Hemolysis in liver disease by itself usually is not of overwhelming clinical importance, but it may contribute to the severity of anemia when coupled with defects in RBC production and the type of gastrointestinal blood loss that occurs in several forms of liver disease. Hemolysis in patients with liver disease has several causes. The spleen may be enlarged as a consequence of portal hypertension and produce a hyper splenic picture, a phenomenon seen commonly in hepatic cirrhosis.
A classic red cell manifestation of liver disease is the appearance of target cells. The literature on RBC shape change in liver disease is considerable. The target cell in cirrhosis has an increased SA:V that appears to be a consequence of increased cholesterol and phospholipid content of the membrane bilayer. The cholesterol increase is usually proportionately greater, resulting in an increased cholesterol to-phospholipid ratio. This increase in lipid probably accounts for the increased RBC surface area, such that more membrane than usual is present in relation to cellular contents. These RBCs probably circulate as bell-shaped RBCs called codocytes. However, on dried blood films, they assume the appearance of target cells. Target cells do not have a shortened survival. Their volume (MCV) is in the normocytic range, in contrast to the microcytic target cells seen in thalassemia and in advanced iron deficiency anemia. The RBCs of patients with liver disease frequently are echinocytes when wet preparations are examined, but these echinocytes are not easily apparent on dried blood smears. The echinocytes seem to be produced by a material in the patient’s plasma that causes normal RBCs to become echinocytic; this material is an abnormal echinocytogenic high-density lipoprotein. Echinocytes do not necessarily have a shortened survival. Some forms of echinocytic RBCs are normally deformable when studied in the ektacytometer or rheoscope.
A brisk, clinically important hemolysis can occur in some patients with severe liver disease. The peripheral smear in these individuals usually shows acanthocytes (i.e., distorted RBCs). Extreme forms are called spur cells, which are probably acanthocytes additionally remodeled by an enlarged spleen and are considerably enriched in cholesterol. They are rapidly removed in the spleen, which is usually enlarged.
Increased RBC membrane proteolytic activity may be a partial explanation for the differences between acanthocytosis and spur cells, and additional pathophysiologic mechanisms may be involved. Although the adult RBC cannot synthesize phospholipids de novo, it can identify and remove peroxidized fatty acid chains that interfere with normal membrane lipid fluidity. When the fatty acid is removed, a lytic lysoderivative remains; therefore, the missing fatty acid chain must be replaced. A store of acyl groups in the form of acylcarnitine exists in RBC membranes. When needed, the fatty acid (i.e., acyl group) is transferred to acyl-coenzyme A and then inserted into the potentially lytic lysophospholipid by the enzyme lysophosphocholine acyltransferase. Lysophosphocholine acyltransferase is inhibited in spur RBCs, and the same inhibition can be produced by heavily loading RBCs with cholesterol in vitro.
In spur cell anemia, the RBCs have an abnormal membrane SA:V ratio, their membrane fluidity is impaired, and they are unable to remove and repair peroxidatively damaged fatty acids. Occasionally, spur cell hemolytic anemia is severe enough to necessitate the consideration of splenectomy. Operative morbidity in such cases is consider able because the underlying liver disease usually produces problems with thrombocytopenia and leukopenia, as well as with procoagulants and intolerance to anesthesia. Spur cell anemia is typically associated with alcoholic cirrhosis, but it can also be seen in patients with nonalcoholic cirrhosis. The anemia tends to be severe and portends a poor prognosis. Transfusions are of limited efficacy because the mem brane abnormalities are acquired by transfused RBCs.
Acute alcoholism can be associated with hypophosphatemia, defined as levels less than 0.2 mg/dL. Such hypophosphatemia presumably interferes with RBC intermediary metabolism, and RBC adenosine triphosphate (ATP) levels fall. Very low ATP levels are associated with RBC rigidity, which leads to fragmentation, loss of surface area, and spheroidicity. The RBCs then are further trapped in the spleen. This hypophosphatemia syndrome can also cause neuromuscular disorders, including weakness, paresthesias, tremors, and seizures. It should be treated aggressively with orally and intravenously administered phosphate supplements. Hypophosphatemia also occurs in patients with cirrhosis, patients receiving total parenteral nutrition whose phosphate intake is not carefully monitored, and patients taking large amounts of phosphate-binding antacids.
Stomatocytosis can occur in severe liver disease and is thought to be a sign of acute alcoholic intoxication. The change in RBC shape can also be seen in acute pancreatitis. The stomatocyte is a cell well on its way to becoming a spherocyte. The reduction in SA:V leads to trapping in the microvasculature of the spleen and other organs of the monocyte–macrophage system, producing various degrees of hemolysis.
