Rohit is 30 years old, and works for a bank. He underwent an ultrasound scan of the abdomen as part of a company ‘health check-up’, and was duly alarmed at his new diagnosis of “fatty liver”. Rohit did not consume alcohol, and had no family history of liver problems.
As ultrasound scanning became widespread, the number of people who get diagnosed with fatty liver is on the rise. With people scouring the internet for information, many are alarmed at what they read and at least some of them worry whether they will die from liver cirrhosis.
This article is written to explain the fascinating mechanisms of fatty liver in significant detail, along with a discussion on its health implications and treatment principles.
The liver - structure and function
The liver is a large gland that sits under the right dome of the diaphragm. It has a multitude of functions, ranging from digestion of food, detoxification of ingested chemicals including alcohol, defense against outside attacks, assembly of body proteins and storage of vitamins, in addition to maintaining nutrition and energy balance.
The liver receives all of the blood collected from the gut through the portal vein, and helps sort out the nutrients and other material that get absorbed into the bloodstream. After the filtration process, the ‘purified’ blood flows out of the liver through the hepatic vein toward the heart for distribution throughout the body.
At a microscopic level, the liver cells are arranged in a beautiful hexagonal pattern, reminiscent of some varieties of mosaic flooring of the past. This honeycomb-shaped three-dimensional filter arrangement helps maximize the efficiency of each liver cell, which involves considerable multitasking. Blood flows gently through this filter, allowing the individual liver cells to process it and eliminate waste products through bile ductules. These tiny drainage pipes collect bile from all of the liver and drain into the main bile duct, which connects the liver to the intestine.
Any toxic substance present in blood is immediately recognized by the liver cell, and is rendered harmless (detoxified) through a series of specialized chemical reactions. Toxins can range from medications of plant or artificial origin, bacterial toxins, ingested alcohol or molecules such as ammonia that are normally produced within the body. These toxins are chemically broken down initially and then rendered water-soluble and non-toxic by adding certain elements to the breakdown products, so they get harmlessly excreted in urine or bile. Such reactions may result in the production of harmful by-products such as free radicals. Sometimes, the liver cell gets damaged by the very nature of this work. Unlike nerve cells or heart muscles that cannot regenerate, hepatocytes possess the amazing albeit limited capacity to be reborn if killed in the line of duty.
Commonly used terms and their meanings
Fatty liver: Accumulation of fat in excess of 5-10 percent of liver weight.
Steatohepatitis: Liver inflammation along with fat deposition. It can be either alcoholic or non-alcoholic (NASH).
NAFLD: Non-alcoholic fatty liver disease. Liver disease that microscopically appears to be alcohol-related, but occurring in a person with no significant history of alcohol use. Can include benign fatty liver or fatty liver with inflammation.
NASH: Non alcoholic steatohepatitis. Active inflammation following liver fat accumulation in a person without significant alcohol use.
What is fat?
The basic unit of fat is triglyceride, which has three fatty acids attached to a glycerol molecule. For those who remember their organic chemistry, fatty acids are composed of chains of carbon atoms, of varying lengths and names. Those fatty acids containing double bonds along their carbon chain are called unsaturated fatty acids, while those with no double bonds are termed saturated. Each fatty acid has a -COOH ending. Glycerol has an -OH ending. When the two combine, they form ester bonds. Triglycerides constitute the bulk of our body fat, and are also found in vegetable fat. When broken down, they generate one glycerol molecule and three molecules of fatty acids.
In addition to being an ingredient of cell membranes, fatty acids are a popular fuel that gets burnt for energy production, yielding greater amount of energy per gram than glucose.
How the liver handles fat, and why fat accumulates in the liver:
Fatty acids, the building blocks of fat, can either reach the liver by blood stream or get manufactured by the liver from other raw materials like fructose or glucose. The liver cell normally disposes of fatty acids by generating energy through oxidation inside mitochondria (the cell’s furnace), manufacturing cholesterol and phospholipids or by transporting them out of the liver as triglycerides to faraway places for storage. Such transport is achieved through specialized transporter particles called VLDL.
When this balance is disrupted, either by excess supply of fatty acids to the liver, increased manufacture of fatty acids inside the liver or by impairment of oxidation and transport, fatty acids accumulate in the liver. As fatty acids and their by-products can be toxic, the liver prefers to store fatty acids in the relatively non-toxic esterified form – that is triglyceride or fat droplets.
Fat accumulates in the liver though various means
1. Too much dietary fat generates more liver fat:
The food that we eat contains carbohydrate, fat and protein. These are broken down into small components and absorbed into the blood stream. Blood flowing into the liver supplies a large amount of fatty acids into the liver cells. When more fatty acid reaches the liver than it can handle, some of it gets stored inside liver cells as fat droplets.
