Review Article
Leise MD, Poterucha J, Kamath PS et. al. Management of hepatic encephalopathy in the hospital. Mayo Clin Proc 2014; 89(2) 241-253.
Working Party for hepatic encephalopathy nomenclature:
Type A HE-- secondary to liver failure
Type B HE enteric hyperammonemia without liver disease
Type C -- is associated with some liver disease.
Severity Grades
I-IV scale
0 normal
MHE normal exam, nild changes visuoperceptive or psychometric tests
I Personality change, attention ddeficit, irritability, depressed state, tremor, dyscoordination
2 Changes sleep/wake cycle,letharygy , mood, behavioral/ cognitive changes; asterixus, ataxic gait, slow/slurred speech
3 Somnolence, confusion , disorientation, amnesia; muscle rigidity, nystagmus, clonus, Babinski sign, hyporeflexia
4 stupor and coma; oculocephalic reflexes, unresponsive
other scale SONIC (spectrum of neurocognitive impairment in cirrhoses)
covert HE (CHE) includes minimal HE (MHE) and grade I HE
overt HE encompasses grade II-IV.
Also
episodic HE
persistent HE impairs day to day executive function
Epidemiology
50 percent of cirrhosis patients develop HE, and prognosis for these patients is worse even taking into account Model End Stage Liver Disease (MELD) scores.
Occurrence of OHE is approximately 22,000 per year
80 % are precipitated by an event such as GI bleed or iinfection
Most patients do not get needed maintenance care after hospital discharge
Reason for readmission is lack of education or inappropriate use of lactulose.
Treatments- Induction therapies for episodic OHE
Nonabsorbale disaccharids-- lactulose (B galactosidofructose) and lactitol (B galactosidosorbitol) reduce ammonia by acifying colon with shift of ammonia to ammonium, shifting colonic flora from urease to nonurease producing bacterial species, and by cathartic effect. Clinical studies are mixed/poor but its still first line in all but most sever cases.
Neomycin, metronidazole,and other antibiotics. -- neomycin is FDA approved for acute but not chronic HE to decrease gut derived bacterial derived ammonia. The evidence is weak, for OHE, and its use complicated by ototoxicity and nephrotoxicity.Possible slight benefit with metronidazole or vancomycin but each are very toxic.
Rifaximin :-- not FDA approved for episodic HE, only for secondary prevention of OHE Trials did not show substantial difference from lactitol but seemed to work faster. RCT of rifaximin v. placebo showed benefit on composite outcome at doses of 1200-2400 mg per day for grades !-3. May be better tolerated than lactitol. A study of grades 3-4 with lactulose + placebo v. lactulose+ rifaximin had more complete reversal in dual treated group (76 v. 51 %), shorter hospital stays and less ten day mortality (49 v. 24 %).
Zinc :Zinc deficiency occurs in 96 % of patients with MELD score of 12. inc is necessary for two smmonia reduction pathways: ornithyl transcarbamylase in liver (ammonia converted to urea) and glutamine sythetase in skeletal muscle (glutamate to glutamine). One of 4 RCT's showed benefit. Caution: zinc should be taken 2 hours before ciprofloxacin, and long term use causes copper deficiency,
L ornithine-L aspartate : aka LOLA stimulates ammonia reduction pathways, like zinc. Best use is in chronic HE. Has been shown to be effective, but is not available in USA
Branched chain amino acids : in cirrhosis, patients have decreased BCAA's and increased aromatic amino acids. BCAA's are a source of glutamate which helps metabolize ammonia in skeletal muscles. Benefits of BCAA's include better albumin synthesis, decreased insulin resistance, less hepatocellular carcinoma, and better immune function. Studies poor quality with mixed results. European Society for Cliical Nutrition and Metabolism recommends 1.2 g/kg / day of protein for compensated cirrhosis, and 1.5 g/kg/day for decompensated cirrhosis. They also have grade A recommendation for standard protein supplementation for HE grade 2 or less, and BCAA for HE grades 3 and 4.
Percutaneous embolization of large portosystemic shunts :In European study , n= 37, for medically refractory patients given this, 59 % were free of HE in 100 days, 48 % in 2 years. 90 % of patients with cirrhosis improved.
Molecular adsorbent recirculating system : aka MARS based on albumin dialysis principle. It removes protein and albumin bound toxins such as bilirubin, bile acids, nitrous oxide and enodogenous benzodiazepines, and non protein bound ammonia. Effect on survival is in question, but HE is improved. It is safe and tolerated and FDA approved for HE related to decompensated liver disease. May reduce availability of certain antibbiotics and has medical contraindications.
