What Causes Elevated Chromogranin A Levels?

Chromogranin A belongs to the family of proteins known as grains that are mostly produced by endocrine and neuroendocrine cells. Therefore, it is an accepted biomarker for the assessment of neuroendocrine tumors. In the past, it was used in the management of patients with tumors of the gastroenteropancreatic origin. However, lately, it has been associated with various other conditions, including both benign and malignant. The sensitivity and specificity of chromogranin A in all of these conditions differ significantly that depends on various factors; therefore, its use is limited as an effective prognostic and predictive biomarker for a narrow spectrum of conditions and diseases. It is specifically used as a biomarker in oncology.(1)

What Causes Elevated Chromogranin A Levels?

Non-Neuroendocrine Tumors

There are various causes of elevated chromogranin A (CgA) levels that are unrelated to neuroendocrine tumors. The most common causes of non-neuroendocrine tumors (false-positive result) encountered in the clinical practice is the use of proton pump inhibitors (PPIs), atrophic gastritis cases and impaired kidney function. (2)

The use of proton pump inhibitors and other acid-suppressive medications stimulate the growth of enterochromaffin cells to secrete CgA resulting in elevated levels of CgA in circulation. PPIs lead to increased concentrations, about 5-10 times of CgA within 5 days of medication intake, which is seen in the early stages of neuroendocrine tumors. Histamine type-1 receptor antagonists are also related to increasing in CgA levels. Kidney failure and reduced renal clearance also lead to elevated levels of CgA.

Chronic heart failure is also associated with increased levels of CgA and the levels are related to the intensity of heart failure.(2)

Other causes of elevated levels of CgA include hypertension, inflammatory bowel diseases, irritable bowel syndrome, pancreatitis, chronic hepatitis, liver cirrhosis, systemic rheumatoid arthritis, systemic lupus erythematosus, chronic obstructive pulmonary disease, Parkinson’s disease, steroid treatment, food intake or strenuous exercise before a test.(2)

Non-neuroendocrine tumors that can lead to elevated levels of CgA include prostate cancer, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, hepatocellular carcinoma, and hematological malignancies. The elevated levels of CgA in prostate cancer are related to progression, poor prognosis and resistance to hormonal therapy. The elevated levels of CgA cannot be used to assess the severity or progression of disease in non-neuroendocrine neoplasms as the tumor size does not correlate with tumor size or disease progression.(2)

Neuroendocrine Tumors

The neuroendocrine neoplasms, such as pheochromocytomas, parathyroid adenomas, medullary thyroid cancer, pituitary tumors (except prolactinomas), pulmonary neuroendocrine tumors including small cell lung cancer and gastroenteropancreatic neuroendocrine tumors (GEP-NETs) secrete CgA. Therefore, the elevated concentration of chromogranin A is used as a marker of tumors in different diseases. A 100% elevation of CgA is seen in gastrinomas, 89% in pheochromocytomas, 80% in neuroendocrine tumors of the small intestine, 69% in non-functioning pancreatic neuroendocrine tumors, and >50% in medullary thyroid cancer.(2)

CgA is the recommended first-line marker of GEP-NETs. It is significant in the diagnosis, prognosis, clinical evaluation after cytoreductive surgery, and follow up of these tumors. The GEP-NETs that secrete CgA are associated with increased tumor burden and recurrence as well as a marker of poor prognosis and reduced survival in ileal and pancreatic neuroendocrine tumors. The decrease in CgA levels has also been used as a marker of response to treatment. The highest levels of CgA are seen in patients with functioning ileal neuroendocrine tumor and carcinoid syndrome along with liver metastases. Metastases to lymph nodes do not cause significant elevation of CgA levels.(1)

The sensitivity and specificity of CgA for various neuroendocrine tumors range from 60-100% and 70-100%, respectively, and the highest value is observed for serotonin-secreting neuroendocrine tumors (carcinoid tumors). Caution should be kept in mind during the interpretation of chromogranin A as various factors can lead to false-positive as well as false-negative results. The greatest value of CgA as a marker of the disease can be seen in metastatic disease to the liver.(2)