What is the clinical significance of Chromogranin A (CHGA)?

From the Guidelines

Chromogranin A is a crucial biomarker for diagnosing and monitoring neuroendocrine tumors (NETs), and its levels should be interpreted with caution due to potential false elevations from various factors, as evident from studies such as 1. When evaluating a patient with suspected NET, a chromogranin A blood test should be ordered as part of the initial workup.

• Normal levels typically range from 0-100 ng/mL, though reference ranges may vary between laboratories.
• Elevated chromogranin A levels can indicate the presence of NETs such as carcinoid tumors, pheochromocytomas, or pancreatic neuroendocrine tumors. However, interpretation requires caution as false elevations occur with:
• Proton pump inhibitor use (medications like omeprazole or pantoprazole) 1.
• Renal failure.
• Heart failure.
• Inflammatory bowel disease.
• And other conditions. Patients should discontinue proton pump inhibitors for at least 2 weeks before testing when possible.

Key Points to Consider

• Serial measurements of chromogranin A can help monitor treatment response and disease progression in patients with confirmed NETs.
• The test's utility comes from chromogranin A's role as a precursor protein stored in secretory granules of neuroendocrine cells, which is released into circulation when these cells are active or proliferating abnormally.
• Elevated chromogranin A levels are associated with shorter survival times for patients with metastatic NETs, as shown in studies like 1, highlighting the importance of accurate interpretation and monitoring. Some studies, such as 1, also discuss the role of chromogranin A in pulmonary neuroendocrine tumors, but the most relevant and recent evidence for clinical practice is provided by 1.

From the Research

Clinical Significance of Chromogranin A (CHGA)

• Chromogranin A (CgA) is a serum marker for neuroendocrine tumors and has also been associated with some non-neuroendocrine tumors 2.
• Elevated CgA levels have been found in approximately 50% of patients with non-neuroendocrine tumors, suggesting a possible role for somatostatin analogues in the treatment of these tumors 2.
• CgA levels can be used as a marker for non-functioning neuroendocrine tumors, for which no peptide marker is available 3.
• Serum CgA measurement has a modest sensitivity for the diagnosis of non-functioning neuroendocrine tumors, but increases in CgA levels combined with imaging may be helpful in detecting tumor progression in patients with neuroendocrine tumors 4.
• CgA can serve as a serum marker for neuroendocrine activity because it is co-released with the peptide hormone content of the secretory granules 3.
• The serum concentration of CgA is elevated in patients with various neuroendocrine tumors, and elevated levels are strongly correlated with tumor volume 3.
• CgA is a more stable and easily manageable marker than plasma levels of serotonin and catecholamines and their urinary metabolites in patients with carcinoids and phaeochromocytomas 3.
• Circulating CgA and its fragments can serve as diagnostic and prognostic disease markers for a wide range of neuroendocrine tumors and other diseases, including cardiovascular, gastrointestinal, and inflammatory diseases 5.
• However, CgA is an unspecific neuroendocrine marker, and its non-specificity and the existence of a number of pathological processes leading to an increase in its concentration can often result in confusion and diagnostic difficulties 6.

Diagnostic and Prognostic Value

• The diagnostic value of serum CgA in well-differentiated non-functioning neuroendocrine tumors has been evaluated, and a cutoff value of 84 ng/mL has been suggested, with a sensitivity of 67% and a specificity of 78% 4.
• Increases in CgA levels combined with imaging may be helpful in detecting tumor progression in patients with neuroendocrine tumors, with a sensitivity of 79% and a specificity of 86% for a 28% increase in serum CgA concentration 4.
• Measuring total-CgA, full-length CgA, specific fragments, and their relative levels can provide a more thorough assessment of the pathophysiological function and diagnostic/prognostic value of the CgA system 5.

Clinical Utility and Potential Pitfalls

• CgA is still the most valuable marker of neuroendocrine tumors, despite its limitations 6.
• The awareness of potential causes influencing the false results of CgA concentrations can simplify diagnosis and treatment 6.
• The molecular structure of CgA is characterized by a number of sites susceptible to the proteolytic activity of enzymes, resulting in the formation of a number of biologically active peptides 6.