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Ammonia levels and the severity of hepatic encephalopathy
Ammonia Levels and the Severity of Hepatic Encephalopathy Victor Wang, MD, MPH, Sammy Saab, MD, MPH
W
hile ammonia levels have been found to be increased in most patients in hepatic coma due to severe liver disease, reports of correlation with the severity of encephalopathy have been inconsistent (1–3). The diagnosis of hepatic encephalopathy is based primarily on the clinical history and exclusion of other causes of altered mental status, in the context of substantial liver dysfunction seen on physical examination. The use of blood ammonia levels has thus been relegated to confirming the clinical suspicion of hepatic encephalopathy when the diagnosis is unclear. In this month’s issue of the Journal, Ong and colleagues challenge the above views and demonstrate that there may be more value to an elevated ammonia level than previously believed (4). The authors found four measures of ammonia levels to be correlated with the severity of hepatic encephalopathy in a prospective analysis of 121 consecutive patients: arterial total ammonia (rs ⫽ 0.61), venous total ammonia (rs ⫽ 0.56), arterial partial pressure of ammonia (rs ⫽ 0.55), and venous partial pressure of ammonia (rs ⫽ 0.52; P ⱕ0.001 for all correlation coefficients). Correlation coefficients between 0.5 and 0.75 are considered to represent moderate-to-good relations. Equally important, Ong et al. found that venous ammonia levels and arterial levels of ammonia were similar in their correlation with severity of hepatic encephalopathy, and that there was no additional advantage of using partial pressure of ammonia instead of total ammonia levels. Arterial or capillary blood sampling is traditionally considered to be better than venous sampling because it provides a more consistent and accurate measurement of ammonia at the blood-brain barrier (1). Partial pressure of ammonia is thought to be more useful to measure because it is gaseous ammonia that enters through the blood-brain barrier (2). Still, the accuracy of measurement depends on the promptness of the assay and delivery of the sample on ice, and ammonia levels can be falsely elevated if tourniquets are used before drawing blood. In
Am J Med. 2003;114:237–238. From the Department of Medicine (VW), West Los Angeles Veterans Administration Medical Center; and Division of Digestive Diseases (SS), Department of Medicine, and Department of Surgery (SS), Dumont–UCLA Liver Transplant Center, University of California, Los Angeles, Los Angeles, California. Requests for reprints should be addressed to Sammy Saab, MD, MPH, Division of Digestive Diseases, 44-138 CHS (MC 168417), UCLA Medical Center, 10833 Le Conte Avenue, Los Angeles, California 90095, or [email protected]. Manuscript submitted October 4, 2002. ©2003 by Excerpta Medica Inc. All rights reserved.
the study by Ong et al., a newer and more reliable enzymatic assay for measuring ammonia was used, strengthening their finding of similarities in the different forms of measurement. There are several issues that deserve mention regarding the role of ammonia in hepatic encephalopathy. First, the results of the current study do not suggest that measurement of ammonia levels should replace a clinical evaluation in the diagnosis of hepatic encephalopathy or assessment of its severity. Indeed, the authors remind us that the clinical history remains the “gold standard.” Second, the role of ammonia in the pathogenesis of hepatic encephalopathy is controversial. Although many other factors have been implicated in the development of hepatic encephalopathy, such as inhibitory neurotransmission through gamma-aminobutyric acid receptors, alterations of the blood-brain barrier transport, decreased oxygen delivery to the central nervous system, astrocyte swelling, and increased levels of chemicals (e.g., mercaptan, short-chain fatty acids, oxindole, serotonin, melatonin) (5–11), ammonia has remained a principal factor in considerations of the pathogenesis of hepatic encephalopathy. Hence, therapies for the condition have mainly involved strategies to reduce blood ammonia levels, such as by decreasing ammoniagenic substrates and ammonia production. Third, there are questions about reproducibility in ammonia quantitation. Since ammonia is measured using prepared kits, measurements are likely to be reproducible in different laboratories. Ammonia does not follow a circadian rhythm and is measured in fasting blood samples. In addition, it is unclear if threshold values exist for ammonia for the diagnosis of hepatic encephalopathy or assessment of its severity. For instance, is there an ammonia level above which one predicts grade 2 or 3 hepatic encephalopathy? Moreover, is there a threshold value that can discriminate between the altered mental status due to hepatic encephalopathy and other causes in patients with liver disease? The data suggest that threshold values may not be applicable. Although Ong et al. noted a correlation between ammonia levels and the severity of hepatic encephalopathy, there was also substantial overlap in ammonia levels for hepatic encephalopathy of grades 0 to 2 and, to some degree, grade 3. The graphs demonstrate an upward trend, but the relation between these two variables may not be linear, especially for the lower grades of encephalopathy. Ong and colleagues have addressed an important question. Indeed, the strong correlation between the severity 0002-9343/03/$–see front matter 237 doi:10.1016/S0002-9343(02)01571-1
Ammonia Levels and Hepatic Encephalopathy/Wang and Saab
of hepatic encephalopathy and ammonia level supports the continued use of ammonia levels in the clinical setting; however, the overlapping levels for grades of hepatic encephalopathy may limit widespread use in clinical research and practice at this time.
