Introduction

Pyruvate kinase deficiency (PKD) is an inherited genetic condition affecting red blood cells (RBCs) which are important for carrying oxygen to tissues around the body. 

In PKD, there are defects in your ‘glycolytic pathway’ (glycolysis) resulting in the premature destruction of RBCs, leading to a condition known as haemolytic anaemia.² ‘Anaemia’ is the term used to describe low levels of RBC in the blood while ‘haemolytic’ refers to RBC breakdown. 

PKD stems from ‘mutations’ in the DNA of the PKLR gene. A gene is a section of DNA that encodes a specific protein. In this case, the PKLR gene encodes an enzyme called ‘pyruvate kinase’. Enzymes are proteins that help speed up reactions. In the process known as glycolysis, the pyruvate kinase enzyme is important for turning glucose (sugar) into ‘Adenosine triphosphate’ (ATP), which is used for energy in cells. Red blood cells rely on glycolysis for their energy impaired glycolysis leads to the premature breakdown of RBC, reducing their lifespan to only a few days to weeks compared to the normal RBC lifespan of 120 days.¹

This destruction of RBC results in anaemia seen in PKD. PKD is inherited in an ‘autosomal recessive’ manner, meaning that both copies of the PKLR gene inherited from both your parents need to be mutated and faulty for you to have PKD.² PKD is one of the most common causes of haemolytic anaemia resulting from a glycolysis pathway deficiency, with an estimated prevalence between 1:20,000 and 1:300,000.¹ You can learn more about PKD here.

In patients with PKD iron overload is seen in all ages. It can follow blood transfusions but can also be due to non-transfusion related iron loading which includes increased intestinal iron absorption related to chronic anaemia and ineffective RBC production (erythropoiesis).² The purpose of this article is to explain chelation therapy as a key strategy for managing iron overloading. 

Understanding iron overload in PKD

Iron overload is the abnormal and increased accumulation of iron in the body. Iron overload can cause serious damage to your body including your heart, liver and pancreas where the excess iron is stored. Too much iron in your body can be toxic, it can lead to: 

• Heart problems such as arrhythmias(abnormal heartbeat rhythms), and heart failure
• Liver problems including cirrhosis (scarring), enlarged liver and liver failure 
• Arthritis
• Diabetes 
• Thyroid, spleen, adrenal gland, gallbladder and pituitary gland problems 
• Reproductive system problems such as erectile dysfunction in men and early menopause in women 

Unmanaged and untreated iron overload can ultimately result in death so seeking treatment to avoid, slow or reverse organ damage is very important. 

Iron overload is common in PKD patients due to the requirement for regular blood transfusions but also due to anaemia leading to increased intestinal iron absorption. While the risk of iron overload is life-long for PKD patients and does not change with age, approximately 50% of children under 18 with PKD have iron overload partly as regular transfusions are more commonly required in children with PKD than in adults. Therefore, children more commonly have a greater risk of iron overload due to transfusion, but this is not always the case.²

Blood transfusions and iron overload in PKD 

Transfusions of RBCs can cause a buildup of iron over time. The body does not have a mechanism for removing iron so, with repeated transfusions iron begins to deposit in the liver, which can lead to an iron overload. Iron overload has occurred in PDK patients following 10-14 transfusions.. Intermittent transfusions are often required in individuals with PKD due to increased haemolysis following acute (short-term) stresses such as a viral infection or injury. The decision to administer RBC transfusions depends on multiple factors such as the impact of anaemia on quality of life.²

Transfusions in children with PKD are common, with 87% of patients under 18 years of age having received 1 or more transfusions in their lifetime. The frequency of patients who receive regular transfusions decreases with age, linked to less regular haemolytic episodes (loss of many RBCs) associated with infections as well as the timing of splenectomy (removal of the spleen to help reduce PDK-linked anaemia). 

However, symptoms of anaemia may then increase with age, resulting in adults who require regular transfusions and therefore have a risk of iron overload.²

Non-transfusion-related iron overload in PKD 

Iron overload occurs commonly in PKD even in the absence of transfusion due to chronic haemolysis or increased gastrointestinal iron absorption.

Chronic haemolysis 

PKD-induced haemolysis may cause severe iron overload. This secondary iron overload can result in chronic liver disease and cirrhosis.³ RBCs contain iron in the form of haemoglobin, the breakdown of RBCs and outflow of haemoglobin into the bloodstream can result in iron overload.⁴ 

Increased gastrointestinal iron absorption

Increased intestinal iron absorption related to chronic anaemia and ineffective erythropoiesis (RBC production) leads to non-transfusion-related iron overload.²

What is chelation therapy?

