Hematology

Hereditary spherocytosis

Hereditary spherocytosis

What every physician needs to know:

Hereditary spherocytosis (HS) refers to a group of disorders characterized by spherical, doughnut-shaped erythrocytes with increased osmotic fragility. The clinical manifestations of the spherocytosis syndromes vary widely. The typical clinical picture of HS combines signs and symptoms of hemolysis (anemia, jaundice, reticulocytosis, gallstones, splenomegaly) with spherocytosis (spherocytes on the peripheral blood smear with increased erythrocyte osmotic fragility) and a positive family history.

Mild, moderate, and severe forms of HS have been described, classified by differences in degree of anemia, hyperbilirubinemia, and reticulocyte count, which is used as a surrogate for the degree of compensation for hemolysis. Initial assessment of a patient with suspected HS should include a family history and questions about history of anemia, jaundice, gallstones, and splenectomy. Physical examination should seek signs such as scleral icterus, jaundice, and splenomegaly.

Are you sure your patient has hereditary spherocytosis? What should you expect to find?

Hereditary spherocytosis typically presents in infancy or childhood but may present at any age. In children, anemia is the most frequent finding (50%), followed by splenomegaly, jaundice, or a positive family history. No comparable data exist for adults. Two thirds to three fourths of HS patients have incompletely compensated hemolysis and mild to moderate anemia. The anemia often is asymptomatic, except for fatigue and mild pallor or, with children, nonspecific parental complaints, such as irritability.

Jaundice is seen at some time in about half of patients, usually in association with viral infections. When present, jaundice is acholuric, that is, unconjugated hyperbilirubinemia without detectable bilirubinuria. Palpable splenomegaly is detectable in most (75 to 95%) older children and adults. Typically the spleen is modestly enlarged (2 to 6cm), but it may be massive. No proven correlation exists between the spleen size and the severity of HS. Typical HS is associated with both dominant and recessive inheritance. Although the recessively inherited forms tend to be more severe, considerable overlap exists.

Approximately 20 to 30% of HS patients have "compensated hemolysis," that is, production and destruction are balanced, and the hemoglobin concentration of the blood is normal. Many of these individuals escape detection until adulthood when they are being evaluated for unrelated disorders, or when complications related to anemia or chronic hemolysis occur. Hemolysis may become severe with illnesses that cause further splenomegaly, such as infectious mononucleosis, or may be exacerbated by other factors, such as pregnancy or sustained, vigorous exercise. Because of the asymptomatic course of HS in these patients, diagnosis of HS should be considered during evaluation of incidentally noted splenomegaly, gallstones at a young age, or anemia resulting from parvovirus B19 infection or other viral infections.

Approximately 5 to 10% of HS patients have moderately severe to severe anemia. Patients with "moderately severe" disease typically have a hemoglobin level of 6 to 8g/dl, reticulocytes approximately 10%, bilirubin 2 to 3mg/dl, and 40 to 80% of the normal red cell spectrin content. Patients with "severe" disease, by definition, have life-threatening anemia and are transfusion dependent. They almost always have recessive HS. Most have isolated, severe spectrin deficiency (less than 40%). Patients with severe HS often have some irregularly contoured or budding spherocytes or bizarre poikilocytes, in addition to typical spherocytes on blood film. In addition to the risks of recurrent transfusions, patients suffer from hemolytic and aplastic crises and may develop complications of severe uncompensated anemia, including growth retardation, delayed sexual maturation, and aspects of thalassemic facies.

Beware of other conditions that can mimic hereditary spherocytosis:

Other causes of spherocytic hemolytic anemia, such as autoimmune hemolysis, clostridial sepsis, transfusion reactions, severe burns, and bites from snakes, spiders, bees, and wasps, should be viewed in the appropriate clinical context. Occasional spherocytes are seen in patients with a large spleen (for example, in cirrhosis) or in patients with microangiopathic anemias, but differentiation of these conditions from HS does not usually present diagnostic difficulties.

HS may be obscured in disorders that increase the surface to volume ratio of erythrocytes, such as obstructive jaundice, iron deficiency, ß-thalassemia trait or hemoglobin SC disease, and vitamin B12 or folate deficiency. In obstructive jaundice, spherocytosis can be obscured by accumulation of cholesterol and phospholipids in the membrane that characteristically accompanies this condition.

