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| | ==[[Hepatic encephalopathy overview|Overview]]== |
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| | ==[[Hepatic encephalopathy historical perspective|Historical Perspective]]== |
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| ==Overview== | | ==[[Hepatic encephalopathy classification|Classification]]== |
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| '''Hepatic encephalopathy''' (sometimes '''hepatoencephalopathy''') is a potentially reversible neuropsychiatic abnormality in the setting of [[liver failure]], whether chronic (as in [[cirrhosis]]), or [[acute liver failure|acutely]]. It can be diagnosed only after exclusion of other neurological, psychiatric, infectious and metabolic etiologies.
| | ==[[Hepatic encephalopathy pathophysiology|Pathophysiology]]== |
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| With severe liver impairment, toxic substances normally removed by the liver accumulate in the [[blood]] and impair the function of [[brain]] cells. If there is also [[portal hypertension]], and subsequent bypassing of the liver filtration system of blood flowing in from the intestines, these toxic substances can travel directly to the brain, without being modified or purified. Signs can include impaired [[cognition]], a flapping tremor ([[asterixis]]), and a decreased level of consciousness including coma ('''hepatic coma''' or '''coma hepaticum'''), [[cerebral edema]], and, ultimately, death.
| | ==[[Hepatic encephalopathy causes|Causes]]== |
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| ==Signs and symptoms== | | ==[[Hepatic encephalopathy differential diagnosis|Differentiating Hepatic encephalopathy from other Diseases]]== |
| ===Presenting===
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| Hepatic encephalopathy leads to changed cognitive function. This can range from subtle deficits in higher mental functions (in mild cases) to [[obtundation]] and coma (in severe cases). Left untreated, severe hepatic encephalopathy can cause death. | |
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| One of the earliest manifestations of hepatic encephalopathy is "day-night reversal". In other words, affected individuals tend to sleep during the day and stay awake at night. Another early manifestation is impairment in spatial perception. This can be made apparent by noting the patient's poor ability to copy or draw various simple images, e.g cube, star, clock. This deficit can also be demonstrated by administering a test which has the patient connect a number of randomly placed dots on a sheet of paper (the "trail test" or "numbers connecting test").
| | ==[[Hepatic encephalopathy epidemiology and demographics|Epidemiology and Demographics]]== |
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| In addition to changed level of consciousness, the hallmark of hepatic encephalopathy on the physical examination is the presence of [[asterixis]]. This is detected by having the patient hold out his outstretched arms and hands and cock his wrists back. In the presence of asterixis, there is a non-synchronized, intermittent flapping motion at the wrists. Asterixis is not specific to hepatic encephalopathy. It may also be seen in states such as [[renal failure]] and [[carbon dioxide retention]].
| | ==[[Hepatic encephalopathy risk factors|Risk Factors]]== |
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| 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>
| | ==[[Hepatic encephalopathy screening|Screening]]== |
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| ===Precipitants=== | | ==[[Hepatic encephalopathy natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| Although the onset of hepatic encephalopathy may simply reflect worsening of underlying liver disease, it may also be due to a number of independent factors, each treatable in its own right. In fact, studies have shown that the majority of cases are due to one (or more) of such precipitating factors. It is critical, then, that a search for possible precipitants be conducted in patients with new-onset hepatic encephalopathy, and specific treatment initiated if such a precipitant is discovered.
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| Virtually any [[metabolism|metabolic]] disturbance may precipitate hepatic encephalopathy. Common culprits are [[hyponatremia]] (often arising as a result of [[diuretic]] treatment or simply as a complication of the [[edema]] typically found in advanced [[cirrhosis]]), [[hypokalemia]] (again, often as a result of diuretic use), [[alkalosis]], dehydration, [[hypoglycemia]] (a condition to which people with cirrhosis are susceptible), and [[renal failure]] of even mild degree.
| | ==Diagnosis== |
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| Likewise, there are a number of medications the use of which may bring on hepatic encephalopathy. These include [[benzodiazepines]] (e.g. [[diazepam]], [[lorazepam]]), [[narcotics]], and [[diuretics]]. Alcohol ingestion, whether or not it was the cause of the patient's liver disease, may also precipitate hepatic encephalopathy.
| | [[Hepatic encephalopathy history and symptoms|History and Symptoms]] | [[Hepatic encephalopathy physical examination|Physical Examination]] | [[Hepatic encephalopathy laboratory findings|Laboratory Findings]] | [[Hepatic encephalopathy electrocardiogram|EKG]] | [[Hepatic encephalopathy CT|CT]] | [[Hepatic encephalopathy MRI|MRI]] | [[Hepatic encephalopathy echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Hepatic encephalopathy other imaging findings|Other Imaging Findings]] | [[Hepatic encephalopathy other diagnostic studies|Other Diagnostic Studies]] |
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| Infection is an important precipitant of hepatic encephalopathy. In some cases, the ''only'' clinical manifestation of the infection is the development of the encephalopathy. In fact, this is a frequent phenomenon in patients whose [[ascites]] has become infected (i.e. [[spontaneous bacterial peritonitis]]).
