Role of Branched Chain Amino Acids in the Management of Hepatic Encephalopathy

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Role of Branched Chain Amino Acids in the Management of Hepatic Encephalopathy
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  World Journal of Medical Sciences 3 (2): 60-64, 2008ISSN 1817-3055© IDOSI Publications, 2008 Corresponding Author: Prof. G.Ali Qureshi, Department of Biochemistry, University of Health Sciences,Khayaban-i- Jamia Punjab, Lahore, Pakistan 60 Role of Branched Chain Amino Acids in the Management of Hepatic Encephalopathy  Aftab Ahmed Soomro, Bikha Ram Devrajani, Rafi A. Ghori, Haresh Lohana and G. Ali Qureshi 11112 Department of Medicine, Liaquat University of Medical and Health Sciences Hyderabad/Jamshoro, Pakistan 1 Department of Biochemistry, University of Health Sciences, Khayabane Jamia Punjab, Lahore, Pakisan 2 Abstract: To know the association of branched chain amino acids (BCAA) in the management of hepaticencephalopathy. Prospective, comparative, non randomized open study. This study was conducted in MedicalUnit-4, LUMHS, Hyderabad, Pakistan from January 2007to October 2007 in indoor patients. Forty Eight (48)cases of chronic hepatic encephalopathy were included for the study.24 patients were kept on branch chainamino acids and 24 patients were on control group. All investigations were done in all cases for the diagnosisand the classification of Chronic Liver Diseases (CLD) including ammonia and serum albumin level. SerumAmmonia and serum albumin level on admission day and sixth day and after four months were done. Recoveryandreoccurrence of hepatic encephalopathy were compared on patients who were on brand chain amino acidsgiven initially intravenously then kept on oral amino acids with those of control group without aminoleban.Those who were on aminoleban showed early improvement and recovery from hepatic encephapathy andsubsequently on follow up visits at four months. Ammonia level which was initially raised decreasedsubsequently on sixth day and on fouth month. And their albumin level also increased at four month follow upcompared to patients who did not received aminoleban. On grounds of above study we recommended branchedamino acids for the treatment and prevention of chronic hepatic encephalopathy. Key words: Hepatic EncephalopathyChronic Liver Disease Aminoleban Branched chain Amino Acids INTRODUCTION low in amino acids as a preparation of treating hepaticThe Major mechanism of hepatic encephalopathySevere HE may be reversed by a nutritional approachdue to liver cirrhosis currently attracting involves thebased on the administration of consistent amount of intoxication and neurotransmitter theories [1,2]. TheBCAA [1].representative agents of intoxication are ammonia,Malnutritionis a common feature of chronic liver methanethiol, phenol and short chain fatty acids. Thefailure CLF. Nutrient requirement is increased because of neurotransmitter theory can be divided into thepresence of a hypercatabolic state [2]. moreover foodfollowing two categories depending upon the types ofdigestion and the absorption are often incomplete [3].aminoacids as the amino acid-neurotransmitter theoryTheincreased muscle protein degradation coupledandgamma aminobutyric (GABA) theory [3,4]. Fischerwith impaired liver function induces a profound alterationand Baldessarini, proponents of the amino acid–of the plasma AA pattern characterized by an elevation inneurotransmitter theory. In patients suffering from hepaticaromatic amino acid AAA phenylalanine (PHE), tyrosineencephalopathy plasma concentration of aromatic amino(TYR) and tryptophan (TRP) and a reduction in branchedacids (AAA) such as phenylalanine, tyrosine and freeamino acids AA (BCAA), valine (VAL), leucine (LEU) andtryptophan, as well as methionine, aspartic acid andisoleucine (ILEU) level [18]. These changes in the plasmaglutamic acid are elevated where as branched amino acidsAA profile very likely play a key role in the pathogenesis(BCAA’s)such as leucine, isoleucine and valine areof HE and may therefore be responsible for the proteindecreased [5]. These researchers suggested that theintolerance seen in CLF patients [19]. Plasma and braincondition would be improved if the plasma amino acidsaccumulation of AAA may in fact cause a severewerenormalized [6]. They then developed an amino acidimpairment of brain neurotransmitter synthesis, in turnsolution (Fischer’s solution) enriched in BCAA’s andcausing HE [20,21]. The decrease in plasma BCAA, whichencephalopathy[7].  