**7.1 Nonadsorable disaccharides**

Nonadsorable disaccharides (Lacutlose and Lactitol) especially Lactulose are considered the first line therapy for HE despite lack of well-designed randomized controlled trial. They are metabolized by the colonic bacteria and form by products that reduce the colonic PH, hence interfering with mucosal uptake of glutamine and reducing the synthesis and absorption of ammonia. There are other proposed mechanism of lactulose in HE such as lactulose modifies the colonic flora which in turn results in shift of urease containing bacteria with lactobacillus, fourfold increased fecal nitrogen excretion due to increase stool volume and it

Hepatic Encephalopathy 503

saccharolytic bacterial flora while reducing proteolytic flora that produce mercaptans, benzodiazepine like substances and ammonia as well. This theory was answered in a

**Probiotics and synbiotics** modify the gut bacterial flora and reduce ammonia levels. Their

**7.4 Agents causing alteration in ammonia metabolism (L-Ornithine L-Aspartate and** 

Urea cycle plays a key role in ammonia metabolism and its excretion by forming urea in periportal hepatocytes or synthesis of glutamine in perivenous hepatocytes. But in cirrhosis, the activities of carbamyl phosphate synthetase enzyme (Urea synthesis) and of glutamine synthesis (glutamine synthesis) are impaired hence as compensation glutamine increased which in turn lead to increased level of ammonia. Therefore ornithine aspartate and benzoate has been used for reducing the ammonia levels by increasing the metabolism to

L-ornithine-L-aspartate (LOLA) activates urea cycle and enhances ammonia clearance. LOLA induces an increase of liver and muscle ammonia metabolism, leading to decreased blood levels, and is able to cross the blood-brain barrier, increasing the cerebral ammonia disposal.(65) One or two sachets of LOLA should be administered three times daily.(4)

Other ammonia excretors like sodium benzoate, sodium phenyl acetate and sodium phenyl butyrate are also reported to show improvement but clear efficacy has not been established yet. Sodium phenyl acetate and Ammonal are the only drugs approved by the Food and Drug Administration for the treatment of acute hyperammonemia and associated

**Branch chain amino acids (BCCA):** As it has been hypothesized that in liver cirrhosis, there has been reversal of aromatic amino acids (AAA) to BCCA which could lead to encephalopathy in patients with cirrhosis. Encephalopathy is presumably caused by increase in levels of AAA for monoamine neurotransmission which lead to transformed neuronal excitability and causing HE. Hence numbers of studies have been done to evaluate the effects of BCCA on HE. BCCA can be given orally as well as in infusion

**Agents used for GABA hypothesis pathway:** GABA receptor complex is the principal inhibitory network in nervous system and seems to be a contributor to neuronal inhibition in HE. This GABA receptor complex contains barbiturates and benzodiazepine receptor sites, chloride channels and a GABA binding site. In cirrhosis, there is an evidence for increase in benzodiazepine receptor ligands in subjects with HE, therefore effects of

Flumazenil, a GABAA receptor antagonist also improves the symptoms in patients with grade 3 or 4 HE but its use is limited due to adverse effects(71). It has been seen that response to treatment with flumazenil is rapid onset with few minutes and then with few hours, more than half of these patients deteriorated with 2-3 hours.(72, 73) Because of its

randomized cross over trial by Gentile S et al group in Italy.(63)

use however is still being investigated.(64)

glutamine and hippurate respectively.

encephalopathy in patients with urea cycle disorders.(66)

benzodiazepine receptor antagonist have been evaluated.(69, 70)

**7.5 Agents used in neurotransmission hypothesis** 

**benzyl benzoate)** 

form.(67, 68)

also helps in reduction of formation potentially toxic short chain fatty acids e.g propionate or butyrate.(50-53)

Lactulose can also be administered orally through a nasogastric tube to unresponsive patients as well as rectally through enemas.

