A Journal Presentation

Pratap Sagar Tiwari ,Resident ,Internal Medicine, NGMC

RIFAXIMIN TREATMENT IN HEPATIC ENCEPHALOPATHY.1

Ref: 1. Bass N.M, Mullen K.D, Sanyal A, Poordad F, Guy Neff G, et al. Rifaximin Treatment in Hepatic Encephalopathy. N Engl J Med. 2010 Mar 25;362(12):1071-81.

BACKGROUND• Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis.

• The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established.

METHODS• In this randomized, double-blind, placebo-controlled trial, 299 patients who were in

remission from recurrent hepatic encephalopathy resulting from chronic liver disease were randomly assigned to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months.

• The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy.

• The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy

RESULTS• Rifaximin significantly reduced the risk of an episode of HE, as compared with placebo,

over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001).

• A breakthrough episode of HE occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group.

• A total of 13.6% of the patients in the rifaximin group had a hospitalization involving HE, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01).

• More than 90% of patients received concomitant lactulose therapy.

• The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events.

CONCLUSIONS• Over a 6-month period, treatment with rifaximin maintained remission from hepatic

encephalopathy more effectively than did placebo.

• Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy.

DISCUSSION1. Blood ammonia level ?

2. The primary end point, the time to breakthrough HE, was evaluated on the basis of the Conn score and asterixis grade, with no dependence on psychometric testing !!!

3. There was no true placebo group (i.e., one receiving neither lactulose nor rifaximin), the effectiveness of rifaximin alone cannot be determined.

4. HE in patients with the rare condition of acute liver failure COULD NOT BE ACCESSED.

5. As in cases of chronic liver failure with history of overt HE usually have the precipitating factors like gi hemorrhage ,electrolyte imbalance and renal impairment so study lacks the efficacy of rifaximin .

PSYCHOMOTRIC TESTS:

• 1- Number connection test

2- Digital symbol test

3- Mini Mental State Examination

4- Block design test.

Number Connection test

Note: The sensitivity and specificity were 87% and 94%, respectively. NCT result was influenced by age and educational background and the sensitivity was low for the scanning of Subclinical HEZhong B, Chen M, Wang J, Yuan Y, Hu P.The value of number connection test in the diagnosis of subclinical hepatic encephalopathy. Zhonghua Nei Ke Za Zhi. 2001 Jan;40(1):13-5

DIGITAL SYMBOL SUBSTITUTION TEST

MINI MENTAL STATE EXAMINATION

Source: Davidson principle and practice of medicine,20 th ed

INTRODUCTION :HEPATIC ENCEPHALOPATHY• Hepatic encephalopathy is a neuropsychiatric syndrome for which symptoms, manifested

on a continuum, are deterioration in mental status, with psychomotor dysfunction, impaired memory, sensory abnormalities, poor concentration, disorientation, and — in severe forms — coma. 1

1. POORDAD FF. THE BURDEN OF HEPATIC ENCEPHALOPATHY. ALIMENT PHARMACOL THER 2007;25:SUPPL 1:3-9

CLINICAL DIAGNOSIS OF HE• The clinical diagnosis of hepatic encephalopathy is based on two concurrent types of

symptoms:

1. impaired mental status 1

2. impaired neuromotor function 2

1. Conn HO, Lieberthal MM. The hepatic coma syndromes and lactulose. Baltimore: Williams & Wilkins, 1979.

2. Córdoba J, Blei AT. Hepatic encephalopathy. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff's diseases of the liver. 10th ed. Vol. 1. Philadelphia: Lippincott Williams & Wilkins, 2007:569-99

PREVALENCE 1

• Signs of HE are observed in nearly 70% of patients with cirrhosis. • 24-53% of patients who undergo portosystemic shunt surgery. • Approximately 30% of patients dying of end-stage liver disease experience significant

encephalopathy, approaching coma.

1. Ferenci P. Hepatic encephalopathy. In: Haubrich WS, Schaffner F, Berk JE, eds. Bockus Gastroenterology. 5th ed. Philadelphia, Pa: WB Saunders; 1995:1998-2003.

