Continuing Education Activity

Pyruvate kinase deficiency (PKD) is the most common enzyme-related glycolytic defect that results in red cell hemolysis. Invariably, PKD results in hereditary non-spherocytic anemia. This activity reviews the evaluation and management of pyruvate kinase deficiency and highlights the role of the healthcare team in improving care for patients with this condition.

Objectives:

• Review the etiology of pyruvate kinase deficiency.
• Describe the appropriate evaluation of patients with pyruvate kinase deficiency.
• Outline the management options available for pyruvate kinase deficiency.
• Summarize the importance of improving care coordination amongst interprofessional team members to improve outcomes for patients affected by pyruvate kinase deficiency.

Introduction

Pyruvate kinase deficiency (PKD) is the most common enzyme-related glycolytic defect that results in red cell hemolysis.[1][2][3][4][5] This disorder is characterized by clinical heterogeneity.[5][6] Heterogeneity results in a variable degree of hemolysis, causing irreversible cellular disruption.[6][7][8] Invariably, PKD results in hereditary non-spherocytic anemia.[9][10] Manifestations occur from the neonatal period through adult life.[10] A myriad of complications could arise from hemolytic anemia.[1][9]

Etiology

Red blood cell (RBC) metabolism hinges on glycolysis. Pyruvate kinase (PK) enzyme is key to this process. PK converts phosphoenolpyruvate to pyruvate.[2] This step yields 50% of RBC ATP. PK modulates NADH production for methemoglobin reduction.[11] These metabolites enable RBCs to function effectively. In PKD, cellular energy efficiency and longevity decrease. Young RBCs are most affected in PKD.[9] PK expression is controlled by the PK-LR gene. The gene is located on chromosome 1q21.[3] PKD follows an autosomal recessive inheritance pattern.[9] Homozygotes and compound heterozygotes are affected. Compound heterozygotes inherit two different mutant alleles.[12] About 300 PKD-causing mutations have been found.[13] The majority of these are missense mutations.[9][13] However, novel mutations have been reported.[14][15] Frameshift, deletion, and insertion type mutations can occur.[16]

Epidemiology

PKD was first discovered in 1961 by Valentine et al.[13] Since this discovery, worldwide reports have emerged. PKD is a rare disorder. The true prevalence of PKD is unknown.[4] Estimated PKD prevalence ranges from 3.2 - 8.5 cases per million of the Western population.[10] However, a prevalence of 1:20,000 has been reported.[13][17] Mutant allele frequency may approach 51 per million.[6] Case clusters are found in Brazil and Tunisia.[6][7] 

Evidence of PKD-related gender differences appears scarce. Specific mutations have higher frequencies in certain communities, such as Pennsylvania Amish and Romani communities.[9] Certain factors could explain this finding. A founder effect indicates the heritability of mutations. Mutations have been traced to specific migrant couples. In addition, consanguinity increases the risk of homozygosity.[17]

Pathophysiology

Cellular integrity of RBCs is maintained by membrane-bound ATPases. ATPases exchange sodium for potassium. This maintains transcellular electrochemical neutrality, cellular fluid balance, and deformability.[8] Lack of PK enzyme decreases RBC ATP production, causing decreased RBC deformability. Intracellular potassium and water loss also occur.[18] This results in RBC damage. PKD manifests with enzyme levels of <25%.[19] Splenic and hepatic capillaries trap defective RBCs. Extravascular hemolysis occurs, causing hepatosplenomegaly. Intravascular hemolysis may also occur, causing hemoglobinuria.[3] Anemia underlies the progressive fatigue in PKD. Increased 2,3-diphosphoglycerate (2,3-DPG) causes oxygen unloading in tissues. This shifts the oxygen dissociation curve rightward.[9] Elevated 2,3-DPG helps compensate for anemia. These mechanisms play out in homozygotic patients. Heterozygote carriers are usually asymptomatic. However, hemolysis may occur in stressful conditions. Chronic hemolysis results in folate deficiency. Extramedullary hemopoiesis has been reported in PKD. 

Neonatal RBCs consume more ATP than in adults.[16] Splenic destruction of reticulocytes causes hyperbilirubinemia, and exchange transfusion to prevent kernicterus may be required. Severe anemia in-utero can result in fetal hydrops. Transfusion-dependent neonatal anemia may occur.[1][20]

Dilutional anemia occurs in the second trimester of pregnancy in these patients. Plasma volume increases more than RBC mass.[21] Maternal hemodilution presumably improves fetal outcomes. It also minimizes postpartum blood loss.[22] PKD may exacerbate physiologic anemia of pregnancy.[9][13] Episodic hemolysis may require RBC transfusion replacement.

History and Physical

Neonates

Manifestations include hyperbilirubinemia and anemia. Surviving neonates have recognizable pallor.[23] Characteristic worsening pallor in the first week occurs. Poor suckling with frequent pauses may occur. Lethargy and poor weight gain may manifest. Tachypnea may indicate heart failure. Hydrops may develop in-utero. Skin edema and birth asphyxia are common. Stillbirth frequently complicates hydrops.[24] Blueberry muffin rashes indicating extramedullary hemopoiesis may occur in these newborns.[13] Yellow skin and sclerae manifest jaundice. Kernicterus may supervene with severe untreated hemolysis.[9][17] 

Older Children and Adults

Older children may present with poor growth, easy fatiguability, and jaundice. Some children may have poor appetite and dizziness.[17] Stress may precipitate hemolytic crises. Physical examination shows icterus and conjunctival pallor. Hepatosplenomegaly due to hemolysis occurs. Extramedullary hemopoiesis may result in frontal bossing.[13] Adults may present with complications. These include gall stones, hemosiderosis, and aplastic anemia.

