Inherited metabolic diseases Flashcards
Autosomal recessive disorder characterised by low serum levels of this protease inhibitor
Alpha-1 antitrypsin deficiency
What is normal function of Alpha-1 antitrypsin deficiency?
Inhibition of neutrophil elastase released at sites of inflammation
Alpha-1 antitrypsin deficiency causes
Pulmonary Emphysema
Morphology of AAT deficiency
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)
Clinical manifestations of AAT deficiency
- 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
Autosomal recessive disorder
Characterised by the accumulation of toxic levels of Copper in many tissues & organs (Liver, Brain and Eye)
Wilson Disease
What causes wilson disease?
Loss-of-function mutations in ATP7B gene (Chromosome 13); ATP7B gene encodes an ATPase metal ion transporter, localised to the Golgi region of hepatocytes
Pathogenesis of wilson’s disease
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.
Morphology of Wilsons disease
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
What are the special stains for copper deposits?
i. Rhodanine stain for Copper & ii. Orcein stain
(for Copper-associated protein)
Diagnosis of wilson’s disease
Demonstration of hepatic Copper content of ≥250μg/g dry weight
Clinical features of wilson’s disease
Acute or Chronic Liver Disease – Neuropsychiatric manifestations (mild Behavioural Changes, frank Psychosis, Parkinson disease-like syndrome)
Tx of wilson’s disease
Long-term therapy with Copper Chelators (D-Penicillamine) & Zinc salts
Characterised by excessive accumulation of body Iron, most of which is deposited in parenchymal organs (e.g. Liver, Pancreas and Heart)
Hemochromatosis
What are the genetic variants of Hereditary Haemochromatosis?
Four distinct genetic mutations, with varying levels of predisposition to iron overload.
What are common causes of secondary iron overload?
Multiple transfusions.
Ineffective erythropoiesis (e.g., β-thalassaemia, myelodysplastic syndromes).
Increased iron intake.
Which organs are most affected by haemosiderin deposition in secondary iron overload?
Liver > Pancreas > Myocardium > Pituitary > Adrenal > Thyroid > Parathyroid glands > Joints > Skin.
Describe the liver’s macroscopic features in iron overload.
Slightly enlarged, dense, chocolate-brown organ.
Development of cirrhosis with intensely pigmented (brown to black) appearance.
What histological changes occur in the liver due to iron overload?
Golden-yellow haemosiderin granules in peri-portal hepatocytes (Prussian blue stain: Blue coloration).
Progressive involvement of the lobule, bile duct epithelium, and Kupffer cells.
Describe pancreatic changes in iron overload.
Intensely pigmented organ.
Diffuse interstitial fibrosis and mild atrophy.
Haemosiderin accumulates in acinar and islet cells, and sometimes in the interstitial fibrous stroma.
What are the heart’s features in iron overload?
Enlarged, strikingly brown-colored organ.
Delicate interstitial fibrosis.
Haemosiderin granules within myocardial fibers.
What are the clinical features of Hereditary Haemochromatosis?
Hepatomegaly.
Skin pigmentation.
Diabetes mellitus.
Cardiac dysfunction.
Atypical arthritis.
How is Hereditary Haemochromatosis diagnosed?
High serum iron and ferritin levels.
Exclusion of secondary causes of iron overload.
What is the management of iron overload?
Phlebotomy.
Use of iron chelators (agents that bind metal ions to reduce their reactivity).