INTRODUCTION — Some red blood cell (RBC) disorders affect the shape of the cells by altering the plasma membrane composition or the ratio of plasma membrane to intracellular volume. Three of the most common morphologies are burr cells (echinocytes), acanthocytes, and target cells. This topic discusses their mechanisms of formation and their usefulness in identifying systemic disorders.
Separate topic reviews discuss:
●Assembly and regulation of the RBC membrane – (See "Red blood cell membrane: Structure, organization, and dynamics".)
●Disorders of the submembrane cytoskeleton – (See "Hereditary spherocytosis" and "Hereditary elliptocytosis and related disorders".)
●Disorders of RBC hydration – (See "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)
TERMINOLOGY AND BEST PRACTICES FOR VIEWING — Burr cells (echinocytes) and acanthocytes are two types of spiculated red blood cells (RBCs).
●Burr cells – Burr cells (echinocytes; from the prefix "echino" [spiny, prickly, sea urchin]) have a uniform array of relatively small spicules that appear as serrated edges distributed evenly across the entire surface of the cell, as shown in the images of a stained blood film (picture 1) and electron microscopy image (picture 2). The spicules are more regular and numerous compared to acanthocytes. They are associated with disorders leading to intracellular adenosine triphosphate (ATP) depletion and can also commonly arise as an artifact from prolonged storage of RBCs prior to storage.
●Acanthocytes – Acanthocytes; from the Greek "acantha" (thorn) have only a few spicules of various sizes at irregular intervals on the cell surface and are denser than echinocytes (picture 3). Some experts consider "spur cell" to be synonymous with acanthocyte, while others consider spur cells to be an extreme form (a subset) of acanthocytes with a single spike or a few spikes, specific to liver disease with increased hemolysis and portending a very poor prognosis. (See 'RBC changes in liver disease' below.)
When acanthocytes are remodeled by the spleen, the spicules become blunter and the associated membrane loss makes them more spherocytic; these cells may be referred to as spheroacanthocytes.
A freshly prepared peripheral blood smear is essential for distinguishing between these cell types, as storage may induce burr cell formation and other morphologic artifacts [1]. (See "Evaluation of the peripheral blood smear", section on 'Slide preparation'.)
A study of the effect of freshly prepared versus dried blood smears in 100 individuals with neuroacanthocytosis and 68 controls (some with other movement disorders and some without any medical diagnosis) found that use of blood that was isotonically diluted with saline and viewed as an unfixed wet prep between two glass slides provided the best sensitivity (100 percent) and specificity (98 percent) for identifying acanthocytes [2]. Performance characteristics were not as good using dried blood smears with ethylenediaminetetraacetic acid (EDTA) blood; use of EDTA blood reduced the sensitivity to 40 percent. Individuals with defined neuroacanthocytosis syndromes had >28 percent acanthocytes (See 'Neuroacanthocytosis' below.); the reference range for controls was determined to be <6.3 percent.
Target cells and stomatocytes are RBCs with an abnormal appearance of the central pallor, due to changes in the lipid membrane composition and the surface-to-volume ratio of the cell.
●Target cells – Target cells (codocyte is the term for the circulating target cell) have an area of central density (a hyperchromic "bulls-eye") surrounded by a halo of pallor (picture 4).
Target cells probably circulate as bell-shaped cells called codocytes. Wet prep smears, made using isotonic saline without drying, demonstrate these bell-shaped cells; the target shape seen on a routine dried peripheral blood smear is probably an artifact due to the redundant cell membrane.
●Stomatocytes – Stomatocytes (from the root "stoma" meaning mouth; also called hydrocytes) have a mouth-shaped area of central pallor, as illustrated in the images from a peripheral blood smear (picture 5) and electron microscopy (picture 2). These cells are discussed separately. (See "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)", section on 'Definitions and classification'.)
Other imaging methods such as scanning electron microscopy (EM) show the actual three-dimensional structure of target cells and stomatocytes.
RBC CHANGES IN LIVER DISEASE — Individuals with liver disease have multifactorial changes in red blood cell (RBC) morphologies and causes of anemia that can include the following [3-6].
Initially, the changes in lipoprotein metabolism can cause accumulation of cholesterol in the RBC membrane that increases surface area, producing target cells [6]. Later, further cholesterol accumulation can cause the membrane to have reduced deformability that leads to spicule formation, producing spur cells, a late change.