The most common side effects associated with over use include dehydration, electrolyte imbalance and abdominal cramping. Previously it is known to cause no improvement in psychometric test performance and mortality(54). Few years back a study conducted in India had shown significant improvement and health related quality of life and psychometric improvement in patients with HE especially with minimal HE.(7)

The lactulose has got some role in preventing recurrent episodes of HE. It was proved by an open label RCT study from India by Sarin group, which suggested that lactulose is also effective in preventing recurrent episodes of HE.(55)

The recommended dose of lactulose is about 15-30ml given twice a day. Lactitol, an alternative to lactulose is considered equally effective and is used in patients intolerant of lactulose, but it is not available in some countries.(56, 57)

#### **7.2 Antibiotics**

Patients intolerant to nonabsorable disaccharides are generally treated with antibiotics, to suppress the bacteria involved in ammonia genesis. There are few antibiotics which have been used for the treatment of HE which had shown limited benefit, which include neomycin, metronidazole, oral vancomycin and very recently Rifaximin.(54)

In fact neomycin was used for treatment of HE for many years based on earlier studies then in early 1990's a double blind randomized controlled trial had no improvement in HE. And also because of its limited systemic absorption which would lead to ototoxicity and nephrotoxicity has lost its use in HE in liver cirrhosis. (58)

Rifaximin, a minimally absorbed oral antibiotic has been approved by FDA for the treatment of chronic HE, on the basis of results of a multicenter, randomized, controlled trials and met analysis.(59) Recently a RCT had shown benefit in prevention of recurrent hepatic encephalopathy over period of 6 months follow up. Subsequently further studies had also shown role of Rifaximin in improving the health related quality of life in patients with HE similarly improvement in Psychometric tests and simulated driving tests.(60-62) The use of this antibiotic is increasing due to few adverse effects and no known drug interactions. The recommended adult daily dose is 1200 mg/day, usually in three divided doses.

Some small studies have also reported the effectiveness of vancomycin and metronidazole, but the data to support their use is not enough.(54)

#### **7.3 Other agents**

**Acarbose**; a hypoglycemic agent and an intestinal a-glucosidase inhibitor which causes decrease in blood ammonia levels and improves mild HE in patients with cirrhosis.(63) It has also been hypothesized that Acarbose promotes the proliferation of intestinal

also helps in reduction of formation potentially toxic short chain fatty acids e.g propionate

Lactulose can also be administered orally through a nasogastric tube to unresponsive

The most common side effects associated with over use include dehydration, electrolyte imbalance and abdominal cramping. Previously it is known to cause no improvement in psychometric test performance and mortality(54). Few years back a study conducted in India had shown significant improvement and health related quality of life and

The lactulose has got some role in preventing recurrent episodes of HE. It was proved by an open label RCT study from India by Sarin group, which suggested that lactulose is also

The recommended dose of lactulose is about 15-30ml given twice a day. Lactitol, an alternative to lactulose is considered equally effective and is used in patients intolerant of

Patients intolerant to nonabsorable disaccharides are generally treated with antibiotics, to suppress the bacteria involved in ammonia genesis. There are few antibiotics which have been used for the treatment of HE which had shown limited benefit, which include

In fact neomycin was used for treatment of HE for many years based on earlier studies then in early 1990's a double blind randomized controlled trial had no improvement in HE. And also because of its limited systemic absorption which would lead to ototoxicity and

Rifaximin, a minimally absorbed oral antibiotic has been approved by FDA for the treatment of chronic HE, on the basis of results of a multicenter, randomized, controlled trials and met analysis.(59) Recently a RCT had shown benefit in prevention of recurrent hepatic encephalopathy over period of 6 months follow up. Subsequently further studies had also shown role of Rifaximin in improving the health related quality of life in patients with HE similarly improvement in Psychometric tests and simulated driving tests.(60-62) The use of this antibiotic is increasing due to few adverse effects and no known drug interactions. The recommended adult daily dose is 1200 mg/day, usually in three divided

Some small studies have also reported the effectiveness of vancomycin and metronidazole,

**Acarbose**; a hypoglycemic agent and an intestinal a-glucosidase inhibitor which causes decrease in blood ammonia levels and improves mild HE in patients with cirrhosis.(63) It has also been hypothesized that Acarbose promotes the proliferation of intestinal

psychometric improvement in patients with HE especially with minimal HE.(7)

neomycin, metronidazole, oral vancomycin and very recently Rifaximin.(54)

or butyrate.(50-53)

**7.2 Antibiotics** 

doses.

