Hepatic encephalopathy: Difference between revisions
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In [[medicine]], '''hepatic encephalopathy''' is "syndrome characterized by central nervous system dysfunction in association with liver failure, including portal-systemic shunts. Clinical features include lethargy and confusion (frequently progressing to coma); asterixis; nystagmus, pathologic; brisk oculovestibular reflexes; [[Decorticate rigidity|decorticate]] and [[Decerebrate rigidity|decerebrate]] posturing; muscle spasticity; and bilateral extensor [[plantar reflex]]es . Electroencephalography may demonstrate triphasic waves."<ref>{{MeSH}}</ref> The [[Babinski sign]] demonstrates abnormal plantar reflexes. | |||
==Classification and grading== | ==Classification and grading== | ||
In the World Congress of | In the World Congress of Gastroenterology 1998 in Vienna, a proposed classification of hepatic encephalopathy was presented to standardize the subclasses. According to this classification, hepatic encephalopathy is subdivided in type A, B and C.<ref name=Ferenci>{{cite journal |author=Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei A |title=Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998 |journal=Hepatology |volume=35 |issue=3 |pages=716-21 |year=2002 |pmid=11870389}}</ref> | ||
* ''Type A (=acute)'' describes hepatic encephalopathy associated with acute liver failure; | * ''Type A (=acute)'' describes hepatic encephalopathy associated with acute liver failure; | ||
* ''Type B (= | * ''Type B (=bypass)'' is caused by portal-systemic shunting without associated intrinsic liver disease; | ||
* ''Type C (=cirrhosis'') occurs in patients with [[cirrhosis]]. | * ''Type C (=cirrhosis'') occurs in patients with [[cirrhosis]]. | ||
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The evaluation of severity of persistent hepatic encephalopathy is based on the West Haven Criteria for semi-quantitative grading of mental status, referring to the level of impairment of autonomy, changes in consciousness, intellectual function, behavior, and the dependence on therapy.<ref name=Ferenci/><ref name=Conn>Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, Levy LL. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. ''Gastroenterology'' 1977; 72: 573-83.</ref>. | The evaluation of severity of persistent hepatic encephalopathy is based on the West Haven Criteria for semi-quantitative grading of mental status, referring to the level of impairment of autonomy, changes in consciousness, intellectual function, behavior, and the dependence on therapy.<ref name=Ferenci/><ref name=Conn>Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, Levy LL. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. ''Gastroenterology'' 1977; 72: 573-83.</ref>. | ||
* Grade 1 | * Grade 1 (also called minimal hepatic encephalopathy - MHE)<ref name="pmid17326150">{{cite journal |author=Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R |title=Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy |journal=Hepatology |volume=45 |issue=3 |pages=549-59 |year=2007 |pmid=17326150 |doi=10.1002/hep.21533}}</ref>- Trivial lack of awareness; Euphoria or anxiety; Shortened attention span; Impaired performance of addition. 67% of cirrhotic patients in one study of outpatients at a liver clinic had MHE.<ref name="pmid17326150"/> | ||
* Grade 2 - Lethargy or [[apathy]]; Minimal disorientation for time or place; Subtle personality change; Inappropriate behavior; Impaired performance of subtraction | * Grade 2 - Lethargy or [[apathy]]; Minimal disorientation for time or place; Subtle personality change; Inappropriate behavior; Impaired performance of subtraction | ||
* Grade 3 - [[Somnolence]] to semi[[stupor]], but responsive to verbal stimuli; | * Grade 3 - [[Somnolence]] to semi[[stupor]], but responsive to verbal stimuli; [[confusion]]; gross disorientation | ||
* Grade 4 - [[Coma]] (unresponsive to verbal or noxious stimuli) | * Grade 4 - [[Coma]] (unresponsive to verbal or noxious stimuli) | ||
==Etiology / cause == | |||
There may be a genetic propensity to hepatic encephalopathy. <ref name="pmid20820037">{{cite journal| author=Romero-Gómez M, Jover M, Del Campo JA, Royo JL, Hoyas E, Galán JJ et al.| title=Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: a cohort study. | journal=Ann Intern Med | year= 2010 | volume= 153 | issue= 5 | pages= 281-8 | pmid=20820037 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20820037 | doi=10.1059/0003-4819-153-5-201009070-00002 }} </ref> | |||
==Diagnosis== | ==Diagnosis== | ||
