CASE REPORT L-ornithin L-aspartate in Hepatic Encephalopathy due to Liver Cirrhosis

1Suzanna Ndraha, 2Marcellus Simadibrata 1 Department of Internal Medicine, Faculty of Medicine, University of Indonesia 2 Division of Gestroenterology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia

Abstrak Introduksi: Asupan protein berlebih dapat menyebabkan ensefalopati hepatikum (EH). Pembatasan protein menjadi kontroversi karena memperburuk malnutrisi. Artikel ini melaporkan kasus EH gizi kurang yang mendapat terapi L-ornitin-L-aspartat (LOLA) disertai diet protein adekuat sesuai dengan status nutrisinya. Kasus: Pasien laki-laki 62 tahun datang dengan keluhan utama penurunan kesadaran sejak 6 jam sebelumnya. Dia telah diketahui menderita penyakit sirosis sejak 6 tahun. Beberapa hari sebelumnya pasien makan banyak putih telur dan ikan. Pada pemeriksaan fisik didapatkan gizi kurang dan kesadaran delir. Encefalopati hepatikum ditegakkan berdasarkan hasil critical flicker test (CFF) yang rendah, dan kadar amonia darah yang tinggi. Pasien mendapatkan diet 35 kcal/kg per hari dan protein 1.5 g/kg/hari. LOLA diberikan untuk menurunkan ammonia darah dan meningkatkan angka critical flicker test. Dalam pemantauan selajutnya didapatkan pasien membaik, critical flicker test (CFF) meningkat dan ammonia darah menurun. Diskusi: Pada kasus ini, EH diterapi dengan LOLA tanpa retriksi protein. EH yang membaik, dalam hal ini kemungkinan akibat LOLA membantu menurunkan kadar amonia darah. Kesimpulan Dengan memberikan LOLA yang dapat menurunkan kadar amonia darah, EH dengan malnutrisi dapat diterapi dengan nutrisi adekuat. Kata-kata kunci: sirosis hati, ensefalopati, L-ornitin L-aspartat, critical flicker test, kadar ammonia darah Abstract Introduction: Excessive protein intake can cause hepatic encephalopathy (HE). Constricting protein in HE is becoming a controversy, because it can worsen malnutrition. This article reports the case of an under nutrition HE which is treated with L-ornithine-L-aspartate (LOLA) and given appropriate diet according to the nutrition status Case A 62-year-old man came with chief complaint of reduced consciousness since 6 hours before admission. He had been diagnosed as liver cirrhosis for 6 years. Several days prior to admission he took high protein diet. Physical examination revealed under nutrition and unconsciousness. Hepatic encephalopathy was confirmed with low critical flicker test (CFF), and high blood ammonia level. He was treated with adequate diet and LOLA to decrease blood ammonia and improve the CFF. During the treatment, consciousness improved to normal, CFF increased and ammonia level decreased.

Discussion In this case of HE was treated with LOLA without protein restriction. The EH improved, in this circumstance maybe cause of LOLA treatment that helps decreasing the plasma ammonia level. Conclusion: By giving LOLA to decrease blood ammonia level, HE with malnutrition could be treated with adequate nutrition. Key words: liver cirrhosis, hepatic encephalopathy, L-ornithine L-aspartate, critical flicker test, blood ammonia level

