Endocrinology and General Medicine — Short Cases

3 Endocrinology and General— Short Cases Karen Siu-Ling Lam, James D. Best, Kathryn Choon-Beng Tan, and Chi-Keung Yeung Overview In the endocrine and general short cases examination, do exactly what you have been asked by the examiner. However, you should always spend 10-15 seconds just looking at the patient as well as the part or system you have been asked to evaluate before even attempting an examination. The general cases include endocrin- ology (usually spot diagnosis), skin conditions, and fundi. In a quick and systematic way, start looking at the face, followed in turn by the head and neck, the trunk and limbs. Inspect the body build, the skin, and finally the bones and joints. Many endocrine and general short cases are spot diagnoses, as the patients usually have obvious and typical clinical features; important clues become evident just by quickly looking at the patient. Become familiar with the possible short cases commonly used in such examina- tions and the physical signs associated with each condition. If you have a-clear idea of what to look for, you are less likely to miss essential features under the stressful conditions of an examination. Familiarity with typical cases will also make it easier to present your findings in a fluent and professional manner.

Case 3.1 Endocrinology and General 41 3.1 Acromegaly Classical signs Prominent supraorbital ridges Large nose Protrusion of the lower jaw (prognathism) Deep voice Oily skin Mouth: thick lips, malocclusion, and increased interdental separation; large tongue (macroglossia) Eye/vision: bitemporal hemianopia, optic atrophy Neck: goitre Hands: large hands with broad palms, spatulate fingers, sweaty palms Feet: large feet, thick heel pads Others: increased blood pressure, osteoarthritis and glycosuria Causes Acromegaly due to excessive growth hormone from a growth hormone secreting pituitary adenoma Important investigations Basal insulin-like growth factor 1: elevated Oral glucose tolerance test (glucose and growth hormone measurements). Growth hormone falls to < 1 ug/L in normal individuals, but is not suppressed in acromegaly. Magnetic resonance imaging of the pituitary: may demonstrate suprasellar extension and compression of the optic chiasm Other anterior pituitary hormones: look for evidence of hypopi- tuitarism and concomitant secretion of prolactin by adenoma.

42 Problem-Based Medical Case Management Case 3.1 Discussion « Regulation of growth hormone secretion: The hypothalamus controls growth hormone synthesis and release by means of growth hormone releasing hormone and somatostatin. Growth hormone secretion can be stimulated by stress, a fall in blood sugar, prolonged fasting, some amino acids (e.g., arginine) and exercise. « Complications of acromegaly: — Facial and skeletal disfigurement — Jaw malocclusion and overbite — Arthropathy — Nerve entrapment, carpal tunnel syndrome — Hypertension and left ventricular hypertrophy — Obstructive sleep apnoea — Diabetes mellitus — Colonic polyps and cancer — Hypopituitarism secondary to mass effect — Visual defects due to optic chiasm compression * Management of acromegaly: — Transsphenoidal surgery — Medical therapy includes: dopamine agonists such as bro- mocriptine and cabergoline; somatostatin receptor agonists (e.g., octreotide), and growth hormone receptor antagonist (pegvisomant). — Adjuvant radiotherapy » Relationship between acromegaly and goitre: Non-toxic goitres are quite commonly present, as part of the visceromegaly seen in acromegaly, and hyperthyroidism may occasionally occur. Pitfalls and tips ¢ Acromegaly is differentiated from Paget’s disease by the pres- ence of soft tissue involvement such as large tongue and thick skin, apart from the typical skull and facial deformities.

Case 3.2 Endocrinology and General 43 Compare the facial appearance with an old photograph of the patient. Note that in children and adolescents, growth hormone hyper- secretion will lead to pituitary gigantism as epiphyseal closure of the long bones has not yet taken place. 3.2 Atopic eczema Classical signs Generalized dry skin, symmetrical eruption with lichenification and excoriation, morphology depends on stages (acute, sub- acute, chronic). Head: predilection for eyelids, Dennie-Morgan infraorbital folds, infra-auricular fissure, periorbital pigmentation Neck: post-inflammatory hyperpigmentation with “dirty neck” appearance at sides of neck Trunk: sometimes erythrodermic, ill-defined erythematous patches, papules or plaques, with or without scale, post-inflam- matory hyperpigmentation and lichenification, excoriation and erosions/crusting indicating secondary infection Limbs: flexural distribution with ill-defined patches or plaques with excoriation and lichenification, frequent involvement of wrists Hands and feet: lichenified papules with pigmentation over finger knuckles, hyperlinearity of palmar creases, frequently involves anterior aspect of ankles, dorsa of feet and hands; painful fissuring and cracking of fingers and palm Associated asthma Causes ° Atopic tendency: genetic predisposition of hypersensitive response to environmental antigens