• Approximately 5.5 million persons in the United States have hepatic cirrhosis, a major cause of complications and death. 1,2

• In 2003, more than 40,000 patients were hospitalized with hepatic encephalopathy, a number that increased to over 50,000 in 2004. 3

1. Poordad FF. The burden of hepatic encephalopathy. Aliment Pharmacol Ther 2007;25:Suppl 1:3-9

2. Munoz SJ. Hepatic encephalopathy. Med Clin North Am 2008;92:795-812.

3. Wright G, Jalan R. Management of hepatic encephalopathy in patients with cirrhosis. Best Pract Res Clin Gastroenterol 2007;21:95-110

• The prevention of episodes of hepatic encephalopathy is an important goal in the treatment of patients with liver disease, 1,2,3,4 especially since symptoms of overt encephalopathy are debilitating and decrease the ability for self-care, leading to improper nutrition and nonadherence to a therapeutic regimen, which in turn leads to severe symptoms, frequent hospitalizations, and a poor quality of life.

1. Poordad FF. The burden of hepatic encephalopathy. Aliment Pharmacol Ther 2007;25:Suppl 1:3-9

2. Munoz SJ. Hepatic encephalopathy. Med Clin North Am 2008;92:795-812

3. Leevy CB, Phillips JA. Hospitalizations during the use of rifaximin versus lactulose for the treatment of hepatic encephalopathy. Dig Dis Sci 2007;52:737-741

4. Bustamante J, Rimola A, Ventura PJ, et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999;30:890-895

APPROACHApproach:1. Assess the severity of liver damage2. Exclude the nonhepatic cause of encephalopathy.3. Recognize and correct the precipitating factors.4. Treat the hyperammonemia :hallmark of most cases of HE

Consider :5. Patients with severe encephalopathy (ie, grade 3 or 4) who are at risk for aspiration should

undergo prophylactic ET intubation.

-Trauma (e.g., subdural hematoma), -Bleeding, Cerebral infarction-Tumors , Abscess

I-Intracranial lesions

-Meningitis ,Encephalitis, -Subarachnoid hemorrhage

2-Infections

-Anoxia, Uremia ,Ketoacidosis -Hypoglycemia, Electrolyte imbalance-Inborn error of urea cycle

3-Metabolic Encephalopathies

-Alcohol: -Acute intoxication -Withdrawal syndrome - Wernicke's syndrome

4-Toxic encephalopathy

5-Neuropsychatric disorders

Differential Diagnosis

PRECIPITATING FACTORS:1

• Renal failure• Gastrointestinal bleeding• Infection• Constipation• Medication: Opiates, benzodiazepines, Antipsychotic• Diuretic therapy ,Paracentesis ,Dehydration, Electrolyte imbalance• Dietary protein overload

1. Blei AT, Córdoba J. Hepatic Encephalopathy. Am J Gastroenterol. Jul 2001;96(7):1968-76

TREATING HYPERAMMONIA1. Treatments to Decrease Intestinal Ammonia Production• Diets• Cathartics• Antibiotics

2. Treatments to Increase Ammonia Clearance• L-ornithine L-aspartate (LOLA)• Zinc• Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate• L-carnitine

DIET• Most patients with HE tolerate =60-80 g of protein /d. • Furthermore, one study administered protein-rich diet (>1.2 g/kg/d) to patients with advanced

disease awaiting liver transplantation, without inducing a flare of encephalopathy symptoms. 1

• Another study randomized patients with severe episodic encephalopathy to low-protein diet Vs high-protein diet, administered via NG tube.2 All patients received the same regimen of neomycin per NG tube. Mental function improved at the same rate in both treatment groups.

1. Guy S, Tanzer-Torres G, Palese M, et al. Does nasoenteral nutritional support reduce mortality after liver transplant?. Hepatology. 1995;22:144A.2. Cordoba J, Lopez-Hellin J, Planas M, et al. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol. Jul 2004;41(1):38-43.

