Elsevier

Journal of Hepatology

Volume 44, Issue 6, June 2006, Pages 1167-1174
Journal of Hepatology

Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2

https://doi.org/10.1016/j.jhep.2006.02.011Get rights and content

Background/Aims

To elucidate the role of systemic inflammation in nonalcoholic fatty liver disease (NAFLD).

Methods

Serum samples in 47 patients with histologically verified NAFLD (22 with simple steatosis and 25 with nonalcoholic steatohepatitis [NASH]), and in 30 age-, sex- and ethnicity-matched healthy controls, were assessed for (i) general markers of inflammation (C-reactive protein [CRP], tumor necrosis factor [TNF]-α, and interleukin [IL]-6), (ii) chemokines (CC-chemokine ligand [CCL] 2/monocyte chemoattractant protein [MCP]-1, CCL19 and CCL21), (iii) adipocytokines related to insulin resistance and inflammation (adiponectin and leptin) and (iv) a marker of oxidative stress (8-isoprostane-F2α).

Results

Serum levels of several inflammatory cytokines were increased in NAFLD as compared to controls, and IL-6 (P=0.017), CCL2/MCP-1 (P=0.008) and CCL19 (P=0.001), but not CRP (P=0.199), remained elevated also after correction for sex, body mass index (BMI) and age. Comparing NASH with simple steatosis, levels of TNF-α (P=0.024) and CCL2/MCP-1 (P=0.012) were elevated and adiponectin (in women) (P=0.001) were decreased also after adjustment for sex, BMI and presence of the metabolic syndrome.

Conclusions

Our results indicate that patients with NAFLD are characterized by a low-grade systemic inflammation. The high CCL2/MCP-1 levels in NASH might be of importance for the conversion from simple steatosis to NASH.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the preferred term for a wide spectrum of liver damage, ranging from simple steatosis, to nonalcoholic steatohepatitis (NASH) and cirrhosis on the basis of longstanding fatty infiltration of the liver [1]. While NASH implies a risk of progressive liver disease [2], simple steatosis is regarded as a benign condition [3], [4].

The ‘two hit hypothesis’ has become an important theoretical framework for understanding the pathogenesis of NAFLD [5]. The ‘first hit’ is fat accumulation within the liver, a process that is closely linked with insulin resistance [6]. In the majority of patients with excess liver fat there will be no or only scarce hepatic inflammation, and the condition will be termed simple steatosis. However, a ‘second hit’ may trigger the necroinflammatory response characterizing NASH.

Irrespective of what kind of ‘second hit’ that triggers the inflammation in NASH, this process is probably, at least partly, mediated through abnormal cytokine production. Thus, tumor necrosis factor-α (TNF-α) has been incriminated to play an important pathogenic role in NASH [7], possibly partly related to its ability to induce oxidative stress. Moreover, as this cytokine may reduce insulin sensitivity [7], it may also be related to the development of simple steatosis, although the data are somewhat conflicting. In contrast to TNF-α, adiponectin, a recently identified adipocytokine with both insulin sensitizing [8] and anti-inflammatory [9] properties, may have protective effect on the development of NAFLD, potentially antagonizing the effects of TNF-α.

While the participation of inflammatory mediators in the pathogenesis of NAFLD is widely recognized, the identification of the different actors, as well as their relative importance, is not fulfilled. Thus, while several studies have explored the role of TNF-α in these disorders [7], [10], [11], much less focus has been directed against the possible involvement of other inflammatory mediators. In particular, although chemokines are of major importance for directing leukocytes into inflamed tissues, there are very few reports on the levels of these chemotactic cytokines in NAFLD.

To further elucidate the role of inflammation in NAFLD, we analyzed serum levels of a wide range of cytokines and adipocytokines in patients with histologically verified NAFLD (i.e. simple steatosis and NASH) trying to clarify if these subgroups of NAFLD were characterized by specific cytokine patterns.

Section snippets

Patients and controls

Forty-seven patients with biopsy-verified NAFLD, being part of a recent published cohort [12], were included in the study (Table 1). In the 25 patients with NASH, the grade of inflammation was mild (n=19) or moderate (n=6), and fibrosis was seen in 17 patients [stage 1 (n=13), stage 2 (n=2), stage 3 (n=1) and stage 4 (n=1)]. Among the 22 patients with simple steatosis two patients had stage 1 fibrosis. The majority of the NAFLD patients had metabolic syndrome according to the definition

Serum levels of inflammatory markers

Both patients with simple steatosis and those with NASH had significantly raised serum levels of IL-6 and CRP compared with healthy controls, with no significant differences between the two groups of patients (Table 3). As for TNFα, a more complex pattern was seen. Thus, while those with simple steatosis tended to have lower TNFα levels than controls, the NASH patients tended to have higher TNFα levels than these healthy individuals, resulting in a significant higher TNFα levels in those with

Discussion

In the present study we show that several serum markers of inflammation are elevated in patients with NAFLD comparing healthy controls. Thus, even after correction for sex, BMI and age, NAFLD was still a significant predictor of IL-6, CCL2/MCP-1 and CCL19 levels. Notably, these inflammatory mediators were elevated not only in patients with NASH, characterized by local hepatic inflammation, but also in patients with simple steatosis. Although the origin of these cytokines is uncertain, our

Acknowledgements

The assistance of Lien My Diep with statistical analyses is greatly acknowledged.

References (39)

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The work was done at the following institutions: Aker University Hospital, Oslo, Norway; Rikshospitalet, Oslo, Norway; Ullevål University Hospital, Oslo, Norway; University of Oslo.

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