Module 7 cont: NAFLD

Question 1

What is NAFLD

Answer 1

A broad term to describe liver disease that are NOT caused by excessive alcohol consumption

Question 2

What is NAFLD strongly associated with

Answer 2

features of obesity, insulin resistance and T2D

Question 3

4 stages of NAFLD

Answer 3

1.Steatosis
2.Non-alcoholic steatohepatitis (NASH)
3.Cirrhosis
4. Hepatocellular carcinoma (HCC) (liver cancer)

Question 4

Reversible stages of NAFLD

Answer 4

Steatosis and NASH

Question 5

Irreversible stages of NAFLD

Answer 5

Cirrhosis and HCC

Question 6

Symptoms of NAFLD

Answer 6

-typically asymmptomatic even in advanced stages - could be mild (fatigue)
-liver enlargement
-pain in upper right quadrant
-jaundice

Question 7

Symptoms of NAFLD (cirrhosis)

Answer 7

-esophageal varices (expanded blood vessels)
-ascites
-easy bruising
-liver cancer

Question 8

NAFLD risk factors

Answer 8

-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

Question 9

“Two-hit hypothesis”

Answer 9

First-hit: lipid accumulation in hepatocyes
Second-hit: inflammation, oxidative stress, etc (steatosis to NASH)

Question 10

Why does steatosis happen

Answer 10

-Imbalance in FFA levels due to an increase in hepatic FFA uptake and synthesis along w a reduction in FFA oxidation and VLDL transport

Question 11

Insulin resistance in the liver

Answer 11

-fails to supress gluconeogenesis

-continues to activate de novo lipogenesis pathway
=increase FFA and TAG accumulation in liver

Question 12

adipose tissue IR and FFA relationship

Answer 12

-increase in FFA (NEFA) release, increased hepatic FFA uptake
-increase TAG lipolysis

Question 13

HSL

Answer 13

enzyme in adipose tissue that breaks down TAG into FFA
-suppressed by insulin

Question 14

2 major contributors to NASH development

Answer 14

-inflammation
-oxidative stress
*caused from lipotoxicity

Question 15

what does dysfunctional adipose tissue release that promotes inflammation

Answer 15

proinflammatory cytokines (IL-1,IL-6.TNFa, etc)

Question 16

Fatty acids are incorporated into what

Answer 16

Saturated –> ceramides (contribute to lipotoxicity)
Mono and poly-unsaturated –> TAG (less toxic, more stable)

Question 17

High saturated fat and inflam relatioonship

Answer 17

induces inflammation and oxidative stress by activating NF-κB

Question 18

Can diet promote the “two-hits” required for NAFLD

Answer 18

-yes, diets high in sugar and saturated fats can

Question 19

what genes are potential modifiers of NAFLD

Answer 19

PNPLA3 and TM6SF2

Question 20

Where is PNPLA3 expressed and what does it do

Answer 20

-expressed in liver and adipose tissue, involved in energy mobilization and storage in lipid droplets

Question 21

PNPLA3 genotypes

Answer 21

GG, CG,CC
GG & CG - greater severity of steatosis, fibrosis and NASH

Question 22

TM6SF2 - which variant is more susceptible to NAFLD & what happens

Answer 22

E167K
Glutamate (E) replaced be lysine (K) at a.a 167

Question 23

NAFLD diagnostic challenges

Answer 23

-undiagnosed in early stages
-noninvasive diagnostic methods lack sensitivity and accuracy
-invasive method (liver biopsy) is current gold standard –> diagnose NASH and indicate severity

Question 24

3 non-invasive diagnostic NAFLD method

Answer 24

1. ultrasound
   2.serm biomarkers
   3.proton magnetic resonance spectrometry