CATHARTICS• Lactulose (beta-galactosidofructose) and lactilol (beta-galactosidosorbitol) are nonabsorbable

disaccharides that have been in common clinical use since the early 1970s. • Patients should take sufficient lactulose as to have 2-4 loose stools per day.• Initial dosing = 30 mL orally, daily or twice daily. The dose may be increased as tolerated.• A/E: ileus, severe diarrhea, electrolyte disturbances, and hypovolemia. • High doses of lactulose (eg, 30 mL q2-4h) may be administered orally or by NG tube to

patients hospitalized with severe HE.• Administered as enema to Comatose patients. The recommended dosing is 300 mL lactulose

plus 700 mL water, q4hrly

EFFECTS OF LACTULOSE

ANTIBIOTICS Neomycin, Metronidazole ,Paramomycin, Quinolones• Initial neomycin dosing is 250 mg orally 2-4 times a day. 1

• A/E: ototoxicity and nephrotoxicity

1. David C Wolf,Hepatic Encephalopathy source: www.emedcine.com Updated: Mar 9, 2011

RIFAXIMIN VS LACTILOL VS RIFAXIMIN+LACTILOL1

• Forty out-patients (29 males, 11 females, mean age: 59 years, range 40-70), with viral liver cirrhosis and chronic HE (1st-2nd degree) were studied. HE was assessed by considering: mental state, asterixis, number connection test (NCT), arterial blood ammonia levels. Patients were randomly assigned to the following treatments: rifaximin (gp R); lactitol (gp L); rifaximin plus lactitol (gp RL). All treatments were continued for 15 days for 3 cycles, intervalled by 15 days .

RESULTS:

• The 3 treatments reduced HE, but with different efficacy: patients of group R and RL significantly (p<0.05) documented a faster improvement in HE degree, a higher percentage of patients which normalized mental state and NCT, a faster improvement of asterixis and a longer persistence of normal ammonia levels than patients of group L.

CONCLUSIONS:

• Rifaximin in combination with lactitol represents an effective and safe treatment of chronic HE.1. Loguercio C, Federico A, DeGirolamo V, Ferrieri A, DelVecchio C.Cyclic treatment of chronic hepatic encephalopathy with

rifaximin.Minerva Gastroenterol Dietol. 2003 Mar;49(1):53-62.

RIFAXIMIN VERSUS NONABSORBABLE DISACCHARIDES IN THE MANAGEMENT OF HEPATIC ENCEPHALOPATHY: A META-ANALYSIS1

• Methods: a meta-analysis of comparative randomized trials of rifaximin and nonabsorbable disaccharides.

• Results: 5 randomized controlled trials were included. There was no significant difference between rifaximin and nonabsorbable disaccharides on improvement in patients with hepatic encephalopathy [relative risk (RR) 1.08; 95% confidence interval (CI), 0.85-1.38; P=0.53]. RR was 0.98 (95% CI: 0.85-1.13; P=0.74) for acute hepatic encephalopathy in 157 patients and 0.87 (95% CI: 0.40-1.88; P=0.72) for chronic hepatic encephalopathy in 96 patients, respectively. There was no significant difference between rifaximin and nonabsorbable disaccharides on diarrhea (RR=0.90; 95% CI: 0.17-4.70; P=0.90). However, a significant difference in favor of rifaximin on abdominal pain (RR=0.28; 95% CI: 0.08-0.95; P=0.04) was identified.

• Conclusion: Rifaximin is not superior to nonabsorbable disaccharides for acute or chronic hepatic encephalopathy in the long-term or short-term treatment except that it may be better tolerated.

1. Qiana J, Xue-Huaa j, Ming-Huac z, Liu-Mingd j, Yong-Pingc c, Wang, Lib W et al.Rifaximin versus nonabsorbable disaccharides in the management of hepatic encephalopathy: a meta-analysis.European Journal of Gastroenterology & Hepatology:November 2008 - Volume 20 - Issue 11 - pp 1064-1070

• The current study differs from previous randomized studies in that it involved a larger group of patients and a longer study period. In previous randomized studies, rifaximin was administered for 21 days or less1,2,3 or intermittently, for 14 or 15 days per month for 3 or 6 months.

1. Bucci L, Palmieri GC. Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy.Curr Med Res Opin 1993;13:109-118

2. Festi D, Mazzella G, Orsini M, et al. Rifaximin in the treatment of chronic hepatic encephalopathy: results of a multicenter study of efficacy and safety. Curr Ther Res Clin Exp 1993;54:598-609

3. Puxeddu A, Quartini M, Massimetti A, Ferrieri A. Rifaximin in the treatment of chronic hepatic encephalopathy. Curr Med Res Opin 1995;13:274-281

• This study shows the superiority of rifaximin therapy over treatment with lactulose alone. More than 90% of patients received concomitant lactulose during the study period.

