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

III. Developing Erythroid Cells
183
Normally, few die within the marrow ( Odartchenko et al. ,
1971 ), but ineffective erythropoiesis is prominent in disorders
of nucleic acid, heme, or globin synthesis. Examples
include folate deficiency, iron deficiency, vitamin B 6 deficiency,
lead poisoning, and thalassemia in humans ( Jandl,
1987 ). Ineffective erythropoiesis also occurs in association
with myeloproliferative and myelodysplastic disorders
( Meyer and Harvey, 2004 ) and congenital dyserythropoiesis
( Holland et al. , 1991 ; Steffen et al. , 1992 ).
2 . Vitamin and Mineral Defi ciencies
Folate is required for normal DNA synthesis. Folate deficiency
impairs the activity of the folate-requiring enzyme
thymidylate synthase ( Jandl, 1987 ). Not only is deoxythymidylate
triphosphate (dTTP) synthesis decreased, but
deoxyuridylate triphosphate (dUTP) accumulates secondarily
in the cell such that some becomes incorporated into
DNA in place of dTTP. Cycles of excision and attempts to
repair these copy errors, with limited thymidine available,
result in chromosomal breaks and malformations and slowing
of the S phase in the cell cycle. Consequently, erythroid
precursors are often large with deranged-appearing nuclear
chromatin; such cells are classified as megaloblastic
cells. Folate deficiency in people causes macrocytic anemia
because fewer divisions occur as a result of retarded
nucleic acid synthesis in the presence of normal protein
synthesis ( Jandl, 1987 ). Possible causes of folate deficiency
include dietary deficiency, impaired absorption, and drugs
that interfere with folate metabolism.
Macrocytic anemias resulting from folate deficiency are
rarely reported in animals. A possible case was reported in
a dog on anticonvulsant therapy ( Lewis and Rebar, 1979 ),
but serum folate was not measured. Megaloblastic precursors
were present in bone marrow of cats with experimental
dietary folate deficiency, but hematocrits and mean cell volumes
(MCVs) remained normal ( Thenen and Rasmussen,
1978 ). However, macrocytic anemia with dyserythropoiesis
was reported in a cat that appeared to have both a folatedeficient
diet and defective folate absorption ( Myers et al. ,
1996 ). Macrocytic anemia has been reported in folate-deficient
pigs ( Bush et al. , 1956 ), but not lambs ( Stokstad, 1968 ).
Vitamin B 12 (cobalamin) deficiency in people causes
hematological abnormalities similar to folate deficiency
because vitamin B 12 is necessary for normal folate metabolism
in humans ( Chanarin et al. , 1985 ). In contrast, vitamin
B 12 deficiency does not cause macrocytic anemia in any
animal species ( Chanarin et al. , 1985 ). Anemia has been
reported in some experimental animal studies, but RBCs
were of normal size ( Stokstad, 1968 ; Underwood, 1977 ),
although slight increases in MCV have been reported in B 12 -
deficient goats fed diets deficient in cobalt ( Mgongo et al. ,
1981 ). Cobalamin deficiency has been reported secondary
to an inherited malabsorption of cobalamin in giant schnauzer
dogs ( Fyfe, 2000 ). Affected animals have normocytic,
nonregenerative anemia with increased anisocytosis and poikilocytosis,
neutropenia with hypersegmented neutrophils,
and giant platelets. Megaloblastic changes in the bone marrow
were particularly evident in the myeloid cell line. The
malabsorption of cobalamin in these dogs apparently results
from the absence of an intrinsic factor-cobalamin receptor
in the apical brush border of the ileum. No blood or bone
marrow abnormalities were recognized in kittens fed a
B 12 -deficient diet for several months ( Morris, 1977 ), but a
normocytic nonregenerative anemia was present in a cobalamin-deficient
cat that probably had an inherited disorder of
cobalamin absorption ( Vaden et al. , 1992 ).
A number of disorders exhibit macrocytic anemias with
megaloblastic abnormalities in the marrow that mimic findings
in human folate or cobalamin deficiency but have had
normal serum levels of these vitamins when measured.
Examples include cats infected with the feline leukemia
virus ( Dunn et al. , 1984 ; Weiser and Kociba, 1983a ), cattle
with congenital dyserythropoiesis ( Steffen et al. , 1992 ), and
myelodysplastic syndromes ( Harvey, 2001 ). In addition,
some miniature and toy poodles exhibit macrocytosis without
anemia and variable megaloblastic abnormalities in the
bone marrow with normal serum folate and cobalamin values
( Canfield and Watson, 1989 ).
Abnormalities in heme or globin synthesis can result in
the formation of microcytic hypochromic RBCs. Cellular
division is normal, but Hb synthesis is delayed; consequently,
one or more extra divisions occur in RBC development,
resulting in smaller cells than normal.
Pyridoxine, vitamin B 6 , is required for the first step in
heme synthesis. Although natural cases of pyridoxine deficiency
have not been documented in domestic animals,
microcytic anemias with high serum iron values have been
produced experimentally in dogs ( McKibbin et al. , 1942 ),
cats ( Bai et al. , 1989 ; Carvalho da Silva et al. , 1959 ), and
pigs ( Deiss et al. , 1966 ) with dietary pyridoxine deficiency.
Erythroid cells with iron-loaded mitochondria, secondary to
impaired heme synthesis, have been demonstrated in pigs
fed a pyridoxine-deficient diet ( Hammond et al. , 1969 ).
With the exception of young growing animals, iron deficiency
in domestic animals usually results from blood loss.
Milk contains little iron; consequently, nursing animals can
easily deplete their body iron store as they grow ( Furugouri,
1972 ; Harvey et al. , 1987 ; Holter et al. , 1991 ; Siimes et al. ,
1980 ). Microcytic RBCs are produced in response to iron
deficiency ( Holman and Drew, 1966 ; Holter et al. , 1991 ;
Reece et al. , 1984 ), but a low MCV may not develop postnatally
in species where the MCV is above adult values at
birth ( Weiser and Kociba, 1983b ). The potential for development
of severe iron deficiency in young animals appears
to be less in species that begin to eat food at an early age.
Chronic iron deficiency anemia with microcytic RBCs
is common in adult dogs in areas where hookworm and
flea infestations are severe ( Harvey et al. , 1982 ; Weiser
and O’Grady, 1983 ). Severe iron deficiency appears to be