INTRODUCTION:

Obesity has been one of the most dangerous and highly progressing problem that has turned itself into an epidemic especially throughout the 20^th and 21^st century. Though there are many types of fatty liver diseases, the most common form are alcoholic and non-alcoholic fatty liver diseases (NAFLD). Both of the different types are similar in such a way that it involves the accumalation of excess fat in liver cells. However, in alcoholic fatty liver disease, it involves the excessive consumption of alcohol along with fat buildup in the liver. Since about 75% of liver disease is of the non-alcoholic origin, it is deemed as the number one killer in terms of liver diseases^[1]. NAFLD affects all ages from children to adults; starting from ages as early as 2 years old. As a person ages, the tendency of having fatty liver will also increase.

This has been proved by a National Health and Nutrition Examination by a Survey that was conducted in the United States. According to the results, about 6% are overweight and 10% are obese adolescents^[2]. Though in different countries, the results differ, one thing that remains for certain is that fatty liver has had an increase in adolescents by an estimation of 174%^[3].

With the growing epidemic of this disease, physicians and patients should be equipped with the knowledge regarding this disease. With that, the aim of this review is to discuss the pathogenesis, diagnostic measures, as well as the treatment options that is available for the management of NAFLD. NAFLD is a continuous process that starts of from being a simple steatosis to NASH and ending with cirrhosis.

NAFLD can be diagnosed by the presence of high levels of lipid deposition in the liver without the excessive consumption of alcohol. In this case, in men; it is higher than 20 g/day and in women; it is higher than 10 g/day. In the case of steatosis; lipids are present in the cytoplasm of hepatocytes in three forms; which are: >55 mg/g in the liver^[4], >5% of the liver weight ^[5]or >5% of the hepatocytes^[6]. NASH involves steatosis along with the presence of damage to the hepatocytes, inflammation of the tissue. Within a period of 10 years, NASH patients will likely to develop cirrhosis^[7].

Cirrhosis will bring about complications in the liver’s ability to process lipid, that can lead to changes in the genes, diet, adipose tissue as well as both the regulation of hormone and the immune system.

PATHOGENESIS:

The pathogenesis of this disease has not been concisely putforward as it is still not fully clear. However, as of now, NAFLD is highly associated with the ‘two hit hypothesis’, insulin resistance, gut microbiota, diet as well as physical activities.

‘Two Hit Hypothesis’:

In the year 1998, this hypothesis was introduced by Day et al^[8]. The two hit hypothesis involves the sequence of two significant events in the body. The first hit is characterized by the accumulation of both triglycerides as well as FFA in hepatocytes. This increase of presence is the result of factors such as; insulin resistance, increased dietary influx and higher amounts of hepatic lipogenesis^[8]. The second hit proceeds to lipid peroxidation,mitochondrial dysfunction and inflammation. As a result, there will be damage to the hepatocyte and results in the formation of liver fibrosis^[8]. The existence of lipid peroxidation can result in the proliferation of stellate cell that will proceed to fibrogenesis that untimely will end in further injury to the liver cells.

Insulin Resistance (IR):

People who have NAFLD commonly can be associated with the reduction in their insulin sensitivity. This occurs not only in the muscles but also in the liver and adipose tissue^[9]. With IR, the adipose tissue will develop a resistance to the anti-lipolytic effect that the insulin possesses and will result in higher deposition of FFA in the liver. When lipid accumulates in the liver, this will automatically leads to distortion in the regulation of insulin secretion, changes in the glucokinase, glucose transporter-2 (GLUT 2); causing a FFA-induced B-cell apoptosis^[10].

Gut Microbiota:

In the gastrointestinal tract, there exist a community of microorganisms known as gut flora or gut microbiota. This set of complex microorganisms has been associated with numerous diseases of the GI tract. Based upon the research that was done by Backhed et al^[11], the result showed that with the presence of this microbiota, the percentage of fat increased from 40% to 60%.

Diet and daily physical activities:

The function of both diet and physical activity comes hand in hand especially in terms of the growing obese problem. In terms of NAFLD, the dietary intake of a person affects not only their calorie intake but also their insulin resistance based upon studies that were conducted. NAFLD is associated with obese people, who are involved in much lower physical activities. This statement is fully justified by the connection between soda and fructose intake with that of NAFLD. With that also comes low intake of antioxidants like Vitamin E, zinc and polyunsaturated fatty acids^[12,13,14].

DIAGNOSIS:

In the diagnosis of NAFLD, there are a few requirements such as; the presence of hepatic steatosis by imaging or histology, absence of any significant alcohol intake, the patient without present history of steatosis and lastly, the absence of any other liver diseases^[15].

In terms of the symptoms that the patient can evaluate themselves is vague, such as feeling tired as well as experiencing abdominal discomfort is the predominant one^[16]. In terms of the physical examination of the patient, factors such as body mass index (BMI), weight and blood pressure can be evaluated^[17].

Screening:

NAFLD is commonly diagnosed by the screening method but they are coincidently diagnosed in relation to other imaging procedures done for other reasons. In patients who are diabetic or who have any other high risk diseases, this method is not generally recommended because there exist many uncertainty regarding the effeciency of the test, the treatment availability, benefits, including the overall cost of the procedure^[18,
15]. At the end of the day, even if NAFLD does somewhat run in the genes, screening does not necessarily have been able to diagnosed it in future generations of the family.

