Ann

Review Article

cu« Biochem

1990; 27: 287-296

Biochemical investigation of hypertension J M Harvey and D G Beevers From the University Department of Medicine. Dudley Road Hospital. Birmingham B18 7QH. UK

Underlying causes of hypertension are found in less than 5 % of cases but they are frequently surgically remediable. Elementary biochemical tests are usually sufficient to exclude most renal and endocrine causes of hypertension. However, young patients with very high blood pressures merit more detailed investigation in specialized centres. As coexistent hyperlipidaemia or glucose intolerance substantially worsen the prognosis for a given level of blood pressure, these two risk factors are worth assessing in all hypertensive patients. Their presence may also alter the choice of antihypertensive drug therapy. About 25 % of the population have raised blood pressure at first screening and about 10 % are in need of drug therapy, so this represents an appreciable load on biochemical laboratories. Most patients, however, need only a single biochemical profile on one occasion, and should be exclusively managed in general practice.

SUMMARY.

Additional key phrases: hyperlipidaemia; glucose intolerance; psychosocial stress

In general, the higher a person's blood pressure, the greater the risk of developing a heart attack, a stroke, left ventricular failure, renal failure or peripheral vascular disease. This gradient of blood pressure versus risk extends down to pressures below the population average. Any definition of hypertension must therefore be purely arbitrary, based on that level of blood pressure where investigation and possible treatment do more good than harm.' As a cardiovascular risk factor, blood pressure must also be seen in the light of other predictors of premature death, particularly cigarette smoking and blood lipid concentrations. When all three risk factors are present, the risk of death is around seven times greater than if only one is present.' In the majority of patients with hypertension the cause is unknown. Underlying diseases such as renal artery stenosis, renal parenchymal disease or over-secretion of aldosterone or catecholamines are found in less than 5 % of hypertensive subjects detected in population surveys (Table 1).3 Reports of higher frequencies of these conditions from specialist units probably reflect selected referral of cases. The aetiology of hypertension in the remaining 95 % is unknown, but epidemiological evidence suggests that the This paper was prepared at the invitation of the Clinical Laboratory Investigation Working Party of the Scientific Committee of the Association of Clinical Biochemists. but does not necessarily reflect their views. Correspondence: Dr J M Harvey.

blood pressure of a population, and therefore the prevalence of hypertension is related to the interplay of genetic and environmental factors," High salt intake, high alcohol intake and obesity all have important influences on blood pressure.' The role of psychosocial stress remains uncertain. Acute stress raises blood pressure acutely but chronic stress has less clear cut effects. The pathophysiology of hypertension is obscure. The final common pathway for raised arterial pressure is known to be increased peripheral arteriolar vasoconstriction.' This, in tum, may be related to the interplay of raised intracellular sodium and calcium concentrations in arteriolar smooth cells,' as well as activity of both circulating" and local renin-angiotensin systems? and central and autonomic nervous system activity." It is not known whether the initial factors causing blood pressure to rise are of central, renal, cardiac or peripheral vascular origin. All four sites have been implicated, but proof is lacking.

PREVALENCE OF HYPERTENSION Aproximately 25 % of the adult population in Europe and North America have hypertension as defined by the WHO criteria of a systolic blood pressure of 160mm Hg of more or a diastolic blood pressure of 95 mm Hg or more." In many people a lower pressure is found on rechecking, and it is important not to base clinical decisions 287

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T ABLE I.

Causes of hypertension

Causes

Comments

I.

Essential (primary) hypertension

Found in 95% of cases. cause unknown but is related to familial tendency. obesity. high alcohol intake and a high salt diet

2.

Renovascular hypertension (a) Atheromatous (b) Fibro-muscular hyperplasia (c) Extrinsic renal artery compression

Usually older patients. may be a consequence of raised BP but may aggrevate it Younger patients. Surgical correction possible Rare

3.

