Fatty liver is the accumulation of fat in liver cells, which is otherwise not a normal place for fat storage. Long standing fat in liver can damage the organ in some people and gives rise to fatty liver disease. Fatty liver can arise from excessive alcohol consumption, in that case it is called alcoholic fatty liver disease. But here we are discussing another type of fatty liver disease, which occurs in people who do not consume significant amounts of alcohol. This is called non-alcoholic fatty liver disease and is related to unhealthy lifestyle and excessive body weight (obesity). This is the most common liver disease worldwide. In the U.S., fatty liver disease is the second most common reason for liver transplantation.
What is the connection between fatty liver and diabetes?
Diabetes is another disease that is linked to unhealthy lifestyle and obesity. That is the reason fatty liver is strongly related to diabetes as well. Not only this, diabetes accelerates the progression of simple fatty liver to more severe liver diseases such as inflammation of liver (technically called non-alcoholic steatohepatitis, NASH), fibrosis, cirrhosis (scarring of liver) and even liver cancer in some patients. These are the long-term liver-related consequences of fatty liver disease.
Fatty liver individuals who have progressed to fibrosis stage are more prone to develop cardiovascular disease (heart attack and stroke) and chronic kidney disease. These are the long-term non-liver-related consequences of fatty liver disease.
How common is fatty liver in diabetes patients?
Fatty liver disease in patients with diabetes is a public health problem. Let’s see the burden of this disease in India. There are more than 72.9 million individuals living with diabetes in India (IDF 2019 data). Among these individuals, 60-70 per cent, that is approximately 50 million, have fatty liver disease. Twenty-five per cent of 50 million individuals, that is 12.5 million, have inflammation of liver (NASH). Among these NASH patients, 1.25 million have cirrhosis (scarring of liver) without significant symptoms. Among these cirrhosis patients, 375,000 patients have decompensated cirrhosis, that is with bleeding through mouth, water retention in the abdominal cavity (ascites) and other liver-related symptoms. Seven per cent of this population, that is 87,500, have liver cancer. The worst thing is that most of these patients remain undiagnosed till they develop severe complications. This is because we have no nationwide screening programme for this condition.
What causes fatty liver disease?
Fatty liver disease, like type 2 diabetes and obesity, is a lifestyle disorder. It stems from long-term over-nutrition and under-activity. When there is unhealthy lifestyle and obesity in individuals with predisposing genetic background, the free fatty acid pool expands in the liver. Free fatty acids are at the central of fatty liver disease. The liver gets free fatty acids mostly from fat depot (adipose tissue). It also gets free fatty acids from diet, by converting glucose and fructose to fatty acids. These fatty acids are partly utilised by the liver for energy production and partly packaged into VLDL (a type of vehicle for triglyceride) to put back into circulation.
When there is no substrate overload (therefore little free fatty acids), these two processes are enough to dispose of all the fatty acids that the liver receives. When there is substrate overload, a good proportion of free fatty acids are esterified and converted to triglyceride, which are then stored in the liver cells as fat droplets. This is simple fatty liver and helps in accommodating excess fatty acids in a benign manner. When these disposal mechanisms are overwhelmed, harmful lipid species (modified free fatty acids) are formed which lead to inflammation in the liver by activating several inflammatory processes. Unbridled inflammatory processes damage liver cells and when the liver repair mechanisms are overwhelmed, liver stellate cells are activated that give rise to fibrosis of the liver. The good news here is that even if there is significant fibrosis, if the initial processes are reversed, for instance by reducing free fatty acid load by lifestyle measures, the fibrosis is reversible.
But when the unhealthy processes remain unchanged and unchecked, the overwhelming fibrotic processes lead to cirrhosis and further complications. The condition is irreversible once it has progressed to the cirrhosis stage.
How should doctors identify high risk patients?
As already mentioned, only a small proportion (10-20 per cent) of patients with simple fatty liver progress to more advanced liver conditions, such as inflammation stage, fibrosis stage or to the cirrhosis stage. In other words, a large number of patients with simple fatty liver remain as such for their whole life without developing other stages of fatty liver disease. So, to tackle this disease at the simple fatty liver stage, beyond lifestyle changes, would not be cost-effective.
Now the million-dollar question is how to identify those patients who are at high risk for progressing to higher stages of the liver disease. A simple answer to this question is that we do not know. A number of studies have revealed that the individuals who have already progressed to fibrosis stage are at higher risk for developing complications, both liver-related (cirrhosis and liver cancer) as well as non-liver-related (heart attack, stroke, chronic kidney disease, etc.).
As fatty liver disease is so prevalent, we can’t do invasive testing (such as liver biopsy) or expensive testing (such as magnetic resonance elastography) for detecting fibrosis stage among all fatty liver disease patients. One doable approach is to apply serological scoring systems that have been developed for this purpose. Two useful scores are fibrosis-4 (Fib-4) and NAFLD-fibrosis score (NFS). We are using fib-4 score for sorting out high-risk fibrosis patients in our facility.
The screening protocol works as follows: Fib-4 scoring is done for all patients with diabetes, which uses four simple parameters, such as age, two liver enzyme levels (SGOT, SGPT) and platelet count. An online calculator gives a score. If the score is less than 1.45, there is 90 per cent probability that this individual has no significant fibrosis.
For this individual, we prescribe standard diabetes care including lifestyle measures (category 1 management). For those patients with Fib-4 score 1.45 or more, we send them for fibroscan. Fibroscan is a non-invasive method for measuring liver stiffness (a surrogate marker of liver fibrosis). When the score is less than 8.0 kPa, they receive category 1 management. When the score is between 8.0 to 12.0 kPa, they are sensitised for liver complications, are motivated to reduce weight by at least 10 per cent, and the anti-diabetic drugs such as pioglitazone, SGLT-2 inhibitors or GLP-1 receptor agonists are prescribed whichever feasible. This is category 2 management.
When the score is more than 12.0 kPa, they receive category 2 management plus they are referred to specialised care (hepatologist) for screening for oesophageal varices, ascites, and liver cancer. This is category 3 management and are kept under specialist surveillance.
Using the above protocol, almost 80 per cent of patients with benign fatty liver are sorted out and only the high-risk patients are identified and further managed.
What should we advise these patients at present?
It should be kept in mind that there is no medication that is approved for fatty liver disease. This is because for approval of a drug for this disease, it has to show significant benefit in reversing fibrosis.
The research is ongoing. However, like type 2 diabetes and obesity, patients with fatty liver disease are encouraged to lose weight by eating healthy and enhancing physical activity. They are also encouraged to avoid alcohol and get vaccinated against preventable Hepatitis A, Hepatitis B and Hepatitis C.
These healthy lifestyle measures are by far the most economical way of managing the condition. The use of pioglitazone, SGLT-2 inhibitors or GLP-1 receptor agonists are only adjunctive for fatty liver disease in patients with diabetes. In these patients, these anti-diabetic drugs are basically prescribed for managing type 2 diabetes.
All the three classes of drugs are also helpful in reducing cardiovascular diseases. SGLT-2 inhibitors and GLP-1 receptor agonists also help in reducing body weight.
References available on request.