Page 644 - Textbook of Pathology, 6th Edition

628 mellitus, hepatic and cardiac dysfunction, arthropathy and MORPHOLOGIC FEATURES. The liver shows varying
hypogonadism. Characteristic bronze pigmentation is the grades of changes that include fatty change, acute and
presenting feature in about 90% of cases. Demonstration of chronic active hepatitis, submassive liver necrosis and
excessive parenchymal iron stores is possible by measure- macronodular cirrhosis. Mallory bodies are present in
ment of serum iron, determination of percent saturation of some cases. Copper is usually deposited in the periportal
transferrin, measurement of serum ferritin concentration, hepatocytes in the form of reddish granules in the
estimation of chelatable iron stores using chelating agent (e.g. cytoplasm or as reddish cytoplasmic coloration, stainable
desferrioxamine), and finally, by liver biopsy. Occurrence by rubeanic acid or rhodamine stains for copper.
of hepatocellular carcinoma is a late complication of Involvement of basal ganglia in the brain is seen in
haemochromatosis-induced cirrhosis. the form of toxic injury to neurons, in the cornea as
greenish-brown deposits of copper in Descemet’s
Cirrhosis in Wilson’s Disease
membrane, and in the kidney as fatty and hydropic
Wilson’s disease, also termed by a more descriptive desig- change.
nation of hepatolenticular degeneration, is an autosomal
recessive inherited disease of copper metabolism, Cirrhosis in αα αα α-1-Antitrypsin Deficiency
characterised by toxic accumulation of copper in many
tissues, chiefly the liver, brain and eye. These accumulations Alpha-1-antitrypsin deficiency is an autosomal codominant
lead to the triad of features: condition in which the homozygous state produces liver
1. Cirrhosis of the liver. disease (cirrhosis), pulmonary disease (emphysema), or both
2. Bilateral degeneration of the basal ganglia of the brain. (page 479). α-1-antitrypsin is a glycoprotein normally
synthesised in the rough endoplasmic reticulum of the
3. Greenish-brown pigmented rings in the periphery of the hepatocytes and is the most potent protease inhibitor (Pi). A
cornea (Kayser-Fleischer rings). single autosomal dominant gene coding for α-1-antitrypsin
The disease manifests predominantly in children and is located on long arm of chromosome 14 that codes for
young adults (5-30 years). Initially, the clinical manifestations immunoglobulin light chains too. Out of 24 different alleles
are referable to liver involvement such as jaundice and labelled alphabetically, PiMM is the most common normal
hepatomegaly (hepatic form) but later progressive phenotype, while the most frequent abnormal phenotype in
neuropsychiatric changes and Kayser-Fleischer rings in the α-1-antitrypsin deficiency leading to liver and/or lung
cornea appear.
disease is PiZZ in homozygote form. Other phenotypes in
SECTION III
PATHOGENESIS. The pathogenesis of Wilson’s disease is which liver disease occurs are PiSS and Pi-null in which
best understood when compared with normal copper serum α-1-antitrypsin value is nearly totally deficient.
metabolism. Intermediate phenotypes, PiMZ and PiSZ persons are
Normally, dietary copper is more than body’s predisposed to develop hepatocellular carcinoma.
requirement. Excess copper so absorbed through the stomach The patients may present with respiratory disease due
and duodenum is transported to the liver where it is to the development of emphysema, or may develop liver
incorporated into α -globulin to form ceruloplasmin, which dysfunction, or both. At birth or in neonates, the features of
2
is excreted by the liver via bile normally. Most of the plasma cholestatic jaundice of varying severity may appear. In
copper circulates as ceruloplasmin. Only minute amount of adolescence, the condition may evolve into hepatitis or
copper is excreted in the urine normally. cirrhosis which is usually well compensated.
In Wilson’s disease, the initial steps of dietary absorp-
Systemic Pathology
tion and transport of copper to the liver are normal but MORPHOLOGIC FEATURES. Pulmonary changes in α-
copper accumulates in the liver rather than being excreted 1-antitrypsin deficiency in the form of emphysema are
by the liver. The underlying defect in chromosome 13 is a described in Chapter 17. The hepatic changes vary
mutation in ATP7B gene, the normal hepatic copper- according to the age at which the deficiency becomes
excreting gene. Eventually, capacity of hepatocytes to store apparent. At birth or in neonates, the histologic features
copper is exceeded and copper is released into circulation consist of neonatal hepatitis that may be acute or ‘pure’
which then gets deposited in extrahepatic tissues such as the cholestasis. Micronodular or macronodular cirrhosis may
brain, eyes and others. However, increased copper in the appear in childhood or in adolescence in which the
kidney does not produce any serious renal dysfunction. diagnostic feature is the presence of intracellular,
Biochemical abnormalities in Wilson’s disease include the acidophilic, PAS-positive globules in the periportal
following: hepatocytes. Ultrastructurally, these globules consist of
1 Decreased serum ceruloplasmin (due to impaired synthesis dilated rough endoplasmic reticulum.
of apoceruloplasmin in damaged liver and defective
mobilisation of copper from hepatocellular lysosomes). Cardiac Cirrhosis
2. Increased hepatic copper in liver biopsy (due to excessive
accumulation of copper in the liver). Cardiac cirrhosis is an uncommon complication of severe
3. Increased urinary excretion of copper. right-sided congestive heart failure of long-standing duration
4. However, serum copper levels are of no diagnostic help (page 99). The common causes culminating in cardiac
and may vary from low-to-normal-to-high depend- ing upon cirrhosis are cor pulmonale, tricuspid insufficiency or
the stage of disease. constrictive pericarditis. The pressure in the right ventricle