Endocrinology and General Medicine — Long Cases

4 Endocrinology and General— Long Cases Karen Siu-Ling Lam, James D. Best, Annie Wai-Chee Kung, and Kathryn Choon-Beng Tan 4.1 Acute confusion (diabetes mellitus) History A 23-year-old man was brought to the accident and emergency department because his family found him to be confused and incoherent. He had been feeling unwell with flu-like symptoms for 2 days. He was also noticed to have significant recent weight loss. Physical examination The patient was confused and dehydrated; his blood pressure was 90/70 mmHg and pulse rate 110/minute. He was hyperventilat- ing (respiratory rate of 30/minute). There was no neck rigidity, the abdomen was soft and non-tender, and no organomegaly was detected. Urine tests revealed presence of ketones and glucose; his blood haemoglucostix reading was 23.4 mmol/L. There was a high anion gap [(Na’ + K'] - [CI” + HCO;") = 25 mmol/L]. Questions 1. What is the most likely diagnosis? ¢ Diabetes mellitus presenting with diabetic ketoacidosis. Differential diagnoses for a high anion gap acidosis: salicy- late overdose, methanol poisoning, lactic acidosis. Potential

Case 4.1 Endocrinology and General 57 6. neurological causes: stroke (less likely in young patients), head injury. . What investigations would you perform? Measure plasma glucose, urine/serum ketones, blood gas analy- sis, electrolytes, and look for precipitating infections (respira- tory, urinary, gastrointestinal, septicaemia, and meningitis). . What are the underlying metabolic abnormalities? Predominant problem is insulin deficiency, leading to impaired peripheral glucose uptake and increased hepatic glucose pro- duction resulting in hyperglycaemia, increased break-down of fat, and hepatic generation of ketone bodies. . What is your initial management? Fluid replacement therapy with large volumes of isotonic saline (polyuria will persist until glucose level is lowered). A central line is useful to guide therapy especially in the elderly with con- comitant cardiac dysfunction. Short-acting insulin preferably given by intravenous route should be started. Frequent monitor- ing of serum potassium and glucose level should be performed. Intravenous potassium replacement is likely to be required. Use of bicarbonate is only indicated in severe acidosis (pH < 7.0), as administration of alkali is associated with potentially serious adverse effects such as hypokalaemia and paradoxical acidosis of cerebrospinal fluid. It is important to treat any underlying infection. . What is your subsequent management? Transfer to subcutaneous insulin injections when the condition is stabilized. The patient should receive diabetes education— general facts about diabetes and the need for insulin, self- monitoring of blood glucose and insulin self-administration, recognition and treatment of hypoglycaemia. What advice would you give the patient to prevent future episodes? Reinforcement of “sick-day rules”: more frequent monitoring of blood glucose during illness and checking urine or blood for ketones. Marked hyperglycaemia can develop and requires tem- porary adjustment of the insulin regimen and, if accompanied by ketosis, patient should seek medical advice.

58 Problem-Based Medical Case Management Case 4.2 7. What are the possible genetic bases for diabetes mellitus? * Type 1 diabetes is a polygenic disorder in which human leuko- cyte antigen class II alleles make the greatest contribution to susceptibility. The common forms of type 2 diabetes are also polygenic in nature. Specific monogenic forms of diabetes mel- litus that may result from genetic defects which regulate insulin action or defects of insulin secretion in b-cells (e.g., maturity- onset diabetes of the young) account for only a small percent- age of diabetic subjects. Pitfalls and tips * Both hypoglycaemia and hyperglycaemia can present as confusion. « Confusion due to hyperglycaemia usually has an insidious onset and is associated with poor glycaemic control and high haemoglucostix readings. Hyperglycaemic patients are dehy- drated and hyperventilation is apparent if there is ketoacidosis. * In non-ketotic hyperosmolar coma, relative insulin deficiency is apparent. Typically, there is severe hyperglycaemia and dehy- dration but no significant hyperventilation or hyperketonaemia, and the patient’s fluid intake capability is often compromised (e.g., due to stroke). Treatment involves rehydration (half- normal saline if plasma Na exceeds 150 mmol/L and provided haemodynamic stability is achieved). Insulin therapy and elec- trolyte replacement are undertaken as for diabetic ketoacidosis. 4.2 Galactorrhoea-amenorrhoea (prolactinoma) History A 30-year-old woman, previously healthy, presented to her general practitioner complaining of milky discharge from her breasts. There was no history of visual impairment, but she complained of amenorrhoea for 4 months.

