Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Portal-Systemic Encephalopathy Treatment & Management

  • Author: Gagan K Sood, MD; Chief Editor: BS Anand, MD  more...
 
Updated: Dec 18, 2014
 

Medical Care

Nonabsorbable disaccharides

Despite the availability of multiple approaches, treatment with nonabsorbed disaccharides remains the mainstay of therapy for hepatic encephalopathy. These agents act by at least 3 mechanisms, as follows:

  • First, luminal bacteria metabolize lactulose and lactitol (beta galactoside-sorbitol). The consequent acidification of the gut lumen leads to ammonia being protonated to the ammonium ion (NH4 +), which is relatively membrane impermeable; therefore, less ammonia is absorbed from the colon.
  • The second benefit to gut luminal acidification is reduction in the number of bacteria present, which reduces the presence of bacterial urease and consequent ammoniagenesis.
  • Lastly, the osmotic effect of nonabsorbed disaccharides enhances gastrointestinal transit.

A typical starting dose for the treatment of chronic hepatic encephalopathy is 20 g lactulose PO bid with the goal of producing 2-3 soft bowel movements daily. Dose increases or reductions may be necessary based on the patient's response. In the acute setting, hepatic encephalopathy may be treated with 20 g lactulose every few hours until a satisfactory result is achieved, but care must be taken to avoid diarrhea that leads to electrolyte depletion and dehydration. Lactulose enemas may be of benefit when a paralytic ileus precludes oral or nasoenteral tube administration. Because the bacterial metabolism of lactulose results in the production of hydrogen, this agent should not be used as a lavage preparation for colonoscopy because electrocautery under these circumstances may produce explosive results.

Clinical evaluations regarding the efficacy of these agents are limited, especially when their widespread use and the potential for adverse reactions are considered. The toxicity of lactulose and lactitol includes gastrointestinal bloating due to bacterial gas production, dehydration, and electrolyte disturbances. The latter may result in a paralytic ileus and, therefore, must be carefully distinguished from the more common bloating. Indeed, these complications of lactulose therapy may paradoxically worsen hepatic encephalopathy. Gastrointestinal upset infrequently leads to a requirement for dose reduction or ultimately discontinuance. It may be less problematic with lactitol.

Antibiotics

Treatment with nonabsorbable antibiotics also is advocated as a treatment of hepatic encephalopathy and may be of particular value in a patient intolerant of lactulose. This may be relevant for a patient with intestinal ileus, in whom the administration of lactulose may generate large volumes of hydrogen gas upon bacterial fermentation. Similarly, patients with multiple electrolyte disturbances or dehydration may benefit from this approach rather than from the use of lactulose.

Neomycin at 1 g PO tid/qid may be used, but it is not recommended for prolonged use. As much as 3% of an oral dose of neomycin may be absorbed systemically, and nephrotoxicity may result. The efficacy of neomycin was questioned when no clinical benefit could be demonstrated by some, when compared to placebo in treatment of acute hepatic encephalopathy.

Oral metronidazole is used with success, but long-term therapy may result in toxicity, including peripheral neuropathy.

Rifaximin is a newer nonabsorbable antibiotic for the treatment of hepatic encephalopathy. The efficacy of rifaximin in the treatment of hepatic encephalopathy has been studied in 20 studies, including 14 randomized controlled studies. In 7 studies, rifaximin was compared to lactulose or lactilol. Results of Cochrane meta-analysis from these studies suggested rifaximin to be significantly more effective than nonabsorbable disaccharides (lactulose or lactilol) in the treatment of hepatic encephalopathy.

In March 2010, rifaximin was approved by the Food and Drug Administration (FDA) to reduce recurrence of hepatic encephalopathy. The approval was based on a phase 3 clinical trial conducted by Bass et al.[1] Bass et al evaluated rifaximin’s ability to reduce the risk of recurrent hepatic encephalopathy (HE).[1] In this double-blind, placebo-controlled, multinational, phase 3 clinical trial, 299 patients received either rifaximin 550 mg or placebo BID. Each group also received lactulose. The primary endpoint—the risk of a recurrent HE episode—was reduced by 58% in the rifaximin group compared with the placebo group (P < .0001). The key secondary endpoint -- risk of experiencing HE-related hospitalization -- was reduced by 50% in patients who received rifaximin compared with those who received placebo (P = .0129).

Another recent trial reported benefits of long-term treatment with rifaximin in maintenance of remission from overt encephalopathy.[2] This study was an open-label maintenance extension of the phase 3 trial of rifaximin in HE, and it reported results of long-term efficacy and survival of 152 rollover patients from the registration trial and 128 new patients treated with rifaximin. The rollover patients were rifaximin (n=70) or placebo (n=82) patients who completed or withdrew from the registration trial with a Conn Score of 2 of less.

Sixty of the 70 rifaximin-treated patients from the registration trial who enrolled in the long-term follow-up remained in remission at study completion or withdrawal, 43 (72%) of these patients did not experience breakthrough overt encephalopathy; the risk of experiencing breakthrough encephalopathy was decreased by 79% compared with their prior 6-month placebo treatment. Changes in the MELD score were minimal in both the registration trial and the open-label extension, regardless of treatment (see the MELD Score calculator). The authors concluded that longer therapy with rifaximin is associated with continued protection from breakthrough HE, with no adverse effect on expected mortality.