●Target cells – Target cells are common in liver disease, due to the alterations in lipid physiology. Details of the mechanism are discussed below. (See 'Pathophysiology and causes (target cells)' below.)
Target cells are not specific for liver disease; they are also seen in thalassemias and other hemoglobinopathies (Hb C, E, and S).
●Burr cells – Burr cells (echinocytes) can be seen in liver disease due to the changes in lipid physiology. (See 'Causes of burr cells' below.)
●Spur cells – Spur cells (a form of acanthocyte (see 'Terminology and best practices for viewing' above)) can be seen in liver disease due to the changes in lipid physiology. Studies have found that they generally correlate with advanced hepatocellular disease, which may be associated with 20 to 30 percent acanthocytes in the peripheral blood [4,7,8]. A small study from Greece suggests that the presence of spur cell anemia in patients with alcoholic cirrhosis predicts for a shortened survival and aids in prioritization of such patients for liver transplantation [9]. Resolution of spur cell anemia after liver transplantation further supports a causal relationship [10]. (See 'Causes of acanthocytes' below.)
●Microcytosis – Microcytosis secondary to iron deficiency may occur if there is gastrointestinal bleeding from erosions, ulcers, or varices (which may be exacerbated by coagulation abnormalities). (See "Microcytosis/Microcytic anemia", section on 'Causes of microcytosis'.)
●Macrocytosis – Excess alcohol use and liver disease can cause macrocytosis by an unclear mechanism. Macrocytosis can also occur with megaloblastic anemia due to folate deficiency or vitamin B12 deficiency. (See "Macrocytosis/Macrocytic anemia", section on 'Overview/common causes'.)
●Hemolysis – Advanced liver disease can be associated with moderate to severe hemolysis, which is associated with reticulocytosis (if bone marrow function is adequate). Causes include membrane changes and hypersplenism. (See "Non-immune (Coombs-negative) hemolytic anemias in adults", section on 'Liver and kidney disease'.)
Splenectomy has also been associated with acanthocytosis and hemolysis. (See 'Splenectomy' below.)
BURR CELLS AND ACANTHOCYTES
Pathophysiology (burr cells and acanthocytes) — The shape of these two types of spiculated cells is thought to be related to changes in the organization of cell membrane components. Although both burr cells and acanthocytes can be seen in liver disease, the mechanisms of their formation appear to differ from each other, as noted in the discussions below.
●Burr cells – Burr cells (echinocytes) can be easily produced in vitro by incubating red blood cells (RBCs) at high pH, high concentrations of extracellular calcium, low albumin concentration, glass surfaces, or prolonged storage. The figure illustrates the mechanism of formation, which involves formation of small spicules (reversible) and fragmentation/breaking of the ends of the spicules, resulting in membrane loss, which is irreversible (figure 1).
In kidney disease, a soluble factor can cause reversible burr cell formation. In liver disease, proteins on the RBC surface can bind to abnormal high-density lipoproteins (HDL) and induce the characteristic conformational changes [11]. (See 'End-stage kidney disease' below and 'Liver disease' below.)
Intracellular ATP depletion is associated with burr cell formation. This mechanism may contribute to burr cells seen with pyruvate kinase (PK) deficiency, severe hypophosphatemia, and prolonged storage [12]. (See 'Causes of burr cells' below.)
In one patient, echinocytes were present in association with a massive splenic hemangioma and disappeared following splenectomy [13].
●Acanthocytes – Acanthocytes result from a combination of changes, including increased RBC membrane cholesterol, increased surface area-to-volume ratio, impaired fluidity of the RBC membrane, reduced ability to withstand membrane tension, and reduced repair/removal of fatty acids damaged by peroxidation [3,14-16]. Increased proteolytic activity in the RBC membrane, possibly due to a circulating factor, and splenic conditioning may also contribute to acanthocyte formation [3,15,17-19]. The RBCs cannot synthesize new phospholipids, and fatty acid damage accumulates.
•Cytoskeletal changes – Focal changes in the submembrane cytoskeleton are likely to be involved in predisposing to acanthocyte formation. One hypothesis from 2004 suggested that changes in Band 3 are responsible [20]. Changes in the phosphorylation status of Band 3 have also been observed [21]. Band 3 has a significant role in maintaining connections between the RBC membrane and the submembrane cytoskeleton; it is also an anion exchange channel (its other name is AE1). (See "Red blood cell membrane: Structure, organization, and dynamics", section on 'Band 3' and "Control of red blood cell hydration", section on 'Anion exchanger (band 3)'.)