Case 4.2 Endocrinology and General 59 Physical examination She had bilateral galactorrhoea, bitemporal hemianopia, and early optic atrophy. Questions 1. 2. What is the most likely diagnosis? Galactorrhoea—amenorrhoea due to hyperprolactinaemia, probably secondary to a tumour in the hypothalamic pituitary region compressing the optic chiasm and leading to bitemporal hemianopia. How does a tumour in the hypothalamic-pituitary region lead to hyperprolactinaemia? ° Basal prolactin secretion is normally kept under tonic inhibition by dopamine from the hypothalamus. Hyperprolactinaemia can occur in any condition which interferes with tonic dopamine secretion, its delivery to the anterior pituitary or its action on the prolactin producing cells. Hypothalamic or pituitary lesions including tumours can therefore cause hyperprolactinaemia by pressure effects of the tumour mass. A functioning pituitary _prolactinoma can also cause hyperprolactinaemia by secret- ing prolactin. Finally, some tumours causing acromegaly may be associated with hyperprolactinaemia as they secrete both growth hormone and prolactin. . What other conditions can also lead to hyperprolactinaemia? Physiological causes such as pregnancy and breast-feeding can lead to hyperprolactinaemia, through the stimulating effects of oestrogen and suckling, respectively. Increased prolactin release ensues during stress, even that induced by the pain of venepuncture. Drugs may give rise to hyperprolactinaemia by depleting dopamine from brain cells (methyldopa), blocking the action of dopamine on its pituitary receptors (chlorpromazine) or increasing the number and activity of the prolactin secreting cells (oestrogens as in oral contraceptives). Hypothyroidism can also cause hyperprolactinaemia as it leads to increased levels of thyrotrophin releasing hormone, which is a prolactin

60 Problem-Based Medical Case Management Case 4.2 releasing factor. Other causes of hyperprolactinaemia include chronic renal failure and conditions affecting the chest wall, such as trauma or herpes zoster. 4. What is the cause of her amenorrhoea? * Hyperprolactinaemia can cause amenorrhoea by interfering with the normal pulsatile release of gonadotrophin releas- ing hormone. Hypothalamic-pituitary tumours may give rise to hypogonadotropic hypogonadism due to hypopituitarism resulting from compression or reduced stimulation of the normal pituitary. 5. How would you confirm your diagnosis? * A basal non-stressed prolactin level should be measured. A level > 10 times the upper limit of normal is almost certainly caused by a prolactinoma, while any level > 3-fold the upper limit would be suggestive. MRI of the pituitary is needed for anatomical confirmation, especially as this patient has visual field loss. 6. How would you manage this patient? » The primary treatment of a prolactinoma is medical; dopamin- ergic agents, such as bromocriptine or cabergoline, normal- ize prolactin levels and shrink the tumours in the majority of patients. Surgery is only indicated if there is drug intolerance or resistance, or poor drug compliance. For other pituitary tumours associated with hyperprolactinaemia, transsphenoidal surgery is the treatment of choice. Whichever treatment strategy is adopted, continued monitoring for the development of associ- ated hypopituitarism is imperative. 7. What is the role of radiotherapy in the management of a prolactinoma? * For patients in whom surgery is indicated, but refused or con- traindicated, radiotherapy can be offered as an alternative. For female patients with prolactin producing macroadenoma, there is a risk of symptomatic tumour enlargement during preg- nancy, which usually responds to resumption of bromocriptine. If there is doubt regarding compliance with regular monitoring during pregnancy, prior radiotherapy to restrain tumour growth is recommended.

Case 4.3 Endocrinology and General 61 8. What are the disadvantages of surgery and radiotherapy? « Surgery carries the risk of post-operative diabetes insipidus, localized bleeding, cerebrospinal fluid leakage, hypopituitarism and recurrence of macroadenomas. Radiotherapy is associated with a high risk of hypopituitarism and years of delay before normalization of hyperprolactinaemia. Pitfalls and tips o Need to remember pregnancy and drugs as causes of galactorrhoea-amenorrhoea 4.3 Hypercalcaemia (primary hyperparathyroidism) History A 48-year-old woman presented to her general practitioner with low back pain for 1 week. She had no other complaint. X-ray of the lumbar spine revealed normal intervertebral disc spaces but osteopenia more advanced than expected for her age. The doctor suspected secondary osteoporosis and ordered some investigations. Preliminary results showed a mildly elevated serum total calcium level of 2.77 mmol/L, and a raised serum parathyroid hormone (PTH) level of 89 pg/mL. Other investigations were normal. Physical examination Normal Questions 1. What are the most common causes of hypercalcaemia? e The two commonest causes are hyperparathyroidism and hypercalcaemia of malignancy. Other less common causes include: excessive intake of vitamin D or calcium,

