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Hepa-Merz

Hepatic Encephalopathy

Hepatic Encephalopathy (HE) - Definition


Hepatic Encephalopathy (HE) is a
Metabolically induced Potentially reversible Functional disturbance of the brain

Occurring with various degrees of severity secondarily


Grade 0-4

Occurring in both acute and chronic liver diseases.


ie. 70% in cirrhotic patient

The mainly cause is a metabolic disturbance


eg. Hyperammonemia

Cirrhosis origins Hepatic Encephalopathy


~80% of patients with cirrhosis may suffer from Minimal HE

Chronic liver disease

Cirrhosis

Minimal HE

Manifest HE

(Pre)Coma

~50% of patients with Minimal HE will progress towards manifest HE within the next 6 months
Ref. Schomerus et al., Dig. Dis. Sci., 26, 7: 622-30, 1981

Hepatic encephalopathy (HE) - Pathogenesis


1. Ammonia 2. Neurotransmitters hypothesis
2.1 Gamma-aminobutyric acid (GABA) 2.2 Catecholamines and false neurotransmitters

3. Aromatic-branched chain amino acid imbalance 4. Short-chain fatty acids 5. Manganese

Development of hyperammonemia
Normal state Hemodynamic causes Metabolic causes

Urea Glutamine NH + 4

Urea Glutamine NH + 4

Urea Glutamine NH + 4

Ref. Hussinger D. und Gerok W. in: Hepatologie (Hrsg. Gerok W. und Blum H.E.), S. 847,1995.

Detoxification of ammonia in the liver

Hussinger, D., Biochem. J. 267: 281290, 1990

Diagnostic possibilities in HE
Evaluation of the clinical picture using West Haven criteria Flicker frequency analysis (critical flicker frequency, CFF) Determination of mental status:
Psychometric tests (e.g. ZVT, LNT, ZST, handwriting)

Neurological investigations:
EEG, MRI, Evoked potentials (eg. Asterixis)

Differential diagnosis Laboratory diagnostics to identify triggering factors:


Blood count, Transaminases, Venous acid-base status, Urea, Creatinine

HE severity according to West Haven criteria

HE State of consciousness grade


latent / Clinically unremarkable but minimal psychometric tests pathological I

Behavior

Neuromuscular symptoms
Fine-motor impairment

Clinically unremarkable, but psychometric tests pathological Impaired concentration and impaired Changes in personality reaction speed disturbances, tiredness (decreased vigilance) Slowing, lethargy Conspicuous changes in personality, temporal disorientation Bizarre behavior, delusions Abolished

Fine-motor impairment

II

Asterixis, slurred speech

III IV

Disorientation, somnolence, stupor Coma

Hyperreflexia and hyporeflexia, asterixis, spasms Areflexia, loss of tone

Modified from the original in Conn H. O. and Bircher J. in: Hepatic encephalopathy: Syndromes and Therapies, 13-26, 1994

Child-Pugh classification of the stages of cirrhosis

Parameter 1 Encephalopathy Grade 0

Number of points 2 Grade I/II 3 Grade III/IV

Billirubin (mg/dl)
Billirubin (mol/l)

or

2
( 34)

2-3
(34-51)

>3
(>51)

Albumin (g/dl)
Prothrombin time (seconds above norm) or INR

> 3.5
1-3 < 1.7

2.8-3.5
4-6 1.8-2.3

< 2.8
>6 > 2.3

The Child-Turcotte criteria, modified from Pugh. The points are added to arrive at the Child-Pugh stage: A (5-6 points), B (7-9), or C (10-15).

Number Connection Test (NCT)

Grade 0 1530 seconds Grade 1 3150 seconds Grade 2 5180 seconds Grade 3 81120 seconds Grade 4 >120 (test cannot be carried out)

Critical Flicker Frequency device (CFF)


Close correlation between CFF and severity of HE Statistically significant correlation between CFF and psychometric tests Good correlation between CFF and arterial ammonia concentration Results not dependent on patients educational level; no training effects

Treatment of Hepatic Encephalopathy options


Evaluate dietary protein Eliminating or remove precipitating factors Drug therapy
Non-absorbable disaccharides (eg. Lactulose, Lactitol) L-ornithine-L-aspartate (LOLA) Branched-chain amino acid (BCAA) Oral antibiotics Flumazenil Probiotics Zinc

Liver transplant

Non-absorbable disaccharides

Lactulose
Dose: 45-90 g/d Titrate to achieve 2-3 soft stool per day or stool pH < 6 Route: oral or enema* (the comparison of efficacy is unclear) Efficacy: 70-80% Tolerability: good Side effects: cramping, diarrhea, flatulence

Ferenci P, Herneth, A, Steindl, P. Semin Liver Dis 1996; 16:329 Conn, HO, et al. Gastroenterology 1977; 72:573

Non-absorbable disaccharides
Cochrane meta-analysis 2004
Thirty randomized trials No effect on mortality; RR 0.41(0.02-8.68, 4 trials) Improvement of HE; RR 0.62 (0.46-0.84, 6 trials) No improvement of HE; RR 0-92 (0.42-2.04, 2 high quality trials) No significant difference between lactulose and lactitol on mortality (2 trials) or improvement of HE (4 trials) but lactitol had fewer side effects Inferior to antibiotics on improvement of HE; RR 1.24 (1.021.50,10 trials)

Oral antibiotics

ATB Neomycin

Trials Lactulose, Placebo

Dose 50-100 mg/kg/d

Efficacy ?, -

AE Ototoxicity and Nephrotoxicity

Metronidazole
Vancomycin Paramomycin Rifaximin

Lactulose, Neomycin
Lactulose Lactulose Lactulose, Lactitol

400 mg bid
250 mg qid 4 g/d 1,200-2,400 mg/d

=
=/+ = =

Peripheral neuropathy
none none none

Strauss E, et al. Hepatogastroenterology 1992; 39:542. Tarao, K, et al. Gut 1990; 31:702. Bucci, L, Palmieri, GC. Curr Med Res Opin 1993; 13:109. Williams, R, et al. Eur J Gastroenterol Hepatol 2000; 12:203.