Serum Markers:

In recent discovery, there are quite a number of serummarkers that can be used for NAFLD diagnosis. The most promising of them all is the usage of cytokeratin-18 fragments^{[16, 19]}. CK18 acts as an indicator for hepatocyte apoptosis that contain 66% of sensitivity and 82% of NASH diagnosis^[20]. However, it is said that CK18 is not readily available commercially^[15].

Other than the usage of CK18, some of the other serum markers include different types of cytokines, acute phase proteins as well as oxidative stress markers.

Radioactive assessment:

Another method of diagnosis that is of current usage because of its low-cost, speed and easy access is via radialogic evaluation. One form of radiology that is currently used is the Ultrasonography (US) that have an estimation of 60% to 94% in terms of sensitivity and 66% to 95% of specificity^[21]. A more enhanced Ultrasonography known as the contrast enhanced ultrasonography has more advantages in terms of an increase in sensitivity especially in diagnosing fatty liver infiltrations^[22]. However, at present, it is not readily available commercial wise.

For the last decade, the invention of transient elastography (TE) allows for the measurement of liver stiffness using the technology of ultrasound^[23]. The procedure that is done includes the introduction of low frequency vibrations to the body tissues and the energy propagation is measured. Similar to that of US, TE usage will produce a less accurate result in obese people. This is shown by the statistics that only 75% of success rate in obese patients compared to an outstanding 97% success rate in patients who are considered not obese^[23].

Out of all of the available radiology diagnosis methods, the usage of magnetic resonance spectoscopy (MRS) shows the most promising results with a success rate of 90%^[24] and accuracy of 100%^[25] in the diagnosis of steatosis. With the usage of this method, the fraction of fat in the liver can be calculated and it is said to be abnormal if the fraction is more than 5.56%^[25]. The downside to this method however is that the patient will be exposed to high amounts of radiation and it is more expensive.

Liver Biopsy:

As of current diagnosis methods, liver biposy has become the number one option out of all the available methods. The main reason behind this is because this is the only method that can differentiate between hepatic steatosis and steatohepatitis. Based upon the current AGA guidelines, thismethod should only be used if the NAFLD patient is of high risk of developing steatohepatitis and advanced fibrosis including the ones that have a metabolic syndrome. The method in liver biopsy is the determination of NAFLD Fibrosis score. During the calculation of this score, factors such as; age, glycemia, BMI, platelet count, albumin, and AST/ALT are taken into account.

TREATMENT:

Lifestyle Management:

The changing of one's lifestyle though may be effective if fully implemented, it may be hard to do. This method involves the change in both diet and exercise.On average, an individual is limited to only 500-1000 kcal per day to achieve this goal for a period of 6-12 months consistently^[26,27,28]. In terms of diet, a carbohydrate-restricted diet should be implemented in NAFLD patients^[29]. Since NAFLD is connected to carbohydrate intake, it can affect the glucose homeostasis and free fatty acid metabolism in the liver. With every 7-10% reduction in body weight, a person is said to have decrease some of the inflammation in NAFLD^[30].

Bariatric Surgery:

Bariatric surgery is a procedure that is done to achive weight loss^[31]. In NAFLD patients, it is said to decrease the characteristics of NAFLD including that of obesity. Eventhough this surgery is not specifically used for NAFLD management, it can help overweight patients who have NAFLD. This surgery serves its purpose in such a way that the insulin sensitivity is increased that will result in the improvement of a persons overall health.

Medicational Management:

Some of the most common types of pharmacological approach includes;

Insulin sensitizers:

· Since NAFLD has a strong connection with that of insulin resistance, metformin and thiazolidinedione (TZDs); which are insulin sensitizers are commonly used in treating NAFLD patients^[32].

· Metformin

· This insulin sensitizer is normally used for treating type 2 diabetes patients through the action and activation of AMPK^[33] . As a result, the peripheral glucose intake is improved, the hepatic gluconeogenesis is reduced and the beta oxidation of FFA is increased^[34].

Lipid lowering drugs:

Though there is no direct benefit to that of NAFLD management, the cardiovascular risk of NAFLD can be reduced with the usage of statins, fibrates and omega-3 polyunsaturated fatty acids^[32].

Hypertension management:

The common method of reducing hypertension in NAFLD patients is by using Angiotensin II receptor blockers (AIIRB). This blocker functions not only to inhibit proliferation of stellate cells, but also to decrease inflammation and fibrosis^[35].

Liver Transplantation:

For patients that have reached a stage where there is liver failure due to NAFLD, the only option that can be done is through liver transplant. Even with this procedure, it is likely that recurrent NASH can develop as a result of metabolic factors as well as the constant usage of immunosuppresion like corticosteroids^[36].

CONCLUSION:

With the increase of obesity rate in both the 20^th and 21^st century generation of humans, NAFLD has become one of the major diseases that have skyrocketed in the process. Though there are many remedies that exist to treat NAFLD, the number one problem that exist is that there is still less exposure to that of the pathogenesis of this disease. Because of this, more advanced research as well as exposure to new diagnostic methods should be searched. With that note, at the end of the day, prevention is better than cure in any circumstances.

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Received on 07.05.2016 Modified on 14.05.2016

Research J. Pharm. and Tech 2016; 9(8):1263-1267.

DOI: 10.5958/0974-360X.2016.00240.7