This is the third part of our series about the condition based on our patient booklet “Fast Facts for Patients and Supporters: Pyruvate Kinase Deficiency”, which is freely available online. This article shows how pyruvate kinase deficiency will affect you or your child.
The symptoms and complications that you or your child experience may be very different from someone else with PK deficiency, as they vary widely between people. The hemolytic anemia caused by PK deficiency can vary from mild to severe, with a typical hemoglobin level of 6–12 g/dL. Normal hemoglobin levels in healthy individuals vary by age and sex, ranging from 10.5–16 g/dL.
Can You Predict Symptom Severity?
Patients and doctors often wonder if there are any laboratory tests or findings early in childhood that might predict the likelihood of certain symptoms, or indicate whether transfusions or a splenectomy might be needed later in life. Researchers are currently looking at these relationships.
To date, studies have found no relationship between the level of pyruvate kinase enzyme activity and the degree of hemolysis. One reason for this is that the most enzyme-deficient red blood cells break down before pyruvate kinase enzyme activity can be measured (i.e. the results of your enzyme activity test come from your healthiest or most PK-sufficient red blood cells).
People with more disruptive PKLR gene mutations are more likely to have complications.
People with lower hemoglobin levels have a higher likelihood of complications. However, anyone with PK deficiency can develop the complications described below.
You may develop yellowing of the whites of your eyes (scleral icterus) and/or yellowing of your skin (facial jaundice) as a result of your PK deficiency. These signs may be apparent all the time or just in times of illness, dehydration or stress.
Although removal of the spleen (splenectomy) improves anemia for most people with PK deficiency, it does not resolve the issue of jaundice/scleral icterus, as the hemolytic process continues after splenectomy.
Why Do Some People Have More Jaundice than Others?
The degree of jaundice or scleral icterus is linked to your total unconjugated bilirubin level. This is determined both by the degree of hemolysis and by your ability to metabolize bilirubin, which is genetically determined.
People with Gilbert syndrome have an inherited abnormality (two copies of a non-working gene) that reduces the production of an enzyme involved in the processing of bilirubin in the liver (i.e. bilirubin is metabolized more slowly). Gilbert syndrome is common (affecting 5–15% of the population), so it is possible for someone to inherit both PK deficiency and Gilbert syndrome. People with Gilbert syndrome often have worsening of their everyday jaundice around the time of puberty.
Your spleen may become enlarged (splenomegaly) as a result of more red blood cells being broken down in the organ. The spleen can further increase in size during hemolytic episodes and/or if you have a viral infection. The spleen is typically enlarged in PK deficiency, but if you have a normal-sized spleen that does not exclude the diagnosis of PK deficiency or the likelihood of increased breakdown of red blood cells in the spleen. If you have severe anemia, removal of the spleen may be beneficial even if your spleen is a normal size.
An enlarged spleen does not typically cause pain. However, if your spleen is significantly enlarged, it may compress the stomach, making you feel full quickly when you eat. An enlarged spleen can also act as a sponge, causing transfused red blood cells and other blood cells (platelets and white blood cells) to get stuck, resulting in lower blood counts.
An enlarged spleen, when it can be felt below the rib cage, can be more at risk of injury, so your doctor is likely to recommend avoiding contact sports.
Hemolytic episodes or crises develop in response to stressors or triggers of hemolysis. These are most often infections and, therefore, are more frequent in childhood. Pregnancy can also be a common hemolytic trigger.
During these episodes, you may find your everyday symptoms, such as fatigue, paleness, scleral icterus, jaundice and/or dark urine, get worse. Your spleen may also increase in size. Blood tests will reveal:
- decreased hemoglobin/hematocrit
- increased reticulocyte count
- increased bilirubin
- increased lactate dehydrogenase (a marker of red blood cell breakdown in the blood vessels).
An aplastic crisis is caused by parvovirus B19 infection (also known as Fifths disease). This common viral infection typically causes a high fever and facial rash.
In people with PK deficiency, parvovirus infection decreases hemoglobin and reduces or stops reticulocyte production in the bone marrow.
This infection can only occur once in your life and self-resolves like other viral infections. Testing for antibodies to parvovirus can diagnose a current or recent infection or a history of previous infection (i.e. immunity to the virus).
In PK deficiency, aplastic crises often require blood transfusions.
Gallstones are a frequent complication in children and adolescents with PK deficiency due to the increased release of unconjugated bilirubin.
Unlike dietary-related gallstones in middle-aged adults, you can develop pigmented (bilirubin) gallstones at any age. The risk of gallstones is life-long due to ongoing hemolysis and will continue even if you have your spleen removed.
Some people with gallstones have no symptoms, or you may have nausea or abdominal pain after eating. Gallstones can also get stuck in the organs and ducts that create and store bile (the biliary system) and can cause significant worsening of baseline jaundice.
Gallstones can also be associated with other complications, such as infection of the gallbladder (cholangitis) or inflammation of the pancreas (pancreatitis). If you are diagnosed with these problems your doctor is likely to recommend surgical removal of your gallbladder (cholecystectomy).
Transfusion-related iron overload. Red blood cells contain iron, so every time you receive a blood transfusion you are putting more iron into your body. The body does not have a mechanism to remove the excess iron, so it can build up and damage your organs. The iron is most commonly deposited in the liver, but it can also be deposited in the heart and hormone-producing organs (endocrine organs).
Iron loading is not associated with symptoms until a significant amount of iron is deposited, so if you receive regular transfusions it is important you are closely monitored for iron loading and remain on treatment (chelation) to remove iron.
Non-transfusion-related iron overload. Even if you do not receive transfusions as part of your treatment, you may still be at risk for iron loading. Regular iron monitoring is important. Transfusion-independent iron loading is common in people with PK deficiency; it can occur at any age and in patients with any hemoglobin level.
Although transfusion-independent iron loading is not well studied in PK deficiency, it is thought that the body responds to the anemia by absorbing more iron, even though there is no iron deficiency. It is not clear why some people with PK deficiency absorb more iron than others. Care should be taken to avoid iron supplements (including multivitamins with iron) and excessive ingestion of foods high in iron (e.g. liver and red meat).
When your body has to make an excessive number of red blood cells every day, blood cell production (hematopoiesis) can begin to occur outside of the bone marrow in organs such as the liver or spleen, or in other locations, such as around the spine or in the chest. This finding is usually diagnosed by a radiology scan and/or a tissue biopsy.
Extramedullary hematopoiesis is not a frequent complication in PK deficiency but is also not uncommon.
Low Bone Density
Low bone density is another potential complication of PK deficiency. The reason for this is not clear but it may be associated with the increased rate of red blood cell production in the bone marrow. You may find it beneficial to pay close attention to your vitamin D and calcium intake.
Pulmonary hypertension (high blood pressure in the arteries in the lungs and the right side of the heart) is an infrequent complication of PK deficiency. It can be detected on routine screening tests, or may cause symptoms including shortness of breath and fatigue. Leg ulcers related to PK deficiency occur in some people, but the cause is not well understood; leg ulcers occur in other types of hemolytic anemia as well.
Other, less common, signs and symptoms may occur so be sure to ask your doctor about any symptoms or problems that you have.
The effects of chronic anemia and/or the treatments associated with PK deficiency can affect your psychological wellbeing. If you are feeling sad, or having difficulty sleeping or other mood-related symptoms, please consult your doctor.
Please check out the other posts of our series here:
Information based on Fast Facts for Patients and Supporters: Pyruvate Kinase Deficiency (Karger, 2019).