**7.3 Other agents** 

patients as well as rectally through enemas.

effective in preventing recurrent episodes of HE.(55)

lactulose, but it is not available in some countries.(56, 57)

nephrotoxicity has lost its use in HE in liver cirrhosis. (58)

but the data to support their use is not enough.(54)

saccharolytic bacterial flora while reducing proteolytic flora that produce mercaptans, benzodiazepine like substances and ammonia as well. This theory was answered in a randomized cross over trial by Gentile S et al group in Italy.(63)

**Probiotics and synbiotics** modify the gut bacterial flora and reduce ammonia levels. Their use however is still being investigated.(64)

#### **7.4 Agents causing alteration in ammonia metabolism (L-Ornithine L-Aspartate and benzyl benzoate)**

Urea cycle plays a key role in ammonia metabolism and its excretion by forming urea in periportal hepatocytes or synthesis of glutamine in perivenous hepatocytes. But in cirrhosis, the activities of carbamyl phosphate synthetase enzyme (Urea synthesis) and of glutamine synthesis (glutamine synthesis) are impaired hence as compensation glutamine increased which in turn lead to increased level of ammonia. Therefore ornithine aspartate and benzoate has been used for reducing the ammonia levels by increasing the metabolism to glutamine and hippurate respectively.

L-ornithine-L-aspartate (LOLA) activates urea cycle and enhances ammonia clearance. LOLA induces an increase of liver and muscle ammonia metabolism, leading to decreased blood levels, and is able to cross the blood-brain barrier, increasing the cerebral ammonia disposal.(65) One or two sachets of LOLA should be administered three times daily.(4)

Other ammonia excretors like sodium benzoate, sodium phenyl acetate and sodium phenyl butyrate are also reported to show improvement but clear efficacy has not been established yet. Sodium phenyl acetate and Ammonal are the only drugs approved by the Food and Drug Administration for the treatment of acute hyperammonemia and associated encephalopathy in patients with urea cycle disorders.(66)

## **7.5 Agents used in neurotransmission hypothesis**

**Branch chain amino acids (BCCA):** As it has been hypothesized that in liver cirrhosis, there has been reversal of aromatic amino acids (AAA) to BCCA which could lead to encephalopathy in patients with cirrhosis. Encephalopathy is presumably caused by increase in levels of AAA for monoamine neurotransmission which lead to transformed neuronal excitability and causing HE. Hence numbers of studies have been done to evaluate the effects of BCCA on HE. BCCA can be given orally as well as in infusion form.(67, 68)

**Agents used for GABA hypothesis pathway:** GABA receptor complex is the principal inhibitory network in nervous system and seems to be a contributor to neuronal inhibition in HE. This GABA receptor complex contains barbiturates and benzodiazepine receptor sites, chloride channels and a GABA binding site. In cirrhosis, there is an evidence for increase in benzodiazepine receptor ligands in subjects with HE, therefore effects of benzodiazepine receptor antagonist have been evaluated.(69, 70)

Flumazenil, a GABAA receptor antagonist also improves the symptoms in patients with grade 3 or 4 HE but its use is limited due to adverse effects(71). It has been seen that response to treatment with flumazenil is rapid onset with few minutes and then with few hours, more than half of these patients deteriorated with 2-3 hours.(72, 73) Because of its

Hepatic Encephalopathy 505

[2] Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, et al. Prognostic

[3] Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic

[4] Cash WJ, McConville P, McDermott E, McCormick PA, Callender ME, McDougall NI.

[5] Bajaj JS, Wade JB, Sanyal AJ. Spectrum of neurocognitive impairment in cirrhosis:

[6] Groeneweg M, Quero JC, De Bruijn I, Hartmann IJ, Essink-bot ML, Hop WC, et al.

[7] Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R. Lactulose improves

have minimal hepatic encephalopathy. Hepatology. 2007 Mar;45(3):549-59. [8] Romero-Gomez M, Boza F, Garcia-Valdecasas MS, Garcia E, Aguilar-Reina J. Subclinical

[11] Gerber T, Schomerus H. Hepatic encephalopathy in liver cirrhosis: pathogenesis,

[12] Butterworth RF. Complications of cirrhosis III. Hepatic encephalopathy. J Hepatol.

[13] Cooper AJ, Plum F. Biochemistry and physiology of brain ammonia. Physiol Rev. 1987

[14] Sundaram V, Shaikh OS. Hepatic encephalopathy: pathophysiology and emerging

[15] Haussinger D, Kircheis G, Fischer R, Schliess F, vom Dahl S. Hepatic encephalopathy in

[16] Olde Damink SW, Jalan R, Dejong CH. Interorgan ammonia trafficking in liver disease.

[17] Rama Rao KV, Norenberg MD. Aquaporin-4 in hepatic encephalopathy. Metab Brain

chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade

[9] Munoz SJ. Hepatic encephalopathy. Med Clin North Am. 2008 Jul;92(4):795-812, viii. [10] Norenberg MD, Jayakumar AR, Rama Rao KV, Panickar KS. New concepts in the

diagnosis and management. Drugs. 2000 Dec;60(6):1353-70.

therapies. Med Clin North Am. 2009 Jul;93(4):819-36, vii.

cerebral edema? J Hepatol. 2000 Jun;32(6):1035-8.

