Role of determination of partial pressure of ammonia in cirrhotic patients with and without hepatic encephalopathy
Introduction
Hepatic encephalopathy is a neuropsychiatric syndrome occurring in patients with severe liver disease and/or portal-systemic shunting [1], [2]. Hepatic encephalopathy is characterized by a wide spectrum of clinical manifestations, ranging from subclinical alterations in the psychometric performance to stupor and coma [2], [3]. The exact pathogenesis of hepatic encephalopathy is still not completely understood but there is a general consensus about the importance of gut-derived nitrogenous substances escaping hepatic detoxification and affecting the central nervous system function [4], [5], [6]. Ammonia is one of these substances, produced both in the colon and in the small bowel and extensively metabolized in the liver. In case of liver failure and/or portal-systemic shunt, blood ammonia concentration may increase and exert its toxic activity on the brain [5], [7]. Although ammonia levels are almost always invariably higher in patients with acute or chronic liver failure, the correlation with the severity of hepatic encephalopathy is often variable and inaccurate [7], [8]. Ammonia determinations, therefore, do not permit reliable identification of patients with hepatic encephalopathy or the distinction from other forms of coma, which may be observed in patients with severe liver disease. For the same reason, ammonia cannot be utilized as a reliable parameter for monitoring patients with hepatic encephalopathy submitted to treatment. This might be due to the fact that in biological samples, ammonia is usually assayed as total ammonia, without distinguishing between ammonium ions (NH4+) and unionized ammonia (NH3) [9]. Only the latter, in fact, is able to freely spread through cell membranes and, therefore, supposed to be mainly responsible for ammonia neurotoxicity [10]. Unionized ammonia increases with the pH and can be estimated using the partial pressure of ammonia (pNH3) calculated from arterial ammonia and pH [11]. Based on the above considerations and on the frequent occurrence of alkalosis in cirrhotic patients [12], [13], it has been postulated that pNH3 rather than total ammonia levels may better explain the phenomenon of pH-dependent ammonia toxicity. Recently, pNH3 has been shown to be superior to total ammonia in the pathophysiological evaluation of hepatic encephalopathy [14].
The aim of the present study was to test the relationship between venous and arterial ammonia as well as pNH3 and hepatic encephalopathy in a group of cirrhotic patients with and without hepatic encephalopathy. Moreover, at variance with previous reports, the dynamics of ammonia determinations and mental status were evaluated in a parallel manner in the same patients during and after the resolution of their neurological symptoms.
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Patients and methods
Forty-two patients with liver cirrhosis were included in the study. Nine subjects without liver disease, undergoing arterial blood gas analysis during the evaluation of their respiratory function, comparable with cirrhotic patients for age and sex, were also included as controls (Table 1). Twenty-seven of the 42 cirrhotic patients were affected by hepatic encephalopathy: seven by persistent hepatic encephalopathy [2] and 20 by episodic hepatic encephalopathy [2]. Their characteristics are
Results
Venous and arterial ammonia and pNH3 were higher in cirrhotic patients than in controls. Among cirrhotic patients, ammonia levels were higher in those with hepatic encephalopathy compared with those without hepatic encephalopathy and was related to the severity of the alteration in the mental state (Table 4 and Fig. 1). The correlation with the degree of hepatic encephalopathy was, however, similar for venous ammonia (r=0.72), arterial ammonia (r=0.76) and pNH3 (r=0.75). The degree of hepatic
Discussion
Ammonia levels are almost invariably high in patients with acute or chronic liver failure but the correlation with the presence and severity of hepatic encephalopathy is often variable and inaccurate [7], [8]. This may be due to the fact that usually venous blood ammonia levels are routinely determined. However, in patients with hyperammonemia due to hepatic insufficiency, ammonia is taken up in significant quantities by the muscle [20] where it is utilized for glutamine formation [21].
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2022, Analytical BiochemistryCitation Excerpt :Other causes of hyperammonemia outside HE include drug-induced hyperammonemia (especially sodium valproate, 5-fluorouracil, asparaginase and regorafenib), surgical procedures like ureterosigmoidostomy and post-transurethral resection of prostate syndrome [21], transfusions [28]. Several studies, either older ones or the most recent, assessed the correlation between ammonia levels and the severity of HE, sometimes with different ways of measuring ammonia (arterial and venous ammonia levels as well as calculation of partial pressure of ammonia (pNH3) from arterial or venous blood [29] [–] [36]. The main findings were that: (1) ammonemia was always elevated in case of HE; (2) ammonia levels may be elevated without any HE symptoms (3) ammonia levels correlated with the severity/grade of HE; (4) in the studies where follow-up data were available, ammonia levels remained sometimes stable and elevated, even among patients no longer presenting with overt HE (i.e. improved following medical treatment) [37] [–] [39].
EASL Clinical Practice Guidelines on the management of hepatic encephalopathy
2022, Journal of HepatologyCitation Excerpt :Diagnosis. Blood ammonia levels correlate with the severity of HE, but patients without manifest HE and even without liver disease can display hyperammonaemia.36,37 Moreover, ammonia may remain elevated after clinical HE resolution.38,39