Renal disease (a) Glomerulonephritis (b) Pyelonephritis (c) Polycystic renal disease (d) Renin secreting tumours (e) Chronic renal failure

Particularly IgA nephropathy Unilateral or bilateral. may be tuberculous Mendelian dominant Very rare Of any cause

Drug induced hypertension (a) Oral contraceptives (b) Hormone replacement therapy (c) Liquorice and carbenoxolone (d) Non steriodal anti-inflammatory drugs (e) Sympathomimetic arnines (f) Corticosteroid and ACTH therapy (g) Nephrotoxic drugs

Hypertension of SO/o of women rarely severe Doubtful Mineralocorticoid-like hypertension Mild elevation of BP and interference with BP lowering drugs Cold cures and nasal decongestants Cushingoid habitus Acute or chronic renal failure

Diabetes mellitus (a) Insulin dependent (b) Non-insulin dependent

Due to diabetic glomerular lesions Sodium retention with renin suppression

Other endocrine diseases (a) Acromegaly (b) Primary hyperparathyroidism (c) Myxoedema (d) Thyrotoxicosis

May have glucose intolerance 50% are hypertensive Rarely hypertensive High systolic blood pressure

4.

5.

6.

7.

Adrenal diseases (a) Catecholamine excess i. Phaeochromocytoma (b) Aldosterone excess i. Aldosterone secreting adenoma ii. Adrenocortical hyperplasia iii. Adrenal carci noma iv. Dexamethasone suppressible hyperaldosteron-

May be bilateral, familial or malignant. Usually symptomatic True Conn's syndrome Not responsive to adrenalectomy Usually excess of other hormones Familial-and rare

ism (c) Cushing's disease

8.

Arterial disease (a) Co-arctation of the aorta (b) Polyarteritis nodosa (c) Systemic lupus erythematosus (d) Pulseless disease, Takayasu's disease (e) Progressive systemic sclerosis

on a single raised blood pressure reading. U Simple non-pharmacological methods which may be of value in lowering blood pressure include moderation of alcohol intake," reduction of dietary sodium intake" and dietary control of obesity if present." Only if the diastolic blood pressure remains above 100 mm Hg (as it does in about 5-10 % of the population) will drug treatment be needed, Such treatment can halve the incidence of stroke and also have a modest beneficial effect on coronary heart disease.":" It should be stressed, however, that patients whose blood pressures are modestly raised on one or two occasions, but whose pressures then settle, do need careful observation, There is a

Usually in children, also in Turners syndrome With renal involvement Develop nephrotic syndrome and renal failure Mainly seen in children Poor prognosis if renal involvement present

trend for blood pressures to rise with advancing age, and patients with higher pressures sustain a faster rise than those with lower pressures. Patients with 'borderline' hypertension should also be assessed on the basis of other cardiovascular risk factors as well as any family history of premature cardiovascular mortality or morbidity. .

RATIONALE FOR INVESTIGATION The value of 'routine' investigation of large numbers of patients has rightly been queried. IS However the careful investigation of hyperten-

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Biochemical investigation of hypertension

sive patients at the time of diagnosis must be seen in the light of their lifelong need for antihypertensive therapy or at best for long-term supervision of blood pressure. The identification of hypertensive patients who are at higher risk on the basis of hype rlipidaemia, renal impairment or glucose intolerance substantially influences their management. A clinician who misses a case of primary hyperaldosteronism because of a failure to measure or to react to a low serum potassium concentration will subject his patient to large and expensive doses of inappropriate or ineffective drug therapy for what is usually a curable condition. Similarly the practitioner who fails to spot that his patient's hypertension is related to a high alcohol intake may well opt for drug therapy costing £ 20 to £ 40 per month for 20 years or more. In many such patients, simple counselling on alcohol moderation causes a sustained fall in blood pressure. The aim of laboratory investigation of hypertensive patients is threefold. First, it is used to TABLE

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exclude the rare identifiable renal or adrenal causes of hypertension; secondly it may help to detect evidence of 'target organ damage', for example, renal impairmant. The third reason for investigation is to detect elevation of serum cholesterol concentration, a low HDL cholesterol level or glucose intolerance as these conditions substantially increase the risk of death for a given level of blood pressure and also influence the choice of antihypertensive drugs. The aim of this review is to discuss in a logical order the tests that may be requested by the clinician, and to discuss their relevance and importance in individual cases (Table 2). Urine dipstick tests Dipstick urinalysis should detect significant proteinuria, haematuria and glycosuria. Rarely, proteinuria may be due to arteriolar fibrinoid necrosis due to the malignant phase of either essential or secondary hypertension. If left untreated this syndrome, which is characterized by retinal haemorrhages and exudates, has a 2-

