Hypertension due to phaeochromocytoma—an unusual cause of multiorgan failure

(Section Editor: K. Kühn)

Nitin Kolhe1, John Stoves1, Donald Richardson1, Alex M. Davison1, and S. Gilbey2

1 Department of Renal Medicine and 2 Department of Endocrinology, St James's University Hospital, Leeds, UK

Keywords: acute renal failure; MIBG scan; multiorgan failure; phaeochromocytoma; proteinuria

Introduction

Phaeochromocytoma is a rare neoplasm, principally of the adrenal medulla. It is classically associated with periodic hypertension and a constellation of intermittent symptoms including headache, sweating, and palpitations. These are attributed to an excessive release of catecholamines (dopamine, adrenaline, noradrenaline) from chromaffin tissue within the tumour. Most phaeochromocytomas are unilateral and are not associated with an endocrine syndrome. Although often histologically benign, they are potentially lethal. We report two cases of phaeochromocytoma presenting with multiorgan failure.

Case 1

A 42-year-old female developed acute symptoms of breathlessness and palpitations. She presented to the emergency department in extremis, with severe dyspnoea, chest tightness, and expectoration of copious pink, frothy sputum. She was clinically cyanosed and had cold peripheries. Blood pressure was initially unobtainable and her pulse was weak at a rate of 120 beats per minute. There were inspiratory crepitations extending to the mid-zones bilaterally.

She was given high-flow oxygen by mask, intravenous frusemide, and a bolus of adrenaline. Initial investigations gave the following results: PO2 5.6 mmHg, PCO2 4.0 mmHg, pH 7.16, base excess 18 mmol/l, lactate 10 mmol/l, plasma sodium 143 mmol/l, potassium 4.7 mmol/l, urea 9.5 mmol/1, creatinine 159 µmol/1, bicarbonate 12 mmol/1, glucose 0.9 mmol/l (3.4–5.7), alanine aminotransferase 375 IU/l (0–35), bilirubin 22 µmol/l, albumin 39 g/l, amylase 441 IU/l, creatine kinase 223 IU/l (28–205), and paracetamol and salicylate undetectable. Chest X-ray showed pulmonary oedema with normal cardiac dimensions,. An electrocardiogram (ECG) showed lateral ST changes consistent with left ventricular strain.

The patient was given intravenous glucose and transferred to the intensive care unit, where she was intubated and ventilated. She remained oligoanuric despite high-dose diuretic therapy. Continuous venovenous haemodialysis (CVVHD) with ultrafiltration was commenced, using bicarbonate dialysate and heparin for anticoagulation. Mean arterial pressure was maintained at 80 mmHg without inotropes. Further blood investigations within 24 h of admission revealed the following: haemoglobin 9.9 g/dl, white cell count 29.9x109/l (neutrophilia), platelets 49x109/l, prothrombin time (PT) 46.1 s, amylase 881 IU/l, albumin 25 g/l, alanine aminotransferase 4140 IU/l, calcium 2.88 mmol/l (2.2–2.6), phosphate 3.18 mmol/l (0.7–l.4), parathyroid hormone (PTH) 119 ng/l (10–65), C-reactive protein (CRP) <5 mg/l, thyroid-stimulating hormone (TSH) 4.28 mIU/l, free T4 8.4 pmol/l, and autoimmune screen negative. An abdominal ultrasound scan and Doppler examination revealed a 7x6x5 cm vascular mass of mixed echogenicity in the right suprarenal area. A CSU specimen grew >105/ml coliforms. A history of intermittent headache and palpitations were documented in her previous case notes.

The patient made satisfactory progress and was extubated within 48 h of admission. She was transferred to ward where haemodialysis support was provided intermittently for a further 4 days. Analysis of two consecutive 24-h collections of urine revealed elevated levels of adrenaline (1.12 and 0.93 µmol/l, normal <0.1 µmol/l) and noradrenaline (1.07 and 0.55 µmol/l, normal <0.5 µmol/l). An echocardiogram during recovery showed trivial mitral regurgitation and good left ventricular systolic function. A Synacthen test excluded primary adrenal insufficiency. Plasma gastro-intestinal and pancreatic exocrine hormones were within normal limits except for mildly elevated gastrin (48 pmol/l, normal <40).

Urine output improved slowly and renal biochemistry returned to normal within 3 weeks of the initial presentation. All other blood investigations gave satisfactory results.

