Regulation of iron metabolism through GDF15 and hepcidin in pyruvate kinase deficiency

Article (PDF Available)inBritish Journal of Haematology 144(5):789-93 · March 2009with60 Reads
DOI: 10.1111/j.1365-2141.2008.07535.x · Source: PubMed
Abstract
Iron absorption is inadequately increased in patients with chronic haemolytic anaemia, which is commonly complicated by iron overload. Growth differentiation factor 15 (GDF15) has been identified as a bone marrow-derived factor that abrogates hepcidin-mediated protection from iron overload under conditions of increased erythropoiesis. Increased concentrations of GDF15 have been reported in beta-thalassaemia patients and GDF15 has been found to suppress hepcidin expression in vitro. To further study the interdependencies of iron metabolism and erythropoiesis in vivo, the concentrations of hepcidin and GDF15 were determined in sera from 22 patients with pyruvate kinase deficiency (PKD) and 21 healthy control subjects. In PKD patients, serum hepcidin levels were 13-fold lower than in controls (2.0 ng/ml vs. 26.2 ng/ml) and GDF15 was significantly higher (859 pg/ml vs. 528 pg/ml). Serum hepcidin concentrations correlated positively with haemoglobin and negatively with serum GDF15. These results suggest that GDF15 contributes to low hepcidin expression and iron loading in PKD.

Figures

Regulation of iron metabolism through GDF15 and hepcidin
in pyruvate kinase deficiency
The key mechanism in the maintenance of iron balance is the
regulation of intestinal uptake of dietary iron. Under condi-
tions of iron depletion, intestinal iron absorption is increased
until iron stores are replete and further iron uptake is inhibited
by the ‘stores regulator’ hepcidin (reviewed in Zoller & Cox,
2005). A peptide hormone, hepcidin inhibits iron absorption
through enterocytes and iron release from macrophages by
inactivating the iron export pump ferroportin (Nemeth et al,
2004; Yamaji et al, 2004). This protective mechanism is
suspended and iron uptake is enhanced despite normal or
even increased body iron in patients with genetic ferroportin
defects (Zoller et al, 2005) and iron loading anaemias.
Differential diagnoses of iron loading anaemia in young
patients include b-thalassaemia and pyruvate kinase (PK)
deficiency (PKD). In patients with b-thalassaemia, deficient
b-globin-chain production and accumulation of a-chains
causes apoptosis of red blood cell precursors, which results
in ineffective erythropoiesis and anaemia of variable severity
that is aggravated by reduced red blood cell survival secondary
to haemolysis (Gu & Zeng, 2002; Rund & Rachmilewitz, 2005).
In PKD patients, anaemia mainly results from decreased red
blood cell survival due to a defect of the key glycolytic enzyme
pyruvate kinase, which is essential for adenosine triphosphate
(ATP) production in mature red blood cells. Although ATP
depletion contributes to haemolysis, the mechanisms for
haemolysis are not clear. In PKD, reduced red blood cell
survival and chronic haemolysis result in increased iron
turnover, but iron accumulation is aggravated by ineffective
erythropoiesis, which may be caused by the metabolic defect of
PKD in erythroid progenitors (Zanella et al, 2001; Aizawa
et al, 2005).
As haemolysis is the key mechanism in PKD and apoptosis
in b-thalassaemia, reticulocytosis is frequently found in PKD
patients whereas reticulocytes are generally low in b-thalass-
aemia patients. These differences are reflected in bone marrow
expansion, which is typically more pronounced in patients
with b-thalassaemia. Given that the demands for iron are high
under conditions of increased erythropoiesis, iron supply by
unimpaired export from macrophages is essential in patients
with b-thalassaemia or PKD. The high requirements for iron
are partly managed through enhanced iron absorption.
Increased red blood cell turnover is associated with
Armin Finkenstedt,
1
Paola Bianchi,
2
Igor
Theurl,
3
Wolfgang Vogel,
1
Derrick R.