Metab Brain Dis. 2009 Mar;24(1):169-81.

Dis. 2007 Dec;22(3-4):265-75.

Vienna, 1998. Hepatology. 2002 Mar;35(3):716-21.

Am J Gastroenterol. 2001 Sep;96(9):2718-23.

Elsevier 2010. p. 1543-46.

May;30(5):890-5.

Jan;103(1):9-16.

Dec;50(6):2014-21.

Dec;22(3-4):219-34.

Apr;67(2):440-519.

2000;32(1 Suppl):171-80.

Jul;28(1):45-9.

Pathophysiology/Diagnosis/Management 9th ed: Saunders, An Imprint of

significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol. 1999

encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology,

Current concepts in the assessment and treatment of hepatic encephalopathy. QJM.

Implications for the assessment of hepatic encephalopathy. Hepatology. 2009

Subclinical hepatic encephalopathy impairs daily functioning. Hepatology. 1998

cognitive functions and health-related quality of life in patients with cirrhosis who

hepatic encephalopathy predicts the development of overt hepatic encephalopathy.

mechanism of ammonia-induced astrocyte swelling. Metab Brain Dis. 2007

short duration effect and variable results of different studies, flumazenil cannot be recommended as routine therapy.

### **7.6 Other treatment options**

#### **7.6.1 Nutritional intervention**

In the past, dietary protein restriction was considered an important component of the treatment of HE. Recent evidence however suggests that excessive restriction can raise serum ammonia levels, as a result of reduced muscular ammonia metabolism.(74) It has also been seen that majority of the patients with advanced liver disease had severe protein calorie malnutrition due to multifactorial reasons including the decreased oral intake, catabolic state etc.(75)

A high-protein diet is therefore recommended for improving the symptoms of HE. The European society for Parenteral and Enteral nutrition recommended an energy intake of 35/40 kcal/kg body weight per day and that patients must eat at least 1.2g/kg of protein daily along with Branched-chain amino acids (BCAA's) and vegetable-based protein.(76) Vegetable and dairy based proteins are preferred to animal proteins because of a high calorie-to-nitrogen ratio. Vegetable based proteins increase colonic motility and enhances intestinal nitrogen clearance. They also reduce colonic PH, which prevents ammonia absorption into gut.(77)

Zinc increases the activity of ornithine transcarbamylase (an enzyme in urea cycle) so zinc supplementation is also recommended for HE especially in patients who don't show any response to lactulose or neomycin.(38)

#### **7.6.2 Prognosis once recovered from HE**

Patients who recovered from HE can have persistent and cumulative neurologic deficits despite achieving normal mental status after receiving medical therapy. Study for North America had shown that patients with overt HE had persistent deficits in working memory, response inhibition and learning when assessed by psychometric tests. Recurrent episodes are associated with severity of underlying disease.(78, 79)

**Conclusion:** HE includes variety of neuropsychiatric symptoms and signs among patients with CLD leading to liver failure. Occurrence of HE indicates worse prognosis and should be kept on liver transplant list wherever it is available. Initial treatment includes the identification and correction of precipitating factors such as electrolyte imbalances, GI bleeding, medications, and sepsis. The main treatment modalities include the nonabsorbable disaccharide, principally lactulose and antibiotics like metronidazole or Rifaximin nowadays.

#### **8. References**

[1] Nevah MI, Fallon MB. Hepatic encephalopathy, Hepatorenal syndrome, Hepatopulmonary syndrome and Systemic complications of Liver disease. Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease,

short duration effect and variable results of different studies, flumazenil cannot be

In the past, dietary protein restriction was considered an important component of the treatment of HE. Recent evidence however suggests that excessive restriction can raise serum ammonia levels, as a result of reduced muscular ammonia metabolism.(74) It has also been seen that majority of the patients with advanced liver disease had severe protein calorie malnutrition due to multifactorial reasons including the decreased oral intake,

A high-protein diet is therefore recommended for improving the symptoms of HE. The European society for Parenteral and Enteral nutrition recommended an energy intake of 35/40 kcal/kg body weight per day and that patients must eat at least 1.2g/kg of protein daily along with Branched-chain amino acids (BCAA's) and vegetable-based protein.(76) Vegetable and dairy based proteins are preferred to animal proteins because of a high calorie-to-nitrogen ratio. Vegetable based proteins increase colonic motility and enhances intestinal nitrogen clearance. They also reduce colonic PH, which prevents ammonia

