Hepatic encephalopathy pathogenesis

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]. 

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)... 

Basile, A.S., Jones, E.A., Skolnick, P. The pathogenesis and treatment of hepatic encephalopathy evidence for the involvement of benzodiazepine receptor ligands. Pharmacol. Rev. 1991 43 27-71... 

Goldstein, G.W. The role of brain capillaries in the pathogenesis of hepatic encephalopathy. Hepatology 1984 4 565-567... 

Jalan, R., Seery, J.P., Taylor-Roblnson, S.D. Review article pathogenesis and treatment of chronic hepatic encephalopathy Aliment. Pharmacol. Ther. 1996 10 681-697... 

Levy, L.J., Losowsky, M.S. Plasma gamma aminobutyric acid concentrations provide evidence of different mechanisms in the pathogenesis of hepatic encephalopathy in acute and chronic hver disease. Hepato-Gastroenterol. 1989 36 494-498... 

Odeh, M. Endotoxin and tumor necrosis factor- in the pathogenesis of hepatic encephalopathy. J. Clin. Gastroenterol. 1994 19 146-153... 

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... 

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. 

Secondary hyperaldosteronism plays a major role in the pathogenesis of edema in patients with cirrhosis. Therefore these patients should initially be treated with spironolactone in the absence of impaired GFR and hyperkalemia. Thiazides may then be added for patients with a creatinine clearance >50 mL/min. For those patients who remain diuretic resistant, a loop diuretic may replace the thiazide. Patients with impaired GFR (creatinine clearance of <30 mL/min) generally will require a loop diuretic, with addition of a thiazide in those who do not achieve adequate diuresis. Care should be taken to avoid hypokalemia, which may precipitate hepatic encephalopathy by increasing ammoniagenesis (Fig. 49-8). ... 

The precise pathogenesis of the central nervous system (CNS) signs and symptoms that accompany liver failure (hepatic encephalopathy) in patients such as Percy Veere is not completely understood. These changes are, however, attributable in part to toxic materials that are derived from the metabolism of nitrogenous substrates by bacteria in the gut that circulate to the liver in the portal vein. These materials "bypass" their normal metabolism by the liver cells, however, because the acute inflammatory process of viral hepatitis severely limits the ability of liver cells to degrade these compounds to harmless metabolites. As a result, these toxins are "shunted" into the hepatic veins unaltered and eventually reach the brain through the systemic circulation ("portal-systemic encephalopathy"). 

The absolute level of ammonia and its metabolites, such as glutamine, in the blood or cerebrospinal fluid in patients with hepatic encephalopathy correlates only roughly with the presence or severity of the neurologic signs and symptoms. y-Aminobutyric acid (GABA), an important inhibitory neurotransmitter in the brain, is also produced in the gut lumen and is shunted into the systemic circulation in increased amounts in patients with hepatic failure. In addition, other compounds (such as aromatic amino acids, false neurotransmitters, and certain short-chain fatty acids) bypass liver metabolism and accumulate in the systemic circulation, adversely affecting central nervous system function. Their relative importance in the pathogenesis of hepatic encephalopathy remains to be determined. 

Butterworth RF, Gigufere JF, Michaud J, Lavoie J, Pomier Layrargues G. Ammonia Key factor in the pathogenesis of hepatic encephalopathy. Neurochem. Pathol., 6, 1-12, 1987... 

Rothstein JD, Olasmaa M. Endogenous GABAeigic modulators in the pathogenesis of hepatic encephalopathy. Neurochemical research 1990 15(2) 193-197 Schmutzhard E. Viral infections of the CNS with special emphasis on herpes simplex infections. Journal of neurology 2001 248(6) 469-477... 

Zieve, L. 1987. Pathogenesis of hepatic encephalopathy. Metab. Brain Dis. 2 147-165. 

In liver failure the plasma concentrations of the aromatic amino acids (AAAs) tyrosine, phenylalanine, and tryptophan increase, probably because they are predominantly broken down in the liver, whereas the plasma levels of BCAAs decrease while they are degraded in excess in muscle as a consequence of hepatic failure-induced catabolism. As AAAs and BCAAs are all neutral amino acids and share a common transporter across the blood-brain barrier (system L carrier), changes in their plasma ratio are reflected in the brain, subsequently disrupting the neurotransmitter profile of the catecholamines and indoleamines (see sections on tyrosine and tryptophan). It has been hypothesized that this disturbance contributes to the multifactorial pathogenesis of hepatic encephalopathy. In line with this hypothesis it has been suggested that normalization of the amino acid pattern by supplementing extra BCAAs counteracts hepatic encephalopathy. 

A study by Rao et al." measured the levels of amino acids using in vivo cerebral microdialysis in the frontal cortex of portacaval-shunted rats administered ammonium acetate to precipitate severe portal-systemic encephalopathy. In comparison to sham-operated control rats, tryptophan levels increased by 63% along with those of other amino acids. However, the experimental animals did not have a significant increase in extracellular fluid concentration of tryptophan, suggesting that increased spontaneous release of tryptophan in cerebral cortex is not implicated in the pathogenesis of hepatic coma. 

---