Pathologic aspects of cirrhosis. A review.

38 Pages·2007·6.65 MB·English

REVIEW
ARTICLE
B
PATHOLOGIC ASPECTS OF
CIRRHOSIS
Pathologic Aspects of Cirrhosis
A Review
Hans Popper, MD, PhD
THE PERIODIC REEVALUATION OF CIRRHOSIS in reviews such as
this shows lingering disagreement about its clinical and pathologic signifi-
cance. At one extreme, elimination of the term cirrhosis has been recom-
mended 1 because it refers to a form of chronic inflammation forwhich no
specific name is used forotherorgans. Theterm, however, has met the test
of time, and in a recent book on liver disease 2 cirrhosis occupies the
longest chapter. Moreover, its incidence in theWestern countries is on the
rise.3 This review, emphasizing pathologic problems, covers a) definition
and classification to assist in diagnosis; b) etiology, important in therapy
when the offending agent can be withdrawn; and c) pathogenesis to help
in prevention by identifying the precursor stage.
Definition and Classification
Discrepancies prevail in definition and classification between different
textbooks and authors. They were only slightly relieved by the Havanna
classification.' Recently, the International Association for the Study ofthe
Liver has recommended a standard nomenclature of liver diseases which
promises to becomne universally accepted." Its outlines are followed here.
Basic Structural Features
Cirrhosis is characterized conventionally by a nodular parenchyma and
widespread fibrosis, with hepatocellular necrosis sometimes listed as a
third component. Cirrhosis is better described as the result of abnormal
reconstruction of the preexisting lobular architecture. The two criteria
which correlate best with the functional manifestations are parenchymal
nodules and septa which link portal with central canals.
Parenchymal nodules are round portions of the parenchyma sur-
rounded by connective tissue which consist of portions of many lobules
(Figure IA) or of one lobule (Figure 1B). (Acinus " is the more functional
From the Stratton Laboratoryforthe StudyofLiverDisease, Mount SinaiSchool ofMedicineof
The City University ofNew York, New York, New York.
Address reprint requests to Dr. Hans Popper, Mount Sinai School of Medicine, Fifth Avenue
and 100th Street, New York, NY 10029.
228
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April1977
designation, but since it is not widely used, it will not be applied here.)
The parenchymal nodule may display normal architectural arrangements
with single-cell hepatocytic plates, particularly when the nodules derive
from the dissection of lobules by septa (passive nodules).7 Usually, it
shows cytologic and more frequently architectural features of regenera-
tion (regenerative nodule). Cytologic features are foci of enlarged hepa-
tocytes with large, often polyploid, nuclei and multinucleate cells. The
architectural features are hepatic plateswhich are twoor more cells thick,
as is normal in lower animals and in human embryos and is often main-
tained until the fifth postnatal year.8 They are recognized by position of
nuclei on the sinusoidal surface (Figure 2A). Architectural changes persist
longer than cytologic ones because of the long life-span of the hepa-
tocytes. Increases in the width of the plates is associated with greater
extension of the hepatocellular surface endowed with perisinusoidal micro-
villi.9 Architectural regeneration is uniform at the periphery of smaller
monolobular nodules but is irregular throughout the multilobular nodules
where multicellular plates border on single-cell plates which may be
narrowed as a result of pressure (differential regeneration) (Figure 2B).
This may be combined with variations in blood distribution. In mono-
lobular nodules the plates converge on a new efferent vessel. In larger
nodules, disturbance of blood flow may be reflected in hepatocellular iron
in the central rather than in the peripheral zone. In histochemical stains,
e.g., for glucose-6-phosphatase, the reaction product varies greatly within
one nodule or in different nodules. With predominant hyperplasia, some
speak of hyperplastic or adenomatous nodules, which are grossly succu-
lent in appearance and of a uniformly different color from others (Figure
3A). This indicates a different chemical composition and a metabolic
regulation independent from that of the entire liver. Nodules not sur-
rounded by connective tissue, as seen in experimental animals on carcino-
genic regimens or in nodular regenerative hyperplasia in man,'0',' do not
indicate cirrhosis.
Septa are connective tissue membranes of various widths.'2 They result
from either collapse of preexisting parenchyma or formation of new
connective tissue fibers. Septa are wide when they form after extensive
collapse of lobular or nodular parenchyma (Figure 5A and B). They cause
functional manifestations when they connect central with portal canals
and contain vessels permitting short circuits of blood flow (Figure 3Band
C).
