Encephalopathies ammonia effects

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]. 

Antibiotics with activity against urease-producing bacteria, such as neomycin [42], paromomycin [44] or metronidazole [45], also reduce the production of intestinal ammonia and have proved to be of value. Vancomycin has also been used in patients with lactulose-resistant chronic encephalopathy [46]. The efficacy of neomycin is similar to that of lactulose [42]. However, a small percentage of this drug is absorbed from the gastrointestinal tract and may cause ototoxic and nephrotoxic effects, especially with continuous use over several months [47]. This drug should be used with particular caution by patients with renal insufficiency. The efficacy of metronidazole for... 

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. 

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. 

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)... 

In patients with diabetes plus liver cirrhosis, acarbose treatment appears to be favourable because it improves the detoxification of ammonia (Muting, 1984). Acarbose induces an increased growth of lactobacteria, lowers intestinal pH and hyperammonaemia, inducing a beneficial effect on portosystemic encephalopathy. It also reduces lipolysis and ketogenesis in cirrhotic patients (Zillikens et at., 1989), following a late evening meal with 100 mg acarbose. 

Another nonabsorbable disaccharide used in the treatment of hepatic encephalopathy is lactitol ( 6-galactosidosorbitol). Compared to lactose, lactitol has the advantage of higher palatability and fewer side effects (e.g., flatulence). Ammonia production in... 

Favourable effect of E. faecium M-74 emiched with organic selenium on chronic hepatic encephalopathy was also demonstrated (Boca et al. 2004). The blood ammonia levels as well as the results from the number-connecting test after 8-9 weeks significantly approached the normal pattern. EEG results were improved and they were often normalised. In another clinical study, the administration of E. faecium M-74 probiotic strain was associated with reduction of serum cholesterol concentrations by 12% after 56 weeks of oral administration (HUvak et al. 2005). 

Ong, J.P., et al., et al.2003. Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med, 114(3) pp. 188-193 Puliyel, J.M. and V. Bhambhani, 2003. Ketoacid levels may alter osmotonicity in diabetic ketoacidosis and precipitate cerebral edema. Arch Dis Child, 88(4) p. 366 Roberts, J.S., et al.2006. Cerebral hyperemia and impaired cerebral autoregulation associated with diabetic ketoacidosis in critically ill children. Crit Care Med, 34(8) pp. 2217-2223 Ryan, C.J., et al.2001. Multisorbent plasma perfusion in fulminant hepatic failure effects of duration and frequency of treatment in rats with grade 111 hepatic coma. Artif Organs, 25(2) pp. 109-118... 

A particularly novel approach to lowering blood and brain ammonia concentrations in liver failure involves the use of 1-camitine and results of a recent study, following up on studies in experimental animals (Therrien et al, 1997) demonstrated a protective effect of L-camitine agonist ammonia-precipitated encephalopathy in cirrhotic patients (Malaguameia et al., 2005). 

Chatauret N, Butterworth RF. Effects of Ever failure on inter-organ trafficking of ammonia Implications for the treatment of encephalopathy. J. Gastroenterol. Hepatol., 19, S219-S223, 2004... 

Therrien G, Butterworth J, Rose C, Butterworth RF. Protective effect of 1-camitine in ammonia-precipitated encephalopathy in portacaval shunted rats Evidence for a central mechanism of action. Hepatology, 25, 551-556, 1997... 

Ammonia metabolism within the muscle may be improved by the administration of L-omithine-L- aspartate (LOLA). Controlled trials suggest that enteral and parenteral formulations of ornithine aspartate significantly reduce blood ammonia levels and have useful therapeutic effects in patients with cirrhosis and encephalopathy (Kircheis et al., 1997 Stauch et al., 1998). Poo et al. (2006) recently showed in a randomized, lactulose-controlled study of oral ornithine-aspartate in 20 patients with clinically overt HE that LOLA in contrast to lactulose significantly improved parameters of mental status, number connection test scores, asterixis scores and EEG. Both lactulose and LOLA reduced serum ammonia levels and improved quaUty of life scores. Since only 20 patients were included in this study the results cannot be considered proof for the superiority of LOLA compared to lactulose, while the data underscore the effect of both agents. Ornithine aspartate is well tolerated in general. From a theoretical point of view the combination of disaccharides and ornithine aspartate may be useful in patients with insufficient efficacy of only one of the two drugs. 

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. 

This synthetic disaccharide, l, P-galactosido-fructose, b been in use abroad for a number of years as an effective cathartic. More recently it has found potential in the treatment of hepatic encephalopathy where it may have considerable advantage over other types of available therapy. 23,124 ijiie mechanism of action in these cases has been described as an "acid dialysis". Since lactulose is not metabolized by human disaccharidases and little is absorbed, 5 it passes to the colon where it is hydrolyzed by bacteria to lactic, acetic, and formic acids. The resultant decrease in the pH of the colonic contents has two effects the pH gradient stimulates passage of ammonia from the plasma to the intestinal lumen, and absorbable ammonia in the lumen is converted to nonabsorbable ammonium ions which are excreted.With the decreased ammonia content of the blood, patients have improved psychologically and behaviorally. 

A57-year-old man taking VPA 1000 mg/day developed hyperammonemic encephalopathy and subsequent coma. He had portal hypertension secondary to history of alcohol abuse and was found to have a portosystemic shxmt, which had previously gone xiimoticed. While asymptomatic hyperammonemia is a relatively common side effect of VPA, encephalopathy and coma are less common. The portosystemic shunt may have prevented metabolism of ammonia in this case [185 ]. Regardless, VPA should be used with caution in a patient with a history of alcohol abuse given the increased risk for liver disease. 

During liver failure, the normal detoxification and synthetic functions of the liver are severely impaired. The liver support device should be able to detoxify and support the synthetic functions of the Uver either to serve as a bridge to liver transplant or permit sufficient liver regeneration so that liver transplantation is not needed. In this regard, the primary purpose of a support device would be to improve overall survival and transplant-free survival. Other possible secondary endpoints include improvements in encephalopathy and renal function, and reductions in measureable toxins and metabolic by-products, including bilirubin, ammonia, urea, and lactate. Ideally, the support device should be effective for both ALF and AOCLF, regardless of etiology. 

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