2. Suggested scheme for investigating and managing patients

First clinic visit

Investigations

Intervention

Urinalysis (dip-Slick) - bacteriological culture

Advise non-pharmacological methods of blood pressure reduction (alcohol. salt, weight). Reduce other cardiovasular risk factors. particularly cigarette smoking. Start treatment if blood pressure very high (e.g., diastolic blood pressure > 120 mmHg) lower threshold if young ( < 50) or male Arrange follow up depending on severity of hypertension (1-2 days to a few weeks)

if haematuria or proteinuria

Serum sodium. urate. cholesterol. potassium. total calcium. creatinine. )' GT Haematological profile Electrocardiogram to detect cardiomegaly Chest X-ray only if indicated (e.g.. clinical evidence of heart failure)

Second clinic visit

Urinalysis-proceed to 24 h urinary protein if persistent proteinuria 24 h urinary metanephrines and intravenous urogram or renal ultrasound scan if young ( < 45 y) severe/persistent hypertension Plasma renin and aldosterone assays if hypokalaernic (on no treatment)

Start treatment if blood pressure still high (distolic blood pressure> 110 mmHg) Defer treatment if blood pressure falling or border line No treatment if DPB < 100mmHg - but arrange follow up Lower thresholds for treatment if young male raised glucose/cholesterol left ventricular hypertrophy/ ischaernic heart disease on ECG raised creatinine Alter treatment and start specific treatments if indicated, e.g. high blood pressure glucose or cholesterol levels

Third and subsequent visits

Urinalysis repeated every visit Intravenous urogram or ultrasound if blood pressure resistant to treatment 24 h urinary metanephrines Arrange further tests in special situations. e.g., CT scan of adrenals, renal arteriography, renal biopsy

Start treatment if persistent hypertension (distolic blood pressure > 100 mmHg) Reinforce advice about weight reduction, alcohol moderation and non-smoking, if applicable Alter treatment to maintain blood pressure control and to avoid adverse clinical and biochemical effects of drugs

Annual check

Serum sodium, potassium. creatinine, urate, cholesterol, glucose, electrocardiogram to ensure efficacy of treatment and to monitor side effects of drugs

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year mortality rate of 80 %.19 Proteinuria may also be due to hypertensive nephrosclerosis (a consequence of hypertension) or to intrinsic renal disease which may be a cause of the hypertension. In any of these, haematuria may also be present but this finding requires careful investigation to exclude renal or bladder carcinoma. Any degree of proteinuria, including that associated with the nephrotic syndrome, may occur with hypertensive nephrosclerosis and the only way of determining whether the hypertension or the renal disease came first is by renal biopsy. Intrinsic renal diseases that cause hypertension include glomerulonephritis (particularly of the IgA and IgG subtypes) and pyelonephritis, either tuberculous or non-tuberculous." In hypertensive patients the presence of proteinuria indicates a substantially worse prognosis for both renal and non-renal disease." Proteinuria may be due to urinary tract infection, the latter giving a positive dipstick test for nitrites and leukocyte esterase." Infections may occur in previously damaged kidneys, or where there is an anatomical abnormality of the urinary tract, and may accelerate the development of chronic renal failure. Glycosuria suggests the diagnosis of diabetes mellitus although a negative test does not exclude the condition. The presence of diabetes will affect the choice of treatment for hypertension as thiazide diuretics are mildly diabetogenic and are best avoided." Glycosuria and hypertension may both be secondary to an endocrine disorder such as phaeochromocytoma, Cushing's syndrome or acromegaly.

First-line biochemical tests All patients with sustained hypertension should have a blood sample taken for measurement of blood glucose and serum sodium, potassium, creatinine, calcium, urate, gamma glutamyl transpeptidase, cholesterol and triglyceride concentrations. Normally these can be measured in the non-fasting state. Sodium Serum sodium levels may be normal or raised in primary hyperaldosteronism (140-150 mmol/L)24 and low or low-normal (l25-135mmoljL) in conditions with secondary hyperaldosteronism such as malignant hypertension and renal or renovascular disease, with or without renal failure. Serum sodium may also be lowered by thiazide or loop diuretics."

