What is the cause of hemolysis in patients with cirrhosis?

Causes of Hemolysis in Cirrhosis

Hemolysis in cirrhosis occurs through multiple distinct mechanisms, with the most important being eriptosis (premature red blood cell death induced by elevated bilirubin and bile acids), hypersplenism with accelerated platelet and red cell turnover, and in specific cases, copper-mediated hemolysis in Wilson's disease. 1

Primary Mechanisms of Hemolysis

Eriptosis and Bilirubin-Induced Red Cell Death

• Elevated bilirubin and bile acids directly induce premature erythrocyte death through a process called eriptosis, creating a vicious cycle where hemolysis generates more bilirubin, which in turn causes more eriptosis 1
• Patients with hyperbilirubinemia demonstrate significantly lower red blood cell counts and significantly higher reticulocyte counts, reflecting this accelerated destruction and compensatory response 1
• The liver's Kupffer cells serve as the primary site for removing these damaged, eriptotic erythrocytes in pathological conditions 1

Hypersplenism and Accelerated Turnover

• Portal hypertension leads to splenomegaly with sequestration and accelerated destruction of red blood cells, affecting up to 80% of cirrhotic patients 1
• Decreased thrombopoietin synthesis, splenomegaly-related sequestration, and accelerated platelet turnover all contribute to cytopenias 2
• The combination of decreased megakaryocyte production and increased splenic sequestration compounds the hematologic abnormalities 2

Low-Grade Intravascular Hemolysis

• Low-grade intrahepatic and systemic activation of the hemostatic system results in consumption of hemostatic proteins and red blood cells 2
• Chronic hemolysis due to hypersplenism is a well-recognized mechanism in cirrhosis 3

Disease-Specific Causes

Wilson's Disease

• In Wilson's disease with cirrhosis, massive copper release from decaying liver cells causes severe Coombs-negative hemolytic anemia, particularly during acute liver failure episodes 2
• Marked hemolysis is commonly associated with severe liver disease in Wilson's disease, occurring as the presenting feature in approximately 10-20% of cases 2
• This can occur as single acute episodes, recurrent episodes, or chronic low-grade hemolysis 2

Alcoholic Liver Cirrhosis

• A soluble variant of the asialoglycoprotein receptor (s-ASGP-R) found in 36% of alcoholic cirrhosis patients can bind to erythrocyte surfaces and cause agglutination and hemolysis through mechanical shear stress 4
• This non-immunological mechanism is particularly prominent in patients with blood group A1 4

Primary Biliary Cirrhosis

• Autoimmune hemolytic anemia can coexist with primary biliary cirrhosis, though this association may be underrecognized 5, 6
• Hemolysis in these patients can cause bilirubin levels to rise out of proportion to the severity of the underlying liver disease, potentially confusing clinical assessment 6

Contributing Factors

Nutritional Deficiencies

• Deficiencies of iron, folate, vitamin B12, and vitamin B6 contribute to anemia and should be optimized, especially before invasive procedures 1

Renal Dysfunction

• Renal insufficiency (creatinine >1.2 mg/dL) is an independent predictor of anemia in cirrhosis, present in 19% of transplant candidates and associated with significantly higher rates of anemia (64% vs 34%) 7

Gastrointestinal Bleeding

• Bleeding from portal hypertension, esophageal varices, and portal hypertensive gastropathy contributes to anemia through blood loss rather than true hemolysis 1

Clinical Pitfalls

• Do not attribute all anemia in cirrhosis to chronic disease or gastrointestinal bleeding—actively investigate for hemolysis, particularly when bilirubin rises disproportionately 6
• In Wilson's disease patients presenting with acute liver failure, suspect copper-mediated hemolysis when you see deep jaundice, low hemoglobin, low cholinesterase, mildly elevated transaminases, and low alkaline phosphatase 2
• Consider autoimmune hemolytic anemia in primary biliary cirrhosis patients who develop anemia years after stable disease or liver transplantation 5
• Measure reticulocyte counts and markers of hemolysis (LDH, haptoglobin) to distinguish true hemolysis from other causes of anemia in cirrhosis 1