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.


  • 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%.
DM (Diabetes Mellitus)23%47%
Metabolic Syndrome41%71%

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.

Non-Alcoholic Fatty Liver Disease: Emerging Concepts in Pathogenesis


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.

Non-Alcoholic Fatty Liver Disease: Emerging Concepts in Pathogenesis

All that Matters

Insulin Resistance and Metabolic factors
Role of Notch signalling
Overweight & Obesity
Genetic factors
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.

Non-Alcoholic Fatty Liver Disease: Emerging Concepts in Pathogenesis

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.

Non-Alcoholic Fatty Liver Disease: Emerging Concepts in Pathogenesis

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.

Non-Alcoholic Fatty Liver Disease: Emerging Concepts in Pathogenesis

Credit: Atish Mukher,iShannon M. Bailey,Bart Staels,Thomas F. Baumert 2019.DOI:

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

Non-Alcoholic Fatty Liver Disease: Emerging Concepts in Pathogenesis

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


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:

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:

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:

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

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