2. Fructose and glucose get converted to fat by the liver:
The carbohydrates in our diet reach the liver in the form of glucose and fructose. Much of it gets burnt as fuel for energy, some glucose gets stored temporarily as glycogen, and any excess is converted to fat particularly during times of carbohydrate excess in diet. Glycogen is our temporary energy store – almost like a checking account that gets used daily to release glucose in between meals. Fat, on the other hand, is our long-term energy reserve, although some of it also gets used to meet our daily energy expenses.
There are important distinctions between fructose (fruit sugar) and glucose, which makes fructose essentially a fat-forming sugar. If glucose as an energy currency is accepted by all body cells, fructose has only limited takers - and is chiefly handled by the liver. The fructose in our diet reaches the liver and gets only partially used for energy generation. Any excess fructose remaining gets converted to fat.
Unlike glucose whose entry into the liver cell is restricted once our energy needs are met, fructose enjoys unlimited entry into the liver cell, and this excess gets freely converted to fat. In fact, animals fed on high fructose diet go on to develop severe fatty liver. The problem with fructose is that unlike glucose, it does not switch off the appetite center in our brain, which means we end up eating more without feeling full.
Fructose is part of cane sugar, fruit juices and is widely used in soft drinks like colas as a cheap sweetening agent. Globally, increasing intake of fructose is now linked with obesity, diabetes and fatty liver.
Food for food vs. food for pleasure
Why do we eat? Fundamentally, there are two regulatory mechanisms of feeding: homoeostatic (which is based on the body’s metabolic needs) and hedonic. The latter is reward-based, stimulating pleasure-centers in the brain such as nucleus acumbens and releasing dopamine, the neurotransmitter molecule associated with pleasure.
If all of us ate only by the first (homoeostatic) mechanism, then theoretically everyone would have ideal body weight, and feeding would become a boring process very similar to filling a car’s fuel tank: you can only put in so much, and the car doesn’t care about the taste or smell of petrol. It is the influence of the hedonic pathway that makes us crave for and enjoy a rich meal, and also tempts us to consume larger portions than we need, sometimes against our better judgment.
The recent discovery of taste buds that recognize fat in addition to the traditional five tastes explains the craving for fatty foods, which could well be part of an evolutionary mechanism to select energy-dense foods for survival.
Fructose and fat in our diet are believed to activate the hedonic pathway in the brain, making us overeat, contributing to over-nutrition, obesity and fatty liver disease.
3. Alcohol causes fatty liver:
Prolonged alcohol use leads to fat accumulation in the liver. The liver initially breaks alcohol down to acetaldehyde, a toxic and unstable by-product. Acetaldehyde is then converted to acetic acid and later to the harmless and versatile acetyl coenzyme A - which may either get used for energy by entering the Kreb’s cycle or, when in excess, gets converted to fatty acids. These fatty acids get stranded in the liver as the transporter mechanisms that ship them out of the liver get disrupted by alcohol. As by-products of alcohol metabolism such as NADH impede the working of the liver cell’s furnace (beta oxidation process in mitochondria) the excess fatty acids can’t be burnt for fuel either. As a result, they get stored as fat inside the liver. Certain medications such as amiodarone, tamoxifen, valproate and steroids can cause fatty liver too.
Alcohol is first broken down by alcohol dehydrogenase, an enzyme normally present in the liver cytoplasm. However, when consumption is excessive, the liver summons a new cytochrome enzyme called CY2PE1 to handle the excess alcohol load. This new pathway generates more toxic products including acetaldehyde and reactive oxygen species (ROS) that cause liver inflammation and damage.
4. Obesity, insulin resistance and fatty liver:
Most of the fatty acids that accumulate in the liver owe their origin to lumps of fat stored in various parts of the body. Fatty acids are released into the bloodstream by the action of the enzyme hormone sensitive lipase on our fat stores.
During fasting, our body cells generate energy from these circulating free fatty acids, and their release is normally triggered by stress hormones such as glucagon and adrenalin that activate the lipase enzyme. Insulin normally keeps this enzyme under check, preventing unwarranted leakage of fatty acids into the bloodstream, for example, after a meal when other sources of energy are readily available.
Insulin resistance is a condition where insulin is unable to perform its actions on the body, and is even denied entry into cells, resulting in higher circulating levels of the hormone. Insulin resistance occurs after immune cells called macrophages invade these fat deposits, releasing harmful substances called proinflammatory cytokines and reducing the levels of a protective substance called adiponectin.
When there is insulin resistance, this lipase enzyme goes into overdrive, needlessly releasing large quantities of free fatty acids from our fat deposits. Through blood, these fatty acids reach the liver, where high levels of insulin preferentially converts them to triglyceride fat droplets, instead of being burnt off as fuel. Some of these fatty acids and their by-products can damage liver cells. The presence of excess fatty acids worsens insulin resistance in the liver, thus creating a vicious circle.
The combination of obesity, diabetes, hypertension and high blood fat levels is called metabolic syndrome, and is a risk factor for heart disease and stroke. Fatty liver is considered the liver manifestation of metabolic syndrome.