• The safety profile of rifaximin appears to be superior to that of systemic antibiotics, particularly for patients with liver disease.

• The occurrence of nephrotoxicity and ototoxicity with the use of aminoglycosides (e.g., neomycin and paromomycin) and of nausea and peripheral neuropathy with prolonged use of metronidazole restricts their use in patients with hepatic encephalopathy. 1,2,3

• Tierney LM Jr, McPhee SJ, Papadakis MA, eds. Current medical diagnosis & treatment. 38th ed. Stamford, CT: Appleton & Lange, 1999:1453-5.

1. Hampel H, Bynum GD, Zamora E, El-Serag HB. Risk factors for the development of renal dysfunction in hospitalized patients with cirrhosis. Am J Gastroenterol 2001;96:2206-2210

2. Gerard L, Garey KW, DuPont HL. Rifaximin: a nonabsorbable rifamycin antibiotic for use in nonsystemic gastrointestinal infections. Expert Rev Anti Infect Ther 2005;3:201-211

• 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.1,2,3

1. Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ. May 1 2004;328(7447):1046. 2. 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. Jan 2003;38(1):51-8.3. Miglio F, Valpiani D, Rossellini SR, et al. Rifaximin, a non-absorbable rifamycin, for the treatment of hepatic encephalopathy. A double-blind, randomised trial. Curr Med Res Opin. 1997;13(10):593-601.

RIFAXIMIN• Rifaximin is a semisynthetic, rifamycin-based non-systemic antibiotic.

• Rifaximin acts by inhibiting RNA synthesis in susceptible bacteria by binding to the beta-subunit of bacterial deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase enzyme.

• It is also used to treat diarrhea caused by E. coli and in irritable bowel syndrome.

• Half life : Approximately 6 hours

• Affected microorganisms: Enteric bacteria

• In March 2010, rifaximin was approved by the FDA to reduce recurrence of hepatic encephalopathy.

ThankyouSources:

Bass N.M, Mullen K.D, Sanyal A, Poordad F, Guy Neff G, et al. Rifaximin Treatment in Hepatic Encephalopathy. N Engl J Med. 2010 Mar 25;362(12):1071-81.

• THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 96, No. 7, 2001• www.emedicine.com hepatic encephalopathy by David C Wolf, MD, FACP, FACG, AGAF, Medical Director of

Liver Transplantation ,updated march 9 ,2011• Harrison’s 17th edition• Davidson’s Principle & practice of Internal Medicine 21 st ed• The Modern Management of Hepatic Encephalopathy by J. S. Bajaj Posted: 04/15/2010; Alimentary

Pharmacology & Therapeutics. 2010;31(5):537-547. © 2010 Blackwell Publishing

PATHOGENESIS• Accumulation of neurotoxins in brain

• Impaired Astrocytes function .[1 ]

• Synergistic neurotoxins

• Excitatory inhibitory neurotransmitters and plasma amino acid imbalance hypothesis

1. Brusilow SW. Hyperammonemic encephalopathy. Medicine (Baltimore). May 2002;81(3):240-9

NEUROTOXINS: AMMONIA HYPOTHESIS

Production• Ammonia is released from several tissues (kidney, muscle), but its highest levels can be found

in the portal vein.• Portal ammonia is derived from both the urease activity of colonic bacteria and the

deamination of glutamine in the small bowel.

Degradation:

-Liver: (synthesis of urea, glutamine)

-Skeletal muscle: alternative target for NH3 detoxification

Glutamine glutamate + Ammonia

AMMONIA HYPOTHESIS …CONTINUE• In acute and chronic liver disease, increased arterial levels of ammonia are commonly seen. • In FHF, elevated arterial levels (>200 mg/dl) have been associated with an increased risk of

cerebral herniation .1

• The blood-brain barrier permeability to ammonia is increased in patients with HE .2

1. Clemmesen JO, Larsen FS, Kondrup J, et al. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 1999;29:648 –53.2. 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;11:337–41.

