CHAPTER 44 ACANTHOCYTOSIS, STOMATOCYTOSIS, & RELATED DISORDERS
CHAPTER 44 ACANTHOCYTOSIS, STOMATOCYTOSIS, & RELATED DISORDERS
PATRICK G. GALLAGHER
Acanthocytosis in Severe Liver Disease
Abetalipoproteinemia (Bassen-Kornzweig Syndrome)
Acanthocytosis with Neurologic Disease and Normal Lipoproteins
Acanthocytosis in other Conditions
Stomatocytosis and Related Disorders
Dehydrated Stomatocytosis/Hereditary Xerocytosis
RH Deficiency Syndrome
Familial Deficiency of High-Density Lipoproteins
Acanthocytes are contracted, dense cells with irregular projections from the red cell surface. They are seen in the blood films of patients with severe liver disease, abetalipoproteinemia, certain inherited neurologic disorders without abetalipoproteinemia, and in association with the inheritance of certain red cell antigen polymorphisms. Erythrocytes in these disorders are characterized by abnormal red cell membrane lipid composition with altered lipid distribution between the inner and outer leaflets of the bilayer. Typically, the hemolytic anemia associated with acanthocytosis is mild to moderate and rarely requires therapy. Stomatocytes are erythrocytes characterized by a wide transverse slit (or stoma) found in the blood films of patients with a variety of acquired and inherited red cell disorders. Stomatocytosis is commonly associated with inherited abnormalities of red cell cation permeability. These disorders are frequently associated with abnormal red cell cation content, hydration, and membrane lipids. There is great heterogeneity in the erythrocyte morphology, laboratory manifestations, and clinical course of the stomatocytosis syndromes. The etiology of these disorders of cation permeability is unknown.
Acronyms and abbreviations that appear in this chapter include: FP, familial pseudohyperkalemia; HARP syndrome,hpoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration with iron deposition; HSt, hereditary stomatocytosis; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; MTP, microsomal transfer protein.
Spiculated red cells are classified into two types, acanthocytes and echinocytes. Acanthocytes are contracted, dense cells with irregular projections from the red cell surface that vary in width and length. Echinocytes have small, uniform projections spread evenly over the circumference of the red cell. These differences are clearly seen in scanning electron micrographs (see Table 22-3)1 but may be difficult to ascertain on standard peripheral blood smears. Acanthocytes are almost always accompanied by echinocytes, but echinocytes may be present alone. Diagnostically, the distinction is not critical, and disorders of spiculated red cells are generally classified together. Normal adults may have up to 3 percent of spiculated erythrocytes on smear, with higher levels found in patients with functional or actual splenectomy, after ingestion of alcohol or certain medications (e.g., indomethacin, salicylates, furosemide), and in premature infants (mean 5.5 percent, range 1–25 percent). Spiculated cells, particularly echinocytes, are common artifacts of blood smear preparation.
Acanthocytes are present in the blood films of patients with severe liver disease, abetalipoproteinemia, certain inherited neurologic disorders without abetalipoproteinemia, and in association with the inheritance of certain red cell antigen polymorphisms such as the McLeod blood group. Abnormal red cell membrane lipid composition and altered lipid distribution between the inner and outer leaflets of the bilayer characterize these conditions. Smaller numbers of acanthocytes (<10 percent) may be seen in patients with myelodysplasia, hypothyroidism, and anorexia nervosa. Echinocytes may be found on the blood films of patients with severe uremia, glycolytic defects, and microangiopathic hemolytic anemia, and transiently after transfusion of stored red cells.
ACANTHOCYTOSIS IN SEVERE LIVER DISEASE
The anemia in patients with liver disease is of complex etiology.2 Common causes include blood loss, iron or folate deficiency, hypersplenism, and marrow suppression from alcohol, malnutrition, hepatitis infection, or other factors. Acquired abnormalities of the red cell membrane may contribute to the anemia in these patients; one is a syndrome of hemolysis with acanthocytosis or “spur” cells, so-called spur cell anemia.3 Although only a small number of patients with end-stage liver disease acquire spur cell anemia, the prevalence of liver disease is so high that these individuals account for the majority of cases of acanthocytosis seen in clinical practice.
