Metabolic Liver Disease

Question 1

Wilson disease

Answer 1

• Increased / toxic copper deposition within liver, cornea (Kayser-Fleischer ring), kidney and central nervous system
• Due to ATP7B mutation (absence or dysfunction of copper transporting ATPase)
• Autosomal recessive
• Oxidative damage to hepatocytes due to toxic accumulation of copper

Labs:
* Elevations of alanine transaminase (ALT) and aspartate transaminase (AST)
* Low serum alkaline phosphatase (ALP)
* Serum ceruloplasmin levels < 50 mg/L
* Increased 24 urine copper > 100 µg in symptomatic, > 40 µg in others
* Liver copper concentration (dry weight) > 250 µg/g

Macro:
* Excessive copper granules can only be seen with a special stain
* Mild to mod fatty change
* Focal hepatocyte necrosis
* Acute and chronic hepatitis
* Cirrhosis following chronic hepatitis

IHC:
* Rhodanine stain for copper
* Orcein stain for copper-associated protein

Question 2

Hemochromatosis

Answer 2

• Most common autosomal recessive disorder in Caucasians
• The main affected gene is the human haemochromatosis protein (HFE) gene is located on chromosome 6 p22. Different mutations leads to the different types of haemochromatosis.

The 2 major mutations:
* C282Y and H63D (penetrance is <100%) - so other factors may be important.
* Subsitution mutations result in changes in bases and in this case the change causes a mis-sense mutation resulting in an altered amino acid in the protein. The most common variant being a cysteine replaced with a tyrosine.
* Excess iron accumulates predominantly in hepatocytes, in a periportal (early) to panlobular (advanced) distribution
* Up to 100 times the chance of developing hepatocellular carcinoma than the general population
* M:F = 2:1
* Men typically develop symptoms at 40 - 60 years old
* Classic triad: Cirrhosis, skin pigmentation, diabetes mellitus
* May also have joint pain, fatigue, abdominal pain

Labs:
* Increased serum iron and ferritin

Micro:
* Iron appears as dark brown granular pigment, predominantly within hepatocytes
* Periportal deposition initially, extending towards zones 2 and 3 with disease progression
* Iron pigment may also be seen in cholangiocytes and Kupffer cells, especially at later stages
* Fibrosis develops over time
* Amount of iron can be graded semi quantitatively
* Scheuer methodology (scale 0 - 4) based on ease of observation of iron granules at various magnifications

Modified Scheuers:
0. No visible iron
1. Some iron seen in zone 1 at high power
2. Iron granules seen easily in zone 1 on low power
3. Iron granules seen easily in zone 2
4. Iron granules seen with naked eye

IHC:
* Prussian blue

Question 3

Alpha-1 antitrypsin deficiency

Answer 3

• Genetic metabolic disorder causing deficiency of alpha-1 antitrypsin deficiency (AAT) and leading to disease in the lungs and liver
• absent/decreased alpha-antitrypsin –> unchecked neutrophillic elastase –> pulmonary emphysema
• AAT encoded by SERPINA1 gene located on chromosome 14
• Normal gene product is PiMM
• Most common deficiency alleles are PiSS and PiZZ
• PiZZ phenotype accounts for most severe cases

Conditions Directly Associated with AATD:
* Emphysema
* Chronic obstructive pulmonary disease (COPD)
* Bronchiectasis
* Liver cirrhosis
* Hepatocellular carcinoma (HCC)
* Neonatal jaundice
* Panniculitis
* Vasculitis
* Chronic sinusitis
* Increased infections
* IBD
* Proliferative glomerulonephritis
* IgA nephropathy

Micro:
* Eosinophilic intracytoplasmic globules in hepatocytes
* Usually in zone 1, near portal triads
* Most suggestive feature of AAT deficiency
* Fibrosis: ranges from minimal periportal fibrosis to cirrhosis
* Mild portal inflammation: predominantly lymphocytic
* Mild steatosis: often in periportal hepatocyte

IHC:
* Diastase resistant periodic acid Schiff (PAS) positive globules
* AAT positive globules

Question 4

Increased bilirubin syndromes

Answer 4

DRs are DIRECT
DIRECT hyperbilirubinaemia
* Dubin Johnson
* Rotor’s

Interests Can Grow
INDIRECT hyperbilirubinaemia
* Crigler-Najjar type 1
* Crigler-Najjar type 2
* Gilbert’s