Zinc increases the activity of ornithine transcarbamylase (an enzyme in urea cycle) so zinc supplementation is also recommended for HE especially in patients who don't show any

Patients who recovered from HE can have persistent and cumulative neurologic deficits despite achieving normal mental status after receiving medical therapy. Study for North America had shown that patients with overt HE had persistent deficits in working memory, response inhibition and learning when assessed by psychometric tests. Recurrent episodes

**Conclusion:** HE includes variety of neuropsychiatric symptoms and signs among patients with CLD leading to liver failure. Occurrence of HE indicates worse prognosis and should be kept on liver transplant list wherever it is available. Initial treatment includes the identification and correction of precipitating factors such as electrolyte imbalances, GI bleeding, medications, and sepsis. The main treatment modalities include the nonabsorbable disaccharide, principally lactulose and antibiotics like metronidazole or Rifaximin

[1] Nevah MI, Fallon MB. Hepatic encephalopathy, Hepatorenal syndrome,

Hepatopulmonary syndrome and Systemic complications of Liver disease. Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease,

recommended as routine therapy.

**7.6 Other treatment options 7.6.1 Nutritional intervention** 

catabolic state etc.(75)

absorption into gut.(77)

nowadays.

**8. References** 

response to lactulose or neomycin.(38)

**7.6.2 Prognosis once recovered from HE** 

are associated with severity of underlying disease.(78, 79)

Pathophysiology/Diagnosis/Management 9th ed: Saunders, An Imprint of Elsevier 2010. p. 1543-46.


Hepatic Encephalopathy 507

[34] Fischer JE, Rosen HM, Ebeid AM, James JH, Keane JM, Soeters PB. The effect of

[35] Lozeva V, Montgomery JA, Tuomisto L, Rocheleau B, Pannunzio M, Huet PM, et al.

[36] Lozeva-Thomas V. Serotonin brain circuits with a focus on hepatic encephalopathy.

[37] Yoshida Y, Higashi T, Nouso K, Nakatsukasa H, Nakamura SI, Watanabe A, et al.

[38] Marchesini G, Fabbri A, Bianchi G, Brizi M, Zoli M. Zinc supplementation and amino

[39] Hermenegildo C, Monfort P, Felipo V. Activation of N-methyl-D-aspartate receptors in

[40] Schliess F, Gorg B, Haussinger D. Pathogenetic interplay between osmotic and

[41] Rose C, Butterworth RF, Zayed J, Normandin L, Todd K, Michalak A, et al. Manganese

[42] Frederick RT. Current concepts in the pathophysiology and management of hepatic encephalopathy. Gastroenterol Hepatol (N Y). 2011 Apr;7(4):222-33. [43] Haussinger D. [Hepatic encephalopathy: clinical aspects and pathogenesis]. Dtsch Med

[44] Bernal W, Hall C, Karvellas CJ, Auzinger G, Sizer E, Wendon J. Arterial ammonia and

[45] Weissenborn K, Ennen JC, Schomerus H, Ruckert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy. J Hepatol. 2001 May;34(5):768-73. [46] Mardini H, Saxby BK, Record CO. Computerized psychometric testing in minimal

[47] Montagnese S, Amodio P, Morgan MY. Methods for diagnosing hepatic

[48] Prakash R, Mullen KD. Mechanisms, diagnosis and management of hepatic

[49] Riggio O, Ridola L, Pasquale C. Hepatic encephalopathy therapy: An overview. World J

encephalopathy. Nat Rev Gastroenterol Hepatol. Sep;7(9):515-25.

and liver dysfunction. Gastroenterology. 1999 Sep;117(3):640-4.

brain microdialysis. Hepatology. 2000 Mar;31(3):709-15.

Wochenschr. 2004 Sep 3;129 Suppl 2:S66-7.

failure. Hepatology. 2007 Dec;46(6):1844-52.

Gastroenterology. 2008 Nov;135(5):1582-90.

Gastrointest Pharmacol Ther. Apr 6;1(2):54-63.

Brain Dis. 2004 Dec;19(3-4):281-312.

1976 Jul;80(1):77-91.

May;40(5):742-8.

Dec;55(6):349-55.

May;23(5):1084-92.

Nov;387(10-11):1363-70.

Metab Brain Dis. 2004 Dec;19(3-4):413-20.

normalization of plasma amino acids on hepatic encephalopathy in man. Surgery.