Focal nodules and septa-such as those in focal nodular hyperplasia
(hamartoma),'3"l around focal lesions (such as primary and secondary
tumors, abscesses, and granulomas), orin subcapsular location as result of
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subserous inflammation-may be confusing in interpretation of surgical
wedge specimens.'5 A question of definition arises if a few nodules and
septa are scattered diffusely throughout the liver following arrested
chronic hepatitis of various etiology. The term cirrhosis should be applied
when they are widespread.
Relation of Cirrhosisto Chronic Hepatitis
Cirrhosis is a scarred end-stage of a chronic inflammation of the liver.
The precursor stage is often designated as chronic hepatitis, sometimes
modified by an etiologic designation. However, the term hepatitis is not
always applied in metabolic disorders or in iron overload diseases. If the
clinical, functional, and morphologic features of the hepatitis pre-
dominate, the diagnosis is chronic hepatitis with cirrhosis (or with transi-
tion to cirrhosis). If the features of cirrhosis and particularly its sequelae
are in the foreground, the term cirrhosis is conventionally applied. While
clinicians and pathologists previously spoke ofdecompensatedcirrhosis in
progressive stages. the emphasis is now placed on chronic hepatitis,
particularly if the latter is the main target of therapy-symptomatic or
withdrawal of the offending agent. In addition to chronic hepatitis with-
out cirrhosis and chronic hepatitis with cirrhosis, there are instances of
cirrhosis in which the precursor inflammatory lesion has subsided or is no
longer detectable and a scar stage of variable extent is the presenting
problem.
Functional Effects of Structural Alterations
Portal Hypertension
The drainage of blood from the liver is impaired by several factors which
contribute in varying degrees to portal hypertension in individual cases.'6
Their clinical importance is identified by radiologic methods, particularly
angiography and venography;'7 by measurement of portal pressure in the
spleen, through the periumbilical vein, or by a transcutaneously inserted
thin needle into the liver; and by measurement ofhepatic venous pressure
by wedging a catheter. The main factor which produces outflow block is
compression of hepatic vein tributaries by regenerative nodules, which is
more effective the smaller the nodules,18 or by fibrosis as in alcoholic liver
injury.'9 A second factor is perisinusoidal fibrosis, the functional signifi-
cance of which is difficult to distinguish from the first. The third is
arteriovenous anastomoses in septa, which bring hepatic arterial pressure
to bear on the portal vein. The fourth is portal tract scarring, and the fifth
is the splenomegaly associated with cirrhosis which, accompanied by a
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reduced splenic vascular resistance, increases blood flow to the liver while
the liver scarring prevents expansion of its vascular bed. The first three
factors raise intrasinusoidal pressure with a tendency towards ascites and
hepatic failure, whereas the last two are presinusoidal and account partic-
ularly for the extrahepatic sequelae of portal hypertension. Any type,
however, may cause phlebosclerosis 20 in the trunk and branches of the
portal vein and thus create a vicious circle.
Hemodynamic Alterations
These alterations result from three factors: a) Diversion of splanchnic
blood from the liver by extrahepatic portosystemic anastomoses, which
are best evaluated by radiologic procedures. Hepatic arterial flow is,
however, increased, and the hepatic artery is enlarged and tortuous.21 b)
Diversion of blood reaching the liver from the hepatic parenchyma by
anastomoses in the septa between afferent branches of hepatic artery and
portal vein and efferent tributaries of the hepatic veins.n'" They are
demonstrated by postmortem injection preparations and by radiologic and
scanning techniques."4 Their functional significance, originally doubted,
has been substantiated by functional studies.2'27 The portal vein flow to
the nodular parenchyma is particularly reduced, as is apparent by radio-
logic study.17"2 The outflow block in advanced cirrhosis slows or even
reverses the portal vein flow.2' c) Reduced efficiency of the intralobular
microcirculation, caused byintrasinusoidal inflammatory cells, continuous
basement membranes around the sinusoids,2' pericellular fibrosis,31 and
lobular distortion.
