11/14/24, 10\:48 AM Pyruvate Kinase Deficiency

Pyruvate Kinase De

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A comprehensive topic overview

Introduction

Pyruvate kinase de
The glycolytic pathway is present in all cells but is particularly vital in red blood cells where it is the main route to ATP
production in the absence of mitochondria. When this pathway is interrupted, red blood cells distort and are removed from
the circulation, leading to haemolytic anaemia.
Prevalence of pyruvate kinase de
the clinically observed frequency is far lower than this.
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Pyruvate kinase de
this may be due to underdiagnosis and misdiagnosis of this rare disease.
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Aetiology

Most cases of pyruvate kinase de
Autosomal dominant inheritance has occasionally been seen and compound heterozygotes (patients heterozygous for two
di
Pyruvate kinase de
or refractory sideroblastic anaemia, or as an adverse e

Pathophysiology

Pyruvate kinase de
PKLR is expressed in red blood cells (RBC) and catalyses the
phosphoenolpyruvate into pyruvate and phosphorylating ADP to make ATP (Figure 1).
Figure 1. Final reaction of the glycolysis pathway, producing pyruvate and ATP,
catalysed by pyruvate kinase.
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This mutation causes loss of enzymatic function, so red blood cells can no longer produce ATP from glycolysis. Without
ATP, the membrane transporter sodium-potassium adenosine triphosphatase slows down, reducing ion in
The cell becomes hypotonic, so water leaves the cell down the osmotic gradient, causing the cell structure to shrink and
distort. Damaged red blood cells are removed from the circulation by the reticuloendothelial system, which removes cells
quicker than they can be produced, resulting in haemolytic anaemia.
Premature red blood cells, called reticulocytes, are released from the strained bone marrow tissue in response to
increased RBC destruction.
Reticulocytes can survive in circulation as they have mitochondria, so can produce ATP by oxidative phosphorylation. They
have a reduced oxygen-carrying capacity when compared to mature RBCs but can compensate for mild anaemia.
As well as a de
Accumulation of 2,3-BPG, causes a shift in the Hb-O­ dissociation curve to the right, increasing oxygen release at the
2
tissues. This allows patients to further compensate for anaemia.
Figure 2. An increase in 2,3-BPG causes a rightwards shift inthe Hb-O 2
dissociation
curve.
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Clinical features

History

Symptoms from pyruvate kinase de
The most common presentation is symptomatic haemolytic anaemia which is often limited to childhood but can also
occur during periods of stress, such as during pregnancy, surgery or infection.
The presentation of anaemia can range from very mild (compensated) anaemia to life-threatening haemolysis.
Typical symptoms of anaemia may include\:
Pallor
Fatigue
Dizziness
Chest pain
Dyspnoea
Growth delay and failure to thrive (children)
Rarely, a
neonates, haemolysis can lead to high levels of bilirubin which can cause neurotoxicity leading to kernicterus.

Clinical examination

Clinical examination may reveal signs of haemolytic anaemia including\:
Jaundice\: sclera often turns yellow
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Splenomegaly and hepatomegaly\: as the spleen and liver contain much of the reticuloendothelial system
Tachycardia\: early response to poor oxygen delivery to the body
Dark urine or stool
Chronic leg ulcers\: poor perfusion to these areas causes delayed healing
Figure 3. Icteric sclera, an early sign of jaundice.
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Di

It is important to distinguish this condition from other causes of haemolytic anaemia including\:
Sickle cell anaemia
Thalassaemia
G6PD de
Hereditary spherocytosis and elliptocytosis
Autoimmune disorders
Infection\: including Epstein-Barr virus, hepatitis or typhoid
Medicines\: including some antibiotics, quinidine, ibuprofen or mismatched blood transfusions

Investigations

Laboratory investigations

Relevant laboratory investigations include\:
Full blood count\: normal Hb, low RBC, high MCV (known as normochromic macrocytic anaemia); can have a slight
increase in WCC and platelets also
Reticulocyte count\: raised due to increased RBC production
Blood
also be seen particularly if patients have had a splenectomy.
Unconjugated bilirubin and iron\: elevated due to increased haemoglobin breakdown
It is also possible to test for proteins involved in the pathology, such as\:
Pyruvate kinase level
2,3-BPG level
Glucose-6-phosphate level\: to rule out G6PD de
Molecular genetic testing for PKLR gene mutation is possible at specialist centres.

