By the end of this presentation, the clinician will be able to:

Hereditary spherocytosis (HS) is hemolytic anemia that is caused by a gene mutation- induced aberration. Either a deciency or dysfunction of one or more of band 3, protein 4.2, ankyrin, and α- and β-spectrin protein defects caused erythro­cytes to change from standard biconcave disc shape into a spherical shape, and the

number of peripheral blood spherocytes increased [1, 2]. Spherocytes are suscepti­ble to damage in the spleen with a manifestation of anemia, jaundice, and spleno­megaly. Osmotic resistance, hypertonic cryohemolysis test, eosin- 5- maleimide (EMA) binding in ow cytometry, sodium dodecyl sulfate- polyacrylamide gel elec­trophoresis (SDS-PAGE), and ektacytometry are used in the diagnosis of HS.However, all tests have specic limitations [3]. Without appropriate laboratory evidence, HS might be easily misdiagnosed as glucose-6-phosphate dehydrogenase deciency (G6PD) , pyruvate kinase deciency [4], autoimmune hemolytic anemia (AIHA) , thalassemia, or diseases of the hepatobiliary system. For this reason, therefore when presented with the constellation of symptoms above, it is pertinent to investigate the possibility of a diagnosis of hereditary spherocytosis. This case also illustrates the pitfall of anchoring biases and how they affect physicians’ abili­ties to make accurate diagnoses. Provided the clinical picture and negative testing results, further investigation into other possible etiologies needs to be considered in all cases till a denitive diagnosis is made.

the reticulocyte ratio was 19%, and the mean sphered corpuscular volume (MSCV) was 71.66 [5]. Total bilirubin of 57.60mol/l, direct bilirubin 19.10mol/l, indirect bilirubin 38.50mol/l, and alanine aminotransferase (ALT) 35U/l were the ndings of liver function testing [5]. Hemoglobin peptide chain analysis revealed no abnor­malities. G6PD activity was within normal limits. IgG antiglobulin tests were nega­tive both directly and indirectly. The bone marrow morphology revealed substantial,

1. Glucose-6-phosphate dehydrogenase deciency (G6PD)

Hereditary spherocytosis was misdiagnosed as autoimmune hemolytic anemia in this case due to nonspecic presenting symptoms and prevalent anchoring biases.

options for treatment and prognosis. The diagnosis of HS is usually based on a com­bination of clinical and family histories, physical examination (for splenomegaly or jaundice), and laboratory data. The variability of clinical manifestation is a primary factor in HS misdiagnosis. In individuals with HS, virus B19 infection can cause aplastic crises, with fever and abdominal discomfort as the presenting signs [7]. Liver dysfunction and skin outbreaks however are infrequent [7]. Patients with moderate HS may not develop anemia and thus be undiagnosed for an extended period of time. Sheikh etal. described a female patient who had scleral jaundice at the age of 14 but was only conrmed with an HS diagnosis when she reported to the hospital with 2 weeks of fatigue at the age of 35. She had no family history sugges­tive of the disease [8]. Considering the fact that G6PD, thalassemia, and AIHA all present with anemia, jaundice, and splenomegaly, HS must be differentiated from these pathologies. In the case that a patient is suspected of having hemolytic ane­mia, red cell indices, a peripheral blood smear, Hb electrophoresis, and DNA analy­sis, as well as the detection of G6PD enzyme activity and a direct antiglobulin test, should be ordered to distinguish G6PD, thalassemia, and AIHA from HS.Hb elec­trophoresis and DNA analysis have historically been used to diagnose thalassemia [9]. G6PD enzyme activity is normally evaluated by quantitative spectrophotomet­ric measurement of the rate of NADPH generation to conrm the diagnosis of G6PD. AIHA is a simple diagnosis based on a patient who has a positive direct antiglobulin test. After excluding thalassemia, G6PD, and AIHA, red cell indices, peripheral blood smear examination, and other evidence suggesting a hemolytic process and/or a membrane defect should be conducted to diagnose HS [9]. Once the patient discussed in Case 1 initially appeared with anemia, jaundice, and raised reticulocytes, the local hospital conducted various tests to rule out other conditions. A direct antiglobulin test was negative, G6PD activity was predicted within normal limits, and hemoglobin peptide chain analysis revealed no abnormalities. Unfortunately, due to the assumption that patients with warm-antibody-type auto­immune hemolytic anemia had negative direct antiglobulin testing, the local hospi­tal did not initiate a further investigation with HS-related studies. As a result, Case 1 was diagnosed with autoimmune hemolytic anemia and was treated for 2 months with a corticosteroid regimen. His hemoglobin, however, did not correct and this therapy was ineffective. Warm-antibody-type autoimmune hemolytic anemia responds to corticosteroid treatment, which would have resulted in a rise in hemo­globin in 1–2months if an accurate diagnosis was made [10, 11]. As a result, Case 1 was misdiagnosed by the local hospital. When a patient is suspected of having AIHA but has a negative direct antiglobulin test, an immunoradiometric assay or analysis of the RBC eluate may be instrumental in nding an autoantibody directed toward one or more RBC antigens before contemplating corticosteroid therapy [9]. The predominant sign of HS in Case 2 was jaundice; the patient did not manifest any symptoms of anemia or splenomegaly. Hemolytic anemia in this patient class is frequently overlooked: they are readily misdiagnosed as having autoimmune hepa­titis or cholelithiasis (the main complication of HS is cholelithiasis). Total, direct, and indirect bilirubin levels can be used to classify jaundice. In addition, patients

with hepatobiliary diseases frequently present with elevated total bilirubin levels, which are primarily due to an increase in direct bilirubin. An investigation into fam­ily history is an important factor in diagnosing HS.Mild HS, for instance, may not manifest as hemolytic anemia and can be detected only after a proband has been discovered with HS.Kataoka etal. cite an example where a 38-year-old male patient with HS was swiftly diagnosed as a result of his daughter [12] being diagnosed. The patient was only noted to have splenomegaly at the point of diagnosis. Case 2 was diagnosed in a similar manner. Nonetheless, not all HS subjects have a family his­tory. Stefan etal. studied 107 instances with HS and concluded that autosomal dom­inant inheritance accounted for 54%, autosomal recessive inheritance for 36%, and spontaneous mutations for 5% and the causes were unknown in roughly 5%. Another study revealed autosomal recessive inheritance in 24/26 instances of moderate HS, whereas the reasons remain unknown in the remaining 2 cases [13]. Subjects with autosomal recessive inheritance and spontaneous mutations have no family history, making them vulnerable to long-term misdiagnosis. Bolton-Maggs etal. advocate the use of an eosin-5-maleimide (EMA) binding test, cryohemolysis test, and SDS­PAGE to reach a denitive diagnosis when a patient has laboratory ndings that are highly indicative of HS with the absence of a family history of the disorder and unusual clinical signs [1]. Bianchi etal. reported that the EMA binding test for band 3-defect-HS had a sensitivity of 93% for HS, a sensitivity of 100% for combined spectrin/ankyrin defects, and a sensitivity of 88% for membrane protein defects [14]. When the percentage of surviving erythrocytes in a cryohemolysis test was