Hepatic Disorders 2009 III

8/8/2019 Hepatic Disorders 2009 III

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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/dayleading 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 hepatitisand cirrhosis). Fulminant liver injury to sudden release of copper in theblood 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 excessof 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.





Copper granules

Wilson Disease











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 onother 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



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Hepatic Disorders 2009 III