AUTHOR AND EDITOR INFORMATION

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• Introduction
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• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
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• Workup
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• Follow-up
• Miscellaneous
• Multimedia
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Background

Acanthocytes (from the Greek word acantha, which means thorn), or spur cells, are spiculated red cells with a few projections of varying size and surface distribution. The cells appear contracted, dense, and irregular. The morphology of acanthocytes in these various conditions is similar, but the pathogenesis and clinical context often greatly differ. In general, the formation of acanthocytes depends on alteration of the lipid composition and fluidity of the red cell membrane.

Acanthocytosis is a red cell phenotype found in various underlying conditions. Abetalipoproteinemia (Bassen-Kornzweig syndrome) and spur cell hemolytic anemia of severe liver disease are the most frequent and most significant underlying conditions associated with acanthocytosis. Acanthocytes also occur in neuroacanthocytosis, anorexia nervosa and other malnutrition states, infantile pyknocytosis, McLeod syndrome, In(Lu) null Lutheran phenotype, hypothyroidism, idiopathic neonatal hepatitis, and myxedema. They are also observed with transient hemolysis and stomatocytosis in individuals with alcoholism and with mild hemolysis and spherocytosis in individuals with congestive splenomegaly. Other conditions associated with acanthocytes include homozygous familial hypobetalipoproteinemia, Zieve syndrome, and chronic granulomatous disease (CGD) associated with McLeod red cell phenotype.

Acanthocytes should be distinguished from echinocytes (from the Greek word echinos, which means urchin). Echinocytes, or burr cells, appear with multiple small projections that are uniformly distributed on the red cell surface. Echinocytes occur in many conditions, including malnutrition associated with mild hemolysis due to hypomagnesemia and hypophosphatemia, uremia, hemolytic anemia in long-distance runners, and pyruvate kinase deficiency. In vitro, elevated pH, blood storage, ATP depletion, calcium accumulation, and contact with glass can lead to formation of echinocytes.

Pathophysiology

The description of acanthocyte pathophysiology s varies among underlying conditions. Acanthocytes can be caused by (1) altered distribution or proportions of membrane lipids or by (2) membrane protein or membrane skeleton abnormalities. In membrane lipid abnormalities, previously normal red cell precursors often acquire the acanthocytic morphology from the plasma. Altered membranes may contain decreased phosphatidylcholine levels but increased levels of cholesterol and sphingomyelin. The imbalance in membrane lipids causes cells to stiffen, wrinkle, pucker, and form spicules because of a relative increase of the outer hemileaflet's surface area compared with the inner hemileaflet's surface area. In membrane protein or membrane skeleton abnormalities, the defect is intrinsic but, again, causes imbalances in inner versus outer leaflet surface areas and abnormal interaction between the membrane skeleton and lipid membrane.

The alteration in plasma lipids in autosomal recessive abetalipoproteinemia caused by the absence of beta-apolipoprotein is best described. Specifically, the lipoproteins apoprotein B (ApoB)–48 and ApoB-100 are deficient because of either abnormal assembly or defective aposecretion, leading to absent cellular secretion from hepatocytes or intestinal epithelial cells. Formation of normal chylomicrons (ie, lipoproteins that contain cholesterol and triglycerides) is inhibited and prevents intestinal absorption of lipids, leading to severe fat malabsorption. In addition to lipid abnormalities and altered membrane integrity, secondary vitamin E–deficient red cells have increased oxidant sensitivity and tend to hemolyze more easily. Acanthocytes in the homozygous form of familial hypobetalipoproteinemia are thought to have a similar pathophysiology.

Severe liver dysfunction of various etiologies can also cause altered plasma lipid composition and acanthocytes (usually called spur cells in this case) because of acquired abnormal red cell membrane lipid composition. The liver dysfunction causes accumulation of an abnormal, apolipoprotein A-II-deficient lipoprotein in plasma. Red cells are loaded with cholesterol by this lipoprotein and acquire an increased cholesterol-to-phospholipid ratio and a surface area preferentially within the outer bilayer leaflet.

Cholesterol-laden red cells are then remodeled in the spleen, resulting in the typical spur cell shape. The molecular mechanisms are not completely clear but may also include influences on membrane protein content and functions. The resulting spur cells are less deformable and are easily trapped in the spleen, conferring markedly shortened red cell survival. Another group of patients with liver dysfunction may have normal red cell membrane lipids, and the pathophysiology in these cases is unknown. This situation is more often seen in children with severe hepatocellular dysfunction.

