Lecture notes on Pheochromocytoma: Hypersecretion of Catecholamines

Pheochromocytoma is a catecholamine-producing tumor

- Catecholamine producing tumors arising from chromaffin tissues

- Rare disorders with an annual detection rate of 2 to 5 per million.

- Hypertension is the most common symptom of Pheochromocytoma

- Other symptoms include palpitation, diaphoresis

- Most pheochromocytoma are benign with only 15% of adrenal tumors and 35% of extra-adrenal tumors being malignant

- Approximately 30% to 40% are hereditary. Mutation of the genes encoding succinate dehydrogenase, MYC associated factor X are some of the identified susceptibility genes.

Biochemical Basis

- Mechanisms of excessive production of catecholamines in the patients with pheochromocytoma is unclear

- the presence of tumors leads to a relatively large increase in the production of O-methylated metabolites.

- Multiple Endocrine Neoplasia syndromes (MEN) mainly MEN2A and MEN 2B manifest as pheochromocytoma in addition to thyroid carcinoma and others.

- MEN 2A (Sipple Syndrome) & MEN 2B are linked to mutation of RET proto-oncogene

-the pathway for the synthesis of catecholamine is described below

Biochemical Diagnosis

- Increased catecholamines (norepinephrine and epinephrine) in plasma and urine

- Increased metanephrines in urine (24hr collection) and plasma.

Treatment

-Surgical removal of the tumors

Biosynthetic Pathway of Catecholamines

Conversion of L-tyrosine to 3,4 dihydroxyphenylalanine (DOPA)

- Catalyzed by an enzyme tyrosine hydroxylase

- Rate limit enzyme for the synthesis of catecholamines

- Tyrosine hydroxylase is abundantly present in dopaminergic and noradrenergic neurons of CNS

- Feedback inhibition of activity by catecholamines

- Sympathetic & medullary systems in the peripheral tissue

- Require tetrahydrobiopterin as a co-factor

Conversion of DOPA to Dopamine

- Catalyzed by an enzyme DOPA carboxylase

- Present in a wide variety of tissue and have broad specificity for aromatic amino acids

- Dopamine formed in the cytoplasm is transported and stored as secretory granules

- Dopamine is exocytosed as the principal neurotransmitter of dopaminergic neurons

- L-Methyl DopA: an analog of inhibits DOPA decarboxylase and is useful for the treatment of hypertension

Conversion of Dopamine to Norepinephrine

- Catalyzed by an enzyme dopamine beta-hydroxylase

- The reaction occurs in noradrenergic neurons and chromaffin cell

Methylation of Norepinephrine to Epinephrine

- Catalyzed by an enzyme phenylethanolamine N-Methyl-Transferase

- S-Adenosyl Methionine serves as a methyl donor

Catabolic Pathway of Catecholamines

- All catecholamines are rapidly cleared from the target cells and circulation by three mechanism

- Reuptake into secretory vesicles

- Uptake in liver

- Degradation

- Degradation of catecholamines involves two enzyme

- Catechol-O-Methyl Transferase (COMT)

- Monoamine Oxidase

- Degradation of dopamine results in the formation of homovanillic acid (HVA)

- Degradation of norepinephrine results in the formation of vanillyl mandelic acid (VMA)

- Degradation of epinephrine results in the formation of metanephrine

- Free catecholamines and metabolites are eliminated filtration into the urine

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