Nonalcoholic Fatty Liver Disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver injuries, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis. NAFLD is associated with insulin resistance, type 2 diabetes mellitus, obesity, hypertriglyceridemia and hypertension; thus, it is regarded as a hepatic component of the metabolic syndrome, and an independent risk factor for cardiovascular disease.

NAFLD and NASH are common causes of chronic liver disease and elevated liver enzymes. Their worldwide prevalence continues to increase with the growing obesity epidemic. Understanding the epidemiology of these pathologies is essential for developing treatment and prevention strategies. The prevalence of NAFLD and NASH in the general population has been assessed with a variety of diagnostic means, such as liver biopsy, non-invasive radiological and ultrasonic techniques, elevated liver enzymes and combinations of clinical variables. Because liver biopsy is not appropriate for population studies, only on the basis of autopsy studies it has been suggested that 3- 5% of individuals in the general population might have NASH, and 20-30% of people in industrialized countries have NAFLD. The prevalence of NAFLD increases with age, it is highest in males between 40-65 years and is higher in Hispanics and lower in African-Americans.

Ultrasound is the non-invasive method most commonly used to assess NAFLD, having a sensitivity of approximately 85% and a specificity of 94% for the detection of moderated fatty liver. Magnetic resonance imaging (MRI) has also been used to perform population studies, but it is less portable and more expensive than US. Among surrogate markers Fatty Liver Index (FLI) has gained much attention.

Several studies have shown that NASH is a risk factor for liver fibrosis. At the same time, most cases of fatty liver and even fibrosis can regress, particularly due to life style modification and weight loss. Based on the well-established strong association of the NAFLD with the metabolic syndrome and the epidemic of obesity, the prevalence of NASH is expected to increase in the next decade, leading to cirrhosis and even HCC. There is a need to perform larger, longitudinal studies that assess the long-term natural history of NAFLD with validated non-invasive biomarkers and by integrating morbidity and mortality data.

The non-alcoholic fatty liver disease (NAFLD) is a significantly increasing cause of chronic liver disease which is strongly associated with obesity and insulin resistance. Due to this association it is considered as the hepatic manifestation of the metabolic syndrome. According to the emerging clinical and epidemiological data patients with NAFLD have an increased morbidity and mortality of cardiovascular diseases (CVD), type 2 diabetes mellitus, chronic kidney disease as well as malignancies, beyond the liver-related mortality. A number of other less established comorbidities can also manifest together with NAFLD, like colorectal cancer, hypothyroidism, obstructive sleep apnea, polycystic ovarian syndrome and osteoporosis.

The majority of the patients however, maybe asymptomatic and the diagnosis is made only incidentally. Obesity, high body mass index (BMI), elevated transaminase levels and/or hyperechogenic ultrasound form the basis for the diagnosis. About 20% of the cases can progress to non-alcoholic steatohepatitis (NASH) and cirrhosis. Fibrosis, however, can be initiated either in simple steatosis or in NASH i.e. due to the most recent results, fibrosis progression is independent of the presence of NASH. In patients with simple steatosis and no inflammation, the fibrosis progression is very slow. The rapid progressors, however, can progress to cirrhosis within 2-6 years. In these patients, hypertension and diabetes are usually also present. The presence and severity of fibrosis on liver biopsy are the best indicators of long-term liver-related outcome in patients with NAFLD. The most important step during diagnosis is risk stratification.

Once a patient with NAFLD develops cirrhosis, he has the same natural history as with other etiologies. Patients with compensated cirrhosis have a 3-4% risk of mortality annually.

With the epidemic of obesity and metabolic syndrome, NAFLD is affecting a large number of the general population than ever before. Its diagnosis and monitoring can be challenging as it is more common in obese patients. It is a reversible condition, and reaching an early diagnosis could help in preventing and reversing the process. If left untreated, it can advance to liver cirrhosis, and lead to hepatocellular carcinoma in some cases. Therefore, its non-invasive accurate and early diagnosis has a significant importance in both patients and clinicians. Radiology has to offer a wide repertoire of methods that can diagnose and monitor this condition. Biopsy is very accurate, and is the only widely accepted method to distinguish NAFLD from other forms of liver disease, but its inconvenience to the patient and the general risks of invasive procedures limits its clinical use. In addition, biopsy cannot be representative to structural changes in the entire organ. Medical imaging until recent advances was not able to compete with biopsy. Non-invasive diagnostic tests that are used include ultrasonography (sonoelastography), computed tomography, and magnetic resonance imaging. Special MRI sequences (Chemical Shift Imaging, Fast SE Imaging, elastography, spectroscopy), which are capable of providing comparable results to biopsy. In contrast to biopsies, these methods provide a non-invasive way of giving a representative assessment of the whole liver.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. Although imaging techniques and serologic testing are important examinations, histology remains the gold standard to establish the diagnosis, to stratify to grade and stage the actual sample. There are two major subtypes of NAFLD, simple steatosis and the progressive form nonalcoholic steatohepatitis (NASH). Simple steatosis is characterized by fat accumulation in hepatocytes. NASH can be diagnosed if, in addition to steatosis, inflammation and hepatocyte damage in the form of ballooning is present in the liver. There may be other histological alterations with variable significance e.g. fibrosis, ductular reaction, granulomas, Mallory-Denk bodies, etc. NASH is a progressive disease, which can end up in cirrhosis. Hepatocellular carcinoma (HCC) is also a well-known complication of NASH. It can develop in cirrhotic and surprisingly in non-cirrhotic stage of NASH. The histological signs of NASH can be substantially different in pediatric patients, than in adults. Several histological scoring systems have been developed for reliable grading and staging of NAFLD. They can be used to follow up the progression of the disease, monitor the efficacy of potential therapies and to compare different studies. Future will decide which one of them proves to be most reliable, and reproducible. Finally, histological diagnosis can be important to distinguish NAFLD from other chronic liver diseases or recognize comorbidities.

