Alcoholic and Non-alcoholic Liver Disease

Question 1

How is alcohol metabolised?

Answer 1

1. ADH in cytoplasm
2. MEOS in smooth ER (CYP450)
3. Catalase in peroxisomes

All produce acetaldehyde

Question 2

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Question 3

What are the risk factors for ALD?

Answer 3

Consumption levels
- Males 40-80g/day
- Females 20-40g/day
- 10-12 years

Women>Men
- lower gastric alcohol dehydrogenase
- smaller volume of distribution
- oestrogen increases gut permeability -> increased endotoxins

Genetics
- ADH polymorphisms
- ALDH polymorphisms
- CYP2E1 polymorphisms

Co-factors:
- viral hepatitis
- iron overload

Question 4

What are the recommended units of alcohol to not increase risk of ALD?

Answer 4

Men - <21 units/week (binging on >8 units increases risk)
Women - <14 units/week (binging on >6 units increases risk)

Question 5

What is the progression of ALD?

Answer 5

Steatosis -> hepatitis -> cirrhosis

Steatosis can resolve with abstinence
- macrovesicular fat with minimal inflammation -> hepatomegaly

Hepatitis usually after years of abuse
- Jaundice, fever, ascites, encephalopathy
- Hepatomegaly
- AST:ALT > 2:1
- Increased INR, Bilirubin, WCC
- Increased Creatinine indicates poor prognosis

Cirrhosis
- Features of chronic liver disease
- Usually present on decompensation

Question 6

What is the pathogenesis of ALD?

Answer 6

Alcohol is toxic to gut -> increased gut permeability -> translocation of bacteria into portal system -> upstream drive inflammation via activation of Kupffer cell -> cytokine release -> activation of stellate cell -> collagen and reticulum laid down -> fibrosis -> cirrhosis

Alcohol is toxic to hepatic mitochondria -> impairment of free fatty acid oxidation -> steatosis -> drives progressive fibrosis -> cirrhosis

Question 7

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Question 8

What is the biochemical picture in ALD?

Answer 8

Liver enzymes:
- AST 2-6x
- AST:ALT >2:1 (>3 is very highly suggestive)
- Elevated GGT

Haematology:
- Macrocytosis - BM toxicity, B12 and folate deficiency
- Thrombocytopenia - BM hypoplasia, portal hypertension
- Leucocytosis - neutrophilia (correlates with severity of hepatic injury)

Carbohydrate deficient transferrin increased

Question 9

How is ALD managed?

Answer 9

Abstinence
Nutrition
Transplantation

Question 10

What is non-alcoholic fatty liver disease?

Answer 10

The pathological and clinical features of ALD in the absence of alcohol

Steatosis -> steatosis with lobular inflammation -> fibrosis -> cirrhosis

Question 11

What are the risk factors for NAFLD?

Answer 11

Metabolic syndrome
- BMI >30
- Increased waist circumference
- Elevated fasting blood glucose (T2DM)
- Serum lipids (hypertriglyceridaemia)
- Elevated blood pressure

Question 12

What is the spectrum of NAFLD?

Answer 12

Simple steatosis (70-75%) -> NASH (20-25%) -> cirrhosis-> liver ca

Question 13

What mortality risk does NAFLD increase?

Answer 13

1. Cardiovascular disease (13-30%)
2. Malignancy (6-28%)
3. Liver-related death (2.8-19%)

Your liver will affect your entire system!

Question 14

What is the pathogenesis of NAFLD?

Answer 14

Two-hit hypothesis:

Insulin resistance acts as primer -> increased FFA’s turnover -> reesterification in hepatocytes -> mitochondrial stress -> free radical production -> lipid perioxidation + cytokine release + FAS ligand upregulation -> inflammation

Question 15

What are the biochemical findings of NAFLD?

Answer 15

Jaundice is not usually found

Liver enzymes:
- Mildly elevated transaminases
- GGT 2-5x elevated
- ALP 2-5x elevated

Question 16

What is the management of NAFLD?

Answer 16

Abstinence from alcohol
Weight reduction
- diet change
- exercise
- will alter skeletal muscle sensitivity to insulin and glucose utilisation
- 10% weight reduction gives increased benefit
Lipid lowering therapy
- Statins
Antidiabetic/insulin sensitising
- intense DM management
- Metformin