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| Sometimes, hepatic encephalopathy arises as a result of patient non compliance with dietary protein restriction. Indeed, given the general lack of palatability of low protein diets, non-compliance is common and, hence, so is its effect to precipitate encephalopathy.
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| Bleeding into the [[stomach]] or [[small intestine]] (both of which occur with increased frequency in people with liver disease and/or [[portal hypertension]]) may also lead to hepatic encephalopathy. Blood contains large quantities of protein in the form of plasma proteins and hemoglobin. Hence, the presence of blood in the stomach or small intestine represents a protein load which, as a result of bacterial metabolism in the lumen of the gut, is converted to potentially toxic products such as ammonia.
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| Certain surgical procedures employed to treat [[portal hypertension]] commonly lead to the development of hepatic encephalopathy. For example, operations to relieve pressure in the portal vein by connecting it to the [[splenic vein]] or other systemic venous vessels, have the effect of diverting incoming intestinal venous blood away from the liver. This means that such ammonia-carrying blood will not be able to be "purified" by the liver. Encephalopathy can result. Similarly, the more recently developed "TIPS" procedure ([[transjugular intrahepatic portosystemic shunt]]) often precipitates hepatic encephalopathy (~30 percent of patients undergoing it).
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| ==Classification and grading==
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| 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>
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| * ''Type A (=acute)'' describes hepatic encephalopathy associated with acute liver failure;
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| * ''Type B (=[[Bypass (surgical)|bypass]])'' is caused by portal-systemic shunting without associated intrinsic liver disease;
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| * ''Type C (=cirrhosis'') occurs in patients with [[cirrhosis]].
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| 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.<ref name=Ferenci/> This is still an important finding, as minimal encephalopathy has been demonstrated to increase the rate of road traffic accidents and violations.<ref>{{cite journal |author=Bajaj JS, Hafeezullah M, Hoffmann RG, Saeian K |title=Minimal hepatic encephalopathy: a vehicle for accidents and traffic violations |journal=Am J Gastroenterol |volume=102 |issue=9 |pages=1903–09 |year=2007 |pmid=17640323 |doi=10.1111/j.1572-0241.2007.01424.x}}</ref>
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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>.
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| * Grade 1 - Trivial lack of awareness; Euphoria or anxiety; Shortened attention span; Impaired performance of addition. 67% of cirrhotic patients may have 'minimal hepatic encephalopathy'.<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>
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| * Grade 2 - Lethargy or [[apathy]]; Minimal disorientation for time or place; Subtle personality change; Inappropriate behavior; Impaired performance of subtraction
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| * Grade 3 - [[Somnolence]] to semi[[stupor]], but responsive to verbal stimuli; Confusion; Gross disorientation
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| * Grade 4 - [[Coma]] (unresponsive to verbal or noxious stimuli)
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| ==Pathogenesis==
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| Due to the presence of scarring within the [[liver]], [[cirrhosis]] leads to obstruction of the passage of blood through the [[liver]] causing [[portal hypertension]]. This means it is difficult for blood from the [[intestine]]s to go through the liver to get back to the [[heart]]. Portal-systemic [[anastomosis|anastamoses]] ("shunts") develop, and portal blood (from the intestinal veins) will bypass the liver and return to the heart via another route without undergoing first-pass detoxification by the liver.
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| Furthermore, in cirrhosis and other forms of liver disease, the damaged liver will not be functioning as well as it should be, so even blood that does travel through the liver may not be as detoxified as it otherwise would be. In fact, if the degree of liver damage and malfunction is severe, then, even in the absence of [[portal hypertension]] and the consequent bypassing of the liver by blood coming in from the intestines, hepatic encephalopathy will still occur. Such may well be the case, for example, following severe injury due to [[acetaminophen]] poisoning or acute viral infection (e.g. [[hepatitis A]]).
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| The toxic substances which accumulate in the setting of liver failure and affect the brain are still not well understood. They have been thought to include [[ammonia]] (NH<sub>3</sub>) and [[mercaptan]]s. Ammonia is normally converted to [[urea]] by the liver and, as with [[mercaptan]]s, is produced by the [[bacterium|bacteria]]l breakdown of protein in the intestines.
