AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

In 1952, Dacie described patients with congenital hemolytic anemia who presented with symptoms and clinical findings similar to those encountered in patients with hereditary spherocytosis (HS).¹ However, in the newly described anemia, the osmotic fragility was normal, and spherocytes were not encountered. In order to differentiate the 2 conditions, the term congenital nonspherocytic hemolytic anemia (CNSHA) type II was introduced. This term was used to describe a heterogenous group of congenital hemolytic anemias of the nonspherocytic type. When the addition of ATP to the incubated RBCs corrects the defect and stops the ongoing hemolysis, the condition is then characterized as CNSHA type II. The addition of glucose to the same specimen of incubated RBCs usually fails to correct the defect.

Pathophysiology

The mature RBC completely depends on glucose as a source of energy. Glucose is usually catabolized to pyruvate and lactate in the major anaerobic glycolytic pathway (see Image 1). In the process, ATP is generated (see Image 2) and plays a major role in maintaining a cation gradient in the RBC, thus protecting the RBC from premature death.

In patients with pyruvate kinase (PK) deficiency, a metabolic block is created in the pathway at the level of the deficient enzyme. Intermediate byproducts and various glycolytic metabolites proximal to the metabolic block accumulate in the RBCs, while such cells become depleted of the distal products in the pathway, such as lactate and ATP. The high level of 2,3-diphosphoglycerate (2,3-DPG; see Image 1) increases the patient's exercise tolerance despite severe anemia. The tolerance increases as a result of the right shift in the hemoglobin-oxygen dissociation curve. However, the lack of ATP disturbs the cation gradient across the red cell membrane, causing the loss of potassium and water, which causes cell dehydration, contraction, and crenation (see Image 3) and leads to premature destruction of the RBC.

However, PK-deficient reticulocytes can circumvent their defect by using the oxidative phosphorylation pathway to produce ATP. This ability is diminished when the reticulocytes are exposed to hypoxia or when they mature to adult red cells; this may explain (1) the ineffective erythropoiesis in the spleen of patients with PK deficiency, (2) why most of the hemolysis occurs when the reticulocytes are trapped in the hypoxic environment of the spleen, and (3) the paradoxic increase in reticulocytes after splenectomy.

Four tissue-specific subunits of PK are known; each subunit helps form an active enzyme for a specific tissue or organ. Both the R subunit (found in the red cell) and the L subunit (found in the liver) are produced from one gene: the PKLR gene, which is located on chromosome 1. For this reason, patients with PK-deficient red cells frequently manifest an associated deficiency in the liver. This fact may explain the high total bilirubin level and the occasional significant rise in the direct fraction in some newborns with PK deficiency. Approximately 180 different mutations of this gene are known to cause PK-deficient hemolytic anemia. The clinical manifestations in PKD patients and the molecular properties of the various mutations have poor correlation. Clinical severity depends on complex interaction of several factors other than the molecular property of the mutations.   

However, the survival of patients with severe PK deficiency depends on a compensatory expression of an isoenzyme (M2PK) widely distributed in various tissues, including the RBCs. In a recent study, the life-threatening course of the anemia was reportedly related to the additional absence of the compensatory enzyme M2PK in the RBCs of a patient with homozygous null mutation of PKLR gene.²

Frequency

United States

A recent population survey revealed the rate of heterozygotes (ie, carriers) for PK deficiency to be 0.14% in Ann Arbor, Mich.

International

Although only several hundred cases of PK deficiency have been reported in the literature, the prevalence is probably much higher. The frequent reports of the predominance of PK deficiency among individuals of northern European ancestry can be questioned based on the increasing number of new cases reported in recent years in different countries and among various ethnic groups. Access to advanced medical facilities, which only recently became available to other ethnic groups, is assumed to be responsible for many of the recent reports, indicating that prevalence in other ethnic groups probably matches the prevalence previously reported among persons of northern European ancestry. In India, in a recent study to screen newborns with jaundice for the presence of PKD, 3.21% of all newborns with jaundice were found to be PK deficient, with a 30-40% reduction in the enzyme activity.³ A population survey  conducted few years ago demonstrated a heterozygote rate of 6% in Saudi Arabia,1.4% in Germany, and only 0.14% in Ann Arbor, Mich.

