What are the causes and management of elevated chromogranin A (CgA) levels?

Causes of Elevated Chromogranin A

Elevated chromogranin A (CgA) is most commonly caused by neuroendocrine tumors, but spurious elevations occur frequently from proton pump inhibitor use, renal failure, liver failure, hypertension, and chronic gastritis—these must be excluded before attributing elevation to malignancy. 1, 2

Neuroendocrine Tumor Causes (True Positives)

CgA is elevated in 60% or more of patients with functioning or nonfunctioning pancreatic neuroendocrine tumors, making it the best general neuroendocrine serum marker available. 1, 2 The frequency and magnitude of elevation varies by tumor type:

High-Frequency Elevations

• Gastrinomas: 100% of patients have elevated CgA 3
• Pheochromocytomas: 89% of patients 3
• Carcinoid tumors: 80% of patients, with the highest absolute levels observed in this group 3, 4
• Nonfunctioning pancreatic NETs: 69% of patients 3

Moderate-Frequency Elevations

• Medullary thyroid carcinomas: 50% of patients 3
• Small cell lung cancer: Less frequently elevated than in well-differentiated NETs 5
• Bronchial typical carcinoids: Characteristic finding per European Society for Medical Oncology 2

Correlation with Disease Burden

CgA levels strongly correlate with tumor volume and metastatic spread. 2, 3, 4 Patients with metastatic disease have significantly higher levels (median 44-64 nmol/L) compared to those with localized disease (median 6 nmol/L). 4 Levels ≥2 times the upper limit of normal are associated with shorter survival (HR 2.8; 95% CI 1.9-4.0; P<0.001). 2

Non-Neuroendocrine Causes (False Positives)

Medication-Induced Elevation

Proton pump inhibitors are the most common cause of spuriously elevated CgA and must be discontinued for at least 1-2 weeks before interpreting results. 1, 2, 6 This is the single most important pitfall to avoid. 6 Antacids can also elevate levels. 1

Organ Dysfunction

• Renal failure/impairment: Causes spurious elevation independent of neuroendocrine pathology 1, 2, 7
• Liver failure/hepatic insufficiency: Elevates CgA independently of tumors 1, 2, 6

Gastrointestinal Conditions

• Atrophic gastritis: Causes elevated CgA due to enterochromaffin-like (ECL) cell hyperplasia 1, 7
• Chronic gastritis: Listed as a cause of false elevation 1, 2

Cardiovascular

• Hypertension: Can increase CgA levels alone 1, 2, 6

Malignancies with Neuroendocrine Differentiation

CgA is elevated in 44% of patients with non-neuroendocrine malignancies when neuroendocrine differentiation occurs. 5 Specific examples include:

• Adenocarcinomas: 6 of 153 patients with adenocarcinomas had elevated CgA, with high proportions of CgA-positive cells detected using sensitive immunohistochemistry techniques 7
• Hepatocellular carcinoma: Elevated in 43% of patients (32 of 79), suggesting possible neuroendocrine differentiation 8

Diagnostic Algorithm for Elevated CgA

Step 1: Exclude False Positives

Before proceeding with tumor workup, systematically rule out:

1. Confirm patient is off proton pump inhibitors for ≥1-2 weeks 2, 6
2. Assess renal function (creatinine, GFR) 2, 6
3. Evaluate liver function (transaminases, bilirubin) 2, 6
4. Check blood pressure 2, 6
5. Evaluate for chronic gastritis or atrophic gastritis 1, 7

Step 2: Imaging Localization

If false positives are excluded, proceed with:

• Multiphasic CT or MRI of abdomen and pelvis as initial imaging 1, 6, 9
• Somatostatin receptor scintigraphy (Octreoscan) to detect tumors missed by CT/MRI 1, 6, 9
• Endoscopic ultrasound (EUS) for suspected pancreatic lesions, particularly small insulinomas 1, 6

Step 3: Syndrome-Specific Biochemical Testing

Based on clinical presentation:

• 24-hour urinary 5-HIAA for carcinoid syndrome (avoid avocados, bananas, coffee for 48 hours before collection) 2, 6, 9
• Fasting gastrin levels for gastrinoma (off PPIs ≥1 week) 1, 6
• Serum VIP for VIPoma with watery diarrhea 6
• Fasting insulin, C-peptide, proinsulin for insulinoma 6

Critical Interpretation Caveats

Markedly elevated CgA levels >300 μg/L have high specificity: Only 2% of control patients versus 40% of NET patients have levels this high, making extreme elevations highly suggestive of neuroendocrine malignancy. 3

Normal CgA does not exclude NET: Since only 60% of NETs have elevated CgA, a normal level cannot rule out the diagnosis. 2, 6

Rising CgA with stable imaging does not mandate treatment change: Asymptomatic patients with stable imaging but rising CgA do not necessarily require new therapy. 2, 6

CgA has limited value in lung NETs: A meta-analysis showed diagnostic sensitivity of only 62% (range 25-93%) with poor predictive value and no correlation with disease state in most studies. 1