Dr.

Deeksha

Flow of presentation
y Definition y Etiology y Pathophysiology y Existing treatments y Newer and experimental agents y Conclusion

HEPATIC ENCEPHALOPATHY
y Complex neuropsychiatric syndrome

characterised by disturbances in consciousness and behaviour , personality changes, flapping tremors and electroencephalographic changes.
y May be acute and reversible or chronic and

progressive.

y Exact data regarding incidence and prevalence is

lacking
y 70% of patients with liver cirrhosis, while clinically unremarkable have pathologic changes on EEG. y Approximately 50% of patients with liver cirrhosis develop HE after surgical portosystemic bypass procedures. y After placement of a TIPS (transjuglar intrahepatic porto systemic shunt) nearly one third of patients develop HE.

Etiology
y y y

Fulminant hepatic failure Acute severe viral hepatitis /drugs/toxins Acute fatty liver of pregnancy Acute hepatocellular necrosis. Chronic liver disease Cirrhosis of all types (70%) Primary liver cancer Surgically induced porto-caval shunts.

y y y

Common precipitants
y Increased nitrogen load

gastrointestinal bleeding excess dietary protein azotemia constipation y Electrolyte and metabolic imbalance hypokalemia alkalosis hypoxia y Drugs narcotics diuretics y Miscellaneous infection surgery acute liver disease progressive liver disease

Pathogenesis
Postulated factors/mechanisms y Ammonia neurotoxicity
y

-Aminobutyric acid hypothesis

y Plasma amino acid imbalance hypothesis y Excitatory inhibitory neurotransmitter

imbalance
y Synergistic neurotoxins

AMMONIA THEORY
Ammonia production y Degradation of urea or protein
y Primary site: gut y Other sites: kidney and skeletal muscles y Gut-generating ammonia: 4g/day y Equilibrium of ammonia and ammonium:

Ammonia elimination
y y y

Transferred to the liver Metabolized by series of urea cycle enzymes Utilized by brain, liver, kidney : synthesize glutamic acid and glutamine Excreted in the urine

Ammonia intoxication
y

Interferes with cerebral metabolism: depletion of glutamic acid, aspartic acid and ATP

Depressed cerebral blood flow and oxygen consumption

Direct neuronal toxicity

Role of GABA
y

amino butyric acid (GABA)

y Principle inhibitory neurotransmitter

y Generated in the gut by bacteria

y Bypasses the diseased or shunted liver.

Amino acid imbalance

y

Increased aromatic amino acids (AAAs): tyrosine, Phenylalanine ,tryptophan Due to the failure of hepatic deamination Decreased branched-chain amino acids (BCAAs): valine , leucine, Isoleucine Due to increased metabolism by skeletal muscle and kidneys Imbalance of plasma amino acids More AAAs enter into blood-brain barrier and CNS Cerebral tryptophan increases synthesis of serotonin (depressant action)

Phenylalanine inhibits tyrosine 3-hydroxylase ( key enzyme for catecholaminergic neurotransmitters)

Tyrosine increases synthesis of tyramine ,octapamine which compete with catecholaminergic neurotransmitters for the same receptor site.

Neurotransmitters
y

Decreased synthesis of normal neurotransmitters L-Dopa Dopamine

Noradrenaline

Enhanced synthesis of false neurotransmitters Octopamine Tyramine

Synergistic neurotoxins
y y

Mercaptans and short chain fatty acids Mecaptans : generated from the degradation of methionine in gut, cause fetor hepaticus

y Both mercaptans and short-chain fatty acids have

direct neuronal cytotoxicity and also inhibit enzymes of urea cycle.

y

Individually, failed to induce HE but displayed synergism .