Increased brain serotonin turnover correlates with the degree of shunting and hyperammonemia in rats following variable portal vein stenosis. J Hepatol. 2004

Effects of zinc deficiency/zinc supplementation on ammonia metabolism in patients with decompensated liver cirrhosis. Acta Med Okayama. 2001

acid-nitrogen metabolism in patients with advanced cirrhosis. Hepatology. 1996

rat brain in vivo following acute ammonia intoxication: characterization by in vivo

oxidative stress: the hepatic encephalopathy paradigm. Biol Chem. 2006 Oct-

deposition in basal ganglia structures results from both portal-systemic shunting

clinical risk factors for encephalopathy and intracranial hypertension in acute liver

encephalopathy and modulation by nitrogen challenge and liver transplant.

encephalopathy in patients with cirrhosis: a multidimensional approach. Metab


[18] Pilbeam CM, Anderson RM, Bhathal PS. The brain in experimental portal-systemic

[19] Mas A. Hepatic encephalopathy: from pathophysiology to treatment. Digestion. 2006;73

[20] Jalan R, Olde Damink SW, Lui HF, Glabus M, Deutz NE, Hayes PC, et al. Oral amino

[21] Blei AT. Infection, inflammation and hepatic encephalopathy, synergism redefined. J

[22] Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The

[23] Shawcross DL, Davies NA, Williams R, Jalan R. Systemic inflammatory response

[24] Moldawer LL, Marano MA, Wei H, Fong Y, Silen ML, Kuo G, et al. Cachectin/tumor

[25] Ahboucha S, Butterworth RF. The neurosteroid system: an emerging therapeutic target for hepatic encephalopathy. Metab Brain Dis. 2007 Dec;22(3-4):291-308. [26] Baulieu EE. Neurosteroids: a novel function of the brain. Psychoneuroendocrinology.

[27] Ahboucha S, Butterworth RF. Pathophysiology of hepatic encephalopathy: a new look

[28] Reversal of hepatic coma by benzodiazepine antagonist (Ro 15-1788). Lancet. 1985 Jun

[29] Lighthouse J, Naito Y, Helmy A, Hotten P, Fuji H, Min CH, et al. Endotoxinemia and

[30] Zeneroli ML, Venturini I, Corsi L, Avallone R, Farina F, Ardizzone G, et al.

[31] Zeneroli ML, Venturini I, Stefanelli S, Farina F, Miglioli RC, Minelli E, et al.

[33] Ahboucha S, Layrargues GP, Mamer O, Butterworth RF. Increased brain concentrations

Aug;140(4):331-45.

Dis. 2003 Mar;18(1):37-49.

Oct;32(4 Pt 1):734-9.

Hepatol. 2004 Feb;40(2):327-30.

FASEB J. 1989 Mar;3(5):1637-43.

1998 Nov;23(8):963-87.

8;1(8441):1324-5.

Jul;58(1):169-70.

43.

cirrhosis. J Hepatol. 2004 Feb;40(2):247-54.

preparation. Hepatol Res. 2004 Mar;28(3):155-60.

failure. Scand J Gastroenterol. 1998 Mar;33(3):310-3.

Clin Gastroenterol Hepatol. 2005 Mar;3(3):197-207.

Suppl 1:86-93.

encephalopathy. I. Morphological changes in three animal models. J Pathol. 1983

acid load mimicking hemoglobin results in reduced regional cerebral perfusion and deterioration in memory tests in patients with cirrhosis of the liver. Metab Brain

systemic inflammatory response syndrome in acute liver failure. Hepatology. 2000

exacerbates the neuropsychological effects of induced hyperammonemia in

necrosis factor-alpha alters red blood cell kinetics and induces anemia in vivo.

at GABA from the molecular standpoint. Metab Brain Dis. 2004 Dec;19(3-4):331-

benzodiazepine-like substances in compensated cirrhotic patients: a randomized study comparing the effect of rifaximine alone and in association with a symbiotic

Benzodiazepine-like compounds in the plasma of patients with fulminant hepatic

Antibacterial activity of rifaximin reduces the levels of benzodiazepine-like compounds in patients with liver cirrhosis. Pharmacol Res. 1997 Jun;35(6):557-60. [32] Stewart CA, Reivich M, Lucey MR, Gores GJ. Neuroimaging in hepatic encephalopathy.

of a neuroinhibitory steroid in human hepatic encephalopathy. Ann Neurol. 2005


Hepatic Encephalopathy 509

[65] Poo JL, Gongora J, Sanchez-Avila F, Aguilar-Castillo S, Garcia-Ramos G, Fernandez-

