El Fe de la TF es el único que pueden utilizar las células.
El Fe de la TF es el único que se regula.
El Fe que rebosa de la TF se une a otras substancias (citratos...) y forma
el NTBI, parte del cual es redox-activo (LPI) y produce daño oxidativo en
Regulación de la hepcidina
El 10% de la población blanca es portadora del gen C282Y.
Penetrancia bioquímica del C282Y +/+ del 36-76%.
Penetrancia de la enfermedad del C282Y +/+ del 2-38% en ♂ y del 1-10% en .
♀
El H63D ocasiona sobrecarga férrica solo si coincide con otra mutación
trascendente (p. ej.: H63D/C282Y).
SEÑALES DE ALARMA
Ferritina >200 ng/ml en mujeres ó 300 ng/ml en varones.
%TF >45% en
+
ó >50 en varones (más sensible y especifica).
↓
hepcidina: para el futuro (marcador genético subrogado).
SITUACIONES CONCRETAS
SITUACIONES CONCRETAS
↑
Ferritina
+
↓
%TF: Descartar inflamación, autoinmunes, neoplasias,
ERC, hepatopatias, alcoholismo, s. metabólico
⇒
la %TF suele ser
normal ó baja (RFA inverso).
↑
Ferritina
+
↓
%TF: no descarta del todo la HC. Formas
aceruloplasminemia y mutaciones FP con PF (probable/ sin trascencencia).
↑
Ferritina
+
↑
%TF + C282Y/C282Y: HC.
↑
Ferritina
+
↑
%TF + C282Y/wt, H63D/wt, H63D/H63D, wt/wt
⇒
RM ó
biópsia.
Consideraciones terapéuticas
FLEBOTOMIAS QUELANTES
Eliminación de Fe
SI
SI
Eliminación de otros metales divalentes
NO
SI
Bloqueo del Fe no transferrínico y
daño oxidativo
NO
SI
Normalización de la Hepcidina
NO
NO
1
2
El Fe de la TF es el único que pueden utilizar las células.
El Fe de la TF es el único que se regula.
El Fe que rebosa de la TF se une a otras substancias (citratos...) y forma
el NTBI, parte del cual es redox-activo (LPI) y produce daño oxidativo en
células susceptibles.
Cells regulate the intake of transferrin-bound iron by altering the
expression of surface transferrin receptor 1 (TfR1). In contexts in
which transferrin becomes highly saturated, additional iron released
into the circulation is bound to low-molecular-weight compounds
(e.g., citrate).11 This non–transferrin bound iron (NTBI) is readily
taken up by certain cell types, including hepatocytes and
cardiomyocytes. The excess uptake of iron as NTBI contributes to
oxidant-mediated cellular injury. A fraction of the circulating NTBI is
redox-active and designated labile plasma iron.
Excess iron injures cells primarily by catalyzing the production of
reactive oxygen species in excess of the capacity of cellular
antioxidant systems. These reactive oxygen species cause lipid
peroxidation, oxidation of amino acids with consequent protein–
3
4
Since the pool of circulating transferrin iron amounts
to less than 3 mg, reticuloendothelial cells represent
the most dynamic iron compartment, turning over
about 10 times per day. Because the rate of iron
turnover by reticuloendothelial cells is quite high,
hepcidin-mediated changes in iron export can result in
rapid and marked changes in serum iron
concentrations.
5
Excessive hepcidin activity leads to iron deficiency and iron-restricted
erythropoiesis, as seen in iron-refractory iron-deficiency anemia (IRIDA) and
the anemia of chronic disease. Diminished hepcidin activity leads to
enhanced intestinal iron absorption and iron overload, which are associated
with hemochromatosis and thalassemia.
6
7
Excessive hepcidin activity leads to iron deficiency and iron-restricted
erythropoiesis, as seen in iron-refractory iron-deficiency anemia (IRIDA) and
the anemia of chronic disease. Diminished hepcidin activity leads to
enhanced intestinal iron absorption and iron overload, which are associated
with hemochromatosis and thalassemia.
8
Regulación de la hepcidina
Four functionally defined hepcidin regulatory pathways are depicted:
erythropoiesis, iron status, oxygen tension, and inflammation. Increased
erythropoiesis is associated with decreased hepcidin expression by mechanisms
that remain to be defined. Candidate signaling molecules from the marrow
include growth differentiation factor 15 (GDF-15) and twisted gastrulation protein
homolog 1 (TWSG1). Increased body iron status increases hepcidin expression
through two mechanisms: a circulating-iron signal provided by ferri-transferrin and
a cellular-iron-stores signal provided by bone morphogenetic protein 6 (BMP-6).
