INTRODUCTION:

Nonalcoholic fatty liver disease is a term used to describe the accumulation of fat in the liver of people who drink little or no alcohol. Non-alcoholic fatty liver disease (NAFLD) is increasingly diagnosed worldwide and is the most common cause of abnormal liver function tests and chronic liver disease in both developed and developing countries. Because of its strong association with central obesity, reduced glucose tolerance, type 2 diabetes mellitus, arterial hypertension and hypertriglyceridaemia, NAFLD is universally considered as the hepatic manifestation of the metabolic syndrome (MS) and insulin resistance is regarded as its key pathophysiological hallmark ^[1][2].

Nonalcoholic fatty liver disease is common and, for most people, causes no signs and symptoms and no complications. But in some people with nonalcoholic fatty liver disease, the fat that accumulates can cause inflammation and scarring in the liver. This more serious form of nonalcoholic fatty liver disease is sometimes called nonalcoholic steatohepatitis. At its most severe, nonalcoholic fatty liver disease can progress to liver failure. Nonalcoholic fatty liver disease is classified as either fatty liver (sometimes referred to as isolated fatty liver or IFL) or steatohepatitis (NASH). In both isolated fatty liver and NASH there is an abnormal amount of fat in the liver cells, but, in addition, in NASH there is inflammation within the liver, and, as a result, the liver cells are damaged, they die, and are replaced by scar tissue ^[2][3].

Why is Non-Alcoholic Fatty Liver disease important?

Non alcoholic fatty liver disease is important for several reasons. First, it is a common disease, and is increasing in prevalence. Second, NASH is an important cause of serious liver disease, leading to cirrhosis and the complications of cirrhosis liver failure, gastrointestinal bleeding, and liver cancer. Third, nonalcoholic fatty liver disease is associated with other very common and serious non-liver diseases, perhaps the most important being cardiovascular disease that leads to heart disease and strokes. Fatty liver probably is not the cause of these other diseases, but is a manifestation of an underlying cause that the diseases share. Fatty liver, therefore, is a clue to the presence of these other serious diseases which need to be addressed. The cause of nonalcoholic fatty liver disease is complex and not completely understood. The most important factors appear to be the presence of obesity and diabetes. It used to be thought that obesity was nothing more than the simple accumulation of fat in the body. Fat tissues were thought to be inert, that is, they served as simply storage sites for fat and had little activity or interactions with other tissues. We now know that fat tissue is very active metabolically and has interactions and effects on tissues throughout the body ^[4].

When large amounts of fat are present as they are in obesity, the fat becomes metabolically active (actually inflamed) and gives rise to the production of many hormones and proteins that are released into the blood and have effects on cells throughout the body. One of the many effects of these hormones and proteins is to promote insulin resistance in cells.

Insulin resistance is a state in which the cells of the body do not respond adequately to insulin, a hormone produced by the pancreas. Insulin is important because it is a major promoter ofglucose (sugar) uptake from the blood by cells. At first, the pancreas compensates for the insensitivity to insulin by making and releasing more insulin, but eventually it can no longer produce sufficient quantities of insulin and, in fact, may begin to produce decreasing amounts. At this point, not enough sugar enters cells, and it begins to accumulate in the blood, a state known as diabetes. Although sugar in the blood is present in large amounts, the insensitivity to insulin prevents the cells from receiving enough sugar. Since sugar is an important source of energy for cells and allows them to carry out their specialized functions, the lack of sugar begins to alter the way in which the cells function ^[5].

In addition to releasing hormones and proteins, the fat cells also begin to release some of the fat that is being stored in them in the form of fatty acids. As a result, there is an increase in the blood levels of fatty acids. This is important because large amounts of certain types of fatty acids are toxic to cells.

