Core Curriculum Handout Presenter: Mamie Dong Preceprot: Sam Ho December 29, 2009
Hepatic Encephalopathy
I. Introduction: HE is a term used to describe a spectrum of neuropsychiatric abnormalities occurring in patients with significant liver disease and/or portosystemic shunting of blood. II. Definition and Nomenclature
A. The first consensus panel to standardize terminology occurred in 1998 (11th World Congress of Gastroenterology, report published in 20022)
Type Nomenclature Subcategory Subdivision A Encephalopathy associated with
Acute liver failure
B Encephalopathy associated with portal-systemic Bypass and no intrinsic liver disease
C Encephalopathy associated with Cirrhosis and portal hypertension or portal-systemic shunts
Episodic HE Precipitated Spontaneous* Recurrent** Persistent HE † Mild (Grade 1)
Severe (Grade 2-4) Treatment-dependent Minimal HE ‡
* No trigger identified ** 2 or more episodes in 1 year † Lasting > 4 weeks ‡ No clinically discernable symptoms
Older terms, such as portal-systemic encephalopathy (PSE) and subclinical encephalopathy are no longer endorsed.
III. Pathophysiology – General Points
A. Nearly all investigators agree that the “toxins” causing HE arise from the gut, but what exactly those toxins are and how they cause HE are still an area of debate B. Patients with total diversion of portal blood around the liver but with normal liver
histology (such as PV thrombus) rarely have overt HE, even after massive variceal bleeding. This is still an area of research/debate and is not well understood. C. “The sensitized brain” – Gut toxins not only play a role in inducing HE, but may
sensitize the brain to other insults. This potentially explains why patients with normal ammonia levels can have classic HE responsive to lactulose.
D. HE is not just a reversible metabolic encephalopathy. Brain atrophy and Parkinsonian signs are also elements of this syndrome.
IV. Pathophysiology – Hypotheses
A. The Original Ammonia Hypothesis – Ammonia is directly neurotoxic Described in the 1950’s when HE was reported in patients taking
Supportive evidence
• Recent studies in the last decade have found a reliable correlation (r=0.6 or higher) between ammonia levels and severity of HE. Previously described lack of correlation is thought to be due to suboptimal lab technique.
• Patients with hereditary urea cycle enzyme defects and hyperammonemia develop encephalopathy
• Most treatments thought to be effective in HE are best explained by an ability to reduce the generation of ammonia and its
absorption from the gut Contradictory evidence
• Unlike in HE, patients with pure hyperammonemia (without liver disease) frequently have seizures
• Controlled trials administering ammonia to cirrhotic patients failed to induce HE
B. The Unifying Ammonia Hypothesis – Ammonia influx to the brain triggers astrocyte swelling and cerebral edema
Originally suggested by Haussinger et al in 2006, now accepted by most HE investigators
The only mechanism for handling excessive ammonia in the brain is catalysis by glutamate synthetase within astrocytes. Accumulation of osmotically active glutamine causes astrocyte swelling, which then leads to a host of downstream events.
In chronic liver disease, cerebral edema tends to be low grade due to compensating efflux of myoinositol.
