Elevated endotoxin levels in non-alcoholic fatty liver disease.
BACKGROUND
Emerging data indicate that gut-derived endotoxin may contribute to low-grade systemic inflammation in insulin resistant states. This study aimed to examine the importance of serum endotoxin and inflammatory markers in non-alcoholic fatty liver disease (NAFLD) patients, with and without type 2 diabetes mellitus (T2DM), and to explore the effect of treatment with a lipase inhibitor, Orlistat, on their inflammatory status.


METHODS
Fasted serum from 155 patients with biopsy proven NAFLD and 23 control subjects were analysed for endotoxin, soluble CD14 (sCD14), soluble tumour necrosis factor receptor II (sTNFRII) and various metabolic parameters. A subgroup of NAFLD patients were re-assessed 6 and 12 months after treatment with diet alone (n = 6) or diet plus Orlistat (n = 8).


RESULTS
Endotoxin levels were significantly higher in patients with NAFLD compared with controls (NAFLD: 10.6(7.8, 14.8) EU/mL; controls: 3.9(3.2, 5.2) EU/mL, p < 0.001); NAFLD alone produced comparable endotoxin levels to T2DM (NAFLD: T2DM: 10.6(5.6, 14.2) EU/mL; non-diabetic: 10.6(8.5, 15.2) EU/mL), whilst a significant correlation between insulin resistance and serum endotoxin was observed (r = 0.27, p = 0.008). Both sCD14 (p < 0.01) and sTNFRII (p < 0.001) increased with severity of fibrosis. A positive correlation was also noted between sTNFRII and sCD14 in the NAFLD subjects (r = 0.29, p = 0.004).Sub-cohort treatment with Orlistat in patients with NAFLD showed significant decreases in ALT (p = 0.006), weight (p = 0.005) and endotoxin (p = 0.004) compared with the NAFLD, non-Orlistat treated control cohort at 6 and 12 months post therapy, respectively.


CONCLUSIONS
Endotoxin levels were considerably increased in NAFLD patients, with marked increases noted in early stage fibrosis compared with controls. These results suggest elevated endotoxin may serve as an early indicator of potential liver damage, perhaps negating the need for invasive liver biopsy. As endotoxin may promote insulin resistance and inflammation, interventions aimed at reducing endotoxin levels in NAFLD patients may prove beneficial in reducing inflammatory burden.
Harte
Alison L
AL
University of Warwick, Unit for Diabetes and Metabolism, Warwick Medical School, Clinical Sciences Research Institute, UHCW, Clifford Bridge Road, Coventry, CV2 2DX, UK.
da Silva
Nancy F
NF
University of Warwick, Unit for Diabetes and Metabolism, Warwick Medical School, Clinical Sciences Research Institute, UHCW, Clifford Bridge Road, Coventry, CV2 2DX, UK.
Creely
Steven J
SJ
University of Warwick, Unit for Diabetes and Metabolism, Warwick Medical School, Clinical Sciences Research Institute, UHCW, Clifford Bridge Road, Coventry, CV2 2DX, UK.
McGee
Kirsty C
KC
University of Warwick, Unit for Diabetes and Metabolism, Warwick Medical School, Clinical Sciences Research Institute, UHCW, Clifford Bridge Road, Coventry, CV2 2DX, UK.
Billyard
Thomas
T
University of Warwick, Unit for Diabetes and Metabolism, Warwick Medical School, Clinical Sciences Research Institute, UHCW, Clifford Bridge Road, Coventry, CV2 2DX, UK.
Youssef-Elabd
Elham M
EM
Biochemistry Dept, National Research Center, Dokki, Giza, Egypt.
Tripathi
Gyanendra
G
University of Warwick, Unit for Diabetes and Metabolism, Warwick Medical School, Clinical Sciences Research Institute, UHCW, Clifford Bridge Road, Coventry, CV2 2DX, UK.
Ashour
Esmat
E
Biochemistry Dept, National Research Center, Dokki, Giza, Egypt.
Abdalla
Mohga S
MS
Chemistry Dept, Faculty of Science, Helwan University, Egypt.
Sharada
Hayat M
HM
Chemistry Dept, Faculty of Science, Helwan University, Egypt.
Amin
Ashraf I
AI
Clinical Pathology Dept, National Institute of Diabetes & Endocrinology, Cairo, Egypt.
Burt
Alastair D
AD
School of Clinical Medicine (Hepatology), Floor 4, William Leech Building, The Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
Kumar
Sudhesh
S
University of Warwick, Unit for Diabetes and Metabolism, Warwick Medical School, Clinical Sciences Research Institute, UHCW, Clifford Bridge Road, Coventry, CV2 2DX, UK.
Day
Christopher P
CP
School of Clinical Medicine (Hepatology), Floor 4, William Leech Building, The Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
McTernan
Philip G
PG
University of Warwick, Unit for Diabetes and Metabolism, Warwick Medical School, Clinical Sciences Research Institute, UHCW, Clifford Bridge Road, Coventry, CV2 2DX, UK.