Potassium Primary hyperaldosteronism (Conn's syndrome) and its non-tumorous variants are almost always associated with marked hypokalaemia, with serum potassium levels as low as 2·0 mmol/L.24 In secondary hyperaldosteronism hypokalaemia is usually less severe and serum potassium may be normal. Measurement of the serum potassium concentration is the most useful screening test for surgically remediable Conn's syndrome. Diuretics are the commonest cause of hypokalaemia and these drugs must be stopped for at least I month before serum potassium measurement. Hypokalaemia may also be due to treatment with carbenoxolone for peptic ulceration or to intestinal potassium loss especially with purgative or laxative abuse. Hypokalaemia is usually associated with a metabolic alkalosis and a high serum bicarbonate concentration. Chronic pyelonephritis may rarely cause hypokalaemia, usually with low bicarbonate levels, due to an acquired renal tubular acidosis." Serum potassium levels may be raised in acute renal failure especially when potassium supplements or potassium sparing diuretics (spironolactone, amiloride or triamterene) are used in conjunction with the angiotensin converting enzyme inhibitors captopril, enalapril or lisinopril. Creatinine Renal or renovascular disease may both cause hypertension, but often renal impairment is due to the hypertensive process and in such cases the prognosis is exceedingly poor. Renal function should be assessed on presentation and annually thereafter in all hypertensives. The best way of assessing changes in renal function is by serial serum creatinine determinations. Those patients with hypertension secondary to chronic renal failure need careful control of their blood pressure as this may slow the otherwise inevitable decline in renal function. Routine estimation of creatinine clearance is not necessary in the vast majority of hypertensive patients. This test may be a more sensitive indicator of loss of renal function, but it is not easily organized in general practice and is inconvenient and sometimes unreliable." When renal impairment is severe and the need for chronic dialysis is considered to be likely in the future, it is helpful to plot serial measurements of the reciprocal of the serum creatinine against time. This provides an indication of whether renal function is deteriorating and gives some indication of whether or when chronic dialysis may be necessary."

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Biochemical investigation of hypertension Calcium Serum calcium concentrations are raised in primary hyperparathyroidism and serum phosphate is usually low. Hypertension is found in about 50 % of these patients." The mechanism of the association is uncertain. It is not explained by hypercalcaemia-induced renal damage or by the height of the serum calcium or parathyroidhormone concentrations, Despite this link, surgical cure of hyperparathyroidism rarely results in any improvement in blood pressure. Hypertension in a hyperparathyroid patient cannot, therefore, at present be regarded as an indication for parathyroidectomy unless there is concurrent renal failure. Thiazide diuretics may rarely cause hypercalcaemia and these drugs should be stopped for a few weeks before rechecking to exclude hyperparathyroidism." If hypercalcaemia persists, then a serum parathyroid hormone assay should be performed.

Urate Serum uric acid is raised in about 40 % of hypertensives with essential hypertension and is more common in those with renal failure." Urate nephropathy may occasionally be the cause of the hypertension. Hyperuricaemia may be caused or aggravated by diuretic therapy although only a small proportion of patients develop clinical gout. 16,)2 In a patient with unexplained hyperuricaemia a careful history may indicate that there is an excessive intake of alcohol. It is uncertain whether a raised serum uric acid level is itself an independent cardiovascular risk factor after allowing for the relationship between uric acid and hyperlipidaemia, obesity, alcohol abuse, drug therapy and the height of the blood pressure." Gamma glutamyl transpeptidase High alcohol intake is a relatively recently recognized cause of a raised blood pressure and the hypertension appears to be readily reversible with reduction or abstinence." It has been estimated that 10-20 % of hypertension may be related to a high alcohol intake, but unless the clinician is altert to this point it may pass unnoticed." Estimation of serum gamma glutamyl transpeptidase activity helps to identify the commonest known cause of hypertension. Serum aspartate transaminase levels may also be raised, and haematological indices may show evidence of macrocytosis with a normal or even a slightly raised haemoglobin level."

