Inherited red cell membrane defect producing spherocytes, hemolysis, splenomegaly, and jaundice.
Also known as: HS, spherocytosis, membrane hemolytic anemia
Overview
Inherited hemolytic anemia caused by defects in red blood cell membrane proteins (ankyrin, band 3, spectrin, protein 4.2) that destabilize the cytoskeleton, producing spherical erythrocytes that lose deformability and are sequestered/destroyed in the spleen.
Epidemiology
Most common inherited hemolytic anemia in people of Northern European descent (~1:2000). Autosomal dominant inheritance in ~75% of cases; recessive forms tend to be more severe. Can present at any age from neonatal jaundice to incidental adult finding.
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Question 1HematologyMedium
A 22-year-old man presents with a lifelong history of intermittent jaundice and fatigue. His mother and sister have had splenectomies in young adulthood. CBC shows Hgb 10.2 g/dL, MCV 86 fL, MCHC 37 g/dL (elevated), and reticulocytosis. Peripheral smear shows numerous small, round, dense red cells lacking central pallor. Direct Coombs test is negative. Which mechanism best explains his anemia?
AReduced red cell glucose-6-phosphate dehydrogenase activity with oxidative hemolysis
BAutoimmune IgG antibodies coating red cells leading to splenic phagocytosis
CDeficient pyruvate kinase activity depleting red cell ATP with splenic hemolysis
DDefective red cell membrane proteins producing fragile spheroid red cells
Reveal answer & full explanation
Correct answer: D — Defective red cell membrane proteins producing fragile spheroid red cells
AReduced red cell glucose-6-phosphate dehydrogenase activity with oxidative hemolysis
BAutoimmune IgG antibodies coating red cells leading to splenic phagocytosis
CDeficient pyruvate kinase activity depleting red cell ATP with splenic hemolysis
DDefective red cell membrane proteins producing fragile spheroid red cells✓
Why Defective red cell membrane proteins producing fragile spheroid red cells is correct
Hereditary spherocytosis is most often autosomal dominant and caused by mutations in vertical-membrane proteins such as ankyrin, spectrin (alpha or beta), band 3, or protein 4.2
Loss of cytoskeletal anchoring leads to membrane budding and conversion of biconcave discs into spheres that become trapped and destroyed in the spleen
Classic findings: hemolytic anemia, splenomegaly, jaundice, pigment gallstones, elevated MCHC, and spherocytes on smear with a NEGATIVE direct Coombs (distinguishing from warm autoimmune hemolytic anemia)
The osmotic fragility test (or eosin-5-maleimide flow cytometry) confirms the diagnosis, and splenectomy is curative for symptoms
Why the others are wrong
Autoimmune IgG antibodies coating red cells leading to splenic phagocytosis — warm autoimmune hemolytic anemia also produces spherocytes but has a POSITIVE direct Coombs test; this patient's Coombs is negative
Reduced red cell glucose-6-phosphate dehydrogenase activity with oxidative hemolysis — G6PD deficiency causes episodic hemolysis triggered by oxidative stress (drugs, infection), not a chronic familial pattern with spherocytes
Deficient pyruvate kinase activity depleting red cell ATP with splenic hemolysis — pyruvate kinase deficiency is also a chronic familial hemolytic anemia, but it is autosomal recessive (not the parent-to-child pattern here), shows echinocytes rather than spherocytes on smear, and has a normal MCHC and normal osmotic fragility
Question 2HematologyMedium
A 16-year-old of Northern European descent is evaluated for several years of intermittent fatigue and scleral icterus. Her mother had her spleen and gallbladder removed as a young adult. On exam she is mildly jaundiced with a spleen tip palpable 4 cm below the left costal margin. Labs show hemoglobin 10.2 g/dL, an MCHC of 37 g/dL, reticulocytes 9%, elevated indirect bilirubin and LDH, and low haptoglobin. The peripheral smear shows numerous small, dense red cells lacking central pallor, and a direct antiglobulin (Coombs) test is negative. Which of the following is the most likely diagnosis?
AHereditary spherocytosis
BG6PD deficiency
CHereditary elliptocytosis
DWarm autoimmune hemolytic anemia
Reveal answer & full explanation
Correct answer: A — Hereditary spherocytosis
AHereditary spherocytosis✓
BG6PD deficiency
CHereditary elliptocytosis
DWarm autoimmune hemolytic anemia
Why Hereditary spherocytosis is correct
Classic triad of chronic hemolytic anemia, jaundice, and splenomegaly with spherocytes (small, dense cells lacking central pallor) on smear and a NEGATIVE direct antiglobulin test.
A red-cell membrane-protein defect (ankyrin, band 3, spectrin, protein 4.2) lowers the surface-to-volume ratio; the rigid spherocytes are trapped and destroyed in the spleen.
Supportive clues here: autosomal dominant family history (mother needed splenectomy and cholecystectomy for pigment stones), Northern European ancestry, and an elevated MCHC (>36 g/dL), which few conditions raise.
Diagnosis is confirmed with eosin-5-maleimide (EMA) binding flow cytometry, which has largely replaced the incubated osmotic fragility test.
