BRANDON C. KU
HISTORY OF PRESENT ILLNESS
A 6-year-old Caucasian girl developed fever, abdominal pain, and pallor 3 days prior to admission. She had one episode of nonbilious emesis. Two days before admission, the family thought she was pale and then “yellow.” On the day of admission, she had a rash on her buttocks and extremities. She complained of feeling dizzy in the morning. She had decreased oral intake and her urine appeared slightly dark. She also had several loose stools.
Six years prior, the patient had been admitted for dehydration and was noted to have anemia at that time. Past surgical history was notable for three surgeries for cleft palate and cleft lip repair. There were no known allergies and she did not require any medications. Her immunizations were up to date. She had also received the hepatitis A vaccination series prior to her vacation in Mexico 1 year ago. There had been no recent travel. She lived with her parents. There were no pets. The mother had her spleen removed after blunt abdominal trauma suffered in a car accident. The mother also required supplemental iron therapy for treatment of anemia. A maternal aunt required removal of her gallbladder at 19 years of age. Multiple family members suffered from diabetes mellitus.
T 38.5°C; HR 142 bpm; RR 24/min; BP 100/50 mmHg; Weight 25 kg (50th percentile)
On general examination, the patient was very pale but alert and oriented. The scelera were mildly icteric. The oropharynx had mild erythema but no exudates or vesicles. The lungs were clear to auscultation. A gallop was appreciated on cardiac examination. The abdomen was soft. A tender spleen was palpated 4 cm below the left costal margin. There was no tenderness in the right upper quadrant. The capillary refill was brisk. The remainder of the examination was normal.
White blood 6300 cells/mm3 (64% segmented neutrophils, 30% lymphocytes, and 6% monocytes). Hemoglobin, 4.5 g/dL; platelets, 179 000/mm3; red cell distribution width was elevated at 16.9; mean corpuscular volume, 78 fL; mean corpuscular hemoglobin concentration, 37 mg/dL; reticulocyte count, 8.4%; total bilirubin, 3.3 mg/dL; unconjugated bilirubin, 2.4 mg/dL; uric acid, 2.3; lactate dehydrogenase, 1136; serum albumin, transaminases, and electrolytes were normal.
COURSE OF ILLNESS
This child was admitted for fever and abdominal pain. Significant anemia was noted on complete blood count. The presence of a gallop with severe anemia prompted a gradual packed red blood cell transfusion. She received empiric ceftriaxone after a blood culture was obtained. The peripheral blood smear suggested a diagnosis (Figure 10-3).
FIGURE 10-3. Peripheral blood smear.
DISCUSSION CASE 10-4
The history of gallbladder surgery in a young aunt certainly raises the possibility of an inherited hemolytic disorder. The mother’s history of splenectomy may be related to splenic laceration due to trauma; however, the history of anemia is intriguing. The differential diagnosis is that of other hemolytic anemias both congenital and acquired. There are other disorders of the red cell membrane and cytoskeleton including spherocytosis, elliptocytosis, and stomatocytosis. Also under consideration are disorders of red cell enzymes (e.g., glucose-6-phosphate dehydrogenase deficiency), drug associated, and autoimmune hemolytic anemia. The differential diagnostic possibilities are broad but spherocytosis is the most common of the congenital causes. Basic laboratory testing allows for the establishment of the correct diagnosis.
The peripheral blood smear revealed numerous small spherocytes (note the lack of central pallor seen in normal red blood cells), wide variation in red blood cell size (anisocytosis), and a paucity of normal red blood cells (Figure 10-3). Causes of spherocytosis include conditions that lead to red cell membrane damage such as immunohemolytic anemias (e.g., autoimmune hemolytic anemia), clostridial toxin, severe burns, Wilson disease, and hereditary spherocytosis. This child had hereditary spherocytosis (HS), a congenital hemolytic anemia caused by defects in proteins comprising the red blood cell skeleton. Subsequent evaluation of other family members revealed mild hereditary spherocytosis in the mother and maternal aunt. The grandparents declined testing.
INCIDENCE AND EPIDEMIOLOGY OF HEREDITARY SPHEROCYTOSIS
Spherocytosis incidence in the United States is 1 in 5000 live births. It is most common in individuals of Northern European descent but does occur in other ethnic groups. Inheritance is usually autosomal dominant but in up to a quarter of the cases family history is negative. In some cases, family members have only minor manifestations. A family history of gallbladder surgery or splenectomy should raise suspicion for underlying hemolytic diseases, including hereditary spherocytosis. In other situations there may be a new mutation or a recessive pattern of inheritance. The defects for this condition are found on chromosomes 1, 8, 14, 15, and 17.
CLINICAL PRESENTATION OF HEREDITARY SPHEROCYTOSIS
Presentation depends to some extent on severity of the spherocytosis. Fatigue due to anemia or episodic jaundice are common complaints. Jaundice may be noted more frequently during viral infections. Most children have splenomegaly (50% of infants and 75%-90% of older children). During the newborn period some cases are detected by severe or prolonged hyperbilirubinemia. Some patients present with gallstones.