Secondary prophylactic maintenance strategies in HE
Lactulose : there is solid evidence for lactulose alone, or in combination with rifaximin. Lactulose or lactulose plus probiotics had less recurrent OHE (37 5, 45 %, and 64 % respectively).
Rifaximin : in rifaximin v. placebo, treated group had less recurrence and rehospitalization than placebo. It is FDA approved for secondary prevention of HE
General approach to induction and maintenance of first episode of HE :
1. Screen for precipitants of OHE including GI bleed, infection, new medications such as opiods and benzodiazepines, constipation, diarrhea, dehydration, alkalosis, hypokalemia, or hypoxemia (seen in 80 % at least one). Then manage precipitant and use lactulose also.
2. For nonresponders, look for other precipitants, reeval the diagnosis, make sure the patient is having 3-4 stools per day. Could then add neomycin (FDA approved but many side effects, or rifaximin which is off label.
3. For patients who benefit use lactulose maintenance therapy especially for Child-Turcotte-Pugh class B/C
General approach to induction and maintenance of recurrence of HE :
1. Same as (1) above; check number of stools with and compliance with lactulose. Review meds
2. If bloating or excessive diarrhea occur with any dose of lactulose, use rifaximin instead. In breakthrough HE on lactulose, add rifaximin (preferred) or neomycin (less preferred).
3. If breaks through on 2 drugs above, perform contrast enhanced CT to look for large intra-abdominal portosystemic shunt, or use MRA if patient is contrast risk. Consider a shunt embolization in CTP class A cirrhosis or low MELD score (< 12-15). 60-90 percent may remit.
4. If embolization is not indicated consider additional treatments such as zinc, LOLA (if available), BCAA
Treatment of Severe HE grades 3-4 :
1. ABC, look for precipitants, lactulose 15-30 cc png q 1-2 hours until 3 stools achieved. Alternative is 300 cc lactulose in 700 cc sterile water in an enema. , may repeat prn. Add rifaximin . If unresponsive, perform head CT/ EEG to check diagnosis. If diagnosis is correct, look for shunt to embolize.; if none use BCAA, zinc and LOA
MHE: Counsel patient about risks of driving
Leise MD, Poterucha J, Kamath PS et. al. Management of hepatic encephalopathy in the hospital. Mayo Clin Proc 2014; 89(2) 241-253.
Working Party for hepatic encephalopathy nomenclature:
Type A HE-- secondary to liver failure
Type B HE enteric hyperammonemia without liver disease
Type C -- is associated with some liver disease.
Severity Grades
I-IV scale
0 normal
MHE normal exam, nild changes visuoperceptive or psychometric tests
I Personality change, attention ddeficit, irritability, depressed state, tremor, dyscoordination
2 Changes sleep/wake cycle,letharygy , mood, behavioral/ cognitive changes; asterixus, ataxic gait, slow/slurred speech
3 Somnolence, confusion , disorientation, amnesia; muscle rigidity, nystagmus, clonus, Babinski sign, hyporeflexia
4 stupor and coma; oculocephalic reflexes, unresponsive
other scale SONIC (spectrum of neurocognitive impairment in cirrhoses)
covert HE (CHE) includes minimal HE (MHE) and grade I HE
overt HE encompasses grade II-IV.
Also
episodic HE
persistent HE impairs day to day executive function
Epidemiology
50 percent of cirrhosis patients develop HE, and prognosis for these patients is worse even taking into account Model End Stage Liver Disease (MELD) scores.
Occurrence of OHE is approximately 22,000 per year
80 % are precipitated by an event such as GI bleed or iinfection
Most patients do not get needed maintenance care after hospital discharge
Reason for readmission is lack of education or inappropriate use of lactulose.
Treatments- Induction therapies for episodic OHE
Nonabsorbale disaccharids-- lactulose (B galactosidofructose) and lactitol (B galactosidosorbitol) reduce ammonia by acifying colon with shift of ammonia to ammonium, shifting colonic flora from urease to nonurease producing bacterial species, and by cathartic effect. Clinical studies are mixed/poor but its still first line in all but most sever cases.
Neomycin, metronidazole,and other antibiotics. -- neomycin is FDA approved for acute but not chronic HE to decrease gut derived bacterial derived ammonia. The evidence is weak, for OHE, and its use complicated by ototoxicity and nephrotoxicity.Possible slight benefit with metronidazole or vancomycin but each are very toxic.
