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Manifestations of disease in PKD
anemia following splenectomy, the patient excelled at school and extracurricular activities. He has maintained a normal social life into adulthood, married, and had children. As a 40-year old man, he underwent quality of life assessments, including the Functional Assessment of Chronic Illness Therapy Fatigue sub- scale [FACIT-F, final score of 48 (score range 0-52)] and the Functional Assessment of Cancer Therapy [FACT-G, score of 96 (score range 0-104)], confirming an excellent quality of life.
Despite his lack of complaints or need for transfusion, he was offered routine PKD screening (as detailed in Table 1) and was found to have a ferritin of 670 ng/mL. Subsequent liver magnetic resonance imaging demonstrated an average liver iron content of 8.9 mg/g dry weight (reference range, 0.17-1.8 mg/g dry weight). After a discussion of the risks of iron overload he was ini- tiated on chelation therapy with deferasirox.
This case illustrates several important points about the spectrum of disease in PKD, most notably the poor corre- lation between symptoms and severity of anemia. In the case described, the patient’s lack of symptoms despite his low hemoglobin was evident both from his high level of functioning and the results of two well-validated quality of life instruments. Patients may be less symptomatic than with other types of anemia for a given hemoglobin level, or occasionally entirely asymptomatic despite severe ane- mia.48 This is in part because 2,3-diphosphogylcerate, an important regulator of the oxygen affinity of hemoglobin, is increased in PKD, which may enhance oxygen deliv- ery.17,49 This increase occurs due to the metabolic block in the glycolytic pathway resulting in upstream accumula- tion of glycolytic intermediates (Figure 4). The resulting P50 and other patient-related factors, such as older age and concurrent medical problems, play a role in symptom bur- den. This is important to recognize as unnecessary trans- fusion of patients who are clinically well can be harmful due to iron loading.
The 2,3-diphosphogylcerate level obtained during the workup of the patient’s anemia prior to the diagnosis of PKD is biochemical evidence consistent with what is observed clinically regarding his excellent tolerance of anemia. Although correlations have been demonstrated between the presence of two non-missense mutations and both more severe disease and worse health-related quality of life,11 genotype may poorly predict phenotype in some patients with PKD.50 The clinical manifestations of the dis- ease are caused by the complex interactions of the PKLR genetic background, concomitant functional polymor- phisms of other enzymes, posttranslational or epigenetic modifications, ineffective erythropoiesis and differences in splenic function.50 Varying degrees of compensatory expression of the PK isozyme normally expressed in leukocytes, PK-M2, in PK-R-deficient erythrocytes appears to influence the clinical severity of PKD as well.51
Similar cases describing relatively asymptomatic PKD patients with even lower hemoglobin levels have been published,52 and indeed a better-than-expected tolerance of anemia in many patients likely explains the not uncom- mon delay observed in time to diagnosis.53 Further studies are needed to characterize the relationship between a given patient’s 2,3-diphosphogylcerate levels, P50 oxygen dissociation curve, clinical phenotype, genotype, and patient-reported quality of life in PKD and in other con- genital hemolytic anemias.
Lastly, this case highlights the occult iron overload com- mon in PKD. Iron overload regularly occurs even in never- transfused patients over a lifetime of chronic hemolysis,
necessitating regular evaluation of iron status in all PKD patients.15 In the completely asymptomatic patient who may only visit the clinic annually, assessment of iron sta- tus and institution of appropriate chelation therapy is easy to overlook, potentially leading to development of end- organ damage.
Special situations
Pregnancy in pyruvate kinase deficiency
CASE: A 24-year old woman (gravida 1, parity 0) with a his- tory of iron-deficiency anemia due to menorrhagia (hemoglobin 9.5-11.0 g/dL) and a clinical diagnosis of Gilbert syndrome pres- ents in the 12th week of pregnancy with anemia and profound fatigue. On evaluation, physical examination is remarkable only for mild pallor and jaundice and a palpable spleen tip. Laboratory testing demonstrates hemoglobin 8.3 g/dL, mean cor- puscular volume 99 fL, absolute reticulocyte count 225x109/L, haptoglobin <20 mg/dL (reference range 30-200 mg/dL), lactate dehydrogenase 267 U/L (reference range 135-214 U/L), nega- tive direct antiglobulin testing, and unremarkable red cell mor- phology on a peripheral blood film. Pyruvate kinase enzyme activity was reduced (3.9 U/g Hb [11-15.6]) and genetic testing revealed the presence of two missense mutations: c.1456C>T (p.Arg486Trp) and c.994G>A (p.Gly332Ser). Other congenital and acquired hemolytic conditions were ruled out by normal osmotic fragility, eosin-5-maleimide binding, ektacytometry, ery- throcyte membrane protein content, hemoglobin electrophoresis, and CD55/59 antigen expression. During pregnancy the patient was closely followed by hematology and obstetrics staff. Because of severe fatigue, she was given a total of 15 units of packed ery- throcytes during pregnancy (on average, a transfusion every 2 weeks) and four additional units at the time of delivery because of postpartum bleeding complications. Following delivery of a preterm but healthy infant, the mother’s anemia improved to a hemoglobin of 9.5 g/dL.
Pregnancy is among the known triggers of hemolysis in PKD, along with infections and erythropoietic stressors. In addition to increased hemolysis, hydremia of pregnancy may further exacerbate anemia in pregnant women. Little is known about fertility and pregnancy in PKD, except for a tendency towards an increased frequency of preterm births and miscarriages, and an increased transfusion need.54,55 Folate supplementation is mandatory and we advise a minimum of 1 mg daily during pregnancy. Fetal growth should be carefully monitored. 2,3-diphosphogyl- cerate levels result in a rightward shift of the oxygen dis- sociation curve of hemoglobin and symptoms may not correlate well with severity of anemia. As in non-pregnant patients, the decision to transfuse is guided by the patient’s symptoms, rather than hemoglobin levels, and by fetal growth as measured by ultrasound.
Given that splenectomy partially ameliorates the ane- mia in PKD, anticipation of pregnancy in a young woman with PKD may be considered as a factor in favor of splenectomy prior to pregnancy.40
Stigmatizing Icterus in pyruvate kinase deficiency
CASE: A 14-year old boy with PKD who has been splenec- tomized arrives at the clinic for routine follow-up. He is able to be physically active to his satisfaction despite his anemia (baseline hemoglobin 9.0 g/dL). His primary complaint during this visit, as was the case in his past several visits, is severe jaundice of the
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