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Glucose The majority of patients with diabetes mellitus are diagnosed by random or post-prandial blood glucose measurements, and a formal glucose tolerance test should be necessary only in equivocal cases. About 50 % of both insulin dependent and non-insulin dependent diabetics also have hypertension," and up to 10 % of hypertensives are also diabetic. The combination of these two conditions becomes increasingly common with advancing age and with increasing levels of obesity, and the prognosis is correspondingly bad." Thiazide diuretics are best avoided." However, the calcium channel blockers and angiotensin converting enzyme inhibitors have no deleterious effects and the latter group may have major benefits by delaying the onset of renal damage." Cholesterol and triglycerides As stated earlier, the presence of hype rlipidaemia substantially worsens the prognosis in a hypertensive patient. Both beta blockers and thiazide duretics (usually the first line drugs for hypertension) may adversely affect plasma lipid profiles":" and it is possible that their use has been responsible for the disappointing impact of antihypertensive therapy on coronary heart disease. Certainly they should be avoided in patients with overt hyperlipidaemia. The calcium channel blockers and angiotensin converting enzyme inhibitors have no such effects on plasma lipids, and the newer alpha receptor blockers terazocin and doxazocin may even modestly reduce lipid levels." All these first-line investigations can be performed rapidly and cheaply using automated analysers. The results may influence the choice of drugs used to control the blood pressure or suggest that the hypertension is secondary to renal or endocrine disease. There is a higher chance of there being an underlying cause of hypertension in younger patients (less than 45 years old) and those with severe (diastolic blood pressure > 120 mm Hg) or difficult-to-control hypertension. Thus, such patients should undergo further investigations even if first-line tests provide no diagnostic clues. Otherwise more detailed tests should be confined to cases where the clinical assessment or the first-line investigations suggest the presence of renal or adrenal disease. Some clinicians may, however, request estimation of 24 h urinary sodium excretion, either to

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detect evidence of a high dietary salt intake or to check compliance with salt restriction. Dipstick urinary chloride tests which give a rough guide to urinary sodium chloride concentration are now becoming available. They may be a useful substitute for 24 h collections, which are so often inaccurately collected." FURTHER INVESTIGATIONS The next line of investigation depends on the cause suspected. Secondary hypertension is commonly due to renal disease and in these cases investigation is mainly radiological although the value of a 'routine' intravenous urogram is very limited." An estimation of 24h urinary protein excretion may help the elucidation of intrinsic renal disease and creatinine clearance estimations and possibly renal biopsy may be useful. In the USA, the routine estimation of plasma renin concentrations or activity has been advocated, but this view is not prevalent in Britain where most hypertensives are managed in the context of general practice." Renovascular hypertension In suspected renal artery stenosis, the investigation is again mainly radiological. Plasma renin levels in peripheral blood may be high or normal. If surgical treatment is to be considered renal vein renin levels may indicate the likelihood of a successful procedure." The narrowed renal artery will supply less blood to the kidney and also renin secretion may be higher on the affected side. A renal vein renin ratio of more than I· 5 to I has been associated with a better chance of cure or amelioration of the hypertension, either at renal artery reconstruction or angioplasty." This ratio is not affected by concomitant use of antihypertensive drugs which stimulate or suppress renin release. Better results have been claimed by calculating the fractional renin secretion from each kidney. Normally the fractional increase in renin concentration in the renal veins is about 0·24 (i.e., (RV-IVC)/IVC = 0·24 where RV is the renal vein renin concentration and IVC the inferior vena cava renin concentration). However, in cases with significant renal artery stenosis and where surgical repair or angioplasty is likely to be successful the value may be 0-48 on the affected side and approximately zero on the contralateral side. 42-48 Renal hypertension The relationship between renal parenchymal

disease and hypertension is variable." Very rarely, a benign renin-secreting tumour (haemangiopericytoma) may be found, mainly in juvenile severe hypertensives.so In these cases there is usually intense secondary hyperaldosteronism with hypokalaemia and very high plasma renin levels. More often unilateral hydronephrosis or 'pyelonephritis' may be detected, but it is uncertain whether these conditions cause the high blood pressure." Surgical correction or nephrectomy may not improve the hypertension so that treatment of these urological conditions is primarily to preserve renal function, rather than to cure the hypertension. Most intrinsic renal diseases are associated with an increased prevalence of hypertension, which is also common in chronic renal failure and after renal allograft transplantation. 49 Conn's syndrome Endocrine causes of hypertension are rare but accurate diagnosis is important as surgical cure may be feasible. Primary hyperaldosteronism or Conn's syndrome is usually suspected when hypokalaemia with high or high-normal plasma sodium levels are found on routine screening." However, the other causes for hypokalaemia in a hypertensive patient must be considered. In malignant hypertension, serum potassium levels may initially be low due to ischaemia of the juxtaglomerular apparatus related to arteriolar renal fibrinoid necrosis. When blood pressures are reduced these lesions heal and the serum potassium levels return to normal. It is not, therefore, worth while investigating further to exclude Conn's syndrome in new cases of malignant hypertension unless hypokalaemia persists after 6 weeks of good blood pressure control. Anyway, malignant hypertension in Conn's syndrome is generally regarded as being rare. 52 Primary hyperaldosteronism occurs in the context of suppressed plasma renin activity (PRA) or concentration with a high plasma aldosterone concentration (PAC) and if the diagnosis is suspected both need to be measured." In equivocal cases, where renin levels are low but plasma aldosterone concentrations are not obviously elevated (a common feature particularly in black and in elderly hypertensives), serial estimations of plasma aldosterone concentration throughout the day or the ratio of plasma aldosterone concentration to renin activity may help to detect genuine Conn's syndrome. Alternatively, a 24 h urinary aldosterone excretion rate may be measured. Another manoeuvre is to use

