Module 7 cont: NAFLD Flashcards
What is NAFLD
A broad term to describe liver disease that are NOT caused by excessive alcohol consumption
What is NAFLD strongly associated with
features of obesity, insulin resistance and T2D
4 stages of NAFLD
1.Steatosis
2.Non-alcoholic steatohepatitis (NASH)
3.Cirrhosis
4. Hepatocellular carcinoma (HCC) (liver cancer)
Reversible stages of NAFLD
Steatosis and NASH
Irreversible stages of NAFLD
Cirrhosis and HCC
Symptoms of NAFLD
-typically asymmptomatic even in advanced stages - could be mild (fatigue)
-liver enlargement
-pain in upper right quadrant
-jaundice
Symptoms of NAFLD (cirrhosis)
-esophageal varices (expanded blood vessels)
-ascites
-easy bruising
-liver cancer
NAFLD risk factors
-T2D and obesity
-found in 70-80% of people who are obese or diabetic
-Age and biological sex
-more common in males, affects mainly middle aged men and elderly (post-menopausal) women
-Genetic variants
-polymorphism of PNPLA3 and TM6SF2 2 potential modifiers of progression and HFE variants
“Two-hit hypothesis”
First-hit: lipid accumulation in hepatocyes
Second-hit: inflammation, oxidative stress, etc (steatosis to NASH)
Why does steatosis happen
-Imbalance in FFA levels due to an increase in hepatic FFA uptake and synthesis along w a reduction in FFA oxidation and VLDL transport
Insulin resistance in the liver
-fails to supress gluconeogenesis
-continues to activate de novo lipogenesis pathway
=increase FFA and TAG accumulation in liver
adipose tissue IR and FFA relationship
-increase in FFA (NEFA) release, increased hepatic FFA uptake
-increase TAG lipolysis
HSL
enzyme in adipose tissue that breaks down TAG into FFA
-suppressed by insulin
2 major contributors to NASH development
-inflammation
-oxidative stress
*caused from lipotoxicity
what does dysfunctional adipose tissue release that promotes inflammation
proinflammatory cytokines (IL-1,IL-6.TNFa, etc)
Fatty acids are incorporated into what
Saturated –> ceramides (contribute to lipotoxicity)
Mono and poly-unsaturated –> TAG (less toxic, more stable)
High saturated fat and inflam relatioonship
induces inflammation and oxidative stress by activating NF-κB
Can diet promote the “two-hits” required for NAFLD
-yes, diets high in sugar and saturated fats can
what genes are potential modifiers of NAFLD
PNPLA3 and TM6SF2
Where is PNPLA3 expressed and what does it do
-expressed in liver and adipose tissue, involved in energy mobilization and storage in lipid droplets
PNPLA3 genotypes
GG, CG,CC
GG & CG - greater severity of steatosis, fibrosis and NASH
TM6SF2 - which variant is more susceptible to NAFLD & what happens
E167K
Glutamate (E) replaced be lysine (K) at a.a 167
NAFLD diagnostic challenges
-undiagnosed in early stages
-noninvasive diagnostic methods lack sensitivity and accuracy
-invasive method (liver biopsy) is current gold standard –> diagnose NASH and indicate severity
3 non-invasive diagnostic NAFLD method
- ultrasound
2.serm biomarkers
3.proton magnetic resonance spectrometry
