Hereditary spherocytosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Zahir Ali Shaikh, MD[2]

Overview

Hereditary spherocytosis is a genetically-transmitted form of spherocytosis, an auto-hemolytic anemia characterized by the production of red blood cells that are sphere-shaped rather than donut-shaped, and therefore more prone to hemolysis.

Historical Perspective

• Hereditary spherocytosis was first described in 1871.
• It is the commonest cause of inherited chronic hemolysis in the northern europe and north america.

Classification

• Hereditary Spherocytosis classified on basis of underlying defect in protein and also on the basis of severity of hemolysis.
• Classification of hereditary spherocytosis on the basis of clinical severity."GeneReviews® - NCBI Bookshelf".

Locus	Gene	Protein	Inheritance	Severity	Comment
SPH1	ANK1	Ankyrin-1	AD/AR	mild-moderate/moderately severe-severe	often transfusion dependant
SPH2	SPTB	Spectrin beta chain,erythrocytic	AD/AR	mild-moderate/severe	1 fatal infantile case described
SPH3	SPTA1	Spectrin alpha chain,erythrocytic1	AR	severe	transfusion dependant
SPH4	SLC4A1	Band3(anion transport protein)	AD	mild-moderate	certain SLC4A1 variants cause disease only when biallelic
SPH5	EPB42	Protein 4.2	AR	mild-moderate	1 moderately severe case described

Classification	Mild	Moderate	Severe
Hemoglobin (g/dl)	110-150	80-120	60-80
Reticulocyte count (%)	3-6	>6	>10
Bilirubin (ug/l)	17-34	>34	>51
Splenectomy	usually not required	indicated during school age, usually before puberty	necessary - delay until 6 years of age if possible

Pathophysiology

• The defects in hereditary spherocytosis lie in the cell membrane.
• The proteins essential for integrity of membrane structure lie immediately under the lipid bilayer, horizental aplha & beta spectrin molecules form heterodimers with linkage to vertical elements- ankyrin, proteins 4.1 & 4.2 and band 3 (a transmembrane protein).
• Different genes code for each of these proteins, therefore hereditary spherocytosis is a hetrogenous disorder which can result from a defect in any one of these proteins.
• The destabilization of membrane leads to both abnormal morphology and reduced red cell life span.
• The shorter the life span of red blood cells, the worse the clinical effects.
• Genetic defect and clinical severity tend to be fairly constant within a given family,but between family varies from mild asymptomatic hemolysis to severe continuous anemia with jaundice.

Causes

• Hereditary spherocytosis is caused by a variety of genetic mutations.
• There are 05 genes associated with hereditary spherocytosis including, alpha spectrin (SPTA1), beta spectrin (SPTB), ankyrin (ANK1), band3 (SLC4A1) and protein 4.2 (EPB42).
• Mutations in one or more of hereditary spherocytosis related genes can cause membrane protein deficiency leading to hereditary spherocytosis.

Molecular and Genetic Characteristics of 5 Erythrocyte Membrane Protein Genes

Gene	Chromosome Location	Membrane Protein	Prevalent Mutations	Heredity	Associated Disease
ANK1	8p11.2	Ankyrin-1	frameshift, nonsense, splicing, novel mutations	autosomal dominant, autosomal recessive	hereditary spherocytosis
SLC4A1	17q21	Band3	missense,frameshift,polymorphism	autosomal dominant	hereditary spherocytosis,distal renal tubular acisosis
SPTA1	1q22-q23	alpha spectrin	SpaLEPRA allele, splicing, frameshift	autosomal recessive	hereditary spherocytosis, hereditary eliptocytosis, hereditary pyropoikilocytosis
SPTB	14q23-q24.1	beta spectrin	splicing, frameshift, nonsense, novel mutations	autosomal dominant	hereditary spherocytosis, hereditary eliptocytosis, hereditary pyropoikilocytosis
EBP42	15q15-q21	protein 4.2	missense, nonsense	autosomal recessive	hereditary spherocytosis

Differentiating Hereditary Spherocytosis from Other Diseases

• Hereditary spherocytosis presents with hemolysis, therefore should be differentiated from following diseases.
  • Autoimmune hemolysis
  • Thermal injury
  • Clostridial septicemia
  • Wilson disease
  • Hemoglobinopathies
  • Hereditary stomatocytosis
  • Congenital dyserythrpoietic anemia type II

Epidemiology and Demographics

• Hereditary spherocytosis is reported worldwide in all racial and ethnic groups.
• It is the most common inherited anemia in the northern European ancestry and north america.
• The reported incidence of hereditary spherocytosis is 1 in 2000 births.
• It is less commonly seen in african american and southeast asian people.

