Spur Cell Anemia

The red blood cell membrane is composed of a lipid bilayer and proteins assembled in a complex manner that protects the red blood cell’s integrity and allows a bidirectional flux of electrolytes, energy, and information between the cell and its environment.[4]  To preserve the red blood cell’s shape and regulate the cell’s deformability and mechanical stability, the plasma membrane is tethered to a filamentous network of proteins known as the membrane skeleton.

The lipid bilayer contains nearly equal quantities (molar ratio of 0.9-1) of unesterified cholesterol and phospholipids asymmetrically distributed between the outer and inner leaflets. Phosphatidylcholine (30% of phospholipids) and sphingomyelin (30%) are found mainly in the outer layer, whereas phosphatidylethanolamine (28%) and phosphatidylserine (14%) reside in the inner layer.

Although the cholesterol contents of the membrane are in equilibrium with the plasma free cholesterol, the uneven distribution of phospholipids is maintained by passive and active processes.

Acanthocytes can result from abnormalities in membrane lipids and proteins. Lipid alterations impact the deposition of cholesterols and phospholipids in the red cell membrane. 

Acanthocytosis in severe liver disease

The formation of spur cells in severe liver disease is a two step process. First, free cholesterol in red blood cells equilibrates with abnormal lipoproteins containing a high ratio of free cholesterol to phospholipid, resulting in the preferential expansion of the outer leaflet and the development of the spur cell shape. Subsequently, remodeling by the spleen leads to the formation of acanthocytes with irregular bizarre projections.[5, 6, 7, 8, 9, 10]

A decrease occurs in polyunsaturated versus saturated and monounsaturated fatty acid content in red blood cells of patients with cirrhosis. This abnormality is more pronounced in patients with spur cell anemia, resulting in altered red blood cell shape and decreased cell fluidity.

An increase in the proteolytic activity of the erythrocyte membrane is also reported in spur cell anemia. The significance and role of this abnormality in changing the shape of the red blood cell and in hemolysis are unknown. [11]

The plasma of some patients exhibits decreased activity of lecithin cholesterol acyltransferase, resulting in increased free cholesterol in the outer layer of the red blood cell membrane as a direct consequence of its increased concentration in the plasma. After acquiring these abnormalities in the plasma, the red blood cells undergo a remodeling process in the spleen, which gives them the spheroidal shape with longer and more irregular projections.

Chorea-acanthocytosis

Alteration of band 3, the anion exchange protein, is thought to play a role in forming acanthocytes in chorea-acanthocytosis. [12]  According to this hypothesis, the red blood cell shape is controlled by the ratio of the outward-facing (band 3o) and inward-facing (band 3i) conformations of band 3. Depending on this ratio, there will be contraction (leading to echinocytosis) or relaxation (leading to stomatocytosis) of the membrane skeleton. [12] Most acanthocytic disorders are associated with acquired abnormalities of the outer leaflet of the lipid bilayer. However, some rare conditions feature normal lipids and abnormal membrane proteins.

Abetalipoproteinemia

In abetalipoproteinemia, B-apoprotein–containing lipoproteins (chylomicrons, very low-density lipoproteins [VLDL], low-density lipoproteins [LDL]) are nearly absent in the plasma. Plasma cholesterol and phospholipids are decreased, with a relative increase of sphingomyelin at the expanse of lecithin. At equilibrium, the sphingomyelin concentration in the outer leaflet increases, resulting in its expansion and acanthocytosis.

McLeod phenotype

The expression of the Kell antigen (the product of a single gene on band 7q23) on red blood cells, white blood cells, and monocytes is under the control of the Kx antigen encoded for by the XK gene on band Xp21.[13]  Both antigens are transmembrane proteins bound by a single disulfide bond. In the McLeod phenotype, the XK gene is deleted and the Kell antigen cannot be expressed, whereas in the Kell null phenotype, the Kell antigen is missing, and the Kx antigen is present at a normal level. The Kell null phenotype is not associated with hematologic disorders. [13]

The close proximity on the short arm of band Xp21 of the genes responsible for chronic granulomatous disease (CGD) of childhood, retinitis pigmentosa (RP), and Duchenne muscular dystrophy (DMD) explains the variable association of the McLeod phenotype with these diseases. Red blood cells from patients with chorea-acanthocytosis syndrome and McLeod phenotype do not show measurable abnormalities of the lipid bilayer.[14]

Focal membrane skeleton heterogeneity has been described as characterized by decreased compactness of the filamentous meshwork in the areas underlying the spikes. This focal weakness allows limited detachment of the lipid bilayer that does not result in membrane loss. The nature of the membrane skeleton abnormality is not known.

Acquired acanthocytosis is associated with advanced liver disease, regardless of the primary cause. Although alcohol abuse is the most common cause of chronic liver disease in Western societies, other entities have been recognized, including nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis.[15]  Anorexia nervosa, hypothyroidism, and myelodysplasia are rare causes of this disorder.