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Biochemical investigation of hypertension dietary sodium loading or saline infusion which normally suppress renin and aldosterone release. In primary hyperaldosteronism the high plasma aldosterone levels are not suppressible by these means and persistently high levels favour the diagnosis of Conn's syndrome. 53 In 1986, Muratanin et al. 54 reported that either a high PAC or a high PACfPRA ratio measured in the supine position after fasting overnight was more specific and sensitive for Conn's syndrome that a low renin level after salt depletion, a high aldosterone concentration after salt loading or a captopril test. Many antihypertensive drugs affect plasma renin and aldosterone concentrations (Table 3) and these need to be stopped for 2 to 4 weeks before meaningful results can be obtained. The only class of drugs which do not interfere with renin assays appears to be the ex-receptor blockers." Once the diagnosis has been made, the differentiation between bilateral adrenal hyperplasia (where adrenalectomy should be avoided) and adrenal adenoma has to be made. In general, adenomas cause more severe hypokalaernia with higher aldosterone levels and greater renin suppression and the patients are generally younger. 56 However, this cannot be relied upon in many cases. An adenoma may be diagnosed using a high resolution CT scan of the adrenal glands or by radio-labelled cholesterol scintiscanning. Adrenal venography with measurement of adrenal vein aldosterone/cortisol ratios may occasionally be useful but only in expert hands, having been replaced by CT scanning. 57 A solitary tumour is probably best removed as there is a good chance of curing the hypertension, and there is also a small possibility of malignancy especially if high levels of other mineralocorticoids are present. 1M However, if operation is contraindicated or bilateral hyperplasia is present then the best treatment is with the aldosterone antagonist spironolactone or with arniloride." Very rarely low-renin hyperaldosTABLE

3.

293

teronism may be familial and responsive to glucocorticoid suppression, so it is probably worth while giving a trial course of dexamethasone to all cases where an adrenal adenoma is not found."

Cushing's disease Cushing's disease is associated with hypertension in about 70-80 % of cases but this is usually mild. The diagnosis may be suspected in a hypertensive patient because of the presence of some of the typical clinical features (Cushingoid facies, abdominal striae, central obesity and hirsutism). Biochemical features include frank diabetes or impaired glucose tolerance, hypertriglyceridaernia, reduced total body potassium (with normal or low serum potassium levels) and raised urinary calcium and hydroxyproline levels secondary to increased skeletal turnover. The simplest screening test for Cushing's syndrome is the overnight dexamethasone suppression test: 1 mg of dexamethasone is taken orally at 10-11 pm and the patient returns to have blood taken for measurement of plasma cortisol the following morning. Measurement of 24 h urinary free cortisol is also a useful test but is open to inaccuracies of collection. In borderline cases, measurement of the diurnal variation of plasma cortisol concentration, or a more formal dexamethasone suppression test may be helpful." If these confirm the diagnosis the next step is to determine the cause, usually with a plasma ACTH assay. When Cushing's syndrome is due to an adrenal tumour the ACTH level is very low, and when it is due to a pituitary adenoma the ACTH is usually 2-5 times the upper limit of normal." If there is an ectopic source of ACTH excretion due to carcinoma of the bronchus the plasma ACTH may be very high, the patients are usually very ill, hypertension is rarely present and the prognosis is usually very poor.

