The current guideline from the European Association for the study of the liver published in 2016, state that non-alcoholic fatty liver disease NAFLD, is defined by presence of steatosis in more than 5% of hepatocytes. The diagnosis can be made on the basis of liver biopsy or an MRI examination. The diagnosis also requires exclusion of secondary causes of liver steatosis, primarily alcohol-related liver injury. Specifically a diagnosis of NAFLD requires that the consumption of alcohol is less than 30 grams per day for men and less than 20 grams per day for women. It's not feasible to do a liver biopsy or an MRI examination in everyone who is suspected of NAFLD. In clinical practice, other more accessible examinations of hepatic steatosis are usually preferred: ultrasound examination, and the controlled attenuation parameter or CAP, which is measured during a transient aristocracy examination. Both examinations have sensitivity and specificity for diagnosing NAFLD around 80%. How could we determine the prevalence of NAFLD in the general population? Ideally, we would be doing a liver biopsy or an MRI examination on everyone in the population. No such studies have been conducted. Instead, studies have used ultrasound or serum biochemistry to diagnose NAFLD. According to a 2018 review by Younossi and colleagues, such studies have reported prevalence proportions between 5% and 44% in the general population across Europe, with an overall prevalence believed to be around 25%, as it is in the United States. The prevalence is higher, around 30% in South America, and lower around 15% in Africa. The best estimate of the global prevalence is 25% and increasing in parallel with the prevalence of obesity and type 2 diabetes. NAFLD is an umbrella term for two distinct conditions: Non-alcoholic fatty liver, NAFL or simple steatosis and non-alcoholic steatohepatitis, NASH. They can only be distinguished on liver histology. NASH is defined by presence of ballooning and lobular inflammation. NAFL is defined by absence of NASH. Fibrosis is common in NASH, but you can have NASH without fibrosis. Thus, an advantage of liver biopsy is that it provides all the key information, diagnosis of NAFLD, distinction between NAFL and NASH and extent of fibrosis. The diagnosis of NAFLD is based on hepatic steatosis, but the prognosis of NAFLD depends on hepatic fibrosis. That's an important difference for many clinical decisions, such as the decision to do a liver biopsy. Not all patients with NAFLD will have a liver biopsy. As hepatologists, we aim to biopsy those who are more likely to have extensive liver fibrosis. We can find them with surrogate measures of fibrosis, that is, transient elastography or the FIB-4 blood test. We also aim to biopsy those who are likely to have NASH as opposed to NAFL. Therefore, we are more likely to biopsy people with multiple components of the metabolic syndrome. Among patients with NAFLD, the prevalence of NASH around the world varies between 7% in Asia and 30% in North America. Considering that the prevalence of NAFLD in the general population is around 25%, the prevalence of NASH in the general population is roughly 2% - 7%. Now, I will turn to the outcomes of NAFLD. The clinically relevant liver related outcomes of NAFLD are: cirrhosis, hepatocellular carcinoma, and death and because NAFLD is closely associated with a metabolic syndrome, development of diabetes, and cardiovascular disease are also highly relevant outcomes for patients with NAFLD. It's been shown in several studies that patients with NAFLD are more likely to die from cardiovascular disease than from liver disease. One of them is a Swedish study by Hagström and colleagues, published in the Journal of Hepatology in 2017. They followed 646 patients with biopsy proven NAFLD. Of the total 214 deaths that were seen on long-term follow-up, 36.9% were from cardiovascular disease, 25.7% were from extrahepatic cancer, 8.4% were from respiratory disease, and 7.9% from liver-related causes. Liver disease is merely number four on the list of most likely causes of death among patients with NAFLD. The main purpose of that study was to examine the association between liver fibrosis and survival of patients with NAFLD. Indeed, survival did depend on the severity of fibrosis; 10-year survival was around 90% for patients with mild fibrosis, F0 to F2, the same as for controls without NAFLD. By contrast, 10-year survival was 85%, for patients with advanced fibrosis, F3, and 75% for patients with cirrhosis, F4. With the respect to the risk of liver disease, this study showed that among patients with NAFLD, those with more severe fibrosis have the highest risk of liver disease. Conversely, those with a low risk of liver fibrosis are unlikely to develop liver disease and that's why we want a non-invasive test, such as transient elastography or the FIB-4 blood test to be able to rule out significant fibrosis. That way we don't have to do a costly and possibly harmful liver biopsy in patients who are very unlikely to develop liver disease. What I have just shown you means that NAFLD is a dose-dependent risk factor for a liver disease. The dose being the severity of liver fibrosis. Is NAFLD also a dose-dependent risk factor for cardiovascular disease? Yes, apparently it is. The association between liver fibrosis, a cardiovascular mortality was examined in another Swedish study published in Hepatology in 2015. The hazard ratio of death from cardiovascular disease increased with the severity of liver fibrosis. Does this mean that fibrosis in the liver causes disease in the heart? No, that's not my interpretation. Instead, my interpretation is that the metabolic syndrome is a dose-dependent risk factor for both liver fibrosis and cardiovascular disease. This interpretation is supported by a study by Alexander and colleagues published in the BMJ in 2019. It showed that the increased risk of cardiovascular disease in patients with NAFLD is explained by established cardiovascular risk factors. It's not caused by NAFLD. NAFLD does not cause cardiovascular disease. NAFLD causes liver disease. That's it. To summarize, this directed acyclic graph, or DAG, is my simplistic representation of the causal relationships between the metabolic syndrome, cardiovascular disease, liver fibrosis, liver disease, and death. Note that the metabolic syndrome is the root cause. Liver fibrosis does not cause cardiovascular disease. Therefore, a treatment to revert liver fibrosis will not affect development of cardiovascular disease. It will however, prevent deaths from liver disease, That ain't bad. Thank you.
