Pathogenesis, Clinical Manifestation, and Diagnosis of Hepatic Encephalopathy

ABSTRACT

The pathogenesis of hepatic encephalopathy (HE) by general consensus is now considered to be a complex multifactorial process. Rather than simply a manifestation of direct ammonia neurotoxicity, HE is now believed to be the result of astrocyte swelling and oxidative stress caused by ammonia and other putative neurotoxins. Mediators of inflammation have also been shown to promote the expression of HE. The clinical manifestations of HE have been known for decades, and clinical evaluation still represents the primary method for diagnosing the overt forms of HE. A minimal form of HE is now recognized, which can be diagnosed by standard psychometric tests. Despite its clinically subtle nature, this form of HE is associated with significant reduction in quality of life. Minimal HE appears to be reversible with standard HE therapy. Detection needs to be simplified so that all physicians can diagnose its presence. This article reviews the pathogenesis, clinical classifications, and diagnosis of HE.

KEYWORDS

Hepatic encephalopathy - diagnosis - pathogenesis - ammonia - minimal hepatic encephalopathy

REFERENCES

• 1 Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei A T. Hepatic encephalopathy-definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998.  Hepatology. 2002;  35 716-721
• 2 Mullen K D. Review of the final report of the 1998 Working Party on definition, nomenclature and diagnosis of hepatic encephalopathy.  Aliment Pharmacol Ther. 2007;  25(suppl 1) 11-16
• 3 Cordoba J, Alonso J, Rovira A et al.. The development of low-grade cerebral edema in cirrhosis is supported by the evolution of (1)H-magnetic resonance abnormalities after liver transplantation.  J Hepatol. 2001;  35 598-604
• 4 Haussinger D, Kircheis G, Fischer R, Schliess F, von Dahl S. Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema?.  J Hepatol. 2000;  32 1035-1038
• 5 Shawcross D L, Davies N A, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.  J Hepatol. 2004;  40 247-254
• 6 Schliess F, Görg B, Reinehr R, Bidmon H, Häussinger D. Osmotic and oxidative stress in hepatic encephalopathy. In: Häussinger D, Kirchles G, Schless F Hepatic Encephalopathy and Nitrogen Metabolism. Dordrecht, The Netherlands; Springer 2006: 20-42
• 7 Zieve L, Ferenci P, Rzepczynski D, Ebner J, Zimmermann C. A benzodiazepine antagonist does not alter the course of hepatic encephalopathy or neural gamma-aminobutyric acid (GABA) binding.  Metab Brain Dis. 1987;  2 201-205
• 8 Norenberg M D, Itzhak Y, Bender A S. The peripheral benzodiazepine receptor and neurosteroids in hepatic encephalopathy.  Adv Exp Med Biol. 1997;  420 95-111
• 9 Bender A S, Norenberg M D. Effect of benzodiazepines and neurosteroids on ammonia-induced swelling in cultured astrocytes.  J Neurosci Res. 1998;  54 673-680
• 10 Jayakumar A R, Rama Rao K V, Kalaiselvi P, Norenberg M D. Combined effects of ammonia and manganese on astrocytes in culture.  Neurochem Res. 2004;  29 2051-2056
• 11 Shawcross D, Jalan R. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.  Cell Mol Life Sci. 2005;  62 2295-2304
• 12 Häussinger D, Córdoba J, Kircheis G et al.. Definition and assessment of low-grade hepatic encephalopathy. In: Haussinger D, Kirchels G, Schless F Hepatic Encephalopathy and Nitrogen Metabolism. Dordrecht, The Netherlands; Springer 2006: 423-432
• 13 Krieger S, Jauss M, Jansen O, Theilmann L, Geissler M, Krieger D. Neuropsychiatric profile and hyperintense globus pallidus on T1-weighted magnetic resonance images in liver cirrhosis.  Gastroenterology. 1996;  111 147-155
• 14 Mullen K D, Cole M, Foley J M. Neurological deficits in “awake” cirrhotic patients on hepatic encephalopathy treatment: missed metabolic or metal disorder?.  Gastroenterology. 1996;  111 256-257
• 15 Adams R D, Foley J M. The neurological disorder associated with liver disease.  Res Publ Assoc Res Nerv Ment Dis. 1953;  32 198-237
• 16 McDermott Jr W V, Adams R D, Riddell A G. Ammonia metabolism in man.  Ann Surg. 1954;  140 539-556
• 17 Ferenci P, Grimm G, Meryn S, Gangl A. Successful long-term treatment of portal-systemic encephalopathy by the benzodiazepine antagonist flumazenil.  Gastroenterology. 1989;  96 240-243
• 18 Schomerus H, Hamster W. Quality of life in cirrhotics with minimal hepatic encephalopathy.  Metab Brain Dis. 2001;  16 37-41
• 19 Morgan M Y. Cerebral magnetic resonance imaging in patients with chronic liver disease.  Metab Brain Dis. 1998;  13 273-290
• 20 Conn H O. Quantifying the severity of hepatic encephalopathy. In: Conn HO, Bircher J Hepatic Encephalopathy: Syndromes and Therapies. Bloomington, IL; Medi-ed Press 1994: 13-26
• 21 Groeneweg M, Quero J C, De Bruijn I et al.. Subclinical hepatic encephalopathy impairs daily functioning.  Hepatology. 1998;  28 45-49
• 22 Prasad S, Dhiman R K, Duseja A, Chawla Y K, Sharma A, Agarwal R. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy.  Hepatology. 2007;  45 549-559
• 23 Lockwood A H. Clinical and laboratory features of hepatic encephalopathy. In: Hepatic Encephalopathy. Boston: Butterworth-Heinemann 1992: 2-31
• 24 Bajaj J S, Saeian K, Verber M D et al.. Inhibitory control test is a simple method to diagnose minimal hepatic encephalopathy and predict development of overt hepatic encephalopathy.  Am J Gastroenterol. 2007;  102 754-760
• 25 Ong J P, Aggarwal A, Krieger D et al.. Correlation between ammonia levels and the severity of hepatic encephalopathy.  Am J Med. 2003;  114 188-193
• 26 Nicolao F, Efrati C, Masini A, Merli M, Attili A F, Riggio O. Role of determination of partial pressure of ammonia in cirrhotic patients with and without hepatic encephalopathy.  J Hepatol. 2003;  38 441-446
• 27 Kramer L, Tribl B, Gendo A et al.. Partial pressure of ammonia versus ammonia in hepatic encephalopathy.  Hepatology. 2000;  31 30-34