Hereditary Spherocytosis

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Hereditary Spherocytosis

• Presented by Dr. Deena Abdel-Hadi
• Moderator Dr. Yousef Abu Osbaa

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Introduction

• Hereditary spherocytosis (HS) is the most common
  red cell membrane disorder. Morphologically,
  spherocytes are rounded cells that have lost the
  ability to change shape.
• Chronic hemolysis is the hallmark of HS. In most
  individuals, the condition is mild requires no
  specific therapy. In severe cases, it results in
  severe anemia, splenomegaly jaundice.
• Splenectomy sometimes is recommended as therapy
  for severe cases can result in amelioration of
  the disease.
• Patients who have undergone splenectomy are _at_
  increased risk for infections with encapsulated
  bacteria.

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Epidemiology Genetics

• HS was described initially in 1871. it is found
  in increased numbers among persons of northern
  European descent.
• The incidence of HS is estimated to be in 1 in
  5000 in the US.
• Most cases are inherited as autosomal dominant
  fashion. Approximately 25 of cases are
  discovered in persons who have no F/H of HS
  these cases are may represent spontaneous
  mutations or recessive forms of the disease.
• Over the past several decades, basic science
  researchers have discovered that abnormalities in
  several of the red cell membrane proteins can
  lead to the clinical manifestations typical of
  HS.

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Epidemiology Genetics

• In European American patients, ankyrin-1
  mutations are the major cause of dominant
  recessive HS in approximately 35 to 65 of
  affected patients 15 to 25 of patients have
  band 3 mutations.
• Japanese patients have mutations primarily in
  band 3, protein 4.2 genes, or both have fewer
  ankyrin gene mutations.
• In pedigrees that have a dominant defect,
  affected family members tend to have similar
  degrees of hemolysis clinical severity.

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Epidemiology Genetics

• In pedigrees that have a dominant defect,
  affected family members tend to have similar
  degrees of hemolysis clinical severity.
• The major complications are
• - aplastic or megaloblastic crisis.
• - hemolytic crisis.
• - cholecystitis and cholelithiasis.
• - severe neonatal hemolysis.

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Pathogenesis

• Regardless of the molecular basis for a case of
  HS, the common denominator of spectrin deficiency
  results in an unstable red cell membrane.
• Disruptions of ankyrin, band 3, or the other
  structural proteins lead to common 2ry defects in
  spectrin assembly, resulting in unstable red cell
  membrane.
• Four abnormalities in red cell membrane proteins
  have been identified and include (1) spectrin
  deficiency alone, (2) combined spectrin and
  ankyrin deficiency, (3) band 3 deficiency, and
  (4) protein 4.2 defects.

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Pathogenesis

• Spectrin deficiency is the most common defect.
  Each is associated with a variety of mutations
  that result in different protein abnormalities
  and varied clinical expression. Most cases of HS
  are heterozygous because homozygous states are
  lethal.
• Lipids are lost from the bi-layer as
  micro-vesicles. As the red cell progressively
  loses surface area, it changes from a biconcave
  disc to sphere.

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Pathogenesis

• As a result of this shape change, the red cells
  lose their ability to circulate freely through
  narrow capillaries in the body.
• The resulting spherocytes become trapped in the
  spleen as they course through the sinuses the
  red cells are engulfed by macrophages.
• Hemolysis causes elevations of unconjugated
  bilirubin the development of gallstones.

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Clinical Aspects

• Signs Symptoms
• HS can present soon after birth. It should
  suspected in the infant in whom jaundice presents
  in the1st 24hrs after birth or in whom jaundice
  persists beyond the 1st postnatal week.
• In the 1st few postnatal months, anemia can
  develop in children who do not mount an adequate
  reticulocyte response.

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Clinical Aspects

• Signs Symptoms
• In later childhood, HS can present with anemia,
  jaundice splenomegaly. Affected patients may
  have mild, moderate or severe anemia.
• Patients who have mild anemia due to HS may have
• - Normal Hg values (11-15 mg/dl)
• - Mildly elevated reticulocyte counts
  (less than 5).
• - Asymptomatic.
• - Little or no splenomegaly occurs.

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Clinical Aspects

• Signs Symptoms
• Patients who have moderate anemia may have
• - Hg concentration (8-12 mg/dl).
• - Moderate splenomegaly.
• - Intermittent jaundice.
• Severe HS is characterized by severe anemia
• - Hg concentration (6-8 mg/dl).
• - Reticulocyte counts often exceed 10.
• - Requires red cell transfusion.
• - an incomplete response to splenectomy.