As with any autosomal recessive condition, the incidence can be higher in ethnic groups and communities with history of consanguinity (eg, a high rate of PK deficiency has been reported among the Pennsylvania Amish).

Mortality/Morbidity

• Morbidity in the newborn with PK deficiency is usually the result of severe anemia, hyperbilirubinemia, or both combined with the adverse effects associated with the management of such conditions. However, the severity of PK deficiency widely varies; it may be the cause of death in utero (or shortly after birth from nonimmune hydrops fetalis) or may be mild and asymptomatic.
• Simple blood or exchange transfusions are of some concern despite the current safety measures used in blood preparation. Simple blood transfusion is an issue for the older patient who is transfusion dependent.
• Patients with splenectomies are at risk because of the procedure; such patients are susceptible to later infections.
• Another cause of morbidity is the development of gallstones. In a recent report, 2 patients with PK deficiency and severe chronic hemolytic anemia have developed iron overload, resulting in liver cirrhosis; both were negative for mutations in the HFE gene.⁴

Race

PK deficiency occurs in all races, although it is thought to be more common in persons of northern European and Chinese ancestry.

Sex

PK deficiency is inherited as an autosomal recessive trait; therefore, both sexes are usually equally affected.

Age

In severe forms, PK deficiency is usually symptomatic in newborns and may be life threatening. Milder cases of PK deficiency are usually missed earlier in life and may not produce any symptoms later in life.

CLINICAL

Section 3 of 11  

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History

• Anemia, jaundice, and splenomegaly are the major findings in the newborn with pyruvate kinase (PK) deficiency.
• Heterozygotes have intermediate enzyme levels and are usually asymptomatic, while homozygotes manifest the clinical symptoms of PK deficiency.
• The severity of the condition widely varies, even among patients with the same level of deficiency. Such variability occurs because, in addition to the symptomatic homozygotes, compound heterozygotes with 2 different mutations (one can be qualitative and the other quantitative) also vary symptomatically.
• In older children, adolescents, and adults with PK deficiency, anemia may range from transfusion dependent to asymptomatic.

Physical

See Pathophysiology and History.

Causes

PK deficiency is an inherited condition that is transmitted as an autosomal recessive gene. Affected individuals are either homozygous for a single mutation or doubly heterozygous for 2 different PK mutations.

DIFFERENTIALS

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Other Problems to be Considered

In the newborn with jaundice and anemia, immune hemolysis (eg, ABO or Rh incompatibility) is easily identified. A diagnosis of pyruvate kinase (PK) deficiency is favored based on a negative Coombs test result, blood group setups, and a peripheral blood film examination that demonstrates no spherocytes but reveals contracted shrunken red cells of the PK deficiency (see Image 3). A normal osmotic fragility may help to differentiate PK deficiency from HS.

Other congenital hemolytic anemias of the nonspherocytic type, hemoglobinopathies, and thalassemia must also be differentiated. Specific tests and family history may help in the differentiation. In older children, autoimmune hemolytic anemia may also manifest with similar symptoms and, therefore, must be considered in the differential diagnosis. A positive Coombs test result, the presence of spherocytes, and the absence of the typical PK-deficient cells on the peripheral blood film examination are the main features that differentiate the 2 conditions.

WORKUP

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Lab Studies

• CBC count, differential blood counts, reticulocyte counts, a serum bilirubin level study, and peripheral blood film examination are the minimal tests required to guide the investigation.
• Normochromic, normocytic, or macrocytic anemia, together with reticulocytosis in the absence of blood loss, is suggestive of hemolysis.
• • A negative Coombs test result helps to exclude immune hemolysis.
  • An elevated direct bilirubin level in the presence of indirect hyperbilirubinemia is not unusual in individuals with pyruvate kinase (PK) deficiency and does not necessarily indicate cholestasis, primary liver disease, or biliary obstruction. This finding was attributed to the deficient liver PK (LPK), an isoenzyme that is usually deficient whenever the red cell PK is deficient because of the common origin of both enzymes (the PKLR gene).
  • A recent report described hypertriglyceridemia in a female aged 6 months with PKD resolving with hypertransfusion regimen. After a splenectomy at age 18 months, she remained transfusion independent with normal serum triglyceride levels.⁵ 
• Enzyme assay and, more recently, DNA analysis involving polymerase chain reaction or single-strand conformation polymorphism are available to confirm the diagnosis and to identify the carrier state, if necessary. However, the enzyme assay might not always be accurate. This inaccuracy is due to the typical selective removal of very deficient red cells from the circulation, leaving only normal cells. Furthermore, the PK activity is usually normal in white cells, platelets, and other tissues in the patient with PK deficiency hemolytic anemia; this may interfere with the enzyme assay.