AMMONIA HYPOTHESIS …CONTINUE• Furthermore, the alterations in neurotransmission induced by ammonia also occur after the

metabolism of this toxin into astrocytes.1,resulting in a series of neurochemical events caused by the functioning alteration of this cell .2

• Additional support for the ammonia hypothesis comes from the clinical observation that treatments that decrease blood ammonia levels can improve hepatic encephalopathy symptoms.3

1. Norenberg MD. Astrocytic-ammonia interactions in hepatic encephalopathy. Semin Liver Dis 1996;16:245–53.2. Haussinger D, Kircheis G, Fischer R, et al. Hepatic encephalopathy in chronic liver disease: A clinical manifestation of astrocyte swelling and low grade cerebral edema? J Hepatol 2000;32:1035– 8.3. Stahl J. Studies of the blood ammonia in liver disease. Its diagnostic, prognostic, and therapeutic significance. Ann Intern Med. Jan 1963;58:1-24

• Glutamine is neuronally inactive, it modifies astrocyte signaling and action of glutamate.

• In hepatic encephalopathy:

1- cerebral glutamine are increased

2- cerebral glutamate decreased• Increased glutamine in astrocytes → osmotic stress → cellular swelling and cellular change,

termed Alzheimer type 2 astrocytosis

NH3

Intestinal protein/bacteria

Reduced hepatic removal

Reduced muscle mass

Alter BBB Astrocyte damage

glutamine

Direct effectsExcitatory pathways

Sources and potential role of ammonia

ADDITIVE MECHANISMS• Benzodiazepinelike substances [1] have been postulated to arise from a specific bacterial

population in the colon .[2] • Other products of colonic bacterial metabolism [3], such as neurotoxic short- and medium-

chain fatty acids, phenols, and mercaptans, are also produced.• Manganese may deposit in basal ganglia and induce extrapyramidal symptomatology . [4]

1. Mullen KD, Jones EA. Natural benzodiazepines and hepatic encephalopathy. Semin Liver Dis 1996;16:255– 64.2. Yurdaydin C, Walsh TJ, Engler HD, et al. Gut bacteria provide precursors of benzodiazepine receptor ligands in a rat model of hepatic encephalopathy. Brain Res 1995;679:42– 8.3. Zieve L, Doizaki WM, Zieve J. Synergism between mercaptans and ammonia or fatty acids in the production of coma: a possible role for mercaptans in the pathogenesis of hepatic coma. J Lab Clin Med 1974;83:16 –28.4. 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;117:640–4.

AMINO ACID IMBALANCE HYPOTHESIS• Abnormal balance between Branched chain Amino Acids (BCAA) and Aromatic Amino Acids

(AAA) .• In Cirrhosis : ↓ BCAA and ↑ AAA

Two consequences :1. ↑ protein catabolism =lean mass2. ↑ Synthesis of false NT and ↓ Synthesis

of normal NT

BCAA = Isoleucine ,Leucine ,valine => metabolised in muscle & brainAAA =Phenylalanine,Tyrosine, Tryptophan => metabolised in liver

Normally Leucine (BCAA) promote protein synthesis & inhibit protein catabolism

SUMMARY

HE may represent the synergistic effects of a number of toxins on an unusually susceptible

nervous system

CLINICAL SUBTYPES

CLASSIFICATION[1]

Types Description Subcategory

A Encephalopathy associated with acute liver failure

B Encephalopathy with porto-systemic bypass and nointrinsic hepatocellular disease

C Encephalopathy associated with cirrhosis or portalhypertension ⁄ porto-systemic shunts

Episodic

Persistent

Minimal

1. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. Mar 2002;35(3):716-21

CLINICAL DETECTION RELATIONSHIP OF HE SUBTYPES

CLINICAL MANIFESTATIONS• Patients with hepatic encephalopathy can presents with a variety of clinical

features ranging from subclinical or minimal confusion to life-threatining coma with cerebral edema (often in fulminant hepatic faliure)

WEST-HAVEN CRIT ERIA F O R HE: 1

Stage Consciousness Intellect and behaviour Neurological findings

0 Normal Normal Normal examination; if impaired psychomotor testing, then MHE

1 Mild lack of awareness

Shortened attention span; impaired addition or subtraction

Mild asterixis or tremor

2 lethargic Disoriented;inappropriate behaviour

Obvious asterixis; slurred speech

3 Somnolent but arousable

Gross disorientation; bizarre behaviour

Muscular rigidity and clonus; Hyper-reflexia

4 Coma Coma Decerebrate posturing

1. Blei AT, Córdoba J. Hepatic Encephalopathy. Am J Gastroenterol. Jul 2001;96(7):1968-76

CLINICAL FEATURES:(IN SETTING OF ACUTE LIVER FAILURE )

Abrupt onset of Symptoms: fever, vomiting ,headacheOn Examination; • Icteric• Marked Fetor hepaticus• Hepatomegaly / splenomegaly: uncommon• F/o ↑ ICP :Systolic HTN, bradycardia, Hyperventilation, seizures, Pupillary dilatation

and CN VI palsy(mass effect ).• Neuropsychiatric picture is more aggressive

CLINICAL FEATURES:(IN SETTING OF CHRONIC LIVER DISEASE )

• Insidious onset

• Long Hx of liver disease .

