The Metabolic Liver Disease NAFLD: A Growing Health Problem

The Metabolic Liver Disease NAFLD: A Growing Health Problem

The World Gastroenterology Organisation WGO and other health care associations identify the metabolic liver disease, NAFLD (nonalcoholic fatty liver disease), as a “growing public health problem.” As many as one in four people worldwide has a nonalcoholic fatty liver today. The number is even as high as 40% in the US and Europe, according to estimates from the European Association for the Study of the Liver (EASL). The organization believes that 12 million are affected in Germany.

The number of people with NAFLD continues to grow

The prevalence of NAFLD has been rising steadily for the last few decades, and the trend is expected to continue. NAFLD is almost always caused by excess body weight, type 2 diabetes, and other metabolic disorders. The lifestyle that causes these risk factors continues to spread. In an effort to emphasize that the metabolism is the most important trigger of NAFLD, many experts prefer to call it “metabolic liver disease.” Currently, however, the abbreviation NAFLD remains the most common term for nonalcoholic fatty liver disease.

NAFLD can cause serious complications

A significant number of patients with NAFLD develop a form of fatty liver called nonalcoholic steatohepatitis (NASH), which can cause serious complications. It also increases the risk of death. Through effective treatments administered at the right time, many complications could be avoided and lives saved. However, the optimal timeframe for treatment often passes unnoticed. Simple tests conducted in the early stages cannot determine whether a patient has developed a mild form of NAFLD or a serious form of NASH (described below). However, when administered at a later stage, treatment is more complex and is sometimes not as successful. That is why the LiSyM systems medicine network focuses on developing new forms of treatment as well as new tests for diagnosing this disease and monitoring its progress.

NAFLD: At Least 5% of the Hepatocytes in the Liver Are Very Fatty

NAFLD occurs when a very high amount of fat has accumulated in the liver. According to the European Association for the Study of the Liver (EASL), the European Association for the Study of Diabetes (EASD), and the European Association for the Study of Obesity (EASO), NAFLD can be diagnosed when:

● Histological examinations of the cells determine that more than 5% of the hepatocytes in the liver are very fatty. (In imaging procedures such as proton magnetic resonance spectroscopy (1H-MRS), the minimum is slightly higher at 5.6 %.)
● The use of alcohol or drugs as well as hepatitis or other diseases can be ruled out as causes.

NAFL and NASH: The Two Forms of NAFLD

The term nonalcoholic fatty liver disease, or NAFLD for short, is an umbrella term that includes two forms of fatty liver: NAFL and NASH. Both forms are very different in their pathology and prognosis.

NAFL (nonalcoholic fatty liver): NAFL, also known as simple fatty liver, is a form in which there is steatosis (accumulation of fat) in the liver, but no other symptoms. The patient’s condition does not worsen, or if it does, only minimally, and complications are rare. “NAFL is not a disease, strictly speaking,” says Professor Dr. med. Peter Jansen, Director of the LiSyM research network. “Many people with a fatty liver don’t develop any health problems as a result throughout their lifetime.”

NASH (nonalcoholic steatohepatitis): In the case of NASH, the liver is also inflamed. The hepatocytes undergo morphological (structural) changes in a process called “ballooning” (described below). Hepatocytes can also transform into connective tissue cells, called fibrosis. This process, if it progresses, can lead to cirrhosis, a condition in which liver function becomes severely impaired or fails altogether. A small percent of NASH patients develops liver cancer (hepatocellular carcinoma, or HCC). As fibrosis increases, the number of liver-related deaths of these patients grows exponentially; their overall mortality rate rises as well.

NAFL or NASH: A Decisive Question

To successfully treat NAFLD, the disease needs to be diagnosed early before the liver is irreparably damaged, that is before it progresses to advanced cirrhosis. Yet, it is difficult to diagnose NAFLD at the optimal point in time for successful treatment for the following reasons.