Non-alcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH) are common causes of chronic liver disease and major components of the metabolic syndrome. NASH is characterized by the presence of steatosis with necro-inflammation and fibrosis, progressing to cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD and NASH originally was regarded as “two-hit” model, suggesting that the accumulation of fat in the liver cells (steatosis) as the first sensitizes the liver to a second hit that triggers a cascade of tissue damages (necro-inflammation and fibrosis). Today, it is widely accepted, that a more complex process, involving multiple parallel metabolic hits is responsible for tissue injury, and that other factors promote disease progression. Thus, now, lipotoxicity, mitochondrial dysfunction, insulin resistance and oxidative stress are considered as the main mechanisms in the pathogenesis of NASH. Reactive oxygen species (ROS), lipid peroxidation products and cytokines are involved in the progression, including the migration of resident hepatic pro-fibrogenic cells, which leads to fibrosis. Hepatocyte death, inflammation, and cellular senescence also play a role in the pathogenesis of the disease. The interaction between inflammatory cells including Th17 cells and other cell types such as hepatocytes, stellate cells, hepatic progenitor cells and ductular components is of pivotal importance, as well as the reactivation of developmental morphogenic signaling pathway, the hedgehog.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of elevated liver enzymes and chronic liver disease in the Western countries. NAFLD has been noted to be common in patients with obesity, hypertension, type 2 diabetes and atherogenic dyslipidemia. In the United States, it is estimated that NAFLD affects 20-30% of the general population. In patients with diabetes, the prevalence of NAFLD has been reported to be 70%. A high prevalence of NAFLD was found in patients with type 2 diabetes and obesity (90%). NAFLD is an independent predictor of future risk of cardiovascular diseases, and metabolic syndrome as well.

Nonalcoholic fatty liver disease and steatohepatitis are the most common chronic diseases of the liver. The process of their development has not yet been fully elucidated. It is characterized by insulin resistance, hepatic lipid accumulation with a secondary pathologic production of free radicals that induce inflammatory processes and fibrosis. There is no evidence-based therapy. It is important to eliminate the pathogenic factors (excess body weight, disordered carbohydrate metabolism, and hyperlipidemia). Potential modalities of a causal therapy include cannabinoid receptor 1 antagonists which do not cross the blood-brain barrier, cannabinoid receptor 2 agonists; selective serotonin 2C receptor agonist, thiazolidinediones, incretins, and dipeptidyl peptidase inhibitors. Additional therapeutic possibilities of the future may target antioxidant defense, immune-mediated mechanisms, apoptosis, and lipogenesis.

Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer and the third leading cause of cancer death in the world. HCC has a poor prognosis unless recognized at an early stage, underscoring the importance of prevention. HCC most often develops in cirrhosis associated with chronic viral, toxic, or genetic liver injury. Notably, HCC has a rising incidence in developed societies with an increasing evidence for the role of nonalcoholic fatty liver disease (NAFLD), which has become the most common liver condition mirroring the spread of obesity and type II diabetes. A significant proportion of HCC associated with NAFLD may occur in the absence of advanced fibrosis or cirrhosis, posing a major challenge to cost-efficient risk stratification. Beyond the strong tumorigenic milieu of cirrhosis, molecular mechanisms of hepatocarcinogenesis in NAFLD include adipose tissue expansion with a pro-inflammatory adipokine profile, general and tissue-specific lipotoxicity, and the cell growth promoting effects of elevated insulin levels. Altered gut microbiota and microRNA deregulation may also contribute to HCC development in NAFLD. After reviewing these topics, the chapter provides a brief overview of the clinical characteristics, screening, and novel opportunities in the chemoprevention of NAFLDrelated HCC.

In the past decade, obesity has reached epidemic magnitude among children and adolescents, thus associated pathologic conditions are increasing simultaneously. These conditions include insulin resistance, type 2 diabetes, metabolic syndrome, cardiovascular diseases (CVD) and fatty liver disease (NAFLD).

NAFLD, previously thought to impact adults only, shares many of the same features of the metabolic syndrome, a highly atherogenic condition. This drew increased focus to study the role of NAFLD in relation to higher overall mortality and morbidity rates and increased prevalence of cardiovascular disease (CVD).

Insulin resistance is the pathophysiologic hallmark of NAFLD, the most common form of chronic liver disease in children in today’s time. It is characterized by triglyceride accumulation with secondary free-radical production, which induces inflammatory processes and fibrosis due to numerous causes and complex mechanism.

Recent studies indicate that NAFLD has high prevalence in obese children, which has serious cosequences without treatment. Early intervention is utmost important when NAFLD is diagnosed, which should include early lifestyle modification (nutrition and physical activity, avoidance of smoking), however, no evidence based therapeutic approaches exist.