Management

Most cases of pyruvate kinase de
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However, severe disease can require hospitalisation to treat life-threatening anaemia.
Management options include\:
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RBC transfusion\: may need to be frequent and regular to survive
Splenectomy\: slows breakdown of premature reticulocytes
Allogenic haematopoietic stem cell transplant\: can cure pyruvate kinase de
and a high mortality rate
Clinical trials are continuing to
gene therapy.
The severity of the disease is judged based on symptoms rather than serum haemoglobin level, as the degree of anaemia
compensation varies between patients.

Complications

Gallstones

High bilirubin levels can lead to gallstone production. The liver normally conjugates bilirubin with glucuronic acid,
increasing the water-solubility of this compound, aiding its excretion from the body.
As bilirubin levels increase vastly, unconjugated bilirubin builds up, which binds with calcium ions to form insoluble
precipitates. These precipitates can then crystallise together and form gallstones.
Gallstones may have no consequence but can lead to biliary colic, cholecystitis, cholangitis and acute pancreatitis.

Iron overload

Pyruvate kinase de
Iron overload is asymptomatic in most patients, although serum ferritin levels should be monitored as chronic iron
overload can result in organ damage\:
Liver\: hepatomegaly, abdominal pain and eventual
Heart\: arrhythmias and cardiac failure
Endocrine organs\: hypogonadism, decreased libido, hyperglycaemia and hyperpigmentation
Treatment of iron overload is typically venesection, although this is poorly tolerated in anaemic patients who may require
the use of iron chelation therapies.

Other complications

Other less common complications of pyruvate kinase de
aplastic crisis (secondary to parvovirus B19 infection) and extramedullary haematopoiesis.
2
Transfusion of blood products, while a necessary treatment for many pyruvate kinase patients, can lead to complications,
including transfusion reactions.

Key points

Pyruvate kinase de
Most cases of pyruvate kinase de
Mutations in the PKLR gene causes disturbance of red cell function, leading to a distorted red cell structure.
Abnormal red blood cells are removed from the circulation, causing the clinical features of haemolytic anaemia.
Many cases do not require treatment, but transfusion, splenectomy and allogeneic stem cell transplants are
sometimes used in the management of these patients.
Pyruvate kinase de
transfusions.
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References

Beutler E., Gelbart T.. E s t i m a t i n g t h e p r e v a l e n c e o f p y r u v a t e k i n a s e d e
p o p u l a t i o n . Published in 2000. Available from\: [LINK]
National Organization for Rare Disorders. P y r u v a t e K i n a s e D e LINK]
Akane. G l y c o l y s i s P E P-P y r . Licence\: [CC-BY-SA].
Komorniczak M., Herráez A. Adapted by Geeky Medics. I n
E CC-BY-SA]
Centers for Disease Control and Prevention (CDC). Y e l l o w i n g o f t h e s k i n a n d e y e s . Licence\: [Public domain]
van Straaten S., Bierings M., Bianchi P., Akiyoshi K., Kanno H., Serra I.B., Chen J., Huang X., van Beers E., Ekwattanakit S.,
Güngör T., Kors W.A., Smiers F., Raymakers R., Yanez L., Sevilla J., van Solinge W., Segovia J.C., van Wijk R.. W o r l d w i d e s t u d y
o f h e m a t o p o i e t i c a l l o g e n e i c s t e m c e l l t r a n s p l a n t a t i o n i n p y r u v a t e k i n a s e d e
[LINK]

Reviewer

Dr Matthew Player
Haematology SpR

Related notes

Acute Myeloid Leukaemia
Anaemia Overview
Chronic Myeloid Leukaemia
Disseminated Intravascular Coagulation (DIC)
Haemolytic anaemia

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Contents

Introduction
Aetiology
Clinical features
Di
Investigations
Management
Complications
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