ETIOLOGY AND PATHOGENESIS
Acanthocyte formation in vivo is a two-step process involving accumulation of free (nonesterified) cholesterol in the red cell membrane and remodeling of abnormally shaped red cells by the spleen.4,5 Acanthocytes result from increased acquisition of free cholesterol from the plasma due to abnormal cholesterol/lipoprotein ratios.4 In severe liver disease, a very high ratio of free cholesterol to phospholipids is found in lipoproteins. Free cholesterol readily partitions into the membrane, where it preferentially associates with the outer leaflet, making it less fluid. The spleen attempts to remodel the membrane leading to rigid, spherical erythrocytes with the characteristic spiculated projections5 (Fig. 44-1). Over time, these poorly deformable cells have difficulty negotiating the narrow sinusoids of the splenic circulation and are hemolyzed (Chap. 5).
FIGURE 44-1 Blood film from a patient with liver cirrhosis and spur cell anemia. The conditioning effect of the spleen is demonstrated by the spheroidal shape of the cells and the remodeling of the spicules. (From Cooper and coworkers5 with permission.)
Spur cell anemia is characterized by a rapidly progressive hemolytic anemia with large numbers of acanthocytes on the blood film.3,6,7 Splenomegaly and jaundice become more prominent accompanied by severe ascites, bleeding diatheses, and hepatic encephalopathy. Spur cell anemia is most common in patients with alcoholic liver disease, but similar clinical syndromes have been described in association with advanced metastatic liver disease, cardiac cirrhosis, Wilson disease, fulminant hepatitis, and infantile cholestatic liver disease.8
Most patients have moderate anemia with a hematocrit of 20 to 30 percent, marked indirect hyperbilirubinemia, and laboratory evidence of severe hepatocellular disease. Blood films reveal significant acanthocytosis (Fig. 44-1). Echinocytes, target cells, and microspherocytes, many with very fine spicules, are found in some patients.
Spur cell hemolytic anemia should be distinguished from other hemolytic syndromes associated with liver disease, including (1) chronic, mild hemolysis with occasional spherocytes seen in patients with congestive splenomegaly, (2) transient hemolysis associated with fatty metamorphosis of the liver and hypertriglyceridemia (which does not appear to have a causal relationship to hemolysis), (3) transient hemolytic anemia with stomatocytosis, and (4) hemolytic anemia with rigid and occasionally spiculated red cells (echinocytes) that has been reported in malnourished alcoholics with severe hypophosphatemia. Spur cell anemia appears to differ from Zieve syndrome, a poorly defined syndrome of hyperlipoproteinemia, jaundice, and spherocytic hemolytic anemia that occurs in alcoholic patients with liver disease.9
THERAPY, COURSE, AND PROGNOSIS
The anemia of spur cell anemia is not usually a significant clinical problem, but it can aggravate preexisting anemias, e.g., due to gastrointestinal bleeding, to the point that erythrocyte transfusion is required. The life span of spur cells is markedly decreased due to splenic sequestration, and, as would be expected, hemolysis abates after splenectomy. However, splenectomy is a dangerous and potentially fatal procedure in these critically ill patients and is generally not recommended. Spur cell anemia is an ominous clinical marker of the terminal stages of liver disease. Prior to the availability of liver transplantation, patients reaching this stage rarely lived for more than a few weeks.
ABETALIPOPROTEINEMIA (BASSEN-KORNZWEIG SYNDROME)
Abetalipoproteinemia is an autosomal recessive disorder characterized by progressive ataxic neurologic disease, celiac disease, retinitis pigmentosa, and acanthocytosis found in people of diverse ethnic backgrounds.10,11
ETIOLOGY AND PATHOGENESIS
The primary molecular defect in this disorder is a failure to synthesize or secrete lipoproteins containing products of the apoprotein B gene.11 In some patients, this is due to lack of microsomal transfer protein (MTP), which catalyzes the transport of triglyceride, cholesterol ester, and phospholipid from phospholipid surfaces.12,13,14 and 15 Microsomal transfer protein, a heterodimer of protein disulfide isomerase and a large 88-kDa subunit, is located in the lumen of hepatic microsomes and intestinal epithelia, the sites of lipoprotein synthesis. Other than apolipoprotein B, microsomal transfer protein is the only tissue-specific component required for secretion of apoprotein B–containing lipoproteins. All lipoproteins that contain apoprotein B are absent in plasma; consequently, preformed triglycerides are not transported from the intestinal mucosa, and plasma triglycerides are nearly absent.11 Plasma cholesterol and phospholipid levels are markedly decreased, with a relative increase of sphingomyelin at the expense of lecithin.