Different genetic variants affecting Band 3 appear to produce different RBC phenotypes, consistent with multiple domains carrying out independent functions. Some variants produce hereditary spherocytosis (HS), a specific 27 base pair deletion causes Southeast Asian ovalocytosis (SAO), and a specific point mutation causes dramatic acanthocytosis and distal renal tubular acidosis. (See "Hereditary spherocytosis", section on 'Band 3 deficiency' and 'Band 3/AE1 A858D variant' below and "Hereditary elliptocytosis and related disorders", section on 'Differential diagnosis'.)
•Lipids – Membrane lipid abnormalities also contribute to acanthocytosis, as seen in liver disease and familial lipid disorders [22]. (See 'RBC changes in liver disease' above and 'Chylomicron retention disease' below and "Low LDL-cholesterol: Etiologies and approach to evaluation".)
Accumulated fatty acid damage occurs because the RBC is unable to synthesize new phospholipids. However, the cell can identify and remove peroxidized fatty acid chains that interfere with normal membrane lipid fluidity [15]. When the fatty acid is removed, a lyso-derivative with lytic activity remains, and the missing fatty acid chain must be replaced. This is accomplished using a storage pool of acyl groups present in the cell membrane in the form of acylcarnitine. When needed, the fatty acid (acyl group) is transferred to acyl-CoA and inserted into the potentially lytic lysophospholipid by the enzyme lysophosphocholine acyl transferase (LAT).
LAT is inhibited in acanthocytes; it can also be inhibited by heavily loading RBCs with cholesterol in vitro [15]. This suggests that the accumulation of excess cholesterol in RBC membranes in individuals with liver disease may be the first step in acanthocyte formation [3,15,18]. The second step involves extensive remodeling of the RBC in the spleen [17,18]. This differs from the mechanism of burr cell formation in liver disease.
Causes of burr cells — In addition to a drying and storage artifact, there are several diverse causes of burr cells.
Slide artifact — Burr cells are often found as artifacts on blood smears. They can be produced in vitro by incubation at high pH or in the presence of high calcium concentrations, exposure to glass surfaces, reduced albumin concentrations, and after prolonged storage.
End-stage kidney disease — Burr cells are seen in patients with end-stage kidney disease (ESKD), and echinocytosis appears to be transiently exacerbated during the first 30 minutes of hemodialysis [23-25]. (See "Chronic kidney disease (newly identified): Clinical presentation and diagnostic approach in adults".)
Incubation of control RBCs in the plasma of patients with ESKD causes burr cells to form, and incubation of RBCs from patients with ESKD in control plasma causes echinocytosis to resolve [23]. These findings are consistent with echinocytosis being caused by a circulating factor associated with ESKD.
Liver disease — (See 'RBC changes in liver disease' above.)
Vitamin E deficiency — Burr cells (and occasional acanthocytes) are a feature of vitamin E deficiency [26]. Previously noted in premature infants due to inadequate dietary vitamin E content, vitamin E deficiency is most likely to be seen in patients who have fat malabsorption, often related to liver disease or cystic fibrosis [27,28]. (See "Overview of vitamin E", section on 'Deficiency'.)
Pyruvate kinase deficiency — Burr cells are occasionally seen in patients with PK deficiency, particularly after splenectomy. They may also be seen with other disorders of the glycolytic pathway, such as glucose-6-phosphate isomerase (GPI) deficiency. (See "Pyruvate kinase deficiency".)
Multisystem Inflammatory Syndrome in Children (MIS-C) — Burr cells have been described in children with MIS-C, the inflammatory syndrome seen after acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). In a series of 20 patients, burr cells were not seen in patients with minimal disease but were identified in 40 percent with severe disease [29].
Woronet's trait — Woronet's trait is a condition described in a single family in 1980 [30]. The proband was a 13-year-old male with marked echinocytosis affecting a small portion of RBCs (5 to 10 percent) that was not explained by testing for common causes of acanthocytosis (RBC enzyme disorders, lipid disorders, cytoskeletal abnormalities, McLeod phenotype). There was mild anemia without hemolysis, and RBC lifespan was normal. His mother and two siblings had similar findings.
Causes of acanthocytes — Many of the causes of acanthocytes are associated with alterations in lipid profile. A significant number of acanthocytes can be seen in liver disease and neuroacanthocytosis. (See 'RBC changes in liver disease' above and 'Neuroacanthocytosis' below.)