The inhibitory control test (ICT) may be a faster way to diagnose hepatic encephalopathy than standard psychometric tests (average administration time of 15 minutes versus 37 minutes) <ref name="pmid17222319">{{cite journal |author=Bajaj JS, Saeian K, Verber MD, ''et al'' |title=Inhibitory control test is a simple method to diagnose minimal hepatic encephalopathy and predict development of overt hepatic encephalopathy |journal=Am. J. Gastroenterol. |volume=102 |issue=4 |pages=754-60 |year=2007 |pmid=17222319 |doi=10.1111/j.1572-0241.2007.01048.x}}</ref> | The inhibitory control test (ICT) may be a faster way to diagnose hepatic encephalopathy than standard psychometric tests (average administration time of 15 minutes versus 37 minutes) <ref name="pmid17222319">{{cite journal |author=Bajaj JS, Saeian K, Verber MD, ''et al'' |title=Inhibitory control test is a simple method to diagnose minimal hepatic encephalopathy and predict development of overt hepatic encephalopathy |journal=Am. J. Gastroenterol. |volume=102 |issue=4 |pages=754-60 |year=2007 |pmid=17222319 |doi=10.1111/j.1572-0241.2007.01048.x}}</ref> | ||
===Asterixis=== | |||
Asterixis, which are "abnormal involuntary movements which primarily affect the extremities, trunk, or jaw that occur as a manifestation of an underlying disease process,"<ref>{{MeSH|Asterixis}}</ref> may help diagnose hepatic encephalopathy. In unresponsive patients, asterixis can be checked by flexing the hips.<ref name="pmid4037757">{{cite journal |author=Noda S, Ito H, Umezaki H, Minato S |title=Hip flexion-abduction to elicit asterixis in unresponsive patients |journal=Annals of neurology |volume=18 |issue=1 |pages=96–7 |year=1985 |month=July |pmid=4037757 |doi=10.1002/ana.410180118 |url= |issn=}}</ref> | |||
===Blood tests=== | |||
====Ammonia==== | |||
The normal plasma level of ammonia is 12 - 48 μmol/L.<ref name="pmid9761809">{{cite journal |author=Kratz A, Lewandrowski KB |title=Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Normal reference laboratory values |journal=N Engl J Med |volume=339 |issue=15 |pages=1063 |year=1998 |pmid9761809= |doi=10.1056/NEJM199810083391508 |url=http://content.nejm.org/cgi/content/full/339/15/1063/ |issn=}}</ref> | |||
{| class="wikitable" align="right" | |||
|+ Venous ammonia and level of encephalopathy.<ref name="pmid12637132">{{cite journal |author=Ong JP, Aggarwal A, Krieger D, ''et al'' |title=Correlation between ammonia levels and the severity of hepatic encephalopathy |journal=The American journal of medicine |volume=114 |issue=3 |pages=188–93 |year=2003 |month=February |pmid=12637132 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0002934302014778 |issn=}}</ref><br/>Number (%) of patients. | |||
! NH<sub>3</sub> level!!Grade 0<br/>(no encephalopathy)!! Grade 1!! Grade 2!! Grade 3!! Grade 4 | |||
|- | |||
| > 50|| 10 (33%)|| 18 (67%)|| 14 (52%)|| 25 (89%)|| 12 (92%) | |||
|- | |||
| 25-20 || 12 (40%)|| 9 (33%)|| 5 (19%)|| 3 (11%)|| 0 | |||
|- | |||
| < 25 || 8 (27%)|| 0 (0%)|| 4 (15%)|| 0 (0)%)|| 1* (8%) | |||
|- | |||
| Total<br/>patients || 30 (100%)|| 27 (100%)|| 2 (100%)3||28 (100%)||13 (100%) | |||
|- | |||
| colspan="6"|*This patient's ammonia level was approximately 20 μmol/L. | |||
|} | |||
The ammonia level can help diagnose encephalopathy.<ref name="pmid12637132">{{cite journal |author=Ong JP, Aggarwal A, Krieger D, ''et al'' |title=Correlation between ammonia levels and the severity of hepatic encephalopathy |journal=The American journal of medicine |volume=114 |issue=3 |pages=188–93 |year=2003 |month=February |pmid=12637132 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0002934302014778 |issn=}}</ref><ref name="pmid13978712">{{cite journal |author=Stahl J |title=Studies of the blood ammonia in liver disease. Its diagnostic, prognostic, and therapeutic significance |journal=Annals of internal medicine |volume=58 |issue= |pages=1–24 |year=1963 |month=January |pmid=13978712 |doi= |url= |issn=}}</ref><ref name="pmid12663235">{{cite journal |author=Nicolao F, Efrati C, Masini A, Merli M, Attili AF, Riggio O |title=Role of determination of partial pressure of ammonia in cirrhotic patients with and without hepatic encephalopathy |journal=Journal of hepatology |volume=38 |issue=4 |pages=441–6 |year=2003 |month=April |pmid=12663235 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0168827802004361 |issn=}}</ref> | |||
{| class="wikitable" | |||
|+ Accuracy of the venous ammonia<ref name="pmid12637132">{{cite journal |author=Ong JP, Aggarwal A, Krieger D, ''et al'' |title=Correlation between ammonia levels and the severity of hepatic encephalopathy |journal=The American journal of medicine |volume=114 |issue=3 |pages=188–93 |year=2003 |month=February |pmid=12637132 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0002934302014778 |issn=}}</ref> | |||
! !![[sensitivity (tests)|sensitivity]]!! [[specificity (tests)|specificity]] | |||
|- | |||
| > 50 μmol/L|| align="center"| 76%|| align="center"|67% | |||
|- | |||
| > 25 μmol/L|| align="center"| 93%|| align="center"| 27% | |||
|} | |||
====Newer blood tests==== | |||