● The early stage of NASH usually goes undetected because a diseased liver is able to compensate functionally for much of the damage at first. The person affected displays no symptoms and has no reason to visit the doctor.
● Currently existing non-invasive tests do not provide sufficient information to distinguish whether NAFLD or NASH is present.
● The only reliable way to test whether a patient has NASH is to conduct a liver biopsy. Compared to non-invasive tests, however, these minor invasive procedures are more complicated and expensive, and mean more stress for the patient. Biopsies also carry a certain degree of risk for the patients, although minimal.
● A non-invasive procedure called ultrasound elastography can be used to detect fibrosis. However, measurements must be repeated many times to determine the stage and the progress of the disease accurately.

New tests and treatments are urgently needed

Currently, there are no effective treatments for advanced cirrhosis. Thus, once the disease has reached this stage, liver function has deteriorated to such an extent that it can no longer be restored. Clinical treatment needs to commence earlier. Thus, simple and dependable non-invasive diagnostic tests are urgently needed to determine as early as possible when NASH has developed, when the situation worsens and becomes critical, and which patients are at greatest risk of reaching this stage. Such new tests, along with new therapeutic approaches, would prevent much suffering. That is why one of the LiSyM network’s primary goals is to close the gaps in knowledge in diagnosis, monitoring, risk assessment, and treatment.

NASH Can Lead to Cancer: Symptoms and Consequences

As many as 20% of people with NAFLD develop NASH. Experts can determine when this process begins by identifying special characteristics in the hepatocytes and their cellular environment. NASH is often accompanied by fibrosis, which, if allowed to progress, can lead to cirrhosis. In later stages, some patients develop structural transformations that can lead to hepatocellular carcinoma (HCC), in other words liver cancer.

NASH manifests as inflammation and ballooning

The prognosis for NASH is considerably worse than for NAFL. In one of every five NASH patients, the disease progresses to cirrhosis. There are currently no simple diagnostic tests for determining when NAFL develops into NASH. None of the non-invasive examination procedures available can reliably distinguish between the two forms. The only reliable methods for distinguishing the two forms are by analyzing liver tissue obtained from a liver biopsy under a microscope or with imaging procedures. These methods can identify the NASH characteristics, ballooning and inflammation, at the cellular level.

● Ballooning of hepatocytes
Ballooning occurs when already fatty hepatocytes store even more fat. Large lipid droplets cause them to swell to one-and-a-half or twice their original size. “The lipid droplets crush everything in the liver cells,” says Dr. Nachiket Vartak, leader of a junior research group in LiSyM. The fatty deposits displace the cytoplasm, which is where most cellular reactions take place, and cause it to deform. Small atrophied inclusions in the cytoplasm, called Mallory-Denk bodies, are often visible in ballooned liver cells. Ballooning damages the hepatocytes ability to function, and the process can lead to cell death (necrosis).

● Inflammation
The accumulation of fat and ballooning put stress on the hepatocytes. This activates hepatic immune cells, especially macrophages. As a result, inflammatory cells, primarily so-called monocytes, infiltrate the liver lobules and often surround the ballooned hepatocytes.

NASH can lead to fibrosis, cirrhosis, and liver cancer

NASH is also characterized by a process called fibrosis, which can culminate in cirrhosis and ultimately liver cancer. In the early stages of NASH, there may be no significant fibrosis of the liver.

● Fibrosis is the abnormal increase in connective tissue
Fibrosis describes in general the process in which connective tissue increases abnormally and collagen fibers become much more frequent. Fibrosis can affect other organs as well as the liver, such as the lungs, kidneys, skin, or bone marrow. In the case of NASH, damage to the liver evidently activates special connective tissue cells called fibroblasts. These begin to reproduce uncontrollably, and more and more interstitial connective tissue permeates the liver. The bands of connective tissue create barriers between the different parts of the liver, and they cut off the liver cells from the vessels that supply them with blood and the nerves that control them. The liver becomes increasingly unable to carry out its normal functions. The various stages of liver fibrosis can be measured according to different systems. Generally, a five-stage system is used: from F0 to F4. Here, F0–F1 indicates no fibrosis to minimal fibrosis, F2 stands for moderate fibrosis, F3 for advanced fibrosis, and F4 for severe fibrosis, or NASH cirrhosis.