44 Problem-Based Medical Case Management Case 3.3 Important differential diagnoses Contact dermatitis (allergic/irritant): distribution corresponding to sites of contact with irritant or allergens, +ve patch test Drug eruption: tends to affect trunk and proximal limbs Seborrhoeic dermatitis: distributed along hairline, medial eye- brows, and nasolabial folds, axillae, groins and scalp Psoriasis: well-defined erythematous plaques with silver scaling on extensor surface of limbs and back, associated arthropathy Dermatophytosis: annular scaly rash with advancing edge and central clearing Important investigations IgE level: elevated Skin swab for bacterial culture Skin patch test/skin prick test for allergens Pitfalls and tips Not recognizing the lichenification and distribution of lesions Not treating the secondary infection, e.g., staphylococcus or streptococcus Personal/family history of atopy 3.3 Cushing’s syndrome Classical signs “Moon face”, acne, hirsutism (due to androgen excess and so not seen in cases due to excess steroid intake), plethora Pigmentation (ACTH-dependent Cushing’s) Truncal obesity, thin arms and legs Limbs: wasting of limbs, bruising, weakness of the muscles of the shoulders and hips (ask the patient to stand up from squat- ting position)

Case 3.3 Endocrinology and General 45 Trunk: buffalo hump, thinning of skin and purple striae over the upper arms, thighs, and abdomen Hypertension and glycosuria Look for clues that may suggest use of steroid (e.g., renal trans- plant, asthma). Causes Cushing’s syndrome due to excessive glucocorticoids Important differential diagnoses latrogenic: due to exogenous steroids ACTH-dependent: pituitary adenoma secreting ACTH, ectopic ACTH syndrome Non-ACTH dependent: adrenal tumours Important investigations 24-hour urinary free cortisol Loss of diurnal thythm of cortisol secretion Screening test: 1 mg overnight dexamethasone suppression test (a.m. level suppressed: normal) Confirmation of Cushing’s syndrome: 48-hour low dose dexa- methasone test (suppressed: normal) ACTH: distinguish between adrenal cause (low level) vs ACTH-dependent Cushing’s syndrome (high level) High dose dexamethasone suppression test: used in the dif- ferential diagnosis of ACTH-dependent Cushing’s syndrome; suppression of cortisol and ACTH consistent with pituitary- dependent Cushing’s disease Corticotrophin releasing factor stimulation test: used in the dif- ferential diagnosis of ACTH-dependent Cushing’s syndrome; rise of ACTH and cortisol consistent with pituitary-dependent Cushing’s disease

46 Problem-Based Medical Case Management Case 3.3 ¢ MRI of pituitary gland, CT or MRI of adrenals as appropri- ate, or search for underlying tumour if Cushing’s due to ectopic ACTH is suspected ¢ Inferior petrosal sinus sampling for ACTH: confirmation and localization of pituitary adenoma producing ACTH Discussion ¢ Complications of Cushing’s syndrome: — Cardiovascular: hypertension, fluid retention — Metabolic risks: glucose intolerance, central obesity, dys- lipidaemia, hypokalaemia — Musculoskeletal and connective tissue: thinning of skin, bruises and striae, proximal muscle weakness, osteoporosis — Immune system: immunosuppression with risks of oppor- tunistic infection - Psychiatric: irritability, depression, psychosis — Androgen excess (not seen in exogenous Cushing’s): acne, hirsutism — For iatrogenic Cushing’s (rarer in endogenous Cushing’s): avascular necrosis, glaucoma, posterior subcapsular cataract « Management of Cushing’s syndrome: — Management of concomitant problems: hypertension, diabe- tes, hypokalaemia — Surgery (aim for cure): transsphenoidal surgery for pituitary lesion; adrenalectomy for adrenal lesion — Medical (control of hypercortisolism while awaiting defini- tive therapy or if residual disease persists post-surgery): metyrapone or ketoconazole (inhibits adrenal steroidogen- esis); cabergoline or pasireotide (inhibits ACTH secretion from pituitary tumours) Interpretation of dexamethasone suppression tests: — Overnight 1 mg or low-dose 48-hour dexamethasone sup- pression test: 9 a.m. serum cortisol suppressed to less than 50 nmol/L in normal individuals. High dose 48-hour dexa- methasone suppression test: 9 a.m. serum cortisol supressed

Case 3.4 Endocrinology and General 47 to less than 50% of basal level in pituitary-dependent Cushing’s syndrome. Interpretation of corticotrophin releasing factor stimulation test: in patients with pituitary-dependent Cushing’s disease, there is arise above baseline of plasma ACTH of over 50% and cortisol of over 20%. 3.4 Diabetic retinopathy Classical signs ° Non-proliferative: microaneurysm, dot and blot haemor- rhages, and hard exudates Pre-proliferative: cotton wool spots, venous beading, haemor- rhages, and intraretinal microvascular abnormalities (IRMA) Proliferative: new vessels at the disc/elsewhere, photocoagula- tion scars; vitreous haemorrhage Important differential diagnoses Hypertensive retinopathy (see 3.7) Central retinal vein thrombosis: Venous tortuosity and dilatation Flame-shaped haemorrhages Cotton-wool spots Papilloedema Secondary neovascularization | Important investigations ° Blood for sugar, haemoglobin Alc Urine for proteinuria Screening for other diabetic complications such as renal, neuro- logical, and cardiovascular diseases