C. Synergistic Neurotoxin Hypothesis – Mercaptans, a byproduct of methionine metabolism, in conjunction with other gut-derived toxins, causes HE
HE has been reportedly induced in animal models and human cirrhotics given oral methionine
Fetor hepaticus, commonly present in patients with or likely to develop HE, has been conclusively proven to be derived from mercaptans
D. False Neurotransmitter Hypothesis – False or weak neurotransmitters, byproducts of liver failure, lead to failure of neurotransmission
Direct injection of octopamine into rat CNS failed to produce any effect Some data suggests that this may play a role in the hyperdynamic
circulation seen in advanced liver disease
E. Plasma Amino Acid Imbalance Hypothesis – Elevated brain levels of tyrosine and phenylalanine in the brain, caused by decreased blood levels of branched chain amino acids, causes HE
Ammonia also influences glutamine transport across the blood-brain barrier
Many nutritional supplements were developed (with low levels of tyrosine and phenylalanine and enriched in branched-chain amino acids), but despite normalization of amino acid ratios, clearcut improvement in HE was difficult to prove
F. GABA / Benzodiazepine Hypothesis – Increased inhibitory GABA-ergic neurotransmission in the CNS due to excess GABA in the brain or elevated endogenous benzodiazepines causes HE
Flumazenil has been showing to be more effective in reversing HE than placebo
Research in determining what these benzodiazepines are and where they come from is ongoing
G. Other Hypotheses
Manganese hypothesis
• Abnormal manganese deposits have been found in certain brain regions (can also be seen on MRI)
• Manganese induces astrocyte swelling in-vivo Endogenous opiate hypothesis
• Case reports of reversal of HE by opiate antagonists
• Fatigue and pruritus, to some extent, can be linked to excessive endogenous opiates
Inflammatory cytokines mediate both decrease in heart rate variability and HE3
Severe zinc deficiency V. Diagnosis
A. There are 2 major components of HE, altered mental status and generalized motor disturbance.
B. Rule out other causes of encephalopathy
Metabolic CNS Toxins Infection
Hypoxia / Hypercapnea CVA Alcohol Sepsis
Hyper / Hypo-natremia Wernicke-Korsakoff syndrome
CNS depressants
Meningitis
Hypoglycemia / Ketoacidosis Seizure / Postictal Encephalitis
Hyper / Hypo-thyroidism Intracranial or subdural hemorrhage
Intracranial abscess
Hypercalcemia Delirium tremens
Adrenal dysfunction CNS infection
Uremia CNS neoplasm
C. Search for precipitating factors – every advanced cirrhotic patient displaying a change in mental status is septic until proven otherwise
Why does GI bleeding precipitate HE?
• Hemoglobin is deficient in isoleucine, and when hemoglobin is digested and absorbed it causes an unbalanced amino acid profile that ultimately leads to disproportionate production of ammonia
• Conceivably, infusion of isoleucine to cirrhotic patients after bleeding may reduce ammonia levels
Sepsis / Infections → hypercatabolic state → increased precursors for ammonia synthesis
Hypokalemic alkalosis → induces renal ammoniagenesis Renal failure → decreased renal ammonia excretion
HCC, Portosystemic shunt → increases ammonia delivery to CNS
Definite Less Certain
Gastrointestinal bleeding CNS-active drugs Zinc deficiency Sepsis / Infections Constipation Beta-blockers
Hypokalemia High protein load Anemia
Renal failure / Urinary obstruction
Portosystemic shunt Oral methionine
Hyponatremia Superimposed liver injury Hypernatremia (free water depletion)
Dehydration Hepatocellular carcinoma
D. Grade / Stage the severity of disease Overt HE is a clinical diagnosis
West Haven Criteria for Semi-quantitative grading of mental status
• The major grading system used for the past 3 decades
• Focuses on mental status
West Haven Criteria for Semi-quantitative Grading of Mental Status Grade 1 Trivial lack of awareness
Euphoria or anxiety Shortened attention span
Impaired performance of addition Grade 2 Lethargy or apathy
Minimal disorientation for time or place Subtle personality change
Inappropriate behavior
Impaired performance of subtraction
Grade 3 Somnolence to semi-stupor, but responsive to verbal stimuli Confusion
Gross disorientation
Grade 4 Coma (unresponsive to verbal or noxious stimuli) Glasgow Coma Scale
• Useful for patients with Grade 3-4 HE
• Incorporates motor components Glasgow Coma Scale
1 2 3 4 5 6
Eyes Does not
open eyes Opens eyes to painful stimuli Opens eyes to voice Opens eyes spontaneously NA NA
Verbal No sounds Incomprehensible
sounds
Inappropriate words
Confused Oriented NA
Motor No
movements Extension posturing to painful stimuli Flexion posturing to painful stimuli
Withdraws to
painful stimuli Localizes painful stimuli
Obeys commands
Other grading systems have been devised in an attempt to incorporate both the West Haven criteria and the GCS, but none have been validated in large multi-center trials
HESA (Hepatic Encephalopathy Scoring Algorithm) – Courtesy of Dr. Hassanein
E. Motor Abnormalities
Hyperreflexia, asterixis, extensor plantar reflexes are often seen
Asterixis is not specific to HE, but its presence in a patient with known liver disease is a fairly reliable sign – presence signifies grade 2 HE, may be diminished in grade 3 HE
Localizing motor signs may be seen in patients with HE without any imaging abnormalities, though stroke and hemorrhage must be ruled out first. These resolve without sequelae as HE resolves.