Drugs which interfere with renin or aldosterone release

Thiazide or loop diuretics

Stimulate renin release leading to secondary hyperaldosteronism

Beta-receptor blockers

Suppress renin relase, with less effect on aldosterone, so may mimic hyperaldosteronism

Angiotensin converting enzyme inhibitors

Reduce aldosterone secretion and raise plasma renin concentration

Calcium channel blockers

Inhibit aldosterone release and raise plasma renin secretion

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Alcohol abuse is now a well recognized cause of a 'pseudo-Cushing's syndrorne'r" The patient may be plethoric, obese and hypertensive and a random plasma cortisol level may be moderately raised. The diagnosis of alcohol-induced pseudoCushing's syndrome is strongly suggested by a normal dexamethasone suppression test and raised serum levels of gamma glutamyl transpeptidase, aspartate aminotransferase and uric acid. These are often associated with a moderately raised mean red cell volume. Pbaeocbromocytoma

Phaeochromocytomas in patients with hypertension are usually suspected on clinical grounds, especially if symptoms of sweating attacks, palpitations, blanching, headaches and weight loss are associated with very labile or paroxysmal hypertension. Almost 10 % of patients with phaeochromocytoma have malignant phase hypertension and they may also be resistant to antihypertensive therapy." In these cases the initial screening tests are usually measurement of urinary catecholamines or their metabolites, most commonly either 4-hydroxy 3-methoxy mandelic acid (HMMA) or metanephrines, the latter being more specific and slightly more sensitive." Measurements are usually made on 24 h collections of urine but, because of the difficulty of making these collections, shorter periods have been used and seem to be usefu1.65,66 The routine estimation of urinary metanephrines cannot be justified in hypertension in general practice as phaeochromocytoma is present in less than I % of all hypertensives. In hospital practice assays should be conducted in symptomatic patients and also in severe or malignant hypertensives, and in those who have proved resistant to conventional antihypertensive drugs, even if they have no paroxysmal symptoms. False positive urine catecholamine results may follow excessive intake of certain fruits, particularly bananas, or foods containing vanilla. Mono-amine oxidase inhibitors, by blocking the degradation of amines, raise metadrenaline levels and depress HMMA excretion. False positive urine screening tests may occur with methyldopa therapy, and false negatives are associated with reserpine treatment." The alcohol withdrawal syndrome may mimic phaeochromocytoma." Plasma catecholamine assays may be superior as the initial test" but this view is not universally held and this assay is not widely available. In most cases unequivocal results will be ob-

tained with these tests although there is a small overlap with essential hypertension. Further discrimination may be obtained by using suppression tests. In normal people and essential hypertensives, most of the circulating catecholamines are derived from sympathetic nerves. After sympathetic blockade with agents such as clonidine, the neurogenic catecholamines are suppressed but autonomous secretion by a phaechromocytoma is not affected." Following suppression, urinary metanephrines are measured and this is best done overnight when neurogenic catecholamines are at their lowest. Other tests such as the pentolinium suppression test are unreliable because of the natural variability of secretion by a phaeochromocytoma. Histamine, tyramine or glucagon provocation tests are also unreliable and may be dangerous. Once the diagnosis of phaeochromocytoma is made the localization of the tumour is best achieved by metaiodobenzylguanidine scanning, computerized tomography or magnetic resonance imaging; surgical excision is mandatory as 10 % of cases have malignant tumours." Tumours may be bilateral or extra-adrenal, and they may recur. Phaeochromocytomas are occasionally familial and associated with the multiple endocrine adenoma syndrome with medullary carcinoma of the thyroid, hyperparathyroidism and Marfanoid habitus." Other conditions causing bypertension Other causes of hypertension not covered here include acromegaly, coarctation of the aorta, the arteritides, progressive systemic sclerosis, the use of the oral contraceptive and sometimes pregnancy. Most of these diagnoses are primarily clinical with hypertension as one of many other manifestations. They have been extensively discussed elsewhere.":" In summary, all hypertensive patients that need antihypertensive drug therapy require a minimum of biochemical investigation, both at presentation and during follow-up. Although the results will be normal in most cases, they may alter the choice of treatment and will indicate the small minority of cases who need further, more complicated investigations. Acknowledements

We are grateful to Mrs Fay Cox for secretarial help and Dr P Gosling and Dr R F Fletcher for technical advice.

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