In neuroacanthocytosis, the plasma lipoproteins are normal, and the formation of acanthocytes may be associated with intrinsic membrane abnormalities. Studies have indicated that abnormal protein formation or abnormal membrane protein trafficking (CHAC mutation) is involved. Electron microscopy studies have shown that membrane protrusions depend on the irregular distribution of the membrane skeletons. Therefore, shape changes are likely related to interactions between membrane skeletons that harbor abnormal proteins and lipid membranes.

These results were also found in acanthocytes due to the McLeod blood group. Individuals with the McLeod blood group or McLeod syndrome lack the Kx antigen, a membrane precursor of the Kell antigen that leads to acanthocytic red cell morphology. The Kell antigen is located on a 93-kD glycoprotein and is associated with the underlying membrane skeleton. Both cell types show significant ultrastructural variability between cells. McLeod acanthocytes also exhibit increased mechanical stability on ektacytometry findings, increased membrane rigidity, decreased potassium content, and an increased frequency of dense cells. Another blood group phenotype, the null Lutheran blood group or In(Lu) Lu(a-b-) red cell phenotype also causes acanthocytes. However, in both blood groups and in neuroacanthocytosis, cells are more resistant to hemolysis than in the previously mentioned disorders.

Acanthocytes are also found in myxedema, in panhypopituitarism, and in 20-65% of hypothyroidism cases. Serum lipid abnormalities with hypothyroidism are common, and patients with acanthocytes may have more severely abnormal lipids than patients with normal-shaped red cells.

Frequency

International

Acanthocytes are found in 50-90% of cells on peripheral blood smear findings in abetalipoproteinemia, which is a rare autosomal recessive disorder with only about 100 cases described worldwide. Acanthocytes are also relatively common in severe liver dysfunction and malnutrition. Spur cell hemolytic anemia of severe liver disease is an uncommon complication and depends on the incidence of the underlying hepatic or hepatotoxic disorder. It occurs most often in patients with alcoholic cirrhosis, which develops in 10-30% of all patients with alcoholism (approximately 10 million in the United States).

The percentage of acanthocytes is usually smaller in the rare conditions of neuroacanthocytosis and McLeod and null Lutheran red cell blood group abnormalities. In hypothyroidism, 20-65% of cases have approximately 0.5-2% acanthocytes on peripheral smear findings.

Mortality/Morbidity

Mortality and morbidity with acanthocytosis due to abetalipoproteinemia is not well described because of the rarity of the disease and the limited prognostic data. Lifespan may be near normal with early diagnosis and adequate vitamin supplementation and dietary restriction but may vary significantly. Death may occur in the second or third decade and is usually determined by the degree and progression of neurological complications. Acanthocytosis due to severe liver dysfunction is a hallmark of high risk for mortality. In neonatal hepatitis, the process resolves in 65% of individuals within weeks to months. Acanthocytosis in infantile pyknocytosis is a transient benign process. In malnutrition, hypothyroidism, and myxedema, the red cell abnormality resolves with appropriate treatment and resolution of the underlying disease.

Race

Acanthocytosis within the various underlying conditions is seen in all ethnicities.

Sex

Acanthocytosis has no sex predominance.

Age

The appearance of acanthocytes depends on the underlying condition. Acanthocytes in infants and children may indicate infantile pyknocytosis, neonatal hepatitis, autosomal recessive abetalipoproteinemia or homozygous familial hypobetalipoproteinemia, McLeod blood group, null Lutheran blood group, CGD with McLeod blood group, hypothyroidism, or severe malnutrition.

CLINICAL

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History

Patients with acanthocytosis may have a history of chronic diarrhea with pale, foul-smelling, and bulky stools; loss of appetite and vomiting; and slow weight gain and decreased growth, possibly including a bleeding tendency. Patients may report symptoms of ataxia, tremors, and visual abnormalities or jaundice, abdominal pain, pallor, dark urine, and recurrent infections. Adolescents and adults may report dyskinesias and cognitive deterioration.