Imaging Studies

• Ultrasonography is occasionally required to document gallbladder stones, which are known to complicate all forms of hemolytic anemias.

Histologic Findings

As a result of the chronic hemolysis, a bone marrow examination reveals erythroid hyperplasia and active marrow. Iron stores may also be increased.

TREATMENT

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Medical Care

• Extremely severe fetal anemia associated with hydrops fetalis usually requires intrauterine transfusion. Phototherapy or exchange transfusion is usually required for severe hyperbilirubinemia in the newborn. Simple blood transfusion is administered for anemia during early childhood and, occasionally, into adulthood.
• In older patients, sporadic blood transfusions are usually required when the anemia becomes severe during infectious episodes, aplastic crisis, or pregnancy.
• Therapeutic intervention with agents that can stimulate the enzyme or circumvent the defect remains experimental.
• Bone marrow transplant may cure the defect; however, the risks of bone marrow transplant outweigh the risk of the disease.

Surgical Care

For surgical care, consider splenectomy and partial splenectomy. However, reports of both failure and success exist with partial splenectomy in patients with pyruvate kinase (PK) deficiency or idiopathic thrombocytopenic purpura (ITP).

• Presurgery antibiotics: Usually prepare patients who require splenectomy by starting prophylactic antibiotics before surgery.
• Presurgery vaccines
• • Polyvalent polysaccharide pneumococcal vaccine is usually administered 1-2 weeks before splenectomy (assuming such children are >2 y).
  • In the rare child younger than 2 years, use the conjugated pneumococcal vaccine.
  • Also administer Haemophilus influenzae type b vaccine; the conjugate form is usually administered in a series of 3 doses when the individual is aged 2, 4, and 6 months.
  • Children who have already received their initial and 12-month booster doses are usually immune and do not require further vaccine before splenectomy. Quadrivalent meningococcal vaccine, used only in children older than 2 years, is also recommended. This vaccine is serogroup specific against groups A, C, Y, and W-135; it is a polysaccharide vaccine (MPSV4) with limited efficacy. The response to this vaccine is not long lasting, and it lacks the anamnestic response on subsequent challenge. For this reason, a new vaccine was licensed in 2005, which is a conjugate tetravalent vaccine (MCV4 [Menactra]). This vaccine has shown a much more durable immunity and a good anamnestic response. Unlike the polysaccharide vaccine, which should not be given to children younger than 2 years, this vaccine is effective in children in this age group. Menactra vaccine will not stimulate protection against infection caused by Neisseria meningitidis other than serogroups A, C, Y, and W-135.
• Splenectomy
• • This surgical procedure is frequently performed to eliminate or to minimize the need for blood transfusion.
  • Always consider splenectomy in the patient who is transfusion dependent.
  • Splenectomy is not curative but may eliminate or decrease the need for blood transfusions.
  • • In an attempt to preserve the splenic function in a young child, 80% of the spleen was removed, with no benefit.
    • A total splenectomy was performed later and proved to be effective.
• Partial splenectomy
• • Partial splenectomy has been used in an attempt to keep splenic tissue to preserve some splenic function.
  • Partial splenectomy is expected to protect the child from the following consequences of asplenia:
  • • Fulminating sepsis with the encapsulated organisms (Streptococcus pneumoniae [in >60%], H influenzae, N meningitidis)
    • Streptococcal and staphylococcal infections, which affect such patients with less frequency
    • Malaria and babesiosis in endemic regions
  • Partial splenectomy has been attempted in various patients with different diagnoses.
  • The procedure is very effective in persons with traumatic splenectomy and in individuals with some of the hemolytic anemias.

