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Why albumin now? Let’s think about albumin measurement methods, the definition of hypoalbuminemia, and microheterogeneity
Nutrition 21 (2005) 1156 –1157 www.elsevier.com/locate/nut
Award for General Nutrition
Why albumin now? Let’s think about albumin measurement methods, the definition of hypoalbuminemia, and microheterogeneity Akiharu Watanabe, M.D.* Department of Clinical Nutrition, Faculty of Health, Science and Technology, Kawasaki University of Medical Welfare, Kurashiki, Okayama, Japan
More than 15 y ago, I administered an enteral feeding formula containing branched-chain amino acid at a high concentration to patients who had liver cirrhosis and observed an increase in serum albumin concentration [1]. This clinical effect was a surprise to me, but simultaneously raised two simple questions: Did this increase directly reflect an increase in albumin production in the liver? Are changes in serum albumin level (e.g., a 0.1-g/dL increase) being accurately evaluated according to the same criteria in all institutions? Some topics concerning albumin have attracted attention in Japan. For example, reports of new albumin measurement methods and microheterogeneity such as glycated albumin in the field of clinical biochemistry, clinical application of a gene recombination type human serum albumin preparation, and a report of a 2.4-fold increase in the death rate after administration of albumin preparations to patients with severe burns compared with electrolyte fluid infusion [2]. I was also interested in the revision of criteria for the appropriate use of albumin preparations because the oxidized (deteriorated) type albumin ratio markedly differed among albumin preparations produced by various manufacturers. Therefore, at the luncheon seminar of the 37th conference of the Japan Society of Hepatology that was held in May 2001, the theme “Why Albumin, Now? Importance of Its Variety and Reevaluation of the Criteria for Hypoalbuminemia” (cosponsor Ajinomoto Pharma Co., Ltd.) was adopted, and I was proposed as the chairman. Taking advantage of this opportunity, I initiated a joint collaboration with university hospitals patients who had liver disease on albumin measurement methods and microheterogeneity. During the period of January 14 and March 21, 2000, I and my colleagues planned to measure albumin by methods such as the immune method in all serum samples collected from outpatients and inpatients with and without liver dis* Corresponding author. Tel.: ⫹086-277-5850. E-mail address: [email protected] (A. Watanabe). 0899-9007/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2005.06.002
ease in the Third Department of Internal Medicine, Toyama Medical and Pharmaceutical University; the First Department of Gastroenterology, Tokai University; the First Department of Internal Medicine, Gifu University; the First Department of Internal Medicine, Iwate Medical University; and the Third Department of Internal Medicine, Osaka City University. I hoped that we would re-evaluate clinical problems of the measurement of serum albumin, which has become too routine to raise problems, and take an interest in microheterogeneity such as oxidized/reduced albumin and glycated albumin. In Japan, branched-chain amino acid preparations are frequently used for hypoalbuminemia that is often observed in patients with liver cirrhosis. Their long-term administration increases the serum albumin concentration by 0.1 to 0.3 g/dL. However, whether this increase in albumin reflects an increase in total albumin in the body cannot be determined unless in vivo neutron activation analysis (body protein monitor) is used. There is also a possibility that the increase in albumin after administration of special amino acid preparations reflects albumin transfer from the extravascular to intravascular pool due to increases in albumin synthesis and degradation [3]. Because albumin is regarded as a protein that is localized in the blood, it is not widely known that its extravascular pool is larger than its intravascular pool. Before the development of branched-chain amino acid preparations, serum albumin concentration was considered to annually decrease by 0.1 to 0.2 g/dL in many patients with liver cirrhosis. When a decrease was observed, a human serum albumin preparation was infused. However, it is of great significance that the new amino acid treatment can increase serum albumin concentration, even though the increase is only 0.1 g/dL. Because a high correlation coefficient was obtained between serum albumin concentration and cumulative survival rate [4], the hepatic pathophysiologic condition improved, prolongation of survival was expected, and clinical effects that could not be observed after conventional treatment methods were clarified. Therefore,
A. Watanabe / Nutrition 21 (2005) 1156 –1157