F. Laboratory and Imaging Assessment Blood Ammonia Testing
• Recently, some studies have shown a correlation (r>0.6) of
ammonia levels with degree of encephalopathy, however this is not sufficient proof to use ammonia testing for diagnosis.
• Major problem: Frequent false positives and false negatives
• Falsely high levels can occur with inappropriately collected samples (must be placed on ice and processed within 30 minutes)
• The only clinical scenario where ammonia testing may be helpful is in the patient without clear underlying liver disease but with marked mental status changes
Brain imaging
• Useful for ruling out other causes of encephalopathy
• Imaging findings in HE patients o CT
Cortical atrophy (worse in alcoholic liver dz) Subtle suggestion of cerebral edema
Rarely frontal cerebral edema can be seen o MRI
Hyperintensity of basal ganglia on T1 weighted images (due to manganese deposits)
Cerebral and cerebellar atrophy Cerebral edema
G. Assess the rare patient with HE but no obvious chronic liver disease Long-standing, undiagnosed, well compensated cirrhosis
• Unlike alcoholic cirrhosis, where portal-systemic shunting and loss of liver function progress at roughly the same rate, patients with hep C or NASH cirrhosis develop large shunts and may exhibit HE before major loss of liver function is observed
Congenital portal-systemic shunts
Portal-systemic shunts due to splanchnic venous thrombosis (ie, portal vein thrombosis)
Non-cirrhotic portal hypertension
Coincidental partial urea cycle enzyme deficiency
Mild liver disease with other entities such as zinc deficiency, Addison’s disease, or hypothyroidism
VI. Minimal Hepatic Encephalopathy (MHE) A. Definition
Previously known as subclinical HE
No clinically discernable symptoms but at least one abnormal neuropsychologic or neurophysiologic test
B. Why is this important?5,6
Studies show that patients have impairments in daily functioning, quality of life, and may be unsafe to drive cars
MHE predicts the occurrence of overt H
Patients who are treated show a significant reduction in blood ammonia levels and improvement in Child-Turcotte-Pugh class
C. Pathogenesis
Mainly a dysfunction of subcortical systems: attention, visual-spatial, fine motor movements
May have impaired immediate memory due to poor cognitive ability, not an impairment in anterograde memory like Alzheimer’s
D. Diagnosis – Not yet widely used clinically, mostly for research purposes
No consensus on how best to diagnose or how often patients should be evaluated
2009 ISHEN guidelines7 recommend 1 of the 2 following battery of tests, takes 20-40 minutes to complete
• PSE-Syndrome Test – designed especially for MHE, but only available in German
o Serial dotting test – 10 rows of 10 circles each, patient is timed on how quickly he/she can draw a dot in the center of each circle
o Line drawing test – patient scored on how quickly and accurately he/she can draw a continuous line between 2 winding lines
o Digit symbol test – involves coding-substitution of symbols for numbers
o Number connection tests A and B – known as “connect the dots” in elementary school
• RBANS – used for all forms of dementia and neurocognitive impairment; also includes tests for memory and language fluency Electrophysiological studies – not readily available
• EEG – can see triphasic spikes
• Visual / auditory evoked potentials
• Flicker fusion detection
E. Treatment - ? lactulose, ? probiotics; not currently standard of care VII. Treatment - Overview
A. 4-pronged approach to treatment Supportive care
Search for and correct precipitating factors
Exclude and treat other causes of altered mental status Start empiric therapy for HE
Reduction of ammonia production and absorption
Lactulose, Lactitol, Lactose Dietary protein restriction Poorly absorbed antibiotics Disaccharide inhibitors Probiotics
Promotion of waste nitrogen excretion
L-Ornithine-aspartate (LOLA) Sodium benzoate
Correction of neurotransmitter abnormalities in the brain
Flumazenil
Branched-chain amino acid-enriched formulations Dopaminergic agents
Narcotic antagonists Zinc repletion Portosystemic shunt
suppression
Liver support systems Liver transplantation
B. Historical issues
