2Hepatic Encephalopathy (HE) - Definition Hepatic Encephalopathy (HE) is aMetabolically inducedPotentially reversibleFunctional disturbance of the brainOccurring with various degrees of severity secondarilyGrade 0-4Occurring in both acute and chronic liver diseases.ie. 70% in cirrhotic patientThe mainly cause is a metabolic disturbanceeg. Hyperammonemia
3Cirrhosis origins Hepatic Encephalopathy ~80% of patients with cirrhosis may suffer from Minimal HEChronic liver diseaseCirrhosisMinimal HEManifest HE(Pre)Coma~50% of patients with Minimal HE will progress towards manifest HE within the next 6 monthsThere 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
4Hepatic encephalopathy (HE) - Pathogenesis 1. Ammonia2. Neurotransmitters hypothesis2.1 Gamma-aminobutyric acid (GABA)2.2 Catecholamines and false neurotransmitters3. Aromatic-branched chain amino acid imbalance4. Short-chain fatty acids5. ManganeseThere 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).
5Development of hyperammonemia Normal stateHemodynamic causesMetabolic causesUreaGlutamineUreaGlutamineUreaGlutamineNH+4NH+4NH+4In 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.
6Detoxification 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
7Diagnostic possibilities in HE Evaluation of the clinical picture using West Haven criteriaFlicker 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 diagnosisLaboratory diagnostics to identify triggering factors:Blood count, Transaminases, Venous acid-base status, Urea, Creatinine
8HE severity according to West Haven criteria gradeState of consciousnessBehaviorNeuromuscularsymptomslatent /minimalClinically unremarkable butpsychometric tests pathologicalClinically unremarkable,but psychometric testspathologicalFine-motor impairmentIImpaired concentration and impairedreaction speed disturbances,tiredness (decreased vigilance)Changes in personalityFine-motor impairmentIISlowing, lethargyConspicuous changes inpersonality, temporaldisorientationAsterixis, slurred speechIIIDisorientation, somnolence,stuporBizarre behavior,delusionsHyperreflexia and hypo-reflexia, asterixis, spasmsUnder 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.IVComaAbolishedAreflexia, loss of toneModified from the original in Conn H. O. and Bircher J. in: Hepatic encephalopathy: Syndromes and Therapies, 13-26, 1994
9Child-Pugh classification of the stages of cirrhosis ParameterNumber of points123EncephalopathyGrade 0Grade I/IIGrade III/IVBillirubin (mg/dl) or22-3>3Billirubin (µmol/l)(≤ 34)(34-51)(>51)Albumin (g/dl)> 3.5< 2.8Prothrombin time(seconds above norm)1-34-6> 6or INR< 1.7> 2.3The 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).
11Critical Flicker Frequency device (CFF) Close correlation between CFF and severity of HEStatistically significant correlation between CFF and psychometric testsGood correlation between CFF and arterial ammonia concentrationResults not dependent on patient’s educational level; no training effects
13Non-absorbable disaccharides LactuloseDose: g/dTitrate to achieve 2-3 soft stool per day or stool pH < 6Route: oral or enema* (the comparison of efficacy is unclear)Efficacy: 70-80%Tolerability: goodSide effects: cramping, diarrhea, flatulenceFerenci P, Herneth, A, Steindl, P. Semin Liver Dis 1996; 16:329Conn, HO, et al. Gastroenterology 1977; 72:573
14Non-absorbable disaccharides Cochrane meta-analysis 2004Thirty randomized trialsNo 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 effectsInferior to antibiotics on improvement of HE; RR 1.24 ( ,10 trials)
15Oral antibiotics ATB Trials Dose Efficacy AE Neomycin Lactulose, Placebomg/kg/d?, -Ototoxicity andNephrotoxicityMetronidazole400 mg bid=PeripheralneuropathyVancomycinLactulose250 mg qid= / +noneParamomycin4 g/dRifaximinLactulose, Lactitol1,200-2,400 mg/dStrauss 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.
