Pyruvate Kinase Deficiency

Pyruvate kinase (PK) deficiency is one of the most common enzyme defects of the erythrocyte. This disorder presents clinically as a haemolytic anaemia, but the symptoms are less severe than haematological indices indicate. This is presumably due to enhanced oxygen delivery as a result of the defect.¹ Clinical severity is very variable, ranging from mild to severe anaemia. Most affected patients do not require treatment.

• Occurs worldwide but most cases have been reported in northern Europe, Japan and the United States.
• The prevalence is estimated at 51 cases per million by gene frequency studies but the observed prevalence in one northern England region was found to be 3.3 cases per million.²

Risk factors

• Family history consistent with autosomal recessive inheritance.³ Many different causative mutations have been identified.⁴
• Although inheritance is clinically autosomal recessive, most affected individuals are compound heterozygous for 2 different mutant alleles.⁵
• Medical conditions such as acute leukaemia, pre-leukaemia, refractory sideroblastic anaemia and complications from chemotherapy can cause an acquired pyruvate kinase deficiency. This type is more common and milder than the hereditary type.

• The severity of haemolysis is very variable, ranging from very mild or fully compensated forms to life-threatening neonatal anaemia requiring exchange transfusions.⁵
• Most problems tend to be limited to early life, and times of physiological stress, e.g. infection.
• Age of onset of inherited pyruvate kinase deficiency correlates with severity. Persons with severe disease usually have onset in the neonatal period or infancy. In most affected persons, pyruvate kinase deficiency is detected during childhood, but in individuals who are mildly affected, pyruvate kinase deficiency may not be detected until late adulthood.
• The age of onset of acquired pyruvate kinase deficiency depends on the nature of the primary disease.

Clinical features

• Birth (severe cases): severe anaemia, severe jaundice, kernicterus.
• Anaemia (mild-to-severe): growth delay, failure to thrive. May become symptomatic during times of physiological stress, including acute illness, particularly viral, and pregnancy.
• Gallstones, usually after the first decade of life, but possibly in childhood.
• Frontal bossing.
• Abdomen: mild to moderate splenomegaly, upper right quadrant tenderness.
• Extremities: chronic leg ulcers.

Other causes of haemolytic anaemia.

• Full blood count: haemoglobin concentration varies from 6-12 g/dL, with a lower concentration early in life. Erythrocytes are normochromic and macrocytic. Reticulocyte count may be increased by 5-15%. Leucocyte and platelet counts may be slightly increased.
• Blood film: features of accelerated erythropoiesis, e.g. polychromatophilia, anisocytosis, poikilocytosis and nucleated red blood cells, may be present.
• Haemoglobin electrophoresis: normal haemoglobin with normal levels of F and A2 haemoglobins.
• Erythrocyte lifespan is moderately-to-severely reduced, depending on the severity of the anaemia. Radio-chromium labelling reveals an immediate period of destruction, followed by a shortened lifespan for the remainder of labelled cells.
• Erythrocyte osmotic fragility is normal.
• Haemoglobin metabolic indices: indirect hyperbilirubinaemia reflects the severity of the haemolytic process. Bilirubin levels of 100 μmol/L are not uncommon and may be much higher. Haptoglobin is reduced in proportion to disease severity.
• Enzyme deficiency testing: the precise diagnosis depends on detecting the deficient enzyme. The enzyme activity rate of most patients who are deficient is 5-25% of normal. False-negative results can occur. Measurement of the intermediate products in the pathway (2,3-DPG and glucose-6-phosphate) help confirm the diagnosis.

• Most individuals who are affected do not require treatment. Individuals who are most severely affected may die in utero of anaemia or require blood transfusions or splenectomy.
• Care is predominantly supportive in nature in mild-to-moderate cases.
• Red blood cell transfusion may be necessary if the haemoglobin value falls significantly. This tends to occur in early childhood and during periods of physiological stress, such as infection and pregnancy.
• Bone marrow transplant has been successful.⁶
• Splenectomy is indicated only for severe anaemia. Splenectomy can reduce anaemia (but does not improve mild anaemia), but haemolysis will continue.

• Cholecystolithiasis is common in the first decade of life for children with severe anaemia. Biliary tract obstruction may occur.
• Splenectomy puts a child at risk from sepsis caused by encapsulated bacteria.
• Chronic transfusions can cause iron overload.

• A wide range of morbidity exists, with some individuals manifesting a mild compensated chronic haemolytic anaemia that does not require medical intervention and other individuals presenting with a severe haemolytic anaemia that usually only requires transfusions during childhood.
• Morbidity and mortality correlate with disease severity and are usually the result of complications.
• Uncomplicated pregnancy, delivery, and birth has been reported despite a decline in haemoglobin to 6.8 g/dL during pregnancy.¹
• Hydrops fetalis can occur.

• DNA testing: because of the large number of gene mutations that result in pyruvate kinase deficiency, DNA analysis is limited. When the mutation is known, the DNA analysis can be limited to specific mutations and is then of greater value in prenatal diagnosis.
• Prenatal enzyme testing is not useful because a large amount of fetal blood is required and the test has a high rate of false-negative results.¹