48 Problem-Based Medical Case Management Case 3.5 Pitfalls and tips « Haemorrhages and exudates also found in hypertensive retinopathy. « Laser scars may be widespread in the periphery of the fundus (grid pattern), appearing like exudates with associated pigment deposition; restriction of the visual field may result. « Vitreous haemorrhage “organization” may result in widespread fibrous scarring and retinal detachment. Discussion » Management of diabetic retinopathy: Medical: good glycaemic and blood pressure control. Laser photocoagulation is indicated for proliferative retin- opathy and some cases of pre-proliferative retinopathy and maculopathy. Vitrectomy; for persistent vitreous haemorrhage. anti-VEGF (vascular endothelial growth factor) agents: for diabetic macular oedema and proliferative retinopathy; (as adjunct to laser therapy/vitrectomy). 3.5 Erythema nodosum Classical signs o Bilateral multiple tender, erythematous, round, subcutaneous nodules on anterior aspects of legs and knees, occasionally on forearms » Resolving into bruise-like or brownish patches < Associated arthralgia especially at ankle joints Causes - Immunologic reaction triggered by a wide range of stimuli * Streptococcal infections = Tuberculosis

Case 3.6 Endocrinology and General 49 ° Drugs, e.g., sulphonamide, oral contraceptive Sarcoidosis, inflammatory bowel disease, Bechet’s syndrome Important differential diagnoses Another panniculitis (inflamed subcutaneous fat nodule), such as erythema induratum Vasculitis, e.g., polyarteritis nodosa, types of panniculitis versus vasculitis revealed by skin biopsy Pre-tibial myxoedema: patient usually has associated features of Graves’ disease. Superficial thrombophlebitis: patient usually has varicose veins and brownish pigmentation at lower parts of the legs. Important investigations Chest X-ray; for tuberculosis (hilar lympadenopathy in sarcoidosis) Mantoux test Blood tests: ESR/C-reactive protein, anti-streptolysin titre, anti-neutrophil cytoplasmic antibodies 3.6 Graves’ disease Classical signs Eyes: proptosis, periorbital oedema, lid lag, lid retraction, che- mosis, ophthalmoplegia Hands: sweaty palms, action tremor, thyroid acropachy, palmar erythema Neck: possible thyroidectomy scar, diffuse enlarged mass over the neck (goitre) that moves on swallowing both on inspection and palpation; auscultate for bruit over the thyroid Limbs: pre-tibial myxoedema (bilateral pinkish, brown dermal plaques); proximal myopathy (ask the patient to stand up from

50 Problem-Based Medical Case Management Case 3.6 squatting position, observe whether assistance from hands is required) « Others: sinus tachycardia, atrial fibrillation, and signs of high output heart failure Causes (neck swelling and thyrotoxicosis) * Graves’ disease: Graves® disease is distinguished from other causes of thyrotoxicosis by presence of typical diffuse thyroid enlargement and ophthalmopathy. « Toxic multinodular goitre ¢ Toxic thyroid adenoma ¢ Subacute thyroiditis Important investigations » Thyroid function test: the screening test is serum TSH; in primary hyperthyroidism TSH is suppressed and serum T4 and/ or T3 elevated. Thyroid autoantibodies: positive TSH receptor autoantibodies (TRAD) in Graves” disease. In other autoimmune thyroid dis- eases, anti-thyroglobulin and anti-thyroperoxidase antibodies are present but not TRAb. + Radionuclide scan: diffusely increased uptake of radioactive iodine in Graves’ disease; patchy inhomogeneous uptake in toxic multinodular goitre; localized area of increased uptake with suppression of uptake in the rest of the thyroid gland with toxic adenoma; decreased/no uptake in subacute thyroiditis e Ultrasound: diffuse enlargement with homogeneous echogenicity Discussion * Aetiology of Graves’ disease: autoimmune disorder associated with the production of stimulatory autoantibodies against TSH receptor (TSH receptor antibody, TRAb)

