Hereditary spherocytosis natural history, complications and prognosis

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• Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Overview

Hereditary spherocytosis can present at any age with any severity, ranging from hydrops fetalis in utero through diagnosis in the ninth decade of life, with variable clinical course depending upon the severity of disease. Majority of affected individuals have mild or moderate hemolysis and known family history, making the diagnosis and treatment relatively easy. Complications include; jaundice, kernicterus, pigment gallstones, hemolytic, aplastic and megaloblastic crises, splenomegaly and leukemia. The prognosis is usually good with early diagnosis, regular followup and management. Patients with mild disease may develop symptoms only with environmental triggers. Many patients who undergo splenectomy are able to maintain normal hemoglobin levels, however patients with severe hereditary spherocytosis may remain anemic postsplenectomy and require regular blood transfusions. Postsplenectomy patients are at increased risk of life threatening infections (sepsis), therefore require vaccinations and antibiotics.

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).

• Hereditary spherocytosis can present at any age and with any severity, with case reports describing a range of presentations, from hydrops fetalis in utero through diagnosis in the ninth decade of life.

• The majority of affected individuals have mild or moderate hemolysis or hemolytic anemia and a known family history, making diagnosis and treatment relatively straightforward. Individuals with significant severe hemolysis may develop additional complications such as jaundice/hyperbilirubinemia, folate deficiency, or splenomegaly.

Hemolytic anemia — A classification for hereditary spherocytosis has been developed based on the severity of anemia and markers of hemolysis (reticulocyte count and bilirubin) ; it characterizes patients as having one of the following:

●Hereditary spherocytosis trait – Normal hemoglobin and reticulocyte count

●Mild hereditary spherocytosis (20 to 30 percent of cases) – Hemoglobin 11 to 15 g/dL; reticulocytes 3 to 6 percent; bilirubin 17 to 34 micromol/L

●Moderate hereditary spherocytosis (60 to 75 percent of cases) – Hemoglobin 8 to 12 g/dL; reticulocytes >6 percent; bilirubin >34 micromol/L

●Severe hereditary spherocytosis (5 percent of cases) – Hemoglobin 6 to 8 g/dL; reticulocytes >10 percent; bilirubin >51 micromol/L

• Neonates may have a relatively normal hemoglobin level at birth that is followed by development of severe anemia, especially during the first three weeks and, in some cases, the first year of life, when the erythropoietic response may not be adequate.
• According to one review, more than half of neonates with hereditary spherocytosis are not anemic during the first week of life .
• However, anemia can develop after several days, and is most likely to be severe during the second or third week of life. Some infants require chronic transfusions during the first year; however, transfusion dependence beyond the first year of life is unusual.

• In older children and adults, the presentation may be that of an incidental finding of hemolysis, hemolytic anemia, or spherocytes on the blood smear or the individual may be symptomatic from anemia, splenomegaly, pigment gallstones, or jaundice. Jaundice due to severe hemolysis is less common after the newborn period.

• In some cases, co-inheritance of another disorder affecting RBC survival such as sickle cell disease or thalassemia can influence the severity of anemia and make diagnosis more challenging.

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
• Infections that impair RBC production in the bone marrow and thus diminish the capacity to compensate for chronic hemolysis may lead to a period of aplasia. A commonly cited cause of transient aplastic crisis is parvovirus B19 infection; other viral or bacterial infections may also cause transient aplasia. This is because individuals with chronic hemolysis are highly dependent on the accelerated production of new RBCs by the bone marrow, and they can experience a rapid drop in hemoglobin level when the bone marrow is unable to compensate for hemolysis. If a patient with hereditary spherocytosis develops a precipitous decline in hemoglobin level or reticulocyte count, testing for parvovirus infection is appropriate.
• Conditions that increase the size of the spleen, such as infectious mononucleosis, may cause increased splenic pooling of RBCs and/or increased hemolysis.
• Individuals who develop folate, vitamin B12, or iron deficiency may be unable to produce sufficient RBCs to compensate for those lost by hemolysis.
• Anemia may worsen during pregnancy, as the RBC mass and plasma volume expand to meet the physiologic needs of the pregnancy. Attention to folic acid supplementation and iron stores are also important so as not to impair RBC production.

Complications of hemolysis — Common complications of hemolysis include neonatal jaundice, splenomegaly, and pigment gallstones.

• Rarely, hemolysis may be severe enough to cause extramedullary hematopoiesis and/or growth delay.
• A small subset of these children may be at risk for iron overload due to increased iron absorption and/or transfusions, although the majority of patients with hereditary spherocytosis do not develop iron overload.
• Other rare complications that have been reported include leg ulcers, priapism, neuromuscular disorders, cardiac disease, and gout; in some cases, these may represent coincidental rather than causal associations.

Neonatal jaundice — hereditary spherocytosis may present in the neonatal period with jaundice and hyperbilirubinemia, and the serum bilirubin level may not peak until several days after birth. Some experts have proposed that hereditary spherocytosis is underdiagnosed as a cause of neonatal jaundice. A requirement for phototherapy and/or exchange transfusion during this period is common.

Splenomegaly — Splenomegaly is rare in neonates, but can often be seen in older children and adults with hereditary spherocytosis. Early reports of family studies found palpable spleen in over three-fourths of affected members, but this may reflect a skewed population with the most severe disease. In these studies, the relationship between disease severity and splenic size was not linear.

Pigment gallstones — Pigment (bilirubin) gallstones are common in individuals with hereditary spherocytosis and may be the presenting finding in adults. Gallstones are unlikely before the age of 10 years but are seen in as many as half of adults, especially those with more severe hemolysis. Gallstones appear to be more common in individuals with Gilbert syndrome.

• Obstructive jaundice or cholecystitis is treated similarly to that in individuals without hereditary spherocytosis. If cholecystectomy is performed, it may be worthwhile to discuss whether splenectomy was also planned, as the procedures could be combined; however, splenectomy should not be routinely performed during cholecystectomy.

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.
• Overall, the long-term outlook for people with hereditary spherocytosis is usually good with treatment. However, it may depend on the severity of the condition in each person.
• People with very mild hereditary spherocytosis may not have any signs or symptoms unless an environmental "trigger" causes symptom onset. In many cases, no specific therapy is needed other than monitoring for  and watching for signs and symptoms. Moderately and severely affected people are likely to benefit from splenectomy.
• Most people who undergo splenectomy are able to maintain a normal hemoglobin level. However, people with severe hereditary spherocytosis may remain anemic post-splenectomy, and may need blood transfusions during an infection.
• In all people who undergo splenectomy, there is a lifelong, increased risk of developing a life-threatening infection (sepsis). Although most septic episodes have been observed in children whose spleens were removed in the first years of life, older children and adults also are susceptible. Fortunately, taking certain precautions can reduce this risk and can prevent minor infections from becoming life threatening.