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CIRRHOSIS OF THE LIVER
Cirrhosis of the liver is a pathologic entity characterized by (1) necrosis of liver cells, slowly
progressive over a long period and ultimately causing chronic liver failure and death; (2)
fibrosis, which involves both central veins and portal areas; (3) regenerative nodules, the
result of hyperplasia of surviving liver cells; (4) distortion of normal hepatic lobular
architecture; and (5) diffuse involvement of the whole liver. A regenerative nodule is an
abnormal mass of liver cells without a normal cord pattern or central venule and surrounded
completely by fibrosis (Figure 43-4).
Figure 43–4.
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Alcoholic cirrhosis of the liver. A: Small regenerative nodules are
separated by coarse bands of collagen in which are found blood vessels,
bile ducts, and inflammatory cells. B: The regenerative nodule is
composed of a disorganized mass of liver cells showing fatty change.
There is no central hepatic vein in the nodule.
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Pathology
Grossly, the liver is enlarged in the early stages, but later it becomes smaller because of cell
loss and fibrous contraction. It is much firmer than normal. Nodularity is the most
characteristic feature (Figure 43-5). Depending on whether the nodules are more or less than
3 mm in size, cirrhosis is classified as macronodular, micronodular, or mixed.
Figure 43–5.
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Cirrhosis of the liver (cut surface), showing diffuse nodularity.
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Histologically, regenerative nodules are characteristic. They are composed of hyperplastic
liver cells organized into irregular plates. Liver cells often show enlargement, with atypical
nuclei—a picture sometimes called "dysplasia" because of the suspicion that such changes
are a precursor of liver cell carcinoma.
The vasculature of the liver is greatly distorted. The fibrous bands obstruct the portal venous
radicles and lead to abnormal fistulous communications between portal veins and hepatic
arterioles, resulting in portal hypertension.
Clinical Features
Cirrhosis is manifested clinically by features of chronic liver failure and portal hypertension
(Figure 43-6). Common presenting symptoms include hematemesis due to rupture of
gastroesophageal varices and ascites. Cirrhosis is an irreversible and progressive disease
that ultimately causes death. The rate of progression is variable.
Figure 43–6.
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Clinical effects of cirrhosis of the liver.
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Cirrhosis is a premalignant lesion. The risk of hepatocellular carcinoma is greatest in
cirrhosis caused by hemochromatosis, virus-induced cirrhosis, cryptogenic cirrhosis, and
alcoholic cirrhosis, in order of decreasing hazard.
Etiologic Types of Cirrhosis
(Table 43-2)
Table 43–2. Etiologic Classification of Cirrhosis.
The terminology of this disorder is confusing and unsatisfactory. Characterizing cirrhosis as
micronodular and macronodular according to the size of the nodules is of little value because
the size of nodules does not correlate with etiology. The terms portal cirrhosis and
Laennec's cirrhosis are no longer used; both denoted micronodular cirrhosis of the
alcoholic type. The term postnecrotic cirrhosis should no longer be used because all forms of
cirrhosis are associated with necrosis of liver cells and are therefore postnecrotic.
Cirrhosis is most usefully classified according to its causes. All etiologic classifications include
a group called cryptogenic cirrhosis (cirrhosis of unknown cause). The incidence of
cryptogenic cirrhosis depends on how diligently the cause is sought and how rigorous the
criteria are for assigning specific causes to individual cases.
CRYPTOGENIC CIRRHOSIS
Hepatic cirrhosis is said to be cryptogenic when complete evaluation of the patient has failed
to identify a cause. Cryptogenic cirrhosis may include cirrhosis following
immune-mediated chronic active hepatitis or following injury due to drugs or
chemicals—because there is no way to identify these causes with certainty. Many patients
with cirrhosis give a history of drug ingestion, but it is difficult to establish a causal role for
the drugs.
ALCOHOLIC CIRRHOSIS
Alcoholic cirrhosis is frequently associated with evidence of fatty change or acute alcoholic
hepatitis. Alcoholic cirrhosis is typically a fatty micronodular cirrhosis (Figure 43-4). In
patients who stop drinking, the nodules are not infrequently larger and fat is absent.
