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Esferocitose hereditária

Image: Peripheral blood smear from patient with hereditary spherocytosis. By: Paulo Henrique Orlandi Mourao. License: CC BY-SA 3.0


Epidemiology

Approximately 1 in 2,000–5,000 Caucasians in the United States and Europe have hereditary spherocytosis. The autosomal dominant inheritance pattern is responsible for three-quarters of all cases, but the disease can also occur due to spontaneous mutation.

Researchers have recently demonstrated that numerous abnormalities in red blood cell membrane proteins can lead to the development of the clinical presentation of hereditary spherocytosis. The most frequently encountered membrane protein defect recognized as the underlying molecular lesion in spherocytosis is ankyrin 1, followed by spectrin and protein band 3.

Some hereditary spherocytosis gene defects can be identified in chromosomes 1, 8, 14, 15, and 17.

Normal Physiology

A red blood cell or erythrocyte is a ≤ 8 micron–wide element of the blood that, apart from being part of circulating blood, needs to be able to pass through the capillary network and the spleen. The diameters of the capillaries and the red pulp’s endothelial passages are 3 and 1 micron wide, respectively, which indicates that the erythrocyte should be able to change shape without fragmenting.

The components responsible for the deformability of red blood cells are as follows:

  • SA/V ratio: The proportion of the area of the erythrocyte’s outer surface divided by the erythrocyte’s volume; this indicates the erythrocyte’s geometry.
  • Mean corpuscular hemoglobin concentration (MCHC): The parameter of the viscosity of erythrocytes.
  • Degree of stability of the erythrocyte’s membrane: Dependent on bending and elastic shear modulus, as well as on yield stress.

The membrane of the erythrocyte comprises a complex combination of proteins between double lipid layers that are positioned on its outer surface. The membrane has multiple penetrating proteins that help it fulfill its biological functions.

The membrane comprises 3 key components:

  1. Non-covalent bonds between approximately 10 billion protein and lipid molecules continuously produce the cell’s thin plasma membrane. These bonds allow for a stable 3D configuration that makes the transformation of the erythrocytes possible.
  2. Asymmetry of the distribution of the protein and lipid molecules, both inside a particular layer and throughout the membrane itself, allows the fluid structure of the plasma membrane to be maintained.
  3. The plasma membrane has two key functions—ie, it acts both as a barrier and a guard—as well, the transmembrane molecular passages have a transporter function, which enables the intra-extracellular passing of nutrients and signals.

Pathophysiology

In hereditary spherocytosis, the defective cell membrane leads to the loss of the ability to change shape as the result of membrane surface area loss.

This loss is caused by several red blood cell membrane protein defects, particularly ankyrin-1, band-3, and spectrum defects. Multiple mutations in the genes responsible for the encoding of these proteins are the primary reason for the hereditary spherocytosis spectrum to appear.

Hemolysis is caused by morphologically unstable erythrocytes that cannot undergo the required transformation and break in the narrowest place of the path, namely the epithelial slits of the spleen’s red pulp.

The hemolysis of affected spherocytes leads to an increase in unconjugated bilirubin, the main degradation product of the erythrocyte, and a decrease in red blood cell count. Elevated bilirubin levels present as kernicterus in neonates.

Signs and Symptoms

The signs and symptoms of hereditary spherocytosis result from the spleen destroying abnormal erythrocytes-spherocytes. The number of spherocytes in circulating blood determines the course of the disease, either in acute or chronic form.

Acute Form

Hereditary spherocytosis presents as anemia and then jaundice, followed by varying degrees of pallor, fatigue, hypoxia, tachycardia, and exercise intolerance.

Chronic Form

Hereditary spherocytosis can manifest in various age groups beginning in the neonate period, in children aged 4–5 years, and in adults. Some children remain asymptomatic.

The chronic form of the disease manifests as severe anemia with pallor, jaundice, fatigue, and exercise intolerance.

Severe cases may be marked by the development of the following features (similar but to a lesser extent than in thalassemia major):

  • Expansion of the diploë of the skull (a medullary cavity, location of normal physiologic hematopoiesis in adults)
  • Expansion of the medullary regions of other bones
  • After infancy, splenomegaly, followed by hypersplenism with decreased white blood cell count and platelets, resulting in pancytopenia
  • Gallbladder sludge, which can accumulate following an elevated level of unconjugated bilirubin resulting from spherocytes degradation
  • Abdominal pain or cramps, resulting from either splenomegaly or pigment stones in the gallbladder
  • Because of the high red blood cell count turnover and heightened erythroid marrow activity, children are susceptible to aplastic crisis as a result of parvovirus infection, and hypoplastic crisis as a result of other infections

Diagnosis

  • Hemoglobin: Usually 6–10 g/dL, but can also be in the normal range
  • Mean corpuscular volume (MCV): Normal level
  • MCHC: Typically elevated in the hereditary form

Evidence of Hemolysis

  • Increased reticulocyte counts, due to an elevated need for red blood cells
  • Indirect hyperbilirubinemia
  • Decreased haptoglobin
  • Presence of gallstones on abdominal ultrasound

Peripheral Blood Smear

  • This is the simplest test to demonstrate spherocytosis
  • Affected red blood cells are smaller and present without the central pale spot that healthy erythrocytes possess
  • This finding is common for all types of spherocytosis, not only the hereditary form

Osmotic Fragility Test

  • This is the gold standard test for diagnosing hereditary spherocytosis.
  • The test measures the ability of red blood cells to resist rupturing (hemolysis) when exposed to liquids of different degrees of salt concentration. Cells will swell and eventually rupture in hypotonic saline due to water influx. In patients with spherocytosis, the red blood cells are more vulnerable to osmotic stress.
  • Although this test is essential for confirming the diagnosis, one-quarter of all cases are missed when it is used.

