Unit I herbs as raw materials, biodynamic agriculture.ppt
Management of hepatic encephalopathy
1. PROF DR NASIR KHOKHAR MD FACP FACG
PROFESSOR OF MEDICINE AND AND
DIRECTOR, DIVISION OF
GASTROENTEROLOGY
SHIFA INTERNATIONAL HOSPITAL
ISLAMABAD
Portosystemic Encephalopathy:
Towards improved management
10. Ammonia Management
Clean the bowel bacteria: Lactulose
Kill the bowel bacteria: antibiotics
Improve ammonia clearance: L-ornithine
L-aspartate
Muscular metabolism
Save brain
11. Empiric therapy of HE
Correction of underlying factor(s)
Reducing production and absorption of
ammonia in gut
12. Precipitating causes of HE
Sepsis
Gastrointestinal hemorrhage
Constipation
Dietary protein overload
Sedatives
Hypokalemia/diuretics/diarrhea
Poor compliance with lactulose
Anesthesia
Ahmed H, et al. Factors precipitating Hepatic Encephalopathy in Cirrhosis Liver
J Postgrad Med Inst Jan 2001;15(1):91-7.
14. Inadequate clinical response
Improvement in 24-48 hours of treatment
If HE persists after 72 hours then consider:
Other causes of encephalopathy
Precipitating factor missed, inadequately
treated
Effective treatment not instituted
Effects of therapy ?lactulose
15. Non-absorbable diasaccharides
Lactulose is a non-absorbable disaccharide that is
fermented in the colon.
The exact mechanism of action remains unclear;
acidification of colonic contents and mass
evacuation of bacteria have been proposed.
Associated with improvement in mental status
Mullen KD, Amodio P, Morgan MY. Therapeutic studies in hepatic
encephalopathy. Metab Brain Dis 2007; 22: 407–23.
Als-Nielsen B, et al. Nonabsorbable disaccharides for hepatic encephalopathy.
Cochrane Database Syst Rev 2004; 2: CD003044.
16. Efficacy of Lactulose and Protein Restriction
Lactulose has no significant effect on mortality in
patients with hepatic encephalophathy compared with
placebo
Protein restriction offers no apparent benefit
May create protein levels insufficient for maintaining positive
nitrogen balance needed in cirrhosis
Shawcross D, Jalan R. Lancet. 2005;365:431-433.
19. Non-absorbable antibiotics
Rifaximin is a non-absorbable antibiotic
Cochrane review recommends the use of non-
absorbable antibiotics.
Given up to 1200 mg/day.
Reduced hospitalization rates after rifaximin therapy
compared with that of lactulose.
The drug expense remains a concern
Alcorn J. Review: rifaximin is equally or more effective than other antibiotics
and lactulose for hepatic encephalopathy. ACP J Club 2008; 149: 11.
20. Rifaximin Study Design
Bass NM, et al. N Engl J Med. 2010;362:1071-1081.
Patients with recurrent HE,
currently inremission
(N = 299)
Rifaximin 550 mg BID*
(n = 140)
Placebo*
(n = 159)
Mo 6
*Concomitant lactulose permitted.
21. Main Findings
Significantly fewer breakthrough HE episodes and significantly
lower rate of hospitalizations involving HE observed among
patients treated with rifaximin vs placebo
Number needed to treat for 6 mos to prevent 1 overt HE episode: 4
Number needed to treat for 6 mos to prevent 1 hospitalization
involving HE: 9
Bass NM, et al. N Engl J Med. 2010;362:1071-1081.
