Liver ammonia

B. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine, calcium, ammonia, liver transaminases, bilirubin, prothrombin time (PT), amylase, serum osmolality and osmolar gap (see p 32 serum levels > 1500 mg/L may increase the osmolar gap by 10 mOsm/L or more), arterial blood gases or oximetry, and EGG monitoring. Valproic acid may cause a falsepositive urine ketone determination. 

Kanamycin, neomycin, and paromomycin are used orally in the management of hepatic coma. In this disorder, liver failure results in an elevation of blood ammonia levels. By reducing tire number of ammoniaforming bacteria in the intestines, blood ammonia levels may be lowered, thereby temporarily reducing some of the symptoms associated with this disorder. 

While ammonia, derived mainly from the a-amino nitrogen of amino acids, is highly toxic, tissues convert ammonia to the amide nitrogen of nontoxic glutamine. Subsequent deamination of glutamine in the liver releases ammonia, which is then converted to nontoxic urea. If liver function is compromised, as in cirrhosis or hepatitis, elevated blood ammonia levels generate clinical signs and symptoms. Rare metabolic disorders involve each of the five urea cycle enzymes. 

The ammonia produced by enteric bacteria and absorbed into portal venous blood and the ammonia produced by tissues are rapidly removed from circulation by the liver and converted to urea. Only traces (10—20 Ig/dL) thus normally are present in peripheral blood. This is essential, since ammonia is toxic to the central nervous system. Should portal blood bypass the liver, systemic blood ammonia levels may rise to toxic levels. This occurs in severely impaired hepatic function or the development of collateral links between the portal and systemic veins in cirrhosis. Symptoms of ammonia intoxication include tremor, slurred speech, blurred vision, coma, and ultimately death. Ammonia may be toxic to the brain in part because it reacts with a-ketoglutarate to form glutamate. The resulting depleted levels of a-ketoglutarate then impair function of the tricarboxylic acid (TCA) cycle in neurons. 

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... 

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. 

Normal phase silica column Chloroform-methanol-ammonia solution (86.8 12.5 0.7) 254 nm Assay of primaquine and hepatic targeting neoglycoalbumin-primaquine in whole blood and liver of mouse by reversed-phase HPLC. [105]... 

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

Liver s main job is to keep up the levels of blood glucose. To do this, it breaks down glycogen and turns on gluconeogenesis. The liver takes lactate and alanine from the circulation and through gluconeogenesis converts it into glucose. The ammonia from the alanine is pushed... 

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. 

Ammonia concentrations in arterial blood of patients with liver failure rise to 0.5-1 mmol/1, in contrast to the normal range of 0.01-0.02 mmol/1. Using positron emission tomography (PET see Ch. 58), increases of the cerebral metabolic rate for ammonia (CMRA), i.e. the rate at which ammonia is taken up and metabolized by the brain, have been reported in chronic liver failure [9]. Increased CMRA in chronic liver failure is accompanied... 

Ammonia has deleterious effects on brain function by direct and indirect mechanisms. Concentrations of ammonia in the 1-2 mmol/1 range, equivalent to those reported in the brain in liver failure, impair postsynaptic inhibition in cerebral cortex and brainstem by a direct effect on Cl extrusion from the postsynaptic neuron. Millimolar concentrations of ammonia also inhibit excitatory neurotransmission. Synaptic transmission from Schaffer collaterals to CA1 hippocampal neurons is reversibly depressed by 1 mmol/1 ammonia, and the firing of CA1 neurons by iontophoretic application of glutamate is inhibited by 2 mmol/1 ammonia [10],... 

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. 

Organic cyanide compounds, or nitriles, have been implicated in numerous human fatalities and signs of poisoning — especially acetonitrile, acrylonitrile, acetone cyanohydrin, malonitrile, and succinonitrile. Nitriles hydrolyze to carboxylic acid and ammonia in either basic or acidic solutions. Mice (Mus sp.) given lethal doses of various nitriles had elevated cyanide concentrations in liver and brain the major acute toxicity of nitriles is CN release by liver processes (Willhite and Smith 1981). In general, alkylnitriles release CN much less readily than aryl alkylnitriles, and this may account for their comparatively low toxicity (Davis 1981). 

The experiments described above indicated amino acids were oxidatively deaminated in liver and their a-amino groups converted to urea. A start on investigations of the mechanism of urea biosynthesis was made by Schultzen and Nenki (1869) who concluded that amino acids gave rise to cyanate which might combine with ammonia from proteins to produce urea. Von Knieren (1873) demonstrated that when he drank an ammonium chloride solution, or gave it to a dog, there was an increase in the formation of urea, without any rise in urinary ammonia. His results were consistent with the cyanate theory but did not eliminate the possibility that urea arose from ammonium carbonate which could be dehydrated to urea ... 

Some toxic effects are reversible. Everyone has been exposed to some agent, household ammonia for example, that produces irritation to the skin or eyes. Exposure ends and, sometimes perhaps with a delay, the irritation ends. Some readers have no doubt been poisoned on occasion by the ingestion of too much alcohol. The effects here also reverse. The time necessary for reversal can vary greatly depending upon the severity of the intoxication and certain physiological features of the person intoxicated. But most people also realize that chronic alcohol abuse can lead to a serious liver disorder, cirrhosis, which may not reverse even if alcohol intake ceases. This type of effect is irreversible or only very slowly reversible. It is important in making a toxicological evaluation to understand whether effects are reversible or irreversible, because one is obviously much more serious than the other. 

Tissue electrodes [2, 3, 4, 5, 45,57], In these biosensors, a thin layer of tissue is attached to the internal sensor. The enzymic reactions taking place in the tissue liberate products sensed by the internal sensor. In the glutamine electrode [5, 45], a thick layer (about 0.05 mm) of porcine liver is used and in the adenosine-5 -monophosphate electrode [4], a layer of rabbit muscle tissue. In both cases, the ammonia gas probe is the indicator electrode. Various types of enzyme, bacterial and tissue electrodes were compared [2]. In an adenosine electrode a mixture of cells obtained from the outer (mucosal) side of a mouse small intestine was used [3j. The stability of all these electrodes increases in the presence of sodium azide in the solution that prevents bacterial decomposition of the tissue. In an electrode specific for the antidiuretic hormone [57], toad bladder is placed over the membrane of a sodium-sensitive glass electrode. In the presence of the antidiuretic hormone, sodium ions are transported through the bladder and the sodium electrode response depends on the hormone concentration. 

Approximately 30% of the urea produced by the liver diffuses into the colon where it is degraded by some of the microorganisms, i.e. those that possess the enzyme urease, to form ammonia... 

Some of the glutamine that is absorbed is metabolised in the enterocytes. It is used, along with glucose, as a fuel to generate ATP (Chapter 8). The ammonia and the alanine that are produced enter the blood for uptake by the liver. 

The physiological relevance together with chnical importance of transamination and deamination is wide-ranging. As an aid to understanding the somewhat complex nature of amino acid metabolism, it can be considered (or imagined) as a metabolic box (represented in Figure 8.13). Some pathways feed oxoacids into the box whereas others remove oxoacids and the ammonia that is released is removed to form urea. The box illustrates the role of transdeamination as central to a considerable amount of the overall metabolism in the liver cell (i.e. protein, carbohydrate and fat metabohsm, see below). 

The aspartate and glutamate produced by these reactions, plus those taken up from the lumen, are metabolised to oxaloacetate and oxoglutarate, respectively, as discussed above. The a-NH2 group in these amino acids is transferred to pyruvate to form alanine, which is released and then taken up by the liver, where the NH2 group is converted to ammonia and then to urea. 

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