1. Hepatic Encephalopathy
Hepa-Merz®
Hepatic Encephalopathy

2. 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

3. 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
There are some 20 million people with chronic liver disease worldwide. According to a WHO report published in 2004, liver diseases rank among the ten most common causes of death. Around 14 million people have cirrhosis of the liver. This is the fifth commonest cause of death in the age group, and a more common cause of death than ischemic heart disease in the age group. On average up to 40% of patients develop manifest hepatic encephalopathy in the course of cirrhosis of the liver. The probability of 5 years’ survival for cirrhosis patients with HE is very low (16-22%) compared to that of cirrhosis patients without HE. The frequency of latent hepatic encephalopathy is between 30 and 70%. Latent hepatic encephalopathy (minimal HE) often goes unrecognized because “verbal intelligence” is not affected.
Using the results of psychometric tests, Schomerus et al. showed that 50% of patients with latent hepatic encephalopathy are not fit to drive a motor vehicle. The fitness to drive of a further 25% was questionable (Schomerus et al., Dig. Dis. Sci., 26, 7: , 1981).
Ref. Schomerus et al., Dig. Dis. Sci., 26, 7: , 1981

4. 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
There are some 20 million people with chronic liver disease worldwide. According to a WHO report published in 2004, liver diseases rank among the ten most common causes of death. Around 14 million people have cirrhosis of the liver. This is the fifth commonest cause of death in the age group, and a more common cause of death than ischemic heart disease in the age group. On average up to 40% of patients develop manifest hepatic encephalopathy in the course of cirrhosis of the liver. The probability of 5 years’ survival for cirrhosis patients with HE is very low (16-22%) compared to that of cirrhosis patients without HE. The frequency of latent hepatic encephalopathy is between 30 and 70%. Latent hepatic encephalopathy (minimal HE) often goes unrecognized because “verbal intelligence” is not affected.
Using the results of psychometric tests, Schomerus et al. showed that 50% of patients with latent hepatic encephalopathy are not fit to drive a motor vehicle. The fitness to drive of a further 25% was questionable (Schomerus et al., Dig. Dis. Sci., 26, 7: , 1981).

5. Development of hyperammonemia
Normal state
Hemodynamic causes
Metabolic causes
Urea
Glutamine
Urea
Glutamine
Urea
Glutamine NH + 4 NH + 4 NH + 4
In the liver, ammonia is detoxified mainly by the synthesis of urea and glutamine. These two detoxification pathways are arranged complementarily and sequentially in the liver acini. Whilst periportal hepatocytes have only a low affinity for ammonia detoxification through urea synthesis, glutamine synthesis occurs exclusively in a small (around 5-10% of all liver parenchyma cells), highly specialized cell population at the perivenous end of the liver acini. These cells (perivenous scavenger cells) are of particular importance for maintaining ammonium homeostasis, as they have high affinity for removing ammonia through glutamine synthesis and therefore serve as a collection system for ammonia that has not been detoxified via upstream urea synthesis. In patients with cirrhosis of the liver two factors impair ammonia detoxification, resulting in hyperammonemia:
- Ammonia formed in the intestine is channeled past the liver by portosystemic collateral circulation.
- The urea-synthesizing capacity of the cirrhotic liver is reduced by over 80%. The same applies to its glutamine-synthesizing capacity, as cirrhosis patients have a severe scavenger-cell deficiency.
Impaired detoxification of ammonia in the liver is partly compensated by increased ammonia uptake in muscles, the muscles’ capacity for ammonia elimination correlating with the muscle mass available.
Ref. Häussinger D. und Gerok W. in: Hepatologie (Hrsg. Gerok W. und Blum H.E.), S. 847,1995.

6. Detoxification of ammonia in the liver
The glutaminase reaction and urea synthesis take place in periportal hepatocytes, whilst glutamine synthesis takes place in a small population of perivenous hepatocytes (scavenger cells) surrounding the central vein. Glutaminase is activated by ammonia and makes ammonia available in the mitochondria, pH- and hormone-dependently, for activation of the urea cycle. This remarkable property of glutaminase, namely its activation by its own product ammonia, makes glutaminase a pH- and hormone-regulated booster of ammonia. Adequate activation of urea synthesis in the periportal hepatocytes is only possible because of this booster effect.
In the periportal-hepatocyte compartment, ammonia is detoxified by a system having a high capacity but low affinity for ammonia. When sufficient quantities of ammonia and ornithine are present, ammonia and HCO3- in the presence of the enzyme carbamoyl phosphate synthetase give a reactive form, carbamoyl phosphate. Carbamoyl phosphate and ornithine form the amino acid citrulline with the aid of the enzyme carbamoyl phosphate transferase. Citrulline is then converted into arginine, and urea splits off with re-formation of ornithine.
Ammonia not detoxified in the urea cycle is detoxified in the perivenous hepatocytes, also known as scavenger cells, through glutamine synthesis. These cells scavenge ammonium ions which have escaped detoxification by urea synthesis, with high affinity (scavenger cells). With the aid of the enzyme glutamine synthetase, glutamate is converted into nontoxic glutamine by coupling with ammonia. The glutamine formed compensates for the consumption of glutamine needed periportally for the activation of the urea cycle.
Overall, glutamine is not used up in detoxification of ammonia (intracellular glutamine cycle).
Häussinger, D., Biochem. J. 267: 281–290, 1990