Liver disease — (See 'RBC changes in liver disease' above.)
Hypothyroidism — Approximately 20 percent of patients with hypothyroidism have a small number of acanthocytes (0.5 to 2 percent) on peripheral blood smears; however, occasional patients have more prominent acanthocytosis [31,32]. (See "Clinical manifestations of hypothyroidism", section on 'Anemia'.)
Thyroid function testing may be indicated when acanthocytes are seen in the absence of any other apparent cause [33]. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults", section on 'Screening'.)
Drug-induced — Transient acanthocytosis, with or without hemolytic anemia, has been reported with some medications. Alterations in lipid profiles may be responsible; however, a causal relationship has not been established.
●Alectinib – Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor. In a series of 43 patients treated with alectinib for advanced non-small cell lung cancer (NSCLC), 41 (95 percent) developed acanthocytosis [34]. Reduced binding of eosin-5-maleimide (EMA), consistent with loss of band 3, was seen in all cases. Anemia was present 73 percent, but only 11 percent had documented hemolysis as the cause.
Additional case reports have described similar findings [35]. The mechanism by which alectinib causes acanthocytosis, and the reason that some patients develop hemolysis and others do not, remain to be determined.
●Prostaglandins – Acanthocytosis and hemolytic anemia followed administration of high-dose misoprostol for medical termination of pregnancy in a 21-year-old [36]. Acanthocytosis resolved spontaneously.
●Statins – Acanthocytosis and hemolytic anemia (hemoglobin 6.7 g/dL) was reported in a 67-year-old patient treated with atorvastatin; the low density lipoprotein (LDL) cholesterol decreased to an extremely low level (6 mg/dL) [37]. Acanthocytosis resolved 11 days after stopping the drug.
Anorexia nervosa — Patients with anorexia nervosa may have acanthocytosis [38,39]. The mechanisms responsible have not been defined, but changes in plasma lipids or RBC membrane proteins may be involved. The anemia seen in patients with anorexia nervosa is more often hypoplastic and not hemolytic or related to the changes in RBC morphology. The acanthocytosis is reversible with improvement in nutritional status [38,40].
Myelodysplastic syndromes — Some patients with myelodysplastic syndromes have 5 to 10 percent acanthocytes; in some cases, acanthocytosis may be the primary reason for referral [41].
More common hematologic findings include dysplastic hematopoiesis with macrocytic RBCs. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Blood smear'.)
Splenectomy — Removal of the spleen has been associated with acanthocytosis, as well as other RBC changes including Howell-Jolly bodies (nuclear fragments), which are very common, and target cells, which are variable. Hypersplenism associated with liver disease can produce similar changes. (See 'Pathophysiology and causes (target cells)' below and 'RBC changes in liver disease' above.)
Some individuals with post-splenectomy acanthocytosis have hemolysis and others do not. Disappearance of acanthocytes after regrowth of an accessory spleen further supports a causal relationship [42].
Neuroacanthocytosis — Neuroacanthocytosis (previously called Levine-Critchley syndrome) encompasses several rare genetic disorders with acanthocytes in the peripheral blood, neuromuscular manifestations, and neurodegeneration. The presence of acanthocytes on the blood smear may be helpful in suggesting the diagnosis. (See "Neuroacanthocytosis".)
These disorders include [21,43-45]:
●Abetalipoproteinemia and hypobetalipoproteinemia
●Chorea-acanthocytosis (ChAc)
●McLeod syndrome (MLS)
●Pantothenate-kinase associated neurodegeneration (PKAN)
●Huntington's disease-like 2 (HDL2)
The percentage of acanthocytes is variable; in one study involving 100 patients with neuroacanthocytosis that evaluated optimally prepared blood smears (see 'Terminology and best practices for viewing' above), all had >28 percent acanthocytes [2]. The degree of neurologic impairment does not correlate with the degree of acanthocytosis on the peripheral blood smear. Mild hemolytic anemia is sometimes seen but is not invariably present.
The basis for acanthocytosis in these disorders is not clear, and laboratory efforts to explore the mechanism of acanthocyte formation have been unproductive [46-48]. The specific gene variants and evaluation and treatment of these disorders are discussed separately. (See "Neuroacanthocytosis".)
Chylomicron retention disease — Chylomicron retention disease (also called Anderson disease) is a rare autosomal recessive disorder characterized by low LDL-cholesterol, severe deficiency of vitamin E and other fat soluble vitamins, and impaired chylomicron production. Mild of acanthocytosis has been reported [49]. (See "Low LDL-cholesterol: Etiologies and approach to evaluation", section on 'Chylomicron retention disease'.)