Risk Factors

• A positive family history is an important risk factor for hereditary spherocytosis, as it is an inherited condition.
• There are no other risk factors have been clearly identified for this condition.

Screening

• The screening test used for hereditary spherocytosis is automated mean cell hemoglobin concentration (MCHC).
• Erythrocyte distribution width when raised is also useful as a powerful screening test.
• The combination of these two tests (MCHC & erythrocyte distribution width) is an excellent predictor for the diagnosis of hereditary spherocytosis.

Natural History, Complications, and Prognosis

Natural History

• The clinical course of hereditary spherocytosis is variable depending upon the severity of disease.
• During infancy, hemoglobin level falls rapidly after 20 days of birth leading to transient & severe anemia, causing inappropriate erythrocyte response and splenic filtering function.
• About 20-30% of patients have mild disease with compensated hemolysis.
• About 60-70% of patients have moderate disease, presenting in childhood but can present at any age.
• About 3-5% of patients have severe hereditary disease with life threatening anemia, requiring regular transfusions to maintain a hemoglobin concentration of greater than 60g/L.
• Without regular transfusions or splenectomy or both, patients may develop kernicterus, severe hemolytic anemia, gallstones, growth retardation, delayed sexual maturation, extramedullary hematopoiesis with hepatosplenomegaly and bony changes (thalassemic facies).

Complications

• The complications of hereditary spherocytosis include:
  • hemolytic anemia
  • jaundice
  • kernicterus
  • cholelithiasis
  • hemolytic, aplastic and megaloblastic crises
  • growth failure
  • leg ulcers
  • skeletal abnormalities resulting from bone marrow expansion
  • multiple myeloma
  • leukemia

Prognosis

• The prognosis of patients with hereditary spherocytosis is usually good with early diagnosis, regular followup and management.
• Patients with hereditary spherocytosis may remain undiagnosed for years if their hemolysis is mild.

Diagnosis

Diagnostic Criteria

• The diagnosis of hereditary spherocytosis can be based on the physical examination, complete red cell count, recticulocyte count, medical history and specific tests, preferentially, the EMA (eosin-5-maleimide binding) test and AGLT (acidified glycerol lysis time).
• The diagnosis can be made at any age, including the neonatal period from day of birth.

Simple Diagnostic Criteria to evoke the Diagnosis of Hereditary Spherocytosis

Clinical Parameters	pallor, splenomegaly, inconstant jaundice
Biological paraneters & erythrocyte indices	dec Hb, inc MCHC, inc %hyperdense cells, inc reticulocytes
Blood smear	Spherocytes (may be absent)
Signs of hemolysis	inc free bilirubin, dec haptoglobin, inc reticulocytes
Erythrocyte coombs test	negative

Specific Biological Examinations for the Diagnosis of Hereditary Spherocytosis

Tests	Principle/feasibility	Sensitivity/Specificity
Osmotic resistance	hemolysis test/routime examination	66%/low
Pink test	hemolysis test/simple test time-out test <3 hours	96%/79-94%
AGLT	Hemolysis test time of test >3 hours	81%/95%
Ektacytometry in osmolar gradient	study of deformity of RBCs single laboratory in France test execution time:24 hours	reference exam
Flow cytometry	labeling of RBCs with eosin 5 maleimide/not available on routine basis test run time >48 h	Being evaluated

History and Symptoms

• As in any other chronic hemolytic states, the signs and symptoms of hereditary spherocytosis (HS) include mild pallor, intermittent jaundice, and splenomegaly. However, signs and symptoms are highly variable. Anemia or hyperbilirubinemia may be of such magnitude as to require exchange transfusion in the neonatal period. The disorder also may escape clinical recognition altogether. Anemia usually is mild to moderate, but is sometimes very severe and sometimes not present.
• Symptoms of hereditary spherocytosis include:
  • Yellowing of the skin and eyes (jaundice)
  • Pale coloring (pallor)
  • Fatigue
  • Irritability
  • Shortness of breath
  • Weakness

Physical Examination

• Splenomegaly is the rule in HS. Palpable spleens have been detected in more than 75% of affected subjects. The liver is normal in size and function.