• Stigmata of Chronic liver disease

• Features of Portal hypertension

INVESTIGATIONS AND MANAGEMENT

INVESTIGATIONS• Clinical Tests (Psychometric tests) and assess level of conciousness with

Glascow Coma Scale

• Liver Function tests with PT/INR• Blood Ammonia level : ↑ (n:19-60 ugm/dl) Raised but does not correlate with degree of encephalopathy.

INVESTIGATIONS TO IDENTIFY THE PRECIPITATING FACTORS

• FOBT • Ascites fluid examination and Culture• CXR • CBC• Urine R/M Examination• Serum Urea, Creatinine ,Electrolytes ,ABG• Consider : Urine screen for benzodiazepine, narcotics• Blood Glucose

• CT Brain /MRI

• EEG

• Lumbar Puncture (for patients with unexplained fever and signs of meningeal irritation)

TREATING HYPERAMMONIA1. Treatments to Decrease Intestinal Ammonia Production• Diets• Cathartics• Antibiotics

2. Treatments to Increase Ammonia Clearance• L-ornithine L-aspartate (LOLA)• Zinc• Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate• L-carnitine

DIET• Most patients with HE tolerate =60-80 g of protein /d. • Furthermore, one study administered protein-rich diet (>1.2 g/kg/d) to patients with advanced

disease awaiting liver transplantation, without inducing a flare of encephalopathy symptoms. [1 ]

• Another study randomized patients with severe episodic encephalopathy to low-protein diet Vs high-protein diet, administered via NG tube. [2 ]All patients received the same regimen of neomycin per NG tube. Mental function improved at the same rate in both treatment groups.

1. Guy S, Tanzer-Torres G, Palese M, et al. Does nasoenteral nutritional support reduce mortality after liver transplant?. Hepatology. 1995;22:144A.2. Cordoba J, Lopez-Hellin J, Planas M, et al. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol. Jul 2004;41(1):38-43.

CATHARTICS• Lactulose (beta-galactosidofructose) and lactilol (beta-galactosidosorbitol) are nonabsorbable

disaccharides that have been in common clinical use since the early 1970s. • Patients should take sufficient lactulose as to have 2-4 loose stools per day.• Initial dosing = 30 mL orally, daily or twice daily. The dose may be increased as tolerated.• A/E: ileus, severe diarrhea, electrolyte disturbances, and hypovolemia. • High doses of lactulose (eg, 30 mL q2-4h) may be administered orally or by NG tube to

patients hospitalized with severe HE.• Administered as enema to Comatose patients. The recommended dosing is 300 mL lactulose

plus 700 mL water, q4hrly

EFFECTS OF LACTULOSE

ANTIBIOTICS

1. Neomycin, Metronidazole ,Paramomycin, Quinolones• Initial neomycin dosing is 250 mg orally 2-4 times a day. 1

• A/E: ototoxicity and nephrotoxicity

1. David C Wolf,Hepatic Encephalopathy source: www.emedcine.com Updated: Mar 9, 2011

2. RIFAXIMIN

• 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.1,2,3

• Similarly, rifaximin was as effective as neomycin and paramomycin. Rifaximin was better tolerated than both the cathartics and the other antibiotics.

1. Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ. May 1 2004;328(7447):1046. 2. 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. Jan 2003;38(1):51-8.3. Miglio F, Valpiani D, Rossellini SR, et al. Rifaximin, a non-absorbable rifamycin, for the treatment of hepatic encephalopathy. A double-blind, randomised trial. Curr Med Res Opin. 1997;13(10):593-601.

