Non-Alcoholic Fatty Liver Disease (NAFLD): A Silent Pandemic

1. What is fatty liver disease? What is Non-alcoholic fatty liver disease (NAFLD)? Is it a metabolic disorder? What are the causes of NAFLD?

Fatty liver disease, also called Hepatic Steatosis, is a condition characterized by excessive fat build up in the liver.¹ Nonalcoholic fatty liver disease (NAFLD) is a type of hepatic steatosis that is considered the hepatic manifestation of metabolic syndrome.² 

Hypertension, obesity with excess fat around the abdomen, high blood triglycerides, low HDL, and insulin resistance (IR) with or without type two diabetes mellitus (T2DM) are a group of risk factors that are strongly linked to developing NAFLD. And the presence of any three of these risk factors defines metabolic syndrome. People having metabolic syndrome are always at risk of developing diabetes mellitus, stroke, cardiovascular disease, and polycystic ovary syndrome.³

Due to the strong association with metabolic disorder, international expert membership on liver pathology recommends calling this “Metabolic Dysfunction Associated Fatty Liver Disease” (MAFLD) instead of NAFLD.⁴

The liver, mainly the hepatocytes control the lipid homeostasis by acquiring fatty acids from the plasma and synthesizing fatty acid in the liver and balancing it by fatty acid oxidation and secretion in the plasma as very low-density lipoprotein- triglyceride. On a daily basis the liver processes large quantities of fatty acids but stores small amounts of triglycerides as cytoplasmic lipid droplets. At first these are small fat vacuoles which gradually increase in size forming macrovesicular steatosis. If it remains unchecked, they coalesce to form fatty cysts which become irreversible. This is the pathology leading to NAFLD, which, at present is the main etiology behind chronic liver disease.^5,6 Even though developing fibrosis in NAFLD is very slow, awareness and understanding the disease may avoid future development of other complications from metabolic syndrome.

2. Is it true that NAFLD is not always a grave condition?

Yes, it is true to a great extent.

NAFLD is a disease of the liver where accumulation of triglycerides within hepatocytes exceeds 5% of liver weight. It includes a spectrum of diseases from simple steatosis or nonalcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH) with inflammation, ballooned hepatocytes, and/or fibrosis which may progress to cirrhosis or even hepatocellular carcinoma. NASH is distinguished from alcoholic fatty liver only from patient history of alcohol consumption.⁷

The older “two hit hypothesis” of NAFLD that included lipid accumulation in hepatocytes followed by hepatic injury and inflammation is replaced by “multiple-hit” hypothesis that correctly interlinks IR, lipotoxicity, immune reaction, gut microbiome, gene variation along with diet and sedentary lifestyles to NAFLD.²

A scoring system incorporating 14 histologic features was proposed by the NASH Clinical Research Network to address the lesions of NAFLD in 2005. The NAFLD activity score (NAS) calculates the sum of scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis on a scale of 0 to 8. A NAS score of ≥ 5 strongly correlates with a diagnosis of “definite NASH” whereas NAS of ≤ 3 correlates with a diagnosis of “not NASH”.^8,9

NASH is further divided into three stages-mild, moderate, and severe stages depending upon the fibrosis in liver. Due to the decline in hepatitis C virus patients, NASH correlated stage 3 (severe) cirrhotic liver changes are an indication for liver transplant.^10,4

It takes 14 years for NAFL to progress to Stage 1 Fibrosis and only seven years for NASH. Within 10-15 years, NASH can develop into cirrhosis in 11%-20% patients. Even though NAFLD is a slow progressive disease, in 20% of people it progresses rapidly. The most common cause of death with NAFLD is cardiovascular disease. NAFLD associated with T2DM doubles the risk of death from cardiac causes and renal failures.¹¹

3. How is NAFLD linked to Insulin Resistance (IR), Type 2 Diabetes Mellitus (T2DM), and Obesity?

IR is central to developing NAFLD. Insulin hormone, released from pancreas lowers blood glucose level to maintain its normal range. When muscle, fat and liver cells do not respond well to insulin to easily take up the circulating plasma glucose, it is known as IR. Along with glucose, insulin also controls fat metabolism by inhibiting lipolysis, stimulating adipogenesis, and increasing re-esterification of free fatty acids (FFA).^12,13