the accurate evaluation of slight changes irrespective of institutions where patients undergo examination was seen to be very important, and a serum albumin measurement method with high accuracy and specificity using standard human albumin became necessary. Simultaneously, another problem arose, i.e., whether the criterion of hypoalbuminemia (3.5 g/dL) as a indicator for the initiation of branchedchain amino acid treatment is correct or should be reevaluated. If re-evaluation is necessary, the establishment of a new criterion is required. However, at present, problems with albumin measurement methods have been suggested, such as the bromcresol green (BCG) method being poorly specific to albumin or the BCP method being markedly affected by oxidized albumin that increases in patients with liver cirrhosis. The albumin concentration determined by the bromcresol purple (BCP) method, which is highly specific to albumin, is about 0.2 g/dL lower than that determined by the BCG method. Conversely, in patients with liver cirrhosis with increased oxidized albumin, the value obtained by the BCG method is 0.1 to 0.2 g/dL higher. This problem should not be ignored as an issue in liver disease. The definition of hypoalbuminemia (ⱕ3.5 g/dL) according to Child’s classification [5] may have been established during the period when the albumin measurement method changed from Tiselius’s electrophoresis to the HAB(C)A method (there was no description of the measurement method in Child’s original book [5]). It is difficult to consider that 3.5 g/dL (normal range 4.6 – 6.7) as established during that period has the same significance as 3.5 g/dL (3.8 –5.3) as obtained by the current pigment binding method. Why is 3.5 g/dL globally used in the current era? I retired from Toyama Medical and Pharmaceutical Uni-
1157
versity at the end of March 2004, and am currently involved in students’ education/research in the Department of Clinical Nutrition, Kawasaki University of Medical Welfare. This report [6] for which I received the award was one that capped my 40 y of research activity in Okayama University and Toyama Medical and Pharmaceutical University. Therefore, my coauthors and I are very pleased and proud at having received this John M. Kinney Award. I express deep gratitude to Ajinomoto Co., Ltd. for their great support for the completion of this article and to Keiko Yasukawa at Asahi Kasei Corporation for instructions in the glycoalbumin measurement method.
References [1] Okita M, Watanabe A, Nagashima H. Nutritional treatment of liver cirrhosis by branched-chain amino acid-enriched nutrient mixture. J Nutr Sci Vitaminol 1985;31:293–303. [2] Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systemic review of randomized controlled trails. Br Med J 1998;318:235– 40. [3] Katou M, Moriwaki H. Assessmental procedure for albumin. In: Watanabe A, editor. Clinical albuminology. Tokyo: Medical Review Co; 1999, p. 57– 64. [4] Gines P, Quintero E, Arroyo V, Teres J, Bruguera M, Rimola A, et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology 1987;7:122– 8. [5] Child CG III, Turcotte JG. Surgery and portal hypertension. In: Child CG III, editor. The liver and portal hypertension. 3rd ed. Philadelphia: WB Saunders; 1964, p. 90. [6] Watanabe A. Clinical problems in serum albumin measurement and clinical significance of albumin microheterogeneity in cirrhotics. Nutrition 2004;20:351–7.
Award for General Nutrition
Why albumin now? Let’s think about albumin measurement methods, the definition of hypoalbuminemia, and microheterogeneity Akiharu Watanabe, M.D.* Department of Clinical Nutrition, Faculty of Health, Science and Technology, Kawasaki University of Medical Welfare, Kurashiki, Okayama, Japan
More than 15 y ago, I administered an enteral feeding formula containing branched-chain amino acid at a high concentration to patients who had liver cirrhosis and observed an increase in serum albumin concentration [1]. This clinical effect was a surprise to me, but simultaneously raised two simple questions: Did this increase directly reflect an increase in albumin production in the liver? Are changes in serum albumin level (e.g., a 0.1-g/dL increase) being accurately evaluated according to the same criteria in all institutions? Some topics concerning albumin have attracted attention in Japan. For example, reports of new albumin measurement methods and microheterogeneity such as glycated albumin in the field of clinical biochemistry, clinical application of a gene recombination type human serum albumin preparation, and a report of a 2.4-fold increase in the death rate after administration of albumin preparations to patients with severe burns compared with electrolyte fluid infusion [2]. I was also interested in the revision of criteria for the appropriate use of albumin preparations because the oxidized (deteriorated) type albumin ratio markedly differed among albumin preparations produced by various manufacturers. Therefore, at the luncheon seminar of the 37th conference of the Japan Society of Hepatology that was held in May 2001, the theme “Why Albumin, Now? Importance of Its Variety and Reevaluation of the Criteria for Hypoalbuminemia” (cosponsor Ajinomoto Pharma Co., Ltd.) was adopted, and I was proposed as the chairman. Taking advantage of this opportunity, I initiated a joint collaboration with university hospitals patients who had liver disease on albumin measurement methods and microheterogeneity. During the period of January 14 and March 21, 2000, I and my colleagues planned to measure albumin by methods such as the immune method in all serum samples collected from outpatients and inpatients with and without liver dis* Corresponding author. Tel.: ⫹086-277-5850. E-mail address: [email protected] (A. Watanabe). 0899-9007/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2005.06.002
