Hereditary spherocytosis (HS) is a congenital hemolytic disorder wherein a genetic mutation coding for a structural membrane protein phenotype causes the red blood cells to be sphere-shaped (spherocytosis), rather than the normal biconcave disk shape. This abnormal shape interferes with the cells' ability to flex during blood circulation, and also makes them more prone to rupture under osmotic stress, mechanical stress, or both. Cells with the dysfunctional proteins are degraded in the spleen, which leads to a shortage of erythrocytes and results in hemolytic anemia.

HS was first described in 1871, and is the most common cause of inherited hemolysis in populations of northern European descent, with an incidence of 1 in 5000 births. The clinical severity of HS varies from mild (symptom-free carrier), to moderate (anemic, jaundiced, and with splenomegaly), to severe (hemolytic crisis, in-utero hydrops fetalis), because HS is caused by genetic mutations in a multitude of structural membrane proteins and exhibits incomplete penetrance in its expression.

Early symptoms include anemia, jaundice, splenomegaly, and fatigue. Acute cases can threaten to cause hypoxia secondary to anemia and acute kernicterus through high blood levels of bilirubin, particularly in newborns. Most cases can be detected soon after birth. Testing for HS is available for the children of affected adults. Occasionally, the disease will go unnoticed until the child is about 4 or 5 years of age. A person may also be a carrier of the disease and show no signs or symptoms of the disease. Late complications may result in the development of pigmented gallstones, which is secondary to the detritus of the broken-down blood cells (unconjugated or indirect bilirubin) accumulating within the gallbladder. Also, patients who are heterozygous for a hemochromatosis gene may exhibit iron overload, despite the hemochromatosis genes being recessive. In chronic patients, an infection or other illness can cause an increase in the destruction of red blood cells, resulting in the appearance of acute symptoms – a hemolytic crisis. On a blood smear, Howell-Jolly bodies may be seen within red blood cells. Primary treatment for patients with symptomatic HS has been total splenectomy, which eliminates the hemolytic process, allowing for normal hemoglobin, reticulocyte and bilirubin levels. The resultant asplenic patient is susceptible to encapsulated bacterial infections, the risk of which can be reduced with vaccination. If other symptoms such as abdominal pain persist, the removal of the gallbladder may be warranted for symptomatic cholelithiasis.

Epidemiology

Hereditary spherocytosis is the heritable hemolytic disorder, affecting 1 in 2,000 people of Northern European ancestry. According to Harrison's Principles of Internal Medicine, the frequency is at least 1 in 5,000 within the United States of America. While HS is most commonly (though not exclusively) found in Northern European and Japanese families, an estimated 25% of cases are due to spontaneous mutations.

Etiology

Hereditary spherocytosis is an erythrocytic disorder of that affects the following red cell membrane proteins in a congenital fashion:

  • Spectrin (alpha and beta) The autosomal recessive inheritance pattern accounts for close to 25% of the clinical cases. The autosomal dominant inheritance pattern accounts for over 75% of the clinical cases. Many positive individuals will not present clinically, thus the etiologic data may be artificially skewed towards the more prominent dominant forms. These dominant forms tend to leave a family history that yields generational splenectomies and black gallstones cholelithiasis. Lastly, an estimated 25% of cases are due to spontaneous mutations.

Pathophysiology

Causative genetic mutations and phenotypic expressions

Hereditary spherocytosis is caused by a variety of molecular defects in the genes that code for the red blood cell proteins spectrin (alpha and beta), ankyrin, band 3 protein, protein 4.2, and other red blood cell membrane proteins: This leads to both splenomegaly and anemia. Should this process continue unchecked chronically, inappropriate regulation of erythropoiesis leads to extramedullary hematopoiesis.

Clinical presentation

HS patients present in a vast array of presentations, from being asymptomatic to the extreme situations of splenic rupture, hemolytic crisis, or in-utero demise.

  • Asymptomatic HS (mild): 20–30% of patients.
  • Infantile-onset HS (moderate): 60–75% of patients.
  • Neonatal or in-utero onset HS (severe): <5% of patients.

The most common presentation will demonstrate jaundice (due to increased unconjugated bilirubin), anemia (with secondary pallor) and a palpable spleen, sometimes with concomitant tenderness (due to splenic congestion and splenomegaly). It is worth noting that a subsection of HS patients will also have incidental black pigmented gallstones made of calcium bilirubinate (a consequence of the extravascular hemolysis), and some of these patients will develop cholelithiasis or the potential complex sequelae of this condition (e.g. cholecystitis, choledocholithiasis, etc).