Witcher,
4
Victor J. Wroblewski,
4
Anthony T. Murphy,
4
Alberto Zanella
2
and Heinz Zoller
1
1
Department of Medicine II, Medical University of
Innsbruck, Innsbruck, Austria,
2
Department of
Haematology, University Hospital Milan, Milan,
Italy,
3
Department of Medicine I, Medical
University of Innsbruck, Innsbruck, Austria, and
4
Biotechnology Discovery Research, Lilly Research
Laboratories, Lilly Corporate Center,
Indianapolis, IN, USA
Received 5 September 2008; accepted for
publication 10 November 2008
Correspondence: Heinz Zoller, MD,
Department of Gastroenterology and
Hepatology, Medical University of Innsbruck,
Anichstraße 35, A-6020 Innsbruck, Austria.
E-mail: heinz.zoller@i-med.ac.at
Summary
Iron absorption is inadequately increased in patients with chronic haemolytic
anaemia, which is commonly complicated by iron overload. Growth
differentiation factor 15 (GDF15) has been identified as a bone marrow-
derived factor that abrogates hepcidin-mediated protection from iron
overload under conditions of increased erythropoiesis. Increased
concentrations of GDF15 have been reported in b-thalassaemia patients
and GDF15 has been found to suppress hepcidin expression in vitro.To
further study the interdependencies of iron metabolism and erythropoiesis
in vivo, the concentrations of hepcidin and GDF15 were determined in sera
from 22 patients with pyruvate kinase deficiency (PKD) and 21 healthy
control subjects. In PKD patients, serum hepcidin levels were 13-fold lower
than in controls (2Æ0 ng/ml vs. 26Æ2 ng/ml) and GDF15 was significantly
higher (859 pg/ml vs. 528 pg/ml). Serum hepcidin concentrations correlated
positively with haemoglobin and negatively with serum GDF15. These results
suggest that GDF15 contributes to low hepcidin expression and iron loading
in PKD.
Keywords: iron, anaemia, pyruvate kinase deficiency, hepcidin, GDF15.
research paper
First published online 22 December 2008
ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 144, 789–793 doi:10.1111/j.1365-2141.2008.07535.x
de-repression of iron absorption and iron release through
suppression of hepcidin (Papanikolaou et al, 2005; Kattamis
et al, 2006). A proposed ‘erythroid regulator’, which is active
even in patients with iron overload, ensures a sufficient supply
of iron to the erythroid marrow by induction of iron
absorption (Finch, 1994).
Tanno et al (2007) recently identified GDF15 as a down-
regulator of hepatic hepcidin expression, which is increased
over a 100-fold in patients with b-thalassaemia major. GDF15
is mainly secreted by erythroblasts, which are highly increased
in b-thalassaemia and PKD patients. The consequence of
increased GDF15 and suppressed hepcidin is increased iron
absorption, which results in iron overload, as no regulated
mode for the excretion of excess iron exists in humans.
Increased serum ferritin levels are found in up to 60% of non-
transfused PKD patients (Zanella et al, 2001) and iron
overload often determines the prognosis of patients with
hereditary non-spherocytic anaemia (Olivieri et al, 1994). Risk
factors for the development of iron overload include repeated
blood transfusions, splenectomy (Pootrakul et al, 1981; Porter,
2001) and HFE genotype (Piperno et al, 1998; Zanella et al,
2005). The present study investigated the recently identified
regulators of iron metabolism, hepcidin and GDF15, in
patients with PKD in order to understand their role and
interaction in the progressive iron accumulation in this type of
chronic anaemia.
Patients and methods
Twenty-two PKD patients from Italy and Austria (mean age
29 years, 11 women) were compared with 21 healthy indivi-
duals (mean age 52 years, 9 women). The molecular defect in
the gene encoding PK (PKLR) was determined by direct
sequencing in all PK-deficient patients and the individual
mutations are listed in Table SI. The mean age of diagnosis in
PKD patients was 18 years. Nine of the PKD patients had been
splenectomized, 13 had received blood transfusions. Transfu-
sion requirements were variable with six patients, who had
received 1–2 units of blood, one patient who had received 8
units of blood and transfusion dependence from birth or
childhood in three patients each.
