NAFLD and MetS

Question 1

Diagnosis of MetS

Answer 1

• abdominal obesity: waist circumference men (>102cm), women (>88cm)
• hypertension: 130/85 mmHg
• dyslipidemia: HDL levels <40mg/dl (men) or <50mg/dl (women). Triglycerides of >150 mg/dl
• fasting blood glucose: >110 mg/dl

Question 2

Definition of NAFLD, prevalence and histopathology of the 4 types

Answer 2

• Definition: liver expression of MetS. Associated with fat accumulation in the liver which causes insulin resistance, progressive damage. Associated with sleep apnoea, PCOS, hypertension, cancers
• primary NAFLD: associated with MetS
• secondary NAFLD: associated with lipodystrophy and medications
• prevalence of 20-30% in western cultures
• histopathology: type 1 (fat alone), type 2 (fat + inflammation), type 3 (fat + ballooning degeneration), type 4 (fat + alcoholic-like hepatitis, sinusoidal fibrosis, hepatocyte injury)

Question 3

Definition of NASH + prevalence

Answer 3

• more severe form of NAFLD
• in 2-3% of the general population but 70% of diabetic patients
• step before cirrhosis

Question 4

Clinical pathway from NAFLD to HCC (with prevalence)

Answer 4

NAFLD -> 30% progress to NASH/fibrosis -> 20-25% progress to cirrhosis-> unknown percentage progress to HCC

Question 5

How is NAFLD linked with MetS (insulin resistance)

Answer 5

• fat deposits in the liver can propagate insulin resistance as this reduces efficiency of insulin receptors in hepatocytes
• NAFLD/NASH can also increase inflammatory cytokines (through NFkB activation) which worsens insulin resistance
• positive feedback mechanism: fat in liver worsens insulin resistance, and increased insulin resistance worsens fat in the liver (as causes adipose tissue to release more NEFA)
• hyperinsulinemia from pancreatic B cells to try and compensate just make the situation worse as eventually they fail and T2DM develops

Question 6

Oxidative stress and NASH

Answer 6

• increased oxidation of fatty acids in liver produces ROS (FA are oxidised due to insulin resistance and production from excess adipose tissue)
• Hepatocytes wear down their supplies of antioxidants
• chronic ROS leads to NASH

Question 7

Pathogenesis of chronic liver disease: what causes insulin resistance? What does insulin resistance lead to?

Answer 7

• cause of insulin resistance: genetics (PI3K), obesity/lifestyle and T2DM or hepatitis C (inhibits insulin signalling and increases TNFa)
• what does insulin resistance lead to: T2DM, CVD, hyperglycaemia (leads to increased ROS which contributes to NASH), hyperinsulinemia (pro-fibrotic which contributes to NASH), increase in free fatty acids which increase NAFLD

Question 8

Diagnosis: radiology

Answer 8

• ultra-sound, MRI and CT all have similar diagnostic rates
• transient elastography (fibroscan) may also be used, but it has higher levels of false-positive rates for those with higher BMI (10% of those with BMI of >28 kg/m2 had fibrosis stage different by 2 levels versus biopsy)

Question 9

Diagnosis: histology

Answer 9

• gold-standard but invasive

- can distinguish between intermediate levels of disease which is difficult to do with imaging or serum blood markers

Question 10

Diagnosis: NAFLD fibrosis score

Answer 10

• used before imaging etc to see a patient’s risk
• comprised of serum blood markers (AST/ALT, serum glucose, platelet count, albumin and patient characteristics (BMI, age, diabetes)
• composite score then determines if further imaging or biopsy is needed

Question 11

Management: intensive lifestyle

Answer 11

• ketogenic diet may be appropriate for helping with insulin resistance
• if lose 5% BW in one year 58% resolved NASH, increased to 90% if lost 10% (with 45% resolution of fibrosis)

Question 12

Management: drugs (metformin, clofibrate, alpha blockers, anti-cytokine, bile acids)

Answer 12

• Metformin: anti-diabetic shown promising results for reducing NAFLD
• clofibrate (lipid-lowering drugs for dyslipidemia) has not shown promising results
• anti-hypertensives (alpha-blockers targeting renin-angiotensive system
• anti-TNFa reduces inflammation and may reduce insulin resistance and NAFLD
• bile acids such as obeticholic acid improves liver histology over 72 weeks by binding to the farnesoid X nuclear receptor which promotes insulin sensitivity and reduces hepatic gluconeogenesis + circulating triglycerides

Question 13

Management: liver transplant

Answer 13

• those with decompensated cirrhosis and HCC may be a candidate
• for those with a BMI of 40+ they are at higher risk of post-op morbidity and mortality
• however, weight loss should not be pursued in decompensated disease due to protein-energy malnutrition
• in compensated disease with HCC, weight loss could be sought
• a dietician needs to evaluate every year on transplant list using SGA, HGS and anthropometry measures to make sure no protein-energy malnutrition