A study concluded that the "determination of 3-nitro-tyrosine in serum, which is easy and not time consuming, is useful to identify patients with MHE, with good sensitivity, specificity, and positive and negative predictive values.". <ref name="pmid21483460">{{cite journal| author=Montoliu C, Cauli O, Urios A, ElMlili N, Serra MA, Giner-Duran R et al.| title=3-nitro-tyrosine as a peripheral biomarker of minimal hepatic encephalopathy in patients with liver cirrhosis. | journal=Am J Gastroenterol | year= 2011 | volume= 106 | issue= 9 | pages= 1629-37 | pmid=21483460 | doi=10.1038/ajg.2011.123 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21483460 }} </ref> This study reported a [[Sensitivity and specificity|sensitivity]] and [[Sensitivity and specificity|specificity]] of 94% and 83%, respectively. In populations similar to those in this study which had a prevalence of minimal hepatic encephalopathy of 35%, the probabilities of minimal hepatic encephalopathy among patients with an abnormal and normal serum 3-nitro-tyrosine above 14 nM were 75.0% and 4.0%, respectively. <ref name="pmid21483460"/> | |||
==Treatment== | ==Treatment== | ||
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===Lactulose=== | ===Lactulose=== | ||
[[Lactulose]] is a compound that will cause osmotic diarrhoea, thus lessening the time available for intestinal bacteria to metabolise protein into ammonia within the bowel. Further, it acidifies the environment in the [[lumen]] of the bowel. This promotes the conversion of lumenal ammonia (NH<sub>3</sub>) to ammonium (NH<sub>4</sub><sup>+</sup>) which, by which virtue of its net charge, should be less readily absorbed into the bloodstream from the bowel lumen. Despite this theoretical and appealing mechanism, a [[meta-analysis]] of [[randomized controlled | [[Lactulose]] is a compound that will cause osmotic diarrhoea, thus lessening the time available for intestinal bacteria to metabolise protein into ammonia within the bowel. Further, it acidifies the environment in the [[lumen]] of the bowel. This promotes the conversion of lumenal ammonia (NH<sub>3</sub>) to ammonium (NH<sub>4</sub><sup>+</sup>) which, by which virtue of its net charge, should be less readily absorbed into the bloodstream from the bowel lumen. Despite this theoretical and appealing mechanism, a [[meta-analysis]] of [[randomized controlled trial]s] by the international [[Cochrane Collaboration]] found benefit, but suggests there is little evidence for its preferred use to treat hepatic encephalopathy.<ref>{{cite journal |author=Als-Nielsen B, Gluud L, Gluud C |title=Nonabsorbable disaccharides for hepatic encephalopathy |journal=Cochrane Database Syst Rev |volume= |issue= |pages=CD003044 |year= |pmid=15106187}}</ref> Indeed, ''any'' drug ([[laxative]]) which speeds up transit through the bowel thereby lessening the time available for bacteria to metabolize protein into ammonia, works just as well. | ||
[[Lactulose]] can be given rectally for patients who cannot take oral medications.<ref name="pmid4682313">{{cite journal |author=Kersh ES, Rifkin H |title=Lactulose enemas |journal=Ann. Intern. Med. |volume=78 |issue=1 |pages=81-4 |year=1973 |pmid=4682313 |doi=}}</ref><ref name="pmid240347">{{cite journal |author=Ratnaike RN, Hicks EP, Hislop IG |title=The rectal administration of lactulose |journal=Australian and New Zealand journal of medicine |volume=5 |issue=2 |pages=137-40 |year=1975 |pmid=240347 |doi=}}</ref><ref name="pmid3301614">{{cite journal |author=Uribe M, Campollo O, Vargas F, ''et al'' |title=Acidifying enemas (lactitol and lactose) vs. nonacidifying enemas (tap water) to treat acute portal-systemic encephalopathy: a double-blind, randomized clinical trial |journal=Hepatology |volume=7 |issue=4 |pages=639-43 |year=1987 |pmid=3301614 |doi=}}</ref> One regimen is 300 mL (200 gm) of [[lactulose]] syrup (10 gm/15 ml) in 1 L of water which is retained for 1 hour, with the patient in the Trendelenburg position.<ref name="pmid11467622">{{cite journal |author=Blei AT, Córdoba J |title=Hepatic Encephalopathy |journal=Am. J. Gastroenterol. |volume=96 |issue=7 |pages=1968-76 |year=2001 |pmid=11467622 |doi=10.1111/j.1572-0241.2001.03964.x}}</ref> | [[Lactulose]] can be given rectally for patients who cannot take oral medications.<ref name="pmid4682313">{{cite journal |author=Kersh ES, Rifkin H |title=Lactulose enemas |journal=Ann. Intern. Med. |volume=78 |issue=1 |pages=81-4 |year=1973 |pmid=4682313 |doi=}}</ref><ref name="pmid240347">{{cite journal |author=Ratnaike RN, Hicks EP, Hislop IG |title=The rectal administration of lactulose |journal=Australian and New Zealand journal of medicine |volume=5 |issue=2 |pages=137-40 |year=1975 |pmid=240347 |doi=}}</ref><ref name="pmid3301614">{{cite journal |author=Uribe M, Campollo O, Vargas F, ''et al'' |title=Acidifying enemas (lactitol and lactose) vs. nonacidifying enemas (tap water) to treat acute portal-systemic encephalopathy: a double-blind, randomized clinical trial |journal=Hepatology |volume=7 |issue=4 |pages=639-43 |year=1987 |pmid=3301614 |doi=}}</ref> One regimen is 300 mL (200 gm) of [[lactulose]] syrup (10 gm/15 ml) in 1 L of water which is retained for 1 hour, with the patient in the Trendelenburg position.<ref name="pmid11467622">{{cite journal |author=Blei AT, Córdoba J |title=Hepatic Encephalopathy |journal=Am. J. Gastroenterol. |volume=96 |issue=7 |pages=1968-76 |year=2001 |pmid=11467622 |doi=10.1111/j.1572-0241.2001.03964.x}}</ref> | ||
