Pyruvate kinase deficiency: symptoms, diagnosis and treatment

Red blood cells carry oxygen around the body. To do their job they need energy, and pyruvate kinase is an enzyme in the pathway that produces it. The Patient.info professional article explains that in PKD the red cell’s energy requirements outstrip its ability to generate ATP, which damages the cell membrane irreversibly, so the damaged cell is destroyed prematurely by the spleen and liver.

The result is haemolytic anaemia, in which red cells are broken down faster than the body can replace them. The European Medicines Agency describes PKD as an inherited disease that is long-term and debilitating because of its symptoms and the periodic blood transfusions that some people need. Patient.info says it is the most common enzyme abnormality of this energy pathway.

Symptoms depend on severity. The EMA lists very pale skin, yellowing of the eyes and skin (jaundice), tiredness, shortness of breath, an enlarged spleen (splenomegaly) and heart problems. Patient.info adds that milder forms may be unnoticed until some physiological stress is experienced, such as pregnancy or a viral infection, that children may have signs of anaemia, growth delay and failure to thrive, and that most cases are found in childhood although mildly affected people may not be detected until late adulthood.

Gallstones are a recognised complication, which Patient.info says occasionally present in childhood but usually after the first decade, and adults may have chronic leg ulcers. Other complications listed are bacterial sepsis after splenectomy and iron overload from many transfusions. Anaemia can worsen during pregnancy or a viral infection, according to the EMA, and can be life threatening.

Diagnosis begins with a blood count and film that show anaemia and signs of accelerated red cell production, such as a raised reticulocyte count and nucleated red blood cells. Patient.info says the blood film features, a reduced red cell lifespan and a raised bilirubin reflect the haemolysis, and that tests for other haemolytic conditions, such as haemoglobin electrophoresis and red cell fragility, are normal.

The precise diagnosis depends on detecting the deficient enzyme, and Patient.info says measuring intermediate products in the pathway helps to confirm it. DNA analysis is limited because of the large number of possible mutations and is of greater value when the mutation is already known. A GP would normally refer to haematology.

Patient.info says management is usually supportive in mild to moderate cases. The EMA adds that at the time its orphan designation was granted there were no satisfactory authorised treatments and that patients received periodic red cell transfusions and, in some, allogeneic stem-cell transplantation.

Patient.info says inheritance is autosomal recessive, meaning a child inherits one altered gene from each parent, who are usually carriers without symptoms, and that most affected people are compound heterozygotes with two different mutations. It notes that prenatal enzyme testing is not useful because of the large amount of fetal blood needed and a high rate of false negatives, and that DNA testing is most useful when the family mutation is known.

Pregnancy outcomes are generally good according to the same article, despite sometimes severe falls in haemoglobin during pregnancy, so pregnancy planning should involve haematology and obstetric teams. Genetic counselling through a clinical genetics service can explain the chance of a child being affected.

See a GP if you have persistent tiredness, pallor, jaundice or breathlessness. Seek urgent medical advice through NHS 111 or A&E if you have a high temperature, particularly after splenectomy, severe breathlessness, chest pain, a very rapid heartbeat or marked yellowing, because anaemia can worsen during a viral infection and sepsis after splenectomy is a recognised risk. Call 999 if you are seriously unwell.

Most of the literature the sources draw on is aimed at clinicians, and patient-facing UK information is limited. The sources identify pregnancy and viral infections as times when anaemia can worsen, and gallstones, iron overload after many transfusions and infection after splenectomy as complications to be aware of. Ask your haematologist what monitoring you need and which team coordinates your care.