[66] Jalan R, Wright G, Davies NA, Hodges SJ. L-Ornithine phenylacetate (OP): a novel

[67] Naylor CD, O'Rourke K, Detsky AS, Baker JP. Parenteral nutrition with branched-chain

[68] Marchesini G, Dioguardi FS, Bianchi GP, Zoli M, Bellati G, Roffi L, et al. Long-term oral

[69] Basile AS, Harrison PM, Hughes RD, Gu ZQ, Pannell L, McKinney A, et al. Relationship

[70] Basile AS, Hughes RD, Harrison PM, Murata Y, Pannell L, Jones EA, et al. Elevated

[71] Goulenok C, Bernard B, Cadranel JF, Thabut D, Di Martino V, Opolon P, et al.

[72] Barbaro G, Di Lorenzo G, Soldini M, Giancaspro G, Bellomo G, Belloni G, et al.

[73] Gyr K, Meier R, Haussler J, Bouletreau P, Fleig WE, Gatta A, et al. Evaluation of the

[74] Vaquero J, Chung C, Cahill ME, Blei AT. Pathogenesis of hepatic encephalopathy in

[75] Charlton M. Branched-chain amino acid enriched supplements as therapy for liver

[76] Plauth M, Cabre E, Riggio O, Assis-Camilo M, Pirlich M, Kondrup J, et al. ESPEN Guidelines on Enteral Nutrition: Liver disease. Clin Nutr. 2006 Apr;25(2):285-94. [77] Amodio P, Caregaro L, Patteno E, Marcon M, Del Piccolo F, Gatta A. Vegetarian diets in

[78] Bajaj JS, Schubert CM, Heuman DM, Wade JB, Gibson DP, Topaz A, et al. Persistence of

hepatic encephalopathy: facts or fantasies? Dig Liver Dis. 2001 Aug-Sep;33(6):492-

cognitive impairment after resolution of overt hepatic encephalopathy.

hepatic encephalopathy. Hepatology. 1994 Jan;19(1):112-21.

meta-analysis. Aliment Pharmacol Ther. 2002 Mar;16(3):361-72.

acute liver failure. Semin Liver Dis. 2003 Aug;23(3):259-69.

disease. J Nutr. 2006 Jan;136(1 Suppl):295S-8S.

Gastroenterology. 2010 Jun;138(7):2332-40.

controlled study. Ann Hepatol. 2006 Oct-Dec;5(4):281-8.

2007;69(5):1064-9.

Oct;97(4):1033-42.

Group. J Hepatol. 1990 Jul;11(1):92-101.

Med. 1991 Aug 15;325(7):473-8.

Hepatology. 1998 Aug;28(2):374-8.

Gut. 1996 Aug;39(2):319-24.

500.

Zertuche M, et al. Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-

treatment for hyperammonemia and hepatic encephalopathy. Med Hypotheses.

amino acids in hepatic encephalopathy. A meta-analysis. Gastroenterology. 1989

branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized double-blind casein-controlled trial. The Italian Multicenter Study

between plasma benzodiazepine receptor ligand concentrations and severity of

brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure. N Engl J

Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a

Flumazenil for hepatic encephalopathy grade III and IVa in patients with cirrhosis: an Italian multicenter double-blind, placebo-controlled, cross-over study.

efficacy and safety of flumazenil in the treatment of portal systemic encephalopathy: a double blind, randomised, placebo controlled multicentre study.


[50] Ferenci P, Herneth A, Steindl P. Newer approaches to therapy of hepatic

[51] Riggio O, Varriale M, Testore GP, Di Rosa R, Di Rosa E, Merli M, et al. Effect of lactitol

[52] Mortensen PB. The effect of oral-administered lactulose on colonic nitrogen metabolism

[53] Mortensen PB, Holtug K, Bonnen H, Clausen MR. The degradation of amino acids,

[54] Bajaj JS. Management options for minimal hepatic encephalopathy. Expert Rev

[55] Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophylaxis of hepatic

[56] Blanc P, Daures JP, Rouillon JM, Peray P, Pierrugues R, Larrey D, et al. Lactitol or

[57] Camma C, Fiorello F, Tine F, Marchesini G, Fabbri A, Pagliaro L. Lactitol in treatment of

[58] Strauss E, Tramote R, Silva EP, Caly WR, Honain NZ, Maffei RA, et al. Double-blind

