Pyruvate kinase deficiency misdiagnosed as thalassemia for more than three decades: a case report

Pyruvate kinase deficiency (PKD) is a rare autosomal recessive enzymatic disorder causing chronic non-spherocytic hemolytic anemia. Pyruvate kinase deficiency is frequently overlooked because its presentation overlaps with more common causes of chronic hemolytic anemia, potentially resulting in prolonged diagnostic delay and inappropriate management. We report a 34-year-old Nepalese man with lifelong anemia who had been managed as thalassemia since infancy. Clinical examination revealed pallor, icterus, and massive splenomegaly. Laboratory investigations demonstrated chronic hemolytic anemia with a hemoglobin level of 8.1 g/dL, reticulocyte count of 12.5%, lactate dehydrogenase of 420 U/L, and total bilirubin of 7 mg/dL. Imaging revealed splenomegaly measuring 20.1 cm and multiple gallstones. The patient underwent laparoscopic splenectomy and cholecystectomy for symptomatic disease. Despite longstanding manifestations of chronic hemolysis, the underlying diagnosis remained unrecognized for more than three decades. Subsequent molecular testing identified a homozygous pathogenic PKLR variant (c.994G>A; p.Gly332Arg), which was confirmed by Sanger sequencing and established the diagnosis of pyruvate kinase deficiency. At three-month follow-up, hemoglobin levels had stabilized at 10–11 g/dL with resolution of fatigue and jaundice. This case highlights the significant diagnostic challenges associated with PKD, particularly in resource-limited settings where access to specialized investigations may be limited. PKD should be considered in patients with chronic hemolytic anemia, splenomegaly, and cholelithiasis when clinical and laboratory findings are not fully explained by more common hematological disorders. Early recognition and molecular confirmation are essential for appropriate management and genetic counseling.