NORMAS DE VALORACIÓN

History

A 34-year-old man complained of severe headaches which had become more frequent and intense over the past six months. He described the headaches as ‘thumping’ and has noticed a rapid heart rate during some headaches. He also indicated that he is feel-ing very anxious followfeel-ing an unpleasant divorce. His GP found his blood pressure to be 180/105 mmHg and commenced treatment with an ACE (angiotensin converting enzyme) inhibitor. Fundoscopy was normal. When the ACE inhibitor failed to control his blood pressure (BP), his treatment was changed to an angiotensin receptor blocker.

However, this too failed to control his BP and so the GP referred him to the hospital hypertension clinic where a range of tests were undertaken, with the 24-hour urine being collected when anti-hypertensive agents had been stopped for 3 days.

Reference range

Sodium 141 mmol/L 135–146 mmol/L

Potassium 3.2 mmol/L 3.2–5.1 mmol/L

Urea 8.5 mmol/L 1.7–8.3 mmol/L

Creatinine 121 μmol/L 62–106 μmol/L

Calcium (adjusted) 2.61 mmol/L 2.15–2.55 mmol/L

Phosphate 0.95 mmol/L 0.87–1.45 mmol/L

Alkaline phosphatase (ALP) 102 U/L 35–104 U/L

Glucose (fasting) 5.4 mmol/L <6.0 mmol/L

24-h urine normetanephrine 6.1 μmol/24 h <3.3 μmol/24 h 24-h urine metanephrine 1.9 μmol/24 h <1.2 μmol/24 h 24-h urine methoxytyramine 2.7 μmol/24 h <2.5 μmol/24 h

Fasting plasma glucose from a sample taken during a severe headache was 8.5 mmol/L.

A repeat 24-hour urine and blood test was arranged – the 24-hour urine was started at the onset of a headache:

Reference range 24-h urine normetanephrine 16.5 μmol/24 h <3.3 μmol/24 h 24-h urine metanephrine 4.9 μmol/24 h <1.2 μmol/24 h 24-h urine methoxytyramine 3.5 μmol/24 h <2.5 μmol/24 h

Chromogranin A 195 pmol/L <60 pmol/L

On the basis of these results, a radioisotope MIBG (iodine-131-meta-iodobenzylguanidine) scan was undertaken.

Case 20: Man with severe headaches 91

QUESTIONS

1. What is the most likely diagnosis?

2. Why was it considered necessary to repeat the urine collection for metanephrines?

3. Which conditions may cause an elevation of metanephrine excretion?

4. Which drugs should be stopped, if clinically safe, before collecting a 24-h urine for metanephrine assay?

5. What is the significance of the chromogranin A finding?

6. What is the explanation for the elevated glucose of 8.5 mmol/L?

7. What might be the significance of the serum calcium level and how might this be followed up?

8. What is the purpose of MIBG imaging?

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92 Section 1: Clinical Chemistry

ANSwERS

1. The most likely diagnosis is phaeochromocytoma based on the second collection, although severe emotional stress is a possible cause for the first set of results.

2. Metanephrine values of between 1–4 × ULN (upper limit of normal) are not diag-nostic, but require further investigation as they may be associated with other condi-tions and drug therapy. There is an advantage in collecting a 24-h urine as soon as an ‘attack’ is noted by the patient, however the effect is more marked if using catecholamine measurements rather than metanephrines.

3. There are a considerable number of conditions which may cause an elevated excre-tion of metanephrines. They are associated with a stress response which is mediated in part by secretion of adrenal medullary hormones. They include acute psychologi-cal stress, hypoglycaemia, obstructive sleep apnoea, vigorous exercise, conditions linked to clinical shock, such as myocardial infarction, severe injury, pulmonary embolus, and use of recreational drugs, such as cocaine. Excessive caffeine intake and nicotine may also influence results.

4. A number of therapeutic drugs are associated with a physiological increase in metanephrine concentrations. In addition, there are drugs which cause analyti-cal interference, but this is very dependent on the method of analysis used by the laboratory. It is preferable to stop these drugs for at least 4 days before starting a urine collection and longer for calcium-channel blockers. Drugs to consider stop-ping before collecting a specimen for metanephrines include drugs used to control hypertension, e.g. beta-blockers (propranolol), alpha-blockers (doxazosin), calcium-channel blockers (felodipine), drugs inhibiting noradrenaline reuptake (amitriptyline, clozapine), amphetamine-related drugs (ritalin) and dopaminergic drugs (methyl-dopa). Avoidance of caffeine, nicotine and vitamin C supplementation may also be advised.

Metanephrine excretion may be reported as total metanephrines or as different fractions, namely metanephrine and normetanephrine. Fractionated metanephrines (as in these results) have a sensitivity of up to 97 per cent and a specificity of about 70 per cent, which makes the assay reliable for detection of phaeochromocytoma but with a rather high false-positive rate – hence the value of repeat estimations, especially following ‘an attack’.

Methoxytyramine is a breakdown product of dopamine and is therefore only raised in dopamine-secreting tumours.

Please note that laboratory tests for phaeochromocytoma may be based on meas-urement of catecholamines or their metabolites, the metanephrines. Further tests may be undertaken on urine or plasma. The interference of drugs is different for catecholamine assays than metadrenalines and may also be specific to the analyti-cal method used. It is therefore essential to discuss the question of interference with the assaying laboratory.

Case 20: Man with severe headaches 93

5. Adrenal medullary tissue is derived from chromaffin cells which secrete chromogra-nin A. Although the use of the test is largely associated with investigation of gas-trointestinal disorders, its elevation is associated with phaeochromocytoma and is used as a second-line investigation. Recent studies have shown a good sensitivity and specificity. Chromogranin levels are claimed to be proportional to tumour mass.

Chromogranin A is used in the diagnosis and monitoring of carcinoid syndrome, although elevated levels may also be found in association with pancreatic cancer and prostate cancer. Liver failure, renal failure and inflammatory bowel disease have also been associated with elevated concentrations.

Proton pump inhibitor drugs should be stopped before measurement of chromogra-nin A as these drugs increase secretion.

6. Increased catecholamine secretion, especially as found during ‘an attack’, will mobi-lize glycogen stores and increase the rate of gluconeogenesis while inhibiting insu-lin release. The net effect is an elevation of blood glucose.

7. The raised serum calcium indicates the possibility of hyperparathyroidism and that the phaeochromocytoma is part of MEN2 (multiple endocrine neoplasia type 2). MEN2 comprises medullary cell carcinoma of the thyroid, phaeochromocytoma and parathyroid adenoma or carcinoma. When found in association with Marfanoid characteristics and mucosal adenomas, it is termed Sipple’s syndrome or MEN2A.

MEN2 is due to a mutation in the pro-oncogene RET and the presence of this muta-tion may be used to assess the risk in family members.

8. MIBG imaging is important not so much as a diagnostic test, but as a localization test. Up to 10 per cent of tumours are found to be bilateral (more in familial cases) and 10–15 per cent are extra-adrenal.

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