The first treatments were with antibiotics such as tetracyclines to reduce production of ammonia by gut flora
Later, poorly absorbed antibiotics, mainly neomycin, became standard of treatment in the 1960’s. However, the first placebo-controlled trials for neomycin didn’t occur until the early 1990’s, and they showed equal
efficacy of neomycin and placebo! Despite this, it continued to be used as a comparison drug for other agents in the years that followed.
Lactulose first appeared in 1966, and was featured in a number of RCTs in the 1970’s. Two early placebo-controlled trials did not show any efficacy. Following, major RCTs were done comparing lactulose to neomycin, and found that neomycin was equivalent to slightly superior to lactulose (possibly due to concomitant use of sorbital to induce diarrhea). The two were marked “eqiavalent”, and thus lactulose came into favor due to fewer side effects.
Modern trials are complicated by several factors, first lactulose is
considered the necessary comparison arm (despite evidence lacking as to its efficacy), IRBs consider it unethical to not treat HE (ie, unable to do placebo controlled trials), and hospitalized patients are always being treated supportively. It is not known what the spontaneous recovery rate from HE is, but some studies have suggested 40-70%.
In a recent study by Sharma et al4 comparing lactulose to placebo in the secondary prevention of HE in 140 patients, lactulose was found to be superior (19.6% vs 46.8%, p=0.001)
VIII. Treatments that reduce ammonia production and absorption in the gut
A. Non-absorbed disaccharides – lactulose (and lactitol-not available in US) Mechanism of action – complex
• Osmotic laxative
• Acidifies lumen of colon, which converts ammonia to ammonium and traps it in the colon and promotes its incorporation into bacterial proteins
• Gut acidity inhibits ammoniagenic bacteria and promotes growth of nonammoniagenic bacteria
• Possibly inhibits intestinal glutaminase activity
Efficacy: Consistently shown to be superior compared to no treatment for minimal HE, proof of efficacy is lacking for overt HE
Dose: lactulose 30cc bid-qid titrated to goal 2-4 soft BMs/day or retention enema 300cc lactulose + 700cc tap water retained for 1 hour
Pros: cheap, has been used for a long time
Cons: sweet, increases intestinal gas production, electrolyte disturbances, particularly hypernatremia (with dehydration)
Contraindications: ileus
B. Poorly absorbed antibiotics – rifaximin (and neomycin-FDA approved for acute HE only, not chronic HE)
Mechanism of action
• Suppresses growth of aerobic intestinal bacteria, which reduces ammonia production in the gut
• Induces malabsorption and villous atrophy in the small intestines
• Possibly reduces glutaminase activity
• Possibly treats small bowel bacterial overgrowth
Efficacy: Rifaximin has been found to be equivalent or superior to lactulose
Dose: First Line
• Rifaximin 400mg PO tid marginally better than lower doses (400mg-550mg bid)
• Neomycin 1gm PO q6h for up to 6 days (if used chronically, 1-2gm/day)
Pros: no diarrhea
Cons: rifaximin is expensive; neomycin can cause ototoxicity and nephrotoxicity
Other antibiotics
• Metronidazole – not FDA approved for HE, but found to be equivalent to neomycin
o Dose: 250mg PO bid
o Cons: Risk of accumulation in patients with advanced liver dz, leading to CNS toxicity, peripheral neuropathy; ?risk of antibiotic resistance, fungal infection
• Vancomycin – one report showed efficacy in lactulose-resistant HE, but popularity faded with outburst of VRE
• Nitazoxanide – pilot study in 2008 looked promising C. Dietary protein restriction – no longer recommended
Protein restriction below maintenance level (0.8g/kg/day) may lead to lean body mass catabolism and may ultimately increase nitrogen load in the circulation
Recent studies have shown that recovery from HE was not delayed if a normal protein diet was delivered in addition to standard HE therapy If oral dietary protein intolerance is truly documented, then patients can be
placed on a vegetable protein diet. Branched-chain amino acid enriched supplements are useful in highly elect protein-intolerant patients, but are expensive.
