Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

278
Chapter | 9 Iron Metabolism and Its Disorders
iron supplementation, chronic hemolytic anemia, repeated
blood transfusions, ineffective erythropoiesis, and possibly
primary liver disease ( Lowenstine and Munson, 1999 ). The
etiology of idiopathic hemochromatosis by definition cannot
be determined.
3 . Hemolytic Anemia
Intestinal iron absorption is increased in animals and humans
with hemolytic anemia and compensatory increased erythropoiesis
( Latunde-Dada et al ., 2006a ). Hepcidin synthesis
is down-regulated and DMT1, DcytB, and ferroportin are
up-regulated during hemolysis in rats induced by phenylhydrazine
( Latunde-Dada et al ., 2006a ).
This increased iron absorption, even with high hepatic
iron stores, documents the importance of erythroid drive
over iron storage in the regulation of iron absorption
( Latunde-Dada et al ., 2006a ). Hemosiderin is typically
increased in macrophages in animals with hemolytic anemia
because of increased phagocytosis of erythrocytes.
However, increased iron absorption associated with persistent
regenerative anemia can also result in iron accumulation
within hepatocytes.
Hemosiderosis, hemochromatosis, and fibrosis develop
in the liver of erythrocyte pyruvate kinase-deficient dogs
secondary to progressive iron overload ( Searcy et al ., 1979 ;
Weiden et al ., 1981 ; Zaucha et al ., 2001 ). Dogs with inherited
pyruvate kinase deficiency also exhibit the progressive
development of myelofibrosis and osteosclerosis, and it is
proposed that the marrow fibrosis, like the cirrhosis, occurs
in response to damage caused by iron overload ( Zaucha
et al ., 2001 ). Pyruvate kinase-deficient dogs generally die
between 1 and 5 years of age because of bone marrow failure
or liver failure ( Harvey, 2006 ).
4 . Repeated Blood Transfusions and
Parenteral Iron Administration
Long-term repeated blood transfusions commonly result
in iron overload in human patients, but animals are rarely
given sufficient transfusions for this to be a risk in veterinary
medicine. Hemochromatosis, with subsequent liver failure,
occurred in a dog given whole blood transfusions every 6 to
8 weeks for 3 years as treatment for pure red cell aplasia
(Sprague et al ., 2003 ). Histological evaluation of the liver
revealed hepatocellular degeneration, bridging portal fibrosis,
lobular atrophy, biliary hyperplasia, and large amounts
of hemosiderin in hepatocytes and mononuclear phagocytes.
The repeated administration of large doses of parenteral iron
to dogs in experimental studies over several years resulted in
hepatic iron overload and cirrhosis ( Lisboa, 1971 ).
5 . Dietary Iron Overload
Some species of wild animals develop iron overload, and
sometimes hemochromatosis, when housed in captivity.
These animals include black rhinoceroses, lemurs, and
birds (most notably mynahs and toucans) ( Lowenstine and
Munson, 1999 ; Paglia et al ., 2001 ). Dietary iron overload
may occur from increased amounts of iron in the diet or
from an alteration in the diet that results in increased absorption
of iron. Compounds including tannins and phytates
in natural diets may chelate much of the dietary iron into
insoluble complexes. When diets fed in captivity contain
less of these inhibitory compounds, iron may be absorbed
in excess of what is needed for hemoglobin synthesis and
other metabolic functions. For example, black rhinoceroses
are browsers in the wild with a diet rich in woody plants,
but they are fed manufactured pellets and domestic forages
in captivity that contain more bioavailable iron ( Paglia et al .,
2001 ). Kinetic studies comparing Fe 2 absorption by enterocytes
from mynahs and chickens revealed a three-fold higher
V max for mynahs, even though liver iron content was at least
10-fold higher in mynahs than chickens ( Mete et al ., 2003 ).
This results from an overexpression of intestinal iron transporters
DMT1 and ferroportin ( Mete et al ., 2005 ). Although
mynahs can down-regulate iron uptake to some extent ( Mete
et al ., 2001 ), this evolutionary adaption to their natural diet
results in excessive iron absorption when they are fed a different
diet in captivity.
6 . Hereditary Hemochromatosis
Most types of hereditary hemochromatosis in humans are
characterized by primary or secondary hepcidin deficiency.
Primary hepcidin deficiency results from a mutation in the
hepcidin gene. Secondary hepcidin deficiency occurs when
there are mutations in the HFE gene, TfR2 gene, or hemojuvelin
gene ( Verga Falzacappa and Muckenthaler, 2005 ).
Murine models of each of these defects have been created
and each results in iron overload ( Vaulont et al ., 2005 ).
The mechanisms by which the protein products of these
genes control hepcidin synthesis remain to be defined.
Iron also accumulates in humans with various mutations
in ferroportin that result in resistance to down-regulation
by hepcidin. Most patients have iron accumulation predominantly
in hepatocytes, but some have iron accumulation
predominantly in macrophages ( Fleming et al ., 2005 ;
Wessling-Resnick, 2006 ).
Hemochromatosis has been described in related Salers
cattle, and it is presumed to be inherited ( House et al .,
1994 ; O’Toole et al ., 2001 ). Affected animals were young
(about 2 years old or less) with a history of poor growth,
weight loss, and poor hair coat. They had iron accumulations
in liver, spleen, lymph nodes, kidney, brain, thyroid,
and other glandular organs. Histopathology of the liver
revealed marked accumulations of stainable-iron in hepatocytes,
Kupffer cells, and arteriolar walls, with bridging
periportal fibrosis. Affected cattle also have markedly
increased iron content in bone, periosteal dysplasia, and
osteopenia resulting in pathological fractures and tooth loss