The Risk of Iron Overload in PK Deficiency | For HCPs

Risk of iron overload

Iron overload—a serious cardiac and liver complication of PK deficiency—can occur regardless of age, transfusion history, or hemoglobin levels1,2

In the PK Deficiency Natural History Study, the incidence of iron overload was high, even among patients not regularly transfused*

  • At the time of enrollment in the Natural History Study, 82% (198/242) of patients were not receiving regular transfusions2
Iron overload as defined by high ferritin or chelation Iron overload as defined by high ferritin or chelation
Cardiac Iron Overload Cardiac Iron Overload

LIC=liver iron concentration.

Data derived for the PK deficiency population drawn from the Pyruvate Kinase Deficiency NHS. The average age in the NHS was 19 years (range 0.1-69.9; n=254).1

*Patients were defined as not regularly transfused if they had received <6 transfusions in the 12 months prior to enrollment.2

Chelation therapy may be indicated with ferritin >1000 ng/mL, LIC >3 mg/g dry weight liver, and/or cardiac iron ≤20 ms.2

Ferritin blood values may underestimate LIC.2

The Pyruvate Kinase Deficiency NHS was funded by Agios Pharmaceuticals.

Pathogenesis of iron overload is multifactorial in patients not regularly transfused, including3,4:

  • Lifelong hemolysis
  • Ineffective erythropoiesis
  • Increased intestinal iron absorption

Case Profile§: Iron Overload in a Patient Not Regularly TRANSFUSED5

Childhood
Transfusion dependence attributed to congenital anemia of unclear etiology
Age 8
Diagnosed with PK deficiency
Splenectomized; transfusion dependence resolved
Age 40
FACIT-F Score: 48 (score range, 0-52)
Ferritin 670 ng/mL (consensus cutoff, 500 ng/mL)
LIC: 8.9 mg/g dry weight (reference range, 0.17-1.8 mg/g dry weight)
Patient initiated on chelation therapy after being advised of the risks of iron overload

FACIT-F=Functional Assessment of Chronic Illness Therapy-Fatigue.

§Due to the variability of the disease, case profiles are not reflective of every patient.

At the individual patient level, ferritin is not a good predictor of LIC, and ferritin <1000 ng/mL does not exclude hepatic iron overload2
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Long-term complications

Dr Fertrin discusses the serious risk of iron overload.

The most typical complication is iron overload…There is evidence to show that patients with PK deficiency who were never transfused still develop iron overload with time.

Dr Fertrin

Regular monitoring for iron overload is key to managing patients with PK deficiency2,4

PK deficiency puts patients at risk for iron overload regardless of age or transfusion history

  • Absent monitoring, iron can build up undetected
  • Patients with iron overload may not display symptoms until damage is severe
  • While clinical experience suggests that iron overload most often presents in an older, more anemic, frequently splenectomized patient population with a higher median total bilirubin, patients as young as 3 years of age have been diagnosed with iron overload

Complications with iron overload may include1,4,6,7

Complications with iron overload
  • Liver cirrhosis
  • Endocrine disorders
  • Cardiac issues
  • Pulmonary hypertension
  • Osteoporosis, osteopenia, bone deformities, and fractures
  • Joint disease

Recommended timing for iron overload assessments in patients with PK deficiency2,4,5

Patients in the Natural History Study were defined as regularly transfused (≥6 transfusions) or not regularly transfused (<6 transfusions) in the 12 months prior to enrollment

Regularly transfused
Patients

Ferritin

  • Every 6 months
  • Every 3 months for patients on
    chelation therapy

Heart and liver MRI

  • Yearly

Patients not regularly
Transfused

Ferritin

  • Yearly
  • Every 3 months for patients on
    chelation therapy

Heart and liver MRI

  • Baseline scan in early adulthood
  • Scan when ferritin >500 ng/mL or as needed
I have been getting transfusions more often, and my iron has been high...and I know the risks that causes...That is a worrying thing.

Maaike

Monitoring is key to identifying iron overload regardless of transfusion history2,4

See why a definitive diagnosis is critical for patients with PK deficiency

See why a definitive diagnosis is critical for patients with PK deficiency

References: 1. Grace RF, Bianchi P, van Beers EJ, et al. Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study. Blood. 2018;131(20):2183​-2192. 2. van Beers EJ, van Straaten S, Morton DH, et al. Prevalence and management of iron overload in pyruvate kinase deficiency: report from the Pyruvate Kinase Deficiency Natural History Study. Haematologica. 2019;104(2):e51-e53. 3. Zanella A, Fermo E, Bianchi P, Valentini G. Red cell pyruvate kinase deficiency: molecular and clinical aspects. Br J Haematol. 2005;130(1):11-25. 4. Grace RF, Layton DM, Barcellini W. How we manage patients with pyruvate kinase deficiency. Br J Haematol. 2019;184(5):721-734. 5. Al-Samkari H, van Beers EJ, Kuo KHM, et al. The variable manifestations of disease in pyruvate kinase deficiency and their management. Haematologica. 2020;105(9):2229-2239. 6. Piperno A, Pelucchi S, Mariani R. Inherited iron overload disorders. Transl Gastroenterol Hepatol. 2020;5:25. doi:10.21037/tgh.2019.11.15 7. Ramakrishnan L, Pedersen SL, Toe QK, Quinlan GJ, Wort SJ. Pulmonary arterial hypertension: iron matters. Front Physiol. 2018;9:641. doi:10.3389/fphys.2018.00641

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