LT11 NASH (MASLD)

Question 1

What does NAFLD stand for and its alternative name?

Answer 1

Non-alcoholic fatty liver disease

Metabolic Dysfunction-Associated Steatotic Liver Disease = MASLD

Question 2

What does steatotic mean?

Answer 2

Refers to the condition of having an abnormal buildup of fat, or lipids, within cells or an organ

Question 3

Why is it important to treat MASLD?

Answer 3

Global prevalence

MASLD leading cause of cirrhosis

Soon be leading cause of Orthotopic Liver Transplantation, Hepatocellular carcinoma, liver related death

Significant cost

Question 4

What is the progression from MASLD and when does this occur?

Answer 4

MASLD becomes MASH when inflammation occurs

Question 5

What does ALD stand for?

Answer 5

Alcohol-related Liver Disease

Question 6

When does MASLD become ALD?

Answer 6

When alcohol intake increases

Question 7

What are other causes of steatosis?

Answer 7

Drug-induced liver disease

Monogenic disease

Miscellaneous

Question 8

What is cryptogenic SLD?

Question 9

What is the adult criteria for MASLD?

Answer 9

Higher BMI

T2D symptoms (hyperglycaemia)

High blood pressure

High triglycerides

High HDL-cholesterol

Question 10

What are the disease drivers of MASLD > metALD > ALD

Answer 10

Cardiometabolic risk

Genetic risk

Alcohol use

Fibrosis stage

Question 11

Describe MASLD progression

Answer 11

Normal liver
MASLD
NASH (Fibrosis stages 1-3)
Cirrhosis (Fibrosis stage 4)
Hepatocellular carcinoma

Question 12

What is the relationship between MASLD and T2D?

Answer 12

Bi-directional synergistic relationship

Question 13

What impact does MASLD have on T2D?

Answer 13

2-5x increase risk of T2D, risk increases with severity of liver fibrosis

Increase peripheral and hepatic insulin resistance = worse HbA1c

Together they ahve higher likelihood of progressive fibrosis and faster rate of fibrosis progression than those without

Double rate of HCC

Reduced sensitivity of ALT, FIB-4

Question 14

What does reduced sensitivity of ALT and FIB4 mean?

Answer 14

ALT: A liver enzyme that can be elevated in liver damage or disease.

FIB-4: A non-invasive score that estimates the severity of liver fibrosis (scarring) using age, AST (another liver enzyme), ALT, and platelet count.

Individuals with Type 2 Diabetes (T2D) may have a lower sensitivity of ALT and FIB-4 scores for detecting advanced liver fibrosis, meaning these tests might be less accurate in identifying liver damage in this population.

Question 15

Describe what hepatic steatosis looks like

Answer 15

Fat deposits in globules

Yellow colour (normally a healthy pink)

Question 16

What are the histologic features of MASH?

Answer 16

From steatosis > steatohepatitis > steatohepatitis with fibrosis > cirrhosis

Question 17

What is steatoheptatitis?

Answer 17

Inflammation

Hepatocyte degeneration

Fibrosis

Question 18

What are the criteris for MASLD diagnosis?

Answer 18

Criteria for diagnosis:

Abnormal ALT or GGT

Bright liver ultra-sound

Low alcohol intake

Negative liver screen

Question 19

What are the tests for diagnosing steatosis?

Answer 19

Imaging-MRS
Ultra-sound
Biopsy

Question 20

What are the tests for diagnosing MASLD?

Answer 20

Biopsy

Biomarkers are in development

Question 21

What are the tests for diagnosing fibrosis?

Answer 21

Biopsy

Fibroscan/ARFI

Standard biomarkers = FIB-4

Expensive biomarkers = ELF, Fibrotest

Question 22

Issuses with liver biopsy

Answer 22

Invasive

Costly

Obesrver variability

Sampling error

Morbidity and motality

Question 23

What is MRI good for?

Answer 23

Differentiating fat and non-fat

So good at looking for steatosis

Question 24

What do the FIB-4 scores tell us?

Answer 24

Less than 1.3 = re-assess FIB-4 every 1-3 years

1.3 to 2.67 = intensify management

Above 2.67 = heptology referral

Question 25

Define aetiology

Answer 25

The cause, set of causes, or manner of causation of a disease or condition

Question 26

What are the causes of MASLD?

Answer 26

High fat and fructose diet Microbiome Genetic susceptibility Insulin resistance = pro-inflammatory Inflammation causes insulin resistance Metabolic inflammation Failure of antioxidant defence

Question 27

What is special about fructose?

Answer 27

Does NOT elicit leptin response Only has 2 metabolic fates = either changes to fat or used in Kreb cycle

Question 28

What are the potential mechanisms responsible for inflammation and fibrosis in MASLD?

Answer 28

Fatty acids cause peroxisome, mitochondria and ER dysfunction Causing ROS, which leads to = OxS, lipid peroxidation and inflammation OxS = causes ATP and NAD depletion, DNA/protein damage and glutathione depletion Lipid peroxidation = fibrosis and heptaic stellate cell activation Inflammation = cytokines and neutrophil chemotaxis

Question 29

What is the lifestyle treatment to MASLD?

Answer 29

No smoking Less alcohol Diet = Exercise Weight loss

Question 30

What drugs help treat MASLD?

Answer 30

Medication associated with weight loss = Exendin-4, Orlistat, Rimonabant Anti-lipases = prevent fatty acid release

Question 31

What role fo stellate cells play in the liver?

Answer 31

Hepatic stellate cells (HSCs) are liver-specific cells located in the space of Disse, vital for liver physiology and fibrogenesis, storing vitamin A, and regulating sinusoidal blood flow, but also playing a role in liver fibrosis and regeneration

Question 32

What is a MASH-targetted treatment?

Answer 32

Resmetiron Againt MASH fibrosis stage 2-3

Question 33

What is the mechanism of action of resmetirom?

Answer 33

Works by selectively activating the thyroid hormone receptor beta (THR-β) in the liver, which is crucial for regulating lipid metabolism and reducing liver fat, while minimizing effects on other organs.