Overview

Pyruvate kinase deficiency (PKD) is a rare genetic disorder caused by mutations in the PKLR gene, leading to chronic haemolytic anaemia.¹ This condition manifests with a broad spectrum of symptoms, ranging in severity, which can require lifelong medical intervention to manage the associated complications.¹ To understand the impact of PKD on life expectancy and quality of life, it is important first to explore its underlying disease mechanism and the diverse clinical traits it presents.

Understanding PKD

Disease mechanism

The cells that make up the human body depend on biochemical reactions within the cytoplasm (glycolysis) and mitochondria (citric acid cycle/TCA cycle and oxidative phosphorylation) to generate energy through a process known as cellular respiration. This essential metabolic pathway provides energy to sustain critical cellular functions, such as DNA replication and cell division. 

Schematic representation of where and how energy is produced during cellular respiration within a typical cell. (Created by Gobika Kugan with BioRender)

However, red blood cells (RBCs) lack both a nucleus and mitochondria, raising the question: How do they generate energy? Unlike other cells, RBCs depend entirely on the cytoplasmic reaction of cellular respiration, known as glycolysis, which can generate energy in small amounts.¹ In glycolysis, the sugar molecule glucose undergoes a series of metabolic reactions, so that it is eventually broken down into pyruvate.¹ Pyruvate kinase (PK) is an enzyme that plays a crucial role in the final step of glycolysis, as it catalyses the conversion of phosphoenolpyruvate (PEP) to pyruvate, resulting in energy production.¹

However, the PK enzyme becomes defective in individuals with the PKLR genetic mutation, which results in its impaired function.¹ The decreased activity of this enzyme will then disrupt the energy production in RBCs, resulting in their premature destruction.¹ 

Signs and symptoms 

PKD can, therefore, reduce the overall RBC count, leading to chronic haemolytic anaemia, which may result in the following symptoms:

Fatigue

RBCs play a crucial role in delivering oxygen to tissues and organs throughout the body. A decrease in RBC count will diminish the oxygen availability, thereby impairing cellular function. This is because oxygen is required to carry out cellular respiration, which supplies cells with energy to carry out vital functions, including muscle contraction.² As a result, individuals may experience reduced physical performance or a feeling of restlessness.²

Enlarged spleen

The spleen, located behind the stomach in the upper left region of the abdomen, plays a crucial role in breaking down RBCs.³ In conditions involving excessive RBC destruction, such as chronic haemolytic anaemia, the spleen becomes overactive, leading to its enlargement.³ This can lead to further complications, as it becomes more vulnerable to rupture, even from minor trauma.⁴

Jaundice

When RBCs break down, they release a pigment known as bilirubin, which is normally processed and eliminated by the liver.⁵ However, excessive RBC destruction leads to an overproduction of bilirubin that accumulates in the skin and eyes.⁵ This results in a condition known as jaundice, where the skin and eyes become more yellow in appearance.⁵ 

Gallstones

These are crystallised deposits that can form in the gallbladder.⁶ The gallbladder is a small organ located under the liver, typically storing bile that is produced by the liver and releasing it into the small intestine to help break down fats.⁷ In chronic haemolytic anaemia, a black stone can form due to the deposition of bilirubin produced from the breakdown of RBCs. This can result in discomfort, particularly after eating greasy and spicy food.⁶ 

Iron overload

The abnormal breakdown of RBCs can result in iron accumulation in various tissues, including the liver, pancreas, heart, skin and joints.⁸ This excess iron can be toxic, as it contributes to the formation of reactive molecules known as free radicals.⁸ As these are highly reactive, they can damage cell membranes and DNA, ultimately causing cell death and leading to organ dysfunction.⁸ 

Broken bones

Iron overload has also been linked to bone weakening, as it increases the risk of broken bones.⁹

Life expectancy in PKD

PKD is considered a rare disorder, as estimates indicate that between 3.2 to 8.5 million individuals in Western populations have been clinically diagnosed with the condition.¹⁰ 

Furthermore, a recent UK study compared the complications and overall survival of 89 patients with PKD to 445 matched control subjects.¹¹ The findings from the study are as follows:¹¹

• Risk of mortality: Increased fivefold 
• Median age at death: 53.9 years
• Commonly affected organs among PKD patients:
  • Biliary system (liver and gallbladder) 
  • Spleen 
  • Heart 

Quality of life considerations

Recognising the impact of PKD on children is crucial not only for enhancing their quality of life but also for supporting healthy growth and ensuring optimal social and psychological development. 

