Discover the causes, symptoms, and management strategies for non-alcoholic fatty liver disease (NAFLD) at Meri Sehat. Stay informed and take control of your liver health.

Non-Alcoholic Fatty Liver Disease (NAFLD)

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Ismail Munir

Overview

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases characterized by fat buildup in the liver, affecting people who consume little to no alcohol. Non-alcoholic fatty liver disease (NAFLD) encompasses a range of diseases, from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and liver failure. 
&nbsp;

The global prevalence rate of NAFLD is estimated to be around 25%<a href="#accordion">[3]</a>. According to research, the incidence and severity of NAFLD vary geographically, with prevalence ranging from 13% in Africa to 32% in the Middle East and 23% in Europe<a href="#accordion">[3]</a>. Ethnic differences have also been discovered. People belonging to black ethnicity show a lower incidence of the disease while Hispanic groups have higher rates of NASH.

NAFLD is associated with diseases, such as type 2 diabetes, central obesity, dyslipidemia, and metabolic syndrome. As a consequence, the incidence of NAFLD has risen from 15% in 2005 to 25% in 2010, in line with the increasing rates of obesity<a href="#accordion">[3]</a>. Furthermore, a Multiethnic Cohort study involving 215,000 patients revealed that NAFLD is the most common reason (52%) behind chronic liver disease across all ethnicities<a href="#accordion">[5]</a>.

A study from Pakistan found an overall NAFLD prevalence of 47%<a href="#accordion">[7]</a>, whereas NASH could only be completely diagnosed in 20 patients (12.3% of the total cases) in Pakistan. According to the study, Pathans had the greatest prevalence of NAFLD (58.5%), followed by Punjabis (44.5%) and Sindhis (35.3%)<a href="#accordion">[7]</a>.

&nbsp;

NAFLD is divided into: 
&nbsp;

Non-alcoholic Fatty Liver Disease (NAFLD) - This is characterized by an excessive amount of fat in the liver cells with little to no liver inflammation or damage. While pain can occur due to liver enlargement, progression to complications or liver damage is rare.

&nbsp;

Non-alcoholic Steatohepatitis (NASH) - This is a form of NAFLD characterized by liver inflammation and damage along with excessive fat in the liver. It may progress to <a href="https://merisehat.pk/disease/cirrohsis">cirrhosis </a>and liver failure.

Approximately&nbsp; 10% to 20% of Americans have NAFLD, whereas only about 2% to 5% suffer from NASH<a href="#accordion">[6]</a>. 
&nbsp;

Fatty liver is a condition characterized by excessive fat buildup in the organ. It can be divided into two main types: non-alcoholic and alcoholic.

While NAFLD results in people who drink little to no alcohol, alcoholic fatty liver disease (AFLD) develops due to alcohol consumption. Alcohol damages the hepatocytes and can lead to inflammation and complications, such as cirrhosis and liver failure. 
&nbsp;

Signs and Symptoms

Fatty liver disease is often referred to as silent liver disease as the disease often goes unnoticed due to the lack of signs and symptoms. However, in some cases, people may experience fatigue and pain or discomfort in the right upper quadrant of the abdomen.

Most people who develop NAFLD, have fatty liver without ever progressing towards a damaged liver and only a few people who develop NAFLD progress toward NASH.

If a person does develop NASH, it may take years for them to become symptomatic. Signs and symptoms of NASH and cirrhosis can include:

<ul>
	<li>Severe fatigue</li>
	<li>Weakness</li>
	<li>Weight loss</li>
	<li>Yellow discoloration of the skin or eyes (<a href="https://merisehat.pk/disease/jaundice-65">jaundice</a>)</li>
	<li>Enlarged spleen</li>
	<li>Spider-like blood vessels visible under the skin</li>
	<li>Abdominal swelling</li>
	<li>Loss of appetite</li>
	<li>Itchy skin</li>
	<li>Pale stools and dark-colored urine</li>
	<li>Ascites</li>
	<li><a href="https://merisehat.pk/disease/edema">Edema </a>of the legs</li>
	<li><a href="https://merisehat.pk/disease/gynecomastia">Gynecomastia</a> 
	&nbsp;</li>
</ul>

Causes

The liver is responsible for a wide array of functions. These range from metabolism to immunity, detoxification, iron storage, blood clotting, digestion, etc. While having small amounts of fat in the liver is normal, an excessive build-up can result in inflammation, damaging the liver. And ultimately affecting the liver&rsquo;s functioning.