Physical

• Hematologic
• • Pallor
  • Jaundice
  • Bleeding
  • Lymphadenopathy
• Ocular
• • Progressive retinitis pigmentosa with loss of night vision, visual acuity, and color vision
  • Nystagmus after age 10 years
  • Ophthalmoplegia with strabismus
  • Progressive exotropia
  • Cataracts
• Gastrointestinal
• • Abdominal distention
  • Failure to thrive, with short stature and decreased weight
  • Hepatomegaly
  • Splenomegaly
  • Ascites
• Neurologic
  • Loss of deep tendon reflexes
  • Decreased sensation to touch, pain, temperature, and position
  • Stocking-glove distribution of hypoesthesia
  • Decreased muscle strength
  • Intention tremors and progressive ataxia with clumsiness and gait disturbances, dysarthria, dysdiadochokinesis, and dysmetria
  • Chorea
  • Mental retardation
  • Altered mental status
  • Fatigue
  • Cold intolerance
• Skin Palmar erythema
• • Spider angiomas
  • Abdominal wall collateral veins
  • Edema
  • Recurrent skin infections
• Skeletomuscular
  • Muscular atrophy
  • Muscle contractures
  • Kyphoscoliosis
  • Pes cavus
  • Pes equinovarus

Causes

• Autosomal recessive abetalipoproteinemia: Heterozygotes are usually healthy. Disease arises from homozygosity for affected alleles. Underlying mutations in the microsomal triglyceride transfer protein (MTTP) gene cause a congenital absence of beta-apolipoprotein in the plasma. Multiple mutations have been described in the MTTP gene, which is localized on chromosome 4. These mutations lead to a lack of functional MTTP complex. MTTP catalyzes the transport of triglyceride, cholesterol ester, and phospholipids between phospholipid surfaces and is required for secretion of ApoB-containing lipoproteins.
• Homozygous autosomal dominant familial hypobetalipoproteinemia: This rare condition is caused by various APOB gene mutations. APOB is located on chromosome 2, and various mutations have been described. This disorder has clinical features similar to abetalipoproteinemia but has milder phenotypes. The synthesis of hepatocyte beta-apoprotein is reduced because of low RNA transcription. Low-density lipoproteins (LDLs) in plasma are decreased.
• Neuroacanthocytosis: This term describes a group of phenotypically and genotypically heterogeneous disorders with acanthocytosis and onset of neurologic symptoms in adolescence or adulthood. Acanthocytosis has a variable percentage and is a diagnostic hallmark. Plasma lipoproteins are normal. Genetic studies distinguish certain entities, of which the core syndromes are autosomal recessive chorea-acanthocytosis (VPS13A, or CHAC, [CHAC is an appositive; they are synonymous] mutation, which encodes for chorein), X-linked McLeod syndrome (XK mutation, which encodes for Kx), pantothenate kinase–associated neurodegeneration (PKAN) (PANK2 mutation), and Huntington disease–like 2 (HDL2) (JPH3 mutation). Red cells of individuals with the McLeod blood group lack Kx antigen, a membrane precursor of the Kell antigen, and may become sensitized, requiring McLeod red cells for transfusions.
• In(Lu) Lu(a-b-) red cell phenotype: This null Lutheran blood group phenotype is caused by inhibition of antigen expression by In(Lu), the inherited, dominantly acting inhibitor. Red cells are abnormally shaped, but no hemolysis is present.
• Severe liver dysfunction due to alcoholic cirrhosis, metastatic liver disease, hemochromatosis, neonatal hepatitis, cholestasis, Wilson disease, severe acute hepatitis, and infantile pyknocytosis
• Transient hemolysis associated with fatty metamorphosis of the liver and hypoglycemia (Zieve syndrome)
• Transient hemolysis and stomatocytosis in alcoholism
• Mild hemolysis and spherocytosis observed in individuals with congestive splenomegaly
• Idiopathic neonatal hepatitis: This may manifest as acanthocytosis and hemolytic anemia, which can be severe. The process resolves after several months in approximately 65% of cases. Cirrhosis occurs in 20% of cases, and hepatocellular necrosis and death can occur in 10-20% of cases.
• Infantile pyknocytosis: Patients with this benign transient process present during the first few days of life with jaundice, mild hepatosplenomegaly, and moderately severe hemolytic anemia. Up to 50% of RBCs may be pyknotic and resemble acanthocytes. Reticulocytes range from 10-20% and are not pyknotic. Transfused RBCs acquire the same pyknotic morphology and are prematurely destroyed, indicating extrinsic causation. The causative mechanisms are unclear. The condition resolves within a mean of 4 months.
• Anorexia nervosa, cystic fibrosis, celiac disease, and severe malnutrition: The mechanism of causation is unclear. Fat malabsorption or insufficient intake and vitamin E deficiency contribute. An abetalipoproteinemialike lipid profile has been described. The morphologic abnormality is reversed with improved nutrition.
• Hypothyroidism: Acanthocytes are found in 20-65% of patients with a frequency rate of 0.5-2%. Evidence of acanthocytes in adults suggests hypothyroidism in up to 90% of cases.
• Myxedema and panhypopituitarism: RBC lipids are normal, and the cell morphology normalizes with appropriate therapy.

