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H. Al-Samkari et al.
skin and scleral icterus. He has been the victim of considerable bullying by other children in his new school over the past year due to the yellow tinge of his skin and eyes. His mother believes it is making him depressed and his grades have fallen over the same period. His total bilirubin is 3.9 mg/dL. He is initiated on pheno- barbital 15 mg daily, resulting in a reduction of his bilirubin to 2.0 mg/dL and significant improvement in the icterus. At his next visit, the patient remarks that the bullying has stopped.
Patients with congenital hemolytic anemia often live with chronic icterus. This is not uncommonly a significant psychological burden and social stigma for patients with PKD with a considerable impact on quality of life. School- aged children and adolescents may face bullying and other negative social consequences. It is important for clinicians to recognize this and address the impact on their patients’ quality of life. Depending upon the degree of impact on a patient’s well-being, treatment may be indicated to address icterus. Low-dose, off-label phenobarbital (15-30 mg daily) could be considered as this agent induces hepat- ic bilirubin metabolism, although the potential side effects of this medication should be carefully explained to the patient and family.56 In especially severe cases, a regular exchange transfusion regimen can be considered to reduce bilirubin levels and alleviate icterus, although this approach was not uniformly agreed upon by all members of the working group.
Disease burden over the lifespan
CASE: A 54-year old woman with PKD presents for routine follow-up. She was diagnosed in childhood and was transfusion- dependent until she underwent splenectomy at the age of 8. This alleviated her need for routine transfusions and she settled at a hemoglobin of 8.0-9.0 g/dL. Between the age of 8 and 49, she required red cell transfusions only five times: in the post-operative setting following cholecystectomy, during pregnancy, and during three acute infectious episodes that resulted in dramatic drops in her hemoglobin and hospitalization. During her late 40s, she noticed slowly worsening exercise tolerance despite no change in her baseline hemoglobin and at the age of 49 began receiving intermittent transfusions to treat fatigue. By the age of 52, she required regular transfusion of two units of red cells every 8 weeks to raise her hemoglobin above 10.0 g/dL. Over time, her tolerance of anemia has diminished further, resulting in a gradual reduction of the interval between transfusions. Currently she requires two units of red cells every 6 weeks. She does not smoke and has no underlying cardiopulmonary disease, including no evidence of pulmonary hypertension.
Patients with PKD are susceptible to hemolytic crises, typically occurring in the setting of acute viral or bacterial infection.41 Hemolytic crises may also be precipitated by pregnancy, surgery, or other major physiological stressors. During a hemolytic crisis, the hemoglobin concentration
drops precipitously and transfusion is frequently required. Similarly, patients can develop aplastic crises secondary to parvovirus B19, which should be suspected in the setting of a hemoglobin drop with a significant reduction in the normally robust reticulocytosis. This possibility can be evaluated with parvovirus B19 serology (including IgM testing) or polymerase chain reaction testing.
The described scenario of a patient who is liberated from transfusions following splenectomy in childhood but decides to start regular transfusions once again in later adulthood due to anemia-related symptoms demonstrates a common but poorly-studied phenomenon in PKD: a reduced tolerance to the same degree of anemia as patients age. This phenomenon was universally recognized by working group members but has not been formally described in the literature. In this patient, an evaluation for cardiopulmonary disease, such as the pulmonary hyperten- sion that can complicate PKD, is warranted.11,25 A decline in cardiopulmonary function also frequently occurs due to non-PKD-related disease or from age-related factors, which can reduce the patient’s ability to compensate for the degree of anemia. Cases such as this one emphasize that transfusion independence in PKD may come and go throughout the patient’s lifespan.
Conclusions
While the management of PKD may change in the near future with the promise of therapeutic advances on the horizon, recognition and diagnosis of the disease by hematologists and institution of proper monitoring and supportive treatments will remain important. This requires an understanding of the manifestations of disease as they relate to diagnosis, treatment, and impact on the patient’s quality of life. With few distinctive clinical signs to suggest the disease, both a high index of suspicion and understanding of the limitations of diagnostic testing are needed to properly diagnose patients. Recognition that transfusions are symptom-directed and that iron overload and other complications are common regardless of the severity of the anemia is critical for proper care of PKD patients. The spectrum of disease in PKD is broad with symptoms varying between patients and within patients over time with age, supporting an individualized approach to monitoring and treatment.
Acknowledgments
HA is the recipient of the National Hemophilia Foundation- Shire Clinical Fellowship Award and the Harvard KL2/Catalyst Medical Research Investigator Training Award and the American Society of Hematology Scholar Award.
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