Consultations

• A hematologist should perform the initial diagnostic workup.
• Advise genetic counseling.
• Consult with a surgeon if splenectomy is considered.

Activity

Patients with hemoglobin levels close to or slightly below the reference range tolerate normal daily activities. Those with severe anemia demonstrate exercise intolerance, and their activity is limited as a result. However, exercise tolerance in children with PK deficiency is somewhat higher than expected given their hemoglobin level. This higher tolerance is thought to be related to the fact that the block in the glycolytic pathway is distal to the production of 2,3-DPG, which accumulates in the RBC, resulting in shift of the hemoglobin-oxygen dissociation curve to the right and enabling a faster oxygen release to the tissues.

MEDICATION

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As in all persons with hemolytic anemias and because of the severe demand for folic acid, the potential for developing megaloblastic anemia can be prevented by administering 1 mg/d of folic acid. Packed RBC transfusion is reserved for persons who develop significant anemia.

Drug Category: Vitamins

Folic acid is used extensively in individuals with hemolytic anemias. Megaloblastic anemia may develop if folic acid is not supplied.

Drug Category: Antibiotics

Patients who undergo splenectomy are prone to fulminating infections with encapsulated organisms, and most are sensitive to penicillins. Some clinicians recommend administration of prophylactic penicillin for 2-3 years following the procedure. Other clinicians recommend administration of prophylactic penicillin for life.

Administer erythromycin instead if the child is sensitive to penicillin.

Drug Category: Vaccines

Pneumococcal polyvalent vaccination (PPV-23) contains 23 serotypes that cause approximately 70% of invasive diseases caused by these organisms. Administer this vaccination 1-2 wk prior to surgery to prevent or minimize future complications. Pneumococcal 7-valent conjugate vaccine (PCV-7) contains 7 serotypes of pneumococcal bacteria largely responsible for invasive disease in young children.

FOLLOW-UP

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Further Inpatient Care

• Periodic follow-up care is required to monitor the patient's hemoglobin level, reticulocyte counts, and possible development of gallbladder stones.
• Always monitor patients with splenectomies for possible fulminating infections. Ensure that such patients continue to receive prophylactic penicillin.

Deterrence/Prevention

• In families known to be affected by pyruvate kinase (PK) deficiency, genetic counseling is the only practical means to prevent the condition. Genetic counseling offers an understanding of the potential risks involved with having children with another carrier. Prenatal diagnosis is feasible; however, the unpredictability of the condition's severity cannot justify advising the termination of pregnancies if the fetus is affected.

Complications

• Severe anemia may result in heart failure.
• The development of gallbladder stones is a known complication of all hemolytic anemias.
• Fulminating infection in patients with splenectomies and transmission of infections due to blood transfusions may occur.
• Sudden worsening of anemia associated with viral infections (eg, Parvovirus B19) can occur, leading to a transient decrease in red cell production (ie, aplastic crisis).

Prognosis

• Most patients maintain an adequate hematocrit level, especially after splenectomy; such patients live a relatively normal life.

Patient Education

• Prevention of complications depends on educating the patient and the parents about the nature of the condition, its genetic nature, expected complications, and all precautions to avoid some of the preventable complications.

MISCELLANEOUS

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Medical/Legal Pitfalls

• The potential medicolegal pitfalls are those related to failure to diagnose pyruvate kinase (PK) deficiency in a neonate with jaundice. The condition may respond to phototherapy and, later, follow a mild clinical course. In such cases, the jaundice may be mistakenly attributed to other more common causes and the parents would not receive genetic counseling, increasing the chance that they will have other children with the same condition.
• Conversely, if the condition is moderately severe and requires repeated blood transfusion, failure to recognize the value of splenectomy in reducing or even eliminating the need for transfusion may represent a liability.