7. 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

8. HE severity according to West Haven criteria
grade
State of consciousness
Behavior
Neuromuscular
symptoms
latent /
minimal
Clinically unremarkable but
psychometric tests pathological
Clinically unremarkable,
but psychometric tests
pathological
Fine-motor impairment I
Impaired concentration and impaired
reaction speed disturbances,
tiredness (decreased vigilance)
Changes in personality
Fine-motor impairment II
Slowing, lethargy
Conspicuous changes in
personality, temporal
disorientation
Asterixis, slurred speech
III
Disorientation, somnolence,
stupor
Bizarre behavior,
delusions
Hyperreflexia and hypo-
reflexia, asterixis, spasms
Under the West Haven criteria, hepatic encephalopathy is divided into five grades of severity on the basis of clinical symptoms and signs and psychometric test findings. The classification is based primarily on the patient’s mental status. The grades run from HE grade 0, in which there is no impairment of consciousness, to HE grade IV, in which there is severe coma. IV
Coma
Abolished
Areflexia, loss of tone
Modified from the original in Conn H. O. and Bircher J. in: Hepatic encephalopathy: Syndromes and Therapies, 13-26, 1994

9. Child-Pugh classification of the stages of cirrhosis
Parameter
Number of points 1 2 3
Encephalopathy
Grade 0
Grade I/II
Grade III/IV
Billirubin (mg/dl) or 2
2-3
>3
Billirubin (µmol/l)
(≤ 34)
(34-51)
(>51)
Albumin (g/dl)
> 3.5
< 2.8
Prothrombin time
(seconds above norm)
1-3
4-6
> 6
or INR
< 1.7
> 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).

10. Number Connection Test (NCT)
Grade 0 15–30 seconds
Grade 1 31–50 seconds
Grade 2 51–80 seconds
Grade 3 81–120 seconds
Grade 4 >120
(test cannot be carried out)

11. 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 patient’s educational level; no training effects

12. 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

13. Non-absorbable disaccharides
Lactulose
Dose: 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

14. Non-absorbable disaccharides
Cochrane meta-analysis 2004
Thirty randomized trials
No effect on mortality; RR 0.41( , 4 trials)
Improvement of HE; RR 0.62 ( , 6 trials)
No improvement of HE; RR 0-92 ( , 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 ( ,10 trials)

15. Oral antibiotics ATB Trials Dose Efficacy AE Neomycin Lactulose,
Placebo
mg/kg/d
?, -
Ototoxicity and
Nephrotoxicity
Metronidazole
400 mg bid =
Peripheral
neuropathy
Vancomycin
Lactulose
250 mg qid
= / +
none
Paramomycin
4 g/d
Rifaximin
Lactulose, Lactitol
1,200-2,400 mg/d
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.

16. 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

17. Probiotics
One RCT, N=97, minimal HE (MHE)
Probiotic vs Fermentable fiber vs Placebo
Probiotic significant increased the fecal content of non-urease-producing Lactobacillus species, reduce blood ammonia and reverse mHE about 50%

18. Therapeutic principle

19. Introducing (L-ornithine-L-aspartate)
Hepa-Merz

20. Hepa-Merz® Granules

21. Hepa-Merz® Infusion Concentrate

22. 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.

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

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

25. Action mechanism of L-ornithine L-aspartate (OA)
Activated
Häussinger, D., Biochem. J. 267: 281–290, 1990

26. (Represent in some of published clinical studies)
The role of L-ornithine-L-aspartate (Hepa-Merz®) in the treatment of HE
(Represent in some of published clinical studies)

27. Clinical data of Infusion
Lowering of ammonia by OA infusion
Administration of 20 g OA i.v. (5 g/h)
100
p < 0.02 83 81 77 80
Fasting ammonia levels μmol
N=126
63 = LOLA
63 = Placebo 64 60
L-ornithine L-aspartate
Placebo 40
Day 0
Day 7
Kircheis G., Nilius R., Held C. et al., Hepatology 25: 1351–1360, 1997

28. Clinical data of Infusion
Improvement in HE as a result of OA infusion
Kircheis G., Nilius R., Held C. et al., Hepatology 25: 1351–1360, 1997

29. Clinical data of Granules
Lowering of ammonia by OA granules
Administration of 3 x 6 g OA granules
100
p < 0.01 93 82 82 80
N=66
34 = LOLA
32 = Placebo
Fasting ammonia levels (µmol/l) 60
L-ornithine L-aspartate 52
Placebo 40
Day 0
Day 14
Stauch S., Kircheis G., Adler G. et al., Hepatology 28: 856–864, (1998)

30. Decreased of Serum ammonia
Oral LOLA Vs lactulose
LOLA versus Lactulose
Only LOLA group
Has better improvement in
Mental status
NCT
Asterixis
EEG
LOLA
Lactulose
Decreased of Serum ammonia
JL Poo; J Góngora; F Sánchez-Ávila et al. Annals of Hepatology 5(4) 2006:

31. 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.

32. Hepa-Merz® General Information's

33. 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

34. 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

35. 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.

36. 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

37. 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

38. 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

39. Interaction with Other Medications
None Known

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