Altering gut flora

The presence of urease-expressing bacterial organisms in the gut microflora forms the basis for efforts to repopulate the gut with nonureolytic organisms, such as Lactobacillus acidophilus and Enterococcus faecium. In theory, this should result in a reduction in colonic ammoniagenesis, but few well-designed studies exist to support the routine clinical application of this approach. Results of small trials with Lactobacillus species are mixed. The use of orally administered Enterococcus species resulted in sustained protection from hepatic encephalopathy in one study and appeared to be safe. Further evaluation of this approach is justified and needed.

The presence of Helicobacter pylori in the gastric mucosa represents another potential source of ammonia because this organism produces urease. Helicobacter ammoniagenesis may be most significant when accompanied by achlorhydria, in part due to increased absorption of nonprotonated ammonia across the gastric mucosa and, possibly, from increased numbers of bacteria. The role of H pylori in the pathogenesis of hepatic encephalopathy remains contentious; however, some investigators have identified it as an independent risk factor for the development of hepatic encephalopathy, while others have not.

One possible explanation for improvement in hepatic encephalopathy following eradication therapy for H pylori is that the antibiotics decreased the gut's colonic population of urease-expressing organisms and those of the gastric mucosa. It appears reasonable to treat patients for H pylori when dictated by routine clinical circumstances (eg, in the treatment of peptic ulcer disease) but not as prophylaxis for hepatic encephalopathy.

Probiotics

Probiotics are not as useful in overt hepatic encephalopathy but have been used with some success in minimal HE. The species that are most efficacious are lactobacilli and bifidobacteria. Probiotics may also reduce bacterial translocation and subsequent endotoxemia and ameliorate the hyperdynamic circulation.

While probiotics appear to reduce plasma ammonia concentration when compared with placebo or no intervention, a Cochrane meta-analysis concluded that probiotics are efficacious in altering clinically relevant outcomes,[3] but further randomized clinical trials are needed. A recent study showed lactulose and probiotics are effective for secondary prophylaxis of HE in patients with cirrhosis.[4]

Ammonia cavengers and activated charcoal

Intravenous sodium benzoate and sodium phenylacetate or the phenylacetate prodrug oral sodium phenylbutyrate can combine with glycine or glutamine to form water-soluble compounds excreted through the kidneys. These agents are not yet approved by the US Food and Drug Administration for this use; they depend on normal renal function for ammonia excretion, and the large therapeutic doses confer a significant sodium load, which can increase fluid retention. Newer ammonia scavengers and orally ingested activated charcoal are being studied.

Glycerol phenylbutyrate (HPN-100, Hyperion Therapeutics) is a new compound that is a prodrug of sodium phenylbutyrate with much lower therapeutic doses needed. It has been used for urea cycle disorders and is undergoing clinical trials for chronic HE.

Orally ingested activated charcoal is also being explored for the treatment of HE. AST-120 is a spherical carbon adsorbent and the molecule adsorbs small molecules (ammonia, lipopolysaccharides, and cytokines). A pilot study shows equal efficacy to lactulose and fewer adverse events.[5]

Increasing ammonia metabolism

Another treatment approach is to increase the metabolism of ammonia with the administration of substrates that permit its incorporation.

Ornithine is a substrate for urea, and aspartate is a substrate for glutamine. Both enteral and intravenous administration of ornithine aspartate (a mixture of the 2 amino acids) are shown in some controlled trials to lower serum ammonia levels and improve mild hepatic encephalopathy by increasing the conversion of ammonia to urea. Trials using ornithine alpha-glutarate did not demonstrate a benefit. In part, this may be because it only supplies one substrate for incorporation of ammonia. Relatively large doses of amino acids (18 g/d PO) appear to be necessary for any clinical benefit.

The mechanism of action of L-ornithine L-aspartate may extend beyond the urea cycle. Administration of ornithine aspartate to portal hypertensive rats results in high concentrations of glutamate in the plasma and CSF and an associated reduction in plasma ammonia. The elevated glutamate concentrations facilitate synthesis of glutamine by glutamine synthase, which is expressed at high levels in the liver, brain, and skeletal muscle. This mechanism may permit further significant reductions in ammonia levels within both the CNS and the systemic circulation. Indeed, increased glutamine synthase expression is induced in skeletal muscle by portocaval shunting.

An increase in plasma concentrations of BCAAs also is an anticipated metabolic consequence of increased glutamate availability. It remains of uncertain significance and does not necessarily contribute to the improvement in hepatic encephalopathy documented in this experimental model.

Sodium benzoate also is shown to be efficacious in reducing serum ammonia. It is conjugated to glycine to form hippuric acid, which is excreted in the urine. Similarly, phenylacetate is conjugated with glutamine to form phenacetylglutamine. Both of these organic acids have been used successfully to treat hepatic encephalopathy in some clinical trials.