Though more common in the obese, fatty liver and NASH can also occur in lean people, many of whom have sedentary lifestyles and high blood fat levels. The term metabolically obese normal weight (MONW) has been used in this context.
NASH and the two-hit hypothesis
Fatty liver is essentially a disorder of fat balance in the liver. As described in some detail above, when the liver accumulates more fat than it can dispatch, fatty liver is the result. On the time line of NAFLD, this is termed the ‘first hit’. At this stage, the stored fat is harmless to the liver, although it could be a marker of underlying insulin resistance.
The liver has intricate built-in mechanisms that protect it from the effects of the accumulated fat. When these mechanisms are overwhelmed, there is inflammation, injury, cell death and fibrosis. This condition is called steatohepatitis or NASH. Such a response, also called ‘second hit’, can occur due to oxidative stress, disordered cellular housekeeping processes (autophagy), genetic predilection, mitochondrial dysfunction, or abnormal hormone milieu.
With researchers still uncovering the mysteries of the second hit, knowledge in this field is evolving, and is now thought to even involve toxins produced by gut bacteria.
When Fatty liver progresses to cirrhosis
When the conditions causing steatohepatitis are not corrected, for example when the person continues to drink alcohol or consumes excess calories despite warnings, then the next stage is destruction of liver cells and scarring of the liver, also called fibrosis. Scarring happens when the normally quiet and sleepy stellate cells (HSC) of the liver get woken up by ongoing injury and transform into myofibroblasts, producing a protein called collagen that gets deposited inside the liver.
Like a city ravaged by constant war, the liver goes through several cycles of damage and rebuilding, eventually resulting in a chaotic architecture with far fewer functioning liver cells remaining: this is called liver cirrhosis. It should be noted that among those with non alcoholic fatty liver without steatohepatitis, the chance of developing cirrhosis is small.
Cirrhosis and cancer:
Just as an error can creep in when we copy a large body of text several times over, there is a chance that one of the new cells is born genetically abnormal following numerous cell divisions, especially after being exposed to unstable molecules and oxidative stress. Such abnormal cells may sometimes go on to produce a colony of cancer cells. This is the reason why people who have liver cirrhosis are at greater risk for liver cancer. In a sense, it is a curse of the original blessing - the innate ability of the liver cells to multiply allows the liver to survive many serious insults, but eventually contributes to liver cancer. Rarely, cancer can occur in NASH even without cirrhosis.
What should be done if there is fatty liver?
The first step is to determine if it is benign fatty liver (steatosis) or fatty liver with associated inflammation (steatohepatitis). While this determination is not easy every time, dedicated scans and blood tests done under the watch of a doctor will help to a large extent. Occasionally, a liver biopsy will be required.
The next step, and the mainstay of treatment, is to eliminate all the reversible factors that contribute to the process. Those who drink alcohol are advised to stop or cut down to very small levels. Those with indulgent dietary habits must strive to restore some order in their eating pattern. The consultation of a dietitian is helpful in tailoring one's diet to best suit the body’s needs, with due consideration for the family’s dietary preferences.
Physical exercise is an essential part of treatment. Exercise reduces insulin resistance and is proven to reduce the impact of fatty liver even when no weight is lost. Continuous exercise of 30 minutes duration at least 5 days a week is advisable.
Scientific research has identified some medications to be effective in only certain subsets of patients with fatty liver disease. Medications are not universally recommended in the treatment of fatty liver at this time and should not be taken without consulting a qualified doctor. It is prudent to stay away from treatment scams, as any medication – herbal or otherwise – can potentially cause liver damage. The number of patients developing liver failure from such unauthorized treatments is enormous.
Weight loss is the most effective step in the management of non-alcoholic fatty liver disease. A body weight reduction of 10 percent will help clear most, if not all of the abnormalities in the liver. More than total body weight, emphasis now is on central or abdominal obesity, which is a predictor of insulin resistance. Thus, in addition to achieving a near-ideal BMI (Body mass index), the waist circumference needs to be brought down too.
The most effective way to reduce body weight is to follow a sustained diet and exercise program at least over a six-month period, preferably under the supervision of a team of experts including a dietitian. For those who are unable to lose weight through such means, intragastric balloon and bariatric surgery are other options, but only after a detailed consultation with the doctor.
In summary, alcohol use, excess calorie intake and insufficient exercise account for the majority of cases of fatty liver. Sugar is the new fat. Contrary to popular belief, fatty liver and associated illnesses are more related to sugary foods than fatty foods. In an increasingly sedentary society where playgrounds are disappearing, and children sit glued to their computers and TV and consume high calorie foods, teaching good health habits to the younger generation is vital in the long-term prevention of fatty liver disease.
(The author is a senior consultant gastroenterologist and deputy medical director, Sunrise group of hospitals)