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Ammonia and Urea

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OBJECTIVES
Define the contributors to the level of ammonia in the circulation, and explain why a mechanism for
disposal of this metabolite is needed
Outline the pathways that lead to ammonia production in the intestinal lumen
Describe extraintestinal sources of ammonia
Describe the metabolic steps involved in the conversion of ammonia to urea in the hepatocyte
Understand the routes for eventual disposal of urea
Explain the consequences of excessive ammonia in the circulation, and the disease states that can lead
to this outcome
Discuss treatments for hepatic encephalopathy

BASIC PRINCIPLES OF AMMONIA METABOLISM

Ammonia (NH 3 ) is a small metabolite that results predominantly from protein degradation. It is highly
membrane-permeant and readily crosses epithelial barriers in its nonionized form.

Role and Significance

Ammonia does not have a physiologic function. However, it is important clinically because it is highly
toxic to the nervous system. Because ammonia is being formed constantly from the deamination of amino
acids derived from proteins, it is important that mechanisms exist to provide for the timely and efficient
disposal of this molecule. The liver is critical for ammonia catabolism because it is the only tissue in which
all elements of the urea cycle, also known as the Krebs-Henseleit cycle, are expressed, providing for the
conversion of ammonia to urea. Ammonia is also consumed in the synthesis of nonessential amino acids,
and in various facets of intermediary metabolism.

AMMONIA FORMATION AND DISPOSITION

Ammonia in the circulation originates in a number of different sites. A diagram showing the major
contributors to ammonia levels is shown in Figure 141. Note that the liver is efficient in taking up
ammonia from the portal blood in health, leaving only approximately 15% to spill over into the systemic
circulation (Figure 142).

Figure 141.

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Sources of ammonia production.

Figure 142.

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Whole body ammonia homeostasis in health. The majority of ammonia produced by the body is excreted by the
kidneys in the form of urea.

Intestinal Production
The major contributor to plasma ammonia is the intestine, supplying about 50% of the plasma load.
Intestinal ammonia is derived via two major mechanisms. First, ammonia is liberated from urea in the
intestinal lumen by enzymes known as ureases. Ureases are not expressed by mammalian cells, but are
products of many bacteria, and convert urea to ammonia and carbon dioxide. Indeed, this provides the
basis for a common diagnostic test, since H. pylori, which colonizes the gastric lumen and has been
identified as a cause of peptic ulcer disease, has a potent urease. Therefore, if patients are given a dose of
urea labeled with carbon-13, rapid production of labeled carbon dioxide in the breath is suggestive of
infection with this microorganism.
Second, after proteins are digested by either host or bacterial proteases, further breakdown of amino acids
generates free ammonia. Ammonia in its unionized form crosses the intestinal epithelium freely, and enters
the portal circulation to travel to the liver; however, depending on the pH of the colonic contents, a portion
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the portal circulation to travel to the liver; however, depending on the pH of the colonic contents, a portion
of the ammonia will be protonated to ammonium ion. Because the colonic pH is usually slightly acidic,
secondary to the production of short chain fatty acids, the ammonium is thereby trapped in the lumen and
can be eliminated in the stool (Figure 142).

Extraintestinal Production
The second largest contributor to plasma ammonia levels is the kidney. You will recall from renal
physiology that ammonia transport by tubular epithelial cells is an important part of the response to whole
body acid-base imbalances. Ammonia is also produced in the liver itself during the deamination of amino
acids. Minor additional components of plasma ammonia derive from adenylic acid metabolism in muscle
cells, as well as glutamine released from senescent red blood cells.

Urea Cycle
As noted earlier, the most important site for ammonia catabolism is the liver, where the elements of
the urea cycle are expressed in hepatocytes. A depiction of the urea cycle is provided as Figure 143.
Ammonia derived from the sources described earlier is converted in the mitochondria to carbamoyl
phosphate, which in turn reacts with ornithine to generate citrulline. Citrulline, in turn, reacts in the cytosol
with aspartate, produced by the deamination of glutarate, to yield sequentially arginine succinate then
arginine itself. The enzyme arginase then dehydrates arginine to yield urea and ornithine, which returns to
the mitochondria and can reenter the cycle to generate additional urea. The net reaction is the combination
of two molecules of ammonia with one of carbon dioxide, yielding urea and water.

