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

VIII. Disorders of Iron Metabolism
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requires iron in the Fe 2 state ( Porra and Jones, 1963 ).
Siderotic inclusions have also been reported in erythroid
cells in copper deficiency in humans ( Gregg et al ., 2002 ).
Zinc toxicity results in copper deficiency (presumably
secondary to impaired copper absorption), hypoferremia,
and microcytic anemia in humans ( Beutler, 2006a ; Fosmire,
1990 ; Gyorffy and Chan, 1992 ), and zinc toxicity, from the
use of galvanized feeding bins, resulted in copper deficiency
and anemia in pigs ( Pritchard et al ., 1985 ).
E. Iron Overload
Iron accumulates in hepatocytes when transferrin saturation
is high. In addition to transferrin-bound iron, the liver
can readily take up NTBI from plasma and iron contained
within heme that is bound to the plasma protein hemopexin.
Ferroportin expression is lower in hepatocytes than in enterocytes
and macrophages, which may help explain why hepatocytes
preferentially accumulate iron in most iron overload
conditions; however, considerable amounts of iron are stored
in macrophages with transfusional iron overload ( Anderson
and Frazer, 2005 ; Rivera et al ., 2005 ). The increased uptake
of iron by hepatocytes results in increased synthesis of apoferritin
and formation of ferritin in cytoplasm and formation
of hemosiderin in lysosomes. Although binding of iron
molecules in these storage proteins minimizes the amount
of “ free ” iron available to catalyze the formation of reactive
oxygen species, oxidation of polyunsaturated phospholipids
within organelles and cellular membranes and oxidative damage
to proteins and DNA may still occur in conditions resulting
in excess intracellular iron accumulation ( Ramm and
Ruddell, 2005 ; Rothman et al ., 1992 ; Ryan and Aust, 1992 ).
Hepatic stellate cells become activated into highly proliferative
myofibroblast-like cells during conditions with excessive
iron accumulation. This activation results in increased fibrogenesis
and subsequently cirrhosis within the liver in conditions
with chronic iron accumulation ( Ramm and Ruddell,
2005 ). Other sites that may accumulate iron, depending on
the cause of iron overload, include pancreas, heart, kidneys,
and endocrine organs ( House et al ., 1994 ; Lowenstine and
Munson, 1999 ).
Serum iron and serum ferritin concentrations are increased
in animals with iron overload, but both can be increased in
other conditions (see serum iron section). Consequently, a
liver biopsy is needed to definitively diagnose iron overload
( Lowenstine and Munson, 1999 ). Excessive accumulation
of iron within hepatocytes can be identified by the staining
of hepatocytes using an iron stain (Perl’s Prussian blue)
and quantified using flame atomic absorption ( Sprague
et al ., 2003 ).
1 . Acute Iron Toxicity
NTBI in plasma may play a significant role in the pathogenesis
of tissue injury in severely iron-overloaded
individuals, especially in individuals with acute iron toxicity
( Koury and Ponka, 2004 ). The amount of iron taken
up by hepatocytes and other cells in acute iron toxicity
far exceeds the ability of these cells to increase apoferritin
synthesis as a protective response. Most fatal cases of
acute iron toxicity in animals have resulted from the parenteral
administration of large doses of iron, and animals
with hypovitaminosis E appear to be especially susceptible
( Arnbjerg, 1981 ). Acute iron toxicity from parenteral iron
administration in calves and goats resulted in clinical findings
including central nervous system signs, vocalization,
respiratory distress, icterus, and death. Pulmonary edema,
hemorrhages on serosal surfaces, and hepatic necrosis were
documented at necropsy ( Ruhr et al ., 1983 ). The oral consumption
of large amounts of iron can also result in central
nervous system signs, hemorrhage, icterus, and pulmonary
edema, but clinical findings can also include vomiting,
bloody diarrhea, and subsequently, dehydration, metabolic
acidosis, and hypovolemic shock. Histological findings
associated with oral iron toxicity include small intestine
ulceration, hemorrhage, and necrosis; pulmonary edema
and hemorrhage; and degenerative changes in kidneys and
liver ( Arnbjerg, 1981 ). Newborn foals exhibited hepatotoxicity
following the oral administration of a digestive paste
containing ferrous fumarate iron at a concentration much
lower than is required for acute iron toxicity in adult animals
of various species ( Mullaney and Brown, 1988 ). This
liver injury may have resulted from increased NTBI uptake
by the liver because serum transferrin is highly saturated
at birth in foals ( Harvey et al ., 1987a ). In addition, iron
absorption may be higher in neonatal foals as reported in
neonatal piglets and rats ( Mullaney and Brown, 1988 ).
Cirrhosis is not a feature of acute iron toxicity except in
animals that survive long enough for fibrosis to develop
( Mullaney and Brown, 1988 ).
2 . Hemochromatosis and Hemosiderosis
The term hemochromatosis refers to the accumulation of
iron in parenchymal cells, resulting in organ injury and
dysfunction. Accumulation of iron within cells (typically
macrophages), without evidence of organ dysfunction, is
termed hemosiderosis . Localized iron overload occurs in
macrophages in areas where hemorrhage has occurred.
Systemic iron deposition may occur in a variety of organs,
but it is especially prominent in hepatocytes ( Lowenstine
and Munson, 1999 ). The accumulation of large amounts
of iron in hepatocytes results in hepatocellular injury,
increased fibrogenesis, and liver failure in severe cases.
Hemochromatosis is classified as primary, secondary, or
idiopathic. Primary hemochromatosis refers to inherited
disorders of iron metabolism resulting in hemochromatosis.
Secondary hemochromatosis refers to disorders in which
iron accumulation occurs secondary to other disorders,
including excessive dietary iron, unnecessary parenteral