Diagnostics

Laboratory testing

Available lab testing that may aid in the diagnosis of HS is as follows:

  • Peripheral blood smear
  • Supportive blood work: mean cell volume (MCV), mean corpuscular hemoglobin concentration (MCHC), red blood cell distribution width (RDW), red blood cell count (RBC), reticulocytes, unconjugated bilirubin, haptoglobin, lactate dehydrogenase (LDH).
  • Eosin-5-maleimide binding test
  • Osmotic fragility test
  • Acidified glycerol lysis test
  • A negative direct antiglobin test (Coombs test)

Common laboratory findings

The common findings of lab testing in setting of a patient with hereditary spherocytosis:

  • Coombs test: Negative (rules-out autoimmune hemolytic anemia)
  • Osmotic fragility test: Positive (Spherocytes will rupture in liquid solutions less concentrated than the inside of the red blood cell. This is due to increased permeability of the spherocyte membrane to salt and water, which enters the concentrated inner environment of the RBC and leads to its rupture. The osmotic fragility test is no longer considered the gold standard for diagnosing hereditary spherocytosis, as it misses ~25% of cases).
  • Acidified glycerol lysis test: Positive (A newer version of the osmotic fragility test that adds glycerol to a hypotonic solution. This produces lysis, a positive test, quicker that the traditional saline version).
  • Supportive blood work:
  • Mean cell volume (MCV): Normocytic (normal range: 80–100&nbsp;fL), or slightly lower. Spherocytes are slightly smaller than normal biconcave red blood cells.
  • Mean corpuscular hemoglobin concentration (MCHC): Increased (normal range: 31–36% Hb/cell). This is secondary to less water being in the cell.
  • Red blood cell distribution width (RDW): Increased (normal range: 11–15%). The spherocytes create variation in the size of the red blood cells on average, thus expanding the distribution.
  • Red blood cell count (RBC): Sometimes increased early (normal range males: 4.3–5.9 million/mm<sup>3</sup>; normal range females: 3.5–5.5 million/mm<sup>3</sup>). The loss of surface area per cells cause the body to mass produce red blood cells. The spleen will filter spherocytes out and change this value.
  • Reticulocytes: Increased (normal range: 0.5–1.5% of the RBC listed above). The body to mass produces red blood cells (reticulocytes being young erythrocytes) even as the spleen filters spherocytes out. This is known as reticulocytosis.
  • Unconjugated bilirubin: Increased (normal range: 0.2–1.2&nbsp;mg/dL). This is caused by heme released into the hepatosplenic circulation by macrophages that have phagocytosed erythrocytes. The unconjugated bilirubin is not soluble in water (blood), so it binds to albumin, and is processed in the liver.
  • Haptoglobin (free): Decreased (normal range: 41–165&nbsp;mg/dL). This is caused by hemoglobin binding to haptoglobin, thus making it no longer "free".
  • Lactate dehydrogenase (LDH): Increased (normal range: 110–295&nbsp;U/L in children). This is due to extravascular hemolysis.
  • Peripheral blood smear: Directly shows spherocytes on microscope.
  • Eosin-5-maleimide binding test: Positive (reduced mean fluorescence), as the test will demonstrate a reduced ability of the eosin-5-maleimide dye to bind to erythrocyte plasma membrane proteins. The process relies upon flow cytometry. Gold standard test that produces results at low cost within ~2 hours.

In chronic cases, patients who have taken iron supplementation, have heterozygous hemochromatosis, or received numerous blood transfusions, iron overload may cause additional health issues. Measuring iron stores is sometimes considered part of the diagnostic approach to hereditary spherocytosis in older patients presenting with heart muscle damage of unknown etiology or liver disease without apparent cause.

Imaging

Ultrasound is often used to evaluate the dimensions of the spleen, and also the gallbladder in preparation for functionally curative splenectomy with or without cholecystectomy.

Treatment

Although research is ongoing, currently there is no genetic-level cure for the myriad of mutations that cause the various presentations of hereditary spherocytosis.

  • Splenic ablation (interventional radiology): This option is non-operative, and is when an interventional radiologist (instead of a surgeon) uses radiologic techniques to coil or cauterize vasculature within the splenic circulation. There are various points in the circulatory pathway where the treatment can be applied to produces varying amounts of retained viability of the spleen, thus giving the option to attempt to preserve splenic immune function.

All operative and interventional treatments require the immunization of HS patients against the influenza virus, SARS-CoV-2, and encapsulated bacteria such as Streptococcus pneumoniae and meningococcus. Antibiotics are no longer recommended for maintenance use, even in post-splenectomy HS patients. Since the spleen is important for protecting against encapsulated organisms, sepsis caused by encapsulated organisms is a possible complication of splenectomy.