An adrenal scintiscan [131I] meta-iodobenzylguanidine ([131I]MIBG) showed increased uptake in the right suprarenal area (Figure 1Go), and a subsequent magnetic resonance imaging (MRI) scan confirmed the presence of a suprarenal mass with no evidence of invasion (Figure 2Go). A presumptive diagnosis of phaeochromocytoma was made.



View larger version (116K):
[in this window]
[in a new window]
 
Fig. 1. [131I]MIBG scan showing increased uptake in the right suprarenal area.

 


View larger version (146K):
[in this window]
[in a new window]
 
Fig. 2. MRI scan (coronal section) showing the presence of suprarenal mass with no evidence of invasion.

 
Phenoxybenzamine (an alpha-receptor blocking agent) was commenced and a laparoscopic adrenalectomy was performed 1 month after the initial presentation. Histology showed a phaeochromocytoma with small areas of necrosis and haemorrhage. There was no evidence of capsular or vascular invasion.

Post-operative urine catecholamine measurements and protein excretion were within normal limits. The patient has subsequently been asymptomatic.

Case 2

A 28-year-old female, with no past medical history, was commenced on propranolol for suspected migraine. She presented acutely to her local hospital with severe headache, backache, retrosternal chest pain, and haemoptysis. An acute cerebrovascular event was suspected, but an urgent computed tomography (CT) scan of the head was normal. The patient's clinical condition deteriorated and she suffered a cardio-respiratory arrest. She was admitted to the local intensive care unit (ICU) and required ionotropic and ventilatory support. She became anuric and was transferred to the regional ICU for specialist ventilatory and dialysis support. She suffered a further cardiorespiratory arrest after transfer. Investigations on admission revealed following: haemoglobin 10.4 g/l, white cell count 18x109/l, urea 15.8 mmol/l, creatinine 512 µmol/l, alanine aminotransferase 4940 IU/l, albumin 27 g/l, calcium 1.79 mmol/l, phosphate 3.73 mmol/l, PT 47.3 s, APTT 75.8 s, INR 3.6, fibrinogen 1.5 g/l, bicarbonate 14.2 mmol/l, amylase 562 IU/l, glucose 3.9 mmol/l, bilirubin 29 µmol/l, creatinine kinase 1250 IU/1, urine dipstick 4+ protein with moderate blood, echocardiogram normal, CT scan of chest showed changes consistent with pulmonary oedema, complements normal, blood cultures no growth, hepatitis serology negative, anti glomerular basement membrane (GBM) negative, antinuclear cytoplasmic antibodies (ANCA) negative, ANA negative, CRP 25.2 mg/l. CVVH was commenced. A portable ultrasound scan of abdomen was normal.

The patient's condition stabilized and she was discharged from intensive care on day 7. A departmental abdominal ultrasound scan revealed a 3.7-cm mass superior and medial to the upper pole of the right kidney. An MIBG scan using 123Iodine as isotope was negative. Blood pressure was consistently elevated at around 170/100 mmHg. Her 24-h (low volume, therefore analysed as random sample) urinary adrenaline was 0.12 µmol/µmol of creatinine (normal <0.3); urinary noradrenaline 0.27 µmol/µmol of creatinine (normal <0.25); urinary dopamine 0.08 µmol/µmol of creatinine (normal <0.7); plasma noradrenaline 10.30 nmol/l (normal <5); plasma adrenaline 1.71 nmol/l (normal <1); PTH 49 ng/ml, TSH 11.24 mIU/l (normal 0.45–7.00), free T4 18.2 pmol/l (normal 9.5–23), calcitonin 1 mIU/l (normal <2). Phenoxybenzamine was commenced for hypertension and in view of persisting oliguria and heavy proteinuria, a kidney biopsy was performed. Histology revealed severe acute tubular necrosis. The urine output improved and the patient became dialysis independent 30 days from the initial presentation. Renal biochemistry and urinary protein excretion subsequently returned to normal.

Laparoscopic adrenalectomy was performed after symptoms were controlled with phenoxybenzamine and propranolol. Histology of resected tissue confirmed the presence of encapsulated phaeochromocytoma with no mitotic activity (Figures 3aGo, bGo). Repeat measurements of plasma and urinary catecholamines were within normal limits.



View larger version (171K):
[in this window]
[in a new window]
 
Fig. 3. (a) An expansile tumour of the adrenal medulla, compressing adjacent cortex (arrow). The tumour is composed of clusters of cells separated by highly vascular stroma, characteristic of phaeochromocytoma (H&E, x40). (b) At high magnification, tumour cells form nests and trabeculae; they have round nuclei, moderate amount of finely granular cytoplasm, without cellular pleomorphism or mitotic activity. Tumour cords are separated by abundant highly vascular stroma (H&E, x200).

