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Pathogenesis of NAFLD Dr . AYASKANTA SINGH IntroductionNASH was described : alcoholic- like liver disease that develops in people who do not drink alcohol Ludwig et al , J.mayo clin proc 1980

NAFLD : Defination Presence of steatosis (accumulation of fat in excess of 5-10% of liver weight ) detected by Imaging/Histopathological study.Exclusion of secondary causes of fatty liver.

Ludwig et al. described the histological findings of fatty liver and coined the term non-alcoholic steatohepatitis (NASH2NAFLD has reached epidemic proportions .Prevalence in India- 24.5% Singh SP et al Trop Gastroenterol 2004

Pathophysiology of NAFLD not well understood .Multifactorial Associated with obesity, diabetes, and insulin resistance, Considered to be the liver manifestation of the metabolic syndrome .Several hypothesis

Spectrum

McCullough et al Clin. Liver Dis. 2004 The 2-hit hypothesisSuggested by Day and James in 1998 .

1st hit Hepatic triglyceride accumulation or Steatosis

2nd hit Inflammatory cytokines/adipokines, mitochondrial dysfunction and oxidative stress, which in turn lead to steatohepatitis and/or fibrosis.2 fundamental lesions in NAFLD : steatosis and steato hepatitis 5The traditional 2-hit hypothesis

The traditional 2-hit hypothesis: steatosis represents the first hit, which then sensitises the liver to injury mediated by second hits Pathogenesis of hepatic steatosis Dysregulation of fatty acid metabolism leads to steatosis .

Disordered energy homoestasis .

Accumulation of triglycerides (TG) are formed from the esterification of FFA and glycerol within the hepatocyte .

FFA accumulation : Lipolysis (hydrolysis of FFA and glycerol from triglyceride) within adipose tissue(64%)De novo lipogenesis (DNL) (26%)Dietary sources (15%). Donnelly KL et al, J Clin Invest 2005 FFA utilization : Beta oxidation of fatty acids Re-esterification to TG and storage as lipid droplets, Packaged and exported as very low density lipoprotein (VLDL)8VLDL particles are formed by the incorporation of TG into apolipoprotein B (apoB) by microsomal transfer protein (MTP).

Aberrant alterations of MTP/apoB synthesis and secretion have been proposed as potential mechanisms. Adams LA ,CMAJ 2005

ObesityObesity and hepatic steatosis strongly correlated .

Visceral fat more noxious than subcutaneous fat .Elevated levels of FFAs in plasma which leads increased hepatic uptakeIncreases splanchnic lipolysis in portal vein . Increasing visceral obesity results in increased production of pro inflammatory cytokines [TNF , IL- 6, and CRP] and decreased production of protective adiponectin . G. Atzmon et al ,Hormone and Metabolic Research 2002

net adipokine profile generated by visceral fat appears more noxious than that of subcutaneous fat 10Lean NAFLDThe lean NAFLD approximately 13.2% of total NAFLD.

Dyslipidemia present in 90% of lean NAFLD patients . IR present in 7.4% patients of lean NAFLD .

Compared to obese NAFLD, the severity of liver histopathology was significantly lower in patients with lean NAFLD . Kumar et al , Ind J of Endocrinology and Metabolism 2013Other studies from India 11-31 % . Thus, althoughobesity is clearly a risk factor for NAFLD, this appears tobe modified strongly by ethnicity, genetic predisposition, orenvironmental factors, which may explain risk of NAFLDin lean subjects.11Insulin ResistanceInsulin resistance is a universal phenomenon in NAFLD G. C. Farrell et al., Hepatology 2002Insulin resistance is intimately related to obesity

Proposed Mechanism :Insulin suppress adipose tissue lipolysis. In situations of IR impaired suppression leads to increased efflux of FFA from adipose tissue .Up -regulation of transcription factor Sterol Regulatory Element Binding Protein-1c (SREBP-1c), a key gene involved in DNL .

Down regulation mitochondrial beta oxidation of FFAs.

In the liver, IR increased intracellular degradation of VLDL and apo B-100.

Forward vicious cycle

Many abnormalities reported in NAFLD : FFAs , TNF- , Nuclear factor kappa (NF-k ), Ceramide SOCS(suppressors of cytokine signaling ) Cytochrome CYP2E1 . Lipid metabolites like diacyl glycerol (DAG) .

Interfere with insulin signalling cascade, and contribute to IR NAFLD : Beyond I R

Hepatic De novo LipogenesisBy product of hepatic gluconeogenesis and results in the synthesis of FFA s in the liver .

Sensitive to insulin resistance

Normally responsible for