What liver conditions can cause an increase in erythropoietin (EPO) levels?

Hepatocellular Carcinoma as the Primary Liver Condition Causing Elevated Erythropoietin

Hepatocellular carcinoma (HCC) is the liver condition that causes elevated erythropoietin levels through ectopic EPO production by malignant hepatocytes. 1

Mechanism of EPO Elevation in HCC

• HCC produces erythropoietin autonomously through hypoxia-independent pathologic mechanisms, representing ectopic hormone production by malignant tumor cells 1

• Immunohistochemical studies have definitively demonstrated EPO production within the cytoplasm and endoplasmic reticulum of HCC cells, but not in normal hepatocytes or other liver cells 2

• Approximately 23% of patients with HCC have elevated serum EPO concentrations, with values ranging up to 344 mU/mL, even in the absence of clinical erythrocytosis 3

• The mechanism involves mitochondrial DNA mutations in HCC cells that impair respiratory metabolism, leading to α-ketoglutarate depletion, hypoxia-inducible factor-α stabilization, and subsequent EPO gene expression 4

Clinical Presentation and Diagnostic Considerations

• Most HCC patients with elevated EPO do not develop overt erythrocytosis because advanced malignancy inhibits erythropoiesis, counteracting the stimulatory effect of EPO 3

• When erythrocytosis does occur with HCC, it portends poor prognosis through respiratory dysfunction and enhanced cancer stem cell self-renewal via autocrine/paracrine EPO signaling 4

• Hepatic vein EPO levels are significantly higher than hepatic artery levels in HCC patients, confirming hepatic production 2

• EPO levels decrease in parallel with tumor markers (AFP, PIVKA-II) following successful HCC treatment, confirming the tumor as the source 2, 5

Important Caveat: Fatty Liver Disease Does NOT Cause EPO Elevation

• Fatty liver disease (NAFLD/NASH) causes anemia through accelerated red blood cell destruction (eryptosis), not erythrocytosis or EPO elevation 6

• If a patient with fatty liver disease presents with elevated EPO or erythrocytosis, investigate alternative causes such as polycythemia vera (JAK2 mutations), chronic hypoxemia, renal tumors, or smoking 6

• Cirrhosis without HCC does not demonstrate enhanced hepatic EPO synthesis, with no significant differences in EPO concentrations across the liver in cirrhotic patients compared to controls 7

Clinical Algorithm

When evaluating elevated EPO in liver disease:

1. Screen for hepatocellular carcinoma with imaging (ultrasound, CT, MRI) and tumor markers (AFP, PIVKA-II) 2, 5

2. If HCC is confirmed, recognize that elevated EPO indicates poor prognosis and consider EPO signaling blockade as a potential therapeutic target 4

3. If no HCC is present, investigate non-hepatic causes of EPO elevation including renal cell carcinoma, cerebellar hemangioblastoma, parathyroid carcinoma, renal cysts, and pheochromocytoma 1

4. Evaluate for hypoxia-driven causes including cardiopulmonary shunts, high-altitude exposure, carbon monoxide poisoning, renal artery stenosis, and hemoglobinopathies 1