In March 2010, rifaximin was approved by the FDA to reduce recurrence of hepatic encephalopathy. The approval was based on a phase 3 clinical trial conducted by Bass et al. [4 ]

ThankyouSources:

Bass N.M, Mullen K.D, Sanyal A, Poordad F, Guy Neff G, et al. Rifaximin Treatment in Hepatic Encephalopathy. N Engl J Med. 2010 Mar 25;362(12):1071-81.

• THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 96, No. 7, 2001• www.emedicine.com hepatic encephalopathy by David C Wolf, MD, FACP, FACG, AGAF, Medical Director of

Liver Transplantation ,updated march 9 ,2011• Harrison’s 17th edition• Davidson’s Principle & practice of Internal Medicine 21 st ed• The Modern Management of Hepatic Encephalopathy by J. S. Bajaj Posted: 04/15/2010; Alimentary

Pharmacology & Therapeutics. 2010;31(5):537-547. © 2010 Blackwell Publishing

TREATING HYPERAMMONIA1. Treatments to Decrease Intestinal Ammonia Production• Diets• Cathartics• Antibiotics

2. Treatments to Increase Ammonia Clearance• L-ornithine L-aspartate (LOLA)• Zinc• Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate• L-carnitine

L-ORNITHINE L-ASPARTATE (LOLA)

• L-ornithine stimulates the urea cycle, with resulting consumption of ammonia and production of urea which is mostly excreted by kidneys.

• LOLA was found to be effective in treating hepatic encephalopathy in a number of European trials.[1,2 ]

1. 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. Jun 1997;25(6):1351-60.

2 .Delcker AM, Jalan R, Comes G. L-ornithine-l-aspartate vs. placebo in the treatment of hepatic encephalopathy: a meta-analysis of randomised placebo-controlled trials using individual data. Hepatology. 2000;32:310A

ZINC SULFATE AND ZINC ACETATE• Zinc sulfate and zinc acetate have been used at a dose of 600 mg orally

every day in clinical trials.• Hepatic encephalopathy improved in 2 studies [1 ]; there was no improvement

in mental function in 2 other studies. [2 ]

1. Marchesini G, Fabbri A, Bianchi G, et al. Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis. Hepatology. May 1996;23(5):1084-92.

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

Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate• Dosing of sodium benzoate at 5 g orally twice a day can effectively control

hepatic encephalopathy.[1]

L-carnitine• L-carnitine improved hepatic encephalopathy symptoms in several small

studies of patients with cirrhosis. [2 ]

1. Sushma S, Dasarathy S, Tandon RK, et al. Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial. Hepatology. Jul 1992;16(1):138-44. 2. Malaguarnera M, Pistone G, Elvira R, et al. Effects of L-carnitine in patients with hepatic encephalopathy. World J Gastroenterol. Dec 7 2005;11(45):7197-202

Treatments to Improve Sleep Disturbance• A trial compared the histamine H1 blocker hydroxyzine to placebo in patients with cirrhosis

and minimal hepatic encephalopathy.[1]

• Sleep efficiency and the patients' subjective quality of sleep improved in patients receiving hydroxyzine (25 mg) at bedtime.

• However, there was no accompanying improvement in cognition, as measured by neurophysiologic tests.

• 1. Spahr L, Coeytaux A, Giostra E, et al. Histamine H1 blocker hydroxyzine improves sleep in patients with cirrhosis and minimal hepatic encephalopathy: a randomized controlled pilot trial. Am J Gastroenterol. Apr 2007;102(4):744-53.

SOME COMMON REASONS FOR HE RESISTANT TO TREATMENT

• Excess purgation leading to dehydration / free water loss

• Failure to identify and treat sepsis

• Ileus, especially in association with azotemia (may need dialysis)

• Undiagnosed concomitant CNS problem

• Profound zinc deficiency

IN THE END..• In the Mx of persistent HE due to surgically created shunting , radiological interventions, such

as ballooning, is required to occlude the TIPS shunt. [1] Other causes of persistence may be an undiscovered source of sepsis, i.e. abscesses, or an inability to tolerate medications prescribed for OHE.

Liver Transplant• The ultimate management goal for OHE is the replacement of the diseased liver. Stewart et al.

showed that OHE worsens prognosis over and above MELD score and results in worsened survival.[2] Therefore, liver transplant work-up is crucial for the management of OHE after correction of the acute insult and prevention of recurrences.