REFERENCES 1. Stahl J. Studies of blood ammonia in liver disease. Ann Intern Med. 1963;58:1–24. 2. Kramer L, Tribl B, Gendo A, et al. Partial pressure of ammonia versus ammonia in hepatic encephalopathy. Hepatology. 2000;31: 30 –34. 3. Venturini I, Corsi L, Avallone R, et al. Ammonia and endogenous benzodiazepine-like compounds in the pathogenesis of hepatic encephalopathy. Scand J Gastroenterol. 2001;36:423–425. 4. Ong JP, Aggarwal A, Krieger D, et al. Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med. 2002; 114:188 –193.
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5. Schafer DF, Jones EA. Hepatic encephalopathy and the gammaaminobutyric-acid neurotransmitter system. Lancet. 1982;1:18 –20. 6. James JH, Escourrou J, Fisher JE. Blood brain neutral amino acid transport activity is increased after portocaval anastomosis. Science. 1978;200:1395–1398. 7. Zieve L, Doizaki WM, Zieve FJ. Synergism between mercaptanes and ammonia and fatty acids in the production of coma: a possible role for mercaptanes in the pathogenesis of hepatic coma. J Lab Clin Med. 1974;83:10 –16. 8. Haussinger D, Kircheis G, Fischer R, et al. Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema? J Hepatol. 2000;32:1035– 1038. 9. Moroni F, Carpenedo R, Venturini I, et al. Oxindole in the pathogenesis of hepatic encephalopathy. Lancet. 1998;351:1861. 10. Yurdaydin C, Hortnagl H, Steindl P, et al. Increased serotoninergic and noradrenergic activity in hepatic encephalopathy in rats with thioacetamide-induced acute liver failure. Hepatology. 1990;12: 695–700. 11. Steindl P, Finn B, Bendok B, et al. Disruption of the diurnal rhythm of plasma melatonin in cirrhosis. Ann Intern Med. 1995;123:274 – 277.
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W
hile ammonia levels have been found to be increased in most patients in hepatic coma due to severe liver disease, reports of correlation with the severity of encephalopathy have been inconsistent (1–3). The diagnosis of hepatic encephalopathy is based primarily on the clinical history and exclusion of other causes of altered mental status, in the context of substantial liver dysfunction seen on physical examination. The use of blood ammonia levels has thus been relegated to confirming the clinical suspicion of hepatic encephalopathy when the diagnosis is unclear. In this month’s issue of the Journal, Ong and colleagues challenge the above views and demonstrate that there may be more value to an elevated ammonia level than previously believed (4). The authors found four measures of ammonia levels to be correlated with the severity of hepatic encephalopathy in a prospective analysis of 121 consecutive patients: arterial total ammonia (rs ⫽ 0.61), venous total ammonia (rs ⫽ 0.56), arterial partial pressure of ammonia (rs ⫽ 0.55), and venous partial pressure of ammonia (rs ⫽ 0.52; P ⱕ0.001 for all correlation coefficients). Correlation coefficients between 0.5 and 0.75 are considered to represent moderate-to-good relations. Equally important, Ong et al. found that venous ammonia levels and arterial levels of ammonia were similar in their correlation with severity of hepatic encephalopathy, and that there was no additional advantage of using partial pressure of ammonia instead of total ammonia levels. Arterial or capillary blood sampling is traditionally considered to be better than venous sampling because it provides a more consistent and accurate measurement of ammonia at the blood-brain barrier (1). Partial pressure of ammonia is thought to be more useful to measure because it is gaseous ammonia that enters through the blood-brain barrier (2). Still, the accuracy of measurement depends on the promptness of the assay and delivery of the sample on ice, and ammonia levels can be falsely elevated if tourniquets are used before drawing blood. In
Am J Med. 2003;114:237–238. From the Department of Medicine (VW), West Los Angeles Veterans Administration Medical Center; and Division of Digestive Diseases (SS), Department of Medicine, and Department of Surgery (SS), Dumont–UCLA Liver Transplant Center, University of California, Los Angeles, Los Angeles, California. Requests for reprints should be addressed to Sammy Saab, MD, MPH, Division of Digestive Diseases, 44-138 CHS (MC 168417), UCLA Medical Center, 10833 Le Conte Avenue, Los Angeles, California 90095, or [email protected]. Manuscript submitted October 4, 2002. ©2003 by Excerpta Medica Inc. All rights reserved.
