Fatty Liver Disease: Types | Causes | Signs and Symptoms |Treatment & Management| Prevention & Reversal of Fatty Liver Disease

National Institute of Diabetes and Digestive and Kidney Diseases (2016) defies fatty liver disease (FLD), also known as hepatic steatosis, as a condition where excess fat builds up in the liver. The amount of fatty acid in the liver depends on the balance between the processes of delivery and removal. In some patients, fatty liver may be accompanied by hepatic inflammation and liver cell death (steatohepatitis). Potential pathophysiologic mechanisms for fatty liver include decreased mitochondrial fatty acid beta-oxidation, increased endogenous fatty acid synthesis or enhanced delivery of fatty acids to the liver and deficient incorporation or export of triglycerides as very low-density lipoprotein (VLDL) (Tommolino, 2018).

At the onset of fatty liver disease, the hepatocytes present small fat vacuoles (liposomes) around the nucleus (microvesicular fatty change). In this stage, liver cells are filled with multiple fat droplets that do not displace the centrally located nucleus. In the late stages, the size of the vacuoles increases, pushing the nucleus to the periphery of the cell, giving characteristic signet ring appearance (macrovesicular fatty change). These vesicles are well-delineated and optically “empty” because fats dissolve during tissue processing. Large vacuoles may coalesce and produce fatty cysts, which are irreversible lesions. Macrovesicular steatosis is the most common form and is typically associated with alcohol, diabetes, obesity, and corticosteroids. Acute fatty liver of pregnancy and Reye’s syndrome are examples of severe liver disease caused by microvesicular fatty change (Goldman, 2003).

Defects in fatty acid metabolism are responsible for pathogenesis of FLD, which may be due to imbalance in energy consumption and its combustion, resulting in lipid storage, or can be a consequence of peripheral resistance to insulin, whereby the transport of fatty acids from adipose tissue to the liver is increased. Impairment or inhibition of receptor molecules (PPAR-α, PPAR-γ and SREBP1) that control the enzymes responsible for the oxidation and synthesis of fatty acids appears to contribute to fat accumulation. In addition, alcohol use disorder is known to damage mitochondria and other cellular structures, further impairing cellular energy mechanism. On the other hand, non-alcoholic FLD may begin as excess of unmetabolised energy in liver cells. Hepatic steatosis is considered reversible and to some extent nonprogressive if the underlying cause is reduced or removed (Reddy & Rao, 2006).

Types of Fatty Liver Disease

There are two main types of fatty liver disease, nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD).

Nonalcoholic Fatty Liver Disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is an umbrella term for a range of liver conditions affecting people who drink little to no alcohol. As the name implies, the main characteristic of NAFLD is too much fat stored in liver cells (Mayo Clinic, 2020).

Sethi (2020) classified nonalcoholic fatty liver disease into nonalcoholic steatohepatitis (NASH) and acute fatty liver of pregnancy (AFLP)

  • Nonalcoholic Steatohepatitis (NASH): Nonalcoholic steatohepatitis (NASH) is a type of NAFLD which occurs when a build-up of excess fat in the liver is accompanied by liver inflammation. When there is an excess fat in the liver and the liver is inflamed for people with no history of heavy alcohol use, it may be diagnosed as NASH. When left untreated, NASH can cause scarring of your liver. In severe cases, this can lead to cirrhosis and liver failure (Sethi, 2020).
  • Acute Fatty Liver of Pregnancy (AFLP): Acute fatty liver of pregnancy (AFLP) is a rare but serious complicationof pregnancy. The exact cause is unknown. When AFLP develops, it usually appears in the third trimester of pregnancy. If left untreated, it poses serious health risks to the mother and growing baby. If diagnosed with AFLP, doctors will want to deliver the baby as soon as possible. Thereafter, the mother is given receive follow-up care for several days after giving birth. The liver health will likely return to normal within a few weeks of giving birth (Sethi, 2020).
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Alcoholic Fatty Liver Disease (AFLD)

According to Sethi (2020), drinking a lot of alcohol damages the liver. The damage inhibits the ability of the liver to properly break down fat. This can cause fat to build up, which is known as alcoholic fatty liver. Alcoholic fatty liver disease (ALFD) is the earliest stage of alcohol-related liver disease. If there’s no inflammation or other complications along with the build-up of fat, the condition is known as simple alcoholic fatty liver.

Alcoholic steatohepatitis (ASH) which is a type of AFLD occurs when a build-up of excess fat in the liver is accompanied by liver inflammation. This is also known as alcoholic hepatitis.  If there is excess fat in the liver and the liver is inflamed for people who drink a lot of alcohol, the person may be diagnosed with ASH. If it’s not treated properly, ASH can cause scarring of the liver. Severe liver scarring is known as cirrhosis which can lead to liver failure (Sethi, 2020).

Signs and Symptoms of Fatty Liver Disease

Cleveland Clinic (2020) noted that people with fatty liver disease often have no symptoms until the disease progresses to cirrhosis of the liver. Some common symptoms may include:

  • Abdominal pain or a feeling of fullness in the upper right side of the abdomen (belly).
  • Nausea, loss of appetite or weight loss.
  • Yellowish skin and whites of the eyes (jaundice).
  • Swollen abdomen and legs (edema).
  • Extreme tiredness or mental confusion.
  • Weakness.