World J. Med. Sci., 3 (2): 60-64, 2008 61compete with AAA for the blood brain transport [22],Inboth groups i.e. group I on conventional therapycontributes greatly to the accumulation of AAA in theand group II on conventional as well as on BCCA,their  brain [17]. Fischer and colleagues have proposed an AAAstatus regarding prothombin time, Albumin level andmixture.serum ammonia level in patients were as follows:BCAA are metabolically very active. In the peripheralThe difference of Prothrombin time in 8 patients wastissues they may be oxidized to produce energy [24] or3 to 6 seconds from control where as > 6 seconds inmay be act as antictabolic factors (particularly leucine) by6 patients were noted in each group.In both group out of stimulating the synthesis and reducing the degradation of24 patients S. albumin level was <2.8mg/dl seen inmuscle protein [25,26]. Indeed, in patients with chronic16 patients and S. albumin level between 2.8 and 3.1mg/dlliver failure (CLF) i.v. BCAA decrease AA and ammoniawere noted in remaining 6 patients. S. albumin and plasma concentrations [27]. BCAA, by competing withS.ammonia level were done on admission day, on 6 dayAAAfor blood brain transport [22], may reduce brainand at 4 months in both groups.entry of AAA.Sincethe first report by Fischer et al [22] a large Data Analysis: The data were evaluated in SPSS versionnumber of aneedotal studies have been carried out which16.0 the Fisher’s exact and Pearson’s chi-square test wasclearly show that severe HE may rapidly reversed by theapplied among the categorical variable and independenti.v. administration of AA mixtures enriched withsamples T test was applied to compare the means amongBCAA[29,33]. These findings have been subsequentlycontinuous variable. The p value < 0.05 was considered asconfirmed by at least 5 randomized, controlled trials [34].statically significant level. PATIENTS AND METHODSRESULTS Thepatients with decompensated Liver cirrhosisRecoveryand recurrence of hepatic encephalopathy(LC), who met the following study criteria werewerecompared on patients who were on BCAA givenenrolled in the patient study.:All the cases of hepaticinitially intravenously than orally with those of groupencephalopathyGrade II coma or a history of hepaticwithout BCAA. Those who were on BCAA showed earlyencephalopathy having HBV and HCV. Both males andimprovement and recovery and subsequently on followfemales were enrolled. Before the start of the study anup visits at four months. They not only showedinformedconsent was obtained from the patients.improvement as for as their ammonia level is concernedOut of 48 patients enrolled, they were dividedwhich was initially raised but ammonia level decreasedinto two groups Group-1 and Group 2, 24 patients weresubsequently at 6 day and on four month follow up.keptin each group. Group 1(24 patients) were kept onTheir albumin level also increased from their initial readingconventional treatment and Group 2 received bothnoticed at four months follow up, compared to patientsconventional as well as branched chain amino acids.Inwho did not received BCAA. Patients in group-2 was ionGroup1 kept on conventional therapy, out of 24 patients,BCAA showed early improvement and recovery and17 were males 7 were females and in Group 2 onsubsequently on follow up visit at four months.Patientsconventional as well as on BCAA out of 24 patients, 17on BCAA showed improvement which initially withoutwere males and 07 were females. As for age distribution isBCAAwas raised but on sixth day and four monthsconcerned again they were divided into two groups. 1 andfollow up it reduced significantly. Albumin level which2, Group 1 on conventional therapy were kept as under:was initially low either remain stabilized or in few patients10 patients from age 30-39 12 from 40-49. while in 2 wereit alsoraised. The mortality rate in group 2 patientschosenover 50 years of age.