In this condition, marrow red cell precursors, nucleated red cells, and reticulocytes have normal shape. Acanthocytosis becomes apparent as the red cells mature in the circulation, worsening with increasing red cell age.16 Incubating normal red cells in abetalipoproteinemic serum does not produce acanthocytes, but normal red cells acquire acanthocytic changes when transfused into an abetalipoproteinemic recipient. Erythrocyte membrane proteins are normal, but lipids are not.17 The cholesterol to phospholipid ratio is normal or slightly increased, reflecting changes in the distribution of plasma phospholipids and a decrease in lecithin-cholesterol acyltransferase (LCAT) activity. The phosphatidylcholine concentration is decreased, and sphingomyelin is correspondingly increased. It has been suggested that in abetalipoproteinemic acanthocytes, excess sphingomyelin is preferentially confined to the outer membrane bilayer leaflet, causing an expansion of its surface area that may be responsible for the irregularities in cell surface contour.
The disorder manifests in the first month of life by steatorrhea. Intestinal biopsy typically reveals engorgement of mucosal cells with lipid droplets. Retinitis pigmentosa, which often results in blindness, and progressive neurologic abnormalities characterized by ataxia and intention tremors develop between 5 and 10 years of age and progress to death in the second or third decade.11
These patients usually have a mild anemia with normal red cell indices and normal or slightly increased reticulocyte counts.10,11,16 Acanthocytosis is prominent, ranging from about 50 to 90 percent of red cells. Despite the lipid abnormalities and frequent concomitant vitamin E deficiency, the hemolysis experienced by these patients is mild, especially when compared to patients with spur cell anemia (see above). It has been suggested that the enlarged, congested spleen in patients with portal hypertension and spur cell anemia worsens the hemolysis, whereas the spleen is normal in patients with abetalipoproteinemia.
The related disorders hypobetalipoproteinemia, normotriglyceridemic abetalipoproteinemia, and chylomicron retention disease are associated with partial production of apolipoprotein B–containing lipoproteins or with the secretion of lipoproteins containing truncated forms of apolipoprotein B.18,19 and 20 Patients with these disorders also may experience neurologic disease and acanthocytosis, depending on the severity of the underlying defect. Even patients with heterozygous hypobetalipoproteinemia may have acanthocytosis, but typically they do not.21
THERAPY, COURSE, AND PROGNOSIS
Treatment includes dietary restriction of triglycerides and supplementation of vitamins A, K, D, and E.11 Water-soluble forms of vitamin E, such as D-a-tocopherol polyethylene glycol succinate, are available for use. The role of vitamin E in the pathophysiology and clinical symptomatology of abetalipoproteinemia is unknown. It has been suggested that vitamin E deficiency is the primary stimulus for secondary manifestations of the disease such as neuropathy. This is based on the observations that vitamin E may stabilize or even improve neuromuscular and retinal abnormalities in these patients and because a similar neuropathy has been observed in patients with chronic cholestasis. Clinically evident vitamin A or D deficiencies are rarely observed.
ACANTHOCYTOSIS WITH NEUROLOGIC DISEASE AND NORMAL LIPOPROTEINS
Chorea-acanthocytosis is a rare autosomal recessive disorder characterized by normolipoproteinemic acanthocytosis and progressive neurodegenerative disease with onset in adolescence or adult life.22 Chorea-acanthocytosis is characterized by progressive orofacial dyskineses with tics, limb chorea, lip and tongue biting; neurogenic muscle hypotonia and atrophy; absent or diminished reflexes; and increased serum creatine phosphokinase. Neuroimaging demonstrates abnormalities of the putamen and the head of the caudate.23 Although variant syndromes of chorea-acanthocytosis have been described, recent linkage of chorea-acanthocytosis in 11 affected families from diverse ethnic backgrounds to a 6-cM region of 9q21 suggests a single disease locus.24
These patients are not anemic, and red cell survival is only slightly decreased. In some, the acanthocytosis may precede the onset of neurologic symptoms. The mechanism of acanthocytosis in chorea-acanthocytosis is unknown. Plasma and erythrocyte membrane lipids, as well as membrane fatty acid composition, are normal except for a high content of saturated fatty acids.25 Red cell membrane fluidity is decreased, and intramembrane particles are unevenly distributed, presumably due to altered lipid fluidity. Increased proteolysis of ankyrin, band 3, and protein 4.2 and increased membrane protein phosphorylation, especially of band 3, may contribute to the cell shape change.26 A point mutation near the COOH-terminus of band 3 has been identified in one unusual kindred with chorea-acanthocytosis.27
Inherited neuroacanthocytosis syndromes other than chorea-acanthocytosis have been described. These include: (1) a recessively inherited syndrome with acanthocytosis, tics, parkinsonism, and occasional motor neuron disease; (2) a mitochondrial myopathy with encephalopathy, lactic acidosis, strokelike symptoms, and acanthocytosis; (3) Hallervorden-Spatz disease (progressive dementia, dystonia, spasticity, pallidal and retinal degeneration) with acanthocytosis; and (4) HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration with iron deposition).