Alcoholic cirrhosis tends to have a slow rate of progression, particularly if the patient stops
drinking. The disease is irreversible and causes death.
VIRUS-INDUCED CIRRHOSIS
Cirrhosis may follow chronic active hepatitis resulting from infection with hepatitis B and C
viruses. Patients who present with cirrhosis may or may not give a history of hepatitis.
Typically, virus-induced cirrhosis is macronodular. Features of chronic active hepatitis may
coexist. Virus-induced cirrhosis tends to progress rapidly, with death due to chronic liver
failure, portal hypertension, or hepatocellular carcinoma.
Cirrhosis caused by hepatitis B virus may be identified by the presence of hepatitis B (HB)sAg
in the serum and in liver cells; orcein stains and immunoperoxidase stains for HBsAg are
positive. A few cases of cirrhosis due to hepatitis B show coinfection with delta hepatitis that
can be demonstrated by immunologic techniques. Patients with cirrhosis caused by
hepatitis C have anti-hepatitis c virus (HCV) antibody in their serum.
BILIARY CIRRHOSIS
Primary biliary cirrhosis causes portal fibrosis, but the changes fall short of the definition of
true cirrhosis because regenerative nodules are usually absent (Figure 43-7).
Figure 43–7.
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Biliary cirrhosis, contrasting the changes of primary versus secondary
disease.
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Secondary biliary cirrhosis occurs in patients with prolonged large bile duct obstruction
(gallstones, stricture, tumor, cholangitis). Marked cholestasis causes liver cell necrosis, and
prolonged cholangitis leads to portal fibrosis (Figure 43-7). Biliary cirrhosis causes a fine
nodularity (micronodules). Features of chronic liver failure and portal hypertension occur
late.
HEMOCHROMATOSIS
Hemochromatosis results from iron overload in the body as demonstrated by increased
serum iron, ferritin, and saturation of iron-binding protein; increased iron stores in the bone
marrow; and the presence of iron in liver cells.
Etiology
Hereditary Hemochromatosis
This is a familial disease with autosomal recessive inheritance of an abnormal gene located
on chromosome 6 in close linkage with human leukocyte antigen (HLA)-A3. The disease
occurs in homozygotes; heterozygotes show slightly elevated serum iron levels. The
mechanism by which the abnormal gene causes iron overload is not certain but is believed to
involve increased intestinal iron absorption.
Secondary Hemochromatosis
Secondary hemochromatosis is the occurrence of iron overload due to recognizable causes
such as the following:
INCREASED DIETARY INTAKE OF IRON
This occurs in the Bantu tribe of Africa, who use iron cooking utensils ("Bantu siderosis"). The
excessive use of iron-containing drugs and iron-rich wine and beer may also cause iron
overload.
IRON INFUSIONS
Usually in the form of repeated blood transfusions for patients with chronic anemias.
LIVER DISEASE
Particularly alcoholic cirrhosis, which is associated with increased iron absorption. The
resulting iron deposition in liver cells may contribute to further liver cell damage.
CHRONIC HEMOLYTIC ANEMIAS
Thalassemia is the most common cause of secondary hemochromatosis. Iron overload is due
to repeated blood transfusions and stimulation of intestinal iron absorption by erythroid
hyperplasia in the bone marrow.
Liver Changes in Hemochromatosis
Iron is deposited as hemosiderin in the cytoplasm of Kupffer cells and hepatocytes.
Hemosiderin appears as golden brown granules in routine microscopic sections (see Chapter
1: Cell Degeneration & Necrosis). The Prussian blue stain for iron produces an intense blue
color. The most accurate assessment of hepatic iron load is by quantitative assay of iron
content in a liver biopsy. Patients with hereditary hemochromatosis show marked elevation
of hepatic iron (> 10,000
g/g of liver dry weight; normal is < 1000
g/g of liver dry weight).
Accumulation of iron in hepatocytes causes cellular degeneration, functional impairment, and
clinical disease. This occurs early in idiopathic hemochromatosis and later in secondary forms
of hemochromatosis. The mechanism by which stored iron causes cell damage is uncertain.
It is believed that free iron accumulates in the cytoplasm when the capacity for storage as
ferritin and hemosiderin is exhausted. Free ferric iron undergoes reduction, causing
abnormal electron transfers and the formation of toxic oxygen-based free radicals.