Recommended protein intake: 0.8-1.5 g/kg/day D. Disaccharide inhibitors – Acarbose
Used for treatment of diabetes
Mechanism of action: inhibits alpha glucosidase activity in the intestines and induces carbohydrate malabsorption; inhibits colonic proteolytic flora Efficacy: randomized controlled crossover trial of 107 cirrhotic patients
showed significant reduction of ammonia and improvement in HE symptoms over placebo10
Cons: not used because package insert says Acarbose is contraindicated in patients with cirrhosis
E. Probiotics
Mechanism of action: attempts to promote nonammoniagenic bacteria in the gut
Lactobacillus acidophilus
Enterococcus SF, Enterococcus faecium – pilot studies equivocalent to lactulose
Cons: concerns about introducing live bacteria into patients who are immunosuppressed
F. Combination of lactulose + rifaximin – Frequently used for difficult to treat cases, but no prospective studies to date
IX. Treatments that promote waste nitrogen excretion
A. LOLA (L-Ornithine-L-Aspartate) – available for research only Mechanism of action:
• Promotes ureagenesis and glutamine synthetase activity in the liver
• Promotes glutamine synthesis and possibly protein anabolism in skeletal muscle
Efficacy: Shown in placebo-controlled trials to have significant effect in grade II HE
Available in enteral and parenteral forms
Pros: well tolerated, only minor GI side effects reported B. L-Ornithine Phenylacetate – animal studies only
Theoretically, phenylacetate component can conjugate with glutamine and be excreted by the kidneys
C. Sodium Benzoate and Sodium Phenylacetate
Mechanism of action – benzoate conjugates with glycine and
phenylacetate conjugates with glutamine (both contain nitrogen from ammonia)
Approved for use in patients with urea cycle enzyme deficiencies
Efficacy: Only 1 trial done so far comparing sodium benzoate to lactulose, judged to be equivalent
Dose: start low, titrate to effect, max 5g PO BID Pros: Available in enteral and parenteral forms, cheap
Cons: Bad taste, high sodium content, GI side effects (esp nausea) D. L-Carnitine – stimulates urea cycle; animal studies only
X. Correction of neurotransmitter abnormalities in the brain A. Flumazenil
Mechanism of action: Endogenous and exogenous benzodiazepine receptor antagonist
Efficacy: Shown to reverse HE in animal models. In human trials, systemic review showed good short term benefit, but no long term benefit and no change in survival
Cons: No long acting formulation available, can cause seizures, agitation, dizziness, nausea/vomiting
B. Branched-chain amino acid (BCAA)-enriched formulations Parenteral formula not useful
Enteral formula may possibly be useful in select protein-sensitive patients for prevention or treatment of HE
Cons: high cost, some studies showed increased mortality ? C. Dopaminergic agents – L-Dopa, bromocriptine
Limited role in HE Third Line
May be helpful for the patient with extrapyramidal symptoms refractory to other therapy (bromocriptine dose 30mg bid)
D. Opiate antagonists
Animal studies show reversal of HE with naloxone; no RCTs have been done in humans
E. Zinc repletion
Zinc deficiency is common in cirrhotics, particularly alcoholics
Efficacy: Only small studies, and results equivocal, but case reports exist of resistant HE responding only to zinc
Dose: elemental zinc 11mg/day for adult males, 8mg/day for adult females Pros: cheap, over the counter
Cons: acute or chronic zinc toxicity can lead to nausea, vomiting, diarrhea, poor appetite, abdominal cramps, headache
XI. Other Treatments