===Antibiotics=== | ===Antibiotics=== | ||
Antibiotics may be given to kill bacteria present in the bowel thereby decreasing bacterial conversion of protein to ammonia (and other toxic substances) there. Although effective, [[neomycin]], a non-absorbable [[aminoglycoside]] antibiotic, is essentially contraindicated; it has been found that a proportion of the ingested dose is indeed absorbed due to increased gut permeability, thus increasing the risk of [[renal failure]] and hearing loss (i.e. two of the potential side effects of neomycin). The former side-effect, in particular, is especially worrisome given the already increased likelihood of renal failure in [[cirrhosis]] and [[portal hypertension]] (i.e. [[hepatorenal syndrome]]). [[Metronidazole]] | Antibiotics may be given to kill bacteria present in the bowel thereby decreasing bacterial conversion of protein to ammonia (and other toxic substances) there. Although effective, [[neomycin]], a non-absorbable [[aminoglycoside]] antibiotic, is essentially contraindicated; it has been found that a proportion of the ingested dose is indeed absorbed due to increased gut permeability, thus increasing the risk of [[renal failure]] and hearing loss (i.e. two of the potential side effects of neomycin). The former side-effect, in particular, is especially worrisome given the already increased likelihood of renal failure in [[cirrhosis]] and [[portal hypertension]] (i.e. [[hepatorenal syndrome]]). [[Metronidazole]] 200 mg four times a day by mouth was similar to neomycin in short a randomized crossover trial.<ref name="pmid7035298">{{cite journal |author=Morgan MH, Read AE, Speller DC |title=Treatment of hepatic encephalopathy with metronidazole |journal=Gut |volume=23 |issue=1 |pages=1-7 |year=1982 |pmid=7035298 |doi=}} [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1419597 PubMed Central]</ref> | ||
====Rifaximin==== | ====Rifaximin==== | ||
[[Rifaximin]] (Xifaxan®), received orphan drug status in 2005 for the treatment of hepatic encephalopathy. In contrast to neomycin, its tolerability profile is comparable to placebo.<ref name="pmid10741936">{{cite journal |author=Williams R, James OF, Warnes TW, Morgan MY |title=Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre study |journal=European journal of gastroenterology & hepatology |volume=12 |issue=2 |pages=203-8 |year=2000 |pmid=10741936 |doi=}}</ref> Multiple clinical trials have demonstrated that rifaximin at a dose of 400 mg taken orally 3 times a day was as effective as lactulose or lactilol at improving hepatic encephalopathy symptoms.<ref name="pmid8325041">{{cite journal |author=Bucci L, Palmieri GC |title=Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy |journal=Current medical research and opinion |volume=13 |issue=2 |pages=109-18 |year=1993 |pmid=8325041 |doi=}}</ref> Similarly, rifaximin was as effective as neomycin and paromomycin.<ref name="pmid1751811">{{cite journal |author=Pedretti G, Calzetti C, Missale G, Fiaccadori F |title=Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics. A double-blind, randomized trial |journal=The Italian journal of gastroenterology |volume=23 |issue=4 |pages=175-8 |year=1991 |pmid=1751811 |doi=}}</ref> Rifaximin was better tolerated than both the cathartics and the other nonabsorbable antibiotics. A number of concerns remain regarding rifaximin's role in the treatment of hepatic encephalopathy. It remains to be determined if rifaximin can improve severe encephalopathy symptoms as rapidly as lactulose. There are also concerns regarding the cost-effectiveness of the medication. | [[Rifaximin]] (Xifaxan®), received orphan drug status in 2005 for the treatment of hepatic encephalopathy. In contrast to neomycin, its tolerability profile is comparable to placebo.<ref name="pmid10741936">{{cite journal |author=Williams R, James OF, Warnes TW, Morgan MY |title=Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre study |journal=European journal of gastroenterology & hepatology |volume=12 |issue=2 |pages=203-8 |year=2000 |pmid=10741936 |doi=}}</ref> Multiple clinical trials have demonstrated that rifaximin at a dose of 400 mg taken orally 3 times a day was as effective as lactulose or lactilol at improving hepatic encephalopathy symptoms.<ref name="pmid8325041">{{cite journal |author=Bucci L, Palmieri GC |title=Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy |journal=Current medical research and opinion |volume=13 |issue=2 |pages=109-18 |year=1993 |pmid=8325041 |doi=}}</ref> Similarly, rifaximin was as effective as neomycin and paromomycin.<ref name="pmid1751811">{{cite journal |author=Pedretti G, Calzetti C, Missale G, Fiaccadori F |title=Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics. A double-blind, randomized trial |journal=The Italian journal of gastroenterology |volume=23 |issue=4 |pages=175-8 |year=1991 |pmid=1751811 |doi=}}</ref> Rifaximin was better tolerated than both the cathartics and the other nonabsorbable antibiotics. A number of concerns remain regarding rifaximin's role in the treatment of hepatic encephalopathy. It remains to be determined if rifaximin can improve severe encephalopathy symptoms as rapidly as lactulose. There are also concerns regarding the cost-effectiveness of the medication. | ||