KELL AND LUTHERAN BLOOD GROUPS
The McLeod syndrome is an X-linked anomaly of the Kell blood group system characterized by a mild compensated hemolytic anemia with variable acanthocytosis and, in some patients, late-onset myopathy or chorea.28,29 The Kell antigen consists of two major protein components: a 37-kDa protein that carries the Kx antigen, a precursor molecule necessary for the Kell antigen expression, and a 93-kDa protein that carries the Kell blood group antigen. Red cells with the McLeod phenotype have no detectable Kx antigen, and they have a marked deficiency of the 93-kDa protein that carries the Kell antigen. The XK gene encodes a novel 444-amino acid integral membrane transporter, and mutations of the XK gene have been identified in McLeod patients.30,31 and 32 Male hemizygotes who lack Kx have 8 to 85 percent of acanthocytes on the blood film and mild, compensated hemolysis. Because of the red cell mosaicism–produced X inactivation, female heterozygote carriers may have occasional acanthocytes on the blood film,29 and women with markedly biased X inactivation may have more severe symptoms.31
McLeod red cells should be distinguished from Kell null (Ko) red cells, which have a normal shape. In Ko cells, only the Kell antigen carrying 93-kDa glycoprotein is absent, while these cells have twice the amount of the Kx antigen.33 It is important to identify patients with McLeod syndrome because if they receive transfusions they may develop antibodies that are compatible only with McLeod syndrome red cells.
The McLeod phenotype has been described in association with chronic granulomatous disease of childhood, retinitis pigmentosa, and Duchenne muscular dystrophy. These variable manifestations may be due to contiguous gene syndromes, as the genetic locus for these disorders is Xp21.34,35 and 36 This may explain the occasional findings of either echinocytes or stomatocytes in Duchenne dystrophy or a choreiform disorder in some subjects with McLeod phenotype. Furthermore, some subjects with the McLeod phenotype exhibit laboratory features of myopathy and, later in life, a neurologic disorder that is first manifested by areflexia and, after the fifth decade, progresses to dystonia and choreiform movements.
Lutheran Blood Group Approximately 1 in 3000 to 5000 people inherit a dominantly acting inhibitor, In(Lu), that suppresses expression of Lua and Lub, the major antigens of the Lutheran blood group system. Patients with the In(Lu) Lu(a-b-) phenotype may have abnormally shaped red cells, including poikilocytes and acanthocytes, without evidence of anemia or hemolysis.37 The osmotic fragility of fresh In(Lu) Lu(a-b-) erythrocytes is normal, but after incubation, the cells lose potassium and become osmotically resistant.38 The identity of the inhibitor has yet to be identified.
ACANTHOCYTOSIS IN OTHER CONDITIONS
A small number of acanthocytes appear in malnutrition resulting from diverse causes, including anorexia nervosa and cystic fibrosis. The red cell shape normalizes after restoration of adequate nutritional status. Very mild acanthocytosis (0.5–2 percent) is common in 20 to 65 percent of patients with hypothyroidism.39 Because hypothyroidism is so much more common than the other disorders that cause spiculated red cells, the finding of acanthocytes on the blood film should prompt consideration of the patient’s thyroid function. This association may unmask undiagnosed cases of hypothyroidism.
