Overview

Pyruvate kinase deficiency (PKD) is a rare genetic disorder that affects the production of pyruvate kinase, an enzyme essential for energy metabolism in red blood cells (RBCs).¹Invariably, PKD results in hereditary non-spherocytic anaemia, which significantly impacts bilirubin metabolism and predisposes patient to various complications.²One such complication is gallstone formation, specifically pigment gallstones- particularly common in individuals with chronic hemolytic states, including those with PKD. It mainly occurs from the neonatal period through adult life.³

Pyruvate kinase deficiency: background and pathophysiology

The PKLR gene mutation causes PKD and results in erythrocytes with impaired pyruvate kinase enzyme activity.⁴ Since RBCs do not have mitochondria, they must rely only on glycolysis for energy. Pyruvate kinase is crucial in the last stages of glycolysis and the production of ATP (energy).⁵ The resultant ATP deficiency causes membrane rigidity, cellular dehydration, and premature destruction of RBC - primarily by the spleen.

Clinical manifestations

• Anemia
• Reticulocytes (immature red blood cells)
• Splenomegaly 
• Jaundice
• Gallstones⁶

Hemolysis in pyruvate kinase deficiency 

• PKD is chronic extravascular hemolysis
• The constant turnover of RBCs increases heme degradation, subsequently elevating bilirubin levels¹
• Unconjugated bilirubin (insoluble in water) frequently builds up in the bloodstream when the liver deals with an elevated bilirubin load. In addition to causing jaundice, the hyperbilirubinemia condition is crucial to the development of gallstone²

Bilirubin metabolism

Gaining an understanding of bilirubin metabolism is essential to interpret hemolysis's aftereffects.

Degraded RBC heme 

↓

Biliverdin

↓

Unconjugated bilirubin

↓

Liver → Bound to albumin.

The enzyme UDP-glucuronosyltransferase (UGT1A1) in hepatocytes converts bilirubin to glucuronic acid, making it water soluble and excretable as bile.

During chronic hemolysis, the liver may become overwhelmed by the increased bilirubin load, leading to a buildup of unconjugated bilirubin in the bile.⁷

Gallstone formation

Mechanism

Gallstones are solid concretions formed within the biliary tract, generally classified as cholesterol, black pigment, or brown pigment stones.⁸ Pigmented stones form in conditions where bilirubin secretion into bile is high, as seen in chronic hemolysis. Stasis and supersaturation further facilitate stone nucleation. Furthermore, bilirubin clearance dynamics are altered by splenic dysfunction or absence (post-splenectomy), which may increase the incidence of stones.

Clinical Evidence linking PKD and gallstones

Pigment gallstones are much more common in PKD patients than in the general population, as reported by numerous studies and case series. Gallstones were found in more than 30% of PKD children by adolescence, according to a paediatric investigation. Changes in bile content and RBC clearance pathways may paradoxically enhance the risk for splenectomised people. Patients often present with biliary colic and cholecystitis, or are found to have stones incidentally during imaging for anaemia evaluation.^2,5

Diagnostic approaches

Laboratory testing, confirmatory enzyme assays, and clinical suspicion are all used in the diagnosis of PKD. Important lab results include:

• Lactate dehydrogenase (LDH), when levels are elevated
• Hyperbilirubinemia
• Reticulocytosis
• Ferritin levels that are normal or elevated
• Abdominal ultrasonography, which shows echogenic structures inside the gallbladder, is used to detect gallstones

Management 

Management of PKD focuses on supportive care

• Folic acid supplementation to support erythropoiesis
• Transfusions in severe anaemia
• Splenectomy to reduce hemolysis, though it may increase gallstone risk

For gallstones

• Cholecystectomy is indicated in symptomatic cases or if complications arise
• Prophylactic cholecystectomy during splenectomy may be considered in certain cases with documented stones
• Regular monitoring of hemolytic markers and gallbladder imaging can guide early intervention and prevent complication⁹

Future directions and research

Emerging gene therapy trials for PKD hold promise in altering the natural course of the disease by restoring pyruvate kinase activity. Research into pharmacologic agents that modulate bilirubin metabolism or bile composition could help prevent gallstone formation. Greater awareness of the hemolysis-gallstone link may lead to earlier screening and intervention in PKD patients.

Summary

Pyruvate Kinase Deficiency (PKD) is a rare genetic disorder that affects the production of pyruvate kinase, an enzyme essential for red blood cell energy metabolism. This deficiency leads to chronic hemolysis, anaemia, and increased bilirubin levels, which can cause gallstones. PKD patients are at higher risk of developing pigment gallstones, particularly black pigment stones. The increased red cell turnover and resultant bilirubin load are central to this process. Early diagnosis, regular monitoring, and a multidisciplinary approach are essential to manage both the hematologic and hepatobiliary complications of this disease. Advances in therapy and preventive care hold promise for improving the quality of life in affected individuals.

FAQs

What is pyruvate kinase deficiency (PKD)?

PKD is a genetic disorder that affects the production of pyruvate kinase, an enzyme essential for red blood cell energy metabolism.

What are the symptoms of PKD?

Symptoms include anaemia, jaundice, splenomegaly, and gallstones.

How does PKD cause gallstones?

PKD leads to chronic hemolysis, which increases bilirubin levels, predisposing patients to pigment gallstone formation.

What type of gallstones are common in PKD patients?

Black pigment stones are common in PKD patients.

How is PKD diagnosed?

Diagnosis involves clinical suspicion, laboratory tests (e.g., LDH, indirect hyperbilirubinemia, reticulocytosis), and confirmatory enzyme assays.

What is the management of PKD?

Management focuses on supportive care, including folic acid supplementation, transfusions, and splenectomy in some cases.