Why the others are wrong
Warm autoimmune hemolytic anemia also produces spherocytes, but the direct antiglobulin (Coombs) test is POSITIVE and there is typically no family history; the negative test here excludes it.
G6PD deficiency is X-linked, with episodic oxidant- or infection-triggered hemolysis showing bite cells and Heinz bodies rather than uniform spherocytes, and would not explain this chronic congenital pattern with a positive maternal history.
Hereditary elliptocytosis is a horizontal cytoskeletal defect causing >25% elliptocytes on smear and usually mild or asymptomatic disease, not dense spherocytes lacking central pallor.
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Family history of hemolytic anemia, jaundice, splenomegaly, early gallstones, or splenectomy
Northern European ancestry
Consanguinity (recessive forms)
Pathophysiology
Mutations in genes encoding vertical membrane-cytoskeleton anchor proteins (ANK1, SPTB, SPTA1, SLC4A1, EPB42) weaken the connection between the lipid bilayer and underlying spectrin network. Surface area is lost via microvesiculation, generating dense spherical cells with reduced surface-to-volume ratio. These rigid spherocytes cannot traverse splenic sinusoids and are removed by splenic macrophages.
Clinical presentation
Symptoms
Neonatal jaundice often requiring phototherapy or exchange transfusion
Fatigue, pallor, exertional dyspnea from chronic anemia
Intermittent scleral icterus, dark urine during hemolytic episodes
Right upper quadrant pain from pigment gallstones (often in adolescence/adulthood)
Sudden worsening with parvovirus B19 infection (aplastic crisis)
Signs / physical exam
Splenomegaly (palpable in most older children and adults)
Jaundice/scleral icterus
Frontal bossing or maxillary hyperplasia in severe untreated childhood disease (extramedullary hematopoiesis)
Classic findings
Triad of hemolytic anemia, jaundice, and splenomegaly with spherocytes on peripheral smear and a negative Coombs test.
Differential diagnosis
Autoimmune hemolytic anemia (warm AIHA) — Spherocytes on smear PLUS positive direct antiglobulin (Coombs) test; no family history; often new-onset
G6PD deficiency — Episodic hemolysis triggered by oxidants/infection; bite cells and Heinz bodies; X-linked
Hereditary elliptocytosis — Elliptocytes (>25%) on smear; usually mild; horizontal cytoskeletal defect
Microangiopathic hemolytic anemia (TTP/HUS, DIC) — Schistocytes, thrombocytopenia, end-organ injury; negative family history
Gilbert syndrome — Isolated unconjugated hyperbilirubinemia without anemia, reticulocytosis, or hemolysis markers
Diagnostic workup
Diagnostic criteria
Hemolytic anemia + spherocytes + negative DAT + family history OR positive EMA binding test. Genetic testing reserved for atypical/severe or recessive cases.
Labs
CBC — normocytic or mildly microcytic anemia with elevated MCHC (>36 g/dL is highly suggestive)
Reticulocyte count — elevated
Peripheral smear — spherocytes lacking central pallor
Direct antiglobulin (Coombs) test — NEGATIVE (distinguishes from AIHA)
Eosin-5-maleimide (EMA) binding by flow cytometry — preferred screening test (high sensitivity/specificity)
Osmotic fragility test (incubated) — historical confirmatory test
Imaging
Abdominal ultrasound — splenomegaly; screen for cholelithiasis in adolescents and adults
Diagnostic algorithm
flowchart TD
A[Hemolytic anemia<br/>+ spherocytes on smear] --> B{Direct Coombs?}
B -->|Positive| C[Warm AIHA]
B -->|Negative| D[EMA binding<br/>flow cytometry]
D -->|Decreased| E[Hereditary<br/>Spherocytosis]
E --> F{Severity}
F -->|Mild| G[Observation<br/>+ folate]
F -->|Moderate| H[Folate<br/>± splenectomy]
F -->|Severe| I[Vaccinate then<br/>total splenectomy]
I --> J[Lifelong PCN<br/>prophylaxis if young]
Diagnostic algorithm distinguishing HS from autoimmune hemolysis and management by severity tier.
Treatment
First-line
Folic acid supplementation (1 mg daily) in moderate-to-severe disease to support compensatory erythropoiesis
Transfusion support for severe anemia or aplastic crisis
Phototherapy or exchange transfusion for severe neonatal hyperbilirubinemia
Elevated MCHC is a useful screening clue — few conditions raise it.
EMA binding flow cytometry has largely replaced osmotic fragility as the test of choice.
Splenectomy resolves anemia and jaundice but does NOT correct the underlying membrane defect — spherocytes persist on smear.
Parvovirus B19 wipes out the reticulocyte response; suspect aplastic crisis when hemoglobin falls and reticulocyte count is paradoxically low.
Vaccinate (pneumococcal, meningococcal, Hib) at least 2 weeks before elective splenectomy.
References
British Society for Haematology — Bolton-Maggs PHB et al. Guidelines for the diagnosis and management of hereditary spherocytosis — 2011 update. Br J Haematol 2012.
ASH Education Program — Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis. Lancet 2008; 372:1411-26.
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