Blood group abnormalities — Acanthocytes have been associated with two abnormalities of blood group systems:
●McLeod syndrome – McLeod syndrome is a type of neuroacanthocytosis. (See 'Neuroacanthocytosis' above and "Neuroacanthocytosis", section on 'Mcleod syndrome'.)
The RBC phenotype is associated with uniformly weak Kell system antigens, due to pathogenic variants in the XK gene, the product of which is required for membrane anchoring of the Kell antigens. (See "Red blood cell antigens and antibodies", section on 'Kell antigens'.)
●Lutheran null phenotype – The Lutheran blood group system has two antigens, a and b. The most common cause of the null Lutheran phenotype, Lu(a-b-), is the presence of an inhibitor called "In(Lu)"; this inhibitor partially suppresses expression of Lu(a) and Lu(b), making them undetectable by standard agglutination tests [50-52]. The In(Lu) inhibitor is encoded by the INLU gene. In addition to Lutheran antigens, it also inhibits expression of other cell surface proteins such as CD44 [52]. (See "Red blood cell antigens and antibodies", section on 'Lutheran blood group system'.)
Approximately 1 in 5000 individuals inherits this dominantly acting inhibitor [50]. Affected patients have abnormally shaped RBCs but no hemolysis. RBC morphology may be normal, poikilocytic, or acanthocytic [50,53].
Band 3/AE1 A858D variant — Pathogenic variants in the SLC4A1 gene, which encodes the RBC membrane protein Band 3 (also called AE1 [anion exchanger 1]), are associated with hereditary spherocytosis. (See "Hereditary spherocytosis".)
The specific Band3/AE1 variant A858D, which results in a single amino acid substitution, aspartic acid instead of the normal alanine at amino acid 858, has been associated with acanthocytosis/spur cell anemia in multiple unrelated individuals.:
●Mild hemolytic anemia and acanthocytosis in seven children who were homozygous for the A858D variant and had compensated hemolytic anemia, metabolic acidosis, and failure to thrive [54].
●Hemolytic anemia, distal renal tubular acidosis (RTA), and acanthocytosis in two unrelated individuals (ages six and 15 years) who were homozygous for the A858D variant [55].
●Compensated hemolysis with 70 to 85 percent acanthocytes, along with profound distal RTA (with hypokalemia-induced quadriparesis), in a 17-year-old child of consanguineous parents who was homozygous for the A858D variant [56].
The mechanism of acanthocytosis with the A858D variant is unexplained. Band 3/AE1 has several functions, include providing cohesion between the RBC membrane and underlying cytoskeleton, facilitating bicarbonate exchange, and linking other proteins such as blood group antigens to the RBC surface.
Other specific variants in SLC4A1 cause distinct syndromes including Southeast Asian Ovalocytosis (SAO) and distal (type 1) RTA. (See "Red blood cell membrane: Structure, organization, and dynamics", section on 'Band 3' and "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Distal (type 1) RTA' and "Hereditary elliptocytosis and related disorders", section on 'Differential diagnosis'.)
Another report described several patients with hereditary spherocytosis (HS) due to variants in the gene that encodes spectrin, several of which are associated with autosomal dominant HS and frequent acanthocytes (8 to 15 percent) [57]. (See "Hereditary spherocytosis", section on 'Overview of gene variants'.)
Laboratory testing unexplained burr cells or acanthocytes — Burr cells and acanthocytes are seen in a number of disorders that are outlined above. (See 'RBC changes in liver disease' above and 'Causes of burr cells' above and 'Causes of acanthocytes' above.)
These abnormalities are usually not associated with hemolysis or a shortened RBC lifespan, with the exception of spur cells in liver disease. If the underlying cause is known, generally no additional testing is needed. However, if the underlying cause is not known, these findings may indicate the possibility of an underlying condition that may require evaluation or treatment. (See 'Management' below.)
If the cause of burr cells or acanthocytes is known, no additional evaluation is required.
If burr cells or acanthocytes are identified in a patient without a known underlying cause, the following may be reasonable for the initial evaluation; this generally can be performed by the primary care clinician:
●Review of the complete blood count (CBC) over time, to determine if there is anemia and if it is worsening.
●Repeat an additional freshly prepared peripheral blood smear with manual review. Storage artifact is a common cause of burr cells.
