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Lange Gastrointestinal Physiology > Section IV. Transport and Metabolic Functions of the Liver > Chapter 14. Ammoniaand Urea >

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 leadto this outcome

Discuss treatments for hepatic encephalopathy

BASIC PRINCIPLES OF AMMONIA METABOLISM

Ammonia (NH3) 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 DISPOSITIONAmmonia 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.



Sources of ammonia production.

Figure 142.



Whole body ammonia homeostasis in health. The majority of ammonia produced by the body is excreted by thekidneys 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



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.



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



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 wellas from metabolism of urea by bacterial ureases.



Excessive amounts of ammonia in the circulation are toxic to the central nervous system, socirculating 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, ammoniacatabolism is decreased, which may increase plasma levels considerably.

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

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

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

STUDY QUESTIONS141. 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?



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 READINGSBrusilow 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.



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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