Which individuals are most at risk for developing hereditary spherocytosis:

HS occurs in all racial and ethnic groups. It is the most common inherited anemia in individuals of northern European ancestry, affecting approximately one in 2,500 individuals in the United States and England. Males and females are affected equally.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Morphology

Erythrocyte morphology in HS is variable. Typical HS patients have peripheral blood smears with easily identifiable spherocytes, smaller dense erythrocytes lacking central pallor. Less commonly, patients present with only a few spherocytes on the film or, at the other end of the spectrum, with many small, hyperdense spherocytes and bizarre erythrocyte morphology with anisocytosis and poikilocytosis. Rarely, spherostomatocytes are seen.

Indices

Most HS patients have mild to moderate anemia, with hemoglobin levels in the 9 to 12g/dl range. Mean corpuscular hemoglobin concentration (MCHC) is increased (greater than 35%), because of relative cellular dehydration in 50 to 70% of patients. In one report, an MCHC greater than 35.4g/dl, and a red cell distribution width (RDW) greater than 14, had a sensitivity of 63%, and a specificity of 100% for the diagnosis of HS. Histograms of hyperdense erythrocytes (MCHC greater than 40g/dl) obtained from laser-based cell counters have been utilized as a screening test for HS. Finally, mean corpuscular volume (MCV) usually is normal, except in cases of severe HS, when MCV is slightly decreased. Typically, MCV is relatively low for the age of the cells in most HS patients, reflecting the dehydrated state of the HS erythrocytes.

Osmotic fragility testing

The reduced surface area to volume ratio, characteristic of spherocytes, increases their susceptibility to osmotic lysis in hypotonic solutions. This is the basis of the osmotic fragility test, in which red cells are suspended in sodium chloride solutions of decreasing tonicity, and the degree of hemolysis determined. Incubation for 24 hours in the absence of metabolic substrate accentuates the osmotic fragility of spherocytes, and makes easier the distinction of this disease from others. The sensitivity of the incubated osmotic fragility test can be outweighed by a loss of its specificity, as increased osmotic fragility is not unique to HS, and is also present in other conditions associated with spherocytosis.

Eosin-5’-maleimide binding

The observations that most spherocytes are deficient in band three, and that the dye eosin-5’-maleimide (EMA) covalently binds band three and Rh (rhesus)-related proteins with a one to one ratio stoichiometry are the basis of the EMA binding test. The binding of fluorescently-labeled EMA to erythrocytes is followed by flow cytometric quantitation, with less signal detected in HS erythrocytes. This method is fast and simple, and appears to have both high sensitivity and specificity. Like osmotic fragility, other erythrocyte abnormalities such as abnormalities of erythrocyte hydration and variants of dyserythropoietic anemia can also yield abnormal results.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of hereditary spherocytosis?

Imaging studies are not required to diagnose HS. Abdominal ultrasonography may indicate the presence of splenomegaly or cholelithiasis.

If you decide the patient has hereditary spherocytosis, what therapies should you initiate immediately?

Unless the patient presents with signs and symptoms of congestive heart failure (CHF) due to severe anemia, usually associated with an aplastic or a hemolytic crisis, immediate therapy is rarely necessary. When the patient does present with signs and symptoms of CHF due to severe anemia, packed red blood cell transfusion, and careful monitoring of the patient's cardiovascular status, are indicated.

More definitive therapies?

Splenectomy cures or alleviates the anemia in the overwhelming majority of patients, reducing or eliminating the need for red cell transfusions. Elimination of the need for chronic blood transfusions has obvious implications for future iron overload and risk of end-organ damage. In addition, the risk of cholelithiasis decreases to background.

What other therapies are helpful for reducing complications?

HS patients should be followed for signs of decompensation during acute illnesses.

Interval ultrasonography to detect gallstones should be performed. In some cases, cholecystectomy may be required.

Patients with hemolysis should receive daily folate supplementation, to prevent megaloblastic disease.

Counselling of family members should be provided.

What should you tell the patient and the family about prognosis?

Splenectomy, which cures or alleviates anemia in almost all HS patients, has a low operative mortality. Postoperative complications of splenectomy include local infection, bleeding, or pancreatitis.

