Inborn Errors of Metabolism: - Hereditary Hemochromatosis - Wilson's Disease - Alpha-1-Antitrypsin Deficiency

INBORN ERRORS OF
METABOLISM
• Hereditary Hemochromatosis
• Wilson’s Disease
• Alpha-1-Antitrypsin Deficiency
Hereditary Hemochromatosis
• Autosomal recessive disorder (one of the most common)

• HFE gene located at chromosome 6
• Most common mutation is a cysteine to tyrosine substitution at aa 282.
• Primary defect lies in the excessive intestinal absorption of iron (4-5 mg/day
leading to 20-50 g of iron storage )
• Subsequent excessive accumulation of body iron in liver and pancreas
• Male predominance 3-7:1
• Many patients are asymptomatic.
• Mostly symptoms appear in 5-6th decade
Hereditary Hemochromatosis:
Classic triad (tetrad)
• Cirrhosis
• Diabetes mellitus
• Skin pigmentation (increased melanin)
• Cardiac failure
Other manifestations
Arthropathy (75%)
Hypogonadism (iron deposition in hypophysis) and leads to loss of libido,
amenorrhea, impotence and body hair losing (50%).
200 fold increased risk of hepatocellular carcinoma than in general population

Diagnosis
High transferrin saturation ( > 60% in men and 50% in women is highly
specific).
•Ferritin concentration (> 1000 mcg/L suggests liver damage with fibrosis /
cirrhosis.
•Liver biopsy is the only way to establish a definitive diagnosis.
When liver biopsy is not feasible, an iron excretion test with desferoxamine (an
iron chelating agent) may have diagnostic implications.
Biochemical determination of hepatic iron concentration in unfixed tissue

(normal <1000 ug of iron /gram dry weight of liver, which exceed 10 000 ug of
iron/gram dry weight of liver)
Computed Tomography (CT) and Nuclear Magnetic Resonance (NMR)
TREATED WITH PHLEBOTOMY & DESFEROXAMINE

Hemochromatosis
Hemochromatosis
Wilson’s Disease
Hepatolenticular degeneration
• Rare autosomal recessive disorder of copper metabolism resulting in
accumulation of copper in organs including liver, brain kidney and cornea.
• ATP7B on chromosome 13 encodes a transmembrane copper-transporting

ATPase, located on canalicular membrane.
• Most common presentation: acute or chronic hepatitis (fulminant hepatitis and

cirrhosis). Fulminant liver injury → to sudden release of copper in the blood
stream and hemolytic anemia.
•
• Neuropsychiatic manifestations: Dystonic signs include slowness of speech,
unsteady gait, dystonic facies and posturing and several forms of psychosis
and neuroses.
• Kayser-Fleischer rings
Pathogenesis
Copper absorption from stomach and duodenum (2 to 5 mg/day) & transport to

liver (complexed with albumin) is normal, where it is incorporated into alpha2
globulin to form ceruloplasmin and is secreted into plasma. The senescent
ceruloplasmin is degraded by hepatocytes (in lysosomes) and delivered to bile
for excretion. Toal body copper is 50-150 mg.
In Wilson's disease, though exact nature of metabolic error is unknown but

there may be defective mobilization of copper from hepatocyte lysosomes for
excretion into bile that results in a progressive acumulation of copper in excess
of the metallothionein-binding capacity in the liver cells and suppression of
apoceruloplasmin synthesis.
Pathologic Features
• No specific features:
-Focal hepatocyte necrosis
-Fatty change
-Glycogen vacuoles in hepatocyte nuclei
-Mallory bodies
-Features of chronic hepatitis or cirrhosis -
Occasionally massive hepatic necrosis
• Copper staining unreliable as a diagnostic method
• Quantitative copper analysis of a biopsy specimen is confirmatory.
Wilson Disease
Copper granules
The Kayser-Fleischer ring denotes neurologic impairment and consists of copper
deposition in the cornea. It presents as a greenish or golden brown ring around
the cornea and is pathognomonic of Wilson's disease.
Diagnosis & Treatment
No one test is completely reliable; diagnosis depends upon a high index of

suspicion and supporting laboratory abnormalities.
Decreased serum ceruloplasmin (<20 mcg/dL),

Increased urinary copper excretion( >100 ug/24 h)
Increased hepatic copper concentration (200-3000 ug/g )
Copper chelation therapy (D-penicillamine)
Serum copper levels are of no diagnostic value (normal 80-160 ug/dL). About 5
percent of patients with Wilson's disease presents with normal values of serum
ceruloplasmin.
Alpha-1-Antitrypsin (A1AT)
Deficiency
• Autosomal recessive disorder characterized by a reduction in serum A1AT
levels.
• A1AT is a general protease inhibitor (Pi) synthesized in the liver. It is a major
inhibitor of the trypsin in normal human serum and also has inhibitory effects on
other proteases, esp. leukocyte proteases.
• The gene encoding A1AT is on chromosome 14.

• Deficiency variants show defect in movement of A1AT from ER to Golgi.
• Pi MM" allele is the most common (Normal). (serum levels of 20-53 mmol/L)
• Deficiency states are associated with the "Z" variant.
• Homozygous patients (PiZZ) have less than 20% normal A1AT levels.
• Phenotype is determined by co-dominant alleles with extremely variable penetrance
Pathologic Features of A1AT
Deficiency
• Round to oval eosinophilic globules within periportal hepatocytes

• PAS (periodic acid-Schiff) positive and resist diastase digestion
• Hepatitis, cholestasis, and/or cirrhosis
• Emphysema (pan-acinar)
A1AT Globules (H&E)
A1AT Globules (PASD)
A1AT Globules (immunohistochemistry)
A1AT Deficiency: Cirrhosis

Inborn Errors of Metabolism: - Hereditary Hemochromatosis - Wilson's Disease - Alpha-1-Antitrypsin Deficiency

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Inborn Errors of Metabolism: - Hereditary Hemochromatosis - Wilson's Disease - Alpha-1-Antitrypsin Deficiency

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INBORN ERRORS OF

• Autosomal recessive disorder (one of the most common)

200 fold increased risk of hepatocellular carcinoma than in general population

Biochemical determination of hepatic iron concentration in unfixed tissue

Computed Tomography (CT) and Nuclear Magnetic Resonance (NMR)

TREATED WITH PHLEBOTOMY & DESFEROXAMINE

• ATP7B on chromosome 13 encodes a transmembrane copper-transporting

• Most common presentation: acute or chronic hepatitis (fulminant hepatitis and

Copper absorption from stomach and duodenum (2 to 5 mg/day) & transport to

In Wilson's disease, though exact nature of metabolic error is unknown but

No one test is completely reliable; diagnosis depends upon a high index of

Decreased serum ceruloplasmin (<20 mcg/dL),

Copper chelation therapy (D-penicillamine)

• The gene encoding A1AT is on chromosome 14.

• Round to oval eosinophilic globules within periportal hepatocytes

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