Hepcidin and GDF15 serum concentrations were determined
in archived serum samples collected between 1995 and 2008 and
stored at )80C. GDF15 serum concentrations were measured
with the DuoSet enzyme-linked immunosorbent assay devel-
opment kit for human GDF15 (R&D Systems, Minneapolis,
MN, USA). For this assay, sera were diluted 1:50 in phosphate-
buffered saline containing 5% fetal calf serum and the
immunoassay carried out according to the manufacturer’s
instructions. Serum hepcidin concentrations were determined
by tandem mass spectrometry detection (Murphy et al, 2007).
An aliquot (100 ll) of plasma or serum was transferred to a 96-
well polypropylene microtitre plate and mixed with 100 ll
aliquot of acetonitrile. Internal standard solution (50 ll) was
added to each well and the microtitre plate was then centrifuged
at 3700 g for 10 min at 5C. After centrifugation, 125 ll of the
protein precipitation supernatant was transferred into a Waters
Oasis HLB 30 lm Elution solid phase extraction plate (Waters
Corporation, Milford, MA, USA) containing 550 ll of distilled
water. Each well of the extraction plate was washed twice with
400 ll of distilled water. Elution was performed with the
addition of 180 llof0Æ05/20/80 (trifluororoacetic acid/water/
acetonitrile, v/v/v) to each well of the plate. The eluant was
collected into a 96-well polypropylene microtitre plate and
evaporated to dryness at 50C using a 96-well microtitre plate
evaporator. The contents of each well of the microtitre plate
were reconstituted with 100 llof0Æ02% aqueous acetic acid and
injected onto a 35 · 2 mm CAPCELL PAK UG C18 column
(Phenomenex Inc., Torrance, CA, USA) packed with 5 lm
particles with 300 A
˚
pore size. The column was maintained at
30C with a column heater. A pair of Shimadzu LC10-AD vp
pumps (Shimadzu Scientific, Columbia, MD, USA) were used
to deliver a programmed gradient at a rate of 0Æ2 ml/min. The
column eluant was connected to an ionspray source on a
Finnigan TSQ Quantum Ultra electrospray mass spectrometer
(Thermo Electron Inc., Waltham, MA, USA) for selected
reaction monitoring of hepcidin. Haematological and serum
iron parameters were determined using standard laboratory
techniques.
Statistical analysis
Variables are expressed as mean or median with range as
indicated and depending on their normality. Quantitative
variables were compared using Student’s t-test or the non-
parametric Mann–Whitney U-test as appropriate. A value of
P <0Æ05 was considered statistically significant. Spearman’s
rank correlation was used for calculating correlations between
the various variable. All statistical analyses were carried out
using the Statistical Package for the Social Sciences (spss)
software package version 15.0.1 (SPSS Inc., Chicago, IL, USA).
Results
Demographic and clinical biochemical parameters of patients
with PKD and controls are summarized in Table I. PKD
patients presented with a significantly lower median haemo-
globin concentration than the control group (94 g/l vs.
145 g/l) and most PKD patients had moderate anaemia.
Reticulocytosis (>2Æ5%) was found in 20 of 22 PKD patients.
PKD patients had a significantly higher median serum ferritin
(334 lg/l vs.114 lg/l) and transferrin saturation (35% vs.
29%) when compared with controls. Clinical biochemical
evidence of iron overload, as indicated by a serum ferritin
concentration of >300 lg/l and a transferrin saturation of
>45%, was present in eight PKD patients.
Despite increased serum iron parameters, serum hepcidin
concentrations were significantly lower in the PKD patient
group when compared with control subjects (Fig 1A). As
GDF15 was reported to counteract the effect of iron overload
A. Finkenstedt et al
790
ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 144, 789–793
on hepcidin expression in patients with b-thalassaemia (Tanno
et al, 2007), we studied serum GDF15 concentrations in
patients with PKD. Mean GDF15 was significantly higher in
PKD patients when compared with control subjects (Fig 1B).
Correlation analysis was performed to study the inter-
dependencies between hepcidin, GDF15 and haematological as
well as serum iron parameters. A negative correlation between
serum hepcidin and GDF15 was found when patients and
controls were included in the analysis (r = )0Æ384, P =0Æ012).