1. Fanelli F, Salvatori FM, Rabuffi P, et al. Management of refractory hepatic encephalopathy after insertion of TIPS: long-term results of shunt reduction with hourglass-shaped balloon-expandable stent-graft. AJR Am J Roentgenol 2009; 193: 1696–702.2. Stewart CA, Malinchoc M, Kim WR, Kamath PS. Hepatic encephalopathy as a predictor of survival in patients with end-stage liver disease. Liver Transpl 2007; 13: 1366–71.

SUMMARY1. HE is a neuropsychiatric syndrome caused by Severe liver disesase.2. Features include change in intellect,personality,emotions, consciousness with or without neurological signs.3. As encephalopathy progresses ,confusion is followed by coma.4. In confusional state, rule out Dellerium tremens, Wernickes encephalopathy. And in Coma, rule out Subdural hematoma which can be due to fall injury in alcoholics.5. Grade the HE as it is useful in assessing response to therapy.6. Look for precipitating factors and manage it.7. Carry out investigations to ruleout other causes of encephalopathy.8. Treat the Hyperammonia as mentioned earlier.

PROTEIN CONTENT• One skinless chicken breast (130g): 41g protein.

• One beef burger or pork sausage: 8g protein.

• Half a can of tuna: 19g protein.

• One portion of cheese (50g): 12g protein.

• One medium egg: 6g protein.

• 150ml glass of milk: 5g protein.

• One tablespoon of boiled red lentils (40g): 3g protein.

• One portion of tofu (125g): 15g protein.

• One slice medium wholemeal bread: 4g protein.

• One slice medium white bread: 3g protein.

Flumazenil• Mechanism of action: Endogenous and exogenous benzodiazepine• receptor antagonistDopaminergic agents – L-Dopa, bromocriptine• Limited role in HE

• Most therapies for HE are directed at reducing the nitrogenous load in the gut, an approach that is consistent with the hypothesis that this disorder results from the systemic accumulation of gut-derived neurotoxins, especially ammonia, in patients with impaired liver function and PSS. 1

• The current standard of care for patients with HE, treatment with nonabsorbable disaccharides lactitol or lactulose, decreases the absorption of ammonia through cathartic effects and by altering colonic pH. 2

• In an study, Sharma et al. reported that lactulose, as compared with placebo, was effective in the prevention of overt HE. 3

1. Munoz SJ. Hepatic encephalopathy. Med Clin North Am 2008;92:795-812.

2. Blei AT, Cordoba J. Hepatic encephalopathy. Am J Gastroenterol 2001;96:1968-1976.

3. Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophylaxis of hepatic encephalopathy: an open label randomized controlled trial of lactulose versus placebo.Gastroenterology 2009;137:885-891.

• In general, the oral antibiotics neomycin, paromomycin, vancomycin, and metronidazole have been effectively used, with or without lactulose, to reduce ammonia-producing enteric bacteria in patients with hepatic encephalopathy.1

• However, some oral antibiotics are not recommended for long-term use because of nephrotoxicity, ototoxicity, and peripheral neuropathy2 and are specifically contraindicated in patients with liver disease. 3

1. Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ 2004;328:1046-1046.

2. Durante-Mangoni E, Grammatikos A, Utili R, Falagas ME. Do we still need the aminoglycosides? Int J Antimicrob Agents 2009;33:201-205.

3. Leitman PS. Liver disease, aminoglycoside antibiotics and renal dysfunction. Hepatology1988;8:966-968

RIFAXIMIN• Rifaximin is a minimally absorbed oral antimicrobial agent that is concentrated in the

gastrointestinal tract, has broad-spectrum activity against gm+ & gm- aerobic and anaerobic enteric bacteria, and has a low risk of inducing bacterial resistance. 1

• In randomized studies, rifaximin was more effective than nonabsorbable disaccharides and had efficacy that was equivalent to or greater than that of other antibiotics used in the treatment of acute HE. 2

1. Debbia EA, Maioli E, Roveta S, Marchese A. Effects of rifaximin on bacterial virulence mechanisms at supra- and sub-inhibitory concentrations. J Chemother 2008;20:186-194

2. Paik YH, Lee KS, Han KH, et al. Comparison of rifaximin and lactulose for the treatment of hepatic encephalopathy: a prospective randomized study. Yonsei Med J 2005;46:399-407

DISCUSSION