Pathogenesis

Clinical staging
stage mental status asterixis EEG 1 Euphoria or depression, mild confusion, slurred speech, disordered sleep Lethargy, moderate confusion +/Usually normal

Abnormal (triphasic slow waves) Abnormal (triphasic slow waves) Abnormal (delta waves)

Marked confusion, incoherent speech, sleeping but arosable coma;initially responsive to noxious stimuli later unresponsive

Targets for treatment

Treatment of precipitating factors

y Constipation y Electrolyte and acid base balance y Infection y Gastro intestinal bleeds y Portosystemic shunts

Current therapies
y Non absorbable disaccharides

lactulose and lactitol

y Antibiotics

vancomycin metronidazole rifaximin

Lactulose y Metabolised to lactic acid and acetic acid y Hostile environment for intestinal bacteria y Reduces ammonia production

y Cause 2~4 soft stool/d y Side-effects: abdominal cramps, diarrhoea, flatulence

Antibiotics
y

Neomycin Alters gut flora, impairs ammonia absorption Impaired hearing or deafness (in long term use) Long term use (>1 month) is not advisable

y Metronidazole

Active against bacteroids and other organisms As effective as neomycin Neurotoxic

y Rifaximin

Relatively safer Adverse effects: flatulence, abdominal pain , constipation , nausea

Alternative therapies
y y

GABA/BZ receptor antagonists Flumazenil ,associated with higher rate of symptomatic improvement than placebo. Effects transient , role as adjunctive therapy. BCAAs Provide safe and well-tolerated source of nutrition in patients with cirrhosis Achieve positive nitrogen balance Improved mental status Efficacy not established

y y y y

L-Dopa and Bromocriptine

y Decreased dopaminergic neurotransmission is a

component of false neurotransmitter theory

y Improvement in chronic portosystemic

encephalopathy
y Constipation and increased prolactin concentration

are side effects.

Need for newer agents

y Current pharmacotherapy limited due to complex

pathophysiology of the disease.

y Minimise the side effects of existing treatment. y Improve morbidity associated with HE. y Development of cost effective treatment.

Newer agents
Probiotics y Multiple beneficial effects in treatment of minimal HE y Decrease total ammonia in portal blood by: a) bacterial urease activity b) ammonia absorption by decreasing pH c) intestinal permeability d) improving nutritional status of gut epithelium.
y Decrease inflammation and oxidative stress in

hepatocyte

hepatic clearance of ammonia

y Studies show improved neuropsychological testing.

L- Ornithine L- aspartate (LOLA) L(LOLA y Substrate for urea synthesis

y Reinforce glutamine synthesis which serves to

detoxify ammonia
y Studies show decrease in ammonia concentration

and symptomatic improvement in mild to moderate hepatic encephalopathy.

Sodium benzoate y Interacts with glycine to form hippurate

y Excreted renally with loss of ammonia ions y Prospective double blind trial reported similar

symptomatic improvement and incidence of adverse effects as lactulose

y Use limited by potential salt overload and unpleasent

taste.

Acarbose glycosidase inhibitor

y Facilitates reduction of bacterial flora in addition to inhibiting conversion of carbohydrates into monosaccharides. y Significant reduction in serum ammonia concentration and symptomatic improvement in encephalopathy y Side effects : abdominal bloating , flatulence, increased frequency of bowel movements.

Zinc
y Cofactor of urea cycle enzymes, enhances hepatic

conversion of amino acids to urea

y Found in vesicles of glutaminergic presynaptic

terminals effecting neurotransmission

y Zn deficiency common in cirrhosis and hepatic

encephalopathy
y Replacement should be considered if the patient is

deficient.

Exprimental agents
Levocarnitine
y Metabolite of lysine degradation. y Carrier of short chain fatty acids across mitochondrial membrane. y Demonstrated decrease in serum ammonia levels and improved mental status. y Evaluated in patients in 2 studies and currently under trials.

Sodium phenylbutyrate
y Converted to phenylacetate, combines with

glutamine to form phenylacetylglutamine.

y Excreted renally with the loss of ammonia ions. y It`s combination with sodium benzoate is

currently approved for hyperammonemia in urea cycle disorders.

y Currently undergoing clinical trials in patients

with cirrhosis and HE(HALT-HE)

Memantine
y Studies demonstrate overactivity of NMDA receptors

in HE.
y Memantine is a NMDA receptor antagonist approved

for alzheimers.
y Significant improvement in clinical grading and

other markers of encephalopathy.

y Currently in pre clinical trials.

Refrences
y Harrison`s principles of internal medicine 17th edition. y Drugs 2010, vol 70,no.9. y Gut 23:801,806. y Hepatology4 :279-287