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| Ammonia can cross the [[blood-brain barrier]], where it causes the support cells of the brain ([[astrocyte]]s) to swell. The swelling of the brain tissue increases [[intracranial pressure]], and can lead to [[coma]] or [[death]] via [[Brain herniation|herniation]] of the brainstem.
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| ==Treatment== | | ==Treatment== |
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| ===Recommendations for the treatment of Hepatic Encephalopathy (DO NOT EDIT)===
| | [[Hepatic encephalopathy medical therapy|Medical Therapy]] | [[Hepatic encephalopathy surgery|Surgery]] | [[Hepatic encephalopathy prevention|Prevention]] | [[Hepatic encephalopathy cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Hepatic encephalopathy future or investigational therapies|Future or Investigational Therapies]] |
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| # In early stages of encephalopathy, lactulose may be used either orally or rectally to effect a bowel purge, but should not be administered to the point of diarrhea, and may interfere with the surgical field by increasing bowel distention during liver transplantation.
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| # Patients who progress to high-grade hepatic encephalopathy (grade III or IV) should undergo endotracheal intubation.
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| # Seizure activity should be treated with phenytoin and benzodiazepines with short half-lives. Prophylactic phenytoin is not recommended.
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| # Intracranial pressure (ICP) monitoring is recommended in ALF patients with high-grade hepatic encephalopathy, in centers with expertise in ICP monitoring, in patients awaiting and undergoing liver transplantation.
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| # In the absence of ICP monitoring, frequent (hourly) neurological evaluation is recommended to identify early evidence of intracranial hypertension.
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| # In the event of intracranial hypertension, a mannitol bolus (0.5-1.0 gm/kg body weight) is recommended as first-line therapy; however, the prophylactic administration of mannitol is not recommended.
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| # In ALF patients at highest risk for cerebral edema (serum ammonia >150 µM, grade 3/4 hepatic encephalopathy, acute renal failure, requiring vasopressors to maintain mean arterial pressure [MAP]), the prophylactic induction of hypernatremia with hypertonic saline to a sodium level of 145-155 mEq/L is recommended.
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| # Short-acting barbiturates and the induction of hypothermia to a core body temperature of 34-35ºC may be considered for intracranial hypertension refractory to osmotic agents as a bridge to liver transplantation.
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| # Corticosteroids should not be used to control elevated ICP in patients with ALF.}}
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| ===Medical Therapy===
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| Even 'minimal hepatic encephalopathy' may benefit from treatment. <ref name="pmid17326150"/>
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| ====Reduce protein intake====
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| Traditionally it has been presumed that excessive protein intake leads to increased generation of ammonia, which, in the setting of severe liver impairment, will accumulate and worsen the hepatic encephalopathy. While very large protein loads (such as [[gastrointestinal hemorrhage]], because blood is rich in protein) are known to precipitate encephalopathy, the need for patients with chronic liver disease patients to be protein restricted has been disproven.<ref>{{cite journal |author=Córdoba J, López-Hellín J, Planas M, ''et al'' |title=Normal protein diet for episodic hepatic encephalopathy: results of a randomized study |journal=J. Hepatol. |volume=41 |issue=1 |pages=38–43 |year=2004 |pmid=15246205 |doi=10.1016/j.jhep.2004.03.023}}</ref> Indeed, because chronic liver disease is a catabolic state, a protein restricted diet would lead to protein malnutrition and a negative [[nitrogen balance]].
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| ====Correction of hypokalemia====
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| 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.<ref name="pmid5958605">{{cite journal |author=Artz SA, Paes IC, Faloon WW |title=Hypokalemia-induced hepatic coma in cirrhosis. Occurrence despite neomycin therapy |journal=Gastroenterology |volume=51 |issue=6 |pages=1046-53 |year=1966 |pmid=5958605 |doi=}}</ref>
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| ====Lactulose====
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| [[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 trials]] 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. | |
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| [[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>
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| ====Antibiotics====
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| 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]] has also been studied.<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=}}</ref>
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| =====Rifaximin=====
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| [[Rifaximin]] (Xifaxan®), receieved 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. | |
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| ====Benzodiazepine receptor antagonists====
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| A [[meta-analysis]] of [[randomized controlled trials]] by the international [[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.
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| ====L-ornithine-L-aspartate====
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| L-ornithine-L-aspartate stimulates the [[urea cycle]], and has shown encouraging results in [[randomized controlled trials]].<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>
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| ==References==
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| {{Reflist|2}}
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| | ==Case Studies== |
| | [[Hepatic encephalopathy case study one|Case #1]] |
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| [[Category:Gastroenterology]] | | [[Category:Gastroenterology]] |