The Role of LOLA

In
Hepatic Encephalopathy

Hariadi M
PIT XIV IPD
Malang 17 Oktober
2014

Introduction
Hepatic Encephalopathy (HE) is a complex neuropsychiatric
syndrome 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.

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 systemic
shunting 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.

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.

The Pathogenesis of HE
The primary source of amonia is the intestine,formed by protein
breakdown
NH3

Normal

Intestine

NH3

urea

Portal vein
Liverdetoxi
cation
Urea cycle

NH3

NH3

Cirrhosis

Intestine

Portal vein

NH3
GI Bleeding

Porto sytemis shunt

Fischers ratio

Kidney

BBB

NH3

Brain

Liverdetoxi
cation
incapable

Kidney

Pathogenesis

Precipitating Factors
Increased Nitrogen Load

Electrolyte-Metab imbalance

Gastrointestinal bleding
Excess dietary protein
Azotemia
Constipation

Others :
Infections,surgery
Superimposed liver disease
Portal systemic shunt

Hypokalemia,alkalosisincre
ased renal production of NH4
Hypoxia
Hyponatremia
Hypervolemiareduced liver
metabolisme of ammonia
Acidosisinhibition of urea
synthesis.

Drugs
Narcotics,CNS depression
Tranguilizer
Sedative
Diureticselectrolyte imbalance and hypovolemia.

Ammonia
Healthy individuals have equilibrium between
production and detoxications.
The main site of synthesis are :
- Intestine,small and large intestine
- Muscle
- Kidney
Ammonia Production
Small intestine,the gradation of glutamine
Large intestine,breakdown of urea and proteins by normal
flora
Muscle,proportion to muscle work
Kidney,increased production when hypokalemia and diuretic
therapy

Ammonia
Production
Small intestine,
-the degradation of glutamine
Large intestine,
-breakdown of urea&proteins
by normal flora
Muscle,
-proportion to muscle work
-degradation of glutamine
glutaminaseammonia.
Kidney,
increased production when:
-hypokalemia
-diuretic therapy

Detoxication
Liver,
-detoxified ammonia urea,glutamine
Brain,
-detoxified into glutamine and glutama
te.

Protein and HE Considerations

No valid clinical evidence supporting protein
restriction in pts with acute ALF
Protein intake < 40g/day contributes to malnutrition
and worsening ALF
Increased endogenous protein breakdown NH3

Susceptibiliy to infection increases under such

catabolic conditions

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 by
gradually increasing oral protein intake every three to five days from a
baseline of 40 g/day
Oral protein not to exceed 70 g/day if pt has hx of hepatic
encephalopathy
Below 70 g/day rarely necessary, minimum intake should not be
lower 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 (<1g/kg)

How Much Protein:

That is the Question??
Up to 1.6g/kg/day protein as tolerated
Low-grade HE (minimal, I, II) should not be
contraindication to adequate protein supply

In patients intolerant of a daily intake of 1 g

protein/kg, oral BCAA up to 0.25 g/kg may be
beneficial to create best possible nitrogen balance
BCAAs do not exacerbate encephalopathy
It should consider in patients with transjugular
intrahepatic port systemic shunt( high incidence for HE)

Management of HE
The principal of Management of HE is to restore the balance
between production and detoxication ox toxic substance
Treatment of precipitating factors
Diet
Intestinal Cleansing
Antibacteria
Ammonia metabolism, includes LOLA
Transplantation

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 ammonia
detoxification, and by that it is considered an ammonia
lowering treatment. Many clinical trials found that LOLA
improved hepatic encephalopathy better than placebo

Transport of Ammonia to the liver for urea synthesis

The Urea Cycle

Carrier of ammonia
-glutamine(most tissue)
-alanine (muscle)

Aspartate Transaminase(AST)

Alanine Transaminase (ALT)

Proposed
Complex
Feedback
Mechanisms
In Treatment
Of HE

Therapy Modulating interorgan ammonia ,aminoacid metabolism

NH3
GS

Glutamate

Glutamine

Circulation

PAG
NH3

Hyperammonia
L-arginine

Cell

LOLA

Ammonia detoxicationMuscle

Purgative
Probiotic
Dietary

LIVER
GUT
Urea

L-ornithine
Phenylacetatr(OP)

Kidney

Phenylacetate/
Benzoate

GS =glutamine synthesis
PAG=phosphate activated glutaminase

Ammonia detoxication

Effect of Lactulose and LOLA on Cirrh/PSE

LOLA
Cirrhosis
and PSE

Randomization(n=20)

Clinical assessment on days

1,7,14

Lactulose

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

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

Plasma Ammonia levels reduction compared to

baseline
160
Lactulose

150
140

LOLA

130
120
110
P< 0,005

100
90
80
70

Baseline

Week 1

Week 2

200

20

170

17

Asterixis

NCT

Effect Lactulose and LOLA on PSE parameters

140

14

110

11

80

50

5
Baseline

Lactulose

LOLA

Week 1

Week 2

Baseline

Week1

188

177

155

184

135

88

P<0,005

Week2

Baseline

Week 1

Lactulose Baseline

LOLA

Week1

Week 2
Week2

15

12

13

14

12

P<0,005

Randomized double-blind placebo controlled

Prospective study on cirrhosis (n=60)
LOLA
(60)

Cirrhosis
N=120

Infusion LOLA,daily 4 h,for 3 consecutive day

20 gr LOLA (4 amp of 10ml each),mixed in
250ml D5%

Lactulosa+Metronidazole

Placebo
(60)

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

The Result
100%

100%

100

P<0,001
83%

80

78%

72%
58%
Grade
3

Grade
4

55%
Grade
2.

MHE

50%

Grade
1

60

40%

LOLA

Placebo

40

20

Partial improvement
MHE
Grade 1
Grade 2
Grade3
Grade 4

0
0
11
6
14

0
100
28
10
38

Complete improvement

No improvement/deterioration
P<0,001

MHE
Grade 1
Grade 2
Grade3
Grade 4

0
0
11
11
14

Significant drop in fasting ammonia was observed in LOLA group compared to the baseline
Signicant decrease of LOS in patients received LOLA

50
0
17
32
12

Conclusion
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 production and the detoxication.
The principal management of HE is to restore the imbalance.
The first important in management is to manage the precipitating
factor such as UGI bleeding,than to reduce the production,to improve 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 of
HE
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.

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 intake deficiency 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

Treatment Strategies used in HE

HE grade I -II
I.. Ammonia lowering strategy
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 of
ammonia to ammonium which is poorly absorbed.
Aggressive use of lactuloseproduction of gas>>,discomfort,diarrhea

Treatment Strategies used in HE

HE grade I -II
I.. Ammonia lowering strategy
e. Nonabsorbable antibiotic Neomycin,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 activated 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.