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

VIII. Ketogenesis and Ketosis
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fast. Neither ketone is excreted at these lower concentrations,
but they do begin to appear in the urine as plasma
levels begin to rise ( Sapir and Owen, 1975 ; Schwab and
Lotspeich, 1954 ; Visscher, 1945 ; Wildenhoff, 1977 ).
However, as the ketone concentrations increase in the glomerular
filtrate, the primary mode of reabsorption is by
diffusion down a concentration gradient as water is reabsorbed
from the tubular lumen. Acetone begins to appear
in the urine as soon as it begins to appear in the plasma
( Widmark, 1920 ); presumably, this effect is due to great
lipid solubility of acetone, which allows it to penetrate cell
membranes with relative ease.
Renal excretion and reabsorption of ketones is approximately
proportional to their filtration rates (or plasma concentrations
if glomerular filtration rate remains constant)
at concentrations found after more than a 1-day fast in
humans and in ruminants ( Kaufman and Bergman, 1974 ;
Wildenhoff, 1977 ). At least some parts of the nephron,
probably beyond the proximal tubule, are less permeable
to ketones than to water because when plasma ketone levels
are substantially increased, the urinary concentration
exceeds the plasma concentration.
The dual mode of ketone reabsorption has an advantage
in that none of this valuable energy source is lost at lower
plasma concentrations; however, there is no transport maximum
for the kidney as a whole, so 80% to 90% of filtered
ketones are reabsorbed regardless of how concentrated
ketones become in the plasma during pathological conditions
or prolonged starvation. Mammals presumably could
have evolved a greater activity of the energy-consuming
ketone transport system. However, the energy cost of continuously
maintaining the system at a higher activity probably
outweighed the survival value of having the system
available during rare periods of prolonged starvation.
E. Pathophysiology of Ketonemia
As discussed earlier, the acetoacetate and 3-hydroxybutyrate
are more powerful acids than the VFA, and in the case
of acetoacetate, they are more powerful than lactic acid.
Not surprisingly, then, a high concentration of ketones in
the plasma results in a metabolic acidosis known as ketoacidosis.
The most significant ketoacidoses commonly
encountered in domestic animals are in diabetes mellitus
and ovine pregnancy toxemia. The ketoacidosis encountered
in these syndromes may cause plasma bicarbonate to
be below 10 mmol/l ( Ling et al ., 1977 ; Reid, 1968 ) and is a
chief contributor to mortality.
The ketoacidosis in diabetes of dogs and cats can be
severe with blood pH being 7.2 or less ( Edwards, 1982 ;
Ling et al ., 1977 ; Schaer, 1976 ). Because plasma ketone
concentrations in diabetic dogs have been reported to average
3.2 mmol/l with some individuals having levels of 7 to
8 mmol/l ( Balasse et al ., 1985 ), the base deficit in extracellular
fluids would be greater than that concentration
for two reasons. First, the distribution space of the ketones
is greater than that of extracellular fluid; second, some
acetoacetate and 3-hydroxybutyrate anions may have been
lost in the urine without equal losses of hydrogen ion
(a mineral ion such as sodium or potassium would have
balanced the electrical charge). Base deficits of more than
15 mmol/l have been reported in spontaneously diabetic
dogs ( Edwards, 1982 ; Ling et al ., 1977 ).
As the metabolic acidosis of diabetes progresses in
dogs, there is increased catabolism of muscle protein
( Balasse et al ., 1985 ). Much of the nitrogen from protein
degradation is diverted into ammonia rather than urea, and
it is ammonium ion that balances most of the electrical
charge on excreted acetoacetate and 3-hydroxybutyrate.
Ketones are really an alternate form of lipid, comparable
to triacylglycerols, LCFA, or VFA, and should be
considered as such in caloric balance ( Williamson, 1971 ).
VFA and ketones are effectively water-soluble forms of
lipids; however, only the ketones can be produced in large
quantities in tissue metabolism.
In fed animals, only a nominal caloric production is
derived from oxidation of ketones; however, in fasted animals
or in some pathological conditions, ketone oxidation
accounts for a substantial quantity of expended calories.
For example, only 3% to 4% of expired carbon dioxide is
derived from 3-hydroxybutyrate in fed cows ( Palmquist
et al ., 1969 ), whereas 30% of expired carbon dioxide is
derived from ketones in fasted pregnant ewes ( Pethick and
Lindsay, 1982 ).
It has been demonstrated in canine perfused liver ( Shaw
and Wolfe, 1984 ) and in vivo in humans ( Binkiwicz et al .,
1974 ; Mebane and Madison, 1964 ; Miles et al ., 1981 ) and
dogs ( Balasse et al ., 1967 ; Paul et al ., 1966 ) by infusing
acetoacetate or 3-hydroxybutyrate that both ketones inhibit
gluconeogenesis. In most of these experiments, there has
been evidence of increased plasma insulin concentrations,
which could account for the diminution in plasma glucose
concentration. The survival value of having ketones inhibit
gluconeogenesis is that in starvation, as ketone concentrations
increase and become available for tissue energy
needs, the rate at which body protein must be catabolized
to supply glucose precursors can decrease.
Not surprisingly in view of the increased insulin levels
usually observed, decreased levels of LCFA were noted
during ketone infusions in some of the experiments mentioned
previously. Thus, increased ketone levels may serve
a negative feedback on rate of lipolysis in adipose and,
therefore, on the plasma levels of ketones themselves.
F. Fasting Ketosis
During fasting, hormonal changes occur that promote lipolysis.
Most important, as less glucose is available from the gut
or from gluconeogenesis in the liver, plasma glucose concentrations
will decrease. Responding to the hypoglycemia,