Diagnosis in Neonates

Anemia rarely manifests in the first 7 days of an infant’s life. A peripheral blood smear may not show spherocytes, as they are not frequently seen. Splenomegaly is rarely present in neonates. The reticular count is rarely elevated.

The most consistent findings are pathological MCHC and MCV parameters.

Future parents should be questioned about their personal and family history of hereditary spherocytosis during prenatal and preconception visits. 

The MCHC/MCV ratio should be determined in the evaluation of the possibility of hereditary spherocytosis in a neonate with a positive family history. Based on a cut-off value of 0.36, the following paths are proposed:

  1. If the value is higher than 0.36, the likelihood of autosomal dominant hereditary spherocytosis should be considered.
  2. If the value is lower than 0.36, spherocytes are looked for in the peripheral blood smear, and, if found, the autosomal dominant form should be considered. A smear that does not detect spherocytes does not exclude the possibility of disease.

Although the genetic basis for the development of hereditary spherocytosis has been well researched and documented, genetic tests are not routinely conducted due to the availability of simpler tests to confirm the diagnosis.

However, the DNA-based method for the detection of membrane protein defects should be considered. Single-strand rapid screening to confirm mutations in recognized regions of genes that are associated with hereditary spherocytosis is also available.

Classification

Hereditary spherocytosis can be divided into 3 classifications based on severity.

Mild

  • Autosomal dominant
  • Hemoglobin level is normal
  • Reticulocytes are below 6%
  • Bilirubin level is between 17 and 34.2 umol/L
  • Some spherocytes are seen on peripheral blood smear
  • Splenectomy is rarely performed
  • Transfusion is rare

Moderate

  • Usually autosomal dominant, but may also be a spontaneous mutation
  • Hemoglobin level is between 60 and 80 g/L
  • Reticulocytes are above 6%
  • Bilirubin level is up to 51 umol/L
  • Spherocytes are seen on peripheral blood smear
  • Splenectomy is performed due to decreased physical ability but may also be needed in patients older than 5 years
  • Transfusions are performed up to 2 times in the neonate period
  • SDS-PAGE electrophoresis shows ankyrin-1, band-3, and protein-4 positive results

Severe

  • Autosomal recessive
  • Hemoglobin level is < 60 g/L
  • Reticulocytes are > 10 5
  • Bilirubin level is < 51 umol/L
  • Microspherocytes and poikilocytosis are seen in peripheral blood smear
  • Splenectomy is performed at the age of 2–3
  • Transfusions are frequently performed
  • SDS-PAGE electrophoresis is positive for ankyrin 1 and band 3

Complications

Common complications of hereditary spherocytosis include the following.

Cholelithiasis

The condition takes place in the gallbladder, where sludge and calculi are formed due to excessive unconjugated bilirubin. This results in:

  • Abdominal pain
  • Potential complications of gallbladder stones, such as cholecystitis
  • Potential carcinoma of the gallbladder
  • Gallstone small bowel obstruction (more frequently)

Hemolytic Episodes

Rapid onset of anemia occurs due to an acute viral infection followed by hyperplasia of the reticuloendothelial system, prolonged serious illness, pregnancy, or other stressful situations.

Aplastic Crises

An aplastic crisis is a rare event that usually occurs after a parvovirus B19 infection. Following the viral attack on red blood cells and precursors within the bone marrow, intermittent aplasia develops, leading to a drop in the reticulocyte count below 1%, as well as a drop in hemoglobin level below 60 g/L.

Aplastic crises typically last for up to 10 days and resolve completely. Parvovirus B19 post-infectious immunity is usually permanent once the crisis has resolved.

Differential Diagnosis

Differential diagnosis should focus on disorders that create anemia, including the following:

  • Acute oxidant injury; spherocytes may develop, though this is unlikely
  • Microangiopathic, macroangiopathic, and immune hemolytic anemias
  • Hemolytic transfusion reactions
  • Hereditary pyropoikilocytosis
  • Zinc toxicity
  • Various kinds of poisoning
  • Severely low phosphate blood levels
  • Neonate cases of ABO incompatibility

Management

Splenectomy

Intervention is effective in almost all cases of hereditary spherocytosis due to the elimination of the main site of spherocyte fragmentation, the spleen. Therefore, restoring the reticulocyte count and bilirubin levels to normal values will prevent common complications. Interventions should only be performed after the age of 6–9 if the clinical course of the disease allows.

Regardless of the severity of clinical presentation, splenectomy should not be performed if the patient is younger than 3 years, even in the setting of frequent transfusions needed to cope with the disease.

Laparoscopic intervention is the gold standard if there are no contraindications. Immunization against Neisseria meningitidis, pneumococci, and Haemophilus should be performed in advance.

Possible complications of surgery include the following:

  • Bleeding
  • Pancreatitis (early complication)
  • Post-splenectomy encapsulated bacterial and parasitic infections (late, severe complication)

Folate Therapy

Folate therapy should be considered in moderate and severe cases, although the benefit of the therapy has not been definitely proven.

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