IR impairs the inhibition of lipolysis in peripheral adipose tissue which leads to increased FFAs in the plasma which are then transported to the liver where it enters the hepatocyte via protein 5 and FAT/CD36. These FFAs are esterified to form neutral triglycerides resulting in hepatic steatosis. High FFA levels due to obesity itself can give rise to IR and metabolic disorder.^14,15

Esterified neutral triglycerides is a detoxification process but nonesterified FFAs are toxic to liver cells. In IR, excessive accumulation of lipids in nonadipose tissues (e.g., Liver) that have limited storage capacity of lipid leads to a phenomenon called lipoapoptosis which results in cell dysfunction and cell death. This is mainly mediated by nonesterified FFAs and not the neutral triglycerides. Saturated long-chain FFAs are considered more toxic in causing apoptosis than unsaturated FFAs.¹⁴

An immune reaction is triggered by this lipid accumulation where liver Kupffer cells and bone marrow-derived pro-inflammatory M1 macrophages secrete inflammatory mediators like the tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 that are responsible for inflammation and fibrogenesis of NASH. The anti-inflammatory M2 macrophages sustain insulin sensitivity via the secretion of anti-inflammatory cytokines such as IL-4 and IL-13. Imbalance of M1 and M2 activities exacerbates IR and NAFLD.¹⁶

Impaired insulin sensitivity leads to insulin hyper-secretion which stimulates de novo lipogenesis via SREBP-1c using dietary fructose.² 

Just like in IR, T2DM and obesity trigger similar reactions to cause NAFLD. It is still unclear as to which condition comes first to cause the rest since they are all linked.

4. Do only obese people develop fatty liver? What are the Genes related to NAFLD?

In the absence of alcohol consumption, NAFLD is closely linked to obesity, IR, T2DM, dyslipidemia, and metabolic syndrome. However, not all obese subjects develop NAFLD and, more importantly, NAFLD can be found in non-obese individuals as well. NAFLD in non-obese, although reported mostly in children and adults of all ethnicities, appears more frequently in Asians.¹⁷

Visceral obesity as opposed to general obesity, high fructose and cholesterol intake, and genetic risk factors are associated with non-obese or “lean” NAFLD. These cases exhibit similar patterns of IR and FFA distribution. Research is still ongoing to define and address this problem worldwide.¹⁸

Management of NAFLD in patients without obesity can be clinically challenging. Recommending weight loss may not be appropriate for lean patients with NAFLD, but dietary modifications and exercise in this group may be beneficial.

Identified NAFLD related genes are- PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13. Variation of these genes are involved in both lipid accumulation and de novo lipogenesis leading to NAFLD.¹⁹

5. What are the symptoms of fatty liver?

Most patients with NAFLD are asymptomatic, but some may describe vague upper abdominal pain, fatigue, and tiredness. Liver may be enlarged in some patients.

To establish a diagnosis of NAFLD, alcohol-associated liver disease must be excluded, and the diagnosis of NAFLD should be entertained only in the absence of significant alcohol use (consumption of less than 20 to 40 gm of alcohol per day in most clinical studies).⁷

6. How is it diagnosed? Other than USG, what blood marker is an indication to avoid worse prognosis?

NAFLD is usually discovered incidentally when the liver biochemical levels are elevated or during abdominal imaging. Ultrasonogram may reveal a “bright” or hyperechoic liver, consistent with fatty liver. CT scan and MRI are excellent at detecting fatty liver. However, these tests cannot confirm the severity of NASH and or fibrosis.²⁰

Liver biopsy is confirmatory for NASH but is an invasive procedure associated with rare but severe complications, including hemorrhage and even death.²¹ Advanced imaging techniques as well as laboratory tests and scoring systems that include AST/ALT ratio, BARD Score, FIB-4 score, NAFLD fibrosis score can be used clinically to exclude advance fibrosis. Liver biopsy can be avoided using the simple AST/ALT ratio.²²

FibroScan is a newer noninvasive liver elastography ultrasound technique used to detect liver stiffness. Liver stiffness is expressed in kilopascals (kPa) and the range of fibrosis or fatty change relating to NAFLD or NASH can be measured by FibroScan.