STOMATOCYTOSIS AND RELATED DISORDERS
Stomatocytes are erythrocytes characterized by a wide transverse slit or stoma (thus stomatocytes) (see Fig. 42-3).40 There is no unifying theory to explain this morphologic abnormality which is an artifact resulting from folding of the cells during blood film preparation. Stomatocytes are seen in a variety of acquired and inherited disorders. The latter are often associated with inherited abnormalities in red cell cation permeability that may be associated with abnormal red cell hydration or membrane lipids.41,42 Disturbances of erythrocyte hydration range from the extremes of dehydration and overhydration. These variants have been divided into provisional categories based on clinical severity, morphology, cation content, lipid and protein composition, genetics, and response to splenectomy (Table 44-1).8
TABLE 44-1 HETEROGENEITY OF THE HEREDITARY STOMATOCYTOSIS SYNDROMES
DEHYDRATED STOMATOCYTOSIS/HEREDITARY XEROCYTOSIS
Dehydrated hereditary stomatocytosis, also known as hereditary xerocytosis or dessicocytosis, is the most common form of the hereditary stomatocytosis syndromes.40,41 and 42 The predominant phenotype associated with this disorder is an autosomal dominant hemolytic anemia with red cell dehydration and decreased osmotic fragility.42,43 Recently, this phenotype has been recently extended to include recurrent fetal loss, hydrops fetalis, and pseudohyperkalemia (see below).
ETIOLOGY AND PATHOGENESIS
The underlying permeability defect is complex and involves a net loss of potassium from the red cells (typically about 20 percent) that is not accompanied by a proportional gain of sodium.41,44 Consequently, the net intracellular cation content and cell water content are decreased. In some cases, erythrocytes also have increased membrane lipids, particularly phosphatidylcholine, and reduced 2,3-BPG content.45 No quantitative abnormalities of membrane lipids and proteins have been noted, except for increased membrane-associated glyceraldehyde-3-phosphate dehydrogenase.
The precise genetic basis of this disorder remains unknown. Dehydrated hereditary stomatocytosis has been mapped to 16q23-qter.46
Patients may present with compensated hemolytic anemia, jaundice, splenomegaly, and gallstones. Recently, this syndrome has been extended to include recurrent fetal loss, hydrops fetalis, and familial pseudohyperkalemia (FP).42,47 Individuals with FP present with asymptomatic hyperkalemia, attributed to an altered passive leak of potassium across the red cell membrane in vitro, similar to the one attributed to be defective in xerocytosis.48 In approximately one third of xerocytosis patients, there is pseudohyperkalemia.42,49 Xerocytosis, hydrops fetalis, and pseudohyperkalemia have been linked in several kindreds.50,51 There appears to be variable penetrance in this disorder, with significant disparity in clinical symptomatology between affected individuals in the same kindred.51 Genetic linkage analyses have mapped the FP locus to the same location as xerocytosis, supporting the hypothesis that these syndromes are due to different mutations in the same gene.52
The hematologic picture is that of mild to moderate hemolytic anemia with increased mean corpuscular hemoglobin concentration (MCHC), a reflection of cellular dehydration. Frequently, the mean corpuscular volume (MCV) is mildly increased, an artifact of Coulter-type electronic counters. In these counters, the conversion of pulse height (from the resistance of a cell passing through an electric field) to a cellular volume is dependent on cell shape. Xerocytes do not deform to the same degree as normal cells, which causes the MCV to be about 10 percent too high. The hematocrit is also affected because it is calculated from the MCV. Blood films do not always reveal stomatocytes, which are more prominent on wet films, but frequently target cells, dessicocytes and spiculated cells are seen (Fig. 44-2). In some of the cells, hemoglobin is concentrated (“puddled”) in discrete areas on the cell periphery. Erythrocyte incubated osmotic fragility is decreased.
FIGURE 44-2 Stomatocytosis and variants. Peripheral blood smear from patients with hereditary xerocytosis (dessicocytosis) (a), stomatocytosis (hydrocytosis) (b), and acquired stomatocytosis due to alcoholic liver disease (c). (Panels (a) and (b) reprinted with permission from Lande and Mentzer.40)
THERAPY, COURSE, AND PROGNOSIS
Most patients experience only mild anemia, and therapy is not required.53 These patients should receive folate supplementation and be monitored for complications of hemolysis.