It is unclear as to what leads to an excessive fat build-up in NAFLD or why some cases progress to inflammation and cirrhosis while others do not. Certain medical conditions, such as obesity, insulin resistance, type 2 diabetes, and hypercholesterolemia have been linked to NAFLD and NASH.

These combined health problems appear to promote the deposition of fat in the liver. For some people, this excess fat acts as a toxin to liver cells, causing liver inflammation and NASH, which may lead to a buildup of scar tissue in the liver<a href="#accordion">[2]</a>. 
&nbsp;

According to the guidelines laid out by the American Association for the Study of Liver Diseases (AASLD), routine screening of patients for NAFLD is not recommended. This is because there is no assurance as to if screening has any advantage during the treatment period. The cost-effectiveness of the screening is also pretty questionable<a href="#accordion">[5]</a>. However, the European Association for the Study of the Liver (EASL) recommends routinely screening people with obesity or metabolic syndrome. They recommend the use of liver enzymes and/or ultrasound<a href="#accordion">[5]</a>. 
&nbsp;

Diagnosis

To diagnose NAFLD, the doctor will start with a complete history and physical examination.

During the medical history, the doctor may gather information on<a href="#accordion">[4]</a>:

<ul>
	<li>The patient&rsquo;s family&rsquo;s medical history, especially any signs of liver disease</li>
	<li>The patient&rsquo;s alcohol intake habits</li>
	<li>Presence of any comorbidities (simultaneously existing disease)</li>
	<li>Drug and alcohol history</li>
	<li>Any recent health changes</li>
	<li>Signs and Symptoms of liver cirrhosis</li>
	<li>Loss of appetite 
	&nbsp;</li>
</ul>

<h5>Physical Exam</h5>

In the examination component, the doctor essentially tries to look for signs of liver inflammation by palpating the abdomen. This allows them to assess for tenderness and hepatomegaly. However, the liver may be inflamed without enlargement. Hence, imaging studies are crucial. 
&nbsp;

<h5>Blood Tests</h5>

Certain blood tests can also help doctors in diagnosing NAFLD. In most cases, elevated liver enzymes point to fatty liver disease. These include the alanine aminotransferase test (ALT) and the aspartate aminotransferase test (AST).

Although elevated liver enzymes are a sign of liver inflammation, NAFLD is not the only disease that can cause it. Therefore, the doctor may order additional tests. 
&nbsp;

<h5>Imaging Studies</h5>

The following imaging scan can help assess for any excessive fat build-up in the liver. They also detect scar tissue in the liver.

<ul>
	<li>Ultrasound</li>
	<li>Computerized Tomography (CT) Scan</li>
	<li>Magnetic Resonance Imaging (MRI) Scan</li>
</ul>

Another test which is known as vibration-controlled transient elastography (VCTE) is also used for the purpose. The mechanism of the imaging modality is to use low-frequency sound waves in order to evaluate how stiff the liver has become. As it helps in understanding the scarring, it can be beneficial in understanding the prognosis. 
&nbsp;

<h5>Liver Biopsy</h5>

A liver biopsy is the most accurate test for NAFLD. It can help determine whether the patient has inflammation or scarring. If the biopsy detects fat but no liver inflammation or damage, then a diagnosis of NAFLD is made, Whereas, if fat is present with inflammation and tissue damage, then NASH is diagnosed. Moreover, the presence of scar tissue in the liver points to cirrhosis. 
&nbsp;

The disease progresses in stages. These include: 
&nbsp;

Simple Fatty Liver (Steatosis) - Steatosis is defined as harmless excessive fat build-up in the liver. It is mostly an incidental finding.

Steatohepatitis - This is a serious form of NAFLD. It is characterized by liver inflammation along with excessive fat in the liver.

Fibrosis - If the disease is allowed to progress, the constant inflammation may cause scar tissue around the liver and surrounding blood vessels. However, the liver continues to function normally.