Case 3.7 Endocrinology and General ~ 51 « Management of Graves’ disease: manage associated hyper- thyroidism by antithyroid drugs, thyroidectomy or radioactive iodine. The thiourea group of agents (carbimazole or propylthi- ouracil) is especially indicated in children and pregnant women. 50% of patients may relapse after one course of antithyroid drug treatment for 18 months. Thyroidectomy or radioactive iodine may be considered if the patient relapses after medical treatment or as first line treatment. (Note: thyrotoxicosis should be controlled with antithyroid drugs before surgery.) e Management of opthalmopathy: 70% of patients with Graves’ disease may have eye problems, ranging from soft tissue involvement (such as periorbital oedema) to severe proptosis, diplopia, and visual impairment. The cause of the ophthal- mopathy is unclear; autoimmunity has been implicated. There is inflammation and swelling of retrorbital tissues. If severe, corticosteroids or other immunosuppressants may be useful. Pitfalls and tips + Absence of thyroid enlargement makes the diagnosis of Graves’ disease less likely but does not exclude it. 3.7 Hypertensive retinopathy Classical signs ° Grade 1: silver wiring ¢ Grade 2: above + arteriovenous nipping Grade 3: above + cotton wool spots, flame-shaped haemorrhages ° Grade 4: above + papilloedema e Arteriosclerotic changes: silver-wiring (increased arteriolar light reflex); arteriovenous nipping (deflection of venule at arte- riovenous crossing points) * Measure blood pressure

52 Problem-Based Medical Case Management Case 3.8 Important investigations + Examine urine for proteinuria. » Assess the heart for left ventricular hypertrophy and heart failure. Discussion « Causes of secondary hypertension: — Renal (e.g.,chronic renal failure, renal artery stenosis, IgA nephropathy) — Vascular (e.g., coarctation of aorta) — Metabolic (e.g., Conn’s syndrome, Cushing’s syndrome, phaeochromocytoma) . — Drugs (e.g., mineralocorticoids and glucocorticoids) ¢ Management of hypertension: treat primary cause; lifestyle changes; management of other coronary risk factors such as cigarette smoking, diabetes, hyperlipidaemia; discuss the types of anti-hypertensive drugs. Pitfalls and tips « Haemorrhages and exudates are also found in diabetic retinopathy. 3.8 Optic atrophy Classical signs * Pale disc with clearly delineated margin (except if the optic atrophy is due to long-standing papilloedema, which is then termed secondary optic atrophy). ¢ Central scotoma may occur.

Case 3.9 Endocrinology and General 53 Causes ° Compression of optic nerve by tumour (e.g., pituitary tumour: look for bitemporal hemianopia) or aneurysm Glaucoma Ischaemic optic neuropathy Friedreich’s ataxia Long-standing papilloedema (from any cause) Multiple sclerosis (causing optic neuritis) Vitamin B12 deficiency 3.9 Osler-Weber-Rendu syndrome (hereditary telangiectasia) Classical signs ° Telangiectasia on face, mucosa (mouth, lips, tongue) and on fingers May have pallor (due to anaemia) No signs of systemic sclerosis Discussion ° Osler-Weber-Rendu syndrome is an autosomal dominant condi- tion. Lesions may occur elsewhere, especially in the gastroin- testinal tract. Patient may present with epistaxis, gastrointestinal haemorrhage and anaemia. Facial and mucosal telangiectasia are also present in patients with systemic sclerosis. However, they have other systemic features (e.g., smooth, shiny, and tight skin over the face and fingers; sclerodactyly, atrophic nails etc.).

54 Problem-Based Medical Case Management Case 3.10 3.10 Papilloedema Classical signs * Loss of physiologic cup » Elevation of disc head * Blurring of disc margins e Distended non-pulsatile veins * Sub-hyaloid haemorrhages at disc margin » Enlargement of blind spot and constriction of peripheral visual field Causes * Increased intracranial pressure » Central retinal vein occlusion * Grade 4 hypertensive retinopathy ¢ Carbon dioxide retention Important differential diagnoses * Papillitis (a form of retrobulbar neuritis): visual acuity consid- erably reduced in papillitis, visual field defect (usually central) and eye movement may be painful. Important investigations * Visual acuity and visual field ¢ Blood gases * Imaging of brain for evidence and cause of raised intracranial pressure

Examination case Endocrinology and General 55 Examination case scenarios i. Examine the neck of this patient. Important signs « Diffuse neck mass that moves with swallowing + Examine for thyroid bruit. « Ask for permission to examine for other hyperthyroid signs. Diagnosis Graves’ disease. Question What are the differential diagnoses if patient is euthyroid? « Controlled Graves’ disease, euthyroid goitre, Hashimoto’s thyroiditis. ii. What do you notice about the physical appearance of this patient? Important signs * Prominent supra-orbital ridge, nose and lips, prognathism « Spade-like hands Diagnosis Acromegaly Question What investigations will you order? « Raised basal level of insulin-like growth factor 1. ’ « Oral glucose tolerance test for non- suppressed growth hormone level. « Pituitary magnetic resonance imaging (skull X-ray may show double floor in sella turcica).