The effects of splenectomy have been variable, with many xerocytosis patients experiencing little or no improvement in their anemia. It has been suggested that xerocytes are so functionally compromised that they are detected and eliminated in other areas of the macrophage-monocyte system. Splenectomy should be carefully considered in patients with hereditary xerocytosis. Several patients have developed hypercoagulability after splenectomy, leading to life-threatening thrombotic episodes.43 It is important to note that all cases of thrombosis have occurred after splenectomy. In vitro, stomatocytic erythrocytes from a splenectomized xerocytosis individual demonstrated increased endothelial adherence compared to stomatocytic erythrocytes from unsplenectomized family members without hypercoagulability.54 In one hypercoagulable xerocytosis patient, pentoxyfylline decreased red cell adherence.54 Fortunately, the majority of hereditary stomatocytosis patients are able to maintain an adequate hemoglobin level, so that splenectomy is not required. Treatment of splenectomized patients with long-term Coumadin has had variable results. In a few severe cases, erythrocyte hypertransfusion has been beneficial. Unfortunately, this procedure is complicated by iron overload, a significant problem even in the absence of transfusion.
Neonates with xerocytosis have required phototherapy, red cell transfusion, and, in some cases, exchange transfusion, for the treatment of anemia and hyperbilirubinemia. In a few cases, in utero transfusion has been required. The presence of hydrops fetalis is not a predictor of the severity of anemia later in life, with some infants going on to experience little or no anemia later in childhood.
DEFINITION AND HISTORY
The overhydrated hereditary stomatocytosis (HSt) syndromes, also known as hereditary hydrocytosis, are characterized by a dominantly inherited hemolytic anemia with red cell overhydration and macrocytosis. This syndrome was first described by Lock and coworkers in a girl with dominantly inherited hemolytic anemia whose blood film contained red cells with a wide transverse slit, stomatocytes.55 Later, abnormal cation transport and cellular overhydration, hallmarks of this disorder, were discovered by Zarkowsky and colleagues.56
ETIOLOGY AND PATHOGENESIS
The principal lesion involves a sodium leak leading to an increase in intracellular sodium and water content and a mild decrease in intracellular potassium.41,44 This is followed by a compensatory increase in the active transport of sodium and potassium by the Na+-K+-ATPase pump, which normally maintains the low intracellular sodium and high potassium concentrations, and an ensuing increase in glycolysis. However, pump hyperactivity is unable to compensate for the vastly increased sodium leak. The molecular basis of this permeability defect is unknown.
The osmotic fragility of hydrocytes is markedly increased because many of the swollen red cells approach their critical hemolytic volume.57 For unexplained reasons, red cell membrane lipids and, consequently, membrane surface area are also increased, but this increase in surface area is insufficient to correct the osmotic fragility. Red cell deformability is decreased.
The red cells of some patients with overhydrated hereditary stomatocytosis (HSt) were found to lack a 31-kDa integral membrane protein called band 7.2b or stomatin.58 Varying degrees of stomatin deficiency were subsequently described in most but not all patients with HSt.42,59 However, the stomatin cDNA from several hereditary stomatocytosis patients was normal.60,61 Mice lacking stomatin exhibit no hemolytic anemia, and their erythrocytes are normal in morphology, cell indices, cation content, and hydration status.62 These results suggest that a defect of stomatin is not the primary defect in HSt but that it may be involved in an as yet undiscovered volume regulatory pathway in the red cell.
The hydrocytosis syndromes are much less common than the xerocytosis disorders. There is moderate to severe anemia.42,56,63,64 Jaundice and splenomegaly are common, as are complications of chronic hemolysis, e.g., cholelithiasis. A tendency for iron overload, independent of transfusion status or splenectomy, has been described. No other organ system abnormalities have been described. Neonatal anemia and hyperbilirubinemia have been reported.
The blood film reveals striking stomatocytosis (Fig. 44-2). In addition to the anemia, red cell indices show decreased MCHC and elevated MCV (Table 44-1). In some patients the macrocytosis is extreme with the MCV up to 150 fl. Erythrocyte osmotic fragility is markedly increased.
THERAPY, COURSE, AND PROGNOSIS
The majority of hydrocytosis patients suffer from significant lifelong anemia. Similar to patients with hereditary spherocytosis (Chap. 43), these patients should be monitored for complications of hemolysis, e.g., cholelithiasis, parvovirus infection, and should receive folate supplementation.
The results of splenectomy in this group of disorders has been variable.8 In some patients, hemolytic anemia is improved, although often not fully corrected, by splenectomy, while in others the severity of hemolysis is unchanged. Splenectomy should be carefully considered in patients with this disorder. Like patients with xerocytosis, several hydrocytosis patients have developed hypercoagulability after splenectomy, leading to catastrophic thrombotic episodes.43 In vivo, venous thromboemboli predominate, sometimes with complicating pulmonary or portal hypertension. This thrombotic risk is independent of postsplenectomy thrombosis, and all cases of thrombosis have occurred in splenectomized patients. Treatment of splenectomized patients with long-term Coumadin has had variable results.43 In severe cases, erythrocyte hypertransfusion has been beneficial. Unfortunately, this procedure is complicated by iron overload, a significant problem even in the absence of transfusion.