[[Rifaximin]] may add to lactulose in preventing episodes of encephalopathy.<ref name="pmid20335583">{{cite journal| author=Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB et al.| title=Rifaximin treatment in hepatic encephalopathy. | journal=N Engl J Med | year= 2010 | volume= 362 | issue= 12 | pages= 1071-81 | pmid=20335583 | |||
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=20335583 | doi=10.1056/NEJMoa0907893 }} </ref> | |||
===Benzodiazepine receptor antagonists=== | ===Benzodiazepine receptor antagonists=== | ||
A [[meta-analysis]] of [[randomized controlled | A [[meta-analysis]] of [[randomized controlled trial]]s by the [[Cochrane Collaboration]] found benefit from [[flumazenil]].<ref name="pmid15106178">{{cite journal |author=Als-Nielsen B, Gluud LL, Gluud C |title=Benzodiazepine receptor antagonists for hepatic encephalopathy |journal=Cochrane database of systematic reviews (Online) |volume= |issue=2 |pages=CD002798 |year=2004 |pmid=15106178 |doi=10.1002/14651858.CD002798.pub2}}</ref> The doses of [[flumazenil]] varied around a median of 2 milligrams over 10 minutes: 'Flumazenil was given as a continuous infusion (12 trials), preceded by bolus injections in two trials. One trial used only bolus injections. Patients received flumazenil at a total dose ranging from 0.2 to 19.5 milligram (median 2 milligram). The median duration of treatment was 10 minutes (range one minute to 72 hours)'. However, the benefit was short. | ||
===L-ornithine-L-aspartate=== | ===L-ornithine-L-aspartate=== | ||
[[L-ornithine-L-aspartate]] stimulates the [[urea cycle]], and has shown encouraging results in [[randomized controlled | [[L-ornithine-L-aspartate]] stimulates the [[urea cycle]], and has shown encouraging results in [[randomized controlled trial]]s.<ref>{{cite journal |author=Poo J, Góngora J, Sánchez-Avila F, Aguilar-Castillo S, García-Ramos G, Fernández-Zertuche M, Rodríguez-Fragoso L, Uribe M |title=Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study |journal=Ann Hepatol |volume=5 |issue=4 |pages=281-8 |year=2006 |pmid=17151582}}</ref><ref name="pmid17151582">{{cite journal |author=Poo JL, Góngora J, Sánchez-Avila F, ''et al'' |title=Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study |journal=Annals of hepatology : official journal of the Mexican Association of Hepatology |volume=5 |issue=4 |pages=281-8 |year=2006 |pmid=17151582 |doi=}}</ref><ref name="pmid9625322">{{cite journal |author=Stauch S, Kircheis G, Adler G, ''et al'' |title=Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study |journal=J. Hepatol. |volume=28 |issue=5 |pages=856-64 |year=1998 |pmid=9625322 |doi=}}</ref> | ||
===Assessment fitness for automobile driving=== | |||
Hepatic encephalopathy, even minimal encephalopathy, can impair driving.<ref name="pmid19686744">{{cite journal| author=Kircheis G, Knoche A, Hilger N, Manhart F, Schnitzler A, Schulze H et al.| title=Hepatic encephalopathy and fitness to drive. | journal=Gastroenterology | year= 2009 | volume= 137 | issue= 5 | pages= 1706-15.e1-9 | pmid=19686744 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&[email protected]&retmode=ref&cmd=prlinks&id=19686744 | doi=10.1053/j.gastro.2009.08.003 }}</ref> | |||
Six states madate that physicians report drivers with medical impairments (California, Delaware, Nevada, New Jersey, Oregon, and Pennsylvania). These states and 25 others grant immunity to physicians who report impaired drivers.<ref name="pmid20728575">{{cite journal| author=Cohen SM, Kim A, Metropulos M, Ahn J| title=Legal ramifications for physicians of patients who drive with hepatic encephalopathy. | journal=Clin Gastroenterol Hepatol | year= 2011 | volume= 9 | issue= 2 | pages= 156-60; quiz e17 | pmid=20728575 | doi=10.1016/j.cgh.2010.08.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20728575 }} </ref> | |||
==References== | ==References== | ||
<references/> | <references/>[[Category:Suggestion Bot Tag]] | ||
[[Category: | |||
Latest revision as of 06:01, 27 August 2024
In medicine, hepatic encephalopathy is "syndrome characterized by central nervous system dysfunction in association with liver failure, including portal-systemic shunts. Clinical features include lethargy and confusion (frequently progressing to coma); asterixis; nystagmus, pathologic; brisk oculovestibular reflexes; decorticate and decerebrate posturing; muscle spasticity; and bilateral extensor plantar reflexes . Electroencephalography may demonstrate triphasic waves."[1] The Babinski sign demonstrates abnormal plantar reflexes.
