Spur cells, or acanthocytes, are large erythrocytes covered with spikelike projections that vary in width, length, and distribution[1] (see image below). Spur cells can be encountered in acquired or inherited disorders. Spur cells are characterized by diminished deformability, which is responsible for their entrapment and destruction in the spleen.
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Acanthocytes with target cells in a patient with advanced liver disease.
Historically, spur cell anemia has been described with advanced alcoholic liver cirrhosis, but it can also be observed in other severe liver diseases.[2] The inherited disorders associated with significant acanthocytosis are characterized by an association with neuromuscular disorders. These diseases are presented together in this article because of the common hematologic feature of peripheral blood acanthocytosis.
The diagnosis should be suspected when a severe anemia requiring frequent red blood cells (RBC) transfusions is combined with progressive liver failure, jaundice, coagulopathy, and encephalopathy. Rapid resolution of spur cell anemia has been observed after liver transplantation; therefore early diagnosis is crucial.[2]
For patient education information, see Cirrhosis, Cholesterol FAQs, and Statins.
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.[3] 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 0.9-1) of unesterified cholesterol and phospholipids that are 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.
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) that may progress to cirrhosis.[4] Anorexia nervosa, hypothyroidism, and myelodysplasia are rare causes of this disorder.
Acanthocytes can result from abnormalities in membrane lipids and proteins. Lipid alterations impact the deposition of cholesterols and phospholipids in the red cell membrane. A case of acquired acanthocytosis in a patient taking atovastatin has been reported. Low density lipoprotein cholesterol was 6 mg/dL (< 100 optimal), down from 128 mg/dL prior to starting atovastatin. Eleven days after stopping atorvastatin the acanthocytosis abated.[5]
Neuroacanthocytosis is the term used for acanthocytosis associated with inherited disorders. Autosomal-recessive disorders, abetalipoproteinemia/aprebetalipoproteinemia (chromosome 2), chorea-acanthocytosis syndrome (band 9q21), and the X-linked McLeod phenotype are among the conditions linked to neuroacanthocytosis.
Formation of acanthocytes
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.
In severe liver disease, free cholesterol in red blood cells equilibrates with abnormal lipoproteins containing a high free cholesterol-to-phospholipid ratio, resulting in the preferential expansion of the outer leaflet and the development of the spur cell shape.[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 the alteration of the red blood cell shape and a decrease of the cell’s 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 the formation of 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]
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.
Five percent of all patients with severe hepatocellular disease develop spur cell anemia. Abetalipoproteinemia is an uncommon disorder. Chorea-acanthocytosis syndrome and McLeod phenotypes are rare; only a few dozen cases have been published in the literature.
Acanthocytosis in abetalipoproteinemia is an autosomal-recessive disease that manifests in the first months of life.
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.
The prognosis of spur cell hemolytic anemia in advanced liver disease is poor, because, frequently, the condition precedes death by a few weeks to months. 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.
Chorea-acanthocytosis syndrome is an irreversible entity with a slow, unrelenting progression of symptoms to death over 8-14 years.
The symptoms of spur cell anemia are related to the anemia and to the underlying disease.
Spur cell anemia in severe liver disease
In spur cell anemia, the hemoglobin level usually falls to less than 10 g/dL and, occasionally, to 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 weeks to months before death and as liver function deteriorates.
The course of spur cell anemia correlates with the liver function. Cases of reversal of the hemolytic anemia have been reported after improvement of liver disease.
Spur cell anemia has been reported in cases of pediatric cholestatic liver disease.[7] 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, RP that may lead to blindness, and fat malabsorption. Symptoms related to the deficiency of lipid-soluble vitamins (ie, A, K, E, 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 causes 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.[15] 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.[15] 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.[16]
The acanthocyte number varies between 25% and 85%, and serum creatine kinase (CK) is elevated. This disorder is also described in association with CGD, RP, and DMD. The deletion of band Xp21 affects all or some of the genetic loci of these 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.
Test findings reveal variable degrees of anemia, with the hematocrit commonly between 15% and 20%. White blood cell and platelet counts may be normal; however, due to the severe and advanced liver disease, they are decreased in most cases.
Reticulocyte count
An increase in the reticulocyte count depends on the degree of the anemia, but it 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 is helpful in screening suspected cases of abetalipoproteinemia. Serum cholesterol, phospholipid, and triglyceride levels are very low. 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.
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, which 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, target cells also may be seen (see the image below), particularly if obstructive jaundice is present.
View Image
Acanthocytes with target cells in a patient with advanced liver disease.
Treatment in cases of acanthocytosis is directed at the underlying disease. Supportive care for patients with reversible liver disease is the mainstay of treatment.
Patients with abetalipoproteinemia may benefit from dietary measures that include triglyceride restriction and lipid-soluble vitamin supplementation.
Anemia can be corrected by red blood cell transfusion. However, the transfused cells become acanthocytic, with shortened life span in the circulation.
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.
Complete resolution of spur cell anemia has been reported after liver transplantation.[17] This phenomenon might be attributed to the normalization of lipid metabolism or to a decrease in portal hypertension and hypersplenism following transplantation.[2]
The poor general status of acanthocytic patients limits the use of surgical care. Splenectomy may improve the hemolytic anemia. However, these patients are severely ill and, in most cases, cannot undergo surgery.
Genetic counseling is offered to families of patients with abetalipoproteinemia and chorea-acanthocytosis syndromes.
Because patients with abetalipoproteinemia cannot absorb triglycerides, a diet restricted in these nutrients may result in significant improvement of symptoms. Supplementation of the diet with lipid-soluble vitamins A, K, E, and D results in further improvement of neurologic and retinal symptoms.
Clinical Context:
Vitamin E protects polyunsaturated fatty acids in membranes from attack by free radicals and protects red blood cells from hemolysis.
Clinical Context:
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.
Clinical Context:
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.
Christopher D Braden, DO, Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital; Medical Director, Deaconess Hospital Outpatient Infusion Centers; Chairman, Deaconess Hospital Cancer Committee
Disclosure: Nothing to disclose.
Coauthor(s)
Issam Makhoul, MD, Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences
Disclosure: Nothing to disclose.
Mansoor Javeed, MD, FACP, Clinical Assistant Professor of Medicine, University of California, Davis, School of Medicine; Consultant, Sierra Hematology-Oncology Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University
Disclosure: Nothing to disclose.
Acknowledgements
James O Ballard, MD Kienle Chair for Humane Medicine, Professor, Departments of Humanities, Medicine, and Pathology, Division of Hematology/Oncology, Milton S Hershey Medical Center, Pennsylvania State University College of Medicine
James O Ballard, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American Society of Hematology
Disclosure: Nothing to disclose.
Marcel E Conrad, MD (Retired) Distinguished Professor of Medicine, University of South Alabama
Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group
Disclosure: Nothing to disclose.
Koyamangalath Krishnan, MD, FRCP, FACP Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University
Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, and Royal College of Physicians
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
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