Zinc supplementation

The urea cycle allows conversion of ammonia to urea. Because 2 of the enzymes in this metabolic pathway require zinc as a cofactor and because reduced plasma zinc levels from increased urinary zinc losses are documented in hepatic encephalopathy, oral zinc supplementation is proposed for the treatment of hepatic encephalopathy.

The measurement of serum zinc levels may not accurately reflect whole-body zinc status, but it would appear reasonable to supplement patients found to have low serum zinc levels with zinc gluconate.

Flumazenil

Treatment efforts with flumazenil, a competitive antagonist of BZPs, are based on the GABA hypothesis; however, results of the small clinical trials performed to date are variable.

In 2 well-designed studies, flumazenil was found to be of value in a limited number of patients but clear factors that might permit their identification were not proposed; therefore, because of the difficulty in establishing a more generalized improvement in patient course and the relatively short action of duration of the drug, it is not of convincing benefit.

Dopamine agonists

Parkinsonian or extrapyramidal symptoms may manifest with hepatic encephalopathy. Treatment with levodopa or bromocriptine is shown to result in improvement in clinical and EEG findings in anecdotal reports and small studies.

Although the use of bromocriptine is advocated for cases of refractory hepatic encephalopathy, well-designed prospective controlled trials have not been conducted.

Albumin

Simón-Talero et al found evidence that a subgroup of patients with advanced cirrhosis and episodic hepatic encephalopathy may benefit from treatment with albumin. In a randomized, prospective, double-blind, controlled trial, 56 cirrhotic patients with an acute episode of hepatic encephalopathy were randomly assigned to receive albumin (26 patients) or saline (30 patients), in addition to commonly administered therapy consisting of laxatives and 1200 mg of rifaximin per day.[6]

The investigators determined that albumin did not aid in reducing the percentage of patients with encephalopathy during the hospitalization period, with no significant difference found between the albumin and saline groups with regard to the percentage of patients at day 4 whose encephalopathy had resolved. At day 90, however, the survival rate in the albumin and saline groups did significantly differ (69.2% vs 40.0%, respectively). The investigators suggested that the development of encephalopathy possibly signals which patients with advanced cirrhosis may benefit from albumin therapy.

Next

Surgical Care

The definitive approach to management of portosystemic encephalopathy is, of course, orthotopic liver transplantation (OLT). Portosystemic encephalopathy as a complication of end-stage liver disease may warrant discussion of orthotopic liver transplantation. Indeed, even CNS structural changes evident on MRI may be reversed slowly following orthotopic liver transplantation; however, a detailed discussion of orthotopic liver transplantation is beyond the scope of this article (see Liver Transplantation).

A retrospective cohort study by Laleman et al indicated that embolization can be used to safely and effectively treat hepatic encephalopathy in patients with large spontaneous portosystemic shunts (SPSSs). The study involved 37 patients with refractory hepatic encephalopathy and a single large SPSS who underwent embolization. Within 100 days following the procedure, 22 patients (59.4%) were free of the encephalopathy, with 18 of them remaining free of it over a mean follow-up period of 697 days. One major, albeit nonlethal, procedure-associated complication occurred in the study.[7]

Previous
Next

Consultations

See the list below:

  • Consultation with a neurologist is of value, especially if doubts exist regarding the etiology of the encephalopathy.
Previous
Next

Diet

See the list below:

  • Nutritional therapy
    • BCAA therapy has been evaluated extensively as a treatment of hepatic encephalopathy. BCAAs are of suggested benefit in lowering production of false neurotransmitters. Vegetable protein–based diets that exclude meat are relatively high in BCAAs and low in aromatic amino acid content. Clinical trials performed to date with vegetable protein–based diets or BCAAs have not demonstrated any consistent or convincing benefit with respect to clinical manifestations of hepatic encephalopathy and do not support their widespread use for treatment or prevention of hepatic encephalopathy.
    • Vegetable protein, however, may have other benefits. In patients with subclinical hepatic encephalopathy, one study demonstrated computer-analyzed EEG findings improved with vegetable protein–based diets, despite the lack of any change in ammonia levels. Urinary 3-methyl-histidine excretion was increased with the use of an animal-protein diet, and the vegetable diet was associated with a decrease in urinary nitrogen excretion; thus, the nitrogen balance tended to be more positive with the vegetable-protein diet.
    • Patients with advanced liver disease often present with poor nutritional status and may develop a negative nitrogen balance exacerbated by acute or recurrent efforts to restrict dietary protein. Although the practice of strictly limiting dietary protein in these patients was advocated until recently, adverse nutritional consequences now appear to outweigh any potential benefit for the prevention of hepatic encephalopathy. In general, patients with chronic liver disease should be advised to eat approximately 1 g of dietary protein per kilogram body weight per day. In this context, BCAAs may be a useful dietary supplement to help preserve skeletal muscle mass via protein sparing, with little risk of precipitating hepatic encephalopathy.
    • With a well-tolerated exogenous source of amino acids, the catabolic metabolism that otherwise results in negative nitrogen balance therefore may be offset. This is of particular importance in patients awaiting orthotopic liver transplantation, in whom a protracted nutritional decline may occur during the long wait for a suitable donor liver.
Previous
Next