Furthermore, a positive correlation between haemoglobin and
serum hepcidin concentration was found for all patients
(r =0Æ813, P <0Æ001). This suggests that anaemia has a
suppressive effect on hepcidin, because this observation was
confirmed when only PKD patients were analysed. In the
group of patients with PKD, a positive correlation between
transferrin saturation and GDF15 was found (r =0Æ466,
P =0Æ033). A trend towards a negative correlation between
hepcidin and reticulocyte count in the PKD group was found,
but this did not reach statistical significance. The results of a
correlation analysis between biochemical parameters and
GDF15 as well as biochemical parameters and hepcidin are
shown in Table SII.
Discussion
Growth differentiation factor 15 has been recently identified as
a negative regulator of hepcidin expression in patients with
b-thalassaemia and in isolated human hepatocytes (Tanno
et al, 2007). This observation suggests that GDF15 is impli-
cated in the pathogenesis of iron overload, which is a frequent
complication of b-thalassaemia (Modell et al, 2000; Rund &
Rachmilewitz, 2005). To further study iron handling in
patients with iron loading anaemias, the concentration of
serum hepcidin and GDF15 as well as haematological and
serum iron parameters were studied in PKD. The mean serum
hepcidin concentration was significantly lower in PKD patients
when compared with healthy controls, despite increased serum
iron parameters in the PKD patient group. Low serum
hepcidin concentrations despite increased iron stores were
associated with significantly higher GDF15 concentrations
when compared with controls and suggest GDF15-mediated
hepcidin suppression as a contributing factor to iron overload
in PKD as previously described for b-thalassaemia (Tanno
et al, 2007).
The principal cause of iron overload in patients with PKD is
hyperabsorption of iron from the diet, which is often
aggravated by repeated blood transfusions. Eight of 15 PKD
patients, who had received a maximum of two transfusions,
showed signs of iron overload as indicated by a serum ferritin
(A)
(B)
Fig 1. Serum hepcidin concentrations are significantly higher in
healthy controls than in PKD patients (P =0Æ022) (A), whereas serum
GDF15 concentrations are significantly lower in control subjects
(P <0Æ001) (B). The circle in figure B indicates an outlier in whom
GDF-15 was 1486 pg/ml.
Table I. Demographic and biochemical parameters of PKD patients
and controls.
Controls PKD Patients P
Number (men/women) 21 (12/9) 22 (11/11) <0Æ001
Age (years)* 52 (28–74) 29 (1–59)
Haemoglobin (g/l) 145 (128–171) 94 (70–129) <0Æ001
Iron* (lmol/l) 5Æ7(2Æ3–28Æ0) 21Æ1(8Æ2–41Æ4) 0Æ06
Ferritin (lg/l) 114 (30–208) 334 (59–3210) 0Æ001
Transferrin* (g/l) 27Æ5 (21Æ2–34Æ7) 24Æ8 (15Æ6–31Æ5) 0Æ04
Transferrin
saturation (%)
29 (15–45) 35 (22–100) 0Æ004
Hepcidin* (ng/ml) 26Æ2(2Æ2–57) 2Æ0 (0–8Æ1) <0Æ001
GDF15* (pg/ml) 528 (82–1486) 859 (249–2187) 0Æ022
*Mean (range).
Median (range).
Iron Regulation in Pyruvate Kinase Deficiency
ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 144, 789–793 791
concentration >300 lg/l or a transferrin saturation >45%. The
impact of blood transfusions on iron status is illustrated by
the observation that median serum ferritin was 921 lg/l in the
patients that had received eight or more transfusions as
compared with a median of 239 lg/l in the subgroup of
patients with two or less transfusions.
As serum iron parameters were increased in our PKD
patients, we also expected increased serum hepcidin levels. In
reality, mean serum hepcidin concentration was about 13-fold
lower in PKD patients than in the control group (Fig 1A). This
observation was in accordance with b-thalassaemia patients, in
whom urinary hepcidin excretion was found to be decreased
despite iron overload (Papanikolaou et al, 2005; Kattamis et al,
2006). The observation that increased GDF15 concentrations
are associated with decreased serum hepcidin concentrations
in PKD supports the hypothesis that GDF15 acts as a negative
regulator of iron absorption under conditions of increased
erythropoiesis.