[59] Jiang Q, Jiang XH, Zheng MH, Jiang LM, Chen YP, Wang L. Rifaximin versus

[62] Bajaj JS, Heuman DM, Wade JB, Gibson DP, Saeian K, Wegelin JA, et al. Rifaximin

[64] Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM. Synbiotic modulation of

meta-analysis. Eur J Gastroenterol Hepatol. 2008 Nov;20(11):1064-70. [60] Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010 Mar 25;362(12):1071-81. [61] Sidhu SS, Goyal O, Mishra BP, Sood A, Chhina RS, Soni RK. Rifaximin improves

and lactulose administration on the fecal flora in cirrhotic patients. J Clin

proteins, and blood to short-chain fatty acids in colon is prevented by lactulose.

encephalopathy: an open-label randomized controlled trial of lactulose versus

lactulose in the treatment of chronic hepatic encephalopathy: results of a meta-

chronic hepatic encephalopathy. A meta-analysis. Dig Dis Sci. 1993 May;38(5):916-

randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy. Hepatogastroenterology. 1992 Dec;39(6):542-

nonabsorbable disaccharides in the management of hepatic encephalopathy: a

psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME Trial). Am J Gastroenterol. 2011

improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. Gastroenterology. 2011 Feb;140(2):478-87 e1. [63] Gentile S, Guarino G, Romano M, Alagia IA, Fierro M, Annunziata S, et al. A

randomized controlled trial of acarbose in hepatic encephalopathy. Clin

gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis.

encephalopathy. Semin Liver Dis. 1996 Aug;16(3):329-38.

and excretion. Hepatology. 1992 Dec;16(6):1350-6.

Gastroenterol. 1990 Aug;12(4):433-6.

Gastroenterology. 1990 Feb;98(2):353-60.

Gastroenterol Hepatol. 2008 Dec;2(6):785-90.

analysis. Hepatology. 1992 Feb;15(2):222-8.

Gastroenterol Hepatol. 2005 Feb;3(2):184-91.

Hepatology. 2004 May;39(5):1441-9.

22.

5.

Feb;106(2):307-16.

placebo. Gastroenterology. 2009 Sep;137(3):885-91, 91 e1.


**25** 

*Spain* 

**Adverse Reactions and** 

A. Lorenzo Hernández1, E. Ramirez1 and Jf. Sánchez Muñoz-Torrero2 *1University Autonoma of Madrid 2University of Extremadura* 

Adverse drug reactions are common and there is an increasing interest in recognizing them. There are several studies that try to identify epidemiology, true incidence in hospitalized and not hospitalized patients and the main concerns about their causes and possible solutions. Gastrointestinal tract, mainly haemorrhages and peptic disease are the most common site of adverse drug reactions; that´s the reason why we should recognize this problem and how to manage. Also we try to review the most common drugs affecting gastrointestinal tract. Less common and, usually less severe, liver disease and pancreatitis can be produced by adverse drug reactions. In this chapter we review theses aspects of adverse drug events, particularly, those related to drugs affecting gastrointestinal tract.

An adverse drug event is an unwanted and unintended medical event related to the use of medications. An adverse drug event is considered an adverse drug reaction (ADR) when there is a causal link between the event and use of the drug. An adverse drug reaction is considered serious when the patients outcome is one of the following: death, lifethreatening, hospitalization (initial or prolonged), disability –significant, persistent or permanent change, impairment, damage or disruption in the patient's body function/structure or physical activities or quality of life, congenital anomaly or require intervention to prevent permanent impairment or damage [Supplementary information in

Causality assessment is necessary to determine the likehood that a drug caused a suspected ADR. There are a number of different methods used to judge causation, the first attempts were proposed by Karch and Lasagna (1977), Lecenthal et al. (1979) and Naranjo et a.l (1981). Most of these approaches to assigning causality are based on the following clinical features: temporal relationship between drug exposure and the onset of adverse drug event, characteristic symptoms and laboratory abnormalities and/or histology, and challengedechallenge-rechallenge (improvement after stopping the suspected drug and reappearance

**1. Introduction** 

Appendix 1].

**2. Definition of adverse drug reactions** 

after starting the agent in question).

**Gastrointestinal Tract** 

[79] Riggio O, Ridola L, Pasquale C, Nardelli S, Pentassuglio I, Moscucci F, et al. Evidence of persistent cognitive impairment after resolution of overt hepatic encephalopathy. Clin Gastroenterol Hepatol. 2011 Feb;9(2):181-3.
