L9-Non-Alcoholic Fatty Liver Disease (NAFLD)

what is non alcoholic fatty liver disease (NAFLD) now called

metabolic dysfunction associated steatotic liver disease (MASLD)

what factors make up the disease phenotype of obesity

• physiology

• economic

• social

• cultural

• political

the complex obesogenic environment tries to map all factors that contribute- very complex

how has the prevalence of obesity in adults changed

it has increased over the years

describe the ‘right-shift’ in population body weight

Normal distribution is slowly shifting to the right  

• At Population level- average person weighs more than generations before 

Personal fat threshold- how much fat you carry until you begin to get ill- personal to each individual based on many factors  

• Getting larger over time 

how is obesity a multi system disease

obesity causes metabolic stress

• leads to systemic inflammation and fibrogenesis (scarring)

Inflammation and scarring in organs 

• In liver its called MASLD 

what is the spectrum of steatotic liver disease (phases MASLD)

1. steatosis (MASL)- fat infiltration- >5% with or without mild inflammation

2. steatohepatitis (MASH)- steatosis & necroinflammation- ballooning hepatocyte degeneration, mallory bodies, megamitochondria

3. cirrhosis- increasing fibrosis, leading to cirrhosis

4. leads to → hepatocellular carcinoma (HCC)

what causes MASLD to lead to cirrhosis

In some people how the fat is handled leads to inflammation and cell death- if continues causes a wound healing response  where the injury and healing is perpetual 

• Eventually leads to cirrhosis 

• Structure of liver changes, blood doesn’t flow properly, RBC numbers diminish 

• Can go on to develop cancer 

what is MetALD, why do some people get it easier

MASLD and increased alcohol intake

MetALD- people who drink just a bit more than they should, not really excessive  

• Would have been fine, only if they weren't overweight 

• Fat in liver makes body more sensitive to the damage alcohol causes 

what are the 5 types of steatotic liver disease (SLD)

1. metabolic dysfunction associated steatotic liver disease (MASLD)

2. MASLD and increased alcohol intake (metALD)

3. alcohol associated/related liver disease (ALD)

4. specific aetiology SLD

5. cryptogenic SLD

what are the forms of specific aetiology SLD

1. drug induced liver injury (DILI)

2. monogenic diseases

3. miscellaneous

describe the interaction between alcohol consumption & metabolic syndrome

Multiple components of the metabolic syndrome independently affected the risk for severe liver disease.

Alcohol was significant even when average alcohol consumption was within the limits currently defining MASLD.

what are the diagnostic definitions of SLD

describe the global prevalence of MASLD in adults

About 1/3 uk population have some form of MASLD 

 

what is the data of the UK MASLD experience

hospital admissions increasing

liver transplant listings for MASLD increasing

How does MASLD progress?

MASLD progresses from steatosis (F0) to fibrosis (F1–F3), cirrhosis (F4), and potentially liver cancer or decompensation.

• Progression speeds up with advanced fibrosis: ~30–35 years (F0–F1), ~19 years (F2), ~6 years (F3).

What is the natural history and progression of MASLD?

• Steatosis ↔ MASH: disease activity can fluctuate or reverse.

• MASH → fibrosis (F1–F4) → cirrhosis → hepatocellular carcinoma.

• Progression depends on factors such as diet and genetics.

• Fibrosis involves ECM formation and remodelling; advanced disease increases liver mortality risk.

What influences MASLD progression and the balance between fibrogenesis and fibrolysis?

• Diet and genetics influence disease progression.

• Fibrogenesis: ECM formation → increased fibrosis.

• Fibrolysis: ECM breakdown/remodelling → reduced fibrosis.

• The balance between these processes determines whether fibrosis progresses or regresses.

• Steatosis and MASH can fluctuate, whereas advanced fibrosis increases liver mortality risk

describe the pathophysiology of complex disease traits

what genes have been identified as being modifiers of pathophysiological processes relevent to MASH

what is the relevance of the gene PNPLA3

identified from GWAS

Single variant associated with greater fat content in liver 

• Also caused more inflammation and scarring of liver  

what is the TM6SF2 (E167K) minor allele carriage associated with

increased steatosis

If carry rare variant form- keep fat in liver- scaring and cirrhosis 

If you have wild type you push fat put of liver and more likely to have heart attack 

describe the pathogenesis of MASLD

• Fat enters liver: from diet, body fat or glucose.

• Insulin resistance: increases fat release from adipose tissue and fat production in the liver.

• Fat accumulation: excess fatty acids are stored as triglycerides, causing steatosis.

• Oxidation: the liver burns fat for energy, but excess processing can produce harmful by-products.