16Branched-chain amino acid Meta-analysis 2004More rapid mental recoveryUnclear result on mortalityAll studies were short durationShould not consider standard treatmentNaylor, CD, et al. A meta- analysis. Gastroenterology 1989; 97:1033
17ProbioticsOne RCT, N=97, minimal HE (MHE)Probiotic vs Fermentable fiber vs PlaceboProbiotic significant increased the fecal content of non-urease-producing Lactobacillus species, reduce blood ammonia and reverse mHE about 50%
22PharmacokineticsL-Ornithine-L-Aspartate is rapidly absorbed and cleavelaged into L-Ornithine and L-AspartateElimination half life of each amino acid is short approximately 40 minBioavailability is 82.2 28% after Infusion or oral administrationSome L-Aspartate appear unchanged in the urine.
23Effect of ornithine on urea synthesis: Substrate of urea synthesis in urea cycleActivator of carbamoyl phosphate synthetase
24Effect of aspartate on glutamine synthesis Substrate in glutamine synthesisCombining of Citrulline to Arginino-Succinate in Urea Cycle
25Action mechanism of L-ornithine L-aspartate (OA) ActivatedHäussinger, 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)
27Clinical data of Infusion Lowering of ammonia by OA infusionAdministration of 20 g OA i.v. (5 g/h)100p < 0.0283817780Fasting ammonia levels μmolN=12663 = LOLA63 = Placebo6460L-ornithine L-aspartatePlacebo40Day 0Day 7Kircheis G., Nilius R., Held C. et al., Hepatology 25: 1351–1360, 1997
28Clinical data of Infusion Improvement in HE as a result of OA infusionKircheis G., Nilius R., Held C. et al., Hepatology 25: 1351–1360, 1997
29Clinical data of Granules Lowering of ammonia by OA granulesAdministration of 3 x 6 g OA granules100p < 0.0193828280N=6634 = LOLA32 = PlaceboFasting ammonia levels (µmol/l)60L-ornithine L-aspartate52Placebo40Day 0Day 14Stauch S., Kircheis G., Adler G. et al., Hepatology 28: 856–864, (1998)
30Decreased of Serum ammonia Oral LOLA Vs lactuloseLOLA versus LactuloseOnly LOLA groupHas better improvement inMental statusNCTAsterixisEEGLOLALactuloseDecreased of Serum ammoniaJL Poo; J Góngora; F Sánchez-Ávila et al. Annals of Hepatology 5(4) 2006:
31SummaryTherapeutic 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.
33Indication of Hepa-Merz For the treatment of hyperammonemia as a result of acute and chronic liver diseases such asliver cirrhosis,fatty liver,hepatitis;Especially for the treatment of incipient disturbances of consciousness (pre-coma) or neurological complications (hepatic encephalopathy)Product Insert
34Indications and Dosage Granules:Treatment in mHE, sHE, HE I , HE II, IIIContaining L-ornithine-L-aspartate 3.0g / 5g / Sachet1-2 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
35Indications and Dosage Infusion Concentrate:HE III, HE IV, Pre Coma, ComaContaining L-ornithine-L-aspartate 5.0g / 10ml / AmpouleDosage 1-4 Amp per dayPre-coma and Coma Up to 8 Amp within 24 Hrs depend on the severity of the conditionMax infusion Rate = 5 Gm/ HourMax Conc. = 6 Amp/ 500 mlInfusion solutions to Mix up; Normal saline, Dextrose, Lactate ringer, Sucrose. etc.
36ToxicologyToxicological 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/ kgReproduction studies on mutagenicity found no abnormalities. There is no need to suspect any carcinogenic potential
37Safety and Tolerability No case of serious adverse drug reaction5% of mild gastro-intestinal disturbance i.e, (nausea vomiting) with infusion therapyNausea is occasional occurred on infusion therapy, with vomiting rarelySymptoms are transient and reversible with reduction of dose or rate of infusionMax rate of infusion is 5 gm (1 Amp) of Hepa-Merz® inf. concentrate per hour is recommended
38Hepa-Merz Contra-indication Due to Hepa-Merz® mechanism-increase formation of Urea and eliminate by kidneyHepa-Merz® is not recommended for patient with severe renal functionSevere renal function = Creatinine level > 3 mg / dl