Hepatic encephalopathy ammonia

Hilgier, W., Puka, M., and Albrecht, J. 1992. Characteristics of large neutral amino acid-induced release of preloaded 1-glutamine from rat cerebral capillaries in vitro effects of ammonia, hepatic encephalopathy, and gamma-glutamyl transpeptidase inhibitors. J. Neurosci. Res. 32 221-226. 

Lactulose is the foundation of pharmacologic therapy to prevent and treat hepatic encephalopathy because its unique mechanism binds ammonia in the gut and facilitates its excretion. 

Increased blood ammonia concentration is characteristic of hepatic encephalopathy, but levels do not correlate well with the degree of impairment. 

In acute hepatic encephalopathy, temporary protein restriction to decrease the rate of ammonia production can... 

Lactulose is the foundation of pharmacologic therapy to prevent and treat hepatic encephalopathy. It is a non-digestible synthetic disaccharide laxative that is hydrolyzed in the gut to an osmotically-active compound that draws water into the colon and stimulates defecation. Lactulose also lowers colonic pH, which favors the conversion of ammonia (NH3) to ammonium (NHf).48 Ammonium is ionic and cannot cross back into systemic circulation it is eliminated in the feces. Lactulose is usually initiated at 15 to 30 mL two to three times per day and titrated to a therapeutic goal of two to four soft bowel movements daily.20 49 50... 

Hepatic encephalopathy Change in mental or neurologic status secondary to progressive liver disease or confusion and disorientation that a patient with advanced liver disease experiences due to accumulation of ammonia. 

Rifaximin has been shown to possess good antibacterial activity against a variety of anaerobic bacteria (table 3) [24, 27, 28], Anaerobes have been shown to be capable of producing ammonia (especially Clostridia), which has been incriminated in the pathogenesis of hepatic encephalopathy [29], The authors suggested that since rifaximin is a nonabsorbable and effective antibiotic against anaerobic flora, it would be an ideal treatment for patients with compromised hepatic function. Eubacterium is inhibited by rifaximin with an MIC90 < 2 pg/ml [27]. 

Baraldi M, Pinelli G, Ricci P, Zeneroli ML Toxins in hepatic encephalopathy The role of the synergistic effect of ammonia, mercaptans and short chain fatty acids. Arch Toxicol 1984 7 103-105. 

Wang V, Saab S Ammonia levels and the severity of hepatic encephalopathy. Am J Med 2003 114 237-238. 

Ong JP, Aggarwal A, Krieger D, Easley KA, Karafa MT, Van Lente F, Arroliga AC, Mullen KD Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med 2003 114 188-193. 

FIGURE 34-3 Positron emission tomography using 13NH3 showing increased brain ammonia uptake in a patient with liver cirrhosis and mild hepatic encephalopathy. CMRA, cerebral metabolic ratio for ammonia HE, hepatic encephalopathy PS, permeability/surface area product. (With permission from reference [9].)... 

Lockwood, A. H., Yap, E. W. H. and Wong, W. H. Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. /. Cereb. Blood Flow Metab. 11 337-341,1991. 

Yamamoto H, Sugihara N. 1987. Blood ammonia levels and hepatic encephalopathy induced by CCH in rats. Toxicol AppI Pharmacol 91 461-468. 

This is a semisynthetic disaccharide which is not absorbed from the GI tract. It produces an osmotic diarrhoea of low pH, and discourages the proliferation of ammonia-producing bacteria. It is therefore useful in the treatment of hepatic encephalopathy. Osmotic laxatives like lactulose, sorbitol, and lactilol rarely cause significant adverse effects. Glycerol suppositories are useful in softening and lubricating passage of inspissated faeces. 

Lactulose (Constulose, Generlac, Enulose, Others) [Laxative/ Osmotic] Uses Hepatic encephalopathy constipation Action Acidifies the colon, allows ammonia to diffuse into colon Dose Acute hepatic encephalopathy. 30-45 mLPO qlh until soft stools, then tid-qid Chronic laxative therapy 30-45 mL... 

Because the CNS is sensitive to ammonia, its metabolism in the brain and the neurotoxicity associated with hyperammonia and hepatic encephalopathy (the proximate source of damage in the latter is also ammonia) is reviewed here. Hepatic encephalopathy (HE) or congenital and acquired hyperammonemia result in excessive ammonia accumulation within the CNS. The condition is due... 

There are several theories behind the cause of hepatic encephalopathy. One of these is that the accumulation of toxins in the brain, particularly ammonia, is the cause. Ammonia is produced in the intestine and is usually metabolised in the liver to urea via the urea cycle. As a result of portosystemic shunting and reduced metabolism in the liver, ammonia serum levels rise as the transformation to urea is reduced. However, the validity of this theory is questionable as not all patients with signs of hepatic encephalopathy have raised serum ammonia levels. Another theory is that patients with hepatic encephalopathy have increased permeability of the blood-brain barrier, and hence the increased toxin levels permeate the brain more than usual, leading to altered neuropsychiatric function. There are also theories relating to increased levels of neurotransmitters, short-chain fatty acids, manganese and increased GABA-ergic transmission. 

Infection, gastrointestinal bleeding or injudicious use of sedatives and diuretics can precipitate hepatic encephalopathy in cirrhotic patients. The pathophysiology is complex but ammonia appears to hold a central role. Derived mainly from the action of colonic urease-containing bacteria, ammonia is... 

