5. The physiopathology and increased morbidity-mortality with the incremental rise of ammonia

Proof of the role of ammonia in pathogenesis of HE has come from the efficacy of therapies aimed to lower plasma ammonia in improving its symptoms. The mechanisms causing brain dysfunction in liver disease are still not known to the full extent. In coma of models of acute liver failure, the effects of ammonia are present in brain swelling, impaired cerebral perfusion, and reversible impairment of neurotransmitter systems [13].

Stemming from this proof of concept, several studies have tried to elucidate the effects of hyperammonemia. First, ammonia is believed to be a direct neurotoxin potentialized by other toxins, such as mercaptans and short-chain fatty acids [14]. Second, it impairs the blood–brain barrier by changing the protein transport [15]. Third, it increases the intracellular osmolality of astrocytes leading to edema and extreme cases, herniation [13, 16]. Lastly, it increases oxidative stress. In one study, oxidative stress markers in the brain of patients with cirrhosis with severe hepatic encephalopathy included elevated levels of protein tyrosine-nitrated proteins, heat shock protein-27, and 8-hydroxyguanosine as a marker for RNA oxidation [17].

In a recent study of patients with cirrhosis, there was significant evidence that ammonia levels correlate with not only the severity of hepatic encephalopathy but also the failure of other organs in cirrhosis and is an independent risk factor for 28 day mortality. This data provided evidence that the ammonia level has a clinically relevant utility in providing important prognostic information, signifying its potential role as a biomarker in identifying patients at high risk of mortality. A reduction in ammonia level was associated with improved survival, confirming it as a potential therapeutic target. Classically in urea cycle disorders ammonia levels above 200 μmol/L were considered a poor prognostic factor [18], but in this study in cirrhotics even ≥79.5 μmol/L was associated with increased mortality, indicating an additional role of ammonia in dictating clinical outcomes [11].

Classically, there was a clear distinction of the harmful effects of the ammonia in acute liver failure due to the osmotic component [13] and in lesser degree in chronic liver disease, stating that ammonia in cirrhosis increased morbidity and not mortality. But newer studies and prospective analysis shows that it can be harmful in similar way, increasing mortality [11]. Further studies are needed to corroborate both the utility and prognostic value of ammonia in the setting of chronic liver disease.

#### 6. Confounding factors and differential diagnosis

Ammonia levels may rise due to reasons other than acute or chronic liver disease. This may include increased urea absorption/production, decreased extrahepatic removal, and reduced participation of liver (Table 1).

Processes that increase urea absorption/production are the main conditions that make up the differential diagnosis. These conditions include gastrointestinal bleeding, renal disease, urinary tract infection with a urease-producing organism (e.g.,

patients with cirrhosis who were given 12 g of BCAAs per day for 2 years, compared with diet therapy and a defined food intake, found a significant decrease in HE and refractory ascites in the treatment group [3]. Because of their poor palatability and high cost, BCAAs are not routinely recommended, but they were important tools in the

The mechanism of how the liver processes the ammonia has been described and involves the following steps: ammonia is produced by the enterocytes from glutamine and by colonic bacterial catabolism of nitrogenous sources, such as ingested protein and secreted urea. It then enters the circulation through the portal vein where the liver metabolizes the majority of the ammonia converting it into urea or glutamine and preventing entry into the systemic circulation. These were demon-

The increase in blood ammonia levels in advanced liver disease is a consequence of impaired liver function and of shunting of blood around/away from the liver. Muscle wasting, a common occurrence in these patients, also may contribute since

The measurement serum ammonia concentration in patients suspected of having HE remains controversial. While it is well known that venous ammonia levels vary immensely and are not useful for screening or following HE [5], arterial ammonia concentrations more accurately correlate with HE as it is further discussed in this chapter. Furthermore, the grade of HE seems to be more closely related to the partial pressure of gaseous ammonia (pNH3) than the total arterial ammonia concentration, since gaseous ammonia readily enters the brain [6]. This can be easily

The accuracy of ammonia determination is influenced by many factors, such as fist clenching, use of a tourniquet, and whether the sample was placed on ice [7]. It is largely recommended that it is tested within an hour of collection, though some agents (sodium borate/l-serine) could potentially stabilize for up to 12 h [8].