Cirrhosis - Cirrhosis is the final and the most severe stage. It occurs years after the onset of inflammation. The liver reduces in size and becomes scarred and lumpy. It should be noted that this damage is irreversible and may lead to liver failure and liver cancer. 
&nbsp;

Treatment

Unfortunately, there is no medical intervention exclusively approved to treat NAFLD<a href="#accordion">[4]</a>. In most cases, appropriate lifestyle changes can help control or reverse the buildup of fat in the liver. Losing up to 10% of body weight is mostly recommended. However, even a 3-5% loss can result in an improvement in risk factors. Other lifestyle changes include:

<ul>
	<li>Quitting alcohol</li>
	<li>Avoiding drugs that are harmful to the liver 
	&nbsp;</li>
</ul>

People diagnosed with NAFLD&nbsp; are advised dietary changes to reduce their risk of complications. These include:

<ul>
	<li>Focus On Fiber: Fiber is essential to help improve the liver&rsquo;s functioning. Foods high in fiber include fresh fruits and vegetables, legumes, and whole grains.</li>
	<li>Limit Certain Foods: Food items that are high in sodium (salt), refined carbohydrates (sweets, white rice, and white bread), saturated fats (red meat, full-fat dairy, and fried foods), and trans-fats need to be limited.</li>
	<li>Avoid Raw Or Undercooked Shellfish: Raw meat or undercooked shellfish may contain bacteria that can make one very sick.</li>
	<li>Drink Loads Of Water: Staying hydrated can improve the liver&rsquo;s health. 
	&nbsp;</li>
</ul>

&nbsp;Note: Cirrhosis is irreversible. Thus, liver transplantation may be the only option in such cases. 
&nbsp;

The most feared complication of both NAFLD and NASH is cirrhosis which is end-stage scarring of the liver. Cirrhosis develops when the liver is injured. While attempting to stop this inflammatory response, the liver produces scarred tissue (fibrosis). Untreated inflammation leads to the spread of fibrosis across the whole liver. 
&nbsp;

If the disease is left untreated, liver cirrhosis can cause<a href="#accordion">[2]</a>:

<ul>
	<li>A buildup of fluid in the stomach (ascites)</li>
	<li>Esophageal varices, which are prone to rupture and bleed</li>
	<li>Confusion, drowsiness, and slurred speech (hepatic encephalopathy</li>
	<li>Liver cancer</li>
	<li>End-stage liver failure. 
	&nbsp;</li>
</ul>

Risk factors are parameters or elements of one&rsquo;s life and health that puts one at a higher risk to develop a disease. The following factors increase the risk of NAFLD<a href="#accordion">[1]</a>: 
&nbsp;

<ul>
	<li>Being overweight or having an &lsquo;apple-like&rsquo; body (fat deposition around the waist)</li>
	<li><a href="https://merisehat.pk/disease/diabetes-a-complete-overview">Type-2 Diabetes</a></li>
	<li>Insulin-resistance</li>
	<li><a href="https://merisehat.pk/disease/polycystic-ovary-syndrome-pcos">Polycystic Ovary Syndrome</a></li>
	<li>Underactive thyroid</li>
	<li><a href="https://merisehat.pk/disease/hypertension-57">Hypertension</a></li>
	<li>High levels of cholesterol</li>
	<li>Metabolic Syndrome</li>
	<li>Being over the age of 50</li>
	<li>Smoking 
	&nbsp;</li>
</ul>

The following measures can help reduce the risk of NAFLD: 
&nbsp;

<ul>
	<li>Opting For A&nbsp;Healthier Dietary Lifestyle - A diet full of vegetables, fruits, whole grains, and healthy fats is recommended</li>
	<li>Avoid Weight Gain - Being overweight and obese are risk factors for NAFLD. Staying active, reducing calorie intake, and adopting a healthy lifestyle can help maintain a healthy weight.&nbsp;</li>
	<li>Exercise - Exercising can help lose weight.</li>
	<li>Managing blood sugar, cholesterol, and triglyceride levels</li>
	<li>Keeping diabetes in check</li>
	<li>Quitting alcohol 
	&nbsp;</li>
</ul>

Recently, researchers tested the efficacy of Lin28 inhibitors for the treatment of hepatic disorders of abnormal lipid deposition, such as NAFLD.