Activity

See the list below:

  • Consider restricting patients with encephalopathy from driving an automobile or operating potentially dangerous machinery. This may be difficult to justify to patients and their families in the absence of formal psychometric testing. Reaction times and judgment typically are impaired. Similarly, a patient may need to perform different job duties in order to avoid physical or, possibly, financial harm. Clearly, these issues may settle themselves because mental status changes resolve completely with therapy. These difficult issues require review on an individual basis and require periodic reassessment.
  • Patients need adequate rest, and their goal should be to sleep at least 8 hours at night. Strenuous activity should be avoided, but regular mild exercise is distinctly advantageous for maintaining bone mass and cardiovascular conditioning in anticipation of the long wait for a donor organ attendant with orthotopic liver transplantation.
Previous
 
 
Contributor Information and Disclosures
Author

Gagan K Sood, MD Associate Professor, Department of Medicine and Surgery, Baylor College of Medicine

Gagan K Sood, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Noel Williams, MD, FRCPC FACP, MACG, Professor Emeritus, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Professor, Department of Internal Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada

Noel Williams, MD, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Additional Contributors

Ann Ouyang, MBBS Professor, Department of Internal Medicine, Pennsylvania State University College of Medicine; Attending Physician, Division of Gastroenterology and Hepatology, Milton S Hershey Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous coauthor, Blake A Jones, MD, to the development and writing of this article.

References
  1. Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010. 362(12):1071-1081.

  2. Mullen KD, Poordad F, Rossaro L, et al. Long term efficacy and survival in patients treated with the gut-selective antibiotic rifaximin (550 mg BID) for the maintenance of remission from overt hepatic encephalopathy. Gastroenterol Hepatol. 2011. 7(6 Suppl 9):1-15.

  3. McGee RG, Bakens A, Wiley K, Riordan SM, Webster AC. Probiotics for patients with hepatic encephalopathy. Cochrane Database Syst Rev. 2011. (11):CD008716. [Medline].

  4. Agrawal A, Sharma BC, Sharma P, Sarin SK. Secondary Prophylaxis of Hepatic Encephalopathy in Cirrhosis: An Open-Label, Randomized Controlled Trial of Lactulose, Probiotics, and No Therapy. Am J Gastroenterol. 2012 Jun 19. [Medline].

  5. Pockros P, Hassanein T, Vierling J, et al. Phase 2, multicenter, randomized study of AST-120 (spherical carbon adsorbent) vs. lactulose in the treatment of lowgrade hepatic encephalopathy. J Hepatol. 2009. 50(Suppl 1):S43-4.

  6. Simón-Talero M, García-Martínez R, Torrens M, et al. Effects of intravenous albumin in patients with cirrhosis and episodic hepatic encephalopathy: a randomized double-blind study. J Hepatol. 2013 Dec. 59(6):1184-92. [Medline].

  7. Laleman W, Simon-Talero M, Maleux G, et al. Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy. Hepatology. 2013 Jun. 57(6):2448-57. [Medline].

  8. Albrecht J, Hilgier W, Rafalowska U. Activation of arginine metabolism to glutamate in rat brain synaptosomes in thioacetamide-induced hepatic encephalopathy: an adaptative response?. J Neurosci Res. 1990 Jan. 25(1):125-30. [Medline].

  9. Amaral OB, Quevedo J, Walz R, et al. Flumazenil and hepatic encephalopathy. Hepatology. 1999 Apr. 29(4):1338-9. [Medline].

  10. Amodio P, Del Piccolo F, Marchetti P, et al. Clinical features and survivial of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests. Hepatology. 1999 Jun. 29(6):1662-7. [Medline].

  11. Avallone R, Zeneroli ML, Venturini I, et al. Endogenous benzodiazepine-like compounds and diazepam binding inhibitor in serum of patients with liver cirrhosis with and without overt encephalopathy. Gut. 1998 Jun. 42(6):861-7. [Medline].

  12. Bansky G, Meier PJ, Riederer E, et al. Effects of the benzodiazepine receptor antagonist flumazenil in hepatic encephalopathy in humans. Gastroenterology. 1989 Sep. 97(3):744-50. [Medline].

  13. Barbaro G, Di Lorenzo G, Soldini M, et al. Flumazenil for hepatic coma in patients with liver cirrhosis: an Italian multicentre double-blind, placebo-controlled, crossover study. Eur J Emerg Med. 1998 Jun. 5(2):213-8. [Medline].

  14. Basile AS, Jones EA. Ammonia and GABA-ergic neurotransmission: interrelated factors in the pathogenesis of hepatic encephalopathy. Hepatology. 1997 Jun. 25(6):1303-5. [Medline].

  15. Bianchi GP, Marchesini G, Fabbri A, et al. Vegetable versus animal protein diet in cirrhotic patients with chronic encephalopathy. A randomized cross-over comparison. J Intern Med. 1993 May. 233(5):385-92. [Medline].

