CME INDIA Presentation by Dr. Gagan Gunjan, MBBS(Hons.), MD (Medicine), Assistant Professor, Medicine, RIMS Ranchi, Jharkhand.
Based on presentation at APICON-2022, Jaipur.
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%|
- 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.
- 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|
|Bile Acid receptors|
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
- 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 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.
- 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
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
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
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