ease in the Third Department of Internal Medicine, Toyama Medical and Pharmaceutical University; the First Department of Gastroenterology, Tokai University; the First Department of Internal Medicine, Gifu University; the First Department of Internal Medicine, Iwate Medical University; and the Third Department of Internal Medicine, Osaka City University. I hoped that we would re-evaluate clinical problems of the measurement of serum albumin, which has become too routine to raise problems, and take an interest in microheterogeneity such as oxidized/reduced albumin and glycated albumin. In Japan, branched-chain amino acid preparations are frequently used for hypoalbuminemia that is often observed in patients with liver cirrhosis. Their long-term administration increases the serum albumin concentration by 0.1 to 0.3 g/dL. However, whether this increase in albumin reflects an increase in total albumin in the body cannot be determined unless in vivo neutron activation analysis (body protein monitor) is used. There is also a possibility that the increase in albumin after administration of special amino acid preparations reflects albumin transfer from the extravascular to intravascular pool due to increases in albumin synthesis and degradation [3]. Because albumin is regarded as a protein that is localized in the blood, it is not widely known that its extravascular pool is larger than its intravascular pool. Before the development of branched-chain amino acid preparations, serum albumin concentration was considered to annually decrease by 0.1 to 0.2 g/dL in many patients with liver cirrhosis. When a decrease was observed, a human serum albumin preparation was infused. However, it is of great significance that the new amino acid treatment can increase serum albumin concentration, even though the increase is only 0.1 g/dL. Because a high correlation coefficient was obtained between serum albumin concentration and cumulative survival rate [4], the hepatic pathophysiologic condition improved, prolongation of survival was expected, and clinical effects that could not be observed after conventional treatment methods were clarified. Therefore,
A. Watanabe / Nutrition 21 (2005) 1156 –1157
the accurate evaluation of slight changes irrespective of institutions where patients undergo examination was seen to be very important, and a serum albumin measurement method with high accuracy and specificity using standard human albumin became necessary. Simultaneously, another problem arose, i.e., whether the criterion of hypoalbuminemia (3.5 g/dL) as a indicator for the initiation of branchedchain amino acid treatment is correct or should be reevaluated. If re-evaluation is necessary, the establishment of a new criterion is required. However, at present, problems with albumin measurement methods have been suggested, such as the bromcresol green (BCG) method being poorly specific to albumin or the BCP method being markedly affected by oxidized albumin that increases in patients with liver cirrhosis. The albumin concentration determined by the bromcresol purple (BCP) method, which is highly specific to albumin, is about 0.2 g/dL lower than that determined by the BCG method. Conversely, in patients with liver cirrhosis with increased oxidized albumin, the value obtained by the BCG method is 0.1 to 0.2 g/dL higher. This problem should not be ignored as an issue in liver disease. The definition of hypoalbuminemia (ⱕ3.5 g/dL) according to Child’s classification [5] may have been established during the period when the albumin measurement method changed from Tiselius’s electrophoresis to the HAB(C)A method (there was no description of the measurement method in Child’s original book [5]). It is difficult to consider that 3.5 g/dL (normal range 4.6 – 6.7) as established during that period has the same significance as 3.5 g/dL (3.8 –5.3) as obtained by the current pigment binding method. Why is 3.5 g/dL globally used in the current era? I retired from Toyama Medical and Pharmaceutical Uni-
1157
versity at the end of March 2004, and am currently involved in students’ education/research in the Department of Clinical Nutrition, Kawasaki University of Medical Welfare. This report [6] for which I received the award was one that capped my 40 y of research activity in Okayama University and Toyama Medical and Pharmaceutical University. Therefore, my coauthors and I are very pleased and proud at having received this John M. Kinney Award. I express deep gratitude to Ajinomoto Co., Ltd. for their great support for the completion of this article and to Keiko Yasukawa at Asahi Kasei Corporation for instructions in the glycoalbumin measurement method.
References [1] Okita M, Watanabe A, Nagashima H. Nutritional treatment of liver cirrhosis by branched-chain amino acid-enriched nutrient mixture. J Nutr Sci Vitaminol 1985;31:293–303. [2] Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systemic review of randomized controlled trails. Br Med J 1998;318:235– 40. [3] Katou M, Moriwaki H. Assessmental procedure for albumin. In: Watanabe A, editor. Clinical albuminology. Tokyo: Medical Review Co; 1999, p. 57– 64. [4] Gines P, Quintero E, Arroyo V, Teres J, Bruguera M, Rimola A, et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology 1987;7:122– 8. [5] Child CG III, Turcotte JG. Surgery and portal hypertension. In: Child CG III, editor. The liver and portal hypertension. 3rd ed. Philadelphia: WB Saunders; 1964, p. 90. [6] Watanabe A. Clinical problems in serum albumin measurement and clinical significance of albumin microheterogeneity in cirrhotics. Nutrition 2004;20:351–7.