  16. Bickford RG, Butt HR. Hepatic coma: the electroencephalographic pattern. J Clin Invest. 1955. 34:790-9.

  17. Bircher J, Buhrer M, Franz K, et al. [1st use of lactitol in the treatment of porto-systemic encephalopathy]. Schweiz Med Wochenschr. 1982 Sep 18. 112(38):1306-7. [Medline].

  18. Bresci G, Parisi G, Banti S. Management of hepatic encephalopathy with oral zinc supplementation: a long-term treatment. Eur J Med. 1993 Aug-Sep. 2(7):414-6. [Medline].

  19. Butterworth RF. Pathogenesis of acute hepatic encephalopathy. Digestion. 1998 Jul. 59 Suppl 2:16-21. [Medline].

  20. Chan H, Hazell AS, Desjardins P. Neurotoxins generated in liver failure cause altered expression of genes coding for key astrocytic proteins. Hepatology. 1999. 30(4):234A.

  21. Charlton MR. Branched chains revisited. Gastroenterology. 1996 Jul. 111(1):252-5. [Medline].

  22. Child CG. Ligature of the portal vein (translation of original by Eck, 1877). Surg Gynecol Obstet. 1953. 375-6.

  23. Conn HO. Trailmaking and number-connection tests in the assessment of mental state in portal systemic encephalopathy. Am J Dig Dis. 1977 Jun. 22(6):541-50. [Medline].

  24. Conn HO, Leevy CM, Vlahcevic ZR, et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology. 1977 Apr. 72(4 Pt 1):573-83. [Medline].

  25. Costa E, Guidotti A. Diazepam binding inhibitor (DBI): a peptide with multiple biological actions. Life Sci. 1991. 49(5):325-44. [Medline].

  26. Córdoba J, Mínguez B. Hepatic encephalopathy. Semin Liver Dis. 2008 Feb. 28(1):70-80. [Medline].

  27. Dasani BM, Sigal SH, Lieber CS. Analysis of risk factors for chronic hepatic encephalopathy: the role of Helicobacter pylori infection. Am J Gastroenterol. 1998 May. 93(5):726-31. [Medline].

  28. de Bruijn KM, Blendis LM, Zilm DH, et al. Effect of dietary protein manipulation in subclinical portal-systemic encephalopathy. Gut. 1983 Jan. 24(1):53-60. [Medline].

  29. Deschenes M, Dufresne MP, Bui B, et al. Predictors of clinical response to transjugular intrahepatic portosystemic shunt (TIPS) in cirrhotic patients with refractory ascites. Am J Gastroenterol. 1999 May. 94(5):1361-5. [Medline].

  30. Eck NV. Ligature of the portal vein. Voen Med J St-Petersburg (Russo). 1877. 130:1-2.

  31. Elkington SG, Floch MH, Conn HO. Lactulose in the treatment of chronic portal-systemic encephalopathy. A double-blind clinical trial. N Engl J Med. 1969 Aug 21. 281(8):408-12. [Medline].

  32. Fabbri A, Magrini N, Bianchi G, et al. Overview of randomized clinical trials of oral branched-chain amino acid treatment in chronic hepatic encephalopathy. JPEN J Parenter Enteral Nutr. 1996 Mar-Apr. 20(2):159-64. [Medline].

  33. Felipo V, Hermenegildo C, Montoliu C, et al. Neurotoxicity of ammonia and glutamate: molecular mechanisms and prevention. Neurotoxicology. 1998 Aug-Oct. 19(4-5):675-81. [Medline].

  34. Ferenci P. Hepatic Encephalopathy. McIntyre N, Benhamou JP, Bircher J, Rizzetto M, Rodes J, eds. Textbook of Clinical Hepatology. Oxford, England: Oxford University Press; 1991. Vol 1: 473-83.

  35. Fischer JE, Baldessarini RJ. False neurotransmitters and hepatic failure. Lancet. 1971 Jul 10. 2(7715):75-80. [Medline].

  36. Flannery DB, Hsia YE, Wolf B. Current status of hyperammonemic syndromes. Hepatology. 1982 Jul-Aug. 2(4):495-506. [Medline].

  37. Genesca J, Gonzalez A, Segura R, et al. Interleukin-6, nitric oxide, and the clinical and hemodynamic alterations of patients with liver cirrhosis. Am J Gastroenterol. 1999 Jan. 94(1):169-77. [Medline].

  38. Germain L, Frexinos J, Louis A, et al. [Double blind study of lactulose in 8 patients with chronic hepatic encephalopathy after portocaval shunt]. Arch Fr Mal App Dig. 1973 Jun. 62(4):293-302. [Medline].

  39. Girard G, Butterworth RF. Effect of portacaval anastomosis on glutamine synthetase activities in liver, brain, and skeletal muscle. Dig Dis Sci. 1992 Jul. 37(7):1121-6. [Medline].

  40. Gitlin N. Hepatic encephalopathy. Zakim D, Boyer T, eds. Hepatology: a textbook of liver disease. 3rd ed. Philadelphia, Pa: WB Saunders; 1996. Vol 1: 605-17.

