Nuclear magnetic resonance based metabolomics and liver diseases: Recent advances and future clinical applications

Table 1 Advantages and disadvantages of nuclear magnetic resonance and mass spectroscopy

	NMR	MS
Sensitivity (detection limit)	Usually micromolar (nanomolar with cryosonde)	Picomolar
Reproducibility	High	Low
Detected	Non targeted approach	Targeted approach
Metabolite	Detect metabolite Only if contain proton on the molecule	Need specific preparation to well detected some metabolites (Lipids…)
Metabolite identification	Easy, using 1D and/or 2D spectra and databases	More difficult, need sometime complementary analysis
Number of know identifiable metabolites	More than 200	More than 4000
Sample	Simple preparation (minimal add of D2O, Buffer and sometime reference)	Preparation more complex (protein extraction, etc.)
	Non destructive method	Destructive method
	Need 400 μL (less than 10 μL with microprobe)	Need few microliters
Type of sample	Liquid (urine, whole blood, serum, plasma, etc.) and intact tissue	Liquid
Cost of machine	Very high	High
Cost of sample analysis	Lower	Higher
Signal acquisition time	5 to 15 min for 1D spectra	Around 10 min
	More longer for 2D spectra (few hours)

NMR: Nuclear magnetic resonance; MS: Mass spectroscopy.

Table 2 Examples of metabolite changes involved in liver diseases in nuclear magnetic resonance based metabolomics approaches

Metabolites	Variation	Model/pathology	Sample	Ref.
2OH butyrate	-	HBV vs HEV	Plasma	[36]
3OH butyrate	+	ximelagatran toxicity	Plasma	[37]
3OH butyrate	+	Cirrhosis (HBV/alcohol) vs controls	Serum	[24]
Acetate	+	acetaminophen toxicity	Urine	[14]
Acetate	+	HCC vs cirrhosis	Serum	[29]
Acetate	-	Cirrhosis severity	Serum	[20]
Acetoacetate	-	Cirrhosis and encephalopathy	Serum	[26]
Acetoacetate	+	Cirrhosis (HBV/alcohol) vs controls	Serum	[24]
Acetoacetate	-	HBV vs alcohol cirrhosis	Serum	[24]
Acetoacetate	-	HBV vs control	Urine	[36]
Acetoacetate	+	AIH vs healthy, PBC, OS and DILI	Plasma	[17]
Acetone	-	HEV vs control	Plasma	[36]
Acetone	+	Cirrhosis (HBV/alcohol) vs controls	Serum	[24]
Acetone	-	Decompensated vs compensated cirrhosis	Serum	[25]
acetone	-	HCC vs Cirrhosis vs controls	Urine	[31]
Acetone	+	AIH vs healthy, PBC, OS and DILI	Plasma	[17]
bile acids	+	Cholangicarcinoma vs other causes	Bile	[38]
Bile acids	+	HCC vs adjacent tissue	Liver tissue	[39]
Carnitine	-	HBV vs control	Plasma	[36]
Citrate	+	AIH vs healthy, PBC, OS and DILI	Plasma	[17]
Choline	-	fibrosis vs cirrhosis	liver tissue	[21]
Choline	+	HCC vs adjacent tissue	liver tissue	[39]
Choline, P-choline	-	Cirrhosis severity	serum	[20]
Creatine	+	AIH vs healthy, PBC, OS and DILI	Plasma	[17]
Creatine	+	high grade HCC vs low grade HCC	Liver tissue	[39]
Dimethylamine	+	AIH vs healthy, PBC, OS and DILI	Plasma	[17]
Fatty acids	-	Biliary tract cancer	Bile	[33]
Fatty acids	-	Non fonctionnal vs fonctionnal graft after liver transplantation	Blood (extraction)	[34]
fatty acids	-	Cirrhosis and encephalopathy	Serum	[26]
fatty acids (HDL)	-	Cirrhosis severity	Serum	[20]
fatty acids (HDL)	-	HCC vs cirrhosis	Serum	[29]
Glutamine	+	AIH vs healthy, PBC, OS and DILI	Plasma	[17]
Glycerol	+	HEV vs control	Plasma	[36]
Glycerol	+	Cirrhosis and encephalopathy	Serum	[26]
GPC	-	mild vs moderate fibrosis vs cirrhosis	Liver tissue	[40]
GPC	+	HCC vs adjacent tissue	Liver tissue	[39]
GPC/P-choline	-	Cirrhosis (HBV/alcohol) vs controls	Serum	[24]
Histidine	+	AIH vs healthy, PBC, OS and DILI	Plasma	[17]
Isobutyrate	+	Cirrhosis (HBV/alcohol) vs controls	Serum	[24]
Isobutyrate	+	HBV vs alcohol cirrhosis	Serum	[24]
LDL	-	Cirrhosis (HBV/alcohol) vs controls	Serum	[24]
LDL	-	decompensated vs compensated cirrhosis	Serum	[25]
lipids	-	HCC vs adjacent tissue	Liver tissue	[39]
lipids	-	high grade HCC vs low grade HCC	Liver tissue	[39]
OH-butyrate	-	Cirrhosis severity	Serum	[20]
P-choline	+	Fibrosis vs cirrhosis	Liver tissue	[21]
P-choline	-	Mild vs moderate fibrosis vs cirrhosis	Liver tissue	[40]
P-choline	+	HCC vs adjacent tissue	Liver tissue	[39]
P-choline	+	Cirrhosis and encephalopathy	Serum	[26]
P-choline/GPC	-	High grade HCC vs low grade HCC	Liver tissue	[39]
Pdt-choline	+	Cholangicarcinoma vs non cancer	Bile	[38]
Pdt-choline	-	Mild vs moderate fibrosis vs cirrhosis	Liver tissue	[40]
P-ethanolamine	+	HCC vs adjacent tissue	Liver tissue	[39]
P-ethanolamine	+	High grade HCC vs low grade HCC	Liver tissue	[39]
P-ethanolamine	+	Fibrosis vs cirrhosis	Liver tissue	[21]
PUFA	-	Mild vs moderate fibrosis vs cirrhosis	Liver tissue	[40]
Pyruvate	+	AIH vs healthy, PBC, OS and DILI	Plasma	[17]
Saturation index	+	Mild vs moderate fibrosis vs cirrhosis	Liver tissue	[40]
Total lipids	+, -	Mild vs moderate fibrosis vs cirrhosis	Liver tissue	[40]
Total choline/lipids	-	Mild vs moderate fibrosis vs cirrhosis	Liver tissue	[40]
Unsaturated FA	+	Fibrose vs cirrhose	Liver tissue	[21]
Unsaturated FA	+	Cirrhosis (HBV/Alcohol) vs controls	Serum	[24]
VLDL	-	Cirrhosis (HBV/Alcohol) vs controls	Serum	[24]
VLDL	-	Decompensated vs compensated cirrhosis	Serum	[25]

HBV: Hepatitis B virus; HBE: Hepatitis E virus; HBC: Hepatitis C virus; HCC: Hepatocellular carcinoma; AIH: Autoimmune hepatitis; OS: Overleap syndrome; PBC: Primary biliary cirrhosis; DILI: Drug induced liver injury; FA: Fatty acid; HDL: High density lipoproteins; LDL: Low density lipoproteins; VLDL: Very low density lipoproteins; P-choline: Phospho-choline; GPC: Glycerol-phospho-choline; P-ethanolamine: Phosphor-ethanolamine; PUFA: Polyunsaturated fatty acids; Pdt-choline: Phosphatidylcholine.