CLINICAL CASES
185
Phosphorylation of phosphorylase kinase partially activates it so that it can
phosphorylate phosphorylase b to its active form. Phosphorylase kinase is
also partially activated by Ca2+; full activation is obtained when it both binds
Ca2+ and is phosphorylated. Conversion of phosphorylase b to phosphorylase
a enables glucose 1-phosphate to be released from glycogen. Thus, glucagon
and epinephrine start a cascade that mobilizes glucose from glycogen and at
the same time inhibits the storage of glucose as glycogen.
When blood glucose levels are elevated, insulin is secreted from the pan-
creatic cells. When insulin binds to hepatic insulin receptors, it results in the
activation of a complex series of kinases that leads to the activation of pro-
tein phosphatase 1. Protein phosphatase 1 dephosphorylates phosphory-
lase kinase, phosphorylase, and inhibitor 1, thus inactivating them and
inhibiting the phosphorolysis of glycogen. It also dephosphorylates glycogen
synthase, converting it to its active form and enabling the storage of glucose as
glycogen. In addition, the liver form of phosphorylase a is inhibited by ele-
vated intracellular concentrations of glucose. Thus insulin favors the storage
of glycogen and inhibits its mobilization.
Although the etiology of the AFLP syndrome is unclear, it does appear to
be a defect affecting mitochondrial processes. Liver biopsy usually will show
mitochondrial disruption and microvesicular fat deposits, indicating decreased
P-oxidation of fatty acids. The fatty acids, since they cannot be efficiently oxi-
dized in the mitochondria, are converted to triglycerides, which build up in the
hepatocyte. The fat infiltration decreases the amount of glycogen that can be
stored and mobilized to maintain blood glucose levels. Gluconeogenesis is
also depressed because ATP is not available from the oxidation of fatty acids.
Thus, blood glucose levels decline.
As noted above, there have been reports that link some cases of AFLP with
a defect in fatty acid metabolism in the fetus. These include fetal deficiencies
of long chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD),
carnitine-palmitoyl transferase 1 (CPT 1), and medium chain acyl-
coenzyme A dehydrogenase (MCAD). The mechanism by which defective
fetal fatty acid oxidation causes maternal illness is not known. However, since
the fetus uses primarily glucose metabolism for its energy needs, it is likely
that toxic products from the placenta, which does use fatty acid oxidation,
cause the maternal liver failure.
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