Neuroacanthocytosis is the term used for acanthocytosis associated with inherited disorders. The autosomal recessive disorders abetalipoproteinemia/aprebetalipoproteinemia (chromosome 2) and chorea-acanthocytosis syndrome (band 9q21), and the X-linked McLeod phenotype are among the conditions linked to neuroacanthocytosis.

More recently, alectinib, an anaplastic lymphokinase (ALK) inhibitor used for the treatment of non–small cell lung cancer, has been associated with spheroacanthocytosis without causing significant hemolytic anemia. A notable increase in the membrane cholesterol content was observed, but no significant abnormalities were present on liver function tests. The specific abnormality induced by alectinib is unknown; it is suggested that the drug affects the cytoskeleton during erythropoiesis.[16]

Spur cell anemia develops in 5% of all patients with severe liver disease. Abetalipoproteinemia is an uncommon disorder, inherited in autosomal-recessive pattern, that manifests in the first few months of life. Chorea-acanthocytosis syndrome and McLeod phenotypes are rare; only a few dozen cases have been published in the literature. Neurologic symptoms appear in patients aged 5-10 years and may progress to death in the second or third decade of life. In chorea-acanthocytosis syndrome, the median age at onset of symptoms is 32 years.

Spur cell hemolytic anemia in advanced liver disease indicates a poor prognosis; frequently, the condition precedes death by a few weeks to months.[17] Most patients die of gastrointestinal bleeding, hepatic encephalopathy, or sepsis.

Patients with abetalipoproteinemia develop functional deterioration early in life and do not survive beyond the third decade.

The course of chorea-acanthocytosis syndrome is slowly progressive, irreversible and, unrelenting. Death occurs within 8 -14 years of symptom onset. 

The signs and symptoms of spur cell anemia are related to the anemia and the underlying disease.

In spur cell anemia, the hemoglobin level usually falls to less than 10 g/dL and occasionally levels as low as 5 g/dL. This fall may be associated with severe jaundice and rapid deterioration of liver function, coagulopathy, and hepatic encephalopathy.

In its chronic presentation, the anemia accompanying the alcoholic cirrhosis is mild, whereas in the acute presentation, the anemia develops over weeks to months as liver function deteriorates.The course of spur cell anemia correlates with liver function. 

Spur cell anemia has been reported in cases of pediatric cholestatic liver disease.[6] In most cases, the condition is transient and resolves with the improvement of underlying liver disease.

Hemosiderosis is reported in 20% of patients undergoing orthotopic liver transplantation for alcoholic liver disease. Spur cell hemolytic anemia is present in 75% of these patients. In the absence of the C282Y/HFE hemochromatosis gene mutation, spur cell hemolytic anemia is postulated to be responsible for the hemosiderosis related to repeated blood transfusions and increasing intestinal iron absorption.

Acanthocytosis in abetalipoproteinemia

The clinical presentation of acanthocytosis in cases of abetalipoproteinemia includes ataxia, retinitis pigmentosa that may lead to blindness, and fat malabsorption. Symptoms related to the deficiency of lipid-soluble vitamins (ie, vitamins A, K, E, and D) may be seen. Spur cells (50-90%) are present on the peripheral smear, and the hemolysis and anemia are mild.

Abetalipoproteinemia is an autosomal-recessive disease that manifests in the first months of life, with steatorrhea, abdominal distention, and growth retardation. Neurologic symptoms appear in patients aged 5-10 years and may progress to death in the second or third decade.

Chorea-acanthocytosis syndrome

The median age at onset of symptoms in chorea-acanthocytosis syndrome is 32 years. Median survival is 8-14 years. Limb chorea is the initial symptom in many cases, but because it may be mild, patients may be able to suppress it for long periods before the other symptoms are evident.

Orofacial tics, buccolingual dyskinesia, and tongue biting that cause major problems with eating and swallowing occur early in the disease course. Neurogenic muscle hypotonia, atrophy, and areflexia are common. Dysarthria develops during the course of the disease and occasionally may be the presenting feature.

Seizures have been described as a late manifestation in well‐established cases, but only rarely as the presenting symptom.[18]  Dementia is relatively common. Organic personality changes with impulsive, easily distracted behavior occur. Apathy and loss of insight are the most consistent symptoms. Other psychiatric symptoms that are encountered include depression, anxiety, paranoid delusions, and obsessive-compulsive features.

An increased number of acanthocytes in peripheral blood is characteristic but not pathognomonic and may appear only late in the course.[18] The percentage of acanthocytes in the peripheral blood varies from 20-50%. Patients do not have anemia.

McLeod phenotype

This condition is characterized by a mild, compensated hemolytic anemia and, occasionally, late-onset myopathy or chorea.[19]  The acanthocyte percentage varies between 25% and 85%, and serum creatine kinase (CK) is elevated. This disorder is also described in association with chronic granulomatous disease, retinitis pigmentosa, and Duchenne muscular dystrophy. The deletion of band Xp21 affects all or some of the genetic loci of those disorders because of their close proximity on the short arm of chromosome X.

