The Role of LOLA in HE

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The Role of LOL

In

Hepatic Encephalopathy

Hariadi M

PIT XIV IPD

Malang 17 Oktober

2014


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Introduction

Hepatic Encephalopathy (HE) is a complex neuropsychiatricsyndrome with disturbances in:

-consciousness

-behavior,personality changes

-fluctuating neurologic signs,asterixis/flapping tremor

-distinctive EEG changes

2 types : - Acute ,reversible

- Chronic and progressive/severeirreversible, co

madeath

The diagnosis of HE is usually one of exclusion.


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Classification of Hepatic Encephalopathy

World Conggres of Gastroenterology

1998

Hepatic

Encephalo

pathy

Type A(=acute)

HE associated with

Acute liver failure,typically

with cerebral edema

Type B(=bypass)

caused by portal systemicshunting without

associated with intrinsic

liver disease

Type C(=cirrhosis)

Occur in cirrhosis,Subdivided in:

Episodic,persistent,

minimal HE(MHE)

MHE,doesnot lead clinically overt cognitive dysfunction,can be demonstrated by neuropsychological studies.


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Pathogenesis

Endogenous Endotoxins

Increased permeability of BBB

Change in neurotransmitter and receptor

Others.

Endotoxins

Ammonia the main candidate of neurotoxin)

Mercaptans

Phenols

Short-chain and Mid-chain fatty acids.


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The Pathogenesis of HE

The primary source of amonia is the intestine,formed by protein

breakdown

Intestine Portal vein

NH3

Liverdetoxi

cation

Urea cycle

NH3

Kidney

urea

Normal

Intestine Portal veinLiverdetoxi

cation

incapable

Kidney

Cirrhosis

Porto sytemis shuntGI Bleeding

NH3 NH3

NH3

NH3

Brain

BBBFischers ratio


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Pathogenesis


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Precipitating Factors

Increased Nitrogen Load Electrolyte-Metab imbalance Drugs

Gastrointestinal bleding

Excess dietary protein

Azotemia

Constipation

Hypokalemia,alkalosisincre

ased renal production of NH4

Hypoxia

Hyponatremia

Hypervolemiareduced liver

metabolisme of ammoniaAcidosisinhibition of urea

synthesis.

Narcotics,CNS depression

Tranguilizer

Sedative

Diureticselectrolyte im-

balance and hypovolemia.

Others :

Infections,surgerySuperimposed liver disease

Portal systemic shunt


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mmonia

Healthy individuals have equilibrium between

production and detoxications.The main site of synthesis are :

- Intestine,small and large intestine

- Muscle

- Kidneymmonia Production

Small intestine,the gradation of glutamine

Large intestine,breakdown of urea and proteins by normalflora

Muscle,proportion to muscle work

Kidney,increased production when hypokalemia and diuretic

therapy


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mmonia

Production Detoxication

Liver,

-detoxified ammonia urea,glutamine

Brain,

-detoxified into glutamine and glutamate.

Small intestine,

-the degradation of glutamine

Large intestine,

-breakdown of urea&proteinsby normal flora

Muscle,

-proportion to muscle work

-degradation of glutamine

glutaminaseammonia.

Kidney,

increased production when:

-hypokalemia

-diuretic therapy


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Protein and HE Considerations

No valid clinical evidence supporting proteinrestriction in pts with acute ALF

Protein intake < 40g/day contributes to malnutritionand worsening ALF

Increased endogenous protein breakdown NH3

Susceptibiliy to infection increases under such

catabolic conditions


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How Much Protein:

That is the Question??

Grade III to IV hepatic encephalopathy

Usually no oral nutrition

Upon improvement, individual protein tolerance can be titrated bygradually increasing oral protein intake every three to five days from abaseline of 40 g/day

Oral protein not to exceed 70 g/day if pt has hx of hepaticencephalopathy

Below 70 g/day rarely necessary, minimum intake should not belower than 40 g/day to avoid negative nitrogen balance.

1.0g/kg/day protein, depending on degree of muscle wasting

BCAA-enriched solutions may benefit protein intolerant (


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How Much Protein:

That is the Question??

Up to 1.6g/kg/day protein as tolerated

Low-grade HE (minimal, I, II) should not becontraindication to adequate protein supply

In patients intolerant of a daily intake of 1 gprotein/kg, oral BCAA up to 0.25 g/kg may bebeneficialto create best possible nitrogen balance

BCAAs do not exacerbate encephalopathy

It should consider in patients with transjugularintrahepatic port systemic shunt( high incidence for HE)


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Management of HE

Treatment of precipitating factors

Diet

Intestinal Cleansing

Antibacteria

Ammonia metabolism, includes LOLA

Transplantation

The principal of Management of HE is to restore the balancebetween production and detoxication ox toxic substance


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L-Ornithine -L-aspartate LOLA)

LOLA is the stable salt of the aminoacids ornithine and

aspartic acid and has been shown to reduce blood ammo

nia concentration and improve psychometric performance

in patients with hyperammonia and HE , when given iv-ously.