DIFFERENTIALS

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Other Problems to be Considered

Congenital conditions
McLeod red cell phenotype and CGD: The gene that controls Kx expression on RBCs is adjacent to the locus involved in CGD. Large deletions in this region may result in the appearance of both CGD and acanthocytic McLeod red cells. Although most patients with CGD do not have both ailments, those with both genes affected have a mild hemolytic anemia.

Acquired conditions

Echinocytes or Burr cells: Acanthocytes should be distinguished from echinocytes (from the Greek word echinos, which means urchin). These cells appear with multiple small projections that are uniformly distributed on the red cell surface. Echinocytes occur in many conditions, including malnutrition associated with mild hemolysis due to hypomagnesemia and hypophosphatemia, uremia, hemolytic anemia in long-distance runners, and pyruvate kinase deficiency. In vitro, elevated pH, blood storage, ATP depletion, calcium accumulation, and contact with glass can lead to formation of echinocytes.

WORKUP

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Lab Studies

• CBC count shows mild-to-moderate normocytic anemia with an elevated reticulocyte count. Peripheral blood smear findings reveal 0.2-90% acanthocytes.
• Iron and folate may be deficient.
• Direct antibody test results are negative.
• Blood group may show McLeod or null Lutheran phenotype.
• Total bilirubin and lactate dehydrogenase levels are elevated, reflecting the degree of hemolysis.
• Liver function tests and total protein and albumin levels are abnormal in liver disease.
• Plasma lipid profile may be abnormal. In abetalipoproteinemia, plasma cholesterol levels are very low, less than 50 mg/dL. Plasma phospholipid levels are very low. Plasma apolipoprotein B is absent. Chylomicrons, very-low-density lipoproteins (VLDLs), and LDLs are absent. Serum triglyceride levels are very low, less than 10 mg/dL. Plasma sphingomyelin levels are relatively increased at the expense of lecithin.
• Levels of fat-soluble vitamins E, A, D, or K are decreased in abetalipoproteinemia, hypobetalipoproteinemia, and malnutrition.
• Prothrombin time (PT) is prolonged in vitamin K deficiency.
• Fecal fat is elevated in abetalipoproteinemia, hypobetalipoproteinemia, and malnutrition.
• MTTP or APOB sequencing may identify mutations (not widely available).
• Endocrine studies may reflect hypothyroidism or panhypopituitarism.

Other Tests

• Nerve conduction velocity test findings show slow nerve conduction and decreased amplitude of sensory potentials.
• Electromyography findings reflect denervation in abetalipoproteinemia.

Procedures

• Perform intestinal and peripheral nerve biopsy when abetalipoproteinemia is suspected.

Histologic Findings

Intestinal biopsy findings show engorgement of mucosal cells with lipid droplets and normal villi, but lack of apolipoprotein B using immunofluorescence. Peripheral nerve biopsy findings reveal paranodal demyelination in abetalipoproteinemia.

TREATMENT

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Medical Care

Treatment of disorders with acanthocytosis depends on the underlying condition.

• Medical care of abetalipoproteinemia includes dietary restriction of long-chain fatty acids, with judicious supplementation with medium-chain triglycerides. Supplementation with lipid-soluble vitamins A, D, E, and K is necessary in large doses.
• Vitamin E supplementation may stabilize neuromuscular and retinal abnormalities. Iron and folate supplementation may be necessary.
• Occupational and physical therapy is recommended to treat progressive neurologic disease.
• Typical care for severe liver disease includes careful fluid management, correction of metabolic disturbances, treatment of hypoglycemia, and careful nutritional management.
• Encephalopathy requires decreasing ammonia production.
• Gastrointestinal bleeding may require surgical intervention. Other therapies appropriate for the underlying disease may be necessary.
• Splenectomy moderates hemolysis; however, it should be reserved for patients in whom the risks of abdominal surgery are considered acceptable.
• Surgical risks are high in the setting of severe hepatocellular disease, portal hypertension, and coagulopathy.
• In spur cell hemolytic anemia of severe liver disease, various lipid-lowering agents have been tried without success.
• Hormone replacement is administered as indicated with endocrine disorders.

