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尿有机酸分析评价功能性营养缺乏、肠道失调和毒性

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发表于 2019-9-3 14:05:56 | 显示全部楼层 |阅读模式
Urinary Organic Acids Profiling for Assessment of Functional Nutrient Deficiencies,Gut Dysbiosis, and Toxicity
尿有机酸分析评价功能性营养缺乏、肠道失调和毒性
[size=10.5000pt]J. Alexander Bralley, PhD, and Richard S. Lord, BS, PhD
CHAPTER CONTENTS
Introduction, 224
Urinary Organics Profiling, 224
Fatty Acid Oxidation, 224
Adipate, Suberate, and Ethylmalonate, 224 Carbohydrate Metabolism, 227
Lactate and Pyruvate, 227 Beta-Hydroxybutyrate, 227
Central Energy Pathway Intermediates, 227
Citrate, Isocitrate, Alpha-Ketoglutarate, cis-Aconitate,
Succinate, and Fumarate, 227 Hydroxymethylglutarate, 227
B-Complex Insufficiency Markers, 228
Alpha-Ketoisovalerate, Alpha-Ketoisocaproate,
and Alpha-Keto-Beta-Methylvalerate, 228 Indicators of a Specific Vitamin Deficiency, 228
Beta-Hydroxyisovalerate, 228
Methylmalonate, 228
Formiminoglutamate, 228
Kynurenate and Xanthurenate, 228
Neurotransmitter Metabolism, 228
Vanilmandelate and Homovanillate, 228
5-Hydroxyindolacetate, 228
Quinolinate and Picolinate, 229
Indicators of Detoxification Function, 229 Glucarate, 229
Orotate, 229
p-Hydroxyphenyllactate, 229
2-Methylhippurate, 229
Alpha-Hydroxybutyrate, 229
Pyroglutamate, 229
Sulfate, 230
Products of Gut Microflora, 230
Phenylacetate, Phenylpropionate, p-Hydroxybenzoate,
p-Hydroxyphenylacetate, p-Hydroxyphenylpropionate, and Tricarballylate, 230
D-Arabinitol Versus Arabinose, 230
D-Lactate, 230
Summary, 230
章节目录
简介,224
泌尿有机物分析,224
脂肪酸氧化,224
己二酸,辛二酸盐和丙二酸二乙酯,224
碳水化合物代谢,227乳酸和丙酮酸,227
β-羟基丁酸,227 中央能源途径中间体,227
柠檬酸盐,异柠檬酸盐,α-酮戊二酸,顺式-乌头酸,琥珀酸盐和富马酸盐,227
羟基甲基戊二酸,227
B族维生素缺乏标记物,228
α-酮异戊酸,α-酮异己酸和α--β-甲基戊酸,228
特异性维生素缺乏指标,228
β-羟基异戊酸,228
甲基丙二酸酯,228亚胺甲基谷氨酸,228
犬尿喹啉酸和黄尿酸 228
神经递质代谢 228
香草基扁桃酸和高香草228
5羟基吲哚乙酸, 228
喹啉酸盐和吡啶甲酸盐,229
解毒功能指标,229
葡萄糖二酸盐,229
乳清酸盐,229
对羟基苯基乳酸,229
2-甲基马尿酸,229
α-羟基丁酸,229
焦谷氨酸,229
硫酸盐,230
肠道菌群产品,230
苯乙酸,苯丙酸,对羟基苯甲酸,
对羟基苯乙酸酯,对羟基苯基丙酸酯和三羧酸酯,230 D-阿拉伯糖醇与阿拉伯糖,230
D-乳酸,230
总结,230
INTRODUCTION
Urinary organic acid analysis for metabolic profiling was used initially to assess inborn errors of metabolism that can cause severe mental retardation or death within the first year of life. The identification of isovaleric acidemia in 1966 was followed quickly by numerous additional acidurias, because the severe enzyme impairments of genetic diseases were found to result in urinary excretion of highly elevated amounts of organic compounds. Profiling of organic acids in urine as a routine laboratory evaluation of chronic diseases is a relatively recent addition to clinical assessment procedures.
最初尿有机酸分析用来评估先天性代谢异常。这些先天性代谢异常可导致在出生后第一年内严重的精神发育迟滞或死亡。 1966年报告首例异戊酸血症之后,有陆续发现大量苯丙酮尿症。遗传性疾病的严重酶损伤,导致尿液中高浓度有机化合物的排泄。尿液中有机酸的分析作为常规慢性病的实验室评估是临床评估程序的一个相对新的补充。
Levels of organic acids in urine can be used to detect functional nutritional defi-ciencies, to identify genetic variants, and to establish the source of toxicants from the environment and gut.2-4 For example, elevated methylmalonic acid (MMA) in urine is a sensitive indicator of functional vitamin B12 deficiency because the vita-min plays a critical role in metabolic clearance of MMA.5,6 Similarly, levels of other organic acids in urine are markers of multiple nutritional deficiencies. Organic acid profiling of urine has been found useful in numerous clinical evaluations, as shown in Table 28-1.
尿液中的有机酸水平可用于检测功能性营养缺乏,识别遗传变异,并确定环境和肠道中有毒物质的来源。2-4例如,尿液中升高的甲基丙二酸(MMA)是敏感的功能性维生素B12缺乏的指标,因为维生素B12MMA的代谢中起关键作用。5,6同样,尿液中其他有机酸的水平是多种营养缺乏的标志。已发现尿液的有机酸分析在许多临床评估中是有用的,如表28-1所示。
URINARY ORGANICS PROFILING
The test is performed on an overnight urine sample and the concentrations of 40 or more compounds are measured by gas chromatography/mass spectrometry (GC/ MS) or liquid chromatography (LC)/MS-MS methods. The information content of the profile is high, but the interpretation is simplified if one keeps in mind that the results answer six questions of clinical relevance:
对过夜尿液样品进行测试,并通过气相色谱/质谱(GC / MS)或液相色谱(LC/ MS-MS方法测量40种或更多种化合物的浓度。该概况的信息内容很高,但如果记住结果,回答六个临床相关性问题,则简化了解释:
1. Is mitochondrial energy production adversely affected?
2. Are functional nutrient deficiencies present?
3. Are neurotransmitters displaying abnormal turnover rates?
4. Is antioxidant protection status insufficient?
5. Is toxicant exposure elevated?
6. Are there elevated growth rates of upper intestinal bacteria or fungi?
1. 线粒体能量产生是否受到不利影响?
2. 功能性营养缺乏是否存在?
3. 神经递质是否表现出异常的周转率?
4. 抗氧化保护状态不足吗?
5. 毒物暴露是否升高?
6. 肠道细菌或真菌的生长速度是否有所提高?
Table 28-2 shows compounds that might appear on a typical quantitative report of organics in urine with some interventions that have been found to help rectify conditions associated with abnormal levels. The supplementary nutrient amounts are given as guides to starting points that might improve clinical outcomes for adults.