  41. Groeneweg M, Gyr K, Amrein R, et al. Effect of flumazenil on the electroencephalogram of patients with portosystemic encephalopathy. Results of a double blind, randomised, placebo-controlled multicentre trial. Electroencephalogr Clin Neurophysiol. 1996 Jan. 98(1):29-34. [Medline].

  42. Guarner C, Soriano G, Tomas A, et al. Increased serum nitrite and nitrate levels in patients with cirrhosis: relationship to endotoxemia. Hepatology. 1993 Nov. 18(5):1139-43. [Medline].

  43. Hassanein TI, Tofteng F, Brown RS Jr, et al. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology. 2007 Dec. 46(6):1853-62. [Medline].

  44. Haussinger D, Laubenberger J, vom Dahl S, et al. Proton magnetic resonance spectroscopy studies on human brain myo-inositol in hypo-osmolarity and hepatic encephalopathy. Gastroenterology. 1994 Nov. 107(5):1475-80. [Medline].

  45. Hazell AS, Desjardins P, Butterworth RF. Chronic exposure of rat primary astrocyte cultures to manganese results in increased binding sites for the 'peripheral-type' benzodiazepine receptor ligand 3H-PK 11195. Neurosci Lett. 1999 Aug 13. 271(1):5-8. [Medline].

  46. Howard ER. Encephalopathy without cirrhosis: hunt the shunt. Gut. 1999 Sep. 45(3):329-30. [Medline].

  47. Häussinger D. Hepatic glutamine transport and metabolism. Adv Enzymol Relat Areas Mol Biol. 1998. 72:43-86. [Medline].

  48. Häussinger D. Low grade cerebral edema and the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology. 2006 Jun. 43(6):1187-90. [Medline].

  49. Ito S, Miyaji H, Azuma T, et al. Hyperammonaemia and Helicobacter pylori. Lancet. 1995 Jul 8. 346(8967):124-5. [Medline].

  50. Jalan R, Olde Damink SW, Hayes PC, et al. Diagnosis of hepatic encephalopathy: will in vivo proton MRS play a role?. Hepatology. 1999 May. 29(5):1605-7. [Medline].

  51. Jenkins RL, Gedaly R, Pomposelli JJ, et al. Distal splenorenal shunt: role, indications, and utility in the era of liver transplantation. Arch Surg. 1999 Apr. 134(4):416-20. [Medline].

  52. Kale RA, Gupta RK, Saraswat VA, et al. Demonstration of interstitial cerebral edema with diffusion tensor MR imaging in type C hepatic encephalopathy. Hepatology. 2006 Apr. 43(4):698-706. [Medline].

  53. Keeling PW, Jones RB, Hilton PJ, et al. Reduced leucocyte zinc in liver disease. Gut. 1980 Jul. 21(7):561-4. [Medline].

  54. Kircheis G, Nilius R, Held C, et al. Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology. 1997 Jun. 25(6):1351-60. [Medline].

  55. Kircheis G, Quack G, Erbler H. L-ornithine L-aspartate in the treatment of hyperammonemia and hepatic encephalopathy. Conn HO, Bircher J, eds. Hepatic encephalopathy: syndromes and therapies. Bloomington, Ill: Medi-Ed; 1994. 373-83.

  56. Kullmann F, Hollerbach S, Holstege A, et al. Subclinical hepatic encephalopathy: the diagnostic value of evoked potentials. J Hepatol. 1995 Jan. 22(1):101-10. [Medline].

  57. Köstler H. Proton magnetic resonance spectroscopy in portal-systemic encephalopathy. Metab Brain Dis. 1998 Dec. 13(4):291-301. [Medline].

  58. Larsen FS, Ejlersen E, Clemmesen JO. Preservation of cerebral oxidative metabolism in fulminant hepatic failure: an autoregulation study. Liver Transpl Surg. 1996 Sep. 2(5):348-53. [Medline].

  59. Larsen FS, Olsen KS, Ejlersen E, et al. Cerebral blood flow autoregulation and transcranial Doppler sonography in patients with cirrhosis. Hepatology. 1995 Sep. 22(3):730-6. [Medline].

  60. Lata J, Hulek P, Fejfar T, et al. [Rifaximin in the treatment of hepatic encephalopathy]. Vnitr Lek. 2002 Jun. 48(6):578-82. [Medline].

  61. Laubenberger J, Haussinger D, Bayer S, et al. Proton magnetic resonance spectroscopy of the brain in symptomatic and asymptomatic patients with liver cirrhosis. Gastroenterology. 1997 May. 112(5):1610-6. [Medline].

  62. Layrargues GP, Rose C, Spahr L, et al. Role of manganese in the pathogenesis of portal-systemic encephalopathy. Metab Brain Dis. 1998 Dec. 13(4):311-7. [Medline].

  63. Lee FY, Lu RH, Tsai YT, et al. Plasma interleukin-6 levels in patients with cirrhosis. Relationship to endotoxemia, tumor necrosis factor-alpha, and hyperdynamic circulation. Scand J Gastroenterol. 1996 May. 31(5):500-5. [Medline].

