The second largest organ in the human body is the liver, weighing roughly three pounds. 1 The liver is located on the upper right side of the abdomen beneath the rib cage. 1, 2 It performs numerous functions in the body including energy metabolism, processing of foods into nutrients used for body processes, and removal of toxic substances from the blood system. 1, 2
A variety of factors can affect the liver; for example, genetic disorders, hepatitis viruses, alcohol abuse, obesity, and diabetes. Damage to the liver may result in scarring or cirrhosis over time, which could lead to liver failure and an increase risk of mortality. 2 Signs and symptoms of liver disease may include jaundice (yellowing of skin and eyes), abdominal pain and swelling, chronic fatigue, nausea or vomiting, loss of appetite, and tendency to bruise easily. 2 Complications will vary depending on the cause of the liver problem. 2
The most common cause of liver disease worldwide is non-alcoholic fatty liver disease (NAFLD), affecting up to a third of adults in developed countries. , 4 NAFLD is characterized by the accumulation of fat in liver cells similar to that in alcoholic liver disease, though it is not caused by alcohol abuse. 1, 5-6 The liver itself contains some fat, but when more than 5-10% of its weight is fat it results in steatosis or fatty liver disease. 1 NAFLD is most common in individuals who are overweight, obese, or diabetic and have high cholesterol or high triglycerides. 1 However, individuals may develop NAFLD without contributing risk factors. 1, 5
Furthermore, NAFLD has been known to cause the liver to swell leading to steatohepatitis in some individuals. This more severe form of NAFLD is called non-alcoholic steatohepatitis (NASH) and it is categorized by inflammation and damage of liver cells causing liver malfunction. 1, 5 Moreover, NASH might worsen and lead to scarring of the liver causing cirrhosis, which can further lead to liver cancer or liver failure. 1, 5-6 The purpose of this literature review is to analyze the pathogenesis and association of NASH with obesity and type 2 diabetes as well as discuss current and potential future treatment of NASH.
Pathogenesis and prevalence of NAFLD/NASH among obese and or diabetic individuals The pathogenesis of NAFLD is not fully understood nor the mechanism of the development and progression of NASH. Currently it is thought that insulin resistance (IR) plays a key role in the initiation of fat accumulation in the liver leading to NAFLD and, potentially, NASH7. According to Higuera-de la Tijera et al, IR affects lipid metabolism by increasing triglyceride synthesis and hepatic uptake of free fatty acids (FFAs). In addition, FFAs are a main source of triglyceride synthesis in the liver; therefore, high levels of FFAs lead to grater accumulation of fat in the liver cells (hepatocytes). Moreover, FFAs and cholesterol can also accumulate in liver mitochondria leading to inflammation and liver injury. 7-9
Furthermore, research indicates an association between unhealthy lifestyles and prevalence of NASH. xx This might be due to diets high in fat and carbohydrate intake, which may lead to increase failure of adaptation of proliferation and differentiation in fat cells (adipocytes). 8 Patients with NAFLD are commonly overweight or obese, and individuals with type 2 diabetes are at an increased risk of developing this disease. 0 Similarly, NASH has been associated with obesity mainly accompanied with type 2 diabetes and present abnormal enlargement of the liver (hepatomegaly). 11 Studies have found that the prevalence of NASH among individuals with both NAFLD and diabetes is 68-87%.
12-13 In addition, obesity might be the largest contributing factor for steatosis in developed countries with up to 75-100% prevalence in obese individuals. xx Obesity in NAFLD has been associated with dysfunctional adipose tissue, causing metabolic dysregulation, high levels of circulating fatty acids, and increased secretions of pro-inflammatory cytokines. 1, 14 If these conditions are left untreated it can result in lipotoxicity, leading to the development of NASH and hepatocellular death in some cases. 9, 13 In diabetic individuals, excess levels of insulin and glucose in the bloodstream can contribute to the synthesis of fatty acids and triglycerides via lipogenesis and eventually increased stores of adipose tissue. 15
Another factor that contributes to the progression of steatosis in diabetic individuals is insulin resistance adipose tissue. 5 Additionally, a diet high in carbohydrate and fructose stimulates de novo lipogenesis which further activates the hepatic inflammatory response. 15 Moreover, studies have shown that NAFLD patients who are diabetic are at an increased risk of developing fibrosis and cirrhosis compared to those who are nondiabetic. 15 Shabhonslidsuk et al found that prevalence of NAFLD in patients with diabetes was about 60%, more commonly seen in diabetic patients who were classified with class 1 or 2 obesity, and in diabetic patients who met criteria for metabolic syndrome.