# In Group 2, who were keptcompared to group 1 was also significantly low.onBCAA as well as conventional therapy their ages andTheresults are as follows, In first week hospital staynumbers are: from 30-39 10 patients. 40-49 were 12 inin group I patients in comparison to group II patients wasnumbers and patients above 50 years of age were 2 inmore than seven days (group 1 = 8 patients 33.3% andnumber The above 48 patients were diagnosed on thegroup 2 =0 patients). P value < 0.001. 8 patients from bases of clinical history / examination / laboratorygroup 2 remained hospitalized for 14 days while only one parameters including prothrombin time, serum albuminpatient remain in hospital for 14 days (group 2 = 1 patientand serum ammonia level.{14.2%} and in group 1 {33.3%}). Those who remained thth  World J. Med. Sci., 3 (2): 60-64, 2008 62morethan 14 days were 16 from group 1 (66.7%) and6Recentinterests focused on the timing of fromgroup 2 (25.0%). The P value < 0.001 which isadministration of BCAA since day time BCAA is usuallysignificant.consumedby energy generation for physical exercise of As for as serum ammonia level is concerned in groupskeletal muscle in liver cirrhosis. Nocturnal BCAA seem1 on conventional therapy it was raised to 110.8 +/- 7.89,to be more favorable as source of protein synthesison sixth day 70.4 +/- 13.90 and at 4 months 50.080 +/- 8.58.by giving higher nitrogen balance [22]. AbnormalWhile in group 2 on BCAA initially it was 120.5 +/- 19.75,aminoacids metabolism in Liver cirrhosis (LC) can beOn sixth day 50.8 +/- 8.16 on 4 months 20.583 +/- 3.855,characterized by decreased concentration of BCAAwith P value < 0.001 which is higly significant. Serumand increased concentration of aromatic amino acidsAlbumin level initially in 16 patients from group 1 and(AAA). In hepatic failure, the metabolism of AAA’s andfrom group 2 was < 2.8 (66.7%) in each group and inmethionine is lowered, leading to elevated concentrations8 patients it remain more than 2.8 to 3.1 i.e. 33.3% in eachin the blood [16]. In contrast in the muscles the catabolismgroup. However in patients on BCAA either it remainof BCAA’s is accelerated, resulting in a decrease in thenear 3.1 or slightly raised at 4 months. Mortality in groupconcentration of BCAA’s [5.] Consequently, Fischer’s2 compared to group 1 was significantly decreased. Aliveratio diminishes and the uptake of AA increased intogroup 1 = 3 (12.5%) and in group 2 = 10 (41.9%) P valuebrain [6,7]. This increased uptake leads to an increase in<0.04. Patients died from group 1 = 21 patients (67.5%)number of neurotransmitters causing encephalopathy.while in group 2 = 14 patients died (58.3%) P value <0.04The AA solution that was developed by Fischer andwhich is significant.Baldessarini 1 for the purpose of normalizing the amino DISCUSSION improvement in patients. The solution has beenProteinenergy malnutrition (PEM) is a commonAdministration is restricted only to intravenous infusion,manifestation in cirrhotic patients with reportedhowever, which limits the patients can be treatedincidences as high as 65-90%. In cirrhosis, proteinpredominantly in patients. Such intravenous infusion aremalnutrition is usually represented by reduced seruminconvenient for the patient with mild and moderatealbumin level and by decreased skeletal muscle volumeencephalopathy, [8,9,17]. In our study, long term clinical(muscular protein). PEM affects largely the outcome ofexperiments was designed so that the uselessness of  patients by determining both their quality of life andaminoleban in treating patients with hepatic failure can besurvival. As an intervention for energy malnutrition,identified more clearly. The neuropsychic symptoms andfrequent meal or late evening snack has recently beenperformance status also improved significantly inrecommended [11,13]. Patients with low plasma BCAApatients. Many patients were eventually able to undertakehave low serum albumin levels and those with high BCAAnormal daily life without assistance. This