  64. Lee JH, Seo DW, Lee YS, et al. Proton magnetic resonance spectroscopy (1H-MRS) findings for the brain in patients with liver cirrhosis reflect the hepatic functional reserve. Am J Gastroenterol. 1999 Aug. 94(8):2206-13. [Medline].

  65. Lockwood AH. Early detection and treatment of hepatic encephalopathy. Curr Opin Neurol. 1998 Dec. 11(6):663-6. [Medline].

  66. Lockwood AH, Yap EW, Rhoades HM, et al. Altered cerebral blood flow and glucose metabolism in patients with liver disease and minimal encephalopathy. J Cereb Blood Flow Metab. 1991 Mar. 11(2):331-6. [Medline].

  67. Lockwood AH, Yap EW, Wong WH. Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J Cereb Blood Flow Metab. 1991 Mar. 11(2):337-41. [Medline].

  68. Loguercio C, Abbiati R, Rinaldi M, et al. Long-term effects of Enterococcus faecium SF68 versus lactulose in the treatment of patients with cirrhosis and grade 1-2 hepatic encephalopathy. J Hepatol. 1995 Jul. 23(1):39-46. [Medline].

  69. Manzoni O, Prezeau L, Marin P, et al. Nitric oxide-induced blockade of NMDA receptors. Neuron. 1992 Apr. 8(4):653-62. [Medline].

  70. Mas A, Rodes J, Sunyer L, et al. Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol. 2003 Jan. 38(1):51-8. [Medline].

  71. Mehndiratta MM, Sood GK, Sarin SK, et al. Comparative evaluation of visual, somatosensory, and auditory evoked potentials in the detection of subclinical hepatic encephalopathy in patients with nonalcoholic cirrhosis. Am J Gastroenterol. 1990 Jul. 85(7):799-803. [Medline].

  72. Mendenhall CL, Rouster S, Marshall L, et al. A new therapy for portal systemic encephalopathy. Am J Gastroenterol. 1986 Jul. 81(7):540-3. [Medline].

  73. Michalopoulos GK, DeFrances MC. Liver regeneration. Science. 1997 Apr 4. 276(5309):60-6. [Medline].

  74. Montague PR, Gancayco CD, Winn MJ, et al. Role of NO production in NMDA receptor-mediated neurotransmitter release in cerebral cortex. Science. 1994 Feb 18. 263(5149):973-7. [Medline].

  75. Moore JW, Dunk AA, Crawford JR, et al. Neuropsychological deficits and morphological MRI brain scan abnormalities in apparently healthy non-encephalopathic patients with cirrhosis. A controlled study. J Hepatol. 1989 Nov. 9(3):319-25. [Medline].

  76. Moorman AF, Vermeulen JL, Charles R, et al. Localization of ammonia-metabolizing enzymes in human liver: ontogenesis of heterogeneity. Hepatology. 1989 Mar. 9(3):367-72. [Medline].

  77. Morgan MH, Read AE, Speller DC. Treatment of hepatic encephalopathy with metronidazole. Gut. 1982 Jan. 23(1):1-7. [Medline].

  78. Morgan MY. Cerebral magnetic resonance imaging in patients with chronic liver disease. Metab Brain Dis. 1998 Dec. 13(4):273-90. [Medline].

  79. Morgan MY, Jakobovits AW, James IM, et al. Successful use of bromocriptine in the treatment of chronic hepatic encephalopathy. Gastroenterology. 1980 Apr. 78(4):663-70. [Medline].

  80. Mullen KD, Szauter KM, Kaminsky-Russ K. "Endogenous" benzodiazepine activity in body fluids of patients with hepatic encephalopathy. Lancet. 1990 Jul 14. 336(8707):81-3. [Medline].

  81. Ong J, Kerr DI. Clinical potential of GABAB receptor modulators. CNS Drug Rev. 2005 Autumn. 11(3):317-34. [Medline].

  82. Perney P, Butterworth RF, Mousseau DD, et al. Plasma and CSF benzodiazepine receptor ligand concentrations in cirrhotic patients with hepatic encephalopathy: relationship to severity of encephalopathy and to pharmaceutical benzodiazepine intake. Metab Brain Dis. 1998 Sep. 13(3):201-10. [Medline].

  83. Pogun S, Dawson V, Kuhar MJ. Nitric oxide inhibits 3H-glutamate transport in synaptosomes. Synapse. 1994 Sep. 18(1):21-6. [Medline].

  84. Pomier-Layrargues G. TIPS and hepatic encephalopathy. Semin Liver Dis. 1996 Aug. 16(3):315-20. [Medline].

  85. Pomier-Layrargues G, Giguere JF, Lavoie J, et al. Flumazenil in cirrhotic patients in hepatic coma: a randomized double-blind placebo-controlled crossover trial. Hepatology. 1994 Jan. 19(1):32-7. [Medline].