Branched-chain amino acid


Meta-analysis 2004
More rapid mental recovery Unclear result on mortality All studies were short duration Should not consider standard treatment

Naylor, CD, et al. A meta- analysis. Gastroenterology 1989; 97:1033

Probiotics
One RCT, N=97, minimal HE (MHE) Probiotic vs Fermentable fiber vs Placebo

Probiotic significant increased the fecal content of nonurease-producing Lactobacillus species, reduce blood ammonia and reverse mHE about 50%

Therapeutic principle

Hepa-Merz
(L-ornithine-L-aspartate)

Introducing

Hepa-Merz Granules

Hepa-Merz Infusion Concentrate

Pharmacokinetics
L-Ornithine-L-Aspartate is rapidly absorbed and cleavelaged into L-Ornithine and L-Aspartate Elimination half life of each amino acid is short approximately 40 min Bioavailability is 82.2 28% after Infusion or oral administration Some L-Aspartate appear unchanged in the urine.

Ornithine
Effect of ornithine on urea synthesis:
Substrate of urea synthesis in urea cycle Activator of carbamoyl phosphate synthetase

Aspartate
Effect of aspartate on glutamine synthesis
Substrate in glutamine synthesis Combining of Citrulline to Arginino-Succinate in Urea Cycle

Action mechanism of L-ornithine L-aspartate (OA)

Activated

Hussinger, D., Biochem. J. 267: 281290, 1990

The role of L-ornithine-L-aspartate (Hepa-Merz) in the treatment of HE


(Represent in some of published clinical studies)

Clinical data of Infusion Lowering of ammonia by OA infusion


Administration of 20 g OA i.v. (5 g/h)
100 Fasting ammonia levels mol
p < 0.02

81 80

83 77 64
N=126 63 = LOLA 63 = Placebo

60

L-ornithine L-aspartate Placebo

40 Day 0 Day 7

Kircheis G., Nilius R., Held C. et al., Hepatology 25: 13511360, 1997

Clinical data of Infusion Improvement in HE as a result of OA infusion

Kircheis G., Nilius R., Held C. et al., Hepatology 25: 13511360, 1997

Clinical data of Granules Lowering of ammonia by OA granules


Administration of 3 x 6 g OA granules
Fasting ammonia levels (mol/l) 100 82 80
N=66 34 = LOLA 32 = Placebo

93

p < 0.01

82

60 52

L-ornithine L-aspartate Placebo

40 Day 0 Day 14

Stauch S., Kircheis G., Adler G. et al., Hepatology 28: 856 864, (1998)

Oral LOLA Vs lactulose

LOLA versus Lactulose

Only LOLA group Has better improvement in


LOLA

Lactulose

Mental status NCT Asterixis EEG

Decreased of Serum ammonia

JL Poo; J Gngora; F Snchez-vila et al. Annals of Hepatology 5(4) 2006: 281-288

Summary
Therapeutic administration of L-ornithine L-aspartate (Hepa-Merz) increases ammonia detoxification in two ways:
Activation of the urea cycle in the liver, through provision of the metabolic substrates ornithine and aspartate. The substrates ornithine and aspartate promote glutamine formation, thereby stimulating ammonia detoxification via glutamine synthesis in the liver, in the brain, and in muscle.

Hepa-Merz General Information's

Indication of Hepa-Merz
For the treatment of hyperammonemia as a result of acute and chronic liver diseases such as
liver cirrhosis, fatty liver, hepatitis;

Especially for the treatment of incipient disturbances of consciousness (pre-coma) or neurological complications (hepatic encephalopathy)

Product Insert

Indications and Dosage


Granules:
Treatment in mHE, sHE, HE I , HE II, III Containing L-ornithine-L-aspartate 3.0g / 5g / Sachet

1-2 Sachets up to 3 times a day (upon severity of symptom) Dissolve granules in 1 glass of water, tea of juice and drink after meal

Indications and Dosage


Infusion Concentrate:
HE III, HE IV, Pre Coma, Coma Containing L-ornithine-L-aspartate 5.0g / 10ml / Ampoule Dosage 1-4 Amp per day Pre-coma and Coma Up to 8 Amp within 24 Hrs depend on the severity of the condition Max infusion Rate = 5 Gm/ Hour Max Conc. = 6 Amp/ 500 ml Infusion solutions to Mix up; Normal saline, Dextrose, Lactate ringer, Sucrose. etc.

Toxicology
Toxicological tests of L-Ornithine-L-Aspartate on rats and dogs following single and repeated dose of infusion over 4 week gave no effect at level of approx. 1,500 mg/ kg Reproduction studies on mutagenicity found no abnormalities. There is no need to suspect any carcinogenic potential

Safety and Tolerability


No case of serious adverse drug reaction 5% of mild gastro-intestinal disturbance i.e, (nausea vomiting) with infusion therapy Nausea is occasional occurred on infusion therapy, with vomiting rarely Symptoms are transient and reversible with reduction of dose or rate of infusion Max rate of infusion is 5 gm (1 Amp) of Hepa-Merz inf. concentrate per hour is recommended

Hepa-Merz Contra-indication
Due to Hepa-Merz mechanism-increase formation of Urea and eliminate by kidney Hepa-Merz is not recommended for patient with severe renal function
Severe renal function = Creatinine level > 3 mg / dl

Interaction with Other Medications


None Known

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