Management of pyruvate kinase deficiency in children and adults.

Pyruvate kinase deficiency (PKD) is an autosomal-recessive enzyme defect of the glycolytic pathway that causes congenital nonspherocytic hemolytic anemia. The diagnosis and management of patients with PKD can be challenging due to difficulties in the diagnostic evaluation and the heterogeneity of clinical manifestations, ranging from fetal hydrops and symptomatic anemia requiring lifelong transfusions to fully compensated hemolysis. Current treatment approaches are supportive and include transfusions, splenectomy, and chelation. Complications, including iron overload, bilirubin gallstones, extramedullary hematopoiesis, pulmonary hypertension, and thrombosis, are related to the chronic hemolytic anemia and its current management and can occur at any age. Disease-modifying therapies in clinical development may decrease symptoms and findings associated with chronic hemolysis and avoid the complications associated with current treatment approaches. As these disease-directed therapies are approved for clinical use, clinicians will need to define the types of symptoms and findings that determine the optimal patients and timing for initiating these therapies. In this article, we highlight disease manifestations, monitoring approaches, strategies for managing complications, and novel therapies in development.

Comorbidities and complications in adults with pyruvate kinase deficiency.

OBJECTIVES: Pyruvate kinase (PK) deficiency is caused by PKLR gene mutations, leading to defective red blood cell glycolysis and hemolytic anemia. Rates of comorbidities and complications by transfusion history and relative to the general population remain poorly quantified. METHODS: Data for patients aged ≥ 18 years with two confirmed PKLR mutations were obtained from the PK deficiency Natural History Study (NCT02053480). Frequencies of select conditions were compared with an age- and sex-matched cohort from a general insured US population without PK deficiency. RESULTS: Compared with the matched population (n = 1220), patients with PK deficiency (n = 122) had significantly higher lifetime rates of osteoporosis, liver cirrhosis, and pulmonary hypertension; splenectomy and cholecystectomy rates were also significantly higher in the 8 years before the index date. Sixty-five (53.3%) patients with PK deficiency were classified as regularly transfused, 30 (24.6%) as occasionally transfused, and 27 (22.1%) as never transfused. Regularly transfused patients were significantly more likely than never transfused patients to have had splenectomy, cholecystectomy, and/or thrombosis. Liver iron overload was reported in 62% of patients and occurred regardless of transfusion cohort. CONCLUSIONS: Even never transfused patients with PK deficiency had higher rates of select comorbidities and complications than individuals without PK deficiency.

Prevalence of pyruvate kinase deficiency: A systematic literature review.

OBJECTIVES: Pyruvate kinase deficiency (PK deficiency) is a rare disorder caused by compound heterozygosity or homozygosity for > 300 mutations in the PKLR gene. To understand PK deficiency prevalence, we conducted a systematic literature review. METHODS: We queried Embase and Medline for peer-reviewed references reporting PK deficiency prevalence/incidence, PKLR mutant allele frequency (MAF) among the general population, or crude results from which these metrics could be derived. RESULTS: Of 1390 references screened, 1296 were excluded after title/abstract review; 60 were excluded after full-text review. Four of the remaining 34 studies were considered high-quality for estimating PK deficiency prevalence. Two high-quality studies identified cases from source populations of known sizes, producing estimates of diagnosed PK deficiency prevalence of 3.2 and 8.5 per million. Another high-quality study derived an estimate of diagnosed PK deficiency prevalence of 6.5 per million by screening jaundiced newborns. The final high-quality study estimated total diagnosed and undiagnosed PK deficiency prevalence to be 51 per million through extrapolation from observed MAFs. CONCLUSIONS: We conclude that prevalence of clinically diagnosed PK deficiency is likely between 3.2 and 8.5 per million in Western populations, while the prevalence of diagnosed and undiagnosed PK deficiency could possibly be as high as 51 per million.

Development of the pyruvate kinase deficiency diary and pyruvate kinase deficiency impact assessment: Disease-specific assessments.

INTRODUCTION: Currently recommended patient-reported outcome (PRO) measures for patients with pyruvate kinase (PK) deficiency are non-disease-specific. The PK Deficiency Diary (PKDD) and PK Deficiency Impact Assessment (PKDIA) were developed to be more targeted measures for capturing the symptoms and impacts of interest to this patient population. METHODS: The instruments were developed based on concept elicitation interviews with 21 adults and modified based on 20 cognitive interviews. The domain structure and item concepts of the PKDD and PKDIA were compared with currently recommended measures, the EORTC QLQ-C30 and the SF-36v2®. RESULTS: The PKDD is a seven-item measure of the core signs and symptoms of PK deficiency. The PKDIA is a 14-item measure of the impacts of PK deficiency on patients' health-related quality of life (HRQoL). Minimal similarities were found between the new measures and the EORTC QLQ-C30 (eg, 43% of concepts were similar to the PKDD; 42% were similar to the PKDIA) and SF-36v2® (57% of concepts were similar to the PKDD; 17% were similar to the PKDIA). CONCLUSIONS: The PKDD and PKDIA fill a gap in the existing outcomes measurement strategy for PK deficiency. Future work includes psychometric evaluation of these newly developed measures.

