What are the causes of anemia in cirrhosis?

Causes of Anemia in Cirrhosis

Anemia in cirrhosis is multifactorial, with the primary mechanisms being portal hypertension-related bleeding (from varices, portal hypertensive gastropathy, and enteropathy/colopathy), nutritional deficiencies (iron, folate, vitamin B12, B6), hypersplenism with splenic sequestration, bone marrow suppression, hemolysis (including spur cell anemia and eriptosis), and renal insufficiency. 1, 2

Portal Hypertension-Related Bleeding

Portal hypertension is the dominant cause of chronic anemia in cirrhosis, manifesting through multiple mechanisms:

• Portal hypertensive gastropathy is the most common bleeding source, identified in 2-12% of acute gastrointestinal bleeding episodes but more importantly causes chronic occult bleeding and chronic anemia in the majority of cases 3
• Portal hypertensive enteropathy (small bowel) and portal hypertensive colopathy (colon) similarly cause chronic bleeding and chronic anemia, though they may occasionally present acutely 3
• Variceal bleeding from esophageal or gastric varices causes acute blood loss 3
• Gastric antral vascular ectasia (GAVE) causes bleeding that is typically not associated with portal hypertension itself but is common in cirrhosis 3, 2

Nutritional Deficiencies

Micronutrient deficiencies are extremely common and significantly contribute to anemia:

• Iron deficiency results from chronic occult or overt gastrointestinal bleeding and is the most common cause overall 1, 2, 4
• Folate (vitamin B9) deficiency is particularly prevalent in alcohol-related cirrhosis due to poor dietary intake and direct alcohol effects 3, 1, 2
• Vitamin B12 deficiency contributes to macrocytic anemia 3, 1, 2
• Vitamin B6 deficiency affects erythropoiesis 1, 2
• Iron supplementation is a significant predictor of hemoglobin increase and improved transplant-free survival 2

Hypersplenism and Splenic Sequestration

Splenic sequestration from portal hypertension causes cytopenias:

• 78% of patients with clinically significant portal hypertension develop cytopenias, including anemia from red blood cell sequestration 1
• Thrombocytopenia affects 80% of cirrhotic patients through this mechanism 1
• The prevalence increases with disease severity 5, 6

Hemolytic Mechanisms

Multiple hemolytic processes contribute to anemia in advanced cirrhosis:

• Eriptosis (premature red blood cell death) is induced by elevated bilirubin and bile acids, creating a vicious cycle where increased red cell destruction generates more bilirubin, which induces further eriptosis 1
• Patients with hyperbilirubinemia have significantly lower red blood cell counts and significantly higher reticulocyte counts 1
• Spur cell anemia occurs due to altered lipid composition of erythrocyte membranes (increased cholesterol-to-phospholipid ratio), leading to splenic sequestration and destruction; this indicates poor prognosis and high mortality risk 7, 4
• The liver's Kupffer cells are the primary site for removing damaged erythrocytes in cirrhosis 1

Bone Marrow Suppression

Direct marrow toxicity occurs through multiple mechanisms:

• Alcohol causes direct myeloid toxicity and is particularly important in alcohol-related cirrhosis 1, 4
• Hepatitis B and C viruses directly suppress bone marrow function 1, 5
• Aplastic anemia is best known as a sequela of viral hepatitis, but some degree of bone marrow inhibition can complicate virtually all advanced liver diseases 4
• In patients receiving interferon-based hepatitis C treatment, hematological adverse events (anemia, neutropenia, thrombocytopenia) are particularly frequent due to portal hypertension, hypersplenism, and direct drug effects 1

Renal Insufficiency

Renal dysfunction independently contributes to anemia:

• Anemia is significantly more common in cirrhotic patients with renal dysfunction (64% versus 34% in those with normal renal function) 8
• Creatinine is an independent predictor of anemia (OR 2.4,95% CI 1.05-5.3) 8
• Renal dysfunction reduces erythropoietin production 8

Clinical Algorithm for Evaluation

When evaluating anemia in cirrhosis, systematically assess:

1. Bleeding history: Look for melena, hematemesis, hematochezia, or occult bleeding 3
2. Nutritional status: Assess dietary intake, alcohol use, and check iron studies, folate, B12, and B6 levels 1, 2
3. Peripheral smear: Identify spur cells, macrocytosis, or other morphological abnormalities 7
4. Reticulocyte count: Elevated counts suggest hemolysis or bleeding; low counts suggest marrow suppression 1
5. Renal function: Check creatinine as an independent contributor 8
6. Viral hepatitis status: Active HBV or HCV can suppress marrow 1, 4
7. Bilirubin levels: Hyperbilirubinemia correlates with eriptosis 1

Critical Pitfalls to Avoid

• Do not assume all anemia is from bleeding—nutritional deficiencies and hemolysis are frequently underdiagnosed, with unclear cases reaching over 50% 4
• Do not overlook the peripheral smear—it is essential for identifying spur cells and other morphological clues 7
• Do not ignore renal function—it independently predicts anemia and is often overlooked 8
• Do not forget that anemia prevalence increases with disease severity, affecting 21% of compensated cirrhosis patients but 70% of all cirrhotic patients 3, 6, 4