●Review medications to identify possible drug-induced causes and determine the temporal relationship.
●Obtain hemolysis testing, including reticulocyte count, bilirubin, lactate dehydrogenase (LDH), and haptoglobin (table 1).
●Obtain liver and kidney function tests.
●Obtain thyroid function testing (for acanthocytes).
●Obtain a lipid panel, if age-appropriate and not recently performed.
Other testing may be appropriate if initial testing is unrevealing or if there is a positive family history of the morphologic changes; this testing is probably best conducted by the specialist (hematologist, lipid specialist, or other specialist depending on patient age and presentation):
●Review of the blood smear for other abnormalities.
●Review of the lipid profile.
●Evaluation for other causes of hemolytic anemia. (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults".)
●Vitamin E level (for burr cells). (See "Overview of vitamin E", section on 'Deficiency'.)
●PK activity (for burr cells). (See "Pyruvate kinase deficiency", section on 'PK-specific testing: Where and how to test'.)
●Genetic testing for specific disorders as suggested by laboratory studies.
The urgency of evaluation (and whether certain tests are performed sequentially or simultaneously) depends on the patient's clinical status and findings on the initial history, examination, and baseline laboratory testing. Some testing listed above is specific for only burr cells or only acanthocytes, but if there is a question about the morphology (or a mixture of morphologies) it may be appropriate for both types of cells.
TARGET CELLS
Pathophysiology and causes (target cells) — The shape of these cells is thought to be related to changes in the ratio of cell membrane to cytoplasmic volume (the surface area-to-volume ratio), with excess, redundant cell membrane causing the target appearance inside the region of central pallor. The increase in surface area-to-volume ratio can be due to increased plasma membrane or decreased intracellular volume.
Increased membrane
●Liver disease – The main cause of increased plasma membrane occurs is obstructive liver disease. (See 'RBC changes in liver disease' above.)
The mechanism involves increased bile salts, which inhibit the enzyme lecithin-cholesterol acyltransferase (LCAT). LCAT normally esterifies cholesterol to cholesterol esters and phosphatidylcholines (lecithins) to lysophosphatidylcholines on the surface of high-density lipoproteins (HDLs) [58]. When LCAT is reduced, excess unesterified cholesterol and phospholipids increase, with a greater proportional increase in cholesterol [3]. This in turn increases the ratio of cholesterol to phospholipids incorporated into the RBC plasma membrane bilayer [59-61]. (See "Lipoprotein classification, metabolism, and role in atherosclerosis".)
The central role of abnormal plasma lipids in the formation of target cells is demonstrated by two laboratory observations. Incubation of RBCs in plasma from patients with obstructive liver disease causes target cells to form in vitro, and incubation of target cells in plasma from patients without liver disease causes loss of the target cell appearance. A clinical correlate is that patients with hereditary spherocytosis who develop gallstones with obstructive jaundice also experience reduced hemolysis and increased osmotic fragility due to increased RBC membrane and improved surface-to-volume ratio [62]. (See "Red blood cell membrane: Structure, organization, and dynamics", section on 'Surface area to volume ratio (SA/V)'.)
●Less common causes:
•Splenectomy – Removal of the spleen has been associated with variable target cells, as well as acanthocytes and other RBC changes including Howell-Jolly bodies (nuclear fragments), which are very common, and target cells, which are variable. (See 'RBC changes in liver disease' above and 'Causes of acanthocytes' above.)
Normally, the spleen removes excess membrane from red blood cells (RBCs), a process called "splenic conditioning" [63,64]. The exact mechanism is not defined, although the reduction in RBC lipid content suggests that lipases may be involved. In the first few weeks following splenectomy, target cells appear, reaching levels of 2 to 10 percent. The cells have increased membrane, increased surface-to-volume ratio, and reduced osmotic fragility [63,65]. These RBCs may eventually lose their excess lipid by conditioning in other sites, leading to the gradual disappearance of target cells.
•Hereditary LCAT deficiency – Hereditary LCAT deficiency is a rare autosomal recessive disorder caused by homozygous pathogenic variants in the LCAT gene. Clinical manifestations include normocytic anemia with prominent target cells [66-70]. HDL cholesterol is low, and there is chronic kidney disease with proteinuria [66,67,70]. Some individuals have corneal opacities, leading to the designation "fish eye syndrome." (See "HDL cholesterol: Clinical aspects of abnormal values", section on 'Inherited causes'.)