Figure 143.

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The urea cycle, which converts ammonia to urea, takes place in the mitochondria and cytosol of hepatocytes.

Urea Disposition
A "mass balance" for the disposition of ammonia and urea is presented in Figure 142. As a small
molecule, urea can cross cell membranes readily. Likewise, it is filtered at the glomerulus and enters the
urine. While urea can be passively reabsorbed across the renal tubule as the urine is concentrated, its
permeability is less than that of water such that only approximately half of the filtered load can be
reabsorbed. Because of this, the kidney serves as the site where the majority of the urea produced by the
liver is excreted. However, some circulating urea may also passively back diffuse into the gut, where it is
acted on by bacterial ureases to again yield ammonia and water. Some of the ammonia generated is
excreted in the form of ammonium ion; the remainder is again reabsorbed to be handled by the liver once
more.

PATHOPHYSIOLOGY AND CLINICAL CORRELATIONS

Hepatic Encephalopathy

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When ammonia degradation is reduced, it can accumulate in the plasma to levels that become
toxic to the central nervous system. Remember that ammonia, as a small, neutral molecule, is relatively
permeant across cell membranes and can easily traverse the blood-brain barrier. If ammonia levels rise
abruptly, in acute liver failure, coma and death can rapidly ensue. More commonly, as in the setting of
chronic liver disease, patients will experience a gradual decline in mental status with confusion and
dementia, followed eventually by coma if the condition is untreated. The increase in plasma ammonia in
liver disease occurs by two mechanisms. First, if hepatocyte function is compromised, there is less capacity
to degrade ammonia coming from the intestine and extraintestinal sites. Second, if blood flow through the
liver is impaired by cirrhosis and portal hypertension has set in (see also Chapter 10), collateral blood
vessels may form that shunt the portal blood flow around the liver, bypassing the residual capacity of the
liver to degrade ammonia (the same is true if a shunt is placed surgically to relieve portal hypertension). It
is likely that both mechanisms contribute to the rise in plasma ammonia in the setting of long-standing
liver disease.

Because the intestine supplies the largest load of ammonia to the circulation, treatments for hepatic
encephalopathy focus primarily on reducing the delivery of ammonia into the portal circulation. A common
technique is to give a sugar, lactulose, which cannot be degraded by mammalian digestive enzymes but is
broken down by bacteria in the colon to form short chain fatty acids. In turn, the pH of the colonic lumen is
decreased and more of the ammonia being formed in that site is protonated and "trapped" as ammonium
ion to be lost to the stool. Similarly, patients can be given a nonabsorbable antibiotic such as neomycin
which reduces the level of bacterial colonization in the intestine, thereby reducing ammonia production.
Finally, patients with liver disease are often advised to follow a low-protein diet, again in an effort to reduce
ammonia production in the intestine. Ultimately, however, the only lasting treatment for hepatic
encephalopathy is a liver transplant, and mental symptoms often are completely reversible if they have not
been too long-standing.

While ammonia is clearly toxic to the central nervous system, it is important to note that it is
probably not the only contributor to hepatic encephalopathy. Indeed, while plasma ammonia levels are
commonly measured in patients with severe liver disease and altered mental status, they do not always
correlate well with the degree of encephalopathy nor are they a reliable index of the effectiveness of
treatment. It is likely that other substances normally detoxified by the liver may also contribute to injury of
the central nervous system, and/or substances produced by the liver, such as specific classes of amino
acids, are needed for central nervous system health. For this reason, there is considerable interest in the
development of artificial liver support devices, consisting of hepatocytes grown on artificial matrices. Other
machines involve artificial approaches to the detoxifying functions of the liver, such as the molecular
adsorbant recycling system (MARS) (note that simple dialysis such as used in renal failure is not effective in
liver failure due to the protein-bound nature of the toxins and metabolites that must be removed from the
circulation). These systems might be used to mitigate the most serious effects of liver failure until an organ
suitable for transplantation can be identified, and indeed, initial clinical trials with prototypes of such
devices are encouraging that hepatic encephalopathy can be reversed, at least temporarily.