62 Problem-Based Medical Case Management Case 4.3 hyperthyroidism, sarcoidosis, active tuberculosis, familial hypocalciuric hypercalcaemia. 2. What investigations would you perform in a patient pre- senting with hypercalcaemia? ¢ Investigations include serum albumin, phosphate, alkaline phosphatase, renal function, PTH and 24-hour urinary calcium excretion. Hypercalcaemia together with hypophosphatae- mia suggest either hyperparathyroidism or hypercalcaemia of malignancy due to secretion of a PTH-like peptide. In the latter case, serum PTH will be suppressed. The clinical diagnosis for this patient is primary hyperparathyroidism. 3. What are the causes of elevated serum PTH levels? * Primary hyperparathyroidism: 80% due to single parathyroid adenoma; 17-20% multiple adenoma or hyperplasia, 1% para- thyroid carcinoma. * Secondary hyperparathyroidism is a physiological increase in PTH level in response to hypocalcaemia. » Tertiary hyperparathyroidism is a result of autonomous secre- tion of PTH after a prolonged duration of secondary hyper- parathyroidism (e.g., in patients with chronic renal failure on dialysis). 4. What other investigations should be carried out in this patient? + Investigations include defining possible complications due to raised PTH or hypercalcaemia: 24-hour urine calcium excretion to document the degree of hypercalciuria; renal function tests; abdominal X-ray and ultrasound of kidneys to detect stones in the urinary tract; bone mineral density (BMD) assessment at the forearm, hip, and spine to assess the degree of bone loss. 5. What is the bone involvement in hyperparathyroidism? » Chronic hyperparathyroidism results in increased osteoclastic activity, increased bone resorption and demineralization, espe- cially in the cortical bone, leading to osteopenia, bone pain, bone deformity, and fracture. Other severe bone lesions include subperiosteal resorption and osteitis fibrosa cystica, bone cysts, “Rugger-jersey spine” and “salt and pepper” skull. It is believed

Case 4.4 Endocrinology and General 63 6. that severe bone disease in primary hyperparathyroidism usually occurs in vitamin D deficient patients. Nowadays most patients diagnosed with primary hyperparathy- roidism have mild disease. Severe bone disease is rare except in severe secondary/tertiary hyperparathyroidism due to chronic renal failure. Bone involvement in terms of osteopenia or osteo- porosis can be detected by BMD assessment, using bone densi- tometry machines. What investigations can be done to help localize the abnor- mal parathyroid gland? ° 7. Methods used to localize hyperactive/abnormal parathyroid glands include: ultrasound, computed tomography (CT), mag- netic resonance imaging (MRI) and radioisotope (thallium/ sestamibi) scanning. In general, the sensitivity of conventional radiological investigations is 50-60%. Better results have been achieved with sestamibi scans. The best strategy is to locate an experienced parathyroid surgeon. Intra-operative ultrasound may be useful. What are the indications for surgery in patients with primary hyperparathyroidism? Since most patients with primary hyperparathyroidism encoun- tered nowadays have mild disease or are diagnosed inciden- tally surgery is indicated only if: serum total calcium 1 mg/dL (0.25 mmol/L) above the upper limit of normal for that labo- ratory), creatinine clearance reduced to < 60 mi/min, renal stone, osteoporosis, and age < 50 years. There is less consen- sus for hypercalciuria (24-hour total urinary ca1c1um excretion > 400 mg or >10 mmol). 4.4 Unexplained weight loss (Graves’ disease) History A 42-year-old woman presented with a 3-month history of palpita- tions and weight loss. She had good appetite, but noticed frequent

64 Problem-Based Medical Case Management Case 4.4 loose stools several times per day. She had normal menstrual cycles. Her mother had a history of thyroid disease. Physical examination Diffuse neck swelling which moved on swallowing. There was a fine resting hand tremor. There was a full range of eye movements. An irregularly irregular pulse of 98/minute was detected, but there were no features of heart failure. Questions 1. What are the different causes of hyperthyroidism associated with a neck swelling? » Graves’ disease, toxic multinodular goitre, toxic thyroid adenoma, and subacute thyroiditis. 2. What is the pathogenesis of Graves’ disease? o Graves’ disease is one form of autoimmune thyroid disease, associated with the production of TSH receptor autoantibodies (TRAD). Stimulating TRADb results in excess thyroid hormone production and thyroid enlargement. 3. What are the possible treatment modalities for this woman? ° Medical therapy includes antithyroid drugs with concomitant beta-adrenergic blocking agents. Partial thyroidectomy (espe- cially if ophthalmopathy is present) and radioactive iodine thyroid ablation (contraindicated in children and during preg- nancy) can be considered. 4. What are the mechanisms of action of anti-thyroid drugs and what are their side effects? e Anti-thyroid drugs inhibit thyroid hormone synthesis: block organification of iodide and coupling of iodotyrosines. In addi- tion, propylthiouracil in high doses also inhibits T4 to T3 con- version. They may also have immunomodulatory effects so as to reduce thyroid autoantibody levels. o Side-effects include rash (5%) and agranulocytosis (0.1%). Rarely there may be cholestatic jaundice, hepatocellular toxic- ity, and acute arthralgia. ANCA (anti-neutrophil cytoplasmic

Case 4.4 Endocrinology and General 65 antibody)-positive vasculitis may occur with long-term use, more with propylthiouracil than with carbimazole. 5. How will you confirm the diagnosis in this patient? o+ Thyroid Function Tests: elevated serum T4 and/or T3 levels with suppressed TSH level. o Increased circulating TRAb. o Radioactive iodine thyroid scan shows diffusely increased uptake (performed if subacute thyroiditis has to be excluded)