Lin28 RNA-binding proteins are stem-cell factors that are crucial in the development of NAFLD. This is because Lin28 regresses the production of let-7 microRNAs. Let-7 inhibits Lin28; hence, establishing a double-negative feedback loop. The Lin28/let-7 axis is like a target for many diseases.

In a recent study, researchers used compound C1632, a drug-like Lin28 inhibitor. Lin28 inhibition triggers the production and secretion of ketone bodies while slowing down the production of lipids or fat. Consequently, a small-molecule Lin28 inhibition was seen to protect against the pathological fat buildup in male mouse models of hepatic steatosis.

Therefore, Lin28 inhibitors are considered to be a powerful candidate for the treatment of NAFLD. 
&nbsp;

Key Points

<ul>
	<li>Nonalcoholic fatty liver disease (NAFLD) is defined as a spectrum of liver diseases characterized by fat buildup in the liver, affecting people who consume little to no alcohol.</li>
	<li>NAFLD encompasses a range of diseases, from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and liver failure.</li>
	<li>The global prevalence rate of NAFLD is estimated to be around 25%.</li>
	<li>NAFLD is the most common cause of chronic liver disease.</li>
	<li>According to the suggested data, around 10% to 20% of Americans have NAFLD, whereas only about 2% to 5% have NASH.</li>
	<li>Steatosis is an excessive fat buildup in the liver and is the initial stage of NAFLD. NASH is the second and a serious form of NAFLD, which is essentially a fatty liver that has now gotten inflamed. If the disease is allowed to progress, the constant inflammation may cause scar tissue called fibrosis.</li>
	<li>Cirrhosis is the final and the most severe stage and takes place years after the onset of inflammation,</li>
	<li>Fatty liver disease is often referred to as silent liver disease because it stays asymptomatic. However, NASH can show symptoms like weakness, fatigue, and yellow discoloration of the skin.</li>
	<li>It should be noted that if you have NASH that advances into cirrhosis, it can lead to symptoms like fluid retention, internal bleeding, muscle wasting, and confusion.</li>
	<li>According to the guidelines laid out by the American Association for the Study of Liver Diseases (AASLD), routine screening of patients for NAFLD is not recommended.</li>
	<li>Other than a history and physical examination, the doctor may, order tests, such as liver function tests, ultrasound, CT, MRI, or a VCTE.</li>
	<li>The best way, so far, to find the severity of the disease and be sure of the disease is a liver biopsy.</li>
	<li>Unfortunately, there is no medical intervention exclusively approved to treat NAFLD.</li>
	<li>Lifestyle changes that include a healthy diet, exercise, quitting alcohol, and managing comorbidities can help control NAFLD and prevent its progression.</li>
	<li>Recent advances show that Lin28 inhibitors are considered to be a powerful candidate for the treatment of liver diseases related to unusual lipid deposition. 
	&nbsp;</li>
</ul>

[1] Non-alcoholic fatty liver disease (NAFLD). NHS choices.

[2] Nonalcoholic fatty liver disease. Mayo Clinic.

[3] Maurice, J., & Manousou, P. (2018). Non-alcoholic fatty liver disease. Clinical medicine (London, England), 18(3), 245–250.

[4] Team THE. Everything you need to know about fatty liver. Healthline.

[5] Pandyarajan, V., Gish, R. G., Alkhouri, N., & Noureddin, M. (2019). Screening for Nonalcoholic Fatty Liver Disease in the Primary Care Clinic. Gastroenterology & hepatology, 15(7), 357–365.

[6] Nonalcoholic fatty liver disease. Nonalcoholic Fatty Liver Disease | Johns Hopkins Medicine.

[7] Shah, A. S., Khan, S., Rahim, H., Chishti, K. A., & Khan, A. G. (2018). Prevalence of non alcoholic fatty liver and Non alcoholic Steatohepatitis in Peshawar Cantonment, Khyber Pakhtunkhwa, Pakistan. Pakistan journal of pharmaceutical sciences, 31(1), 193–198.

[8] Lekka, E., Kokanovic, A., Mosole, S. et al. Pharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease. Nat Commun 13, 7940 (2022).