53-Year-Old Woman With Abdominal Pain, Anemia, and Indirect Hyperbilirubinemia
A 53-year-old woman from Vietnam with a reported past surgical history of cholecystectomy and splenectomy presented to the emergency room with a three-day history of right upper quadrant abdominal pain and fatigue. While her physical exam was notable for mild tenderness at palpation to the right upper quadrant, she otherwise appeared healthy, with a blood pressure reading of 130/80, heart rate of 89 beats per minute, respiratory rate of 16 breaths per minute, and oxygen saturation level of 100% on room air. Laboratory findings can be seen below (Table 1). The patient’s diagnostic workup included an abdominal ultrasound and computed tomography scan, both of which showed hepatomegaly measuring 18 cm and a prior splenectomy but were otherwise unremarkable. A peripheral blood smear showed microcytosis, reticulocytosis, nucleated red blood cells (RBCs), and Howell-Jolly bodies.
Given the above findings, the patient was questioned further on her family history. She noted having been told she was anemic since childhood but had no other known family members with anemia. She stated that her spleen was surgically removed due to it being enlarged and causing abdominal pain. She additionally noted that she gets recurrent fevers and chills with her abdominal pain every few months. Therefore, further workup was obtained, including a thick and thin blood smear to rule out malaria, a hemoglobin electrophoresis, and a thalassemia gene mutation analysis (Table 2).
Table 1. Laboratory results
| Value | Patient value | Range |
| White blood cell count | 17.5 K/μL | 4.5-10 K/μL |
| Hemoglobin | 7.2 g/dL | 13.6-17.2 g/dL |
| Hematocrit | 26.5% | 36-44% |
| Mean corpuscular volume | 79.5 fL | 82-97 fL |
| Red cell distribution width | 19.1% | 12-15% |
| Platelet count | 379 K/μL | 160-360 K/μL |
| Total bilirubin | 3.3 mg/dL | <1 mg/dL |
| Direct bilirubin | 0.6 mg/dL | <0.3 mg/dL |
| Absolute reticulocyte count | 352 x 109/L | 26-116 x 109/L |
| Reticulocyte index (corrected) | 5% | 0.5-2% |
| Haptoglobin | 23 mg/dL | 30-200 mg/dL |
| Lactate dehydrogenase | 167 U/L | 135-225 U/L |
| Ferritin | 4,127 ng/mL | 10-150 ng/mL |
| Direct Coombs test | Negative for immunoglobulin G or complement component 3 | Negative |
Table 2. Hemoglobin electrophoresis
| Hemoglobin (Hgb) electrophoresis | Patient value | Range |
| HgbA | 81.7% | >96% |
| HgbA2 | 1% | 2.2-3.2% |
| HgbF | <1% | <1% |
| HgbCS | 2.8% | 0 |
| Hemoglobin gene analysis | homozygote c.427T > C (p.*143Glnext*31) |
Which of the following is the most likely diagnosis?
A. Alpha-thalassemia minor
B. Hemoglobin Constant Spring
C. Beta-thalassemia
D. Hemoglobin E
Discussion
Answer: B. Hemoglobin Constant Spring (HgbCS)
Hemoglobin Constant Spring (HgbCS) is a type of alpha-thalassemia caused by a point mutation at the termination codon of an alpha 2-globin gene rather than the usual HBA1 and/or HBA2 gene deletion in other forms of alpha-thalassemia. This mutation results in the synthesis of elongated alpha-globin chains, which causes them and the hemoglobin to be unstable. HbCS is prevalent among Southeast Asian populations, especially in Vietnam. Accurate diagnosis and genetic counseling are essential, particularly in regions with high prevalence of alpha-thalassemia. Genetic testing is the gold standard for diagnosis.
Compared to other alpha-thalassemias, HgbCS patients tend to have more hemolysis and a near-normal mean corpuscular volume (MCV). The pathophysiology behind this is not well understood but may be related to characteristically overhydrated RBCs and increased membrane rigidity. This increased membrane rigidity leaves the RBCs prone to lysis, thus resulting in more severe hemolytic anemia. Homozygosity on HgbCS leads to an alpha-thalassemia intermedia-type disease, with hemolytic anemia, jaundice, and hepatosplenomegaly.
The differential diagnosis for hemolytic anemias is broad (Table 3). However, hemolytic anemias share similar features, including elevated lactate dehydrogenase, hyperbilirubinemia, low/undetectable haptoglobin, and elevated reticulocyte count with a reticulocyte index of greater than 2. Diagnosis of HgbCS can be challenging due to its atypical presentation with hemolytic properties, relatively normal MCV, and low concentration of RBCs, especially heterozygotes. It is important to keep this disease as a differential diagnosis when evaluating patients with hemolytic anemia.
Table 3. Differential diagnosis of hemolytic anemia
| Class | Disease Examples | Laboratory tests | Treatment | |
| 1 | Enzymopathy | G6PD deficiency, PK deficiency | Enzyme activity level | Avoidance of stressors (Splenectomy can be considered.) |
| 2 | Membranopathy | Hereditary elliptocytosis, hereditary spherocytosis | Eosin-5′-maleimide binding assay | Splenectomy (Avoid splenectomy for dehydrated hereditary stomatocytosis.) |
| 3 | Hemoglobinopathy |
Sickle cell disease
Thalessemia |
Hemoglobin electrophoresis
Hemoglobin electrophoresis, genetic testing |
Supportive care, disease-modifying therapies (hydroxyurea, glutamine, crizalizumab, voxelotor, gene therapy, and HSCT) Supportive care, luspatercept, HSCT (Splenectomy can be considered for transfusion-dependent patients.) |
| 4 | Autoimmune hemolytic anemia | Warm or cold autoimmune hemolytic anemia | Coombs test/DAT | Treat underlying condition, corticosteroid, rituximab, intravenous gamma globulin |
| 5 | Alloimmune | Hemolytic transfusion reactions, HDFN | Coombs test/DAT | Supportive care |
| 6 | Infectious | Malaria, babesia, leishmania, clostridium, bartonella | Blood smear | Infection-specific |
| 7 | Microangiopathic hemolytic anemia | TTP, DIC, HUS, HELLP | Peripheral smear, ADAMTS13 activity level, coagulation test, stool culture, blood culture | Disease-specific |
Abbreviations: DAT, direct antiglobulin test; DIC, disseminated intravascular coagulation; G6PD, glucose-6-phosphate dehydrogenase; HDFN, hemolytic disease of the fetus and newborn; HELLP, hemolysis, elevated liver enzymes, and low platelet count; HSCT, hematopoietic stem cell transplantation; HUS, hemolytic uremic syndrome; PK, pyruvate kinase; TTP, thrombotic thrombocytopenia purpura.
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Drs. Jones, Nwachukwu, and Lara-Martinez indicated no relevant conflicts of interest.
Acknowledgment: This article was edited by Drs. Sydney Dunn Valadez and Urshila Durani.