Non-Alcoholic Fatty Liver Disease: Emerging Concepts in Pathogenesis

CME INDIA Presentation by Dr. Gagan Gunjan, MBBS(Hons.), MD (Medicine), Assistant Professor, Medicine, RIMS Ranchi, Jharkhand.

Based on presentation at APICON-2022, Jaipur.

Non-Alcoholic Fatty Liver Disease: Emerging Concepts in Pathogenesis

Problem is Bigger than Perceived!

An epidemic of new millennium!
A burden worldwide!
The term Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of liver lesions.
Today NAFLD almost parallels the epidemic of Obesity & DM.

Prevalence

NAFLD accounts for 25% of adult population worldwide.
The prevalence ranges in South America to 31% and the Middle East to 32% , along with uprising trends now in Asian countries also.
In Japan it has exceeded 50%, and it’s almost 50% in Korea being followed by Singapore, India and China. Currently Africa has the lowest prevalence of 14%.

CO-MORBIDITY	NAFLD	NASH
OBESITY	51%	82%
DM (Diabetes Mellitus)	23%	47%
Metabolic Syndrome	41%	71%
Hyperlipidaemia,Dyslipidemia	69%	72%
Hypertension	39.34%	67.97%

How Develops?

The pathogenesis of NAFLD still remains unclear.
Much advancement has been made in the past few decades to understand the pathogenesis of NASH.
It is not confined to any particular factor, rather it is multifactorial.
The metabolic factors, genetic variations & environmental factors along with diet, lifestyle & circadian clock plays an important role to promote the accumulation of this fat in liver, particularly the hepatocytes.
The characteristic feature that defines NAFLD is Triglyceride accumulation inside the liver.
This occurs as a result of imbalance between influx and efflux of fatty acids.
As a result, there is 3-5 times increase in hepatic de novo lipo-genesis in these patients as compared to normal population.
This over burdening of liver by excessive accumulation of Triglycerides leads to consumption of a majority of antioxidant mechanisms of the cell.

Credit: HCV-triols.com

Concepts Emerge

No doubt, the absolute risk is higher in obese & diabetic patients (for any given BMI).
NAFLD & BMI shows a linear relationship i.e., higher BMI (37.5–40 Kg/m2) accounting for higher risk.
The lean populations are equally affected with NAFLD. The prevalence of such patients ranges from 10 – 30%.
Various studies have demonstrated an association between lean NAFLD and metabolic risk factors like hyperglycemia, dyslipidemia, and visceral adiposity.
The atherogenic Dyslipidemia – raised Triglycerides and low-density lipoproteins (LDL), particularly increased small dense LDL are known to promote NAFLD.
NAFLD has higher prevalence in men as compared to women.
Probably estrogen has a protective role in pre-menopausal age-group.
Once menopause is attained, the risk of NAFLD rises dramatically in females & longer this duration of estrogendeficiency, higher the risk of fibrosis.
Earlier the patho-physiology was based on two hit pathogenesis.
But now we have come up with a concept of “Multiple Hit Pathogenesis.”
It states that multiple etio-pathogenic factors act in a sequential, parallel & synergic way, leading to NAFLD.

All that Matters

Insulin Resistance and Metabolic factors

Role of Notch signalling

Overweight & Obesity

Genetic factors

Diet

Gut Microbiota

Iron deposits

Bile Acid receptors

Circadian Clock

Insulin Resistance and Metabolic Factors

The role of Insulin receptors cannot be ignored.
It stimulates glucose utilization and favors accumulation of lipid by acting on various insulin sensitive organs like muscle, adipose tissue & liver.
In the state of insulin resistance, the insulin-sensitive lipase does not get suppressed and this leads adipose tissue to release a great amount of non-esterified fatty acids (NEFA) in the bloodstream.
This leads to ectopic deposition of fat in liver, pancreas and other organs. These cells consequently become more prone to developing resistance to insulin

Role of Notch Signalling

Notch signaling has been found to regulate angiogenesis and thus favours atherosclerosis.
It is a highly-mechanized system involving ligands, receptors and intra-cellular proteins.
It affects virtually every metabolic organ further causing liver steatosis & fibrosis.
Also, it favors differentiation of M1 macrophage phenotype – the main factor causing systemic inflammation & peripheral insulin resistance.
Researchers have recently come up with established association between sarcopenia, steatosis & fibrosis in NAFLD.