  86. Quero JC, Hartmann IJ, Meulstee J, et al. The diagnosis of subclinical hepatic encephalopathy in patients with cirrhosis using neuropsychological tests and automated electroencephalogram analysis. Hepatology. 1996 Sep. 24(3):556-60. [Medline].

  87. Rao VL, Butterworth RF. Neuronal nitric oxide synthase and Hepatic Encephalopathy. Metab Brain Dis. 1998 Sep. 13(3):175-89. [Medline].

  88. Read AE, McCarthy CF, Heaton KW, et al. Lactobacillus acidophilus (enpac) in treatment of hepatic encephalopathy. Br Med J. 1966 May 21. 1(5498):1267-9. [Medline].

  89. Riggio O, Efrati C, Catalano C, et al. High prevalence of spontaneous portal-systemic shunts in persistent hepatic encephalopathy: a case-control study. Hepatology. 2005 Nov. 42(5):1158-65. [Medline].

  90. Riggio O, Masini A, Efrati C, et al. Pharmacological prophylaxis of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled study. J Hepatol. 2005 May. 42(5):674-9. [Medline].

  91. Riggio O, Merlli M, Pedretti G, et al. Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt. Incidence and risk factors. Dig Dis Sci. 1996 Mar. 41(3):578-84. [Medline].

  92. Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med. 1997 Aug 14. 337(7):473-9. [Medline].

  93. Rose C, Butterworth RF, Zayed J, et al. Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction. Gastroenterology. 1999 Sep. 117(3):640-4. [Medline].

  94. Rose C, Michalak A, Pannunzio P, et al. L-ornithine-L-aspartate in experimental portal-systemic encephalopathy: therapeutic efficacy and mechanism of action. Metab Brain Dis. 1998 Jun. 13(2):147-57. [Medline].

  95. Sandford SL, Tarter RE, Sclabassi R, et al. Sensory information processing in patients with nonalcoholic cirrhosis. Short-latency visual, auditory, and somatosensory event-related potentials. J Neurol Sci. 1987 Sep. 80(2-3):269-76. [Medline].

  96. Sanyal AJ, Freedman AM, Shiffman ML, et al. Portosystemic encephalopathy after transjugular intrahepatic portosystemic shunt: results of a prospective controlled study. Hepatology. 1994 Jul. 20(1 Pt 1):46-55. [Medline].

  97. Schumacher IK, Okamoto T, Kim BH, et al. Transplantation of conditionally immortalized hepatocytes to treat hepatic encephalopathy. Hepatology. 1996 Aug. 24(2):337-43. [Medline].

  98. Stauch S, Kircheis G, Adler G, et al. Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study. J Hepatol. 1998 May. 28(5):856-64. [Medline].

  99. Strauss E, Tramote R, Silva EP, et al. Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy. Hepatogastroenterology. 1992 Dec. 39(6):542-5. [Medline].

  100. Sushma S, Dasarathy S, Tandon RK, et al. Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial. Hepatology. 1992 Jul. 16(1):138-44. [Medline].

  101. Taylor-Robinson SD, Oatridge A, Hajnal JV, et al. MR imaging of the basal ganglia in chronic liver disease: correlation of T1-weighted and magnetisation transfer contrast measurements with liver dysfunction and neuropsychiatric status. Metab Brain Dis. 1995 Jun. 10(2):175-88. [Medline].

  102. Unseld E, Krishna DR, Fischer C, et al. Detection of desmethyldiazepam and diazepam in brain of different species and plants. Biochem Pharmacol. 1989 Aug 1. 38(15):2473-8. [Medline].

  103. Uribe M, García-Ramos G, Ramos M, et al. Standard and higher doses of bromocriptine for severe chronic portal-systemic encephalopathy. Am J Gastroenterol. 1983 Aug. 78(8):517-22. [Medline].

  104. Van der Rijt CC, Schalm SW, De Groot GH, et al. Objective measurement of hepatic encephalopathy by means of automated EEG analysis. Electroencephalogr Clin Neurophysiol. 1984 May. 57(5):423-6. [Medline].

  105. Weissenborn K, Kolbe H. The basal ganglia and portal-systemic encephalopathy. Metab Brain Dis. 1998 Dec. 13(4):261-72. [Medline].

  106. Weissenborn K, Scholz M, Hinrichs H, et al. Neurophysiological assessment of early hepatic encephalopathy. Electroencephalogr Clin Neurophysiol. 1990 Apr. 75(4):289-95. [Medline].

  107. Yen CL, Liaw YF. Somatosensory evoked potentials and number connection test in the detection of subclinical hepatic encephalopathy. Hepatogastroenterology. 1990 Jun. 37(3):332-4. [Medline].

  108. Yurdaydin C, Karavelioglu D, Onaran O, et al. Opioid receptor ligands in human hepatic encephalopathy. J Hepatol. 1998 Nov. 29(5):796-801. [Medline].

  109. Zullo A, Rinaldi V, Meddi P, et al. Helicobacter pylori infection, plasma ammonia levels, and psychometric testing in cirrhotic patients. Am J Gastroenterol. 1999 Aug. 94(8):2214-8. [Medline].

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.