In advanced liver disease, jaundice, hepatosplenomegaly, ascites, altered mental status, and bleeding diathesis may be present. In abetalipoproteinemia, ataxia and decreased visual acuity are the main findings.

Chorea-acanthocytosis syndrome is characterized by limb chorea, orofacial dyskinesia, muscle atonia, and atrophy.

Findings on the workup for spur cell anemia include the following:

• Complete blood cell count - Variable degrees of anemia are present, with the hematocrit commonly between 15% and 20%. White blood cell and platelet counts may be normal; however, they are decreased in most cases due to severe, advanced liver disease.
• Reticulocyte count - An increase in the reticulocyte count depends on the degree of the anemia, but the count is usually greater than 5%. In certain cases, the reticulocyte count may be decreased as a result of concomitant folate deficiency.
• Liver function tests - Hyperbilirubinemia, predominantly indirect bilirubin, is present, and its increase parallels the hemolysis. Synthetic liver function is decreased, as evidenced by low levels of albumin and fibrinogen and prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT).
• Plasma lipids - This study helps screen suspected cases of abetalipoproteinemia. These patients have very low levels of serum cholesterol, phospholipid, and triglyceride. Lipoprotein electrophoresis reveals the absence of beta-lipoproteins. 
• Blood typing - Kell antisera react poorly with red blood cells, white blood cells, or both in the McLeod phenotype.
• Serum creatine kinase - In McLeod syndrome, the creatine kinase levels are increased.
• Erythrocyte sedimentation rate (ESR) - In patients with neuroacanthocytosis, particularly McLeod syndrome and chorea acanthocytosis, ESR tends to be low. It decreases as the fraction of acanthocytes increases. ^[20]
• Intestinal biopsy in abetalipoproteinemia - This procedure reveals the presence of fat droplets within the mucosal cells.

This study is the mainstay for the diagnosis of spur cell anemia. It reveals the presence of red blood cells with thornlike surface projections that are variable in size.

Characteristically, a high percentage of acanthocytes is present, equal to or greater than 20% of the erythrocytes observed. In cases of liver disease, particularly if obstructive jaundice is present, the smear may also reveal target cells (ie, erythrocytes in which hemoglobin is concentrated in the center and on the periphery, with a colorless zone in between, creating a "bullseye" appearance; see the image below)

Acanthocytes with target cells in a patient with advanced liver disease.

Treatment in cases of acanthocytosis is directed at the underlying disease.

Complete resolution of spur cell anemia has been reported after liver transplantation.[21] This phenomenon might be attributed to the normalization of lipid metabolism or a decrease in portal hypertension and hypersplenism following transplantation.[2]   

Patients with acanthocytosis should abstain from alcohol use. Abstinence from alcohol use may result in the nearly complete disappearance of acanthocytes in the peripheral blood in patients with mild to moderate alcoholic liver cirrhosis. Abstinence from alcohol is also the best preventive measure for spur cell anemia.

Anemia can be improved by red blood cell transfusion. However, the transfused cells become acanthocytic, with shortened life span in the circulation.

The poor general status of acanthocytic patients limits the use of splenectomy, which can potentially improve hemolytic anemia. However, these patients are severely ill and, in most cases, cannot undergo surgery.

Patients with abetalipoproteinemia may benefit from dietary measures that include triglyceride restriction and lipid-soluble vitamin supplementation.

Because patients with abetalipoproteinemia cannot absorb triglycerides, a diet restricted in these nutrients may significantly improve symptoms. Vitamin E can prevent the progression of the disease in these patients, and supplementation of the diet with lipid-soluble vitamins A, K, E, and D results in further improvement of neurologic and retinal symptoms.

Genetic counseling is offered to families of patients with abetalipoproteinemia and chorea-acanthocytosis syndromes. 

In patients with acanthocytosis due to abetalipoproteinemia cannot absorb triglycerides, vitamin E supplementation can prevent the progression of the disease, and supplementation of the diet with lipid-soluble vitamins A, K, E, and D results in further improvement of neurologic and retinal symptoms.

Class Summary

Vitamins are used to meet necessary dietary requirements and are used in metabolic pathways, as well as DNA and protein synthesis.

Vitamin A (Aquasol A, A-Natural-25, A-25)

Vitamin A is a cofactor in many biochemical processes.

Vitamin E (Alph-E, E-Gems, Aquasol E, Gamma-E Gems)

Vitamin E protects polyunsaturated fatty acids in membranes from attack by free radicals and protects red blood cells from hemolysis.

Phytonadione (MEPHYTON)

Vitamin K is a fat-soluble vitamin absorbed by the gut and stored in the liver. It is necessary for the function of clotting factors in the coagulation cascade. Phytonadione is used to replace the essential vitamin K forms not obtained in sufficient quantities in the diet or to further supplement levels.

Cholecalciferol (Vitamin D3, Bio-D-Mulsion Forte, Delta D3)

This agent stimulates absorption of calcium and phosphate from small intestine and promotes release of calcium from bone into blood. Use for treatment of vitamin D deficiency or prophylaxis of vitamin D deficiency.