KEY CONCEPTS
Ammonia in plasma is derived from protein degradation and deamination of amino acids, as well
as from metabolism of urea by bacterial ureases.

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Excessive amounts of ammonia in the circulation are toxic to the central nervous system, so
circulating levels are carefully regulated in health.

The intestine supplies the majority of plasma ammonia.

The liver is the site of ammonia catabolism via the Krebs-Henseleit, or urea cycle.

The urea produced is mostly excreted by the kidneys.

In the setting of liver disease, particularly if blood is shunted away from the liver, ammonia
catabolism is decreased, which may increase plasma levels considerably.

Increases in plasma ammonia, and perhaps other toxins, are associated with a condition known as
hepatic encephalopathy, a serious condition.

Treatments for hepatic encephalopathy focus predominantly on reducing the ammonia load coming
from the colon.

Currently, the only definitive treatment is liver transplantation, but liver assist devices may play a
supportive role in the future.

STUDY QUESTIONS
141. In health, ammonia formed in the colon is partially excreted in the stool. Which of the following
allows for this excretion?
A. Limited diffusion of ammonia across colonocytes
B. Short chain fatty acid production
C. Active secretion of ammonia by colonocytes
D. Absorption of ammonium ions
E. Uptake by bacteria
142. A 70-year-old man with long-standing alcoholic liver disease is noted to have progressively
worsening confusion and disorientation. Loss of the function of which cell type accounts for his altered
mental state?
A. Kupffer cells
B. Hepatocytes
C. Colonocytes
D. Vascular endothelial cells
E. Stellate cells
143. A patient with severe portal hypertension is treated surgically by the placement of a shunt
connecting the portal vein to the vena cava. Which of the following will pertain after the surgery compared
to before?
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to before?
Risk of encephalopathy Risk of variceal bleeding
A. Increased

Decreased

B. Decreased

Decreased

C. Unchanged

Decreased

D. Increased

Increased

E. Decreased

Increased

F. Unchanged

Increased

144. Patients with advanced liver disease are at increased risk of sepsis due to bacteria derived from the
colon. Which of the following treatments for hepatic encephalopathy would also reduce the risk for sepsis?
A. Low protein diet
B. Lactulose
C. Neomycin
D. Passage of blood through a hepatocyte column
E. MARS
145. A patient with bladder cancer has his bladder removed, and his ureters surgically anastomosed to
the colon. He subsequently develops liver disease. Which of the following outcomes of liver disease would
he be particularly susceptible to, compared to a liver disease patient with an intact urinary system?
A. Jaundice
B. Hypoglycemia
C. Ascites
D. Encephalopathy
E. Esophageal varices

STUDY QUESTION ANSWERS

141. B
142. B
143. A
144. C
145. D

SUGGESTED READINGS
Brusilow SW, Horwich AL. Urea cycle enzymes. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The
Molecular and Metabolic Basis of Inherited Disease. New York: McGraw-Hill; 1995:11871232.
Jones EA. Pathogenesis of hepatic encephalopathy. Clin Liver Dis. 2000;4:467485. [PMID: 11232201]
Mendler M, Donovan J, Blei A. Central nervous system and pulmonary complications of end-stage liver
disease. In: Yamada T, Alpers DH, Kaplowitz N, Laine L,Owyang C, Powell DW, eds. Textbook of
Gastroenterology. 4th ed. Philadelphia: Lippincott Williams and Wilkins; 2003:24452467.
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Gastroenterology. 4th ed. Philadelphia: Lippincott Williams and Wilkins; 2003:24452467.

Olde Damink SW, Deutz NE, Dejong CH, Soeters PB, Jalan R. Interorgan ammonia metabolism in liver
failure. Neurochem Int. 2002;41:177188.
Vaquero J, Chung C, Cahill ME, Blei. AT. Pathogenesis of encephalopathy in acute liver failure. Semin Liver
Dis. 2003;23:259269. [PMID: 14523679]

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