Outcome at Mo 6 Rifaximin, n (%)
(n = 140)
Placebo, n (%)
(n = 159)
HR for Time to
First Event
(95% CI)
P Value
Breakthrough HE 31 (22.1) 73 (45.9) 0.42 (0.28-0.64) < .001
Hospitalization 19 (13.6) 36 (22.6) 0.50 (0.29-0.87) .01
22. Summary of Key Conclusions
Rifaximin significantly more effective than placebo at preventing
additional episodes of HE over 6-mo period in patients with
recurrent HE in remission
Risk of breakthrough HE reduced by 58%
Risk reduction consistent across nearly all patient subgroups
Majority of patients (> 90%) in both arms received concomitant
lactulose
Rifaximin also resulted in significant 50% reduced risk of
hospitalization due to HE
Rifaximin well tolerated with no increased incidence of adverse
events, serious adverse events, or infections compared with
placebo
Bass NM, et al. N Engl J Med. 2010;362:1071-1081.
23. L ornithine L aspartate
LOLA can improve overt HE I or II patients
Hospital stay was reduced.
Data do not support the use of LOLA for patients
with subclinical hepatic encephalopathy.
Trials detecting efficacy and safety were of high
quality.
Abid S, et al. Efficacy of infusion of L-ornithine L-aspartate in cirrhotic patients
with portosystemic encephalopathy: a placebo controlled study.
J. Hepatol. 2005; 42 (Suppl. 2): 84.
24. Sodium benzoate
Sodium benzoate and sodium phenylacetate bind
with ammonia substrates and thus take them out of
the circulation.
One small study reported that sodium benzoate was
as effective as lactulose in reducing ammonia levels
and improving cognitive function.
Severe accidental overdose has been reported
Sushma S, et al. Sodium benzoate in the treatment of acute hepatic
encephalopathy: a double-blind randomized trial. Hepatology 1992;16:138–44.
25. Zinc
Zinc deficiency is common in cirrhosis.
Zinc administration has the potential to improve
hyperammonemia by increasing the activity of
ornithine transcarbamylase, an enzyme in the urea
cycle.
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
Bresci G, et al. Management of hepatic encephalopathy with oral
zinc supplementation: a long-term treatment. Eur J Med. 1993;2(7):414-6.
26. Detoxification systems
The molecular adsorbant recirculating system
(MARS) removes protein-bound and water-soluble
toxins.
A short-term (5-day), multicenter, randomized study
compared the use of MARS with standard medical
therapy.
Significantly more rapid improvement in mental
status was observed in the MARS group (p=0.044).
The role of albumin dialysis unclear.
Hassanein TI, et al. Randomized controlled study of extracorporeal albumin
dialysis for hepatic encephalopathy. Hepatology 2007;46: 1853–62.
27. Probiotics
Probiotics are live, microbiologic dietary
supplements (e.g., yogurt).
Work by depriving pathogenic bacteria of substrates
and providing fermentation products for beneficial
bacteria.
Two small studies reported neuropsychological
improvement in patients with MHE.
Malaguarnera M, et al. Bifidobacterium longum with fructo-oligosaccharide (FOS)
treatment in minimal hepatic encephalopathy: a randomized, double-blind,
placebocontrolled study. Dig Dis Sci 2007;52:3259–65.
Bajaj JS, et al. Probiotic yogurt for the treatment of minimal hepatic
encephalopathy. Am J Gastroenterol 2008;103:1707–15.
29. Other Management
Alternative targets for ammonia reduction
Kidneys produce, excrete significant ammonia
Volume expansion promotes excretion, reduces plasma ammonia
Muscle converts ammonia to glutamine in hyperammonemia
L-ornithin L-aspartate (LOLA) increases muscle detoxification
Reduction in inflammation and potential infection
Targets: nitric oxide, proinflammatory cytokines, free radicals
Liver detoxicification via liver support systems
Reduction in cerebral hyperemia, intracranial
hypertension
Moderate hypothermia treatment reduces cerebral blood flow
Shawcross D, Jalan R. Lancet. 2005;365:431-433.
30. Liver transplant
The ultimate management goal for OHE is
the replacement of the diseased liver.
Therefore, liver transplant work-up is
crucial for the management of OHE after
correction of the acute insult and prevention
of recurrences.