28-2显示了可能出现在尿液中有机物的典型定量报告中的化合物,其中一些干预措施已被发现有助于纠正与异常水平相关的病症。补充营养素,可以改善成人的临床结果。
FATTY ACID OXIDATION 脂肪酸氧化
已二酸, 辛二酸, 乙基丙二酸
Adipate and suberate are short-chain dicarboxylic fatty acids produced by an alternate oxidation pathway called ω-oxidation, which occurs in peroxisomes. Their production is normally low because the predominant pathway is β-oxidation in the mitochondria. However, transport of fatty acids into the mitochondria requires carnitine as a carrier. Suboptimal levels of carnitine result in inadequate transfer of fatty acids into the mitochondria and subsequent
己二酸和辛二酸是由称为ω-氧化的替代氧化途径产生的短链二羧酸脂肪酸,其发生在过氧化物酶体中。 它们的产量通常很低,因为主要途径是线粒体中的β-氧化。脂肪酸向线粒体的转运需要肉碱作为载体。低水平的肉碱导致脂肪酸不充分转移到线粒体中。
TABLE 28-1 Clinical Applications of Organic Acids in Urine Testing 28-1有机酸在尿液检测中的临床应用
CONDITION
COMPOUND(S)
REFERENCE(S)
Acidosis with metformin
酸中毒与二甲双胍
Lactate
乳酸
81, 82
Acute appendicitis
急性阑尾炎
5-Hydroxyindoleacetate            5-羟基吲哚乙酸
83
Adult neurologic complaints and breathing problems
成人神经系统疾病和呼吸问题
Pyroglutamate
[size=10.5000pt]
焦谷氨酸
84
Alcoholic delirium tremens
酒精性震颤性谵妄
Vanillylmandelate, homovanillate   香草基扁桃酸和高香草酸
85
Anemia
贫血
Methylmalonate
甲基丙二酸
86
Arginine-responsive hyperammonemia
精氨酸反应性高氨血症
Orotate
乳清酸盐
88
Attention deficit hyperactivity disorder
注意力减少多动障碍
Homovanillate 高香草酸
[size=10.5000pt]
87, 89
Bacterial overgrowth syndromes in acutely ill infants and children
急性婴儿和儿童的细菌过度生长综合症
p-Hydroxyphenylacetate
[size=10.5000pt]
[size=10.5000pt]
对羟基苯乙酸
90
Biotin-responsive orificial skin lesions, lethargy, hypotonia, and alopecia
[size=10.5000pt]
生物素反应性口腔皮肤病变,嗜睡,肌张力减退和脱发
[size=10.5000pt]3-Hydroxyisovalerate
[size=10.5000pt]
3-羟基异戊酸
91
Birth asphyxia
出生窒息
Lactate, pyruvate, 3-hyroxybutyrate, 4-hydroxyphenyllacetate,
[size=10.5000pt]2-hydroxybutyrate, 2-oxo-isocaproate, 2-oxo-3
乳酸,丙酮酸,3-羟基丁酸,4-羟基苯基乙酸酯,
[size=10.5000pt]3-2-羟基丁酸酯,2-氧代-异己酸酯,2-氧代-3-甲基戊酸酯
[size=10.5000pt]
92
Calcium urolithiasis
钙尿石症
Citrate
柠檬酸盐
93
Carnitine-responsive familial Reye-like syndrome
肉碱反应性家族性赖氏样综合征
Pyruvate, α-ketoglutarate, α-ketoadipate
丙酮酸,α-酮戊二酸,α-酮己二酸
94
Cerebral palsy
脑瘫
Fumarate
富马酸
95
Chronic fatigue syndrome
慢性疲劳综合症
Succinate
琥珀酸
96
Chronic lactic acidosis (weakness, shortness of breath)
慢性乳酸性酸中毒(虚弱,气短)
Alpha-ketoglutarate, α-hydroxybutyrate
α-酮戊二酸,α-羟基丁酸酯
97
Encephalomyelopathy
[size=10.5000pt]
脑脊髓病
Alpha-ketoglutarate, succinate, adipate, suberate
α-酮戊二酸,琥珀酸,己二酸,辛二酸
98
Encephalopathy
脑病
[size=10.5000pt]D-Lactate
D-乳酸
99
Folate deficiency developmental disorders
叶酸缺乏发育障碍
[size=10.5000pt]4-Hydroxyindoleacetate, homovanillate
[size=10.5000pt]
4-羟基吲哚乙酸盐,高香草酸
100
Glycine-responsive malnutrition
甘氨酸反应性营养不良
Pyroglutamate
焦谷氨酸
101
Gut flora and Klebsiella-specific metabolites
[size=10.5000pt]对
肠道菌群和克雷伯菌特异性代谢物
Benzoate, phenylacetate, p-hydrophenylpropionic,
Dihydroxyphenylacetate
苯甲酸盐,苯乙酸盐,羟基苯丙酸盐,二羟基苯乙酸盐
102, 103
Hemoblastoses and nephroblastoma
[size=10.5000pt]
血管母细胞瘤和肾母细胞瘤
p-Hydroxyphenyllactate
[size=10.5000pt]
对羟基苯
104
Hepatic detoxification
肝脏解毒
Pyroglutamate
焦谷氨酸
105
Phenol exposure
苯酚暴露
o-Cresol
邻甲酚
106
Pregnancy decrease of biotin status
妊娠期生物素状况下降
3-Hydroxyisovalerate 3-羟基异戊酸
107
Recent alcohol use
最近使用酒精
5-Hydroxyindoleacetate 5-HIAA
108
Riboflavin-responsive 核黄素反应
inspiratory stridor 吸气性喉鸣
[size=10.5000pt]
Ethylmalonate 乙基丙二酸
109
Sleep-waking rhythm 睡眠-觉醒节律
[size=10.5000pt]
Tartrate 酒石酸
110
Thiamin-responsive maple syrup urine disease
硫胺敏感的枫糖尿病
Alpha-ketoisovalerate
[size=10.5000pt]
α异戊酸
111
Toluene exposure
甲苯暴露
Hippurate
马尿酸
112
Vitamin deficiency in the elderly
老年人维生素缺乏症
Homocysteine, 2-methylcitrate
同型半胱氨酸,2-甲基柠檬酸
113
Xylene exposure
二甲苯暴露
2-Methylhippurate 甲基马尿酸盐
114
[size=10.5000pt]
[size=10.5000pt]
[size=10.5000pt]
[size=10.5000pt]
[size=10.5000pt]
[size=10.5000pt]
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TABLE 28-2 Quick Reference to Clinical Significance of Abnormal Levels of Organics in Urine 28-2快速参考尿液中有机物异常水平的临床意义
NAME
ABNORMALITY异常
POTENTIAL INTERVENTION*可能的干预
METABOLIC PATHWAY    代谢路径
Carbohydrate Metabolism碳水化合物代谢
[size=10.5000pt]
[size=10.5000pt]
[size=10.5000pt]
[size=10.5000pt]
Lactate
乳酸
[size=10.5000pt]H
CoQ10, 50 mg tid 每日三次
Mitochondrial electronic transport system
线粒体电子传输系统
丙酮酸
[size=10.5000pt]H
B complex, 1 capsule tid; B1, 100 mg tid; lipoic acid,
100 mg tid
B族复合物,1粒胶囊每日三次; B1100mg 每日三次; 硫辛酸,100毫克每日三次
Aerobic/anaerobic energy production
有氧/无氧产生
Beta-hydroxybutyrate
β-羟基丁酸
[size=10.5000pt]H
Chromium picolinate, 200 mcg bid
吡啶甲酸铬,200 mcg 每日两次
Ketosis
酮症
Fatty acid oxidation
脂肪酸氧化
[size=10.5000pt]
[size=10.5000pt]
[size=10.5000pt]
Adipate, suberate, ethylmalonate
[size=10.5000pt]
己二酸,辛二酸,乙基丙二酸酯
[size=10.5000pt]H
肉碱250毫克一天三次;  B2100mg 每日两次;  B5
500mg 每日两次;
胆碱,100毫克每日三次; 维生素C1000毫克每日三次; CoQ10150毫克
Mitochondrial vs peroxisomal fatty acid oxidation
[size=10.5000pt]
线粒体与过氧化物酶体脂肪酸氧化
Energy Production       能量生产
[size=10.5000pt]
[size=10.5000pt]
[size=10.5000pt]
Citrate 柠檬酸盐
[size=10.5000pt]L
Aspartic acid, 500 mg
天冬氨酸,500毫克
Anaplerotic  回补
Cis-aconitate 顺乌头酸
[size=10.5000pt]H
Arginine, 1000 mg; iron, 18 mg; N-acetylcysteine,
1000 mg bid
精氨酸,1000毫克; 铁,18毫克;  N-乙酰半胱氨
酸,1000 mg 每日两次
Citric acid cycle  三羟酸循环
Isocitrate 异柠檬酸
[size=10.5000pt]H
Arginine, 1000 mg; B3, 100 mg
Magnesium, 400 mg; manganese, 20 mg
精氨酸,1000毫克;  B3100mg镁, 400mg; 锰,20毫克
Citric acid cycle 三羧酸循环
Alpha-ketoglutarate
α-酮戊二酸
[size=10.5000pt]L
Alpha-KG, 300 mg; glutamine, 1-5 g
Alpha-KG300毫克; 谷氨酰胺,1-5
Anaplerotic 回补
[size=10.5000pt]
[size=10.5000pt]H
[size=10.5000pt]B-complex, 1 每日三次; lipoic acid, 100 mg
B复合[size=10.5000pt]物1 每日三次; 硫辛酸,100毫克
Citric acid cycle 三羧酸循环
Succinate 琥珀酸
[size=10.5000pt]L
Isoleucine, 1000 mg 每日三次; valine, 1000 mg 每日三次
异亮氨酸,1000毫克每日三次; 缬氨酸,1000毫克每日三次
Anaplerotic回补
[size=10.5000pt]
[size=10.5000pt]H
Magnesium, 500 mg
镁,500毫克
Magnesium, 500 mg
Fumarate 富马酸
[size=10.5000pt]L
Tyrosine, 1000 mg bid; phenylalanine, 500 mg bid
酪氨酸,1000 mg 每日两次; 苯丙氨酸,500 mg 每日两次
Anaplerotic 回补
Malate
苹果酸盐
[size=10.5000pt]H
B3, 100 mg tid
B3100毫克每日三次
Citric acid cycle 三羧酸循环
Specific Vitamin Indicators
特殊维生素指标
[size=10.5000pt]
[size=10.5000pt]
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Alpha-ketoisovalerate,
α-ketoisocaproate, α-keto-
β-methylvalerate
阿尔法异戊酸,
α-酮异己酸盐,α-酮基-β-
甲基戊酸盐
[size=10.5000pt]H
B complex, 1 capsule tid; B1, 100 mg tid; lipoic acid, 100 mg tid
B复合物,1粒胶囊;  B1100mg tid; 硫辛酸, 100毫克tid
BCAA catabolism
BCAA支链氨基酸分解代谢
[size=10.5000pt]
Kynurenate
犬尿胺酸
[size=10.5000pt]H
B6, 100 mg
B6100mg
Kynurenin
犬尿氨酸
Xanthurenate
黄尿酸
[size=10.5000pt]H
B6, 100 mg
B6100mg
Kynurenin
犬尿氨酸
Beta-hydroxyisovalerate
β羟基丁酸
[size=10.5000pt]H
Biotin, 5 mg bid; magnesium, 100 mg bid   生物素5 mg 每日两次; 镁,100毫克每日两次
[size=10.5000pt]
Isoleucine catabolism
异亮氨酸分解代谢
Methylmalonate
甲基丙二酸酯
[size=10.5000pt]
H
B12, 1000 mcg tid
B121000 mcg 每日三次
Leucine catabolism
亮氨酸分解代谢
FIGLU
胺亚甲基谷氨酸
[size=10.5000pt]H
Folic acid 叶酸
Histidine catabolism
组氨酸分解代谢
Hydroxymethylglutarate
羟甲基戊二酸
H/L
CoQ10, 50 mg tid
CoQ1050毫克每日三次
Cholesterol and CoQ10 biosynthesis
胆固醇和辅酶Q10生物合成
Detoxification indicators
排毒指标
[size=10.5000pt]
[size=10.5000pt]
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Glucarate
葡萄糖二酸盐
[size=10.5000pt]H
Glycine, GSH, NAC, 500-5000 mg/day
甘氨酸,谷胱甘肽, N-乙酰半胱氨酸(500-5000毫克/
Detoxifying liver enzyme induction
解毒肝酶诱导
Orotate
乳清酸盐
[size=10.5000pt]H
Alpha-KG, 300 mg tid; arginine, 1-3 g/day; aspartic acid,
500 mg bid; magnesium, 300 mg
α-酮戊二酸,300毫克每日三次; 精氨酸,1-3/; 天冬氨酸,
500毫克bid; 镁,300毫克
Ammonia clearance by urea cycle vs pyrimidine synthesis pyrimidine synthesis
[size=10.5000pt]
尿素循环氨与嘧啶合成的清除率
p-Hydroxyphenyllactate
对羟基苯乳酸
[size=10.5000pt]
[size=10.5000pt]H
Vitamin C up to 100 mg/kg
维生素C高达100毫克/千克
Prooxidant and carcinogen
促氧化剂和致癌物质
[size=10.5000pt]2-Methylhippurate       2-甲基马尿酸
[size=10.5000pt]
H
Avoidance of xylene
避免二甲苯
Hepatic glycine conjugation
肝脏甘氨酸结合
Alpha-hydroxybutyrate   α-羟基丁酸酯
[size=10.5000pt]H
NAC, 1000 mg; glutathione, 300 mg; lipoic acid, 600 mg
Taurine, 500 mg bid; glutathione, 300 mg    N-乙酰半胱氨酸1000毫克; 谷胱甘肽,300毫克; 硫辛酸,600mg
[size=10.5000pt]
Hepatic glutathione synthesis
肝谷胱甘肽合成
Pyroglutamate
焦谷氨酸
[size=10.5000pt]H
[size=10.5000pt]
Glutathione-requiring γ-glutamyl pathway
需要谷胱甘肽的γ-谷氨酰基途径
[size=10.5000pt]
Sulfate
硫酸盐化
[size=10.5000pt]
[size=10.5000pt]L
[size=10.5000pt]
Glutathione turnover
谷胱甘肽周转
[size=10.5000pt]
Neurotransmitter Metabolism
神经递质代谢
[size=10.5000pt]
[size=10.5000pt]
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Vanilmandelate, homovanillate           香草基扁桃酸和高香草酸
L/H
Tyrosine may stimulate rates of catecholamine production;
contraindicated for patients taking MAO inhibitors
酪氨酸可能会刺激儿茶酚胺的产生;
对于服用MAO单胺氧化酶抑制剂5-羟基吲哚乙酸盐的患者禁忌[size=10.5000pt]
Catecholamine catabolism, neurotransmitter metabolites
儿茶酚胺分解代谢,神经递质代谢产物
5-Hydroxyindolacetate     5-羟吲哚醋酸
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[size=10.5000pt]5-Hydroxytryptophan can stimulate rates of serotonin production; contraindicated for patients taking SSRI
5-羟色氨酸可以刺激血清素的比率生产; 服用SSRI的患者禁忌
Serotonin catabolism by monoamine oxidase
单胺氧化酶的5-羟色胺分解代谢
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Quinolinate 喹啉
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Magnesium, 300 mg
Kynurenin
Dysbiosis Markers (Products
of Abnormal Gut Micro-
flora)(肠道微生物异常产物
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300mg
犬尿氨酸
Products of bacterial growth:
benzoate, hippurate,
phenylacetate,
phenylpropionate,
p-hydroxybenzoate,
p-hydroxyphenylacetate,
tricarballylate,
p-hydroxyphenylproprionate
D-lactate
Products of yeast growth
D-Arabinital
细菌生长产物:苯甲酸盐,马尿酸盐,苯乙酸乙酯,苯丙酸酯,对羟基苯甲酸酯,对羟基苯乙酸酯,三羧酸 对hydroxyphenylproprionate
d乳酸
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If any of these compounds is high, the possibility of dysbiosis is reinforced. Glutamine, 10-30 g daily, and
free-form amino acids normalize gut permeability. Take appropriate steps to ensure favorable gut microflora population.
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如果这些化合物中的任何 一种都很高,则增强了生态失调的可能性。谷氨酰胺,每日10-30克和自由形态的氨基酸使肠道通透性正常化。采取适当措施,确保有利的肠道微生物群体。
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酵母生长的产物
D Arabinital
Numerous interferences in pathways and cellular energy control mechanisms
在途径和细胞能量控制机制中存在许多干扰
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BCAA, branched chain amino acids; bid, twice daily; CoQ10, coenzyme Q10; FIGLU, formiminoglutamate; GSH, glutathione; H, high; KG, ketoglutarate; L, low; MAO, monoamine oxidase; NAC, N-acetyl-L-cysteine; SSRI, selective serotonin reuptake inhibitor; tid, three times a day.
*Supplemental dosages are in the upper range of aggressive repletion.
BCAA,支链氨基酸,每天两次; 辅酶Q10,胺亚甲基谷氨酸,谷胱甘肽高,α酮戊二酸低,单胺氧化酶,N-乙酰基-L-半胱氨酸选择性5-羟色胺再摄取抑制剂每天三次。
*补充剂的量在积极补充的上限范围内。
compensation via ω-oxidation, producing elevated urinary lev-els of adipate and suberate. Similar carnitine transport impair-ment leads to elevation of urinary ethylmalonate. Urinary concentrations of all three of these compounds are elevated in overt enzyme failure, but the patterns of elevations in milder carnitine deficiencies vary.
通过ω-氧化补偿,使尿液中己二酸和辛二酸升高。 类似的肉碱运输损伤导致尿乙基丙二酸酯升高。所有这三种化合物的尿浓度在明显的酶失效中升高,但较轻的肉碱缺乏的升高模式各不相同。
Symptoms include periodic mild weakness, nausea, fatigue, hypoglycemia, sweaty feetodor, recurrent infections, and increased free fatty acids. Patients may also exhibit a Reye-like syn-drome with dicarboxylic aciduria, which has been associated with various metabolic toxins generated from viral infections that affect mitochondrial function. Mild heterozygotic forms of dicarboxylic aciduria may be commonly seen clinically and may go unrecog-nized. The enzymes involved also respond to environmental toxin exposure with altered lipid metabolism, which can lead to impaired immune responsiveness.7,8 Supplementation of carnitine and riboflavin is indicated when urinary adipate, suberate, or ethyl-malonate is elevated. (See Chapter 74 for a full discussion of this useful nutrient.)
症状包括周期性轻度虚弱,恶心,疲劳,低血糖,“汗脚”气味,反复感染和游离脂肪酸增加。患者还可能表现出具有二羧酸尿症的Reye(赖氏)样综合征,其与由影响线粒体功能的病毒感染产生的各种代谢毒素相关。二羧酸尿症的轻度杂合形式可能在临床上常见,并且可能未被认识到。所涉及的酶也响应环境毒素暴露,脂质代谢改变,这可导致免疫反应性受损。7,8当尿中己二酸,辛二酸,或丙二酸乙酯升高时,表明补充肉碱和核黄素。(有关这种营养素的完整讨论,请参阅第74章。)
CARBOHYDRATE METABOLISM 碳水化合物代谢
Lactate and Pyruvate 乳酸和丙酮酸
For each molecule of glucose carried through the glycolytic path-way, two molecules of pyruvate are produced. The conversion of pyruvate into acetyl-coenzyme A requires the pyruvate dehydro-genase enzyme complex that is dependent on cofactors derived from thiamin, niacin, riboflavin, pantothenic acid, and lipoic acid. Elevations of pyruvate may reflect failure of the enzyme because of a functional need for increased B vitamins, particu-larly thiamin and pantothenic acid. Levels of pyruvate in the tissues are further controlled by the biotin-containing protein pyruvate carboxylase, which controls the first step in the forma-tion of glucose from pyruvate. Multiple forms of pyruvate car-boxylase deficiency, some of which are biotin responsive, have been reported.9
对于通过糖酵解途径携带的每个葡萄糖分子,产生两个丙酮酸分子。丙酮酸转化为乙酰辅酶A,需要丙酮酸脱氢酶复合物,其依赖于衍生自硫胺,烟酸,核黄素,泛酸和硫辛酸的辅因子。丙酮酸盐的升高可能反映酶的失效,因为功能性需要增加B族维生素,特别是硫胺和泛酸。组织中丙酮酸的水平进一步受含有生物素的蛋白质丙酮酸羧化酶的控制,其控制丙酮酸形成葡萄糖的第一步。已报道多种形式的丙酮酸羧化酶缺乏症,其中一些是生物素反应性的。9
Any accumulation of pyruvate can lead to concurrent eleva-tions of lactate through the action of lactate dehydrogenase. Lac-tate accumulates when there is a block in the final oxidative phosphorylation (ox/phos) stage of energy production. Such a block results in inactivation of the citric acid cycle (CAC). Coenzyme Q10 (CoQ10) has been used in cases of lactic acidosis associated with ox/phos impairments.10,11 Increased lactate is a common acidotic condition that can be caused by a variety of metabolic problems. Decreased lactate is seen in people who are physically inactive. Highly trained athletes have such efficient conversion of lactate to glucose that they have lactate levels below the 2.5 percentile.
丙酮酸的任何积累都可以通过乳酸脱氢酶的作用导致乳酸同时升高。当能量产生的最终氧化磷酸化(ox / phos
阶段存在阻滞时,乳酸积累。 这种嵌段导致柠檬酸循环 CAC)的失活。 辅酶Q10CoQ10)已被用于与ox / phos 损伤相关的乳酸酸中毒。10,11乳酸增加是一种常见的酸性疾病,可由多种代谢问题引起。在身体不活动的人身上可以看到乳酸减少。训练有素的运动员可以将乳酸转化为葡萄糖,使乳酸水平低于2.5%。
Beta-Hydroxybutyrate β-羟基丁酸
Beta-hydroxybutyrate is a ketone body that becomes elevated in conditions of impaired glucose oxidation, where free fatty acids are used as the predominant energy source. Ketone bodies can be thought of as a transportable form of acetate resulting from oxidation of fatty acids. Elevations of β-hydroxybutyrate seen in overnight collection urine specimens might indicate inefficient use or mobilization of carbohydrate stores. Excessive fatigue on exertion is the most common symptom associated with ketosis. Chromium and vanadium supplementation may support carbohydrate use by improving insulin receptor activation.
β-羟基丁酸酯是一种酮体,其在葡萄糖氧化受损的条件下升高,其中游离脂肪酸被用作主要的能量来源。酮体可以被认为是由脂肪酸氧化产生的可运输形式的乙酸盐。在过夜收集的尿液样本中看到的β-羟基丁酸酯的升高可能表明碳水化合物储存或调动的使用效率低。劳累,过度疲劳是与酮症相关的最常见症状。补充铬和钒可通过改善胰岛素受体激活来支持碳水化合物的使用。
CENTRAL ENERGY PATHWAY INTERMEDIATES 中央能量通路中间体
Citrate, Isocitrate, Alpha-Ketoglutarate, cis-Aconitate, Succinate, and Fumarate 柠檬酸盐,异柠檬酸盐,α-酮戊二酸盐,顺式乌头酸,琥珀酸盐和富马酸盐
Citrate, isocitrate, α-ketoglutarate (α-KG), cis-aconitate, succi-nate, and fumarate are intermediates in the CAC. Most of the enzymes of the CAC require specific vitamin-derived cofactors and minerals for their function. When the enzyme rates slow due to deficiency of their cofactors, abnormal spilling of CAC inter-mediates into urine can occur. For example, in cytochrome C oxi-dase deficiency, there is inefficient removal of the primary product of the CAC, reduced nicotinamide adenine dinucleotide, and citrate, malate, fumarate, and α-KG all increase.12 CoQ10 defi-ciency can also result in elevations of CAC intermediates (see sec-tion on Hydroxymethylglutarate). Aggressive dosing with carnitine, CoQ10, and other nutrients has been used to help nor-malize mitochondrial function in genetic mitochondriopathies.23
柠檬酸盐,异柠檬酸盐,α-酮戊二酸(α-KG),顺式乌头酸盐,琥珀酸盐和富马酸盐是CAC(柠檬酸循环)中的中间体。CAC(柠檬酸循环)的大多数酶需要特定的维生素衍生的辅因子和矿物质才能发挥其功能。当酶由于其辅因子缺乏而速度缓慢时,可能发生CAC(柠檬酸循环)中间体异常,溢出到尿液中。例如,在细胞色素C 氧化酶缺乏症中,CAC的初级产物去除效率低,烟酰胺腺嘌呤二核苷酸减少,柠檬酸盐,苹果酸盐,富马酸盐和α-酮戊二酸(α-KG均增加。12 CoQ10缺乏症也可以导致CAC(柠檬酸循环)中间体升高(参见羟甲基戊二酸酯部分)。 肉碱,辅酶Q10和其他营养素的剂量已被用于帮助遗传线粒体病的线粒体功能正常化。23
Mild inborn errors of energy metabolism that may be compati-ble with survival, at least into young adulthood, but not with nor-mal development of mental and neurologic functions, have been associated with the excretion of elevatedα-KG. 24 The clinical het-erogeneity of neurometabolic disorders and the importance of organic acid analysis in the diagnosis of static encephalopathy were underscored by the finding of excretion of excess fumaric acid in a 5-year-old girl with a previous diagnosis of cerebral palsy.25
轻微的先天性能量代谢问题,会影响精神和神经功能的正常发展,α-KG(α-酮戊二酸升高有关。24神经代谢紊乱的临床异质性和有机酸分析在静态脑病诊断中的重要性通过发现先前诊断为脑瘫的5岁女孩中过量富马酸的排泄而得到进一步证实。25
Urinary levels of citrate, a marker of acid-base status, normally decrease with age.26 Metabolic compensation in glycogen storage disease type 1a leads to low urinary citrate concentration and higher incidence of nephrolithiasis. Citrate supplementation may help avoid urinary calculi in patients with low urinary citrate lev-els.27 Drinking bicarbonate-rich mineral water has also been shown to help raise urinary citrate concentration, and this dietary change has been suggested to prevent the recurrence of calcium oxalate and uric acid stones.28
尿液中柠檬酸盐水平是酸碱状态的标志,通常随着年龄的增长而降低。26 型糖原贮积病的代谢补偿,导致尿液中 低柠檬酸盐浓度和更高的肾结石发病率。柠檬酸盐补充剂可能有助于避免低尿酸柠檬酸盐水平患者的尿路结石。27 饮用富含碳酸氢盐的矿泉水也有助于提高尿柠檬酸盐浓度,这种饮食改变有助于防止草酸钙的复发和尿酸结石。28
Intermediates of the cycle can also be derived from amino acids. This may explain the energy-boosting effect that some individuals report when they take free-form amino acid supplements. The effect results from the conversion of specific amino acids directly into CAC intermediates needed for the energy-producing cycle. The fatigue-reducing effect of supplementation of aspartate salts and α-KG acid has been attributed to such a mechanism.9,20 Sup-plementation of the precursors serves to drive the cycle and generate reducing equivalents used in the electron transport chain in which adenosine triphosphate is produced via oxidative phosphorylation.
该循环的中间体也可以衍生自氨基酸。这可以解释一些人在服用游离形式氨基酸补充剂时所报告的能量增强效应。 该效果是由特定氨基酸直接转化为能量产生循环所需的CAC(柠檬酸循环)中间体产生的。补充天冬氨酸盐和α-KG(α-酮戊二酸)后产生的疲劳减少效果归因于这种机制。9,20前体的补充用于驱动循环并产生用于电子传递链中的还原当量,其中三磷酸腺苷是通过氧化磷酸化产生。
Hydroxymethylglutarate
Hydroxymethylglutarate (HMG) is the metabolic precursor of cholesterol and CoQ10. Low levels may reflect inadequate synthe-sis and possible deficiency of CoQ10. The statin drugs lower cho-lesterol by blocking the conversion of HMG into mevalonate. They cause elevated urinary HMG and lowered serum CoQ10 lev-els.21 CoQ10 is used in the mitochondrial oxidative phosphoryla-tion pathway for adenosine triphosphate synthesis and is a potent antioxidant because it lowers the undirected flow of electrons onto molecular oxygen. It has been employed extensively as a cardiovas-cular protective agent.22
羟基甲基戊二酸(HMG)是胆固醇和CoQ10的代谢前体。低水平可能反映出CoQ10的合成不足和可能的缺乏。 他汀类药物通过阻断HMG转化为甲羟戊酸来降低胆固醇。它们引起尿HMG升高和血清CoQ10水平降低。21 CoQ10用于三磷酸腺苷合成的线粒体氧化磷酸化途径是一种有效的抗氧化剂,因为它可以降低电子在分子氧上的无向流动。 它已被广泛用作心血管保护剂。22
CoQ10 has also been used successfully to improve mitochon-drial function in clinical situations of cardiac and skeletal muscle weakness and cramping, and in the extreme, mitochondrial encephalomyopathy.23,24 The coenzyme has been found helpful in the treatment of fatigue, particularly when both lactate and pyruvate are elevated. Such responses reflect the inability of mito-chondrial oxidative phosphorylation to proceed efficiently, possi-bly because of CoQ10 deficiency.
CoQ10也成功地用于改善心脏和骨骼肌无力和痉挛以及极端线粒体脑肌病的临床情况中的线粒体功能。23,24已发现辅酶用于治疗疲劳,特别当乳酸和乳酸丙酮酸升高。这反映了线粒体氧化磷酸化不能有效进行,可能是因为CoQ10缺乏。
B-COMPLEX INSUFFICIENCY MARKERS B族维生素缺乏的生物标志物
Alpha-Ketoisovalerate, Alpha-Ketoisocaproate, and Alpha-Keto-Beta-Methylvalerate
α-酮异戊酸,α-酮异己酸和α--β-甲基戊酸
Ketoacids derived from the branched chain amino acids isoleu-cine, leucine, and valine are α-ketoisovalerate, α-ketoisocaproate, and α-keto-β-methylvalerate, respectively. They are formed by the removal of the amine group in branched chain amino acid catabo-lism and are excreted in large amounts along with their amino acid precursors in the inherited disorder known as maple syrup urine disease. There are several known metabolic disorders in the path-ways of catabolism of the ketoacids. The reactions require enzymes similar to pyruvate dehydrogenase that use the B-complex cofac-tors B1, B2, B3, B5, and lipoic acid. Elevations of the branched chain ketoacids provide a functional assessment of the sufficiency of these vitamins, especially thiamin.25
衍生自支链氨基酸异亮氨酸,亮氨酸和缬氨酸的酮酸分别是α-酮异戊酸,α-酮异己酸和α--β-甲基戊酸。它们通过去除支链氨基酸分解代谢中的胺基而形成,并且在其被称为枫糖尿病的遗传性疾病中与其氨基酸前体一起大 量排泄。在酮酸的分解代谢途径中存在几种已知的代谢紊乱。该反应需要与丙酮酸脱氢酶相似的酶,其使用B-复合物辅因子B1B2B3B5和硫辛酸。支链酮酸的升高提供了这些维生素,特别是硫胺素。
25
INDICATORS OF A SPECIFIC VITAMIN DEFICIENCY 特定维生素缺乏的指标
Beta-Hydroxyisovalerate
Beta-hydroxyisovalerate is an ideal marker compound for evaluat-ing biotin status because it is produced in the high-flux pathway for degradation of the most abundant dietary amino acid, isoleu-cine. The carboxylase enzyme that is necessary for the step that clears β-hydroxyisovalerate requires the active form of biotin; human biotin deficiency has been shown to quickly produce ele-vation of urinary β-hydroxyisovalerate.26 Beta-hydroxyisovalerate is elevated in inherited disorders of multiple carboxylase insuffi-ciency because biotin is the cofactor for the mitochondrial carbox-ylase enzymes.27 Symptoms of multiple carboxylase deficiencies include alopecia, rash, Candida dermatitis, unusual odor to the urine, immune deficiencies, and muscle weakness. Biotin defi-ciencies of various degrees develop in a substantial minority of normal pregnancies and in patients receiving long-term therapy with anticonvulsants.26,28 Other possible indications of biotin deficiency are elevations of lactate and alanine in urine and accu-mulations of odd-chain fatty acids in plasma or red cell mem-branes.29 Supplementation of biotin may improve these conditions.
β-羟基异戊酸是一种用于评估生物素状态的理想标记化合物,因为它是在高通量途径中产生的,用于降解最丰富的膳食氨基酸异亮氨酸。清除β-羟基异戊酸的步骤所必需的羧化酶需要活性形式的生物素人体生物素缺乏已被证明可以迅速使尿液中β-羟基异戊酸的升高。26β-羟基异戊酸在多种羧化酶不足的遗传性疾病中升高,因为生物素 是线粒体羧化酶的辅助因子。27多种羧化酶缺乏的症状包括脱发,皮疹,念珠菌性皮炎,尿液异常气味,免疫缺陷 和肌肉无力。大部分正常妊娠和接受抗惊厥长期治疗的患者都会出现不同程度的生物素缺乏症。26 28生物素缺乏的其他可能迹象是尿液中乳酸和丙氨酸升高以及奇数链脂肪酸的积累。血浆或红细胞膜。29生物素的补充可以改善这些条件。
Methylmalonate 甲基丙二酸
Methylmalonate is converted into succinic acid by means of a vita-min B12dependent enzyme, methylmalonyl CoA mutase. The lack of vitamin B12 impairs this conversion, leading to elevation of urinary methylmalonate.30 If both homocysteine and methylmal-onate are elevated, both vitamin B12 and folate functional defi-ciencies are indicated. Folate supplementation is suggested if homocysteine alone is high, and vitamin B12 supplementation is needed if methylmalonate alone is elevated.
通过维生素B12依赖性酶甲基丙二酰辅酶A变位酶将甲基丙二酸转化为琥珀酸。 缺乏维生素B12会损害这种转化, 导致尿甲基丙二酸升高。30如果同型半胱氨酸和甲基丙二酸都升高,则表明维生素B12和叶酸功能缺陷。如果单独使用高半胱氨酸,建议补充叶酸,如果单独使用甲基丙二酸酯,则需要补充维生素B12
Formiminoglutamate 亚胺甲基谷氨酸
Formiminoglutamate (FIGLU) is a biochemical marker of folic acid deficiency. Histidine metabolism is interrupted in the absence of adequate levels of folic acid, causing accumulation of FIGLU acid elevation of levels in urine.31 Because of the linkage between folate and vitamin B12, FIGLU may be a more sensitive marker for vitamin B12 deficiency than methylmalonate. In a cohort of 15 leukemia cases, three patients showed elevated FIGLU, whereas the entire group had normal methylmalonate levels.32 A child with failure to thrive and vomiting had a genetic variant in the vitamin B12dependent FIGLU transferase enzyme in which nor-mal serum folate and vitamin B12 values were present with gross excretion of FIGLU.33
FormiminoglutamateFIGLU)是叶酸缺乏的生化标记物。在没有足够水平的叶酸的情况下,组氨酸代谢被中断,导致FIGLU在尿液中的水平累积31由于FIGLU叶酸和维生素B12之间的关联性FIGLU可能是比甲基丙二酸更敏感的维生素B12缺乏标记物。在一组15例白血病病例中,3例患者显示FIGLU升高,而整个组甲基丙二酸水平正常。 32一名发育不良并呕吐的儿童,其体内依赖维生素B12FIGLU转移酶发生了一种基因变异,在这种酶中,正常血清叶酸和维生素B12的含量与FIGLU的总排泄有关。33

Kynurenate and Xanthurenate
黄尿酸和犬尿喹啉酸
The hepatic kynurenin pathway that is responsible for clearing excess tryptophan is impaired by vitamin B6 deficiency in such a way that the intermediates, kynurenate and xanthurenate, accu-mulate and spill into urine. These two markers are much higher in the kidney than in blood. The precursors kynurenine and 3-hydroxykynurenine are formed in the liver, but they appear in urine as total kynurenine.34 As xanthurenate excretion increases, niacin production from tryptophan decreases.35 Pregnancy may have independent effects on kynurenine excretion, and studies in rats indicate that the effects of pregnancy and diet are additive.36
负责清除过量色氨酸的肝脏犬尿氨酸途径受到维生素B6 缺乏的损害,使得中间体,黄尿酸和犬尿喹啉酸,积聚并溢出到尿液中。这两种标记物在肾脏中的含量远远高于血液中的含量。前体犬尿氨酸和3-羟基犬尿氨酸在肝脏中形成,但它们在尿液中以总犬尿氨酸的形式出现。34随着犬尿喹啉酸排泄增加,色氨酸产生的烟酸减少。35妊娠可能对犬尿氨酸的排泄有独立影响,并且对大鼠的研究表明怀孕和饮食的影响是相加的。36
NEUROTRANSMITTER METABOLISM 神经递质代谢
Vanilmandelate and Homovanillate 香草基扁桃酸和高香草酸
Vanilmandelate (VMA) (also called vanillylmandelate) is the principal metabolite of the catecholamine epinephrine. Low uri-nary levels have been associated with low central nervous system (CNS) levels of the neurotransmitter. Symptoms associated with this condition are depression, sleep disturbances, inability to deal with stress, and fatigue. Treatments aimed at improving protein digestion and supplementation of the amino acid precursors can normalize neurotransmitter levels in the CNS.37 The much more commonly encountered conditions of elevated adrenal gland output resulting from chronic stress produce high urinary levels of VMA. Because of the rapid clearance rate for this hormone, high VMA indicates an elevated catecholamine turnover rate, but does not necessarily indicate elevated concentration of the hormones in blood.
扁桃酸(VMA)(又称香草扁桃酸)是儿茶酚胺肾上腺素的主要代谢物。低尿素水平与低中枢神经系统(CNS)水平的神经递质有关。与此相关的症状包括抑郁、睡眠障碍、无法应对压力和疲劳。旨在改善蛋白质消化和补充氨基酸前体的治疗可使中枢神经系统中的神经递质水平正常化。慢性应激导致肾上腺输出升高是一种更为常见的情况,可导致尿VMA水平升高。由于这种激素的清除率很快,VMA高表明儿茶酚胺的周转率升高,但不一定表明血液中激素浓度升高。
Homovanillate (HVA) is the principal product of dopamine catabolism. Elevated urinary values indicate increased production and turnover of dopamine. VMA is highly elevated by pheochro-mocytomas, and both VMA and HVA are measured in screening and prognosis for hemoblastoses and neuroblastoma.38,39
高香草酸(HVA)是多巴胺分解代谢的主要产物。尿值升高表明多巴胺的产生和循环增加。嗜铬细胞瘤使扁桃酸VMA升高,扁桃酸VMA高香草酸HVA均可用于血管母细胞瘤和神经母细胞瘤的筛查和预后测定。
5-Hydroxyindolacetate 5-羟基吲哚乙酸(5-HIAA
Catabolic breakdown of serotonin leads to excretion of 5-hydroxyindoleacetate (5-HIA). Abnormally high levels of this metabolite result from increased rates of serotonin release from the CNS, argentaffin cells in the gut, or platelets. Carcinoid tumors composed of chromaffin tissue can also release large amounts of serotonin. Serotonin is necessary for control of gut motility because it activates smooth muscle activity. Inadequate produc-tion of serotonin leads to constipation. Low levels have also been associated with depression, fatigue, insomnia, suicide, attention deficit disorder, and behavioral disorders. When 5-HIA levels are low, dietary therapy should focus on improving protein digestion and increasing consumption of foods high in tryptophan. (See Chapter 58 for discussions of hypochlorhydria and pancreatic insufficiency.) These actions minimize the need for oral trypto-phan or 5-hydroxytryptophan use.
血清素分解分解导致5-羟吲哚乙酸(5-HIA)的分泌。这种代谢产物的异常高水平是由中枢神经系统、肠内嗜银细胞或血小板中血清素释放速率增加造成的。由嗜铬组织构成的类癌肿瘤也能释放大量的血清素。血清素是控制肠道运动所必需的,因为它能激活平滑肌的活动。血清素分泌不足会导致便秘。低水平也与抑郁、疲劳、失眠、自杀、注意力缺陷障碍和行为障碍有关。当5-HIA水平较低时,饮食治疗应侧重于改善蛋白质消化和增加高色氨酸食物的摄入量。(见第58章关于低氯酸钠和胰腺功能不全的讨论。)这些措施减少了口服色氨酸或5-羟色氨酸的需要。
Quinolinate and Picolinate 喹啉酸盐和吡啶甲酸盐
The hepatic kynurenin pathway that was previously mentioned as the origin of urinary xanthurenate and kynurenate is also opera-tive in the brain. However, the normal end products in the brain are quinolinic and picolinic acids that serve to modulate brain activity via regulating N-methyl-d-aspartate (NMDA) receptors. In contrast to the unreliability of other neurotransmitter levels in urine for assessing CNS status, urinary quinolinate and picolinate are directly related to their concentrations in the brain, where their formation is specifically stimulated by the inflammatory cytokine interferon-γ.12 Urinary quinolinate rises in parallel with neopterin as both compounds reflect the process of inflamma-tion.40 However, quinolinate is a specific agonist for glutamatergic N-methyl-d-aspartate receptors, thus contributing directly to the hyperexcitation of inflammation in the brain.41
肝犬尿氨酸通路之前被认为是黄尿酸和犬尿胺酸的来源,在大脑中也起作用。 然而,大脑中的正常最终产物是喹啉酸和吡啶酸,它们通过调节N-甲基-d-天冬氨酸(NMDA)受体来调节大脑活动。与其他评估中枢神经系统状态的尿液中神经递质水平不可靠性相反,尿喹啉酸盐和吡啶甲酸盐与其在大脑中的浓度直接相关。它们的形成受到促炎性细胞因子干扰素-γ的特异性刺激。12尿喹啉酸盐与新蝶呤平行上升,因为这两种化合物都反映了炎症过程。40然而,喹啉酸盐是谷氨酸N-甲基-d-天冬氨酸受体的特殊激动剂,因此直接导致大脑中炎症的过度兴奋。41
INDICATORS OF DETOXIFICATION FUNCTION 解毒功能指标
Glucarate葡萄糖二酸盐
Glucaric acid (glucarate) is the oxidation product of glucuronic acid. It is a by-product of the predominant liver Phase II detoxifica-tion reactions involving glucuronic acid conjugation. A great vari-ety of drugs, environmental toxins, food components, and products of gut microbial metabolism are prepared for excretion by gluc-uronidation. Decreased glucarate is an indicator of reduced overall hepatic function, whereas elevation of this compound is an indica-tion of enzyme induction caused by potentially toxic exposures.42,43
葡萄糖酸是葡萄糖醛酸的氧化产物。它是主要的肝脏II期解毒反应的副产品,通过葡糖醛酸化作用排泄多种药物,环境毒素,食物成分和肠道微生物代谢产物。葡萄糖酸盐的降低是肝功能下降的一个指标,而这种化合物的升高则是潜在毒性暴露引起的酶诱导的一个指标
The excretion of d-glucarate is considered a marker of the via-bility of hepatocytes and is a useful clinical prognostic predictor in biliary atresia.44 Most exposures that result in stimulation of hepatic cytochrome P-450 activity result in increased excretion of glucarate. For example, urinary d-glucarate is elevated in pesticide-exposed groups.45 Patients with clinically quiescent chronic pancreatitis also show elevations of urinary glucarate, indicating a relationship of toxic metabolite stress to heightened free radical activity and hence to the genesis of chronic pancreati-tis.46 Glucarate measurements have been advanced as useful bio-markers to xenobiotic exposure, being particularly useful as a screening tool in reproductive epidemiology.47
d-葡萄糖酸盐的排泄被认为是肝细胞存活率的标志,是胆道闭锁的一个有用的临床预后预测指标。刺激肝细胞色素P-450活性的大多数暴露会导致葡萄糖酸盐分泌增加。例如,农药暴露组尿中d-葡萄糖酸盐含量升高。45例临床慢性胰腺炎患者尿葡萄糖酸盐水平升高,提示毒性代谢物应激与自由基活性升高有关,从而与慢性胰腺炎的发生有关。46 .葡萄糖酸盐的测量作为对外来生物接触的有用的生物标记已得到改进,特别有用作为生殖流行病的一种筛查工具
Orotate 乳清酸
Orotic acid accumulation is a sensitive marker of ammonia buildup. Ammonia (via glutamine) is normally disposed of by forming carbamoyl phosphate, which enters the urea cycle. When there is insufficient capacity for detoxifying the load of ammonia, carbamoyl phosphate leaves the mitochondria and stimulates the synthesis of orotic acid.48 Increased orotic acid production is a sensitive indicator of arginine availability. Most of the symptoms that develop after arginine deprivation can largely be accounted for by a diminished efficiency of ammonia detoxification. Greater orotic biosynthesis was observed with rising ammonia concentra-tions in rat, mouse, and human livers, and was reduced by in vitro arginine supplementation.49
乳清酸积累是氨积累的敏感标志物。氨(通过谷氨酰胺)通常通过形成氨基酰基磷酸盐来处理,而进入尿素循环。当氨负荷没有足够的解毒能力时,磷酸氨基甲酰离开线粒体,刺激合成乳清酸。48 增加的乳清酸产生是精氨酸可用性的敏感指标。精氨酸缺乏后出现的大多数症状在很大程度上可以归因于氨解毒效率的降低。在大鼠、小鼠和人类肝脏中,随着氨浓度的升高,可以观察到更大的乳清生物合成,并且可以通过体外补充精氨酸来减少这种生物合成。
Genetic medium-chain acyl CoA dehydrogenase deficiency and other disorders of fatty acid oxidation may appear long after infancy in some patients, such as those with a clinical diagnosis of Reyes syndrome. These disorders may mimic defects in the urea cycle, such as that reported for a 13-year-old girl with hyperam-monemic encephalopathy and orotic aciduria caused by ornithine transcarbamylase deficiency.50 Responses should include steps to stimulate ureogenesis, including α-KG, magnesium, and aspartic and glutamic acids.
在某些患者婴儿期后,如临床诊断为Reye综合征的患者,可能会出现遗传中链酰基辅酶a脱氢酶缺乏和其他脂肪酸氧化障碍。这些紊乱可能会模仿尿素循环中的缺陷,例如一个13岁的女孩因鸟氨酸转甲氨酰基转移酶缺乏而导致的高钠血症性脑病和多尿症。50反应应包括措施刺激尿素生成,包括α-KG-(α-酮戊二酸)、镁、和天冬氨酸和谷氨酸。
p-Hydroxyphenyllactate 对羟基苯甲酸盐
p-Hydroxyphenyllactate (HPLA) is a carcinogenic metabolite of tyrosine that increases lipid peroxidation in the liver.51 Methyl p-hydroxyphenyllactate (MeHPLA) is an important cell growthregulating agent, and tumor cells contain esterase enzymes that hydrolyze the compound to the free acid, HPLA.52 HPLA is an important regulator of normal and malignant cell growth, and it appears to mediate the cancer-promoting effects of estrogen. MeHPLA blocks uterine growth in vivo and inhibits growth of MCF-7 human breast cancer cells in vitro.53 High doses of ascor-bic acid (100 mg/kg body weight daily) were shown to arrest or significantly inhibit the excretion of HPLA in patients with hemo-blastoses and nephroblastoma.54 HPLA may also be produced by some microbes that could inhabit the gut, but the cell proliferative and prooxidant functions are of greater clinical relevance.55
对羟基苯甲酸盐(HPLA)是酪氨酸的一种致癌代谢物,可增加肝脏的脂质过氧化。51甲基对羟基苯基乳酸(MeHPLA)是一种重要的细胞生长调节剂,肿瘤细胞中含有酯酶,可以将化合物水解为游离酸,HPLA。52 HPLA是正常和恶性细胞生长的重要调节因子,似乎能介导雌激素的促癌作用。MeHPLA在体内阻断子宫生长,在体外抑制MCF-7人乳腺癌细胞的生长。53大剂量的抗坏血酸(每日100毫克/公斤体重)在血细胞母细胞瘤和肾母细胞瘤患者中被证明可以抑制或显著抑制HPLA的分泌。54 HPLA也可能是由一些能够在肠道内生存的微生物产生的,但其细胞增殖和促氧化剂功能具有更大的临床相关性
2-Methylhippurate 2-甲基马尿酸
2-Methylhippurate is a biotransformation metabolite of the com-mon solvent xylene. Elevations indicate an exposure to this poten-tially toxic compound.56,57 Although there are three positional isomers of xylene, the ortho form is virtually always present, so only the 2-methyl isomer of hippurate is necessary for detecting and monitoring exposure to the solvent.58 A study of spray paint-ers showed elevated methylhippurate, indicating recent exposure to xylene.59 Patient counseling in avoidance of these compounds is indicated. Glycine supplementation may also be considered to ensure maximal rates of conjugation to clear body burdens of xylene. This is especially the case when benzoate is found elevated in urine (see discussion of benzoate later).
2-甲基马尿酸是一种常见溶剂二甲苯的生物转化代谢产物。数值高表明接触了这种具有潜在毒性的化合物。虽然二甲苯有三种位置异构体,但邻位异构体几乎总是存在的,所以检测和监测暴露于溶剂的情况只需要马尿酸2-甲基异构体。58 .一项喷漆研究显示,马尿酸甲酯升高,表明最近接触二甲苯。59 .建议患者避免使用这些化合物。补充甘氨酸也可以考虑确保最大的共轭速率,以清除二甲苯的身体负担。尤其是在尿液中发现苯甲酸盐升高时(请参阅后面对苯甲酸盐的讨论)
Alpha-Hydroxybutyrate  α-羟基丁酸酯
Alpha-hydroxybutyrate is a by-product of the conversion of cysta-thionine to cysteine for hepatic glutathione synthesis. When demand for glutathione increases due to oxidative stress or detoxi-fication requirements, the flow through this pathway increases with concomitant increases in the excretion of α-hydroxybutyrate. The enzyme α-hydroxybutyrate dehydrogenase occurs at high con-centrations in cardiac muscle tissue, and its elevation in serum is widely used to estimate infarct size and reperfusion effectiveness.60 A series of urinary organic acid profiles performed on an autistic child exposed to xylene indicated that α-hydroxybutyrate was excreted at higher levels when epinephrine was stimulated.61 These findings are consistent with observations of α-hydroxybutyrate dehydrogenase changes in mice caused by acute stress.62
羟基丁酸是半胱氨酸和半胱氨酸的副产物,用于肝谷胱甘肽的合成。谷胱甘肽的需求增加时由于氧化应激或解毒需求,通过这个途径增加随之而来的增加α羟基丁酸脱氢酶的排泄。α羟基丁酸脱氢酶在心脏肌肉组织以高浓度发生,及其血清中的升高被广泛用于评估梗塞面积大小和再灌注效果。60对暴露于二甲苯的自闭症儿童进 行的一系列尿有机酸谱当刺激肾上腺素时,α-羟基丁酸 盐以较高水平排出。61这些发现与急性应激引起的小鼠α-羟基丁酸脱氢酶变化的观察结果一致。62
Pyroglutamate 焦谷氨酸
Pyroglutamate (sometimes called 5-oxoproline) is a cyclic form of glutamic acid. Small amounts are always present in overnight urine because the substance is produced as an intermediate in the γ-glutamyl cycle used in a renal recovery pathway involving active transport of amino acids.63 This process uses glutathione as a car-rier and requires glycine to reform glutathione. When glycine is insufficient, there is net conversion of glutathione to pyrogluta-mate, so this pathway conserves amino acids at the expense of glutathione. Pyroglutamaturia in an adult receiving antibiotic therapy is evidence for a renal-associated mechanism.64 Other cases of pyroglutamaturia accompanying homocystinuria indicate a glutathione-wasting mechanism leading to elevated urinary pyroglutamate.65 Supplemental glycine and N-acetylcysteine can replenish the intermediates in the γ-glutamyl cycle and help rebuild total body glutathione.66,67
焦谷氨酸(有时称为5-氧代脯氨酸)是谷氨酸的环状形式。过量尿液中总是存在少量焦谷氨酸,因为该物质是γ-谷氨酰循环 中的一种中间体,用于涉及氨基酸主动转运的肾脏恢复途径。63该过程使用谷胱甘肽作为载体并需要甘氨酸进行改造谷胱甘肽当甘氨酸不足时,谷胱甘肽净转化为焦谷氨酸,因此该途径以谷胱甘肽为代价保存氨基酸。 接受抗生素治疗的成人中的热性谷氨酰胺尿症是肾相关机制的证据。64其他伴有高胱氨酸尿症的焦虑性血尿症病例表明谷胱甘肽消耗机制导致尿焦谷氨酸升高。65补充甘氨酸和N-乙酰半胱氨酸可以补充γ-谷氨酰循环中的中间体,帮助重建全身谷胱甘肽。66,67
Sulfate 尿硫酸盐
Urinary sulfate is an inorganic compound sometimes reported on profiles of organic acids. It is measured in a separate assay and is included because of its added value in assessing the functioning of the detoxification pathways. Sulfation pathways are used in Phase II liver detoxification for the biotransformation of drugs, steroid hormones, and phenolic compounds, among others. Uri-nary sulfate has been used to assess the bodys reserve of sulfur-containing compounds (especially glutathione) used in Phase II pathways. These stores need replenishment when the sulfate/cre-atinine ratio is low. Administration of glutathione, in combina-tion with oral cysteine, taurine, and salts of sulfate, is used to replenish sulfur pathways and restore the hepatic supply of inor-ganic sulfate.68,69 Glutathione levels in the liver can be increased 35% in normal individuals by supplementation of Silybum mari-anum (see Chapter 123).
尿硫酸盐是一种无机化合物,有时在有机酸谱上报道。它是在一个单独的试验中测量的,由于它在评估解毒途径功能方面的附加价值而被包括在内。磺化途径用于II期肝脏解毒,用于药物、类固醇激素和酚类化合物等的生物转化。硫酸尿素已被用于评估体内用于II期通路的含硫化合物(尤其是谷胱甘肽)的储量。当硫酸盐/ 肌酸酐比值较低时,这些物料需要补充。谷胱甘肽与口服半胱氨酸、牛磺酸和硫酸盐联合使用,可补充硫通道,恢复肝内硫酸甘油酯的供应。补充水飞蓟可以使正常人肝脏中的谷胱甘肽水平提高35%(见第123)
PRODUCTS OF GUT MICROFLORA 肠道菌群产物
Several studies have used the appearance of unique products of microbial metabolism in urine as an indicator of the abnormal overgrowth of unfavorable intestinal microflora, a condition some-times called gastrointestinal dysbiosis.Such a condition has been related to a wide variety of symptoms due to pathogenic toxins produced by the populations of microflora. For example, no false-negative results and only 2% of false-positive results for small bowel disease and bacterial overgrowth syndrome were found in a study of urinary p-hydroxyphenylacetate in 360 acutely ill babies and chil-dren.70 Some compounds are absorbed and enter the detoxification pathways of the liver to be excreted as products that can serve as sensitive indicators of changes in gastrointestinal flora.71
一些研究利用尿液中微生物代谢的独特产物的出现,作为肠道菌群异常过度生长的指标,这种情况有时被称为“肠道失调”。“这种情况与微生物群产生的致病性毒素引起的各种症状有关。例如,在一项针对360名重症婴儿和儿童的尿液对羟基苯乙酸盐的研究中,没有发现小肠疾病和细菌过度生长综合征的假阴性结果,也只有2%的假阳性结果。70 一些化合物被吸收并进入肝脏的解毒途径,作为产品排泄出来,作为胃肠道菌群变化的敏感指标
Phenylacetate, Phenylpropionate, p-Hydroxybenzoate, p-Hydroxyphenylacetate, p-Hydroxyphenylpropionate, and Tricarballylate
苯乙酸盐,苯丙酸盐,对羟基苯甲酸盐,对羟基苯乙酸盐, 对羟基苯丙酸盐和三羧酸盐
For individuals with normal, healthy intestinal function, the com-pounds phenylacetate, phenylpropionate, p-hydroxybenzoate, p-hydroxyphenylacetate, p-hydroxyphenylpropionate, and tri-carballylate should not appear as more than background concen-trations in urine. Except for tricarballylate (derived from dietary carbohydrates), they are produced by microbial action on dietary polyphenolic compounds and all are markers of bacterial growth in the gut. p-Hydroxyphenylacetic aciduria has been found useful in detecting small bowel disease associated with Giardia lamblia infestation, ileal resection with blind loop, and other diseases of the small intestine associated with anaerobic bacterial over-growth.70 Use of antibiotics such as neomycin, which acts primar-ily against aerobic bacteria, can encourage the growth of Giardia and anaerobic bacteria, which then produce greater amounts of these compounds.72
对于具有正常、健康肠道功能的个体来说,化合物苯乙酸盐、苯丙酸盐、对羟基苯甲酸盐、对羟基苯乙酸盐、对羟基苯丙酸盐、三羧酸盐不应超过尿液中的背景浓度。除了三羧酸盐(来源于膳食碳水化合物),它们都是由微生物对膳食多酚化合物的作用产生的,都是肠道细菌生长的标志。对羟基苯乙酸在检测蓝氏贾第鞭毛虫感染引起的小肠疾病、回肠盲肠切除和其他小肠厌氧菌过度生长引起的疾病方面已被发现很有用。抗生素的使用,如对需氧细菌起主要作用的新霉素,可以促进贾第鞭毛虫和厌氧菌的生长,而这些细菌随后会产生更多的这种化合物。
Other gastrointestinal disorders, including cystic fibrosis of the pancreas, celiac disease, and unclassified enteritis, have been associated with increased excretion of p-hydroxybenzoate, phenylacetate, and p-hydroxyphenylacetate. Patients with cystic fibrosis had elevations of p-hydroxyphenylacetate even while undergoing pancreatin therapy. Variations in the relative amounts of these compounds observed with this type of gastrointestinal disturbance are an indication that the patterns of excretion are apparently determined by the microbial flora present in the patients intestinal lumen.73 Tricarballylate is produced by aerobic bacteria that quickly repopulate in the gut of germ-free animals.74 Tricarballylate build up due to overgrowth of Acidaminococcus fermentans or Selenomonas ruminantium in the lumen of sheep produced magnesium deficiency that could be fatal.75 Tricarbal-lylate lowers magnesium because of tight binding in the gut and in blood. Magnesium absorption is reduced and excretion is increased.
其他胃肠道疾病,包括胰腺囊性纤维化、腹腔疾病和未分类的肠炎,与对羟基苯甲酸盐、苯乙酸盐和对羟基苯乙酸盐排泄增加有关。囊性纤维化患者即使在接受胰酶治疗时,对羟基苯基乙酸盐也会升高。这些化合物在这种胃肠道紊乱中相对含量的变化表明,排泄模式显然是由患者肠道腔内的微生物菌群决定的。三羧酸盐是由好氧细菌产生的,这些好氧细菌能在无菌动物的肠道内迅速繁殖。羊肠腔内发酵酸球菌或反刍硒单胞菌过度生长而形成的三羧酸盐,会产生可能致命的镁缺乏。Tricarbal-lylate能降低镁的含量,因为它能在肠道和血液中紧密结合。镁的吸收减少,排泄增加。
D-Arabinitol Versus Arabinose  D-阿拉伯糖醇与阿拉伯糖
Arabinitol is a sugar alcohol that is a product uniquely produced by anaerobic fungal growth in the gut. d-Arabinitol is produced by fungal metabolism, and detection of elevated urinary d-arabinitol is considered the optimal way of monitoring immu-nocompromised patients for invasive candidiasis.76,77 In contrast, arabinose is a carbohydrate that has no relationship to growth of any form of yeast or fungi in or on the human body, although some laboratories may report the compound as a marker.
阿拉伯糖醇是一种糖醇,是一种由肠道中厌氧真菌生长产生的独特产物。d-阿拉伯糖醇由真菌代谢产生,检测尿中阿拉伯糖醇升高被认为是监测免疫功能低下患者侵袭性念珠菌病的最佳方法。与此相反,阿拉伯糖是一种碳水化合物,它与人体内或体外的任何形式的酵母或真菌的生长没有关系,尽管一些实验室可能会将这种化合物作为标记来报道。
D-Lactate d-乳酸
Like many other normal human intestinal bacteria, Lactobacillus acidophilus produces the d-isomer of lactic acid from the fermen-tation of undigested dietary carbohydrate. L. acidophilus is usually regarded as a favorable organism because moderate amounts of d-lactate can be racemized to L-lactate and oxidized to carbon dioxide by intestinal and hepatic enzymes. The organism produces other desired products and helps discourage colonization by pathogens. Under conditions of carbohydrate malabsorption, however, d-lactate output can exceed metabolic conversion capac-ity and accumulate, causing systemic acidosis and encephalopa-thy.78,79 Elevated urinary d-lactate is characteristic of this condition. Other bacteria, such as Bacteroides fragilis and Klebsi-ella, also can produce d-lactate, but they lack the ability to prolif-erate in the highly acidic environment created by high accumulations of lactic acid. d-Lactic encephalopathy has been found in a high percentage of patients with short bowel syndrome after intestinal resection, and high d-lactate excretion has been found in antibiotic-associated diarrhea.80
与许多其他正常人类肠道细菌一样,嗜酸乳杆菌从未消化的膳食碳水化合物的发酵过程中产生乳酸的d-异构体。嗜酸乳杆菌通常被认为是一种有益的微生物,因为适量的d乳酸可以外消旋成L乳酸,并通过肠道和肝脏酶氧化成二氧化碳。这种生物产生其他所需的产物,并有助于阻止病原体的定植。然而,在碳水化合物吸收不良的情况下,d-乳酸的输出量会超过代谢转换能力而累积,导致全身性酸中毒和脑积水。78,79尿d-乳酸升高是本病的特点。其他细菌,如脆弱拟杆菌和克雷伯氏菌,也能产生d乳酸,但在乳酸大量积累形成的高酸性环境中,它们缺乏产生丙二酸的能力。在肠切除术后短肠综合征患者中发现d乳酸性脑病的比例较高,抗生素相关性腹泻中发现d乳酸排泄较高
SUMMARY 总结
Measurement of organics in the urine has become an indispens-able clinical tool. The profile provides a wide array of metabolic functional markers at a relatively low cost. Multiple factors involved in energy production, carbohydrate metabolism, func-tional nutritional status, fatty acid metabolism, detoxification, gut biosis, and neurotransmitter metabolism can be assessed from a single overnight urine specimen. Many of the detected abnormal-ities can be corrected through the appropriate use of dietary changes, lifestyle improvements, and nutritional and botanical supplements.
尿液中有机物的测定已成为临床必不可少的检测手段。该图谱以相对较低的成本提供了一系列广泛的代谢功能标志物。从一个隔夜尿样中可以评估涉及能量生产、碳水化合物代谢、功能营养状况、脂肪酸代谢、排毒、肠道生物和神经递质代谢的多个因素。许多检测到的异常可以通过适当使用饮食改变、生活方式改善、营养和植物补充剂来纠正。
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