Long-term complications include the risk of postsplenectomy sepsis and cardiovascular disease. Splenectomy failure is uncommon, resulting from an accessory spleen missed at surgery, or from development of splenunculi as a consequence of autotransplantation of splenic tissue during surgery. Accessory spleens occur in 15 to 40% of patients and must always be sought. Recurrence of hemolytic anemia years, or even decades, following splenectomy should raise suspicion of an accessory spleen, particularly if Howell-Jolly bodies are no longer found on blood film. Definitive confirmation of ectopic splenic tissue can be achieved by a radiocolloid liver–spleen scan.

The use of prophylactic antibiotics postsplenectomy for prevention of postsplenectomy sepsis is controversial.

Pre-splenectomy and, in severe cases, postsplenectomy, HS patients should take folic acid (mg/day orally) to prevent folate deficiency.

After a patient is diagnosed with HS, family members should be examined for the presence of HS. A history, physical examination for splenomegaly, and screening laboratory studies including complete blood count, examination of the peripheral blood smear, and a reticulocyte count, should be obtained for parents, children, and siblings, if available.

What if scenarios.

N/A

Pathophysiology

The hallmark of HS erythrocytes is loss of membrane surface area relative to intracellular volume, accounting for the spheroidal shape and decreased deformability of the red cell. The loss of surface area results from increased membrane fragility caused by defects in proteins of the erythrocyte membrane, including ankyrin, band 3, spectrin, and protein 4.2. Increased fragility leads to membrane vesiculation and surface area loss. Splenic trapping of nondeformable spherocytes, followed by conditioning and destruction of these abnormal erythrocytes, causes the hemolysis experienced by HS patients.

What other clinical manifestations may help me to diagnose hereditary spherocytosis?

When obtaining family and medical history, important questions to ask include history of anemia, fatigue, pallor, jaundice, gallstones or splenectomy.

Jaundice may be more apparent during intercurrent illnesses.

Typical physical signs may include pallor, jaundice, icterus, and splenomegaly.

Rarely, HS patients develop signs of gout, leg ulcers, or a chronic erythematous dermatitis on the legs. Extramedullary masses of hematopoietic tissue, particularly alongside the posterior thoracic or lumbar spine or in the kidney hila, which may spontaneously bleed or simulate a cancerous mass, may develop. Other rare associated manifestations include hematologic malignancy and the presence of angioid streaks in the eyes.

What other additional laboratory studies may be ordered?

Other tests used in the diagnosis of hereditary spherocytosis are not widely used in the United States (for example, the glycerol lysis test, the Pink test, hypertonic cryohemolysis, and the skeleton gelation test), although cryohemolysis testing is popular in Europe. The former two tests, which employ glycerol to retard the osmotic swelling of red cells, are preferred in some laboratories because they are easy to perform, and can be adapted to microsamples. Specialized testing, such as ektacytometry, membrane protein studies, and genetic analyses are available for studying difficult cases or when additional information is desired.

Other laboratory manifestations in HS are markers of ongoing hemolysis. Reticulocytosis, increased bilirubin, increased lactate dehydrogenase, increased urinary and fecal urobilinogen, and decreased haptoglobin, reflect increased erythrocyte production or destruction.

What’s the evidence?

Barcellini, W, Bianchi, P, Fermo, E. "Hereditary red cell membrane defects: diagnostic and clinical aspects". Blood transfusion. vol. 9. 2011. pp. 274-277.

[An up to date review of practical issues and pathophysiology.]

Bennett, V, Heally, J. "Organizing the fluid membrane bilayer: diseases linked to spectrin and ankyrin". Trends Mol Med. vol. 14. 2008. pp. 28-36.

[Provides a more science based description of how the red cell membrane is constructed and how it functions.]

Casale, M, Perrotta, S. "Splenectomy for hereditary spherocytosis: complete, partial or not at all". Expert Rev Hematol. vol. 4. 2011. pp. 627-635.

[A very good discussion of the pros and cons of splenectomizing patients with chronic hemolytic anemias, especially hereditary spherocytosis.]

Perrotta, S, Gallagher, PG, Mohandas, N. "Hereditary spherocytosis". Lancet. vol. 372. 2008. pp. 1411-1426.

[A less up to date but particularly readable review of the disease.]
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