Introduction Liver cirrhosis is the end of various type of liver disease, it can evoke various complications such as reduce of liver synthetic function (coagulopathy), reduce liver capability for detoxification (Hepatic Encephalopathy), and portal hypertension with all its complications [1,2]. Hepatic Encephalopathy (HE) is one of all liver cirrhosis that brings high morbidity and mortality effect. The incidence rate of HE in liver cirrhosis are various from 30-45% [3] and also 50-70% [4], where most of it considered as minimal HE. Increases of ammonia level in the blood, among others is the effect of over intake protein and gastrointestinal bleeding, until now is considered to have the major role in HE pathogenesis [4,5]. Due to that, the management of HE especially tend to reduce the amount of ammonia in the blood, besides to overcome the initiating factor. The efforts to reduce the amount of ammonia in the blood are done by giving lactulose, antibiotics for intestine sterilization, and constrict the protein intake. Constricting protein intake in HE nowadays is becoming a controversy, because it can worsen malnutrition [6]. Few research reports that malnutrition can increase mortality rate in liver cirrhosis [6,7]. Contrariwise nutrition improvement can increase muscle mass, which is needed for ammonia detoxification. For the nutrition improvement a diet 25-35 kcal/Kg per day and protein 1-1.5g/Kg/day is suggested. LOLA nowadays started to be used to overcome EH cause its proven can reduce ammonia level in the blood [8], LOLA stimulates the urea cycle and glutamine synthesis, which is the important mechanism in ammonia detoxification [9,10]. With the intake of LOLA intend to reduce the ammonia level in the blood, so that it is unnecessary to constrict protein intake in liver cirrhosis patient with malnutrition. This article reports the case of hepatic encephalopathy which is treated with LOLA and given 35 kcal/kg/day diet and 1.5g/kg/day protein. . Case Patient is a 62 years old man who was brought in the emergency ward with chief complaint of reduced consciousness which manifested as having difficulty in speaking since 6 hours prior to hospital admission. From his present history of illness, patient has been experiencing fatigue and loss of balance since 3 days prior to admission. Furthermore, patient constantly feels drowsy therefore his sleeping hours have increased in both duration and

frequency and family members are often unable to comprehend what the patient says. 6 hours prior to admission, he was unable to recognize the people around him, further deterioration of speech skills therefore family members decided to bring him to the emergency ward of RS Tebet Jakarta. Patient was diagnosed with liver cirrhosis due to hepatitis B infection 6 years prior to admission. His symptoms were swollen abdomen and feet which resolved every time he received medications from the doctor. He always performed his check-up routinely every month up to this incident; furthermore, he also pays high attention on his daily diet which was specifically recommended by a nutritionist. However, since several days prior to admission, patients serum albumin level had been low, therefore his wife decided to add more fish into his daily diet. During physical examination in the emergency ward, patient was deemed with severely ill condition, delirious. His body height was 168 cm; his weight was at 62 kg and mid arm muscle circumference (MAMC) of 228 mm. He had normal blood pressure, no signs of fever, however abnormalities were found in his eyes which had anemic conjunctiva and icteric sclera. Other abnormalities seen were spider nevi on the chest and palmar erythem on his extremities. In addition, collateral veins were discovered on his abdomen with enlarged spleen up to shuffner II, with no signs of ascites or extremity edema, and a flapping tremor was also noticeable. Laboratory results on admission showed a condition of pancytopenia (Hb 11,7 g/dl, leukocyte 3270/uL, platelets 65.600/uL, LED 50 mm/jam. Electrolyte balance and prothrombine time were under normal limits. Albumin 2,4 g/dl, total bilirubin 1,98 mg/dl, SGOT 75 iu/L, SGPT 32 iu/L. Urinalysis tests showed no abnormalities and were under normal limits. Current working diagnosis on arrival is hepatic encephalopathy due to increased protein intake on cirrhotic patient due to chronic hepatitis B infection. Pancytopenia was suspected due to hypersplenism with liver cirrhosis. To confirm this diagnosis, USG of the abdomen is planned to confirm the cirrhosis, blood ammonia level as well as critical flicker test (CFF) to confirm hepatic encephalopathy. Patient is given a diet of 2100 calories daily with 90 grams protein along with substituted branch chained amino acids (BCAA), L-ornithine L-aspartate (Hepamerz) I.V. 20 grams of (4 ampoules) /day in 250 ml of infuse line for 5 days and later replaced with oral route 3 x 6 grams for 2 weeks in order to reduce the ammonia levels in the blood. Lactulose of PO 4 x 15 ml is administered to facilitate transit to reduce further breakdown of ammonia. During the follow up, we acquired the abdominal USG results which confirmed the diagnosis of liver cirrhosis and splenomegaly with minimal ascites. Ammonia level shows 189 mol/L (normal < 50 mol/L), CFF 33,8 Hz (normal 39 Hz). These results further strengthen the diagnosis of hepatic encephalopathy on liver cirrhosis. After 2 days of treatment, patients condition improved with increased consciousness level up to fully alert, and no flapping tremor was noticeable. Repeated measurement of blood ammonia levels shows an improvement (reduction up to155mol/L) and furthermore, CFF has increased up to 38.8 Hz. Discussion This is a case of liver cirrhosis with the complication of encephalopathy due to excessive protein intake. Excessive protein intake is one of several initiating factor of HE that cause increased ammonia production [1]. Encephalopathy diagnosis was proven with the increased of ammonia level, supported the theory that acknowledge that ammonia hold an important role in the HE mechanism. Laboratory results shown 2,4 g/dl albumin level, 1,98 mg/dl total bilirubin level, normal prothrombine time, minimal ascites (under control) and minimal encephalopathy