MULTIMEDIA

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Media file 1:  The Embden-Meyerhof pathway.
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Media type:  Graph

Media file 2:  Pyruvate kinase in the Embden-Meyerhof pathway.
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Media type:  Graph

Media file 3:  Peripheral blood smear in a child with splenectomy and pyruvate kinase deficiency.
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Media type:  Photo

REFERENCES

Section 11 of 11

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1. Dacie JV, Mollison PL, Richardson N, et al. Atypical congenital haemolytic anaemia. Q J Med. Jan 1953;22(85):79-98. [Medline].
2. Diez A, Gilsanz F, Martinez J, et al. Life-threatening nonspherocytic hemolytic anemia in a patient with a null mutation in the PKLR gene and no compensatory PKM gene expression. Blood. Sep 1 2005;106(5):1851-6. [Medline].
3. Kedar PS, Warang P, Colah RB, Mohanty D. Red cell pyruvate kinase deficiency in neonatal jaundice cases in India. Indian J Pediatr. Nov 2006;73(11):985-8. [Medline].
4. Hilgard P, Gerkin G. Liver cirrhosis as a consequence of iron overload caused by hereditary non-spherocytic hemolytic anemia. World J Gastroenterol. Feb 2005;11(8):1241-4. [Medline].
5. Rao A, Hulbert M, Wilson DB. Severe hypertriglyceridemia in an infant with red cell pyruvate kinase deficiency. Indian Pediatr. Apr 2007;44(4):303-5. [Medline].
6. Aizawa S, Kohdera U, Hiramoto M, et al. Ineffective erythropoiesis in the spleen of a patient with pyruvate kinase deficiency. Am J Hematol. Sep 2003;74(1):68-72. [Medline].
7. Nathan DG, Oski FA. Hematology of Infancy and Childhood. 5^th ed. Philadelphia, Pa: WB Saunders Co; 1998.
8. Nathan DG, Oski FA, Sidel VW, Diamond LK. Extreme hemolysis and red-cell distortion in erythrocyte pyruvate kinase deficiency. II. Measurements of erythrocyte glucose consumption, potassium flux and adenosine triphosphate stability. N Engl J Med. Jan 21 1965;272:118-23. [Medline].
9. Rennels M, King J, Ryall R, et al. Dosage escalation, safety and immunogenicity study of four dosages of a tetravalent meninogococcal polysaccharide diphtheria toxoid conjugate vaccine in infants. Pediatr Infect Dis J. May 2004;23(5):429-35. [Medline].
10. Robinson MA, Loder PB, de Gruchy GC. Red-cell metabolism in non-spherocytic congenital haemolytic anaemia. Br J Haematol. Jul 1961;7:327-39. [Medline].
11. Sandoval C, Stringel G, Weisberger J. Failure of partial splenectomy to ameliorate the anemia of pyruvate kinase deficiency. J Pediatr Surg. Apr 1997;32(4):641-2. [Medline].
12. Tanaka KR, Valentine W, Miwa S. Pyruvate kinase (PK) deficiency hereditary nonspherocytic hemolytic anemia. Blood. Mar 1962;19:267-95. [Medline].
13. Valentine WE, Tanaka KR, Miwa S. A specific erythrocyte glycolytic enzyme defect (pyruvate kinase) in three subjects with congenital non-spherocytic hemolytic anemia. Trans Assoc Am Physicians. 1961;74:100-10. [Medline].
14. Zanella A, Fermo E, Bianchi P, Valentini G. Red cell pyruvate kinase deficiency: molecular and clinical aspects. Br J Haematol. Jul 2005;130(1):11-25. [Medline]. [Full Text].
15. Zanella A, Fermo E, Bianchi P,etal. Pyruvate Kinase deficiency : The genotype-phenotype association. Blood Rev. Jul; 2007;(4):217-31. [Medline].
16. Zarza R, Pujades A, Garcia J, et al. [Molecular study of red cell pyruvate kinase deficiency in 15 patients with chronic hemolytic anemia. Group of Erythropathology of Hematology and hemotherapy Association of Spain (HHAS)]. Med Clin (Barc). May 8 1999;112(16):606-9. [Medline].
17. Zuelzer WW, Robinson AR, Hsu TH. Erythrocyte pyruvate kinase deficiency in non-spherocytic hemolytic anemia: a system of multiple genetic markers?. Blood. Jul 1968;32(1):33-48. [Medline].

Article Last Updated: Jul 31, 2007