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H. Al-Samkari et al.
recognized that glycolytic defects could lead to hemolytic anemia.5 PKD was first described as a cause of hereditary hemolytic anemia in 1961 by Valentine and colleagues.6 Pyruvate kinase (PK) catalyzes the conversion of phosphe- nolpyruvate to pyruvate and is the rate-limiting enzyme in erythrocyte energy production, which is an exclusively anaerobic process. As only one of two glycolytic enzymes that generates ATP, homozygous or compound heterozy- gous loss-of-function mutations in the PKLR gene, which encodes erythrocyte PK, result in erythrocyte ATP short- age. This ATP deficiency presumably results in a reduced capacity to maintain the red cell membrane and dimin- ished erythrocyte deformability, resulting in a shortened lifespan and destruction in the spleen. Because patients experience mainly extravascular hemolysis, splenectomy frequently improves anemia.7 A striking difference between PKD and most other hereditary hemolytic ane- mias is the dramatic post-splenectomy reticulocytosis characteristic of PKD, which typically increases 50% or more over pre-splenectomy counts. Reticulocytes have a much higher ATP requirement as compared with mature red cells but can rely on oxidative phosphorylation for energy. However, in the hypoxic splenic environment, PK- deficient reticulocytes must rely on glycolysis, which does not meet the ATP needs, leading to hemolysis.8-10 In the absence of the spleen, reticulocyte survival increases.
The clinical manifestations of PKD are heterogenous and the severity varies considerably, from fetal hydrops with intrauterine demise to incidentally discovered asymptomatic fully compensated hemolysis to a severe transfusion-dependent anemia from birth through old age.11-13 Patients’ symptoms often do not correlate with the severity of anemia, adding an additional dimension of complexity in disease management.14 Complications include iron overload, pulmonary hypertension, endocrinopathies, osteoporosis and bone fractures, extramedullary hematopoiesis, gallstones, and lower extremity ulcers, among others.11 PKD is characterized by a high prevalence of iron overload regardless of whether patients require regular transfusions, necessitating moni- toring in all patients and frequent institution of iron chela- tion therapy.15
Beyond splenectomy and hematopoietic stem cell transplantation, treatment has been largely supportive from the time PKD was first described.16,17 This is rapidly changing. A small molecule allosteric activator of PK is under development, with safety and efficacy demonstrat- ed in phase I and II trials;18,19 it is currently being investi- gated in phase III trials. Following on the success of gene therapy in animal PKD models20 and humans with tha- lassemia and other hematologic disorders,21,22 a clinical trial of gene therapy for PKD was launched in 2019. Now more than ever before, it is critical for hematologists to elucidate the specific diagnoses of patients with congeni- tal hemolytic anemias, including PKD, and institute prop- er interventions. The promise of effective targeted thera- pies has greatly revived interest in PKD, but published data remain limited and no evidence-based guidelines for the management of these patients exist. This article, developed and written by ten international experts in PKD, reviews the manifestations and spectrum of disease in patients and highlights the most common, most impor- tant, and most challenging presentations of this disease. To develop this report, this PKD Burden of Disease work- ing group had multiple focused online discussions over
the course of 1 year and an in-person meeting in San Diego (CA, USA). Given that many providers have limit- ed experience caring for patients with PKD, hypothetical case presentations based on the collective PKD patient care experience of the working group are included to introduce each section and illustrate the key signs, symp- toms, and complications which outline the scope and spectrum of disease in PKD.
Diagnostic challenges
The newly-diagnosed adult patient
CASE: A 29-year old man with a history of ulcerative colitis, inflammatory anemia, and cholecystitis (cholecystectomy per- formed at the age of 27) is referred for further workup of hemolytic anemia with a negative direct antiglobulin test. He underwent colectomy at the age of 17 for ulcerative colitis. Following colectomy, his chronic anemia (hemoglobin 9.0-11.0 g/dL) improved to a new baseline of 11.5-12.5 g/dL. He has long-standing hyperbilirubinemia that has been attributed to Gilbert syndrome, although genetic confirmation of this has not been performed. Currently his laboratory evaluation is remark- able for the following: hemoglobin 10.9 g/dL, mean cell volume 106 fL, absolute reticulocyte count 1,030 × 109/L, indirect biliru- bin 3.7 mg/dL, lactate dehydrogenase 476 U/L, and unde- tectable haptoglobin. The direct antiglobulin test is negative. A peripheral blood film is nonspecific and hemoglobin electrophore- sis is unremarkable. Testing for paroxysmal nocturnal hemoglo- binuria, erythrocyte membrane defects, and glucose-6-phosphate dehydrogenase deficiency is negative. PK activity is 1.2 U/g hemoglobin (reference range, 6.7-14.3 U/g hemoglobin). A diagnosis of PKD is confirmed by genetic testing revealing com- pound heterozygosity for two missense mutations in the PKLR gene: c.1091G>A (p.Gly364Asp) and c.1529G>A (p.Arg510Gln).
Patients with PKD who are regularly transfused or have severe hemolytic anemia are typically diagnosed in the neonatal period or in early childhood. Patients who have never or rarely been transfused, however, are frequently diagnosed as adults.23 These patients typically have mild- to-moderate anemia that can be misdiagnosed as tha- lassemia trait (without genetic confirmation), iron defi- ciency (often in a menstruating woman), more common hemolytic anemias (e.g. hereditary spherocytosis), or inflammatory anemia. Patients can also evade early diag- nosis because of normal or near normal hemoglobin con- centrations in the setting of well-compensated hemolysis. Complications resulting from PKD, such as hyperbiliru- binemia, gallstones, and iron overload, can often be mis- taken as discrete diagnostic entities attributed to other causes, such as Gilbert syndrome or hereditary hemochromatosis.
Recognition of even the mildest forms of disease is important for several reasons. Although the frequency of certain complications is highest in patients with two drastic PKLR mutations, many complications, including hemolysis, gallstones, iron overload, and aplastic crises are not uncom- mon in patients with two missense mutations and mild anemia.11 Folic acid supplementation is recommended in essentially all patients to prevent deficiency due to rapid cell turnover; recognition of increased folate requirements is particularly important in women of childbearing age. Iron overload is common even in patients who never receive red cell transfusion due to chronic hemolysis15 and may lead to
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haematologica | 2020; 105(9)