shown that liver function level of the patient is classified as Child Pugh B so the possibility of HE due to endogen factor is not likely. Flicker test nowadays considered as a sensitive test, simple, and reliable to diagnose minimal HE in liver cirrhosis [11, 12]. The CFF of 33,8 0,58 Hz in this patient showed the existence of HE cause by increased ammonia level due to increased protein intake priory. The patient has 22,1 kg/m2 BMI (Body Mass Index) that shows normal nutritious, but apparently from MAMC shows that actually the patient has started to undergo minor malnutrition. It was known that the weight of liver cirrhosis patients is more affected by ascites and edema, therefore calculation and measurement using MAMC is more suggested to evaluate nutrition status [14]. Patient is treated with adequate nutrition, with branch chain amino acid (BCAA) substitute, in order to maintain the nutrition status. To overcome the risk of increasing ammonia level, patient is given LOLA 20 g intravenous (4 ampoules dissolved in 250 cc carrier solution over 4 hours) for 5 days followed by LOLA granules 6 g three times daily for 2 weeks. It appears that the diet treatment given to this patient did not worsen EH, in this circumstance maybe cause of LOLA treatment that helps decreasing the plasma ammonia level. Conclusion In this case, nutritional status in liver cirrhosis was measured base on MAMC. EH was diagnosed based on CFF and blood ammonia level. The patient is given appropriate diet according to the nutrition status to avoid worsening of the malnutrition. However, EH is improving due to LOLA treatment which can reduce plasma ammonia level. References 1. Munoz SJ. Hepatic Encephalopathy. Med Clin N Am. 2008; 92:795812 2. Kusumobroto HO. Sirosis hati. Dalam Sulaiman HA, Akbar HN, Lesmana LA, Noer HMS. Buku Ajar Ilmu Penyakit Hati. 1st ed. Jakarta: Jayabadi; 2007. p.335-45 3. Kim WR, Brown RS, Terrault NA, El-Serag H. Burden of Liver Disease in the United States: Summary of Workshop. Hepatology. 2002;36(1):227-42 4. Poordad FF. Review article: the burden of hepatic encephalopathy. Aliment Pharmacol Ther. 2006; 25 (Suppl. 1): 39 5. Kramer L, Tribl B, Gendo A, Zauner C, Schneider B, Ference P. et al. Partial Pressure of Ammonia Versus Ammonia in Hepatic Encephalopathy. Hepatology 2000;31:30-34. 6. Norenberg MD, Jayakumar AR, Rama Rao KV, Panickar KS. The peripheral benzodiazepine receptor and neurosteroids in the pathogenesis of hepatic encephalopathy and amonia neurotoxicity. In Hussinger, Kircheis G, Schliess F. Hepatic Encephalopathy and nitrogen metabolism. The Netherlands: Springer; 2006. p. 143-59 7. Abdo AA. An evidence-based update on hepatic encephalopathy. Saudi J Gastroenterol 2006;12:8-15 8. Henkel AS, Buchman AL. Nutritional support in patients with chronic liver disease. Nature clinical practice. Gastroenterology and Hepatology 2006;3(4): 202-09 9. Kircheis G, Hussinger D. Management of Hepatic Encephalopathy. Conference Proceedings. Journal of Gastroenterology and Hepatology 2002;17:S260-7

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