Rifaximin :-- not FDA approved for episodic HE, only for secondary prevention of OHE Trials did not show substantial difference from lactitol but seemed to work faster. RCT of rifaximin v. placebo showed benefit on composite outcome at doses of 1200-2400 mg per day for grades !-3. May be better tolerated than lactitol. A study of grades 3-4 with lactulose + placebo v. lactulose+ rifaximin had more complete reversal in dual treated group (76 v. 51 %), shorter hospital stays and less ten day mortality (49 v. 24 %).
Zinc :Zinc deficiency occurs in 96 % of patients with MELD score of 12. inc is necessary for two smmonia reduction pathways: ornithyl transcarbamylase in liver (ammonia converted to urea) and glutamine sythetase in skeletal muscle (glutamate to glutamine). One of 4 RCT's showed benefit. Caution: zinc should be taken 2 hours before ciprofloxacin, and long term use causes copper deficiency,
L ornithine-L aspartate : aka LOLA stimulates ammonia reduction pathways, like zinc. Best use is in chronic HE. Has been shown to be effective, but is not available in USA
Branched chain amino acids : in cirrhosis, patients have decreased BCAA's and increased aromatic amino acids. BCAA's are a source of glutamate which helps metabolize ammonia in skeletal muscles. Benefits of BCAA's include better albumin synthesis, decreased insulin resistance, less hepatocellular carcinoma, and better immune function. Studies poor quality with mixed results. European Society for Cliical Nutrition and Metabolism recommends 1.2 g/kg / day of protein for compensated cirrhosis, and 1.5 g/kg/day for decompensated cirrhosis. They also have grade A recommendation for standard protein supplementation for HE grade 2 or less, and BCAA for HE grades 3 and 4.
Percutaneous embolization of large portosystemic shunts :In European study , n= 37, for medically refractory patients given this, 59 % were free of HE in 100 days, 48 % in 2 years. 90 % of patients with cirrhosis improved.
Molecular adsorbent recirculating system : aka MARS based on albumin dialysis principle. It removes protein and albumin bound toxins such as bilirubin, bile acids, nitrous oxide and enodogenous benzodiazepines, and non protein bound ammonia. Effect on survival is in question, but HE is improved. It is safe and tolerated and FDA approved for HE related to decompensated liver disease. May reduce availability of certain antibbiotics and has medical contraindications.
Secondary prophylactic maintenance strategies in HE
Lactulose : there is solid evidence for lactulose alone, or in combination with rifaximin. Lactulose or lactulose plus probiotics had less recurrent OHE (37 5, 45 %, and 64 % respectively).
Rifaximin : in rifaximin v. placebo, treated group had less recurrence and rehospitalization than placebo. It is FDA approved for secondary prevention of HE
General approach to induction and maintenance of first episode of HE :
1. Screen for precipitants of OHE including GI bleed, infection, new medications such as opiods and benzodiazepines, constipation, diarrhea, dehydration, alkalosis, hypokalemia, or hypoxemia (seen in 80 % at least one). Then manage precipitant and use lactulose also.
2. For nonresponders, look for other precipitants, reeval the diagnosis, make sure the patient is having 3-4 stools per day. Could then add neomycin (FDA approved but many side effects, or rifaximin which is off label.
3. For patients who benefit use lactulose maintenance therapy especially for Child-Turcotte-Pugh class B/C
General approach to induction and maintenance of recurrence of HE :
1. Same as (1) above; check number of stools with and compliance with lactulose. Review meds
2. If bloating or excessive diarrhea occur with any dose of lactulose, use rifaximin instead. In breakthrough HE on lactulose, add rifaximin (preferred) or neomycin (less preferred).
3. If breaks through on 2 drugs above, perform contrast enhanced CT to look for large intra-abdominal portosystemic shunt, or use MRA if patient is contrast risk. Consider a shunt embolization in CTP class A cirrhosis or low MELD score (< 12-15). 60-90 percent may remit.
4. If embolization is not indicated consider additional treatments such as zinc, LOLA (if available), BCAA
Treatment of Severe HE grades 3-4 :
1. ABC, look for precipitants, lactulose 15-30 cc png q 1-2 hours until 3 stools achieved. Alternative is 300 cc lactulose in 700 cc sterile water in an enema. , may repeat prn. Add rifaximin . If unresponsive, perform head CT/ EEG to check diagnosis. If diagnosis is correct, look for shunt to embolize.; if none use BCAA, zinc and LOA
MHE: Counsel patient about risks of driving
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