5. Metabolic liver diseases

Question 1

Types of metabolic liver diseases

Answer 1

1. Hemochromatosis
2. Wilson disease
3. alpha1-antitrypsin deficiency
4. Non-alcoholic fatty liver disease

Question 2

Definition of hemochromatosis

Answer 2

Excessive accumulation of iron within the body (normal = 2-6g)

Question 3

Pathogenesis of hemochromatosis

Answer 3

1. Hereditary hemochromatosis
   - Mutations of genes encoding proteins involved in iron homeostasis (HFE, transferring receptor 2, hepcidin, hemojuvelin)
2. Acquired hemochromatosis (aka hemosiderosis)
   - Parenteral iron overload (transfusions, long-term hemodialysis)
   - Ineffective erythropoiesis (thalessemia, myelodysplastic syndromes)
   - Increased oral iron intake (Bantu siderosis)

Question 4

Pathological effects & complications of hemochromatosis

Answer 4

1. Iron deposition in liver
   - pigment cirrhosis
2. Iron deposition in pancreas
   - diabetes mellitus (due to destruction of islets)
3. Iron deposition in heart
   - Arrhythmias
   - Cardiomyopathy
4. Iron deposition in skin
   - Skin pigmentation
5. Iron deposition in joints
   - Atypical arthritis
6. Iron deposition in endocrine glands
   - Hypogonadism (amenorrhea, impotence, libido loss)

Question 5

Definition of Wilson disease

Answer 5

Genetic disorder causing accumulation of copper within the body

Question 6

Pathogenesis of Wilson disease

Answer 6

1. AR disorder caused by mutation of ATP7B gene
   - Encodes a copper transporting ATPase on hepatocyte canalicular membrane
2. Results in accumulation of copper due to:
   - Impaired copper excretion into bile & faeces
   - Impaired incorporation of copper into ceruloplasmin (copper + apoceruloplasmin) meant for copper transport in the blood
3. Copper accumulation primarily occurs within the liver, brain (especially the basal ganglia) & eye

Question 7

Pathological effects & complications of Wilson disease

Answer 7

1. Accumulation of copper in liver
   - Cirrhosis associated with Wilson disease
2. Accumulation of copper in basal ganglia
   - Chorea
   - Mild behavioural changes
   - Frank psychosis
3. Accumulation of copper in eye
   - Kayer-fleischer rings

Question 8

Pathogenesis of Alpha1-antitrypsin deficiency

Answer 8

1. AR disorder caused by mutation of alpha1-antitrypsin gene
   - Encodes alpha1-antitrypsin, an anti-protease which balances the action of endogenous proteases
2. Deficiency variants of alpha1-antitrypsin are abnormally folded & polymerize, accumulating within hepatocytes
   - Triggers ER stress response, damaging hepatocytes

Question 9

Pathological Effects & Complications of Alpha1-antitrypsin deficiency

Answer 9

1. Liver
   - Cirrhosis associated with alpha1-antitrypsin deficiency
2. Lung
   - Emphysema (due to imbalance of protease-antiproteases, resulting in net destruction of elastic tissue within septal walls)

Question 10

Definition of non-alcoholic fatty liver disease

Answer 10

A group of idiopathic conditions that have in common the presence of hepatic steatosis (fatty liver) which occur in individuals who do not consume alcohol, or do so in very small quantities

Question 11

Types of non-alcoholic fatty liver disease

Answer 11

1. Simple hepatic steatosis
2. Steatosis accompanied by minor inflammation
3. Non-alcoholic steatohepatitis (NASH)

Question 12

Associations with non-alcoholic fatty liver disease

Answer 12

1. Obesity
2. Dyslipidemia
3. Insulin resistence & hyperinsulinemia

Question 13

Pathological Effects & Complications of non-alcoholic fatty liver disease

Answer 13

1. Cryptogenic cirrhosis (cirrhosis of unknown origin)

2. Contributes to progression of other liver diseases such as HCV infection & hepatocellular carcinoma