Causes and Risk Factors of Fatty Liver Disease

Sethi (2020) stated that the cause of fatty liver disease is not entirely clear. However, genetics may play a role. Specific genes may increase the chances of a person developing NAFLD by up to 27%. Some health conditions which can increase the risk of developing NAFLD are:

  • having overweight or obesity
  • high blood pressure
  • type 2 diabetes
  • metabolic syndrome, which is a group of medical conditions and characteristics linked to obesity.
  • insulin resistance
  • High levels of fat in a person’s blood, such as high cholesterol and triglycerides, contribute to the risk of developing fatty liver disease.
  • Less common causes of fatty liver disease include hepatitis C infection, rapid weight loss, and some medications, including diltiazem and glucocorticoids.
  • Excess consumption of alcohol causes alcoholic fatty liver disease. The liver breaks down alcohol and removes it from the body. As alcohol breaks down, it releases harmful toxins that can damage liver cells and cause inflammation.

Treatment and Management of Fatty Liver Disease

Tommolino (2018) stated that no definitive pharmacologic therapy has been approved for treatment of nonalcoholic fatty liver disease (NAFLD). Management of NAFLD should include treating the associated obesity, hyperlipidemia, insulin resistance, and type 2 diabetes. Although alcohol-induced hyperhomocysteinemia (which has been associated with endoplasmic reticulum stress leading to apoptosis and up-regulation of lipid synthesis) and its correction by betaine have been studied in animal models, no definite role of the use of betaine to treat alcoholic fatty liver in humans is available. Weight loss and control of comorbidities appear to slow the progress of NAFLD and may reverse some of the steatosis and fibrosis. In a randomized trial, improvement on liver biopsy was seen after a 7% weight loss resulting from lifestyle changes (improved diet, exercise, and behavioral modification) (Promrat, Kleiner, Niemeier, et al., 2010). No established treatment is available for nonalcoholic steatohepatitis (NASH). Although no proven medical therapy is available, a study by Foster et al found that atorvastatin 20 mg, combined with vitamins C and E, is effective in reducing the odds of having hepatic steatosis by 71% in healthy individuals with NAFLD after 4 years of active therapy (Foster, Budoff, Saab, Ahmadi, Gordon, & Guerci, 2011).

Chalasani, Younossi, Lavine, et al, (2018) pointed out that the 2018 practice guidelines from the American Association for the Study of Liver Diseases (AASLD) include the following recommendations regarding treatment of NAFLD:

  • Weight loss of 3%-5% of body weight generally reduces hepatic steatosis, but up to 10% weight loss may be needed to improve necroinflammation.
  • A combination of reduced calorie diet and moderate intensity exercise may aid in sustaining weight loss, along with aggressive modification of cardiovascular risk factors.
  • Patients with NAFLD should not consume heavy amounts of alcohol; data are insufficient to make recommendations with regard to nonheavy alcohol consumption.
  • Pharmacologic treatments should be limited to individuals with biopsy-proven NASH and fibrosis.
  • Vitamin E 800 IU/day improves liver histology in nondiabetic adults with biopsy-proven NASH; it should therefore be considered as a first-line pharmacotherapy for this patient population, and the risks and benefits should be discussed with the patient prior to starting treatment.
  • Omega-3 fatty acids may be considered for hypertriglyceridemia in patients with NAFLD, but it is premature to recommend them for the specific treatment of NAFLD or NASH.
  • Metformin is not recommended as a specific treatment for liver disease in adults with NASH.
  • Pioglitazone may be used to treat steatohepatitis in both patients with and without type 2 diabetes with biopsy-proven NASH, but the risks and benefits should be thoroughly discussed with the patient prior to initiation of treatment.
  • Glucagon-like peptide (GLP)-1 agonists have been studied to treat liver disease in patients with NAFLD or NASH; however, it is still premature to consider these agents as treatment options at this time.
  • Foregut bariatric surgery is not contraindicated in otherwise eligible obese individuals with NAFLD or NASH but without established cirrhosis; however, it is premature to consider foregut bariatric surgery as an established option to treat NASH specifically.
  • Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are not recommended to treat NASH or NAFLD.
  • Statins can be used to treat dyslipidemia in patients with NAFLD and NASH, but they should not be used specifically to treat NASH, pending evidence from randomized controlled trials. Statins should be avoided in patients with decompensated cirrhosis.
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Abstinence from Alcohol

Abstinence from alcohol may reverse steatosis in patients with alcohol-related fatty liver. The steatosis usually resolves within 2 weeks of discontinuance of alcohol. Almost all authorities agree that abstinence from alcohol improves survival and is the cornerstone of long-term management in these patients. Management of patients with alcoholism and fatty liver often requires recognition and treatment of alcohol withdrawal (Tommolino, 2018).