Classification and grading
In the World Congress of Gastroenterology 1998 in Vienna, a proposed classification of hepatic encephalopathy was presented to standardize the subclasses. According to this classification, hepatic encephalopathy is subdivided in type A, B and C.[2]
- Type A (=acute) describes hepatic encephalopathy associated with acute liver failure;
- Type B (=bypass) is caused by portal-systemic shunting without associated intrinsic liver disease;
- Type C (=cirrhosis) occurs in patients with cirrhosis.
In addition, the duration and characteristics of hepatic encephalopathy were classified into episodic, persistent and minimal. The term minimal encephalopathy (MHE) is defined by patients with cirrhosis who do not demonstrate clinically overt cognitive dysfunction, but who show a cognitive impairment on neuropsychological studies.[2] This is still an important finding, as minimal encephalopathy has been demonstrated to increase the rate of road traffic accidents and violations.[3]
The evaluation of severity of persistent hepatic encephalopathy is based on the West Haven Criteria for semi-quantitative grading of mental status, referring to the level of impairment of autonomy, changes in consciousness, intellectual function, behavior, and the dependence on therapy.[2][4].
- Grade 1 (also called minimal hepatic encephalopathy - MHE)[5]- Trivial lack of awareness; Euphoria or anxiety; Shortened attention span; Impaired performance of addition. 67% of cirrhotic patients in one study of outpatients at a liver clinic had MHE.[5]
- Grade 2 - Lethargy or apathy; Minimal disorientation for time or place; Subtle personality change; Inappropriate behavior; Impaired performance of subtraction
- Grade 3 - Somnolence to semistupor, but responsive to verbal stimuli; confusion; gross disorientation
- Grade 4 - Coma (unresponsive to verbal or noxious stimuli)
Etiology / cause
There may be a genetic propensity to hepatic encephalopathy. [6]
Diagnosis
The inhibitory control test (ICT) may be a faster way to diagnose hepatic encephalopathy than standard psychometric tests (average administration time of 15 minutes versus 37 minutes) [7]
Asterixis
Asterixis, which are "abnormal involuntary movements which primarily affect the extremities, trunk, or jaw that occur as a manifestation of an underlying disease process,"[8] may help diagnose hepatic encephalopathy. In unresponsive patients, asterixis can be checked by flexing the hips.[9]
Blood tests
Ammonia
The normal plasma level of ammonia is 12 - 48 μmol/L.[10]
| NH3 level | Grade 0 (no encephalopathy) |
Grade 1 | Grade 2 | Grade 3 | Grade 4 |
|---|---|---|---|---|---|
| > 50 | 10 (33%) | 18 (67%) | 14 (52%) | 25 (89%) | 12 (92%) |
| 25-20 | 12 (40%) | 9 (33%) | 5 (19%) | 3 (11%) | 0 |
| < 25 | 8 (27%) | 0 (0%) | 4 (15%) | 0 (0)%) | 1* (8%) |
| Total patients |
30 (100%) | 27 (100%) | 2 (100%)3 | 28 (100%) | 13 (100%) |
| *This patient's ammonia level was approximately 20 μmol/L. | |||||
The ammonia level can help diagnose encephalopathy.[11][12][13]
| sensitivity | specificity | |
|---|---|---|
| > 50 μmol/L | 76% | 67% |
| > 25 μmol/L | 93% | 27% |
Newer blood tests
A study concluded that the "determination of 3-nitro-tyrosine in serum, which is easy and not time consuming, is useful to identify patients with MHE, with good sensitivity, specificity, and positive and negative predictive values.". [14] This study reported a sensitivity and specificity of 94% and 83%, respectively. In populations similar to those in this study which had a prevalence of minimal hepatic encephalopathy of 35%, the probabilities of minimal hepatic encephalopathy among patients with an abnormal and normal serum 3-nitro-tyrosine above 14 nM were 75.0% and 4.0%, respectively. [14]
Treatment
Even 'minimal hepatic encephalopathy' may benefit from treatment. [5]
Reduce protein intake
The role of protein restriction is controversial.[15]
Correction of hypokalemia
Concommittent hypokalemia should be corrected as hypokalemia increases renal ammonia production and may promote conversion of ammonium into ammonia which can cross the blood-brain barrier.[16]
Lactulose
Lactulose is a compound that will cause osmotic diarrhoea, thus lessening the time available for intestinal bacteria to metabolise protein into ammonia within the bowel. Further, it acidifies the environment in the lumen of the bowel. This promotes the conversion of lumenal ammonia (NH3) to ammonium (NH4+) which, by which virtue of its net charge, should be less readily absorbed into the bloodstream from the bowel lumen. Despite this theoretical and appealing mechanism, a meta-analysis of [[randomized controlled trial]s] by the international Cochrane Collaboration found benefit, but suggests there is little evidence for its preferred use to treat hepatic encephalopathy.[17] Indeed, any drug (laxative) which speeds up transit through the bowel thereby lessening the time available for bacteria to metabolize protein into ammonia, works just as well.