 

Discussion

These two cases demonstrate several important clinical points, which will be considered after a brief overview of epidemiology, clinical features, investigation, and management of phaeochromocytoma.

Epidemiology
The incidence of phaeochromocytoma is about 0.1% in the hypertensive population. Phaeochromocytomas typically arise from the adrenal medulla but may develop from chromaffin cells in or around sympathetic ganglia. Eighty per cent of tumours are unilateral, predominantly right sided. Ten per cent are bilateral (usually familial). Five per cent of familial cases follow an autosomal dominant pattern of inheritance and occur either alone or in combination of multiple endocrine neoplasia (MEN) 2a, MEN 2b, Von Recklinghausen's disease, or Von Hippel Lindau retinal cerebellar haemangioblastoma. About 10% of phaeochromocytomas in adults are extra-adrenal and are more likely to be malignant. In children 25% phaeochromocytoma are bilateral and 25% are extra-adrenal. It has been hypothesized that necrosis and changes in blood flow within the tumour may trigger release of catecholamines.

Clinical features
Sixty per cent of patients have sustained hypertension, whereas the remainder have only transient elevation of blood pressure during a crisis. The crisis typically consists of headache, profuse sweating, palpitations, chest or abdominal pain associated with nausea and vomiting and apprehension with an impending sense of doom.

Beta-blocker therapy can produce unopposed alpha-receptor stimulation and thereby increase the risk of a crisis. Crises may be precipitated by other drugs such as opiates, indirectly acting sympathomimetic drugs such as methyldopa, tricyclic antidepressants such as imipramine, guanethidine, adrenocorticotrophins, and glucagon.

Catecholamines excess may produce various arrhythmias such as sinus bradycardia, sinus tachycardia, and supraventricular tachycardia. Cardiomyopathy, either congestive or hypertrophic with concentric or asymmetric hypertrophy, may develop secondary to the toxic effects of catecholamines and/or chronic hypertension [1]. Rarely, patients present acutely with multi-system organ failure and pulmonary oedema. Renal failure in such instances may be due to intense intra-renal vasoconstriction caused by catecholamines in addition to cardiogenic shock.

There may be transient but massive proteinuria, which might be explained by hyperfiltration due to increased intra-glomerular hydrostatic pressure (constriction of efferent arterioles) or increased glomerular basement membrane permeability [2]. Rhabdomyolysis is due to intense vasoconstriction of blood vessels [3]. Hypotension may occur, possibly as a result of rapid fluctuation in vascular tone and suppression of baroreceptor signalling. Some tumours may secrete a variety of vasodilatory compounds.

There are many other reported features associated with phaeochromocytoma. Hypercalcaemia may be due to associated hyperparathyroidism as a part of MEN 2a syndrome [4]. Catecholamines stimulate triglyceride synthesis, and hence patients may have increased plasma triglyceride [5]. Increased production of interleukin-6 and decreased heat dissipation along with increased basal metabolic rate may increase the body temperature. Catecholamine-induced carbohydrate intolerance may lead to hyperglycaemia in 50% of patients [5].

Investigations
Elevated urinary catecholamines support a diagnosis of phaeochromocytoma. A reliable laboratory result depends on a 24-h urinary collection being obtained during a crisis. The collected urine must be acidified and refrigerated. The patient should be at rest, on no medications, and with no recent exposure to contrast media.

Urinary vanillyl mandelic acid is less specific. False positive results may occur because of concurrent therapy with methyldopa, levodopa, labetolol, clonidine withdrawal, hypoglycaemia, raised intracranial pressure and strenuous exercise. Plasma catecholamines may be normal or slightly elevated in one-third of patients with phaeochromocytoma.

Localization of the tumour is achieved by ultrasonography, computerized tomography, MRI, or an MIBG radioisotope scan. The radioiodine is taken up by the tumour cells during synthesis of catecholamines. The sensitivity and specificity of MIBG scanning has been reported as 87.5 and 100% respectively, with a positive predictive value of 100% and a negative predictive value of 77.7% [6]. [123I]MIBG scan gives superior dosimetry and better detection efficiency as compared to [131I]MIBG scan. In addition, the false negative rate with [131I]MIBG scan may be as high as 13% [7,8]. Some tumours do not accumulate MIBG, as in case 2, and may be better detected with positron emission tomography using 2-[fluorine-18]-fluoro-2-doexy-D-glucose (FDG) as the isotope [9].