Complete blood count. Patients with hereditary spherocytosis have varying degrees of anemia, reticulocytosis, elevated mean corpuscular hemoglobin, and hyperbilirubinemia. In mild forms, the hemoglobin may be normal (compensated hemolysis). Those with moderate or moderately severe spherocytosis have a hemoglobin level that ranges from 6 to 10 g/dL and a reticulocyte count of 8% or greater. Those with severe spherocytosis typically have hemoglobin levels less than 6 g/dL and reticulocyte counts greater than 10%. The MCHC exceeds the normal value in about one-third of affected patients. The finding of an MCHC greater than 35 g/dL has a sensitivity of 70% and a specificity of 86% in diagnosing hereditary spherocytosis. The MCV is usually normal but the red cell distribution width is elevated due to the mixed population of small spherocytes and large reticulocytes.
Peripheral blood smear. The finding of spherocytes on peripheral blood smear is characteristic. Spherocytes are round, dense, hyperchromic red cells that lack the typical central pallor and biconcavity of normal red blood cells. They are present in 25%-35% of patients with mild spherocytosis but on almost all patients with moderate or severe disease. In contrast to some other causes of hemolytic disease, spherocytes and microspherocytes are the only abnormal cells visualized on the peripheral blood smear in patients with hereditary spherocytosis. In severe hereditary spherocytosis, the spherocytes may appear dense, contracted, or budding. Nucleated red blood cells are not usually seen. Howell-Jolly bodies are seen in only 4% of patients prior to splenectomy.
Osmotic fragility test. Normal red blood cells have a high surface-to-volume ratio (more membrane than they need). When normal red blood cells are suspended in a hypotonic saline solution they expand due to the influx of fluid. The extra membrane present allows the cells to expand and gradually take the shape of a sphere, a conformation that efficiently minimizes the surface area relative to volume. As the solution becomes progressively hypo-tonic, the normal red cells become more spherical and ultimately burst, releasing hemoglobin into the solution. In spherocytes, the red cell surface area is already decreased relative to volume at the start. Cells that start with a low surface-to-volume ratio (e.g., spherocytes) reach the spherical limit at a higher saline (less hypotonic) concentration than normal cells. The fragility is calculated by measuring the percent lysis at specific saline concentrations.
Other studies. The glycerol lysis test measures the rate rather than extent of hemolysis. The hyper-tonic cryohemolysis test is based on the fact that spherocytes are particularly sensitive to cooling in hypertonic solutions. In contrast to the other tests, this test is independent of the surface-to-volume ratio. Other findings in children with hereditary spherocytosis such as unconjugated hyperbilirubinemia and increased fecal urobiloinogen reflect chronic hemolysis.
Patients with hereditary spherocytosis require folic acid supplementation to keep up with their chronic hemolysis (usually 0.5-1 mg/day orally). Patients with spherocytosis may require transfusion in the acute phase. Splenectomy can reduce or eliminate the need for transfusion. Most often splenectomy is delayed until the patient reaches 5 or 6 years of age, a time when the risk of pneumococcal sepsis has decreased considerably. Children evaluated for splenectomy should receive vaccination with both the heptavalent pneumococcal conjugate and the pneumococcal 23-valent polysaccharide vaccines. Postsplenectomy, penicillin prophylaxis is generally recommended.
Complications related to hereditary spherocytosis include gallstones, hemolytic crises, and aplastic crises. Bilirubinate gallstones can be asymptomatic or can cause cholecystitis or biliary obstruction. Ultrasonography detects these pigmented stones and some specialists recommend routine abdominal ultrasounds every 5 years. Hemolytic crises occur commonly in children with hereditary spherocytosis, usually in association with viral syndromes. Transient jaundice, emesis, and abdominal pain characterize the hemolytic crisis. Most children do not require specific treatment but the development of severe anemia may lead to hospitalization and packed red blood cell transfusion. Aplastic crises occur less frequently than hemolytic crises but severe anemia may precipitate congestive heart failure. Aplastic crises frequently occur following parvovirus B19 infection.
1. Michaels LA, Cohen AR, Zhao HMA, et al. Screening for hereditary spherocytosis by use of automated erythrocyte indexes. J Pediatr. 1997;130:957-960.
2. Evans TC, Jehle D. The red cell distribution width. J Emerg Med. 1991;9:72-74.
3. Gallagher PG, Lux SE. Disorders of the erythrocyte membrane. In: Nathan DG, Orkin SH, Ginsburg D, Look AT, eds. Nathan and Oski’s Hematology of Infancy and Childhood. 6th ed. Philadelphia: Saunders; 2003:560-684.
4. Tse WT, Lux SE. Red blood cell membrane disorders. Br J Haematol. 1999;104:2-13.
5. Delhommeau F, Cynober T, Schischmanoff PO, et al. Natural history of hereditary spherocytosis during the first year of life. Blood. 2000;95:393-397.
6. Bolton-Maggs PH, Langer JC, Iolascon A, et al. Guidelines for the diagnosis and management of hereditary spherocytosis – 2011 update. Br J Haematol. 2012;156:37-49.
7. Casale M, Perrotta S. Splenectomy for hereditary spherocytosis: complete, partial or not at all. Expert Rev Hematol. 2011;4:627-635.