• Liver damage: oxidative stress causes cell damage and death, leading to inflammation (MASH) and potentially fibrosis.

What are the 2 ways fat enters and leaves the liver?

• Enters: import from dietary fat/adipose tissue; fat synthesis from glucose.

• Leaves: esterification into triglycerides exported as VLDL; oxidation to produce energy.

How does insulin resistance increase fat accumulation in the liver?

• Adipose insulin resistance reduces insulin's inhibition of HSL → increased fat breakdown and fatty acid release into blood.

• The liver remains relatively insulin-sensitive, so high glucose and insulin stimulate fat synthesis.

• Result: increased fatty acid supply and turnover in the liver.

How can excess fatty acids cause liver damage in MASLD?

• Fatty acids are converted into relatively inert triglycerides, initially protecting liver cells.

• Eventually, excess fatty acids overwhelm the liver's processing capacity.

• Mitochondrial β-oxidation: main pathway for producing energy via the electron transport chain.

• Other pathways (e.g. ω-oxidation): can produce harmful by-products.

• These processes can contribute to oxidative stress, liver cell damage and cell death.

How does excess fat cause MASH?

• Insulin resistance increases fat synthesis in the liver and fatty acid release from adipose tissue.

• Fatty acid accumulation causes triglyceride storage (steatosis).

• Excess fatty acids produce harmful lipid intermediates and ROS, causing oxidative stress.

• This leads to liver cell damage and death, inflammation and MASH.

How does fibrogenesis occur in liver disease?

• Liver injury activates hepatic stellate cells (HSCs).

• Activated HSCs produce excess extracellular matrix (ECM).

• This causes fibrosis (scar tissue formation).

• Activated HSCs also promote inflammation and tissue remodelling.

• Excessive ECM accumulation leads to progressive fibrosis and potentially cirrhosis.

what are tests for MASLD based on

Anything that predicts scaring in the liver, suggests MASLD 

• Amount of scaring counted on 4 point scale  

• F3,4 worried about, risk of liver related death 

what is the basic pathway of testing for/diagnosing level of scarring

Start by looking at risk factors, calculate fib score, routine tests and age, depending on results do a blood test 

what is the simple score for predicting presence of advanced F3/4 fibrosis

Fib scores , cheap tests, quick for ruling out disease, if low probs don’t have a lot of scarring right now 

what does your fib score show for prognosis

If fib score is high, means scarring in liver, and prognostic marker, not a good sign, predictor of liver and heart death 

• Can be used to monitor disease overtime too 

what is the proposed SLD patient pathway

what are the second line non invasive tests for MASLD

2 types of second line test  

1. Biomarkers 

2. Measure hardness of liver, hard= scarred 

how can we address factors influencing behaviours that drive obesity & MASLD

• support healthy lifestyle choices

• personalised behaviour interventions

interventions tailored to stage of readiness for change

provide motivation and support compliance

sensitive to cultural, social and economic considerations that influence ability to change behaviour

can weight loss be an effective treatment for NAFLD / MASLD

293 patients- 12 month lifestyle modification- calorie intake and exercise

what are the 4 principles of treatment when targeting MASLD

1. target obesity- lifestyle (diet/exercise), bariatric surgery

2. target the metabolic syndrome- reduce CVD risk whilst selecting medication with additional liver directed benefits

• insulin resistance/T2D

• hypertension

• dyslipidemia

3. target the liver disease- ameliorate steatohepatitis and prevent progression to fibrosis and cirrhosis

4. minimise down stream complications such as HCC

how can pathophysiological processes be targeted

1. metabolic targets

2. anti-inflammatory targets

3. anti-fibrotic targets

what are some metabolic targets for treating MASLD

• targets related to insulin resistance and or lipid metabolism

• targets related to lipotoxicity and oxidative stress

what are some anti inflammatory targets for treating MASLD

1. targets related to inflammation and immune activation

2. targets related to cell death (apoptosis and necrosis)

what are some anti fibrotic targets for treating MASLD

targets related ro fibrogenesis and collagen turnover

what is the rationale for thyroid hormone receptor beta agonists to treat MASH

↓ Lowers LDL-cholesterol

↓ Lowers triglycerides

↓ Lowers liver fat, potentially reducing lipotoxicity, MASH

Resmetirom (THR-β) for MASH: Phase 3 Study Results

Incretins: Effects of Mono, Dual & Triple Agonists

Multiple Effects of FGF21 in MASLD

1. FGF21 analogues possess a “directly” acting antifibrotic mechanism of action.

2. FGF21 analogues reduce liver steatosis while activating intra- cellular pathways to protect hepatocytes against stress.

3. FGF21 analogues also increase insulin sensitivity and reduce dyslipidemia.

what are the FGF21 agonists in development