Management
Non-selective alpha blockers are the preferred anti-hypertensive therapy as hypertensive crises have been reported when selective alpha 1 blockers have been used. Initial control of blood pressure should be achieved with phenoxybenzamine, which should be given for 8–10 days prior to surgery during which time the intra-vascular status should be normalized. Beta blockers may then be added to control tachycardia. Serial cardiac echocardiography may help to detect cardiomyopathy and avert complication during or after the surgery. Prior to surgery there is a risk of precipitating hypertension, and after surgery there is risk of hypotension because of precipitous reduction in vascular tone. Premedication with atropine should be avoided as it can cause tachycardia. In addition, morphine and phenothiazines should be avoided as they cause increased catecholamine release.

Teaching points

Several features of phaeochromocytoma are highlighted in the index cases. Firstly, neuroendocrine tumours are often histologically benign but may produce serious complications [3,4,10]. Secondly, a diagnosis of phaeochromocytoma should be formally excluded in cases where symptoms such as anxiety, headache and palpitations occur frequently. This is especially important, as treatment for conditions that present similarly (migraine, anxiety neurosis) may encourage use of beta-blocker therapy and thereby increase the risk of complications arising from unopposed alpha-receptor stimulation. Thirdly, the occurrence of hypercalcaemia and hypoglycaemia should prompt further investigations to exclude a multiple endocrine disorder (e.g. MEN2a) [4]. Bundle branch block, a raised creatinine phosphokinase, and a grossly elevated protein–creatinine index have been occasionally reported in other cases of phaeochromocytoma and may provide useful clues where there is diagnostic uncertainty [2,3]. Finally, early sonographic imaging of the suprarenal area may provide important information with which to guide management. [131I]-MIBG scan may be needed for improved visualization [6,7,8]. Tumours which do not accumulate MIBG may need positron emission tomography scan and administration of FDG [9].

Acknowledgments

The authors wish to thank Mr Landsdown for his surgical support in the management of both cases and Dr Judie Wyatt for histopathology slides and the results.

Notes

Supported by an educational grant from

Correspondence and offprint requests to: A. M. Davison, Renal Unit, St James's University Hospital, Beckett Street, Leeds LS9 7TF UK. Email: alex.davison{at}gw.sjsuh.northy.nhs.uk Back

References

  1. Hamada N, Akamatsu A, Joh T. A case of pheochromocytoma complicated with acute renal failure and cardiomyopathy. Jpn Circ J1993; 57: 84–90[ISI][Medline]
  2. Takabatake T, Hawabata M, Ohta H et al. Acute renal failure and transient, massive proteinuria in a case of phaeochromocytoma. Clin Nephrol1985; 24: 47–49[ISI][Medline]
  3. Shemin D, Cohn PS, Zipin SB. Pheochromocytoma presenting as rhabdomyolysis and acute myoglobinuric renal failure. Arch Intern Med1990; 150: 2384–2385[Abstract]
  4. Lorz W, Cottier C, Imhof E, Gyr N. Multiple organ failure and coma as initial presentation of pheochromocytoma in a patient with multiple endocrine neoplasia (MEN) type II A. Intensive Care Med1993; 19: 235–238[ISI][Medline]
  5. Rofougaran R, Mooraki A, Bastani B. Insulin requiring diabetes mellitus, hyperlipidemia and anginal chest pains as prominent features of pheochromocytoma. Am J Nephrol1997; 17: 474–476[ISI][Medline]
  6. Clesham CJ, Kennedy A, Lavender JP, Dollery CT, Wilkins MR. Meta-iodobenzylguanidine (MIBG) scanning in the diagnosis of pheochromocytoma. J Hum Hypertens1993; 7: 353–356[ISI][Medline]
  7. Lynn MD, Shapiro B, Sisson JC et al. Pheochromocytoma and the normal medulla: improved visualisation with I-123 MIBG scintigraphy. Radiology1985; 155: 789–792[Abstract]
  8. Gough IR, Thompson NW, Shapiro B, Sisson JC. Limitations of 131 I-MIBG scintigraphy in locating pheochromocytomas. Surgery1985; 98: 115–120[ISI][Medline]
  9. Shulkin BL, Koeppe RA, Francis IR et al. Pheochromocytoma that do not accumulate meta-iodobenzylguanidine: localisation with PET and administration of FDG. Radiology1993; 186: 711–715[Abstract]
  10. Raman GV. Pheochromocytoma presenting with cardiogenic shock and acute renal failure. J Hum Hypertens1987; 1: 237–238[ISI][Medline]