Ammonia is a degradation product of nitrogen-containing compounds (mainly
proteins and amino acids) and is generated by the metabolism in
all living organisms. Dietary protein contains approximately 16% nitrogen,
and the excess nitrogen from the amino acids that are not incorporated
back into proteins is excreted in the urine as urea. Urea is produced
in the liver by an enzymatic process that is dependent on an intact
urea cycle. When the urea cycle malfunctions, urea is produced and
nitrogen in the form of ammonia accumulates in blood and tissues.
The physiology of ammonia production and disposal is summarized
in Figure 145-1. In humans and other mammals, most
of the ammonia that circulates in the bloodstream originates in
the intestine via two main mechanisms. The first is circulating
glutamine, most of which is produced in the muscle, is taken up
by the intestinal mucosa, where it is used as an energy source after
deamination by glutaminase releasing free ammonia. The second mechanism
for intestinal ammonia production involves the intestinal bacterial
flora, which releases ammonia by splitting urea and by oxidizing
amino acids. The ammonia produced in the intestine is absorbed into
the portal circulation, where ammonia concentration is approximately
10 times higher than in the peripheral blood. More than 90% of
portal ammonia is converted to urea in the liver by a series of
enzymatic reactions that comprise the urea cycle, which is most
active in periportal hepatocytes. The remaining ammonia that escapes
the urea cycle is trapped in perivenous hepatocytes to produce glutamine.
Ammonia is also produced from glutamine by glutaminase in the distal
renal tubule as a mechanism of urine acidification, but this occurs
only when the blood pH becomes abnormally acidic. Since ammonia is
readily diffusible and extremely toxic to the brain (the only organ
that displays toxicity from high ammonia levels), its level in the
blood needs to be maintained at nontoxic, relatively low levels. The
normal level of free ammonia in plasma of humans is usually less
than 35 μmol/L. Levels less than 50 μmol/L
are considered safe while levels above 100 μmol/L
are frequently associated with a range of clinical symptoms, including
lethargy, vomiting, and altered consciousness. The severity of symptoms
usually correlates with the degree of hyperammonemia, but this correlation
may vary in different patients—while some patients may
show severe brain dysfunction at ammonia levels between 100 and
200 μmol/L, others may function normally
at a similar degree of hyperammonemia. The reasons for this phenomenon
Human ammonia physiology. The complete urea cycle resides
exclusively in the liver. The intestine is a source of ammonia and
citrulline. Most of the ammonia that is absorbed from the intestine
is converted to urea in the liver. Ammonia concentration in the
portal blood is approximately 10 times higher than in systemic blood.
The citrulline produced in the intestine bypasses the liver ...
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