Disease Diagnosis	Liver Stiffness Result	Fibrosis Score	Your Liver
Non-Alcoholic Fatty Liver Disease (NAFLD or NASH)	2 to 7 kPa	F0 to F1	Is Normal
	7.5 to 10 kPa	F2	Has Moderate Scarring
	10 to 14 kPa	F3	Has Severe Scarring
	14 kPa or Higher	F4	Has Cirrhosis

7. Why is NAFLD so common these days? Why are lean people also suffering from it?

It is estimated that 25% of the general population have NAFLD. By 2030 the percentage of patients with NASH and F2 fibrosis may increase by 48%, F3 fibrosis may increase by 88%, and cirrhosis by 118%. Cirrhosis related to both NAFLD and NASH is increasing significantly with every decade.²⁴

Consumption of high fructose and high fat diet are directly related to insulin resistance and thus NFALD. In Bangladesh and worldwide NFALD is evident is lean and underweight adults. Undernutrition that results in metabolic disturbances, impaired lipid turnover may lead to undetected hepatic fat and visceral fats in underweight adults. Starvation induced lipolysis might be an underlying cause. Genetic predisposition, T2DM, family history are also contributors of NAFLD in lean people.²⁵

8. Is NAFLD reversible? How to prevent progression and avoid getting NFALD?

NAFLD is reversible. Modification of lifestyle and diet are the foundation of reversing NAFLD. Regular exercise, reversing sedentary lifestyle, having diet enriched with vegetables, less saturated fat and less refined carbohydrates are key. Monounsaturated fatty acids help improve the condition. The Mediterranean diet is suggested to be the best in gradually improving the severity of NAFLD and is enriched with fruits, vegetables, whole grains, nuts, legumes, fish, and low consumption of red meats with moderate alcohol intake.

Controlling comorbid metabolic syndromes like IR, T2DM, obesity, hypertension, dyslipidemia will help arrest NAFLD.²⁶

In children, the incidence of NAFLD has also increased over the pastdecade. Although the majority of children with NAFLD are overweight or obese, there is an increasing subset of children with normal bodymass index with so-called lean NAFLD.

9. How can NAFLD be managed with drugs and lifestyle?

Medications approved for T2DM, and obesity help in inhibiting the progress of NAFLD. When managing comorbidities, drugs with possible liver-related benefits should be considered. Overall increase activity level and individualized prescriptive exercise are more sustainable and have benefits independent of weight loss in NAFLD.

Despite high prevalence of NAFLD and NASH there are still no Food and Drug Administration (FDA)-approved drugs to halt the progress of disease. Data suggests that patients losing 10% of their weight had a 90% complete resolution of their NASH as well as an improvement of fibrosis in 45%.²⁷

Bariatric surgery with 30% weight loss with remission of T2DM reduces mortality related to cardiac and cancer causes in patients with NASH.²⁷

Patients with NASH without having diabetes, heart disease and or cirrhosis are sometime given Vitamin E.²⁶ Thiazolidinediones improves insulin sensitivity. Metformin is used in patients with T2DM and has shown efficacy in NAFLD. Small studies showed statins and omega-3 fatty acids benefits as well.²⁸

Semaglutide &/or Pioglitazone are indicated in T2DM/ obesity in patients with NASH. But data on Semaglutide, Pioglitazone, and Vitamin E do not demonstrate antifibrotic benefit. Metformin, Ursodeoxycholic acid, dipeptidyl peptidase-4, statins, and silymarin are also not suitable for NASH as they do not offer a meaningful histological benefit.²⁹

Early screening in high-risk populations with T2DM, obesity, metabolic complications, and family history of cirrhosis may identify the asymptomatic cases which in turn can help people reduce the risks of disease progression.