Iron chelation therapy is the administration of ‘chelation agents’; these are drugs that bind with iron to form substances that can be easily excreted from the body and therefore prevent the toxic build-up of iron. Three chelation drugs have been approved for the treatment of iron overload: Deferiprone, Deferoxamine, and Deferasirox. These chelators act to lower tissue iron levels and prevent iron overload complications. Iron chelation therapy is the only therapeutic option to prevent excessive iron accumulation in conditions where iron overload coexists with anemia.⁵

When is chelation therapy needed in PKD?

Chelation therapy should strongly be considered if the liver iron concentration is greater than 5 mg/g or if Ferritin (ferritin is a protein that binds to iron and stores it in your body) is greater than 800 μg/L and if transferrin saturation with iron (transferrin is a mix of carbohydrate and protein that binds iron) is greater than 60%, even in the absence of transfusions. Chelation is also prescribed following regular transfusion.²

Indicators for initiating chelation therapy:
Serum ferritin

Estimating serum ferritin (mg/L) is the most employed diagnostic tool for assessing body iron stores.⁵ Recordings of high serum ferritin could warrant initiation of chelation therapy. 

Liver iron concentration (via MRI)

A more accurate method to evaluate iron overload is measuring the liver iron concentration, which usefully closely correlates with total body iron, and is a good indicator for the diagnosis of iron overload. Liver iron concentration can be measured by liver biopsy or by a noninvasive method of biomagnetometry. Magnetic resonance imaging (MRI) potentially provides the best noninvasive technique for examining the body's distribution of excess iron.⁵

History of transfusions

Following a history of regular transfusion, chelation will be required to remove the excess iron that accompanies transfusions. A haematologist will be involved in monitoring and decision-making regarding the need for chelation. Patients will have their iron levels monitored using an MRI assessment. Iron overload can be defined as liver iron concentration >5 mg/g determined via MRI or ferritin >800 μg/L and TS >60% (if MRI is not available).² 

Monitoring iron in PKD patients

Types of iron chelators used

Deferoxamine/Desferrioxamine (Desferal)

Deferoxamine (DFO) is a widely used chelation agent for the management of transfusion-dependent anaemias. It is administered either under the skin (subcutaneously) or into a vein (intravenously). The dose and frequency of treatment is patient-specific. DFO is widely used and some people experience no side effects, while others may experience:

• Irritation or blisters on the skin where the needle is placed 
• Ringing of the ears (tinnitus)
• A decrease in night vision

The high cost and rigorous requirements of DFO are disadvantages of this treatment; however, coadministration or alternating use of DFO and another chelator may allow a decrease in dosage of both drugs and improve compliance.⁶

Deferasirox (Exjade) 

Deferasirox is particularly good at removing iron from the liver. The drug is taken orally once a day as a tablet that dissolves in water. Possible side effects include:

• Nausea, sickness and diarrhoea, though these often resolve
• Stomach pain and indigestion
• Kidney problems
• Skin rashes
• Blurred vision 

Deferiprone (Ferriprox)

Deferiprone is especially effective in removing iron from the heart and is taken orally three times daily. However, Deferiprone can reduce the body’s ability to fight infection by lowering a type of white blood cell. Other possible side effects include: 

• Reddish brown colour of your urine 
• Nausea and sickness 
• Increased appetite 
• Stomach and joint pain 

Deferiprone may be used alone or in combination with other chelators. Deferiprone has been used extensively as a substitute for DFO in clinical trials. Deferiprone alone fails to achieve a negative iron balance in a large number of patients and is less effective than DFO. However combined use of DFO and Deferiprone results in successful depletion of iron stores in patients previously failing to respond to treatment.⁶

Summary 

In summary, iron overload is common in PKD, even without frequent transfusions. Iron overload can occur in PKD due to chronic haemolysis resulting in a need for regular transfusion (transfusion related), or due to increased intestinal iron absorption and ineffective RBC production linked to chronic anaemia resulting in non-transfusion-related iron loading. Chelation therapy allows excess iron to be removed from the body preventing organ damage due to the iron overload. Monitoring of iron levels and appropriate treatment with chelation drugs, when required to prevent and treat iron overload, is important as this will lead to better patient outcomes.