Inherited metabolic diseases

Question 1

Autosomal recessive disorder characterised by low serum levels of this protease inhibitor

Answer 1

Alpha-1 antitrypsin deficiency

Question 2

What is normal function of Alpha-1 antitrypsin deficiency?

Answer 2

Inhibition of neutrophil elastase released at sites of inflammation

Question 3

Alpha-1 antitrypsin deficiency causes

Answer 3

Pulmonary Emphysema

Question 4

Morphology of AAT deficiency

Answer 4

Hepatocytes with round to oval cytoplasmic globules (PAS+ and PASd+ [DD:Glycogenosis of Diabetic Hepatopathy, and Glycogen Storage Diseases])
Patterns of Hepatocyte injury associated with PiZZ homozygosity:
* Marked Cholestasis with Hepatocyte necrosis in newborn
* Childhood Cirrhosis
* Smoldering Chronic Hepatitis
* Cirrhosis (apparent late in life)

Question 5

Clinical manifestations of AAT deficiency

Answer 5

• Cholestasis: 10-20% of newborns with AAT deficiency
• Chronic Hepatitis
• Cirrhosis or Pulmonary disease
• Cirrhosis (middle aged to older patients)
  Complications:
• Hepatocellular Carcinoma (2-3% of adults with PiZZ genotype)
  Treatment: Orthotopic Liver transplantation

Question 6

Autosomal recessive disorder
Characterised by the accumulation of toxic levels of Copper in many tissues & organs (Liver, Brain and Eye)

Answer 6

Wilson Disease

Question 7

What causes wilson disease?

Answer 7

Loss-of-function mutations in ATP7B gene (Chromosome 13); ATP7B gene encodes an ATPase metal ion transporter, localised to the Golgi region of hepatocytes

Question 8

Pathogenesis of wilson’s disease

Answer 8

Normal Copper Absorption to Liver: Initial steps intact, but lack of ATP7B activity disrupts:

Copper binding to Apoceruloplasmin.
Excretion of Copper into bile.
Copper Accumulation in Hepatocytes: Causes toxic injury via:

Free radical formation.
Binding to sulfhydryl groups in cellular proteins.
Displacement of metals in hepatic metalloenzymes.
Escape of Free Copper into Circulation:

Oxidant generation → Red cell hemolysis.
Deposition in tissues (brain, cornea, kidneys, bones, joints, parathyroid glands), leading to:
Tissue damage through similar mechanisms.

Question 9

Morphology of Wilsons disease

Answer 9

Fatty Liver Disease (with mild to moderate Steatosis, Steato-Hepatitis and similar
patterns of Scarring)
Acute Hepatitis-like injury: In its most severe form, manifests as Fulminant Hepatic
Failure
Chronic Hepatitis-like picture, with coexistence of Fatty Liver Disease features;
Progression of Chronic Hepatitis → Development of Cirrhosis

Question 10

What are the special stains for copper deposits?

Answer 10

i. Rhodanine stain for Copper & ii. Orcein stain
(for Copper-associated protein)

Question 11

Diagnosis of wilson’s disease

Answer 11

Demonstration of hepatic Copper content of ≥250μg/g dry weight

Question 12

Clinical features of wilson’s disease

Answer 12

Acute or Chronic Liver Disease – Neuropsychiatric manifestations (mild Behavioural Changes, frank Psychosis, Parkinson disease-like syndrome)

Question 13

Tx of wilson’s disease

Answer 13

Long-term therapy with Copper Chelators (D-Penicillamine) & Zinc salts

Question 14

Characterised by excessive accumulation of body Iron, most of which is deposited in parenchymal organs (e.g. Liver, Pancreas and Heart)

Answer 14

Hemochromatosis

Question 15

What are the genetic variants of Hereditary Haemochromatosis?

Answer 15

Four distinct genetic mutations, with varying levels of predisposition to iron overload.

Question 16

What are common causes of secondary iron overload?

Answer 16

Multiple transfusions.
Ineffective erythropoiesis (e.g., β-thalassaemia, myelodysplastic syndromes).
Increased iron intake.

Question 17

Which organs are most affected by haemosiderin deposition in secondary iron overload?

Answer 17

Liver > Pancreas > Myocardium > Pituitary > Adrenal > Thyroid > Parathyroid glands > Joints > Skin.

Question 18

Describe the liver’s macroscopic features in iron overload.

Answer 18

Slightly enlarged, dense, chocolate-brown organ.
Development of cirrhosis with intensely pigmented (brown to black) appearance.

Question 19

What histological changes occur in the liver due to iron overload?

Answer 19

Golden-yellow haemosiderin granules in peri-portal hepatocytes (Prussian blue stain: Blue coloration).
Progressive involvement of the lobule, bile duct epithelium, and Kupffer cells.

Question 20

Describe pancreatic changes in iron overload.

Answer 20

Intensely pigmented organ.
Diffuse interstitial fibrosis and mild atrophy.
Haemosiderin accumulates in acinar and islet cells, and sometimes in the interstitial fibrous stroma.

Question 21

What are the heart’s features in iron overload?

Answer 21

Enlarged, strikingly brown-colored organ.
Delicate interstitial fibrosis.
Haemosiderin granules within myocardial fibers.

Question 22

What are the clinical features of Hereditary Haemochromatosis?

Answer 22

Hepatomegaly.
Skin pigmentation.
Diabetes mellitus.
Cardiac dysfunction.
Atypical arthritis.

Question 23

How is Hereditary Haemochromatosis diagnosed?

Answer 23

High serum iron and ferritin levels.
Exclusion of secondary causes of iron overload.

Question 24

What is the management of iron overload?

Answer 24

Phlebotomy.
Use of iron chelators (agents that bind metal ions to reduce their reactivity).