● Cirrhosis
When an organ becomes stiff, scarred and shrinks in size due to chronic inflammation and ongoing fibrosis, experts call this cirrhosis. In this process, the functional tissue of the organ degenerates. In the final stage of liver cirrhosis, the liver cannot fulfill any of its functions.

● Hepatocellular carcinoma
Patients with NASH are at greater risk of developing hepatocellular carcinoma (HCC). The level of risk of developing a tumor depends on the observation period and the patient’s medical history. For example, the stage of the fibrosis when observation begins, accompanying diseases, and genetic predisposition all play a role. According to EASL, 0.25–7.6 in 100 NASH patients with advanced fibrosis or cirrhosis develop HCC within roughly five years.

Nutrition, Lifestyle, and Genetic Predisposition Are All Risk Factors

The root causes of the metabolic liver disease, NAFLD, and its subform, NASH, can be found in nutrition and the overall lifestyle. A high intake of calories, fat – especially unsaturated fatty acids from refined carbohydrates, sweetened drinks, and fructose – all promote NAFLD. These are also the basis of what experts refer to as the Western diet, or Western pattern diet, so named because it is so prevalent in industrial countries. Many people in the West consume excessive amounts of red meat, non-nutritional calories, processed food, heavily sweetened drinks, sweets, fried foods, butter, and eggs. At the same time, their intake of fruit, vegetables, whole grains, fish, poultry, legumes, and low-fat dairy products is too low.
Lack of exercise also contributes to excess weight, high blood pressure, as well as sugar and fat metabolic disorders. Few people in industrial countries exercise enough and at the right intensity.
Finally, researchers have identified several gene variants that have an impact on the fat content of the liver. They also influence the liver’s susceptibility to NAFLD and the disease’s progress. However, not enough is known currently about the extent of the effect they have.

The most important, known risk factors for NAFLD/NASH include the following:
● Age
● Western diet
● Obesity
● Type 2 diabetes, or insulin resistance
● Gender: Men are more likely to develop NAFLD/NASH than women, although women are at higher risk of developing advanced fibrosis
● Genetic predisposition, such as certain variants in the PNPLA3 gene (patatin-like phospholipase domain-containing 3)

More than two of every three patients with NAFLD have a metabolic syndrome (see below), which is a combination of metabolic disorders (see below). Other disorders, such as obstructive sleep apnea (OSA), as well as ethnicity can also have an impact on the level of risk.

Metabolic Syndrome and NAFLD Are Connected

NAFLD is primarily caused by metabolic disorders. Studies have shown that nonalcoholic fatty liver is connected to metabolic syndrome, which encompasses several metabolic disorders, all of which can be traced back to a Western diet. The International Diabetes Foundation (IDF) defines the metabolic syndrome as a combination of the following symptoms:
● Excess body weight, especially around the waist, with the waist measuring ≥ 94 cm for men and ≥ 80 cm for women
● Increased arterial blood pressure of ≥ 130/85 mmHg, or ongoing treatment for hypertension
● An increased fasting blood sugar level of 100 mg/dl (5.6 mmol/L), or ongoing treatment for type 2 diabetes
● Increased concentration of triglycerides in the serum of more than 150 mg/dl (1.7 mmol/L)
● A HDL cholesterol count of less than 40 mg/dl (1.0 mmol/L) for men and less than 50 mg/dl (1.3 mmol/L) for women.

Any of these factors on their own can increase the risk of developing not only NAFLD, but also cardiovascular diseases. When combined, these symptoms not only increase a person’s risk of disease, they also mutually enhance one another.

For more information:
EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Journal of Hepatology 2016 Vol. 64: 1388-1402

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