may representhavehigh albumin [5]. Hyperammonemia is a commonan improvement in the quality of life. The prognosis of LCmanifestation of cirrhotic patients due to impaired hepaticis dependent on various factors such as total bilirubincapacity to detoxicated ammonia. Instead, skeletaland albumin in the serum, ascites and encephalopathy asmusclesand, to a lesser extent the brain clear bloodwell as nutritional condition [18].Malnutrition has beenammonia by incorporating ammonia in the process ofreported to be one of the major risk factors responsible for glutamine production from glutamate. The precursorthe death due to hepatic failure [19,20]. The patientsglutaminerequires BCAA for its synthesis. Thus, whenreceiving aminoleban EN were still alive at the end of 6-exposed to hyperammonemia, skeletal muscle take upmonths study period. Consequently Aminoleban EN wasBCAA from the plasma to enhance their ability to degradeconsidered to be effective in prolonging the life span of ammonia [16]. In contrast, cirrhotic patients lose hepaticpatients with decompensated LC. BCAA are known for storageof glycogen due to liver atrophy and also gettheir use an energy source. They also compete for entryresistant to insulin in their peripheral tissues. Majority ofacross the blood brain barrier [21] with neutral aminosuch BCAA oxidation is supposed to occur in skeletalacids that are precursors of monoamines [22], act asmusclesand contribute to enhanced uptake of BCAAdetoxicants for ammonia and accelerated proteinfrom plasma by skeletal muscles [17].synthesis in muscle while inhibiting the break down of acidbalance can bring about a rapid symptomaticwidely used in the treatment of hepatic failure [9,12].  World J. Med. Sci., 3 (2): 60-64, 2008 63 Table 1: Demographic profile of the patients (n = 48)Age(in years), Mean±SD (Range)41.2±7.2(30 – 55)Gender: nutritional improvement with little adverse reactions as Male34(70.8%)Female14(29.2%)Age distribution:30 to 3920(41.6%)40 to 4924(50%)50 and above4(8.4%)Table 2:Investigations of the patients done during their hospital stay andfollow upProthrombine Time3 to 618(75.0%)18(75.0%)NS> 66(25.0%)6(25.0%)Serum Albumin< 2.816(66.7%)16(66.7%)NS2.8 to 3.18(33.3%)8(33.3%)Table 3: Hospital stay, mortality and observationsGroup 1Group IIConventionalConventionaltreatmenttreatment & BCAAParameter(n = 24)(n = 24)P valueHospital stay:1 to 7 days08(33.3%)< 0.001*8 to 14 days8(33.3%)1(4.2%)> 14 days16(66.7%)6(25.0%)Mortality:Alive3(12.5%)10(41.7%)0.04Dead21(87.5%)14(58.3%)Recurrence of Hepatic Coma (observed during 4 months)Up to 4 times3(12.5%)0Up to 3 times6(25.0%)2(8.3%)Upto 2 times9(37.5%)3(12.5%)One time2(8.3%)2(8.3%) Nil4(16.7%)17(70.8%)0.003*  P  value is statistically highly significantTable 4: Serum Ammonia level of patientsGroup 1Group IIConventionalConventionaltreatmenttreatment & BCAAParameter(n = 24) (n = 24)P valueSerum ammonia level:Initial110.8 ± 7.89120.5 ± 19.750.03On 6 Day 70.4 ± 13.9050.8 ± 8.16< 0.001* th On 4 months 50.080 ± 8.580020.583 ± 3.8551< 0.001*Results are expressed as Mean ± Standard Deviation*  P  value is statistically highly significant muscular protein. In conclusion, long term administrationof the enteral amino acid nutrient, aminoleban EN, led towell as the improvement of the quality of life and performance status. Aminoleba EN was thus able to prolong the life span of patients with decompensated LC. CONCLUSION Inadvanced liver cirrhosis long term nutritionalsupplementswith oral BCAA is useful to prevent progressive hepatic failure and improves surrogatemarkers and health status. It also raises plasma albuminlevel,improves quality of life of patient and decreaseincidence of subsequent hepatic encephalopathy in these patients. From our study it is observed that nutritionalfactor plays a significant role both in the pathogenesis aswell as management of hepatic encephalopathy. Theadministration of solution rich in BCAA leads to mentalrecoveryfrom acute hepatic encephalopathy in patientswith liver cirrhosis. REFERENCES 1.Fischer, J.E., et al  . 1971. False neurotransmitters andhepatic failure. 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