Evaluation

Laboratory evaluation is indicated for neonatal anemia or hyperbilirubinemia. Childhood chronic anemia with splenomegaly warrants investigation. Transfusion-dependent patients require evaluation.[4] Complete blood count characterizes anemia. Hemoglobin levels vary for different severities of PK deficiency. A blood smear shows normochromic cells. Polychromasia with echinocytes may be seen. Spherocytes are absent. Macrocytosis indicates folate deficiency.[3] Reticulocytosis does not correlate with hemolysis.[9] LDH is elevated, and haptoglobin is low. Coombs' test and osmotic fragility are negative. Hemoglobin electrophoresis is normal.

PK activity level is key to the diagnosis. PKD suspicion is warranted with near-normal PK levels. In these cases, adjusted measures are necessary. RBC age-corrected PK enzyme levels are low. Pyruvate kinase/hexokinase activity ratio is also low.[4]

Genetic analysis showing PKLR mutations is diagnostic. Mutation types are elucidated by this method. 

Iron overload is a risk in PKD. Regular screening with iron studies may reveal its onset.[25] Hyperferritinemia may herald the onset of iron overload.[9] Magnetic resonance imaging (MRI) for hemosiderosis is useful in selected patients.

Treatment / Management

Supportive therapy is important in chronic anemia. Folic acid supplementation is advocated for children. Pregnancy and hemolytic crises also warrant supplementation. These states are associated with increased folate demand. Blood transfusion ameliorates anemia. Decisions for transfusion must be justifiable. Good decisions are based on patient-specific presentations, which may prevent iron overload in patients.[25] Increasing intervals between transfusion can reduce risk.[13]

Splenectomy is indicated for massive splenomegaly. This eliminates the risk of traumatic rupture. Severe anemia may also benefit from splenectomy. Total splenectomy is advocated in late childhood. Vaccination for encapsulated bacteria is required post-splenectomy.[13] Prophylactic antibiotics are also beneficial.[26]

Hemosiderosis requires iron-chelation therapy with desferrioxamine. However, this should be stopped before pregnancy.[27]

PKD patients can successfully navigate pregnancy. Pre-pregnancy surveillance for complications is essential. These include viral screening and maternal echocardiography. Appropriate counseling is required before screening tests.[28] Folate supplementation helps prevent fetal malformations. Transfusion should be reserved for symptomatic anemia. A hemoglobin level of less than 8 g/dL also requires transfusion.[27] Management by hematologists and obstetricians is essential. Fetal surveillance is advisable for suspected growth restriction.[28] Preterm delivery occurs in 10% of cases.[25]

Differential Diagnosis

The differential diagnoses of PKD include other causes of hemolytic anemia. Immune hemolysis and enzyme deficiencies are considerations. Antibody-mediated hemolysis occurs with blood-group incompatibility. Coombs' positivity characterizes blood-group incompatibility.[18] ABO and Rhesus incompatibility cause hydrops fetalis, whereas neonatal anemia with jaundice occurs in survivors. RBC membrane defects, such as hereditary spherocytosis, can also cause hemolysis. Spherocytes are easily evident on blood smears. Positive family history is usually found. Osmotic red cell lysis is also present. Flow cytometric diagnosis is the gold standard, and decreased ankyrin or spectrin expression is diagnostic.[29]

Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive condition. It is the most common inherited enzymopathic cause of hemolytic anemia. Males are commonly affected. Rarely, females with lyonization are affected. African-American and Mediterranean heritage is common.[30] Hemolytic triggers include infections, medication, and oxidant stress. History and assaying enzyme activity aid diagnosis.[31]

Prognosis

Prognostication in PKD is highly variable. Disease severity and early care modify outcomes. Severe anemia and hemosiderosis are unfavorable and portend risk, particularly in pregnancy.[9][27]

Complications

Complications may arise from hemolysis or therapy. Neonatal hyperbilirubinemia may be the first manifestation.[9] Hemolysis causes iron loading and hemosiderosis. Pigment gall stones commonly complicate PKD, and at least 30% of patients develop cholelithiasis.[13] Transfusions may also result in iron loading. Pre-transfusion screening reduces blood-borne viral transmission. Aplastic anemia from parvovirus B-19 infection is infrequent.[13] Extramedullary hemopoiesis may present with unusual masses. Paravertebral or intraabdominal masses require careful follow-up.[32] Pregnancy may be complicated by growth restriction.[33]

Deterrence and Patient Education

Continuous patient education on infections is essential. Infection prevention may limit hemolytic episodes. Vaccination, prophylactic folate, and antibiotics are pertinent. Premarital education is essential in PKD prevention. Educating prospective couples helps in psychological preparation. Screening partners for carrier status is advisable.[27] Pre-pregnancy evaluation and advice are vital.

Pearls and Other Issues

Liver failure is unusual in PKD. However, a report has been made. A careful review of other causes is required. Remarkably, PKD may protect against malaria. Studies from Sub-Saharan Africa and Asia are supportive in this regard.[2][34]

Enhancing Healthcare Team Outcomes

PKD frequently poses a diagnostic dilemma. Causes of neonatal hyperbilirubinemia are myriad. Detecting PKD requires careful evaluation. Recently, PKD-specific patient-reported outcome measures were designed. [Level 5][1] This tool requires trials for widespread acceptability. Nonetheless, PKD-specific measurements are necessary. Interprofessional care assures the best outcomes. Hematologist and obstetrician-led pregnancy care are vital. Psychologists can provide patients critical support. Depression screening and prevention should be prioritized. Expert care will identify patients requiring support. Research into oral PK activators is on-going. Gene therapy is possible but not recommended.[13] Surgical management of massive splenomegaly may be required.[9]