The release of hormones, proteins, and fatty acids from fat cells affects cells throughout the body in different ways. Liver cells, like many other cells in the body, become insulin resistant, and their metabolic processes, including their handling of fat, become altered. The liver cells increase their uptake of fatty acids from the blood where fatty acids are in abundance. Within the liver cells, the fatty acids are changed into storage fat, and the fat accumulates. At the same time, the ability of the liver to dispose of or export the accumulated fat is reduced. In addition, the liver itself continues to produce fat and to receive fat from the diet. The result is that fat accumulates to an even greater extent ^[6][7].

Causes

The cause of nonalcoholic fatty liver disease is complex and not completely understood. The most important factors appear to be the presence of obesity and diabetes. It used to be thought that obesity was nothing more than the simple accumulation of fat in the body. Fat tissues were thought to be inert, that is, they served as simply storage sites for fat and had little activity or interactions with other tissues. We now know that fat tissue is very active metabolically and has interactions and effects on tissues throughout the body ^[8].

Symptoms

As with many other types of chronic liver disease, most patients with NAFLD are asymptomatic.

The liver disease is often discovered incidentally during routine laboratory examination when a hepatic panel reveals an elevated ALT level. NAFLD is the most common cause for unexplained persistent elevation of ALT levels once hepatitis C and other chronic liver diseases have been excluded. When symptoms occur they are usually nonspecific. Vague right upper quadrant abdominal pain, fatigue, and malaise are the most common of these nondescript symptoms. Rarely, pruritus, anorexia, and nausea may develop. Jaundice, abdominal distension (ascites), gastrointestinal bleeding, and confusion (encephalopathy) are all indicative of advanced liver disease (decompensated cirrhosis), occurring late in the course ^[10][11].

When the liver disease is far advanced (cirrhosis), signs and symptoms of cirrhosis predominate. These include :

Excessive bleeding due to the inability of the liver to make blood-clotting proteins

· Jaundice due to the inability of the liver to eliminate bilirubin from the blood

· Gastrointestinal bleeding due to portal hypertension that increases the pressure in intestinal blood vessels

· Fluid accumulation due to portal hypertension that causes fluid to leak from blood vessels and the inability of the liver to make the major blood protein, albumin

· Mental changes (encephalopathy) due to the liver's inability to eliminate chemicals from the body that are toxic to the brain. Coma may occur.

· Liver cancer

Diagnosis

As previously discussed, fatty liver generally does not cause symptoms or signs, and any symptoms and signs are more likely to be due to the accompanying diseases such as obesity, diabetes, vascular disease, etc. In anyone with obesity or diabetes, fatty liver should be suspected. In a minority of patients, abnormal liver tests are found on routine blood testing although the abnormalities usually are mild. Probably the most common method by which nonalcoholic fatty liver disease is diagnosed is by imaging studies like ultrasonography, computerized tomography (CT), and magnetic resonance imaging (MRI); that are obtained for reasons other than diagnosing nonalcoholic fatty liver disease. Nonalcoholic fatty liver disease also may be discovered when patients develop complications of the liver disease - cirrhosis, liver failure and liver cancer - due to the presence of NASH .The diagnosis of NAFLD is suspected in patients with elevated amino transferases and, in many cases, evidence of the metabolic syndrome. The distinction between NASH and simple steatosis cannot reliably be made without liver biopsy. However, it is clear that biopsy as a screening tool to distinguish these two conditions is impractical as a population-based approach. Additionally, definitive diagnosis of NAFLD and NASH requires exclusion of the multiple other causes of hepatic steatosis ^[12][13].

Treatment Management of Associated Conditions

No effective treatment has been demonstrated to alter the natural history of NAFLD. In the absence of therapeutic modalities of proven efficacy, therapy is directed towards correction of the risk factors for NASH ^[14].

Weight Management

An appropriate diet and exercise program is important. Several anecdotal studies have shown that moderate, sustained, and gradual weight loss may lead to an improvement in liver biochemistries and histology. However, there are no randomized clinical trials of weight control as a treatment for NAFLD. Obese subjects may also benefit from weight loss because of its benefits on their cardiovascular risk profile. The optimal rate and degree of weight loss have not been established, and in patients with a high degree of fatty infiltration, very rapid weight loss may cause worsening of steatohepatitis and may precipitate liver failure. Also, the risk of gallstone disease increases exponentially when the rate of weight loss exceeds 1.5 kg/week. Pharmacologic and bariatric surgical strategies have also been described as aggressive modalities for controlling weight. It remains to be proven whether the risk-to-benefit ratio of appetite suppressing medications justifies their use in NAFLD ^[13][15].

