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Hepatic Encephalopathy
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
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.
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)
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
III IV
Modified from the original in Conn H. O. and Bircher J. in: Hepatic encephalopathy: Syndromes and Therapies, 13-26, 1994
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).
Grade 0 1530 seconds Grade 1 3150 seconds Grade 2 5180 seconds Grade 3 81120 seconds Grade 4 >120 (test cannot be carried out)
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
Efficacy ?, -
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.
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
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
Activated
81 80
83 77 64
N=126 63 = LOLA 63 = Placebo
60
40 Day 0 Day 7
Kircheis G., Nilius R., Held C. et al., Hepatology 25: 13511360, 1997
Kircheis G., Nilius R., Held C. et al., Hepatology 25: 13511360, 1997
93
p < 0.01
82
60 52
40 Day 0 Day 14
Stauch S., Kircheis G., Adler G. et al., Hepatology 28: 856 864, (1998)
Lactulose
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.
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
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
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
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
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