- Top of page
- Patients and methods
- Author contribution
Non-alcoholic Fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide.1 Its clinical relevance arises from the fact that a considerable proportion of subjects (20–30%) develop a condition namely non-alcoholic steatohepatitis (NASH) that is a potentially progressive hepatic disorder leading to end-stage liver disease and hepatocellular carcinoma.1, 2 In addition NAFLD is considered the hepatic manifestation of insulin resistance (IR), and is therefore strongly associated with metabolic syndrome, obesity, type 2 diabetes, dyslipidemia and hypertension,3 also representing, together with the above cited conditions, an independent cardiovascular risk factor.4
Uric acid (UA), the final oxidation product of purine metabolism involved in gouty arthritis and kidney stones genesis, has been found to be also associated with different cardiometabolic diseases, like hypertension, kidney disease, metabolic syndrome and cardiovascular disease.5, 6 In these settings, available data prompted to speculate that hyperuricemia is not only an epiphenomenon of metabolic alterations, but also a factor directly involved in the pathogenesis of the above cited disorders.
In this line, considering the link between cardiometabolic alterations and NAFLD, some studies investigated the potential relation between NAFLD and UA levels.7–15 In particular some studies showed that high UA serum levels were associated with the ultrasonographic diagnosis of NAFLD,7–11 independently of metabolic risk factors, and with ALT levels also after correction for HBsAg and anti-HCV positivity.12 In addition, prospective studies observed that baseline high UA serum levels were an independent predictor over time of the development of ultrasonographic liver steatosis.13–15 Finally a recent article also identified an independent association between higher UA serum levels and development over time of cirrhosis or death for cirrhosis in a large USA database of subjects observed between 1971 and 1975.12
All above presented data therefore suggest an association between NAFLD and UA. However, these works have been performed in patients with clinical diagnosis of NAFLD, while, in this setting, no data exist about the potential association between UA serum levels and histological severity of the liver disease.
With this in mind, in a homogeneous cohort of biopsy-proven NAFLD patients, we aimed to assess the potential association between UA serum levels and histological liver damage.
- Top of page
- Patients and methods
- Author contribution
In this study of 166 compensated patients with histological diagnosis of NAFLD, mostly overweight or obese and at high prevalence of metabolic syndrome, we found that hyperuricemia was associated with histological features of the liver disease, representing an independent risk factor for higher steatosis, lobular inflammation and NAS.
Literature data showed that higher UA serum levels are associated with metabolic syndrome and its components.5, 6 Due to the strong association between these features and NAFLD other works also highlighted a link between UA serum levels and NAFLD.7–15 However, all these studies found a relationship between UA serum levels and clinically diagnosed NAFLD (ultrasound evidence or laboratory surrogates of steatosis), while data on patients with biopsy-proven NAFLD are lacking.
In our study we found that the severity of steatosis was independently associated not only with lobular inflammation, but also with hyperuricemia. This finding is in line with different studies in Asiatic and Italian populations demonstrating an independent link between UA and clinically diagnosed NAFLD,7–11 or hypertransaminasaemia.12
To the best of our knowledge, this is the first study that assessed the potential association between hyperuricemia and severity of liver damage in NAFLD patients. In this line the novel finding of this article lies in the identification of an independent association between the presence of hyperuricemia and the severity of both lobular inflammation and NAS in a cohort of histologically diagnosed NAFLD patients. In particular we found that lobular inflammation was independently associated with both older age and UA levels. Similarly, we found that a NAS ≥ 5, expression of liver inflammatory alterations suggestive of a diagnosis of NASH, was independently associated with hyperuricemia, after correction for and together with IR, a well-known factor linked to the pathogenesis of NASH. Our data therefore are in line with recent studies that identified in higher UA levels not only an independent predictor of NAFLD occurrence among large cohorts of Asiatic subjects,13–15 but also a predictor of cirrhosis development and cirrhosis-related death in a large cohort of American subjects.12 These epidemiological evidences, together with our data on a well characterised biopsy-proven group of NAFLD patients therefore suggest a pathogenic role of UA on the severity of liver damage. In this line recent studies strongly suggested to consider hyperuricemia a direct factor in the pathogenesis of metabolic disorders like hypertension or impaired glucose tolerance, and not an epiphenomenon of the same metabolic alterations.5, 25, 26
Although this study was not designed to clarify the pathogenetic link between UA and severity of liver disease in NAFLD patients, a few hypotheses may be put forward according to the literature. Experimental data showed that UA is able to induce endothelial dysfunction, IR, oxidative stress and systemic inflammation,5, 6 all factors involved in NAFLD pathogenesis.1 In particular a recent mouse model showed that hyperuricemia might be partially responsible for the pro-inflammatory endocrine imbalance in the adipose tissue (increased monocyte chemotactic protein-1 and decreased adiponectin production), which is an underlying mechanism of the low-grade inflammation and IR in subjects with NAFLD.27 In line with these experimental data we found a relation between higher UA serum levels and lower adiponectin serum levels in our NAFLD patients, suggesting, together with the above cited study, a possible interference of UA on adiponectin expression, such as one of the possible mechanisms by which UA could act in the pathogenesis of NAFLD.
Interestingly we found that a high NAS was also independently associated with female gender. We have no explanation for this issue, and further large scale studies should be designed to explore what is the pathogenic stem of this association. However, consistent with our data, we can hypothesise that the higher prevalence of metabolic syndrome and the higher HOMA values found in our population among women compared with men, could partially explain our results.
Finally, we found no association between significant fibrosis and UA, while we confirmed IR and NAS, well-known risk factors for fibrosis,28–30 as independently associated with significant fibrosis. Our data are not in contrast to the finding of Afzali and colleagues,12 that identified higher UA baseline serum levels as a predictor of cirrhosis development in a large cohort of patients without histological characterisation of liver damage. In fact, according to our data (direct relation between NAS and UA) and to those of Afzali et al.,12 it is possible to speculate that UA might participate in the progression of liver disease and finally in the cirrhosis development, by promoting and amplifying liver inflammation.
Our data therefore identified in hyperuricemia, a new potential pathogenetic trigger for NAFLD patients, suggesting that the pharmacological correction of this disorder, together with lifestyle counselling, could impact on disease severity and disease progression.
The main limitation of this study lies in its cross-sectional nature, making it impossible to dissect the temporal relation between hyperuricemia and histological severity of NAFLD. A further methodological question is the potentially limited external validity of the results for different populations and settings. Our study included a cohort of Italian subjects enrolled at a tertiary care centre, who may be different from the majority of prevalent cases of NAFLD in the general population. Lack of data on the prevalence of hyperuricemia in a matched control population, and on serum levels of other adipocytokines, and on liver expression of pro-inflammatory cytokines and adipocytokines, might also affect interpretation of the results.
In conclusion, this study, on a cohort of patients with histological diagnosis of NAFLD, showed an independent link between hyperuricemia and the severity of liver damage. In particular we found that hyperuricemia was independently associated with the severity of steatosis, lobular inflammation and NAS, representing, together with IR, a potential relevant factor in the pathogenesis of NAFLD. These results, needing further validation in large scale studies, could also suggest testing hyperuricemia as a new therapeutic target in future intervention trials on NASH patients.