Lactulose can be given rectally for patients who cannot take oral medications.[18][19][20] One regimen is 300 mL (200 gm) of lactulose syrup (10 gm/15 ml) in 1 L of water which is retained for 1 hour, with the patient in the Trendelenburg position.[21]
Antibiotics
Antibiotics may be given to kill bacteria present in the bowel thereby decreasing bacterial conversion of protein to ammonia (and other toxic substances) there. Although effective, neomycin, a non-absorbable aminoglycoside antibiotic, is essentially contraindicated; it has been found that a proportion of the ingested dose is indeed absorbed due to increased gut permeability, thus increasing the risk of renal failure and hearing loss (i.e. two of the potential side effects of neomycin). The former side-effect, in particular, is especially worrisome given the already increased likelihood of renal failure in cirrhosis and portal hypertension (i.e. hepatorenal syndrome). Metronidazole 200 mg four times a day by mouth was similar to neomycin in short a randomized crossover trial.[22]
Rifaximin
Rifaximin (Xifaxan®), received orphan drug status in 2005 for the treatment of hepatic encephalopathy. In contrast to neomycin, its tolerability profile is comparable to placebo.[23] Multiple clinical trials have demonstrated that rifaximin at a dose of 400 mg taken orally 3 times a day was as effective as lactulose or lactilol at improving hepatic encephalopathy symptoms.[24] Similarly, rifaximin was as effective as neomycin and paromomycin.[25] Rifaximin was better tolerated than both the cathartics and the other nonabsorbable antibiotics. A number of concerns remain regarding rifaximin's role in the treatment of hepatic encephalopathy. It remains to be determined if rifaximin can improve severe encephalopathy symptoms as rapidly as lactulose. There are also concerns regarding the cost-effectiveness of the medication.
Rifaximin may add to lactulose in preventing episodes of encephalopathy.[26]
Benzodiazepine receptor antagonists
A meta-analysis of randomized controlled trials by the Cochrane Collaboration found benefit from flumazenil.[27] The doses of flumazenil varied around a median of 2 milligrams over 10 minutes: 'Flumazenil was given as a continuous infusion (12 trials), preceded by bolus injections in two trials. One trial used only bolus injections. Patients received flumazenil at a total dose ranging from 0.2 to 19.5 milligram (median 2 milligram). The median duration of treatment was 10 minutes (range one minute to 72 hours)'. However, the benefit was short.
L-ornithine-L-aspartate
L-ornithine-L-aspartate stimulates the urea cycle, and has shown encouraging results in randomized controlled trials.[28][29][30]
Assessment fitness for automobile driving
Hepatic encephalopathy, even minimal encephalopathy, can impair driving.[31]
Six states madate that physicians report drivers with medical impairments (California, Delaware, Nevada, New Jersey, Oregon, and Pennsylvania). These states and 25 others grant immunity to physicians who report impaired drivers.[32]
References
- ↑ Anonymous (2024), Hepatic encephalopathy (English). Medical Subject Headings. U.S. National Library of Medicine.
- ↑ 2.0 2.1 2.2 Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei A (2002). "Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998". Hepatology 35 (3): 716-21. PMID 11870389.
- ↑ Bajaj JS, Hafeezullah M, Hoffmann RG, Saeian K (2007). "Minimal hepatic encephalopathy: a vehicle for accidents and traffic violations". Am J Gastroenterol 102 (9): 1903–09. DOI:10.1111/j.1572-0241.2007.01424.x. PMID 17640323. Research Blogging.
- ↑ Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, Levy LL. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology 1977; 72: 573-83.
- ↑ 5.0 5.1 5.2 Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R (2007). "Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy". Hepatology 45 (3): 549-59. DOI:10.1002/hep.21533. PMID 17326150. Research Blogging.
- ↑ Romero-Gómez M, Jover M, Del Campo JA, Royo JL, Hoyas E, Galán JJ et al. (2010). "Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: a cohort study.". Ann Intern Med 153 (5): 281-8. DOI:10.1059/0003-4819-153-5-201009070-00002. PMID 20820037. Research Blogging.
- ↑ Bajaj JS, Saeian K, Verber MD, et al (2007). "Inhibitory control test is a simple method to diagnose minimal hepatic encephalopathy and predict development of overt hepatic encephalopathy". Am. J. Gastroenterol. 102 (4): 754-60. DOI:10.1111/j.1572-0241.2007.01048.x. PMID 17222319. Research Blogging.
- ↑ Anonymous (2024), Asterixis (English). Medical Subject Headings. U.S. National Library of Medicine.
- ↑ Noda S, Ito H, Umezaki H, Minato S (July 1985). "Hip flexion-abduction to elicit asterixis in unresponsive patients". Annals of neurology 18 (1): 96–7. DOI:10.1002/ana.410180118. PMID 4037757. Research Blogging.
- ↑ Kratz A, Lewandrowski KB (1998). "Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Normal reference laboratory values". N Engl J Med 339 (15): 1063. DOI:10.1056/NEJM199810083391508. Research Blogging.