Overweight and Obesity

Adipose tissue is associated with production of adipo-kines or adipo-cytokines
Adiponectin & Resistin are two such major adipose-specific adipokine which has got powerful anti-inflammatory and insulin sensitizing effects.
There exists an inverse correlation between adiponectin levels and hepatic steatosis.

Credit: PolyzosJannis KountourasChristos S. Mantzoros. /j.metabol.2018.11.014

Genetic Factors

Several genetic mutations associated with lipid metabolism are involved in risk, development and severity of NAFLD.
This involves multiple intracellular & extracellular events in various cell molecules or rather I would say ‘crosstalk events between the liver & other organs’.
The two mainly associated genes associated with NAFLD & NASH include PNPLA3(Patatin like phospholipase) & the loss of function in transmembrane 6 super-family-member-2 (TM6SF2) due to a single nucleotide poly-morphism.

Diet & Gut Microbiota

Both Carbohydrates & Fat are notorious.
Fructose has been found to be an extremely lipogenic substrate and hence European guidelines are against the consumption of fructose-containing beverages and foods.
Chronic intake of fructose alters the “microbiota fingerprint” causing damage to tight gut junctions thus increasing bacterial translocation and causing systemic inflammation and NASH.
Liver being one of the most exposed organ to bacterial translocation, Damage to mucosal barrier is common.
Substances such as pathogen-associated molecular patterns (PAMPs) and Toll-like receptor 4 are known to mediate fatty acid induced inflammation and further progression of NAFLD to NASH.

Iron Deposits

Iron is a highly reactive element and its excess deposition may lead to ROS formation, inflammation & fibrosis.
HFE gene mutations, Iron overload & metabolic disorders go hand in hand favouring hepatic lipid peroxidation, DNA damage, apoptosis and a direct cytotoxic effect.

Circadian Clock

A lot many metabolic pathways in our body like sleeping, waking, fasting, feeding, hormonal secretions typically exhibit the circadian clock.
Bile acid synthesis too gets influenced by these mechanisms as are the immune system and inflammatory responses in our body and thus contributes to the underlying patho-physiology of NAFLD.
Hence we cannot ignore the role of circadian clock in NAFLD, with CNS (central nervous system) being a coordinator of all these factors.
Still, further studies and research are needed in this area to look for the clinical and therapeutic implications of circadian rhythm regulation.

Credit: Atish Mukher,iShannon M. Bailey,Bart Staels,Thomas F. Baumert 2019.DOI:https://doi.org/10.1016/j.jhep.2019.03.020

Final Points:

Liver Fat Flames and Frames…Keep No Inflammation Inside!

NAFLD is a global challenge to our healthcare system and has risked the development of NASH, cirrhosis and liver cancer for a significant proportion of the world’s population.
Its pathogenesis is complex and multifactorial involving genetic, environmental and metabolic factors.
Initial theories were based on a “2-hit hypothesis;” but this has now enlarged to a “Multiple-hit hypothesis.”
Newer concepts are constantly emerging in the literature but still we have a far way to go.
Further studies and trials are needed to characterize NAFLD development and its progression.

CME INDIA Tail Piece

Courtsey: Nonalcoholic Fatty Liver Disease (NAFLD) Name Change: Requiem or Reveille? Shivaram P. Singh, Prajna Anirvan, Reshu Khandelwal, Sanjaya K. Satapathy journal of Clinical and Translational Hepatology 2021;9(6):931-938

References:

1. Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics.Stergios A. PolyzosJannis KountourasChristos S. Mantzoros.| VOLUME 92, P82-97, MARCH 01, 2019Published:November 28, 2018DOI:https://doi.org/10.1016/j.metabol.2018.11.014

2. Circadian Rhythms in the Pathogenesis and Treatment of Fatty Liver DiseaseAnand R. SaranShravan DaveAmir Zarrinpar.VOLUME 158, ISSUE 7, P1948-1966.E1, MAY 01, 2020 Published:February 12, 2020DOI:https://doi.org/10.1053/j.gastro.2020.01.050

3. The circadian clock and liver function in health and diseaseAtish MukherjiShannon M. BaileyBart StaelsThomas F. Baumert.VOLUME 71, ISSUE 1, P200-211, JULY 01, 2019Published:March 28, 2019DOI:https://doi.org/10.1016/j.jhep.2019.03.020

4. Husam M. Salah,Ambarish Pandey,Anzhela SolovevaJ Am Coll Cardiol Basic Trans Science. 2021 Nov, 6 (11) 918–932