The mechanism of target cell formation in hereditary LCAT deficiency is similar to liver disease.
Decreased volume — Decreased intracellular volume occurs in conditions in which intracellular hemoglobin is decreased [71]:
●Thalassemia – Alpha and beta thalassemia can both cause target cells when severe (especially transfusion-dependent beta thalassemia and hemoglobin H disease). (See "Pathophysiology of thalassemia", section on 'Terminology and disease classification'.)
●Other hemoglobinopathies – Target cells (or target-like cells) can also be seen in sickle cell disease and hemoglobin C (Hb C), Hb D, and Hb E disease. (See "Hemoglobin variants including Hb C, Hb D, and Hb E".)
●Iron deficiency – Iron deficiency can cause target cells, especially when iron deficiency anemia is severe. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Stages of iron deficiency'.)
●Xerocytosis – Xerocytosis is a less common cause of decreased intracellular volume. Xerocytes are dense, hyperchromic RBCs caused by solute loss that induces osmotic water loss. RBC dehydration also usually produces target cells, Hereditary xerocytosis (HX) can be caused by pathogenic variants in one of several genes that control RBC hydration. (See "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)", section on 'Xerocyte formation'.)
Laboratory testing target cells — In many cases, the condition causing target cells is already known, and no further evaluation is needed.
If target cells are found in an individual for whom the cause is not known, testing is appropriate to identify the cause. This testing can generally be performed by the primary care clinician, although specialist input may be appropriate if there is uncertainly in deciding which tests to perform or in interpreting the results.
The first step is to review the patient's clinical status and the complete blood count (CBC), including RBC indices, RBC count, and other RBC morphologies.
Additional laboratory testing after review of the CBC may include the following; this generally can be performed by the primary care clinician:
●Iron studies – Iron studies are especially important in premenopausal females, as well as individuals with microcytosis and a low RBC count and prior to performing hemoglobin analysis. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)
●Hemoglobin analysis – Hemoglobin analysis, typically using a protein-based method, is especially important in individuals with suspected hemoglobinopathy or thalassemia, including those with anemia since birth or early childhood and with an increased RBC count. Iron studies should be performed, and iron deficiency corrected, prior to obtaining this testing. Routine iron supplementation should not be administered without iron studies, as individuals with thalassemia often have iron overload. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Protein chemistry methods' and "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Patient with suspected thalassemia'.)
●Liver function testing – Liver function tests are especially important in older individuals with risk factors for liver disease, individuals with new onset target cells, and those who lack evidence of iron deficiency or thalassemia (absence of microcytosis, normal or increased iron stores, normal RBC count, normal hemoglobin analysis). (See "Liver biochemical tests that detect injury to hepatocytes".)
●Lipid panel – A lipid panel is appropriate if there are signs of liver disease or if iron studies, hemoglobin analysis, and liver function tests are unrevealing. Many individuals will already have had a lipid panel done for primary prevention of cardiovascular disease. (See "Overview of primary prevention of cardiovascular disease", section on 'Dyslipidemia' and "Screening for lipid disorders in adults".)
●Genetic testing – Genetic testing for LCAT deficiency is only appropriate if there is a positive family history of the disorder, a very low HDL cholesterol, or other clinical features associated with the disorder. (See 'Increased membrane' above and "HDL cholesterol: Clinical aspects of abnormal values", section on 'Inherited causes'.)
MANAGEMENT — Not all disorders associated with burr cells, acanthocytes, or target cells cause hemolysis or hemolytic anemia.
●If hemolysis and anemia are absent, no specific treatment is required, although treatment may be indicated for the underlying disorder.
●If a specific underlying cause is found, decisions about treatment depend on the severity of hemolytic anemia and the other manifestations of the underlying disorder. Specific management recommendations for these disorders are provided in separate topic reviews on each disorder.
●As long as chronic hemolysis is occurring, we suggest folic acid supplementation. A typical dose is 1 mg daily. This can be omitted if the individual is consuming a folate-rich or folic acid-supplemented diet. This practice is based on the known increased consumption of folates when erythropoiesis is increased.
●Attention to other conditions that can cause anemia is also important if present, especially the more common causes of anemia including vitamin B12 and folate deficiencies, iron deficiency, and anemia of chronic disease/anemia of inflammation (ACD/AI). (See "Treatment of vitamin B12 and folate deficiencies" and "Treatment of iron deficiency anemia in adults" and "Anemia of chronic disease/anemia of inflammation".)
