Phaeochromocytoma and Diabetes Mellitus

Phaeochromocytomas are rare tumors arising from the intra or extra-adrenal chromaffin cells that produce, store and metabolise catecholamines. Ninety percent of them arise from the adrenal medulla and the rest (para-gangliomas) arise from extra-adrenal sites. Most phaeochromocytomas are either solitary or sporadic but sometimes they occur in familial endocrine tumour syndromes such as MEN IIa, IIb, von Recklinghausen’s neurofibromatosis and von Hipple Lindau disease. The prevalence of phaeochromocytoma can be estimated at 1:2,500 to 1:6,500 patients in Western countries. Phaeochromocytomas occur most often during young- to mid-adult life. Less than 10% of phaeochromocytomas are malignant. New onset hyperglycaemia or worsening of pre-existing diabetes may be the presenting feature in some patients with phaeochromocytoma. Very rarely, a patient with a phaeochromocytoma may present in diabetic ketoacidosis.

Historical aspects

The first description of the adrenal glands was in 1563 by Bartolomeo Eustachio, while the first study on the tumour of the adrenal glands is attributed to Felix Frankel, who, in 1886, described an 18-year-old woman with bilateral adrenal neoplasms. Later, in 1912, the pathologist Ludwig Pick formulated the descriptive term Phaeochromocytoma (from Greek: phaios, meaning dark, because the cells are stained with potassium dichromate; cromos, which refers to stained cells; kytos, meaning cell and oma meaning tumour). The first surgical removal of a phaeochromocytoma was performed by Cesar Roux in 1926 in Europe and by Charles Mayo in the USA in 1927.

Effects of catecholamines on glucose metabolism

Normally epinephrine is the predominant catecholamine secreted from adrenal medulla and it gets converted to norepinehrine by methylastion by the glucocorticoid dependant enzyme phenylethanolamine-M-methyltransferase (PNMT).[1] Epinephrine is more potent than norepinephrine in producing hyperglycemia because of its higher affinity to the β-2 adrenergic receptors. [2] Hyperglycaemic effect of epinephrine is due to its action on pancreatic β-cells and liver. In the pancreas, epinephrine inhibits insulin secretion mostly by stimulating α-2 adrenergic receptor and probably by inducing glucagon secretion via β adrenergic receptor. In the liver, epinephrine increases transient glycogenolysis and sustained gluconeogenesis by stimulating β-2 adrenergic receptors. This process is augmented by the increased availability of the gluconeogenic precursors like lactate, glycerol and alanine generated by β adrenergic stimulation of muscle glycolysis and adipose tissue lipolysis. β-2 adrenergic stimulation also induces insulin resistance at muscles resulting in reduced peripheral glucose utilisation. There has also been suggestion of post receptor insulin resistance caused by epinephrine.

Hyperglycaemia in Phaeochromocytoma

Epidemiological data on the prevalence and incidence of diabetes in patients with phaeochromocytoma is rather limited. In different series, approximately 35-50% of phaeochromocytoma patients were noted to have hyperglycaemia. [3] [4] Unlike the normal adrenal medulla that predominantly secretes epinephrine, most pheochromocytomas, especially large and extra-adrenal tumours, secrete norepinephrine as the predominant catecholamine. Hyperglycaemia, found in some patients with phaechromocytoma, is due to the most of the above mentioned mechanisms.

Clinical presentation

New onset hyperglycaemia or worsening of pre-existing diabetes may be the presenting feature in some patients with phaeochromocytoma. A varying combination of the classical features of catecholamine excess, such as headache, palpitation, anxiety, chest or abdominal pain, sustained or paroxysmal hypertension, excessive sweating in a newly diagnosed diabetic patient, or worsening of glycaemic status in a previously well controlled diabetic patient with some or all of the above features should arouse the suspicion of a phaechromocytoma. Many a times, the classical symptoms are absent, and the diagnosis is suspected only after an incidental discovery of an adrenal mass on imaging in a newly diagnosed or previously detected diabetic patient.

Diagnosis

Diagnostic criteria for diabetes mellitus are not any different in patients with co-existing phaeochromocytoma than those applicable to patients without a phaeochromocytoma. In an asymptomatic patient with a co-existing phaeochromocytoma, a fasting (8 hours) plasma glucose value ≥126 mg/dl (7.0 mmol/l) OR a 2-h plasma glucose value ≥200 mg/dl (11.1 mmol/l) during a 75g OGTT (with either value remaining elevated when repeated on another occasion) OR a casual plasma glucose ≥200 mg/dl (11.1 mmol/l) in a symptomatic patient is diagnostic of diabetes mellitus.