Neonates with hydrocytosis have required phototherapy, red cell transfusion, and in some cases, exchange transfusion for the treatment of anemia and hyperbilirubinemia.
Some of the reported cases of hereditary stomatocytosis share features of both hereditary xerocytosis and hereditary hydrocytosis. These disorders have been characterized as intermediate syndromes (Table 44-1).8 Characteristically, these patients have both stomatocytes and/or target cells on blood film. Erythrocyte osmotic fragility is either normal or slightly increased. Red cell sodium and potassium permeability is somewhat increased, but the intracellular cation concentration and the red cell volume are either normal or slightly reduced. In a few patients, red cells undergo spontaneous in vitro hemolysis after storage at 5°C (41°F), hence the designation cryohydrocytosis.40,65
A dominantly inherited hemolytic anemia with stomatocytosis, occasional target cells, and spherocytes, as well as a decreased osmotic fragility, in which the main red cell membrane abnormality involved a near 50 percent increase in phosphatidylcholine and a corresponding decrease in phosphatidylethanolamine has been described.66,67 In wet preparations, about 30 percent of the cells were stomatocytes. The molecular basis of this syndrome is unclear. Since abnormalities in membrane phospholipid composition have not been systematically investigated, it is uncertain whether the disorder represents a distinct disease entity.
RH DEFICIENCY SYNDROME
Rh deficiency syndrome designates rare individuals who have either absent (Rhnull) or markedly reduced (Rhmod) Rh antigen expression, mild to moderate hemolytic anemia associated with the presence of stomatocytes, and occasional spherocytes on the peripheral blood film.68,69 The structure, localization, and possible functions of the Rh antigens are reviewed in Chap. 137.
The genetic bases of the Rh deficiency syndrome are heterogeneous, and at least two groups can be defined. The amorph type is due to mutations of RH30, the RhD and RhE polypeptides.70,71 The regulatory type, is due to mutations of RH50, a modulator of Rh gene expression.72,73,74,75 and 76 Studies of these rare patients have provided evidence that both the Rh locus and Rh50 are required for the expression and function of Rh as a multimeric complex in the red cell membrane.
Red cells of some Rhnull patients have increased osmotic fragility reflecting a marked reduction of membrane surface area.77 These cells are also dehydrated, as indicated by decreased cell cation and water content and increased cell density. The potassium transport and the Na+/K+ pump activity are increased, possibly because of reticulocytosis. Hemolytic anemia is improved by splenectomy.
FAMILIAL DEFICIENCY OF HIGH-DENSITY LIPOPROTEINS
Severe deficiency or absence of high-density lipoproteins leads to accumulation of cholesteryl esters in many tissues, leading to clinical findings of large orange tonsils and hepatosplenomegaly. Reported hematologic manifestations include a moderately severe hemolytic anemia with stomatocytosis.78 Membrane lipid analyses have shown a low cholesterol content leading to a decreased ratio of cholesterol to phospholipid and a relative increase in phosphatidylcholine at the expense of sphingomyelin.
Few stomatocytes (3 to 5 percent) are commonly found on blood films of normal subjects. A prospective analysis of films from a large number of hospitalized patients revealed an overall incidence of stomatocytosis (>5 percent of stomatocytes) of 2.3 percent.79 Fifty-nine percent of these patients had 5 to 20 percent stomatocytes, 35 percent had 20 to 50 percent stomatocytes, and 6 percent had more than 50 percent stomatocytes. A wide variety of medications and diagnoses including malignant neoplasms, cardiovascular disease, hepatobiliary disease, and alcoholism were associated with stomatocytosis. Additional studies are required to determine which associations are specific and reproducible. For instance, acquired stomatocytosis is common in alcoholics, particularly those with acute alcoholism (Fig. 44-1).80 Vinca alkaloids, e.g., vincristine and vinblastine, may induce hemolysis with increased sodium permeability and stomatocytosis in the doses used for chemotherapy of leukemias and lymphomas.81,82 The molecular basis of stomatocytosis in these conditions is unknown; it is rarely associated with clinically significant hematologic abnormalities.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn