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非酒精性脂肪性肝病患者粪便短链脂肪酸含量测定的临床意义
DOI: 10.3969/j.issn.1001-5256.2022.06.016
伦理学声明：本研究2019年8月1日通过青海大学附属医院伦理委员会审批，批号为P-SL-201958，患者及家属均签署知情同意书。
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明：李惠、王学红、马臻棋参与研究的思路设计，修改文章关键内容；马文霞、杨丽萍参与研究数据的获取过程。
Clinical significance of the determination of fecal short-chain fatty acids in patients with nonalcoholic fatty liver disease
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摘要:
目的 通过分析非酒精性脂肪性肝病(NAFLD)各疾病谱患者粪便短链脂肪酸(SCFA)含量及非酒精性脂肪性肝炎(NASH)高危患者治疗前后粪便SCFA含量的差异，初步探讨SCFA肠道代谢与NAFLD各疾病谱发生发展的关系。 方法 选取2020年7月—2021年7月青海大学附属医院临床诊断为NAFLD的患者共90例，分为单纯性脂肪肝(NAFL)组(n=30)、NASH组(n=30)、非酒精性脂肪性肝纤维化组(n=30)，选取同期健康体检者40例作为对照组，收集4组研究对象病例资料、粪便SCFA含量, 以及NASH高危患者10例治疗干预3个月后临床指标和粪便SCFA含量。满足正态分布的计量资料多组间比较采用方差分析，组内比较采用配对样本t检验；不满足正态分布的计量资料采用Kruskal-Wallis H检验，组内比较采用配对样本的Wilcoxon符号秩和检验，相关性分析采用Spearman相关分析，诊断性评价采用ROC曲线分析。 结果 非酒精性脂肪性肝纤维化组戊酸、己酸含量显著高于健康对照组，NAFL组戊酸、己酸含量显著低于健康对照组(P值均＜0.05)；非酒精性脂肪性肝纤维化组戊酸、己酸含量显著高于NAFL组(P值均＜0.05)；非酒精性脂肪性肝纤维化组戊酸含量显著高于NASH组(P＜0.05)；NASH组己酸含量显著高于NAFL组(P＜0.05)。NASH组高危患者治疗后糖化血红蛋白、空腹血糖(FPG)、TG、TC、ALT、AST、GGT、总胆汁酸(TBA)、PT、尿酸(UA)、受控衰减参数(CAP)、肝脏硬度值(LSM)均明显低于治疗前(Z值分别为-2.805、-2.703、-2.193、-2.599、-2.805、-2.701、-2.803、-1.988、-2.807、-2.803、-2.803、-2.668，P值均＜0.05)；NASH组高危患者治疗后乙酸、丙酸含量均显著高于治疗前(Z值分别为-2.803、-2.803，P值均＜0.05)；异丁酸含量低于治疗前(Z=-2.803，P＜0.05)；戊酸诊断非酒精性脂肪性肝纤维化的AUC为0.842，最佳界值为141.42 μg/g，灵敏度86.7%，特异度70%；己酸诊断非酒精性脂肪性肝纤维化的AUC为0.819，最佳界值为6.93 μg/g，灵敏度70%，特异度85%。 结论 戊酸、己酸可能促进NAFLD疾病谱发展；乙酸、丙酸对NAFLD患者肝脏可能存在一定程度的保护作用，异丁酸可能促进NASH的发生发展；乙酸、丙酸对肝脏的保护作用可能进一步导致糖化血红蛋白、FPG、TG、TC、ALT、AST、GGT、TBA、PT、UA、CAP、LSM等指标的降低；戊酸、己酸诊断价值劣于三型前胶原肽，但优于四型胶原、透明质酸，推测以戊酸为141.42 μg/g、己酸为6.93 μg/g为临界值可作为早期筛查非酒精性脂肪性肝纤维化的辅助诊断指标。 Abstract:Objective To investigate the association of the metabolism of intestinal short-chain fatty acids (SCFAs) with the development and progression of the disease spectrum of nonalcoholic fatty liver disease (NAFLD) by determining the content of fecal SCFAs in patients with different NAFLD diseases and the change in the content of fecal SCFAs after treatment in patients at a high risk of nonalcoholic steatohepatitis (NASH). Methods A total of 90 patients who were diagnosed with NAFLD in The Affiliated Hospital of Qinghai University from July 2020 to July 2021 were enrolled and divided into simple nonalcoholic fatty liver (NAFL) group with 30 patients, NASH group with 30 patients, and nonalcoholic fatty liver fibrosis group with 30 patients, and 40 individuals who underwent physical examination during the same period of time were enrolled as control group. Related case data and fecal SCFAs content were collected for the four groups, and related clinical indices and fecal SCFAs content were collected for 10 patients at a high risk of NASH after 3 months of intervention. The analysis of variance was used for comparison of normally distributed continuous data between multiple groups, and the paired samples t-test was used for comparison within each group; the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups, and the paired samples Wilcoxon signed rank sum test was used for comparison within each group; a Spearman correlation analysis was used to investigate the correlation between variables; the receiver operating characteristic (ROC) curve analysis was used for diagnostic evaluation. Results Compared with the control group, the nonalcoholic fatty liver fibrosis group had significantly higher contents of valeric acid and caproic acid, and the NAFL group had significantly lower contents of valeric acid and caproic acid (all P < 0.05); the nonalcoholic fatty liver fibrosis group had significantly higher contents of valeric acid and caproic acid than the NAFL group (P < 0.05); the nonalcoholic fatty liver fibrosis group had a significantly higher content of valeric acid than the NASH group (P < 0.05); the NASH group had a significantly higher content of caproic acid than the NAFL group (P < 0.05). After treatment, the high-risk patients in the NASH group had significant reductions in HbA1c, fasting plasma glucose (FPG), triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), total bile acid (TBA), prothrombin time (PT), uric acid (UA), controlled attenuation parameter (CAP), and liver stiffness measurement (LSM) (Z=-2.805, -2.703, -2.193, -2.599, -2.805, -2.701, -2.803, -1.988, -2.807, -2.803, -2.803, and -2.668, all P < 0.05); for these patients, the contents of acetic acid and propionic acid after treatment were significantly higher than those before treatment (Z=-2.803 and -2.803, both P < 0.05), and the content of isobutyric acid after treatment was significantly lower than that before treatment (Z=-2.803, P < 0.05). In the diagnosis of nonalcoholic fatty liver fibrosis, valeric acid had an area under the ROC curve (AUC) of 0.842, with a sensitivity of 86.7% and a specificity of 70% at the optimal cut-off value of 141.42 μg/g; caproic acid had an AUC of 0.819, with a sensitivity of 70% and a specificity of 85% at the optimal cut-off value of 6.93 μg/g. Conclusion Valeric acid and caproic acid may promote the development of NAFLD disease spectrum. Acetic acid and propionic acid may have a certain protective effect on the liver of NAFLD patients, and isobutyric acid may promote the development and progression of NASH. The protective effect of acetic acid and propionic acid on the liver may further lead to the reductions in HbA1c, FPG, TG, TC, ALT, AST, GGT, TBA, PT, UA, CAP, and LSM. Valeric acid and caproic acid have an inferior diagnostic value to PIIIP N-P and a superior diagnostic value to type IV collagen and hyaluronic acid. Valeric acid with the optimal cut-off value of 141.42 μg/g and caproic acid with the optimal cut-off value of 6.93 μg/g can be used as the auxiliary diagnostic indicators for the early diagnosis of nonalcoholic fatty liver fibrosis. -
Key words:
- Non-alcoholic Fatty Liver Disease /
- Liver Cirrhosis /
- Fatty Acids, Volatile /
- Feces
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图 1 SCFA及PⅢP N-P、Ⅳ-C、HA、LN诊断非酒精性脂肪性肝纤维化ROC曲线
Figure 1. ROC curve of SCFA and PⅢP N-P, Ⅳ-C, HA and LN in the diagnosis of nonalcoholic fatty liver fibrosis
表 1 4组研究对象人口学资料比较
Table 1. Comparison of demographic data of four groups of subjects
项目 健康组
(n=40)NAFL组
(n=30)NASH组
(n=30)非酒精性脂肪性肝纤维化组
(n=30)统计值 P值 性别[例(%)] χ2=4.267 0.234 男 23(57.5) 17(56.7) 23(76.7) 16(53.3) 女 17(42.5) 13(43.3) 7(23.3) 14(46.7) 年龄(岁) 49.10±10.85 53.40±9.00 49.03±11.21 47.03±11.79 F=1.869 0.138 
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表 2 4组研究对象临床生化指标比较
Table 2. Comparison of clinical biochemical indexes of four groups
项目 健康组(n=40) NAFL组(n=30) NASH组(n=30) 非酒精性脂肪性肝纤维化组(n=30) 统计值 P值 BMI(kg/m2) 20.75±1.62 25.18±2.731) 28.28±3.151)2) 26.70±2.281)2)3) F=62.852 ＜0.001 HbA1c(%) 5.00(4.43~5.58) 5.30(4.45~6.65) 7.95(7.60~8.33)1)2) 7.85(7.23~9.03)1)2) H=84.220 ＜0.001 FPG(mmol/L) 4.80(4.40~5.27) 6.90(5.73~8.03)1) 6.75(5.45~7.80)1) 8.20(7.20~9.13)1) H=57.614 ＜0.001 TG(mmol/L) 1.01(0.70~1.30) 2.17(1.35~3.41)1) 2.16(1.48~3.05)1) 2.90(2.10~4.30)1) H=62.740 ＜0.001 TC(mmol/L) 4.47±0.74 4.69±0.83 4.52±1.13 4.93±0.73 F=1.831 0.145 ALT(U/L) 25.00(21.00~30.50) 28.50(19.75~33.25) 87.00(50.50~150.00)1)2) 50.00(31.50~73.25)1)2) H=64.890 ＜0.001 AST(U/L) 21.80(18.00~27.00) 20.50(17.75~23.50) 37.50(27.50~62.25)1)2) 36.50(21.75~63.75)1)2) H=36.106 ＜0.001 ALP(U/L) 94.00(78.25~119.75) 87.50(74.00~107.00) 101.50(91.50~121.75) 109.00(81.25~137.50) H=6.409 0.093 GGT(U/L) 25.00(19.00~31.75) 30.50(24.75~39.00) 102.00(57.50~268.75)1)2) 78.50(40.50~123.00)1)2) H=69.178 ＜0.001 TBil(μmol/L) 18.25(16.40~21.78) 13.95(11.23~18.68)1) 17.80(11.10~26.70) 11.90(8.83~17.20)1)3) H=22.698 ＜0.001 DBil(μmol/L) 2.50(1.90~2.98) 4.15(3.33~5.20)1) 4.90(4.13~8.00)1) 3.75(2.53~5.25)1)3) H=52.403 ＜0.001 IBil(μmol/L) 16.13±2.93 11.04±5.091) 13.09±7.121) 8.95±4.061)3) F=13.548 ＜0.001 TBA(μmol/L) 4.74(3.80~5.34) 4.04(2.30~6.87) 4.71(3.73~7.41) 7.52(4.09~9.87)1)2) H=12.455 0.006 Alb(g/L) 48.12±3.51 43.60±3.291) 41.70±4.571) 45.25±3.971)3) F=17.546 ＜0.001 GLB(g/L) 26.21±6.36 26.32±2.90 26.83±4.40 27.67±5.40 F=0.554 0.646 PT(s) 10.95(9.80~11.60) 9.90(9.68~10.23)1) 10.20(9.68~10.63) 9.75(9.45~10.33)1) H=17.139 0.001 APTT(s) 27.38±2.37 23.47±2.661) 24.97±4.641) 23.33±4.091) F=10.407 ＜0.001 UA(μmol/L) 301.00(258.50~328.75) 310.00(243.25~440.50) 347.00(292.75~429.75)1) 321.50(286.25~380.50) H=11.066 0.011 CAP(dB/m) 177.66(155.25~198.00) 290.50(258.25~316.50)1) 334.50(295.00~359.75)1) 313.50(262.25~342.50)1) H=81.927 ＜0.001 LSM(kPa) 4.65(4.13~5.28) 4.00(3.68~4.85) 6.25(5.30~7.38)1)2) 9.60(8.85~10.48)1)2)3) H=89.958 ＜0.001 注：与健康组比较，1)P＜0.05；与NAFL组比较，2)P＜0.05；与NASH组比较，3)P＜0.05。
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表 3 4组研究对象SCFA水平测定
Table 3. Determination of short chain fatty acids level of four groups of subjects
项目 健康组(n=40) NAFL组(n=30) NASH组(n=30) 非酒精性脂肪性肝纤维化组(n=30) 统计值 P值 乙酸(μg/g) 1463.63±408.10 1438.24±539.47 1259.68±467.97 1343.57±436.10 F=1.339 0.265 丙酸(μg/g) 702.74±241.86 747.38±349.46 756.53±421.36 710.30±321.60 F=0.212 0.888 异丁酸(μg/g) 68.74(48.83~104.64) 50.09(16.91~94.80) 66.99(24.30~106.96) 50.40(35.02~83.74) H=2.763 0.430 丁酸(μg/g) 700.38±300.18 567.76±329.82 591.70±282.18 763.35±343.67 F=2.644 0.052 异戊酸(μg/g) 64.60(45.13~102.57) 47.00(16.94~74.37) 65.61(21.95~112.67) 47.64(20.28~77.13) H=4.635 0.201 戊酸(μg/g) 123.18(102.53~159.78) 52.64(7.38~128.77)1) 99.85(31.73~232.23) 204.17(160.05~236.48)1)2)3) H=36.082 ＜0.001 己酸(μg/g) 4.92(3.81~6.16) 1.33(0.87~2.94)1) 6.39(1.61~28.03)2) 7.96(5.95~10.45)1)2) H=36.414 ＜0.001 注：与健康组比较，1)P＜0.05；与NAFL组比较，2)P＜0.05；与NASH组比较，3)P＜0.05。
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表 4 治疗前后临床指标比较
Table 4. Comparison of clinical indexes before and after treatment
项目 治疗前 治疗后 Z值 P值 HbA1c(%) 7.75(7.28~8.35) 3.80(3.43~4.80) -2.805 0.005 FPG(mmol/L) 7.30(5.45~7.95) 4.70(4.13~5.33) -2.703 0.007 TG(mmol/L) 2.40(1.45~3.20) 1.42(1.32~1.58) -2.193 0.028 TC(mmol/L) 4.49(3.95~5.43) 3.64(3.15~4.23) -2.599 0.009 ALT(U/L) 151.00(119.50~168.50) 34.00(21.00~42.75) -2.805 0.005 AST(U/L) 51.50(32.75~113.50) 19.50(17.75~21.25) -2.701 0.007 ALP(U/L) 108.50(93.50~121.50) 83.50(73.50~97.50) -1.939 0.052 GGT(U/L) 100.50(67.50~136.25) 24.50(19.00~30.25) -2.803 0.005 TBil(μmol/L) 19.30(16.90~37.25) 20.70(19.30~21.70) -0.459 0.646 DBil(μmol/L) 5.20(4.25~9.15) 4.05(2.35~7.00) -1.580 0.114 IBil(μmol/L) 13.45(8.45~19.40) 17.95(17.18~19.03) -1.172 0.241 TBA(μmol/L) 7.43(4.28~9.14) 3.45(3.05~4.56) -1.988 0.047 Alb(g/L) 45.60(41.15~48.08) 46.50(43.80~52.93) -1.784 0.074 GLB(g/L) 25.30(21.80~27.35) 27.15(23.98~36.63) -1.886 0.059 PT(s) 10.15(9.90~10.75) 7.05(5.83~7.73) -2.807 0.005 APTT(s) 23.10(22.15~26.23) 23.05(21.38~25.38) -0.561 0.575 UA(μmol/L) 427.50(340.00~542.00) 225.50(168.75~298.50) -2.803 0.005 CAP(dB/m) 328.00(287.75~353.00) 159.50(131.25~223.75) -2.803 0.005 LSM(kPa) 5.90(4.80~7.40) 4.00(3.18~4.70) -2.668 0.008
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表 5 治疗前后SCFA水平比较
Table 5. Comparison of SCFA level before and after treatment
项目 治疗前 治疗后 Z值 P值 乙酸(μg/g) 1052.69(678.66~1621.09) 1412.39(1118.70~1865.72) -2.803 0.005 丙酸(μg/g) 787.81(338.24~1142.04) 955.57(556.52~1273.95) -2.803 0.005 异丁酸(μg/g) 49.82(17.00~106.54) 22.71(9.05~61.05) -2.803 0.005 丁酸(μg/g) 711.04(327.18~852.75) 690.86(549.47~967.25) -1.070 0.285 异戊酸(μg/g) 38.48(16.84~120.40) 41.37(22.29~71.78) -0.866 0.386 戊酸(μg/g) 86.00(16.34~294.74) 40.97(25.31~101.97) -1.784 0.074 己酸(μg/g) 2.41(1.52~13.41) 2.45(1.78~3.32) -0.764 0.445
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表 6 肠道内主要微生物数量及其代谢产物
Table 6. The number of major microorganisms in the gut and their metabolites
菌属 粪便中平均菌数
(log10, CFU/g)主要发酵产物 拟杆菌属 11.3 乙酸、丁酸、琥珀酸 双歧杆菌属 10.2 乙酸、乳酸、甲酸 真杆菌属 10.7 乙酸、丁酸、乳酸 瘤胃球菌属 10.2 乙酸 消化链球菌属 10.1 乙酸、乳酸 梭菌属 9.8 乙酸、丙酸、丁酸、乳酸 乳杆菌属 9.6 乳酸 链球菌属 8.3 乙酸、乳酸
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