Insulin Resistance

IR is believed to be a central mechanism involved in the development of hepatic steatosis. IR can be targeted through a multifaceted approach involving weight loss, surgical intervention, or pharmacological therapy ^[14]

Lipid-Lowering Agents

Hypertrigly ceridemia is often associated with NAFLD, hence the rationale for lipidlowering agents in its management. There are no data on the use of 3-hydroxy-3- methylgutaryl–coenzyme A reductase inhibitors for the treatment of NAFLD ^[16].

Pharmacologic Therapy Offering Hepatocyte Protection

A handful of therapeutic agents thought to offer protection have been used in NAFLD patients.

Ursodeoxycholic acid (UDCA), and the anti-oxidants, betaine and vitamin E, have peer-reviewed published data. Other drugs, e.g., lecithin, β-carotene, selenium, and Nacetylcysteine, lack randomized controlled data ^[17].

Betaine

Betaine, a normal component of the metabolic cycle of methionine, is a precursor of S-adenosyl

methionine, a hepatoprotective factor. A potential role in the treatment of NASH was suggested in a pilot study involving 10 adult patients, where, after 1 year, there was a significant improvement in both biochemistry and histology ^[18].

Antioxidants

Vitamin E has been studied in NASH because of its general effects of opposing inflammation. It has been shown to reduce liver fat and inflammation and possibly fibrosis, but its long-term effectiveness and safety have not been well-studied. Moreover, treatment of patients with vitamin E who do not have NASH is associated with a higher mortality. Vitamin E can be used for treating NASH, but it should be used selectively (not in all patients), and patients should understand the potential risk ^[15][19].

Omega-3-Fatty Acid

Small studies have shown some benefit with omega-3-fatty acids in reducing liver fat in nonalcoholic fatty liver disease, and larger studies are underway. In large groups of individuals (not selected because of the presence or absence of nonalcoholic fatty liver disease), omega-3-fatty acids were shown to reduce cardio vascular events such as heart attacks and overall mortality. Therefore, omega-3-fatty acids may be appropriate treatment for patients with nonalcoholic fatty liver disease and the metabolic syndrome because these patients have a high incidence of cardiovascular disease and death ^[20].

Diseases Associated With Non-Alcoholic Fatty Liver Disease

· Fatty pancreas

· Hypothyroidism

· Colon polyps

· Elevated blood uric acid

· Vitamin D deficiency

· Polycystic ovaries

· Obstructive sleep apnea ^[21]

CONCLUSION

NAFLD is an increasingly important chronic liver disease with a wide spectrum of histopathology, ranging from bland steatosis to cirrhosis. Insulin resistance and oxidative stress play critical roles in pathogenesis. NAFLD is often asymptomatic and discovered incidentally on routine laboratory screening. It may occur in isolation or in association with other liver diseases, such as HCV. Non-alcoholic fatty liver disease is and will continue to be a major liver health issue in Western countries in the coming decades. The exact pathogenesis and natural history are still being defined. Simple steatosis is very prevalent, but fortunately does not appear to progress to advanced liver disease in majority of individuals. Those with the NASH variant have a poorer prognosis, with a significant proportion progressing to advanced fibrosis. This is a slow process, but will begin to appear in younger individuals as the obesity prevalence in children continues to rise. A major challenge is finding a diagnostic scheme to distinguish this aggressive histological variant without resorting to liver biopsy.

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Received on 03.06.2016 Modified on 20.06.2016

Research J. Pharm. and Tech 2016; 9(10):1782-1785.

DOI: 10.5958/0974-360X.2016.00360.7