- ↑ 11.0 11.1 11.2 Ong JP, Aggarwal A, Krieger D, et al (February 2003). "Correlation between ammonia levels and the severity of hepatic encephalopathy". The American journal of medicine 114 (3): 188–93. PMID 12637132. [e]
- ↑ Stahl J (January 1963). "Studies of the blood ammonia in liver disease. Its diagnostic, prognostic, and therapeutic significance". Annals of internal medicine 58: 1–24. PMID 13978712. [e]
- ↑ Nicolao F, Efrati C, Masini A, Merli M, Attili AF, Riggio O (April 2003). "Role of determination of partial pressure of ammonia in cirrhotic patients with and without hepatic encephalopathy". Journal of hepatology 38 (4): 441–6. PMID 12663235. [e]
- ↑ 14.0 14.1 Montoliu C, Cauli O, Urios A, ElMlili N, Serra MA, Giner-Duran R et al. (2011). "3-nitro-tyrosine as a peripheral biomarker of minimal hepatic encephalopathy in patients with liver cirrhosis.". Am J Gastroenterol 106 (9): 1629-37. DOI:10.1038/ajg.2011.123. PMID 21483460. Research Blogging.
- ↑ Córdoba J, López-Hellín J, Planas M, et al (2004). "Normal protein diet for episodic hepatic encephalopathy: results of a randomized study". J. Hepatol. 41 (1): 38–43. DOI:10.1016/j.jhep.2004.03.023. PMID 15246205. Research Blogging.
- ↑ Artz SA, Paes IC, Faloon WW (1966). "Hypokalemia-induced hepatic coma in cirrhosis. Occurrence despite neomycin therapy". Gastroenterology 51 (6): 1046-53. PMID 5958605. [e]
- ↑ Als-Nielsen B, Gluud L, Gluud C. "Nonabsorbable disaccharides for hepatic encephalopathy". Cochrane Database Syst Rev: CD003044. PMID 15106187.
- ↑ Kersh ES, Rifkin H (1973). "Lactulose enemas". Ann. Intern. Med. 78 (1): 81-4. PMID 4682313. [e]
- ↑ Ratnaike RN, Hicks EP, Hislop IG (1975). "The rectal administration of lactulose". Australian and New Zealand journal of medicine 5 (2): 137-40. PMID 240347. [e]
- ↑ Uribe M, Campollo O, Vargas F, et al (1987). "Acidifying enemas (lactitol and lactose) vs. nonacidifying enemas (tap water) to treat acute portal-systemic encephalopathy: a double-blind, randomized clinical trial". Hepatology 7 (4): 639-43. PMID 3301614. [e]
- ↑ Blei AT, Córdoba J (2001). "Hepatic Encephalopathy". Am. J. Gastroenterol. 96 (7): 1968-76. DOI:10.1111/j.1572-0241.2001.03964.x. PMID 11467622. Research Blogging.
- ↑ Morgan MH, Read AE, Speller DC (1982). "Treatment of hepatic encephalopathy with metronidazole". Gut 23 (1): 1-7. PMID 7035298. [e] PubMed Central
- ↑ Williams R, James OF, Warnes TW, Morgan MY (2000). "Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre study". European journal of gastroenterology & hepatology 12 (2): 203-8. PMID 10741936. [e]
- ↑ Bucci L, Palmieri GC (1993). "Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy". Current medical research and opinion 13 (2): 109-18. PMID 8325041. [e]
- ↑ Pedretti G, Calzetti C, Missale G, Fiaccadori F (1991). "Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics. A double-blind, randomized trial". The Italian journal of gastroenterology 23 (4): 175-8. PMID 1751811. [e]
- ↑ Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB et al. (2010). "Rifaximin treatment in hepatic encephalopathy.". N Engl J Med 362 (12): 1071-81. DOI:10.1056/NEJMoa0907893. PMID 20335583. Research Blogging.
- ↑ Als-Nielsen B, Gluud LL, Gluud C (2004). "Benzodiazepine receptor antagonists for hepatic encephalopathy". Cochrane database of systematic reviews (Online) (2): CD002798. DOI:10.1002/14651858.CD002798.pub2. PMID 15106178. Research Blogging.
- ↑ Poo J, Góngora J, Sánchez-Avila F, Aguilar-Castillo S, García-Ramos G, Fernández-Zertuche M, Rodríguez-Fragoso L, Uribe M (2006). "Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study". Ann Hepatol 5 (4): 281-8. PMID 17151582.
- ↑ Poo JL, Góngora J, Sánchez-Avila F, et al (2006). "Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study". Annals of hepatology : official journal of the Mexican Association of Hepatology 5 (4): 281-8. PMID 17151582. [e]
- ↑ Stauch S, Kircheis G, Adler G, et al (1998). "Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study". J. Hepatol. 28 (5): 856-64. PMID 9625322. [e]
- ↑ Kircheis G, Knoche A, Hilger N, Manhart F, Schnitzler A, Schulze H et al. (2009). "Hepatic encephalopathy and fitness to drive.". Gastroenterology 137 (5): 1706-15.e1-9. DOI:10.1053/j.gastro.2009.08.003. PMID 19686744. Research Blogging.
- ↑ Cohen SM, Kim A, Metropulos M, Ahn J (2011). "Legal ramifications for physicians of patients who drive with hepatic encephalopathy.". Clin Gastroenterol Hepatol 9 (2): 156-60; quiz e17. DOI:10.1016/j.cgh.2010.08.002. PMID 20728575. Research Blogging.