Initially, the liver is slightly enlarged. Over a long period of time, there is progressive loss of
liver cells accompanied by fibrosis—leading to cirrhosis, which is commonly macronodular.
Hepatic hemochromatosis progresses rapidly and may be complicated by hepatocellular
carcinoma.
Changes in Extrahepatic Tissues
Iron deposition occurs in many other tissues: The pancreas, myocardium, skin, endocrine
glands, and joints are commonly affected, producing the extrahepatic clinical manifestations
of hemochromatosis (Figure 43-8). Increased pigmentation of the skin and pancreatic islet
destruction result in bronze diabetes, which is an alternative name for hemochromatosis.
Figure 43–8.
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Clinical manifes tations of hemochromatosis.
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WILSON'S DISEASE
Wilson's disease is an autosomal recessive disorder characterized by (1) defective excretion
of copper into bile; (2) increase in total body copper, resulting from unchanged absorption in
the face of decreased biliary excretion; (3) accumulation of copper in the cytoplasm of liver
cells, complexed to an abnormal protein; (4) decreased ceruloplasmin level in plasma; and
(5) increased "free" copper in plasma, causing increased urinary excretion of copper and
deposition of copper both in cells and in connective tissue. The primary defect is in the liver
cell and is corrected by liver transplantation.
Liver Changes in Wilson's Disease
Liver involvement is responsible for the dominant clinical features. Intracellular copper
produces an injury manifested as a progressive microvacuolar fatty change and focal liver cell
necrosis. It may present, usually in late childhood, as acute hepatitis clinically resembling
viral hepatitis. With continuing liver cell necrosis, it progresses to fibrosis and finally to
cirrhosis with chronic liver failure. Increased copper levels in the liver can be demonstrated
biochemically. Histochemical methods (rubeanic acid stain) are not always positive because
of the abnormal protein binding of the copper in liver cells.
Extrahepatic Changes in Wilson's Disease
Copper deposition in the brain involves the basal ganglia (particularly the lenticular
nucleus), thalamus, red nucleus, and dentate nucleus of the cerebellum, all of which show
atrophy, slight brown discoloration, and cavitation. Microscopically, the neurons are
decreased in number, representing chronic cell necrosis. Reactive astrocytic proliferation is
present. These changes produce clinical features of extrapyramidal dysfunction. Wilson's
disease is also called hepatolenticular degeneration.
Deposition of copper in Descemet's membrane at the sclerocorneal junction is important
for clinical diagnosis because it produces a characteristic greenish-brown ring
(Kayser-Fleischer ring) at the corneal edge. This is not seen with the naked eye until a late
stage of the disease but can be recognized early by slit-lamp examination. Copper deposition
in the eye does not cause visual impairment.
ALPHA1-ANTITRYPSIN DEFICIENCY
(See also Chapter 35: The Lung: II. Toxic, Immunologic, & Vascular Diseases)
Severe
1-antitrypsin
( -antiprotease) deficiency occurs in homozygous PiZZ individuals
and is a rare cause of cirrhosis, usually with onset during childhood. The abnormal gene
results in hepatic synthesis of an abnormal
1-antitrypsin
molecule that accumulates in the
liver cell cytoplasm, appearing as eosinophilic globules. These globules are present in liver
cells in the peripheral part of the lobule and stain positively with periodic acid-Schiff (PAS)
stain. They also stain by immunoperoxidase methods using antibody against
1-antitrypsin.
The demonstration of these globules establishes the diagnosis, which can be further
confirmed by absence of
1-antitrypsin
in the blood.
GALACTOSEMIA
Galactosemia is a rare inherited disease caused by deficiency of galactose-1-phosphate
uridyl transferase. Galactose metabolites accumulate in the liver, causing injury. Affected
patients present in early infancy following feeding of milk (which contains lactose, a
disaccharide of glucose and galactose). Cholestasis, fatty change, and cirrhosis progress
rapidly to liver failure. Galactosemia is also associated with cataracts and mental retardation.
Galactosemia is routinely looked for in neonatal screening tests. Diagnosis in a neonate
followed by administration of a diet that contains no milk products prevents liver damage.