Encephalopathy ammonia

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. 

Ammonia (NH3) is just one of the toxins implicated in HE. It is a metabolic by-product of protein catabolism and is also generated by bacteria in the GI tract. In a normally functioning liver, hepatocytes take up ammonia and degrade it to form urea, which is then renally excreted. In patients with cirrhosis, the conversion of ammonia to urea is retarded and ammonia accumulates, resulting in encephalopathy. This decrease in urea formation is manifest on laboratory assessment as decreased blood urea nitrogen (BUN), but BUN levels do not correlate with degree of HE. Patients with HE commonly have elevated serum ammonia concentrations, but the levels do not correlate well with the degree of central nervous system impairment.20... 

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]. 

Ammonia Bacterial flora Benzodiazepines, endogenous Encephalopathy, hepatic Liver cirrhosis Rifaximin... 

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... 

Zeneroli ML, Ventura E, Baraldi M, Penne A, Messori E, Zieve L Visual evoked potentials in encephalopathy induced by galactosamine, ammonia, dimethyldisulfide and octanoic acid. Hepatology 1982 2 532-538. 

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. 

L The answer is a. (Hardman, p 922) Lactulose is a synthetic disaccharide (galactose-fructose) that is not absorbed. In moderate doses, it acts as a laxative. In higher doses, it is capable of binding ammonia and other toxins that form in the intestine in severe liver deficiency and that are believed to cause the encephalopathy. Loperamide is an antidiarrheal opioid lorazepam is a CNS depressant loxapine is a heterocyclic antipsychotic. 

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. 

The urea cycle is essential for the detoxification of ammonia. The urea cycle (Fig. 40-5) converts ammonia to urea (10-20g/day in the healthy adult). A urea cycle enzymopathy, whether associated with cirrhosis or an inherited metabolic defect, often causes a hyperammone-mic encephalopathy and irreversible brain injury (see also Ch. 34). 

In patients who develop unexplained lethargy, vomiting, or changes in mental status, consider hyperammonemic encephalopathy and measure an ammonia level. 

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... 

The relationship of hyperammonemia to valproic acid-associated encephalopathies has been questioned after a study of ammonia concentrations in 55 asymptomatic patients taking valproic acid showed that 29 had ammonia concentrations above the reference range, the highest being 140 pmol/l (1180). 

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. 

This patient has a massively raised ALT, indicating considerable hepato-cyte damage. All functions of the liver are likely to be affected, including reduced secretory and excretory function, demonstrated in this case by a raised bilirubin reduced synthetic function, shown by the raised INR (albumin is imaffected at this time due to its long half life) reduced metabolic function, indicated by accumulation of ammonia and other toxins leading to encephalopathy. Blood flow through the liver is likely to be unaffected, as there is no cirrhosis/portal hypertension. As with all other functions of the liver, this patient s ability to metabolise drugs is likely to be severely affected. Renal function is also impaired secondary to paracetamol toxicity. 

Evaluate for urea cycle disorders, as hyperammonemic encephalopathy, sometimes fatal, has been associated with valproate administration in these uncommon disorders urea cycle disorders, such as ormithine transcarbamylase deficiency, are associated with unexplained encephalopathy, mental retardation, elevated plasma ammonia, cyclical vomiting, and lethargy... 

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)... 

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