• Other important clues are jaundice and upper right abdominal pain indicative of gallbladder disease. This is especially important if the patient has a family history of gallbladder disease.
• Any patient who presents with profound and sudden anemia and reticulocytopenia with the aforementioned physical findings also should have HS in the differential diagnosis.

Laboratory Findings

Initial testing

• CBC and RBC indices – All individuals with suspected HS based on family history, neonatal jaundice, or other findings should have a complete blood count (CBC) with reticulocyte count and red blood cell (RBC) indices. The mean corpuscular hemoglobin concentration (MCHC) is often the most useful parameter for assessing spherocytosis; an MCHC ≥36 g/dL is consistent with spherocytes. A low mean corpuscular volume (MCV) is also helpful in some cases, especially in neonates, but variable degrees of reticulocytosis make the MCVless useful in older children and adults.
• Blood smear review – All individuals with suspected HS should have a blood smear reviewed by an experienced individual. In a peripheral blood smear, the abnormally small red blood cells lacking the central pallor i.e. spherocytes are seen. Other abnormal RBC shapes, and the degree of polychromatophilia, which reflects reticulocytosis.
• Coombs testing – If hemolysis is present, Coombs testing (also called direct antiglobulin testing [DAT]) is usually done to eliminate the possibility of immune-mediated hemolysis, which may be due to hemolytic disease of the fetus and newborn (HDFN) in neonates or autoimmune hemolytic anemia (AIHA) in older children and adults. The results of testing may also be useful to the transfusion service if transfusion is indicated. Coombs testing in HS is negative.

Confirmatory tests

• EMA binding ●Osmotic fragility ●Glycerol lysis ●Cryohemolysis

Imaging Findings:

• There are no particular other imaging findings associated with HS.

Other Diagnostic Studies:

• • In certain atypical cases in which further characterization of the RBC cytoskeletal/membrane proteins is needed, gel electrophoresis can be done using RBC ghosts, or DNA sequencing can be performed.

Treatment

Medical Therapy

• As with most inherited hemolytic anemias, treatment is directed at preventing or minimizing complications of chronic hemolysis and anemia. There are no specific treatments directed at the underlying red blood cell (RBC) membrane defect.

• If a neonate is suspected of having HS (eg, based on positive family history and neonatal jaundice), treatment can be initiated for HS without awaiting diagnostic confirmation. This may include therapy for hyperbilirubinemia and, in severe cases, transfusion or even exchange transfusion [83
• The goals of pharmacotherapy for hereditary spherocytosis are to reduce morbidity and prevent complications. Folic acid supplementation is indicated to prevent megaloblastic crisis.

Surgery

• Generally, the treatment of HS involves presplenectomy care, splenectomy, and management of postsplenectomy complications.
• In pediatric cases, splenectomy ideally should not be performed until a child is older than 6 years because of the increased incidence of postsplenectomy infections with encapsulated organisms such as S pneumoniae and H influenzae in young children.
• Partial splenectomies are increasingly used in pediatric patients, as this approach appears to both control hemolysis and preserve splenic function.

Prevention

In general, once the diagnosis and baseline severity of HS in a child are established, it is not necessary to perform repeated blood tests unless there is an additional clinical indication (such as intercurrent infection and pallor, or an increase in jaundice). A routine annual review is usually sufficient together with an open door policy for potential complications such as parvovirus infection, or abdominal pain, which may trigger investigation for gallstones.

Case Studies

Case #1

External links

• Online Mendelian Inheritance in Man (OMIM) 182900
• A picture of spherocytes from Medline