A. Liver support systems – covered in more detail in Cristina’s and Dr. Hassanein’s grand rounds
MARS (albumin dialysis), biologic systems
Appear to improve HE, but ? survival benefit, very expensive B. Closure or downsizing of portosystemic shunts (spontaneous or artificial)
TIPS is relatively contra-indicated in patients with grade 2 or higher HE Episodes of HE may occur within the first few months after TIPS and can
be managed medically
TIPS downsizing or closure is necessary for severe and intractable HE. One study showed critical low threshold for portal pressure gradient was <5mm Hg8
Splenic artery embolization (to reduce shunting) can be helpful for highly select cases
C. Total colectomy - decreases colonic absorption of nitrogenous substances; described in the literature in the 1970’s-1980’s
D. Liver transplantation – Largely reverses HE, but may have permanent mild residual symptoms
E. AST-120 – currently undergoing phase II trial
An oral adsorbent used in Japan to delay initiation of dialysis in patients with ESRD. Binds ammonia, bile acids, inflammatory mediators. F. NMDA-receptor antagonists – animal studies only
Theory: ammonia leads to overstimulation of NMDA receptors
Efficacy: Rats given ammonia developed sx of HE which were reversed by administration of NMDA-receptor antagonists
XII. HE resistant to treatment - It is actually very rare to be unable to arouse a patient (at least temporarily) from severe HE, no matter how bad their liver function has become. Look for other reasons of AMS in these patients.
Third Line
References
1) Mullen KD. Hepatic Encephalopathy. In Editors Boyer TD, Wright TL, Manns MP. Hepatology, 5th
edition. Saunders Elsevier 2006. Chapter 18.
* All studies mentioned in this handout that were discussed in this textbook are not listed separately here.
2) 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 Congress of
Gastroenterology, Vienna, 1998. Hepatology 2002;35:716-721.
3) Mani AR, Montagnese S, Jackson CD, et al. Decreased heart rate variability in patients with cirrhosis relates to the presence and degree of hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2009. 296(2):G330-8. Epub 2008 Nov 20.
4) 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(3):885-91.
5) Das A, Dhiman RK, Saraswat VA, Verma M, Naik SR. Prevalence and natural history of subclinical
hepatic encephalopathy in cirrhosis. J Gastroenterol Hepatol. 2001. 16(5):531-5.
6) Bustamante J, Rimola A, Ventura PJ, et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol. 1999. 30(5):890-5.
7) Randolph C, Hilsabeck R, Kato A et al. Neuropsychological assessment of hepatic encephalopathy:
ISHEN practice guidelines. International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN). Liver Int. 2009. 29(5):629-35.
8) Chung HH, Razavi MK, Sze DY, et al . Portosystemic pressure gradient during transjugular
intrahepatic portosystemic shunt with Viatorr stent graft: what is the critical low threshold to avoid medically uncontrolled low pressure gradient related complications? J Gastroenterol Hepatol 2008. 23(1):95-101.
9) Al Sibae MR, McGuire BM, et al. Current trends in the treatment of hepatic encephalopathy. Ther
Clin Risk Manag 2009. 5(3):617-26.
10) Gentile S, Guarino G, Romano M, et al. A randomized controlled trial of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol 2005. 3(2):184-91.
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)
• Long-acting sedative use
• Undiagnosed concomitant CNS problem (eg, hypothyroidism, hemorrhage)
• Overly efficacious portosystemic shunt procedure