L-Ornithine L-asprtate(LOLA) acts as substrat:

to stimulate the urea cycle(urea genesis) and

glutamine synthesis,degradation -ketoglutarate)

which are important mechanisms in ammoniadetoxification, and by that it is considered an ammonia

lowering treatment. Many clinical trials found that LOLA

improved hepatic encephalopathy better than placebo


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Alanine Transaminase (ALT)

Aspartate Transaminase(AST)The Urea Cycle

Transport of Ammonia to the liver for urea synthesis

Carrier of ammonia

-glutamine(most tissue)

-alanine (muscle)


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Proposed

Complex

Feedback

Mechanisms

In Treatment

Of HE

Th M d l ti i t i i id t b li


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GS

PAG

GlutamineGlutamate

NH3

NH3

Cell

Circulation

Hyperammonia

LOLA

Muscle

L-ornithine

Phenylacetatr(OP)Kidney

Phenylacetate/

Benzoate

GUTLIVER

L-arginine

Urea

Purgative

Probiotic

Dietary

GS =glutamine synthesis

PAG=phosphate activated glutaminase

Therapy Modulating interorgan ammonia ,aminoacid metabolism

Ammonia detoxication

Ammonia detoxication


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Effect of Lactulose and LOLA on Cirrh/PSE

Cirrhosis

and PSERandomization(n=20)

LOLA

Lactulose

Clinical assessment on days

1,7,14

Baseline clinical characteristic nearly the same(age,gender,grade cirrhosis,virus(C)

HE parameters :mental status,NCT,ammonia levels,asterixis )


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70

80

90

100

110

120

130

140

150

160

Baseline Week 1 Week 2

Lactulose

LOLA

Plasma Ammonia levels reduction compared to

baseline

P< 0,005


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Effect Lactulose and LOLA on PSE parameters

50

80

110

170

140

200


NCT

Lactulose Baseline Week1 Week2

188 177 155

LOLA 184 135 88

5

8

11

17

14

20


Asterixis

15 12 13

LOLA 14 12 6

Lactulose Baseline Week1 Week2

P


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Randomized double-blind placebo controlled

Prospective study on cirrhosis (n=60)

Cirrhosis

N=120

LOLA

(60)

Placebo

(60)

Lactulosa+Metronidazole

Infusion LOLA,daily 4 h,for 3 consecutive day

20 gr LOLA (4 amp of 10ml each),mixed in

250ml D5%

Infusion distiled water daily 4 h,for 3 consecu

tive day ,4 amp of 10ml each,mixed in

250ml D5%

Primary outcomes : improvement/deterioration of HEs grade(based on NCT,WH criteria)

Secondary outcomes: LOS,improvement of fasting ammonia levels,mortality rates

Improvement HE grade,definitely,it improves to 2 grade from baseline,partially only 1 grade


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The Result

0

20

40

60

80

100

Complete improvement

100%

50%

MHE

Grade

1Grade

2.

100%

78%

55%

Grade

3

83%

58%

Grade

4

72%

40%

LOLA

Placebo

P


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onclusion

The main candidate of toxic substance in the pathogenesis of HE is

ammonia.

The primary source of ammonia production is GI tract

The development of HE is due to the imbalance between the pro-

duction and the detoxication.

The principal management of HE is to restore the imbalance.

The first important in management is to manage the precipitatingfactor such as UGI bleeding,than to reduce the production,to im-

prove the metabolism of ammonia.

Cleansing of the bowel is still the main tool in management of HE.

LOLA was found safe as an adjuvant therapy in the management ofHE

LOLA showed significant improvement in patients with grade 1 or

MHE,and better outcome with advanced grade of HE compared to

placebo and similar result compare to lactulose.


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Treatment Strategies used in HE

HE grade I -II

I.. Ammonia lowering strategy

a.Dietary protein suppplementation

-high protein diet 1-1,5 protein /kg BW

-calory,25-40 kcal/kg BW/day

b.BCAA

-substrat protein synthesis,conserving restoring muscle mass-less protein intakedeficiency BCAAaccumulation AAAincrease false

neurotransmitter,permeability BBB

-metaanalysis had failed to find concensus

c.Probiotic,in critical ill and malnourisheddefensive bacteria declinebacterial translocasi

-action of probiotic:- influence on enterocytre glutaminase,reduce synthesa ammonium

-reduce bacterial translocation-modulate proinflammatory response

-modulate gut permeability

-bypass small bowel and get fermented by colonic bacteria to form

lactic acid,acetic and butiric acidexpulse ammoniogenic bacteria


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HE grade I -II


d.Purgative

-an agent which cleanses the bowel by increasing the evacuation of luminal contentsre

duce intestinal ammonia productionremain the most widely used therapy for HE.

1.Non-absorbable disaccharide,the mechanism of action ? maybe :

- enhanced growth of nonurease-producing bacteria- catharsis,secondary to bowel acidificationreducing ammonia absorption

- proliferation of healthy bacteria by providing additional carbohydrate and thus

nitrogen(even as ammonia) into protein

- providing carbon and energyspare bacterial ammonia metabolism

Lactulosa passes through the small bowel completely undigested;once in the colon,

lactulose is fermented by anerobic bacteri.yields important weak acidacidification ofammonia to ammonium which is poorly absorbed.

Aggressive use of lactuloseproduction of gas>>,discomfort,diarrhea


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HE grade I -II


e. Nonabsorbable antibioticNeomycin,Rifaximin

- inhibit the growth or to kill susceptible ammoniagenic bacterial species

-comparable with lactulose

f. Modulator interorgan Ammonia metabolism

In liver failure,the relative activities of cellular glutamine synthesis(GS)and phosphate acti-vated glutaminase (PAG) influence interorgan ammonia and amino acid metabolism.

With a loss of hepatic urea cycle capacity,hyperammonia is predominately due to worsening

intestinal and renal ammonia efflux,with skeletal muscle having the potential to increase its

ability to detoxify ammonia.

The Role of LOLA in HE

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