Of note is the observation that serum hepcidin concentra-
tions were highly heterogeneous in the control group, ranging
from 2Æ2 ng/ml to 57 ng/ml. Hepcidin is regulated by various
factors including iron stores, inflammation, erythropoietic
activity and hypoxia. Neither C-reactive protein nor serum
ferritin concentrations, as surrogate parameters of iron stores
and systemic inflammation, were correlated with hepcidin. The
significant variation of serum hepcidin concentrations in the
control group may therefore reflect the true biological
variability of hepcidin as a sensitive regulator of iron
homeostasis in humans.
Hepcidin as a ‘gate-keeper’ of iron uptake appears to be
inhibited by increased red blood cell production despite iron
overload in animal models and patients with haemolytic
anaemias (Nicolas et al, 2002; Weizer-Stern et al, 2006).
GDF15 could be the ‘hormone’ that signals bone marrow
activity and iron requirements to the gut by suppression of
hepatic hepcidin production. Increased erythropoiesis was
found in 20 of 22 PKD patients as indicated by reticulocytosis
of >2Æ5%. The observed positive correlation between haemo-
globin and hepcidin supports a direct effect of tissue oxygen-
ation via hypoxia-inducible transcription factor 1a (HIF1a)on
hepcidin, but the hierarchy of GDF15 and HIF1a in the
regulation of hepcidin expression remains unknown (Peys-
sonnaux et al, 2007).
The implication of other factors regulating iron absorption
is further supported by the observation that GDF15 serum
concentrations were only very mildly increased in PKD
patients (mean 859 pg/ml) compared with the extreme levels
reported for b-thalassaemia major patients (mean 66 000 pg/
ml). Although the results from GDF15 quantifications in
different laboratories may not be directly comparable, GDF15
concentrations measured in PKD patients are similar to those
measured in sickle cell disease patients (mean 880 pg/ml)
(Tanno et al, 2007). In both cases, concentrations were below
the threshold of GDF15 concentration that suppressed HAMP
mRNA in primary hepatocytes in vitro (Tanno et al, 2007).
A negative correlation between GDF15 and serum hepcidin
(r = ) 0Æ384, P =0Æ012) was found when the patients and
controls were included in the analysis. The lack of correlation
in the patient group suggests that GDF15 is only a
co-determinant of hepcidin expression at the serum concen-
trations found in PKD. Hepcidin is a key regulator of iron
absorption, and a positive correlation between serum ferritin
and hepcidin has been reported for patients with inflammation
and iron overload (Nemeth et al, 2003). In PKD patients, no
correlation between hepcidin and ferritin was found. This
observation suggests that iron-mediated regulation of hepcidin
is abrogated in PKD. In conclusion, serum hepcidin concen-
trations are low in PKD patients, in whom increased GDF15
concentrations may contribute to hepcidin suppression and
increased iron absorption.
Acknowledgements
This work was supported by the Austrian Science Fund Project
19579 and the ‘Verein zur Fo
¨
rderung der Forschung in
Gastroenterologie und Hepatologie an der Medizinischen
Universita
¨
t Innsbruck’.
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Supporting information
Additional Supporting Information may be found in the
online version of this article:
Table SI. Individual mutations of PKD patients.
Table SII. Correlation analysis of biochemical parameters
and GDF15 and hepcidin in the overall group (A), in the PKD
patient group (B) and the control group (C).
Please note: Wiley-Blackwell are not responsible for the
content or functionality of any supporting materials supplied
by the authors. Any queries (other than missing material)
should be directed to the corresponding author for the article.
Iron Regulation in Pyruvate Kinase Deficiency
ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 144, 789–793 793
    • "Hepcidin was assessed in plasma [50,51], serum [48,52,53,55,56,68], and urine [47,49]. Seven of ten human studies analyzed hepcidin using mass spectrometry [47,49505153,55,68] and three studies used ELISAs [48,52,56]. Unfortunately, hepcidin values from the human studies cannot be directly compared to each other because hepcidin assays have not been standardized, and different methods yield different absolute values and normal ranges, although they correlate strongly [65]. "
    [Show abstract] [Hide abstract] ABSTRACT: Hepcidin is the master regulator of systemic iron bioavailability in humans. This review examines primary research articles that assessed hepcidin during pregnancy and postpartum and report its relationship to maternal and infant iron status and birth outcomes; areas for future research are also discussed. A systematic search of the databases Medline and Cumulative Index to Nursing and Allied Health returned 16 primary research articles including 10 human and six animal studies. Collectively, the results indicate that hepcidin is lower during pregnancy than in a non-pregnant state, presumably to ensure greater iron bioavailability to the mother and fetus. Pregnant women with undetectable serum hepcidin transferred a greater quantity of maternally ingested iron to their fetus compared to women with detectable hepcidin, indicating that maternal hepcidin in part determines the iron bioavailability to the fetus. However, inflammatory states, including preeclampsia, malaria infection, and obesity were associated with higher hepcidin during pregnancy compared to healthy controls, suggesting that maternal and fetal iron bioavailability could be compromised in such conditions. Future studies should examine the relative contribution of maternal versus fetal hepcidin to the control of placental iron transfer as well as optimizing maternal and fetal iron bioavailability in pregnancies complicated by inflammation.
