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. 

-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