●On occasion, spur cell hemolytic anemia is severe enough to necessitate consideration of splenectomy. The operative morbidity in such cases is considerable, because there may be concomitant thrombocytopenia and leukopenia due to hypersplenism or other conditions. Splenectomy is generally avoided unless hemolytic anemia is severe and does not improve with other interventions. The final decision is individualized in consultation with a specialist in the specific underlying disorder, to ensure that nonsurgical options have been appropriately considered and optimally used.
Severe liver disease can also cause abnormalities in hemostasis and intolerance to anesthesia. (See "Hemostatic abnormalities in patients with liver disease".)
SUMMARY AND RECOMMENDATIONS
●Pathophysiology – Abnormalities of the red blood cell (RBC) membrane can lead to abnormal RBC morphologies. Burr cells (echinocytes) have uniform small spicules (picture 1); acanthocytes have irregular large spicules (picture 3); and target cells (picture 4) have a "bulls-eye" area of central density within the region of central pallor. (See 'Terminology and best practices for viewing' above.)
•Burr cells and acanthocytes – Burr cells can be induced in vitro and in vivo by numerous extracellular factors (pH, calcium, glass, circulating substances in kidney or liver disease); the figure illustrates initial reversible and later irreversible steps (figure 1). Acanthocytes can be caused by a variety of changes that alter the RBC membrane fluidity, including increased membrane cholesterol and reduced repair/removal of fatty acids. A specific domain of Band 3 may be involved.
•Target cells – Target cells are caused by increased surface area-to-volume ratio, which can occur via increased plasma membrane or decreased intracellular volume. Increased membrane is often due to lipid disorders, and decreased volume is often due to hemoglobin disorders (iron deficiency anemia and thalassemia).
●Causes and evaluation – Often the cause will be known from the medical history, and no further evaluation is needed. If the cause is unknown, it is worthwhile to conduct an evaluation that may include history of other medical conditions and syndromic features. History of splenectomy should be considered, and the complete blood count (CBC) and RBC indices should be reviewed. Liver disease can cause all three morphologies, as well as others. (See 'RBC changes in liver disease' above.)
•Burr cells – (See 'Causes of burr cells' above and 'Laboratory testing unexplained burr cells or acanthocytes' above.)
-Laboratory artifact – Repeat blood smear with freshly prepared blood sample.
-End-stage kidney disease (ESKD) or liver disease – Kidney and liver function tests.
-Vitamin E deficiency – Vitamin E level.
-Pyruvate kinase (PK) deficiency – PK activity.
-Multisystem Inflammatory Syndrome in Children (MIS-C) – Evaluation for symptoms of MIS-C and for prior infection with SARS-CoV2.
•Acanthocytes – (See 'Causes of acanthocytes' above and 'Laboratory testing unexplained burr cells or acanthocytes' above.)
-Liver disease – Liver function tests.
-Hypothyroidism – Thyroid function tests.
-Drug-induced – Medication review, lipid panel.
-Anorexia nervosa – Clinical evaluation.
-Myelodysplasia – Hematologist evaluation if suspected.
-Rare disorders (neuroacanthocytosis, chylomicron retention disease, blood group abnormalities, Band 3 A858D variant) – Specific testing listed above. (See 'Laboratory testing unexplained burr cells or acanthocytes' above.)
•Target cells – (See 'Target cells' above.)
-Iron deficiency – Iron studies.
-Thalassemia – Hemoglobin analysis (after iron studies are done and iron deficiency corrected if present).
-Hemoglobinopathy – Hemoglobin analysis, particularly for Hb C, D, and E.
-Liver disease – Liver function tests.
-Lecithin-cholesterol acyltransferase (LCAT) deficiency – Lipid panel.
●Management – Isolated morphologic changes without anemia or hemolysis may not require treatment, although treatment of the underlying condition causing the changes may be appropriate. Other causes of anemia such as concomitant vitamin B12, folate, or iron deficiency should be reviewed and treated as required.
For individuals who have chronic hemolytic anemia, we suggest folic acid supplementation (Grade 2C). Individuals with a folate-rich or folic acid-supplemented diet may reasonably omit folic acid if they are not folate-deficient.
Splenectomy is generally avoided unless hemolytic anemia is severe and does not improve with other interventions. (See 'Management' above.)
ACKNOWLEDGMENTS
We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.
The UpToDate editorial staff also acknowledges the extensive contributions of William C Mentzer, MD, to earlier versions of this and many other topic reviews.