    Full-text · Article · Aug 2014
    • "Treatment of primary human hepatocytes with high concentrations of GDF15 suppresses hepcidin mRNA expres- sion [8]. GDF15 concentrations are increased in several disorders hallmarked by ineffective erythropoiesis, such as the thalassaemias, CDAI and pyruvate kinase deficiency [8][9][10][11]. In this study, we have analysed markers of erythropoiesis and iron overload, as well as serum GDF15 and hepcidin concentrations in patients with CDAI and CDAII. We show that GDF15 concentrations are significantly increased in the serum of CDAI and CDAII patients compared to healthy controls, with CDAI patients exhibiting significantly higher concentrations than CDAII patients. "
    [Show abstract] [Hide abstract] ABSTRACT: Congenital dyserythropoietic anaemias (CDAs) are heterogeneous, hereditary disorders hallmarked by ineffective erythropoiesis and tissue iron overload. Growth differentiation factor 15 (GDF15) was suggested to mediate iron overload in iron-loading anaemias, such as the thalassaemias and CDAI by suppressing hepcidin, the key regulator of iron absorption. Here, we show that serum GDF15 concentrations are elevated in subjects with CDAI and CDAII. Despite similar disease characteristics, CDAI patients present with significantly higher GDF15 concentrations compared to CDAII patients. Hepcidin concentrations are inappropriately low in CDAII patients considering the severe hepatic iron overload associated with this disorder. GDF15 significantly correlates with the degree of anaemia (Hb), the response of erythropoiesis (reticulocyte index) as well as with iron availability in the serum (transferrin saturation). The observation that GDF15 is elevated in CDAII patients is consistent with the proposal that GDF15 is among the erythroid factors down-regulating hepcidin and contributing to iron overload in conditions of dyserythropoiesis.
    Article · Apr 2011
    • "Pyruvate kinase deficiency results in defective glycolysis resulting in erythroblast apoptosis and peripheral blood hemolysis [28] [29]. Pyruvate kinase deficiency is being investigated as a separate cause of ineffective erythropoiesis, but iron overloading is less consistent among these patients [30]. Other erythroid disorders associated with some degree of ineffective erythropoiesis include chronic pernicious anemia, hereditary spherocytosis, and sickle cell anemia [31] [32]. "
    [Show abstract] [Hide abstract] ABSTRACT: Erythropoiesis describes the hematopoietic process of cell proliferation and differentiation that results in the production of mature circulating erythrocytes. Adult humans produce 200 billion erythrocytes daily, and approximately 1 billion iron molecules are incorporated into the hemoglobin contained within each erythrocyte. Thus, iron usage for the hemoglobin production is a primary regulator of plasma iron supply and demand. In many anemias, additional sources of iron from diet and tissue stores are needed to meet the erythroid demand. Among a subset of anemias that arise from ineffective erythropoiesis, iron absorption and accumulation in the tissues increases to levels that are in excess of erythropoiesis demand even in the absence of transfusion. The mechanisms responsible for iron overloading due to ineffective erythropoiesis are not fully understood. Based upon data that is currently available, it is proposed in this review that loading and overloading of iron can be regulated by distinct or combined mechanisms associated with erythropoiesis. The concept of erythroid regulation of iron is broadened to include both physiological and pathological hepcidin suppression in cases of ineffective erythropoiesis.
    Full-text · Article · May 2010
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