Inherited metabolic diseases Flashcards

1
Q

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

A

Alpha-1 antitrypsin deficiency

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2
Q

What is normal function of Alpha-1 antitrypsin deficiency?

A

Inhibition of neutrophil elastase released at sites of inflammation

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3
Q

Alpha-1 antitrypsin deficiency causes

A

Pulmonary Emphysema

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4
Q

Morphology of AAT deficiency

A

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)

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5
Q

Clinical manifestations of AAT deficiency

A
  • 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
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6
Q

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

A

Wilson Disease

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7
Q

What causes wilson disease?

A

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

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8
Q

Pathogenesis of wilson’s disease

A

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.

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9
Q

Morphology of Wilsons disease

A

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

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10
Q

What are the special stains for copper deposits?

A

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

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11
Q

Diagnosis of wilson’s disease

A

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

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12
Q

Clinical features of wilson’s disease

A

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

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13
Q

Tx of wilson’s disease

A

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

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14
Q

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

A

Hemochromatosis

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15
Q

What are the genetic variants of Hereditary Haemochromatosis?

A

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

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16
Q

What are common causes of secondary iron overload?

A

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

17
Q

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

A

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

18
Q

Describe the liver’s macroscopic features in iron overload.

A

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

19
Q

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

A

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

20
Q

Describe pancreatic changes in iron overload.

A

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

21
Q

What are the heart’s features in iron overload?

A

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

22
Q

What are the clinical features of Hereditary Haemochromatosis?

A

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

23
Q

How is Hereditary Haemochromatosis diagnosed?

A

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

24
Q

What is the management of iron overload?

A

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