Epidemiological Study of Hereditary Hemolytic Anemia in the Korean Pediatric Population during 1997-2016: a Nationwide Retrospective Cohort Study.

BACKGROUND: Hereditary hemolytic anemia (HHA) is a rare disease characterized by premature red blood cell (RBC) destruction due to intrinsic RBC defects. The RBC Disorder Working Party of the Korean Society of Hematology established and updated the standard operating procedure for making an accurate diagnosis of HHA since 2007. The aim of this study was to investigate a nationwide epidemiology of Korean HHA. METHODS: We collected the data of a newly diagnosed pediatric HHA cohort (2007-2016) and compared this cohort's characteristics with those of a previously surveyed pediatric HHA cohort (1997-2006) in Korea. Each participant's information was retrospectively collected by a questionnaire survey. RESULTS: A total of 369 children with HHA from 38 hospitals distributed in 16 of 17 districts of Korea were investigated. RBC membranopathies, hemoglobinopathies, RBC enzymopathies, and unknown etiologies accounted for 263 (71.3%), 59 (16.0%), 23 (6.2%), and 24 (6.5%) of the cases, respectively. Compared to the cohort from the previous decade, the proportions of hemoglobinopathies and RBC enzymopathies significantly increased (P < 0.001 and P = 0.008, respectively). Twenty-three of the 59 hemoglobinopathy patients had immigrant mothers, mostly from South-East Asia. CONCLUSION: In Korea, thalassemia traits have increased over the past 10 years, reflecting both increased awareness of this disease and increased international marriages. The enhanced recognition of RBC enzymopathies is due to advances in diagnostic technique; however, 6.5% of HHA patients still do not have a clear diagnosis. It is necessary to improve accessibility of diagnosing HHA.

The burden of disease in pyruvate kinase deficiency: Patients' perception of the impact on health-related quality of life.

OBJECTIVES: This study explored how signs and symptoms of pyruvate kinase (PK) deficiency, a rare hemolytic anemia caused by mutations in the PKLR gene, impacts patients' health-related quality of life (HRQoL). METHODS: Interviews with 21 adults with PK deficiency in the United States, Netherlands, and Germany were conducted. Participants were asked to describe signs, symptoms, and impacts of the disease on their daily lives. Interviews were transcribed and analyzed using qualitative analysis methods. RESULTS: The most common signs and symptoms reported were yellow eyes (n = 19), tiredness (n = 18), yellow skin (n = 17), fatigue (n = 15), low energy (n = 13), and shortness of breath (n = 13). Furthermore, signs and symptoms of PK deficiency negatively impact the ability to perform physical activities, appearance, social activities, emotional states, activities of daily living, leisure activities, work and/or school, sleep, and cognitive states of those living with PK deficiency. A conceptual model is presented that further demonstrates the profound impact that signs and symptoms of PK deficiency have on dimensions of patients' HRQoL. CONCLUSIONS: This is the first study that provides patient perspective on the burden of living with PK deficiency and lays the foundation for future studies to examine the effect of pharmacologic interventions on overall HRQoL for patients living with PK deficiency.

Erythrocyte glucose-6-phosphate dehydrogenase and pyruvate kinase activities in hemoglobin H disease.

Erythrocyte glucose-6-phosphate dehydrogenase (G6PD) and pyruvate kinase (PK) activities were studied in hemoglobin H (HbH) patients by spectrophotometric method, cytochemical method and the methemoglobin reduction (MR) test for the detection of heterozygous G6PD deficiency. G6PD deficiency was found in 7 of 64 cases (10.9%), including 3 cases of genotype alpha 1/alpha 2 and 4 cases of genotype alpha 1/CS. None of the HbH patients was found to be PK-deficient. Spectrophotometrically determined G6PD and PK activities were significantly higher in HbH patients than in normals (p less than 0.001), whereas the MR test yielded a significantly lower percentage of residual methemoglobin in HbH patients than in normals (p less than 0.05). All three methods were efficient in the detection of hemizygous G6PD deficiency in HbH patients, but not in G6PD-deficient females.