Reduction of dietary protein reduces ammonia production and has long been used to prevent hepatic encephalopathy. Any potential benefit against encephalopathy must be tempered by the knowledge that most patients with severe liver disease are malnourished. Protein from vegetable sources is often better tolerated than animal-derived protein, at least in part due to its higher fibre content which accelerates transit through the gut. 

Owing to the multitude of factors interfering with the ammonia concentration as well as to the multifactorial pathogenesis of hepatic encephalopathy (HE), it is understandable that there is no correlation between the levels of ammonia and the prevailing HE stage. Nevertheless, a hyperammonia syndrome is generally presumed if concentrations in the venous or arterial plasma reach 135-170 4g/dl. A value of > 150 gg/dl can be attributed to coma stage I. Here, the arterial ammonia level correlates better with HE than do the values found in venous blood, (s. pp 56, 266)... 

Synergistic neurotoxicity (L. Zieve, 1981) None of these substances or mechanisms is "comagenic in itself. Nevertheless, if present at the same time - even in low quantities) ) - they can cause the development of hepatic encephalopathy. The neurotoxicity of ammonia can be enhanced by these substances. (115)... 

Basile, A.S., Jones, E.A. Ammonia and GABA-ergic neurotransmission interrelated factors in the pathogenesis of hepatic encephalopathy. Hepatology 1997 25 1303-1305... 

Hnber, M., Rossle, M., Siegerstetter, V., Ochs, A., Haag, K., Kist, M., Blnm, H.E. Helicobacter pylori infection does not correlate with plasma ammonia concentration and hepatic encephalopathy in patients with cirrhosis. Hepato-Gastroenterol. 2001 48 541 -544... 

Kramer, L., Trlbl, B., Gendo, A., Zauner, C., Schneider, P., Ferenci, P., Madl, C. Partial pressure of ammonia versus ammonia in hepatic encephalopathy. Hepatology 2000 31 30—34... 

Norenberg, M.D. Astrocytic-ammonia interactions in hepatic encephalopathy. Semin. Liver Dis. 1996 16 245-253... 

Venturini, L, Corsi, L., Avallone, R., Farina, F., Bedogni, G., Baraldi, C., Baraldi, M., Zeneroli, M.L. Ammonia and endogenous benzodia-zepine-like compounds in the pathogenesis of hepatic encephalopathy. Scand. J. Gastroenterol. 2001 36 423-425... 

Walker, C.O., Schenker, S. Pathogenesis of hepatic encephalopathy with special reference to the role of ammonia. Amer. J. Clin. Nutr. 1970 23 619-632... 

The indication for administering BCAA in patients with hepatic encephalopathy to compensate amino-acid imbalance was proposed by J.E. Fischer et al. in 1974, and implemented parenterally. However, oral application of BCAA for an adequate treatment period also has beneficial effects on cirrhosis and HE (7.) improvement in protein tolerance and the nutritional condition, (2.) improvement in cerebral functions (II8, 122), probably due to an amelioration of liver function, (2.) stimulation of ammonia detoxification with a positive nitrogen balance (118), (4.) reduction in or normalization of AAA levels, and (5.) promotion of glutamine synthesis with a favourable effect on the cells of the immune system and on renal function. By means of BCAA, it was possible to prolong the survival time and delay the occurrence of liver failure in rats with CC -induced cirrhosis. (123, 126) However, there are diverging results, which need further clarification. In principle, the use of BCAA is considered to be a necessary form of supplementary treatment for catabolic metabolism in cirrhosis (124,125, 127, 128, 130-132), in (also latent) HE and after curative resection of hepatocellular carcinoma. (I2l) (s. p. 280)... 

The pathophysiology of hepatic encephalopathy is not completely understood but includes an increased sensitivity to dietary proteins. Ammonia concentrations are always increased with acute encephalopathy and usually increased with chronic encephalopathy. A reduction of plasma ammonia is often associated with symptomatic improvement. However, since plasma ammonia concentrations do not correlate with the severity of the encephalopathy, it has been suggested that other factors are involved. It is now recognized that a variety of neurotransmitter systems are dysfunctional in hepatic encephalopathy, but the exact cause for the changes is not known. One important contributor is the endogenous benzodiazepine agonist system, but other abnormalities must be invoked to explain all the findings. ... 

The diagnosis of hepatic encephalopathy is made on clinical grounds. Plasma ammonia concentrations are rarely helpful, either for diagnosis or for monitoring the patient s disorder normal ammonia concentrations are helpful in excluding hepatic encephalopathy as a cause of cerebral dysfunction. An exception is a patient who presents with acute encephalopathy of unknown cause. Elevated ammonia concentrations in that situation suggest acute hepatic failure or Reye s syndrome. 

Venturini I, Corsi L, AvaUone R, Farina F, Bedogni G, Baraldi C, et al. Ammonia and endogenous benzodi-azepine-like compounds in the pathogenesis of hepatic encephalopathy. Scand J Gastroenterol 2001 36 423-5. 

Bachmann C, Colombo JP. Acid-base status and plasma glutamine in patients with hereditary urea cycle disorders. In Soeters PB, Wilson )HP, Meijer AJ, eds. Advances in ammonia metabolism and hepatic encephalopathy, 1st ed. Amsterdam Elsevier, 1988 72-8. 

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