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Clinical Aspects

• Signs Symptoms
• Children who have moderate to severe anemia may
  have poor exercise tolerance, poor growth
  academic difficulties.
• Older individuals develop bilirubin stones may
  present with cholecystitis.

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Laboratory Evaluation

• Lab tests is helpful in both establishing the
  diagnosis of HS classifying the severity of
  illness.
• In the initial evaluation, it often is useful to
  study relatives as well as individual patients.
  Most patients have a ( ve) F/H of HS.
• The peripheral blood smear in HS shows numerous
  spherocytosis that appear as red cells that do
  not have any central pallor, decreased mean
  corpuscular diameter, increased density are
  smaller than usual. Larger bluish cells
  (polychromasia) also may be seen.

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Laboratory Evaluation

• The CBC Retic count reveal a low Hb
  concentration high Retic count.
• The mean corpuscular Hb concentration (MCHC)
  usually high _at_ greater than 35 mg/dl 2ry to mild
  cellular dehydration.
• The mean corpuscular volume (MCV) may be low
  (this relatively low MCV reflect membrane loss
  cell dehydration) or high if there is
  substantial reticulocytosis.

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Laboratory Evaluation

• The most sensitive test to help detect HS is the
  incubated osmotic fragility test performed after
  incubating RBCs for 18-24 hours under sterile
  conditions at 37C based on the principle that
  red cells swell rupture when incubated in
  hypotonic solutions.
• - Because spherocytes have reduced cell
  membranes, they swell _at_ higher concentrations of
  saline than do normal red cells Hemolysis of HS
  cells may be complete at a solute concentration
  that causes little or no lysis of normal cells.

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Laboratory Evaluation

• - Because spherocytes have reduced cell
  membranes, they swell _at_ higher concentrations of
  saline than do normal red cells
• - Not uncommonly, some individuals with HS have
  a normal fresh osmotic fragility test result.
• - Osmotic fragility after prolonged incubation
  at 37C usually is abnormal.

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Laboratory Evaluation

• Other tests results that support the diagnosis
  of HS include
• - Elevated unconjugated hyperbilirubinemia.
• - Elevated LDH level.
• - Low haptoglobin level.

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Differential Diagnosis

• Spherocytes often are seen in cases of
• 1) ABO incompatibility (ve Cooms test).
• 2) Burns.
• 3) Venom intoxication.
• 4) Pyro-poikilocytosis.
• 5) Unstable Hb variants.

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Management of HS Complication

• General Management
• 1) They may not require any specific therapy.
• 2) Annual physical examination to document growth
  development of the child.
• 3) Special attention should be paid to
  documenting the size of the spleen.
• 4) A CBC Retic count should be performed if
  the Retic count is not in response to the ongoing
  hemolysis, the patient may be developing iron or
  folic acid deficiency.

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Management of HS Complication

• Red Cell Transfusion
• Indications
• 1) Exacerbation of anemia (Hb less than 8 mg/dl)
  2ry to blood loss (trauma, surgery).
• 2) Hypoplastic crisis due to parvovirus B19
  infection, which infect the red cells progenitors
  in the BM induce 1-2 wk period of red cell
  aplasia that reflect severe drop in the Retic
  count .
• 3) Hypersplenism.
• 4) Poor growth.
• 5) Chronic fatigue.

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Management of HS Complication

• Splenectomy
• Indications
• 1) Severe anemia (Hb less than 8 mg/dl).
• 2) Poor growth.
• 3) Chronic fatigue.
• 4) Extramedullary hematopoiesis (frontal
  bossing).

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Management of HS Complication

• Splenectomy

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Management of HS Complication

• Splenectomy

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Management of HS Complication

• Splenectomy

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Management of HS Complication

• Cholecystectomy
• Chronic hemolysis in HS often leads to the
  development of gallstones in the teenage years.
• Some experts recommend U/S Screening for
  gallstones every few years after age 5.

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Management of HS Complication

• Cholecystectomy
• Cholecystectomy is recommended for painful,
  symptomatic gallstones or bile duct obstruction.
• It also may be performed _at_ the time of
  splenectomy if gallstones are found
  pre-operatively on U/S Scan.

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Prognosis

• In most cases of HS, the hemolytic anemia is not
  severe is well compensated by a healthy bone
  marrow.
• Patients requiring splenectomy experience
  improvement in their anemia jaundice, but do
  remain _at_ increased risk for infection with
  encapsulated bacteria.
• Older individuals are _at_ high risk for gallstones
  may require Cholecystectomy.

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