The ferri-transferrin signal acts through transferrin receptors 1 and 2 and is
modulated by the hemochromatosis protein HFE. The BMP-6 signal acts through
its receptor and is modulated by the BMP coreceptor hemojuvelin and by
neogenin. Decreased oxygen tension leads to decreased hepcidin expression by
increasing the transcription of two genes, matriptase-2 and furin, that are
responsive to hypoxia-inducible factor (HIF). Matriptase-2 cleaves hemo juvelin
from the cell surface, preventing its function as a coreceptor. Furin cleaves
hemojuvelin during processing to produce a soluble form that serves as a BMP-6
decoy. Infections and other forms of inflammation increase hepcidin expression
9
Disorders of the Hepcidin–Ferroportin Axis
Of the six disorders in this group, five have a classic hereditary hemochromatosis phenotype (elevated transferrin saturation, elevated serum ferritin, normal hematocrit, and tissue iron overload). The
pathophysiology of these five conditions is similar:inadequate or ineffective hepcidin-mediated down-regulation of ferroportin.
Las mutaciones de la FP con GOF (por pérdida de regulación por la hepcidina) son fenotipicamente similares a la forma clásica pero con la hepcidina normal ó alta. Las mutaciones de FP con LOF (perdida función FP) quedan confinadas al SRE, sin elevación de la ST, BI ni hepatopatía. No se sabe sus consecuencias ni si se benefician de flebotomias.
Ferroportin mutations (type IV): Mutations in a gene encoding for ferroportin (SLC40A1) are responsible for two different phenotypes (figure 3). (See 'Ferroportin mutations' above.)
Macrophage type: These "loss of function" mutations result in excess accumulation of iron in macrophages, with resulting high serum ferritin, normal to reduced transferrin iron saturation, and a mild anemia.
Hepatic type: — These "gain of function" mutations allow iron to be absorbed in excess of need, with patients manifesting high levels of ferritin and hepcidin, increased transferrin saturations, and typical deposition of iron in the hepatic parenchyma.
Disorders of Erythroid Maturation
The down-regulation of hepcidin persists despite iron overload.58 Erythrocyte transfusions contribute substantially to the iron burden in patients with these disorders.
Disorders of Iron Transport
insufficient delivery of transferrin bound iron for the synthesis of heme, despite iron stores. The consequent iron-restrictive erythropoiesis, anemia, or both contribute to low hepcidin
levels and thus iron overload.
O no se carga la TF (aceruloplasminemia), o falta la TF, o del DMT1 (no se carga Fe desde la mitoconcria). El resultado final es la pérdida de la señal de ferriTF, con el consiguiente descenso de hepcidina y
reabsorción de Fe.
10
El 10% de la población blanca es portadora del gen C282Y. Penetrancia bioquímica del C282Y +/+ del 36-76%.
Penetrancia de la enfermedad del C282Y +/+ del 2-38% en ♂ y del 1-10% en .♀ El H63D ocasiona sobrecarga férrica solo si coincide con otra mutación
trascendente (p. ej.: H63D/C282Y).
11
12
13
SEÑALES DE ALARMA
Ferritina >200 ng/ml en mujeres ó 300 ng/ml en varones.
%TF >45% en + ó >50 en varones (más sensible y especifica).
↓
hepcidina: para el futuro (marcador genético subrogado).
SITUACIONES CONCRETAS
SITUACIONES CONCRETAS
↑
Ferritina
+
↓
%TF: Descartar inflamación, autoinmunes, neoplasias,
ERC, hepatopatias, alcoholismo, s. metabólico
⇒
la %TF suele ser
normal ó baja (RFA inverso).
↑
Ferritina
+
↓
%TF: no descarta del todo la HC. Formas
aceruloplasminemia y mutaciones FP con PF (probable/ sin trascencencia).
↑
Ferritina
+
↑
%TF + C282Y/C282Y: HC.
↑
Ferritina
+
↑
%TF + C282Y/wt, H63D/wt, H63D/H63D, wt/wt
⇒
RM ó
biópsia.
14
15
16
Consideraciones terapéuticas
FLEBOTOMIAS QUELANTES
Eliminación de Fe SI SI
Eliminación de otros metales divalentes NO SI
Bloqueo del Fe no transferrínico y
daño oxidativo NO SI Normalización de la Hepcidina NO NO
➢