Investigations for the detection of a phaeochromocytoma in a patient with pre-existing or newly detected diabetes mellitus are essentially the same as those for a patient without hyperglycaemia. Recommended initial tests are 24-h urinary free catecholamines and fractionated metanephrines, or plasma fractionated metanephrines or both. The diagnostic accuracy may be slightly better with the measurements done in plasma than urine, but the facility is not widely available. An elevation of more than 4-fold above the normal upper reference interval is associated with close to 100% probability of the presence of a catecholamine-secreting tumour but any elevation more than 2-fold above the normal upper reference interval necessitates the initiation of investigations to localise a phaeochromocytoma. Contrast enhanced CT scan[5] or MRI is the method of choice for tumour localisation. 123I- or 131I-meta-iodobenzylguanidine (mIBG) scan is specific for the detection of these lesions.[6]

Treatment of hyperglycaemia in a patient with a phaeochromocytoma

The severity of hyperglycaemia in patients with phaeochromocytoma is variable. In previously non-diabetic patients, usually it is either impaired glucose tolerance or mild to moderate hyperglycaemia not requiring insulin therapy.[7] Very rarely, diabetic ketoacidosis is a presenting feature of phaeochromocytoma. In patients with pre-existing diabetes, while undergoing evaluation of suspected pheochromocytoma, treatment of hyperglycaemia is no different than that in a diabetic patient without a phaeochromocytoma. Metformin remains the first line therapy unless contraindicated and just before and after any contrast study. Metformin improves insulin sensitivity at the hepatic site. There is not much evidence that other oral hypoglycemic agents have got any adverse effect and as such, they are not contraindicated. Studies have shown that α- and β- adrenergic receptor blockers, while effectively controlling cardiovascular symptoms, do not essentially reverse the hyperglycaemic effects of catecholamines, suggesting either that the dose of the adrenergic receptor blocking agents needed to control cardiovascular manifestations of pheochromocytoma is different than that needed for the normalisation of glucose metabolism, or there are other factors which may influence carbohydrate homeostasis apart from catecholamines. Definitive treatment of hyperglycaemia secondary to phaeochromocytoma is the surgical removal of the tumour once the diagnosis is confirmed.[8][9] Usual preparations and precautions for the management of a phaeochromocytoma are necessary before and during the surgery. Insulin is the treatment of choice during the peri-operative period. Most of the metabolic abnormalities, including hyperglycaemia, are corrected following the surgical removal of the tumour. Close monitoring of blood glucose and titration of insulin dose is mandatory since many patients develop hypoglycaemia after removal of the tumour.

References

  1. ^ Manger, W.M. and R.W. Gifford, Pheochromocytoma. J Clin Hypertens, 2002. 4(1): p. 62-72

  2. ^ Fonseca V,Boulox PM,.Phaeochromocytoma and paraganglioma. Bailliere’s clinical endocrinology and metabolism.1993;7:509-44.

  3. ^ Sacca L,Morrone G,Cicala M.Influence of epinephrine,norepineprine ans isoproterenol on glucose metabolism in normal man.J Clin Endo Metab 1980;50:680-4

  4. ^ Werbel SS,Ober KP.Phaechromocytoma:update on diagnosis,localization and management

  5. ^ Pacak K et al. (2007) Pheochromocytoma; Diagnosis, Localization and Treatment. Malden: Blackwell Publishing

  6. ^ Mukherjee JJ, Peppercorn D, Reznek RH, Patel V, Kaltsas G, Besser M, Grossman AB. CT imaging of PEffect of non-ionic contrast medium on circulating catecholamine levels. Radiology 1997; 227-231

  7. ^ Kaltsas GA, Mukherjee JJ, Grossman AB. The value of radiolabelled MIBG and octreotide in the diagnosis and management of neuroendocrine tumours. Annals Of Oncology 2001; 12 Suppl 2:S47-50

  8. ^ La Batide-Alanore, Agnèsa; Chatellier, Gillesb; Plouin, Pierre-Françoisa. Diabetes as a marker of pheochromocytoma in hypertensive patients. Journal of Hypertension: September 2003 - Volume 21 - Issue 9 - pp 1703-1707

  9. ^ Evanthia Diamanti-Kandarakis1, Evangelia Zapanti1, Maria-Helen Peridis2, Panayiotis Ntavos1, George Mastorakos2 Insulin resistance in pheochromocytoma improves more by surgical rather than by medical treatment .Hormones (Athens). 2003 Apr-Jun;2(2):119.

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