In infants and young children, PKD can lead to poor feeding, low energy, and irritability, which may contribute to inadequate growth and development.¹

Older children may experience symptoms more similar to adults, such as difficulty concentrating, persistent fatigue, or shortness of breath during physical activities.¹ As a result, this can affect their daily functioning, making them less inclined to participate in social activities, which can negatively impact their social development.¹

Concerns about long-term complications, such as organ damage from iron overload and frequent medical interventions, including blood transfusions, iron chelation therapy, or even splenectomy, can add to the physical and psychological burden.¹ 

Additionally, jaundice may cause some individuals to become more self-conscious about their appearance, potentially affecting their emotional well-being.¹ 

Advances in treatment and their impact on prognosis

Current treatment

The current therapies for PKD primarily focus on managing symptoms and improving RBC function, as there is no definitive cure for the condition. The main therapeutic approaches include:

Blood transfusions

This medical procedure involves transferring donated blood to an individual suffering from severe anaemia.¹² While transfusions can help alleviate fatigue and other symptoms, long-term transfusions can lead to iron overload, which may require additional treatments such as iron chelation therapy.¹³ 

Iron Chelation Therapy

To prevent or treat iron overload resulting from frequent blood transfusions, iron chelation therapy is administered.¹⁴ Chelators are chemical compounds that bind to metal ions; therefore, iron chelators such as deferasirox or deferoxamine are used to bind to excess iron within cells and promote its removal from the body, thereby preventing organ damage.¹⁴ 

Splenectomy

Surgical removal is recommended for an extremely enlarged spleen to eliminate the risk of rupture.¹⁵ Once this procedure is performed, patients may require vaccinations and/or prophylactic antibiotics, as the splenectomy is known to increase the risk of infections.¹⁵ Although this treatment may be necessary for some individuals, it is important to recognise that it carries an increased risk of thrombosis, which can lead to serious complications if not properly managed.¹⁶ 

These therapies, individually or in combination, aim to manage the disease by improving the quality of life and reducing complications. However, ongoing research and clinical trials continue to explore additional treatment options and refine existing therapies to better address the needs of PKD patients.

Emerging therapies 

Mitapivat is the first FDA-approved treatment specifically developed for PKD. The Phase III clinical trials have demonstrated its potential as a PK activator by increasing haemoglobin levels and reducing transfusion dependence in some adults.¹⁷ This activator functions by enhancing the activity of the defective PK enzyme, which helps restore the RBC metabolism and reduce haemolysis.¹⁷ However, it is important to note that the use of mitapivat in the UK remains uncertain, as NICE, the national health guidance body, has not recommended its use due to insufficient submitted evidence.

Gene therapy is an emerging treatment strategy that aims to correct the underlying genetic defect in PKD.¹ Although it is still in the experimental stages, it holds promise for providing a long-term solution by introducing a functional version of the PKLR gene into patients' cells.¹

Coping strategies and support for patients and families

PKD requires several approaches to address both the physical and emotional challenges associated with the condition. The following are examples of approaches that can help: 

1. Regular medical monitoring can help manage symptoms and prevent complications
2. Talking therapies or peer networks can be valuable in addressing emotional distress and improving mental well-being
3. Educating family members, teachers, and caregivers about PKD can help them identify associated behavioural changes and ensure that patients receive the necessary support in their daily lives
4. Staying informed about advancements in treatment options and participating in clinical trials, when appropriate, may provide access to emerging therapies that can improve quality of life

Summary

PKD is a rare genetic disorder that causes chronic haemolytic anaemia due to impaired RBC metabolism. While it is not typically fatal, its severity varies, and complications such as enlarged spleen, iron overload, and gallstones can influence life expectancy. Quality of life is a significant concern, as symptoms like fatigue and jaundice can affect daily activities and lead to emotional and social challenges. Although current treatments primarily focus on symptom management, ongoing research continues to explore new therapeutic options, offering hope for improved outcomes.