Our collective understanding of health and wellbeing over time has revealed that disease is caused and exacerbated by multiple factors. These are usually called risk factors, and often, the more risk factors present, the higher the probability of developing a disease or experiencing faster progression of that disease.

Risk factors can be divided into two groups:

1.) Innate or Genetic risk factors

2.) Environmental and Lifestyle risk factors

These two categories are similar to the “Nature versus Nurture” debate on issues like personality and child development, and there is wide consensus that both genetic and environmental factor, through a complex interplay, influence an individual’s life across all facets of their being. While these plays out at the level of the individual, we also see patterns or associations with race and ethnicity, when understanding risk. Similarly, there are environmental and lifestyle patterns that are associated with increased risk, often termed the social determinants of health (SDOH) which include education levels, socio-economic class, geography and access to health services.

Simply put for NAFLD, a person’s risk of developing NAFLD and progression to NASH is determined by their genetic risk and the life they live!  With advances in medical and social science, research and studies are underway to see if genes and their expression can be manipulated to reduce the genetic risk; and if altering the lifestyle factors can reduce environmental risk. These are exciting fields of study that will potentially yield new interventions in prevention and reversal of NAFLD and NASH.

Below is a bit more detail on some of these risk factors:

Inflammation 

Inflammation is part of the human body’s defense mechanism that results from activation of the immune system. This is usually in response to a “foreign invader” typically a germ (bacteria, virus, fungi), a chemical, or a substance / object. The immune system comprises many mediators of inflammation, which are chemical signals that start a chain reaction of defenses for the body, and varieties of cell types, that have different roles in defending the body. Essentially, any “irritant” in the body causes inflammation.

There are circumstances however, where there is immune dysregulation, when the immune cells attack its own tissues in the body (by reading them as foreign), or when the response is excessive. This is manifested as auto-immune disease and the mechanism and triggers of which have a ways to go in understanding. 

When fat accumulates in liver cells (fatty liver), it is called steatosis, and this causes the cells literally to “get fat” and enlarge. These cells irritate the tissues and can even burst, which causes more irritation from the fat leaking in the liver tissue. The resulting irritation causes inflammation, which is called steatohepatitis. Inflammation, like a cut on skin, is usually followed by a scab, which in the liver is fibrosis.

There are many scientists who are questioning whether the inflammation in the liver starts somewhere else in the body, and then lands up (or localizes) in the liver. The most likely place where this could start would be the gut, which after absorption, drains into the liver for metabolism of nutrients, carbohydrates, proteins, and fat. Any conditions that cause inflammation in the gut, can potentially travel to the liver, and the largest influencer of gut health is food.

The Microbiome

Expanding on then understanding of inflammation and how it potentially starts in the gut, is gut environment. It is interesting to note that the human body is made up of more cells that are “foreign” rather than what we consider to be our “own” - that is, made up what we consider to be our own genetic material. So, the human body is a complex entity of cells and organisms (mainly bacteria), all working together in a physiological symphony.

The microbiome is the bacteria content, proportions, and quantities in the gut that work with the digestive enzymes to metabolize the food we eat. They help the breakdown of food so that we can derive the energy and nutrients from what we eat. The microbiome is influenced by what we eat, when we eat, and how we eat. It also follows the adage of “what you put in, is what you get out.”  With increased consumption of processed, preservative-containing, chemical dyes, and poor food preparation, the impact on the microbiome (and how it activates and interacts with the digestive system) is manifesting with increases in many bowel related inflammatory conditions including coeliac, gluten-sensitivity, inflammatory bowel disease and others.

This is an exciting field of study and we hope to learn more of the influence of the microbiome on digestion, the liver, and human health.

Diabetes Mellitus

Diabetes Mellitus, particularly Type 2 Diabetes (T2D), has a complex metabolic relationship with NAFLD and NASH. T2D is usually late onset diabetes (not from childhood but presents in adulthood) and arises as a result of insulin resistance rather than insulin deficiency. Insulin resistance is when there is sufficient amount of insulin, but cells in the body are unable to be “triggered” to take up glucose. T2D is usually managed with oral hypoglycemics, which are pills rather than using injectable insulin.

The prevalence of diabetes among the NAFLD and NASH patients is estimated to be 22.51% and 43.63%, respectively, which is much higher than the prevalence of diabetes in the general population (8.5%).

The interaction between T2D and NAFLD/NASH are as follows[1]:

1. The lifestyle factors that predispose to the development of T2D, are also the same risk factors that lead to the development of NAFLD
2. Patients who have NAFLD are at increased risk for developing T2D
3. Patients with T2D and NAFLD, are at increased risk of progressing faster to NASH, fibrosis, and cirrhosis

The key intervention is excellent control of T2D together with modifying lifestyles to reduce risk.

Obesity

Obesity refers to an individual with additional weight. Specifically, obesity is measured with the BMI (body mass index) which is calculated by dividing the height by the weight-squared. The range of BMI calculations follows as:

It is important to note that the BMI is a generalizable tool to classify weight and the associated risks. It can be inaccurate or unrepresentative in certain ethnic groups or populations, and also with people who may be very fit.