Consultations

• Gastroenterologist
• Nutritionist
• Ophthalmologist
• Neurologist
• Hematologist
• Orthopedist

Diet

Restriction of long-chain fatty acids and judicious supplementation with medium-chain triglycerides is necessary in abetalipoproteinemia.

MEDICATION

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Treatment of abetalipoproteinemia includes dietary restriction of triglycerides, supplementation with medium-chain triglycerides, and supplementation of lipid-soluble vitamins A, D, E, and K in high doses. Occasionally, patients have associated iron or folic acid deficiencies, necessitating supplementation with oral iron and folic acid.

Drug Category: Vitamins and cofactors

These agents are organic substances required by the body in small amounts for various metabolic processes. They are classified as fat- or water-soluble. Vitamins A, D, E, and K are fat-soluble; biotin, folic acid, niacin, pantothenic acid, the B vitamins (ie, B-1, B-2, B-6, B-12), and vitamin C are generally water-soluble. These agents are clinically used for the prevention and treatment of specific vitamin-deficiency states.

Drug Category: Trace elements

These agents are inorganic substances found in small amounts in the tissues and are required for various metabolic processes.

FOLLOW-UP

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Further Outpatient Care

• Consider diet restrictions and nutritional supplementations. Regular monitoring of vitamin A, vitamin E, folate levels, iron studies, and other parameters is recommended, depending on the underlying condition.

Complications

• Acanthocytosis may induce variable degrees of hemolytic anemia, depending on the underlying condition.
• In abetalipoproteinemia, complications include chronic mild hemolysis with mild anemia and a moderately shortened red cell survival. Occasionally, anemia is more severe because of secondary iron and folate deficiency. Malabsorption or celiac syndrome leads to steatorrhea and failure to thrive in the first year of life. Retinitis pigmentosa develops within the first decade of life with night blindness and progressive loss of visual field and acuity. Ophthalmoplegia may eventually develop. Neurologic changes begin in the first-to-second decade of life, are progressive, and include sensory disturbances, movement disorders, muscle weakness, and mental retardation. Ataxic neurologic disease is progressive, with loss of ambulation by the third decade of life.
• In neuroacanthocytosis, hematologic manifestations are usually minimal, but neurologic symptoms are progressive and include dyskinesias, cognitive deterioration, and progressive neurodegeneration, mainly of the basal ganglia.

Prognosis

• Complications of abetalipoproteinemia progress to cause death in the second or third decade.
• The clinical course of spur cell anemia is progressive and usually fatal because of end-stage liver disease.

Patient Education

• The Genetics Home Reference from the US National Library of Medicine provides excellent updated information and multiple links for further study on abetalipoproteinemia.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Acanthocytes should not be confused with echinocytes.
• Abetalipoproteinemia is a rare disorder in children. The diagnosis may initially be missed or delayed.
• Autosomal recessive abetalipoproteinemia must be differentiated from the homozygous form of familial hypobetalipoproteinemia. The presentation of both disorders is similar, but hypobetalipoproteinemia is clinically milder.

MULTIMEDIA

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Media file 1:  This image (magnified X 2000) shows the spiculated thorny RBCs (acanthocytes) as observed in an individual with abetalipoproteinemia. These are indistinguishable from the acanthocytes shown in Image 2, which are observed in an individual with spur cell hemolytic anemia. Used with permission from Little, Brown and Company.
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Media type:  Photo

Media file 2:  This image (magnified X 2000) demonstrates acanthocytes in an individual with spur cell hemolytic anemia associated with alcoholic cirrhosis. Acanthocytes, unlike echinocytes or burr cells (see Image 3), have fewer spicules. Used with permission from Little, Brown and Company.
	View Full Size Image
Media type:  Photo

Media file 3:  This image (magnified X 2000) shows echinocytes, or burr cells, a universal feature of uremia. The spicules of acanthocytes vary in length and width and project nonuniformly from the cell surface, while burr cells have regularly spaced, smoothly rounded crenulations. The second morphologic feature of RBCs in an individual with uremia is the presence of ellipsoid cells. Used with permission from Little, Brown and Company.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
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Article Last Updated: Dec 28, 2006