the study by Ong et al., a newer and more reliable enzymatic assay for measuring ammonia was used, strengthening their finding of similarities in the different forms of measurement. There are several issues that deserve mention regarding the role of ammonia in hepatic encephalopathy. First, the results of the current study do not suggest that measurement of ammonia levels should replace a clinical evaluation in the diagnosis of hepatic encephalopathy or assessment of its severity. Indeed, the authors remind us that the clinical history remains the “gold standard.” Second, the role of ammonia in the pathogenesis of hepatic encephalopathy is controversial. Although many other factors have been implicated in the development of hepatic encephalopathy, such as inhibitory neurotransmission through gamma-aminobutyric acid receptors, alterations of the blood-brain barrier transport, decreased oxygen delivery to the central nervous system, astrocyte swelling, and increased levels of chemicals (e.g., mercaptan, short-chain fatty acids, oxindole, serotonin, melatonin) (5–11), ammonia has remained a principal factor in considerations of the pathogenesis of hepatic encephalopathy. Hence, therapies for the condition have mainly involved strategies to reduce blood ammonia levels, such as by decreasing ammoniagenic substrates and ammonia production. Third, there are questions about reproducibility in ammonia quantitation. Since ammonia is measured using prepared kits, measurements are likely to be reproducible in different laboratories. Ammonia does not follow a circadian rhythm and is measured in fasting blood samples. In addition, it is unclear if threshold values exist for ammonia for the diagnosis of hepatic encephalopathy or assessment of its severity. For instance, is there an ammonia level above which one predicts grade 2 or 3 hepatic encephalopathy? Moreover, is there a threshold value that can discriminate between the altered mental status due to hepatic encephalopathy and other causes in patients with liver disease? The data suggest that threshold values may not be applicable. Although Ong et al. noted a correlation between ammonia levels and the severity of hepatic encephalopathy, there was also substantial overlap in ammonia levels for hepatic encephalopathy of grades 0 to 2 and, to some degree, grade 3. The graphs demonstrate an upward trend, but the relation between these two variables may not be linear, especially for the lower grades of encephalopathy. Ong and colleagues have addressed an important question. Indeed, the strong correlation between the severity 0002-9343/03/$–see front matter 237 doi:10.1016/S0002-9343(02)01571-1
Ammonia Levels and Hepatic Encephalopathy/Wang and Saab
of hepatic encephalopathy and ammonia level supports the continued use of ammonia levels in the clinical setting; however, the overlapping levels for grades of hepatic encephalopathy may limit widespread use in clinical research and practice at this time.
REFERENCES 1. Stahl J. Studies of blood ammonia in liver disease. Ann Intern Med. 1963;58:1–24. 2. Kramer L, Tribl B, Gendo A, et al. Partial pressure of ammonia versus ammonia in hepatic encephalopathy. Hepatology. 2000;31: 30 –34. 3. Venturini I, Corsi L, Avallone R, et al. Ammonia and endogenous benzodiazepine-like compounds in the pathogenesis of hepatic encephalopathy. Scand J Gastroenterol. 2001;36:423–425. 4. Ong JP, Aggarwal A, Krieger D, et al. Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med. 2002; 114:188 –193.
238
February 15, 2003
THE AMERICAN JOURNAL OF MEDICINE威
5. Schafer DF, Jones EA. Hepatic encephalopathy and the gammaaminobutyric-acid neurotransmitter system. Lancet. 1982;1:18 –20. 6. James JH, Escourrou J, Fisher JE. Blood brain neutral amino acid transport activity is increased after portocaval anastomosis. Science. 1978;200:1395–1398. 7. Zieve L, Doizaki WM, Zieve FJ. Synergism between mercaptanes and ammonia and fatty acids in the production of coma: a possible role for mercaptanes in the pathogenesis of hepatic coma. J Lab Clin Med. 1974;83:10 –16. 8. Haussinger D, Kircheis G, Fischer R, et al. Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema? J Hepatol. 2000;32:1035– 1038. 9. Moroni F, Carpenedo R, Venturini I, et al. Oxindole in the pathogenesis of hepatic encephalopathy. Lancet. 1998;351:1861. 10. Yurdaydin C, Hortnagl H, Steindl P, et al. Increased serotoninergic and noradrenergic activity in hepatic encephalopathy in rats with thioacetamide-induced acute liver failure. Hepatology. 1990;12: 695–700. 11. Steindl P, Finn B, Bendok B, et al. Disruption of the diurnal rhythm of plasma melatonin in cirrhosis. Ann Intern Med. 1995;123:274 – 277.
Volume 114