Diet and Weight Loss

No specific dietary restrictions are needed in patients with simple alcoholic steatosis. Patients with alcoholic fatty liver may have deficiencies of vitamins, minerals, and trace elements. Adequate replacement of these deficiencies should be a part of management. Protein-calorie malnutrition is a common finding in patients with alcoholic liver disease (ALD) and is associated with the major complications observed with cirrhosis. Consequently, it is vital to recognize and understand the significance of malnutrition in these patients. A low-fat American Diabetes Association (ADA) diet is recommended, and a weight loss goal of 1-2 pounds per week is suggested. Diets associated with improvement include those restricted in rapidly absorbed carbohydrates and those with a high protein-to-calorie ratio. Weight loss should be gradual, moderate, and controlled. Mounting evidence indicates that high-fructose diets (eg, sodas and preserved foods) are factors for developing fatty liver and that their elimination may reverse fatty liver.  The mechanism appears to be related to depletion of adenosine triphosphate (ATP), as well as to increased uric acid production from excess fructose. In mouse models of NASH, a high-fat diet combined with a high-fructose diet (equivalent to the typical American “fast food diet”) resulted in more liver damage than a high-fat diet alone (Tommolino, 2018).

Treatment of the Underlying Disease

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Patients with celiac sprue who follow a gluten-free diet can experience reversal of fatty liver disease. Patients with growth hormone deficiency who receive growth hormone can experience reversal of NASH (Takahashi, Iida, Takahashi, et al., 2007).

Exercise

Multiple human studies have shown that exercise added to diet appears to improve the results and increase insulin sensitivity by increasing muscle mass. Exercise that includes both cardiovascular fitness and weight training should improve NASH. Cardiovascular fitness often results in weight loss. Weight training will increase the muscle mass and improve insulin sensitivity. Combining these two activities helps relieve the underlying derangements of NASH (Tommolino, 2018).

Pharmacologic Therapy

A number of studies have been initiated to evaluate the therapeutic roles of lipid-lowering agents and insulin sensitizers in the management of fatty liver. Specifically, thiazolidinediones (eg, pioglitazone and rosiglitazone), metformin, gemfibrozil, and atorvastatin have all been found to yield laboratory and histologic improvement in small uncontrolled trials (Georgescu & Georgescu, 2007).

Prevention and Reversal of Fatty Liver Disease

According to Better Health Channel (2018), there are no medical or surgical treatments for fatty liver, but some steps may help prevent or reverse some of the damage. In general, if you have fatty liver, and in particular if you have NASH, you should:

  • lose weight – safely. This usually means losing no more than half to one kilogram (one to two pounds) a week
  • lower your triglycerides through diet, medication or both
  • avoid alcohol
  • control your diabetes, if you have it
  • eat a balanced, healthy diet
  • increase your physical activity
  • get regular check-ups from a doctor who specialises in liver care.

References

Better Health Channel (2018). Liver-fatty disease. Retrieved from https://www.betterhealth.vic.gov.au/health/ConditionsAndTreatments/liver-fatty-liver-disease#prevention-and-reversal-of-fatty-liver-disease on 1st May, 2021.

Chalasani, N., Younossi, Z., Lavine, J.E., et al. (2018). The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 67(1):328-57.

Cleveland Clinic (2020). Fatty liver disease. Retrieved from https://my.clevelandclinic.org/health/diseases/15831-fatty-liver-disease#symptoms-and-causes on 1st May, 2021.

Foster, T., Budoff, M.J., Saab, S., Ahmadi, N., Gordon, C. & Guerci, A.D. (2011). Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial. Am J Gastroenterol. 106(1):71-7.

Georgescu, E.F. & Georgescu, M. (2007). Therapeutic options in non-alcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study. J Gastrointestin Liver Dis. 16(1):39-46.

Goldman, L. (2003). Cecil Textbook of Medicine – 2-Volume Set, Text with Continually Updated Online Reference. Philadelphia: W.B. Saunders Company.

Mayo Clinic (2020). Nonalcoholic fatty liver disease. Retrieved from https://www.mayoclinic.org/diseases-conditions/nonalcoholic-fatty-liver-disease/symptoms-causes/syc-20354567 on 1st May, 2021

National Institute of Diabetes and Digestive and Kidney Diseases (2016). Nonalcoholic Fatty Liver Disease & NASH”. Retrieved from https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/all-content on 1st May, 2021.

Promrat, K., Kleiner, D.E., Niemeier, H.M., et al. (2010). Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 51(1):121-9.

Reddy, J.K. & Rao, M.S. (2006). Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. American Journal of Physiology. Gastrointestinal and Liver Physiology. 290 (5): G852-8. doi:10.1152/ajpgi.00521.2005.

Sethi, S. (2020). Everything You Need to Know About Fatty Liver. Retrieved from https://www.healthline.com/health/fatty-liver on 1st May, 2021.

Takahashi, Y., Iida, K., Takahashi, K., et al. (2007). Growth hormone reverses nonalcoholic steatohepatitis in a patient with adult growth hormone deficiency. Gastroenterology. 132(3):938-43.

Tommolino, E.(2018). Fatty Liver. Retrieved from https://emedicine.medscape.com/article/175472-overview on 1st May, 2021

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