Thus, ammonia should be collected in an extremity without trauma with arterial blood, collected in chilled tubes with ammonia-free sodium heparin (green top) or ethylenediaminetetraacetic acid (EDTA; purple top), placed on ice, and delivered rapidly to the laboratory (within an hour). Some chemicals could stabilize for posterior measurement, but more studies are needed to confirm that these agents

Normal values for ammonia concentration may differ depending on age groups. It

proof of concept of liver's importance in ammonia homeostasis.

Figure 1.

28

Branched-chain amino acids.

Liver Disease and Surgery

strated through careful studies of the urea cycle and its disorders [4].

muscle is also an important site for extrahepatic ammonia removal.

3. Appropriate measurement and collection

calculated with ammonia levels when correlating with pH.

will not influence in other reactions and measurements.

4. Correlation of levels and development encephalopathy

can be often higher in newborns, with the upper limit of normal of ammonia

#### Table 1.

Differential diagnosis for elevated ammonia levels.

Proteus mirabilis), ureterosigmoidostomy, parenteral nutrition, high-dose chemotherapy, and systemic Mycoplasma hominis or Ureasplasma spp. infection in lung transplant recipients.

tap water, milk/molasses, and lactulose. The efficacy of enema administration has

The use of laxatives, especially non-absorbable disaccharides, has been the cornerstone of the treatment HE. Oral lactulose or lactitol (the latter is not available in the United States) are thought to have an in vitro benefit over other laxatives. This is due their multi-mechanistic properties. Not only do they cause catharsis but they convert ammonia to ammonium and also reduce intestinal pH, thereby reducing ammonia absorption. These agents improve symptoms in patients with acute and chronic encephalopathy when compared with placebo but do not improve psychometric test performance or mortality. Side effects are common and include abdom-

Oral antibiotics have been used with the aim of modifying the intestinal flora and lowering stool pH to enhance the excretion of ammonia. Antibiotics are generally used as second-line agents after lactulose or in patients who are intolerant of non-absorbable disaccharides. Rifaximin given orally in a dose of 550 mg twice daily was approved in 2010 for the treatment of chronic hepatic encephalopathy and reduction in the risk of recurrence of overt encephalopathy in patients with advanced liver disease. The tolerability and side-effect profile of rifaximin are superior to those of lactulose, albeit at greater financial cost. Other antibiotics, including neomycin, paromomycin, metronidazole, and vancomycin, have been studied in small trials and case series, but some may have an increased side effect

Agents that may modify intestinal flora and modulate the generation or intestinal absorption of ammonia have been evaluated as potential treatments. Acarbose, an intestinal α-glucosidase inhibitor used to treat type 2 diabetes mellitus, inhibits

7.2 Inhibiting ammonia production: antibiotics (neomycin, paromomycin, metronidazole, rifaximin, and vancomycin), laxatives (disaccharideslactulose/lactitol, polyethylene glycol), and modification of flora

inal cramping, bloating, flatulence, and electrolyte imbalance.

profile and the effectiveness of others are not well established.

not been evaluated [19].

Table 2.

Ammonia

31

(Lactobacillus SF68, acarbose)

Mechanisms used in treatment of hyperammonemia.

DOI: http://dx.doi.org/10.5772/intechopen.88044

Within the conditions that decrease extrahepatic removal of ammonia, diseases affecting the muscles such as severe muscle exertion/heavy exercise are worth noting.

Reduced participation of liver in the removal of ammonia may occur in any cause of portosystemic shunting of blood, such as in hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) and portal hypertension with collateral formation.

Two other groups of conditions are considered controversial in their role in the development of hyperammonemia: congenital disorders (certain inborn errors of metabolism such as urea cycle defects and organic acidemia) and medication induced (valproic acid, barbiturates, narcotics, diuretics, alcohol, and salicylate-Reye syndrome). Some authors classify both as a cause for hyperammonemia while others would englobe in subgroups of liver diseases as they are believed to have similar pathophysiology [19, 20].
