buccal mucosa and an old appendicectomy scar DIAGNOSIS Addisons disease

Cushings syndrome and disease

Cushings syndrome Glucocorticoid/cortisol excess Cushings disease Glucocorticoid/cortisol excess due to elevated ACTH production from anterior pituitary gland

Cushings syndrome
Clinical features Tissue wasting, myopathy, thin skin, purple abdominal striae, easy bruising Osteoporosis Water retention, hypertension 6

 Plethoric moon-face Susceptibility to infection, poor wound healing Hirsutism Causes of Cushings syndrome EXCLUDE Exogenous corticosteroid treatment Pseudo Cushings syndrome - depression, alcohol excess, obesity - < 2% Cushings disease 68% (pituitary) Female preponderance (3-8:1), peak age 30-50yrs Ectopic ACTH production 12% Classically small cell bronchial carcinoma Adrenal gland Adenoma 10%, carcinoma 8%, hyperplasia 1% Diagnosis Confirm glucocorticoid excess Outpatient screening 24 hour urinary free cortisol excretion (5-10% false negative rate) 1mg overnight dexamethasone suppression test (2% false negatives, up to 20% false positives in inpatients) Suppressed cortisol reflects normal biofeedback axis False positives/pseudo-Cushings - depression, obesity, alcoholism Cause Loss of diurnal rhythm Midnight and 9am cortisol Diurnal cortisol variation lost in Cushings syndrome (usually peak 89am and nadir 12 midnight) Measure ACTH Suppression supports adrenal source Investigations Low dose dexamethasone suppression test Low dose 0.5mg qds with baseline and 48 hour cortisol Complete suppression at 48 hrs is normal result False positives (i.e. lack of suppression) possible in alcoholism or depression High dose dexamethasone suppression test High dose DST 2mg qds for 48 hours Cortisol falls by > 50% (90% of patients) in Cushings disease Minimal suppression in 90% of ectopic production cases Special Investigations Corticotrophin releasing hormone (CRH) stimulation Exaggerated rise in cortisol and ACTH in 95% of pituitary dependent Cushings syndrome (Cushings disease) Cortisol elevation by > 20% ACTH elevation by > 50% 7

 Inferior petrosal sinus sampling (IPSS) ACTH sampling from each side of the pituitary with CRH stimulation Aids differentiation between pituitary and ectopic disease Diagnostic Clues Other causes Cushings syndrome Loss of cortisol Circadian rhythm, increased urinary cortisol, no suppression on 1mg Overnight Dexamethasone Suppression Test Adrenal tumour Undetectable ACTH (biofeedback) - adrenal CT scan ACTH-dependent Cushings syndrome Unprovoked hypokalaemia suggests ectopic cause Very high ACTH favours ectopic source Cushings disease Exaggerated CRH stimulation test Treatment Cushings Disease Transphenoidal adenohypophysectomy (TSA) Bilateral adrenalectomy if not cured by above Ectopic source Locate and remove Adrenal hyperplasia Location and removal of adenoma/adrenal gland Adrenal carcinoma may only be amenable to hormone blocking therapy

Case 3
36-year old woman who had put on weight over the past year Saliva cortisol tests done by a lab in America with high levels interpreted as stress O/E Thin skin - plethoric face, moon-shaped Buffalo hump of fat over T1 vertebra Abdominal obesity with muscle wasting on her limbs Proximal limb muscle weakness DIAGNOSIS Cushings syndrome

Nelsons Syndrome
Development of aggressive ACTH secreting pituitary tumour in patients treated with bilateral adrenalectomy for Cushings disease (after failed pituitary surgery) Aetiology - removal of negative feedback Clinical features Headaches, visual field defects, ophthalmoplegia Hyperpigmentation +++

Prevented by pituitary TSA surgery for Cushings disease (assuming all tumour is removed)

Pituitary Tumours

Prolactinoma 10 cases/million Commonest functioning pituitary tumour Micro and macro Non-functioning adenoma (NFA) - 6 cases/million Stalk compression may result in hyperprolactinaemia GH (acromegaly) - 4 cases/million May have associated hyperprolactinaemia due to common progenitor cell ACTH (Cushings disease) - 2 cases/million Local complications Upwards Headaches, optic chiasm disturbance (bitemporal hemianopia) Laterally - cavernous sinuses Cranial nerve palsies (IIIrd, IVth, VIth) Downwards Sphenoid sinus, CSF leak, meningitis Hydrocephalus

Prolactinoma
Prolactin Under INHIBITORY pituitary control Inhibited by dopamine (or dopamine agonists) Increased by Prolactinoma (primary pituitary adenoma) Pituitary stalk compression (large tumour) Drugs - dopamine ANTAGONISTS Stress Symptoms Galactorrhoea Amenorrhoea Impotence 9

Macroprolactin IgG associated prolactin No biological activity Increased measurement on assay Polyethylene glycol precipitation removes IgG complexed prolactin, then re-analysis will give correct concentration of biologically active component

Case 4

28-year old woman presented to her GP after 12 months amenorrhoea to ask about fertility treatment On questioning Weight steady (BMI 23) No hirsutism Regular menstruation between ages of 13 and 27 Bilateral galactorrhoea on gentle manipulation for 12-18 months Investigations Visual fields Serum prolactin Anterior pituitary hormone profile IGF-1 FSH, LH TSH, fT4, fT3 Cortisol +/- SST

Hormone deficiency
GH reduced energy/exercise tolerance, weight gain FSH/LH impotence, reduced libido, infertility TSH fatigue, weight gain, cold intolerance

KEY CONCEPTS AND FACTS

Endocrine systems rely on biofeedback for regulation The higher endocrine control centres are the pituitary and hypothalamus Destruction/overactivity of an endocrine organ produces primary deficiency/excess; interruption/ overactivity of higher centres produces secondary deficiency/excess Endocrine investigations often require dynamic testing of response to specific stimulus Testing for deficiency assess response to stimulation 10

 Hormonal overactivity is diagnoses by lack of suppression to normal negative feedback loop. Addisons disease Usually autoimmune Potentially fatal if not rapidly recognised Diagnosis short synacthen test Treatment glucocorticoid and mineralocorticoid replacement Cushings syndrome Syndrome is excess glucocorticoid/corisol - adrenal or ectopic Disease is pituitary cause excess ACTH Diagnosis can be difficult Outpatient screening 24 h urine free cortisol 1 mg overnight dexamethasone suppression test Hyperprolactinaemia Macroprolactin Dysconnection inhibitory control Micro vs macroadenoma

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