With obesity, the obvious manifestation is the appearance of someone looking fat. But what is not seen, is the accumulation of fat in the organs of the body. This is known as visceral adiposity. Specifically, when fat accumulates in the liver, it is NAFLD, which can then progress.

There are also other tests for estimating fat content in the body known as impedance, and also composite indicators (looking at many features/parameters), which include waist circumference and wrist circumference for example, to give a better understanding of the weight and fat balance ion the body according to frame.

People who have obesity are at increased risk for many diseases and health conditions, including the following: 

• All-causes of death (mortality)
• High blood pressure (hypertension)
• High LDL cholesterol, low HDL cholesterol, or high levels of triglycerides (dyslipidemia)
• Type 2 diabetes
• Coronary heart disease
• Stroke
• Gallbladder disease
• Osteoarthritis (a breakdown of cartilage and bone within a joint)
• Sleep apnea and breathing problems
• Chronic inflammation and increased oxidative stress
• Some cancers (endometrial, breast, colon, kidney, gallbladder, and liver)
• Low quality of life
• Mental illness such as clinical depression, anxiety, and other mental disorders
• Body pain and difficulty with physical functioning

There are many approaches and interventions to weight-loss and the principle of “one size fits all” does NOT work. Each individual requires customization of their weightloss strategy.

Hypertension

Hypertension is a common risk factor for cardiovascular disease, and is part of the broader metabolic syndrome constitution of diseases. Hypertension is an independent predicator of NAFLD, and NAFLD also predisposes to the development of hypertension. It is thought that the mechanism of action for hypertension and NALD is related to insulin resistance, which is linked to weight increase and type 2 diabetes.

It is important to note that these conditions are difficult to attribute their contribution exclusive correlation to disease, given that the co-morbidities associated with NAFLD are several and tend to exacerbate each other.

The diagram below shows the bi-directional nature of hypertension and NAFLD:

Metabolic Syndrome

Metabolic syndrome is a cluster of conditions that occur together, increasing the risk of heart disease, stroke and type 2 diabetes. These conditions include increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels [2].

The development of nonalcoholic fatty liver disease (NAFLD) is strongly associated with the metabolic syndrome as reflected by the fact that approximately 90% of the patients with NAFLD have more than one feature of metabolic syndrome and about 33% have three or more criteria [3]. Lipotoxicity plays a predominant role in the pathophysiology of both entities. It leads to accumulation of triglycerides in the liver as a result of an imbalance among the uptake, synthesis, export, and oxidation of fatty acids.

Genetics

Over the past few years, several studies have identified genes associated with NAFLD/NASH. The I148M PNPLA3 variant has been identified as the major common genetic determinant of NAFLD. Other variants to have a significant contribution include TM6SF2, MBOAT7 and GCKR. These sequences have

Investigating these sequences can be beneficial if an individual has for example, a family member who has/had NAFLD/NASH, although the type of inheritance is not clearly understood. This means that while the genetic risk may be present, the role of epigenetics is a more important determinant if an individual will develop disease. Epigenetics are the environmental and lifestyle “modifiers,” “influencers”, or “triggers” that can start the pathogenesis of disease. This still remains the mainstay for managing NAFLD/NASH, and patients interested in genetic screening should speak with their hepatologists and also ensure adequate pre-test genetic counseling.

Trends in medical science are also exploring gene therapy or “manipulation”, which apply that cause more severe disease associated with mutations[4].

Polycystic Ovary Syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is a hormonal and metabolism problem, usually experienced by premenstrual women. PCOS is associated with a higher rate of NAFLD/NASH and is accompanied with obesity and insulin resistance.

The patient demographic should be a pointer to suspect PCOS associated NAFLD/NASH that is, premenstrual women, obese, and diabetic. Once again, the principles of treatment include diet, exercise, and weight loss. Multi-disciplinary team management would be the same as for NAFLD/NASH, but it is also include an obstetrician / gynecologist and/or endocrinologist [5].

HIV/AIDS

NAFLD/NASH in patients living with HIV/AIDS results from the viral infection and the drugs used to treat HIV/AIDS. The immune action in response to the virus can cause insulin resistance, while particular classes of drugs can cause NAFLD/NASH due to its impact on fat metabolism.

With effective therapies available to treat HIV/AIDS, life expectancy has increased if not normalized to the general population in some settings. HIV positive patients bear the same risk profile for the general population. Like with all co-morbidities of NAFLD/NASH, effective management of the co-morbid illness is important, and using the effective HIV drug combination can reduce risk of NAFLD/NASH [6].

Lean People

Because of the absence of the physical features that are typically present with NAFLD/NASH patients, lean NASH is often underrecognized and underreported. The commonest cause of lean NASH is metabolic, but it can rarely occur as a result of drug toxicity, infections, and genetic disorders.

Lean individuals are defined as those who have a normal body mass index (BMI) based on ethnic-specific cutoffs and display the classic histopathologic features of NASH (the microscopic changes), which include steatosis, lobular inflammation, and hepatocyte ballooning. The notion that NAFLD/NASH is therefore not limited to obese or overweight patients. It is the role of the primary care provider or physician to have an index suspicion, based on other factors. For example, we know that Asian populations tend to have increased risks of cardiovascular disease and type 2 diabetes at lower BMIs compared with other populations [7].