The effect of weight loss on NAFLD/NASH: current treatment There are no medications for treating NAFLD, at present. The fundamental treatment for NAFLD aims at addressing metabolic risk factors via weight loss through lifestyle interventions including diet and exercise. 16 In recent studies diet and exercise have been shown to improve histology of the liver.
A recommended diet of 1,200 kcal/day and moderate exercise for 60 min/day was shown to improve steatosis in a cohort study of highly motivated liver donors. 7 High-intensity training, three times a week over 12 weeks, for 30-40 minutes was also shown to reduce hepatic steatosis. 18 Furthermore, Vilar-Gomez et al found that NASH patients with a >5% weigh loss had a 58% reduction of NASH and patients who had a >10% weigh loss were shown a 90% resolution of NASH and 45% regression of fibrosis, however this was shown to have a minimal effect on glucose control.
Other treatments that have been studied but have not been effective for example treatments of IR, drugs that induce weight loss, statins, cytoprotective agents and antioxidants, and blocker angiotensin receptor 2. 1 Potential future treatments for NFLD/NASH in obese/diabetic individuals The gut microbiome plays an important role in the understanding of the pathology of type 2 diabetes. 20 In a small experimental study, NASH patients who received probiotic treatment for 6 months were shown to have a reduction of fat accumulation in liver and lower levels of aspartate aminotransferase, an enzyme that is elevated in patients with hepatitis or cirrhosis. 21
Most recently, the gut-liver axis has been recognized as a key role in obesity, NAFLD, and NASH pathogenesis and progression. The gut microbiome and immune system actively interact and regulate inflammation, IR, gut permeability, and blood endotoxins. 8, 22 Furthermore, studies show that two groups of beneficial bacteria, Bacteroidetes and Firmicutes, make up the majority of the microbes in the human gut though ratio has been known to change particularly in obese individuals. 23 Ley et al found that obese individuals have a decreased proportion of Bacteroidetes compared to lean individuals.
This low percentage of Bacteroidetes has been associated with factors linked to the development of NAFLD (e. g. yperinsulinemia, increased gene expressions for de novo lipogenesis) in animal models. 24 Also, percentage of Bacteroidetes in NASH patients has been shown to be significantly lower independent of BMI and dietary intake compared to patients with simple steatosis and healthy individuals. 25 Energy balance may be disturbed by the low proportion of Bacteroidetes enabling more efficient bacteria in extracting energy from the diet to flourish. 25-26
However, weight loss by lifestyle interventions has been shown to increase Bacteroidetes in obese individuals as well as improve liver histology. 7-18, 23 Though, there is still a lot to research with regards to therapeutic manifestations and modifying gut microbiota via prebiotics, probiotics, and fecal transplantation. 27 Discussion and Conclusion Prevalence of NAFLD and NASH has been increasing along with obesity and diabetes rates worldwide. It has been well established that obesity and diabetes have a strong association with the NAFLD and NASH. The gold standard for diagnosis of NASH is a liver biopsy, though complications may be associated with it.
Currently the treatment for NAFLD/NASH focuses on modifying contributing factors such as obesity and diabetes. Modifications of lifestyle factors, especially dietary intake and exercise play a key role in improving and preventing the progression of NAFLD. Several pharmacological methodologies have been studied but lack effectiveness. One recent therapeutic option being studied are pre- and probiotics. The gut microbiome has contributed to the understanding of both obesity and type 2 diabetes pathology and may potentially have a role in future treatments of NAFLD/NASH.