The hemodynamic alterations deprive the body of some of the liver
function,' independent of the functional status of the hepatocytes. He-
patic insufficiency may thus develop on a circulatory basis alone. More-
over, intestinal bacteria may bypass theliver. This explains gram-negative
bacteremia " or spontaneous peritonitis.' More frequent is endotoxemia,
explained by vascular bypass as well as by inadequate function of Kupffer
cells,-" which normally destroy such enterogenous toxins. Endotoxemia
has been held responsible for many systemic manifestations of cir-
rhosis " such as hvpotension, leukocytosis, alteration of renal function,
and some of the alterations of extrahepatic circulation (including increase
of peripheral blood flow, cardiac output, blood volume, ventilation, and
reduction of renal perfusion, arterial saturation, and peripheral vascular
resistance, as well as vascular changes in the skin). Bacterial and some
viral antigens bypassing the liver and reaching the lymphatic system alter
the immune status independent of sensitization by hepatocellular anti-
gens. This explains the hypergammaglobulinemia in cirrhosis, and its
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accentuation by shunt operations.38 Bypass also accounts for other sys-
temic manifestations in cirrhosis, such as disturbance of hormone meta-
bolism and faulty hepatic inactivation of gastrin.39 Although increase in
peptic ulcers from shunts is not established, they are more frequent in
cirrhosis.40
Since the hepatocytes require for their integrity only a fraction of the
parenchymal blood flow, some diversion need not significantly impair
hepatocellular function. However, if blood flow is further impaired by
additional factors, such as gastrointestinal hemorrhage from varices or
ulcers, or septicemia, hepatocellular necrosis develops in the center of
lobules and nodules preceded by thinning of the plates or by steatosis
(Figure 4A). Necrosis is grossly apparent by dark discoloration of the
nodular center. This should be distinguished from a diffuse colorvariation
ofthe nodules. Histologically, eosinophilic necrosis is accompanied by loss
of cells replaced by macrophages intermixed with granulocytes. The
differential diagnosis ofnecrosis from other causes is seldom difficult. This
necrosis may cause death but, being rare in biopsy specimens, accounts
but little for self-perpetuation; it is the morphologic substrate of hepatic
failure following shunt operations.
The alteration of hepatic circulation is not only the key feature of
cirrhosis butalso themain targetofits therapy andthusjustifies the term.
Additional features accompany, or are caused by, the altered hepatic
circulation. They include:
a)reducedfunctional mass ofhepaticparenchyma is recognized even in
enlarged livers in which the blood flow may be decreased.4'
b) increase ofhepatic lymph flow results primarily from postsinusoidal
portal hypertension.42 The thoracic duct is engorged and sclerotic 4' and
the hepatic lymphatics are dilated.44 Alterations of the serosal surface in
association with ascites were visualized in experimental cirrhosis.45 Ascites
is caused not only by increased lymph flow but also byexcessive exudation
from peritoneal capillaries due to sodium sequestration caused by altered
hormone metabolism in the liver. Hypoalbuminemia may also play a role.
The different contributions of these factors influence therapy of ascites in
cirrhosis.
c) alteration of the bile flow occurs in two directions. Increased sinu-
soidal pressure favors excess secretion of bile of reduced concentration.46
In both human and experimental cirrhosis the intrahepatic bile duct
system is tortuous and increased in weight.47 Moreover, cholestasis may
occur on either a mechanical or a chemical basis. The former results from
periductal scarring, especially in the biliary forms. The nature ofthe latter
is not established (intrahepatic cholestasis).48 It is sometimes accentuated
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April1977
focally in hyperplastic portions of nodules. Prolonged cholestasis maylead
to excess deposition of copper, mainly in periportal distribution,4' e.g., in
biliary cirrhosis, in other types of cholestatic cirrhosis, and in that asso-
ciated with a-l-antitrypsin deficiency.'5 Whether the excess copper dep-
osition contributes to liver cell injury and calls for therapy remains to be
established.
d) Excess iron storage in periportal hepatocytes develops sometimes
spontaneously and more frequently after shunt operation;5' it may be
explained by increased arterial blood flow. The actual incidence is con-
troversial, and only rarely do the functional consequences ofiron overload
become a problem.
Cirrhosis is conventionally considered an irreversible scar stage. How-
ever, the irreversibility is in dispute. The turnover of collagen fibers
suggests the possible regression of septa. Thinning and even dis-
appearance of septa and relobulation of nodules has been observed in
experimental studies.5' In man, regression of cirrhosis of iron overload
type has been described."
Aatomic iand Fucl aficaton
Establishment of the presence of cirrhosis is clinically far more useful
than its classification, which mainly serves epidemiologic comparisons.
Except for an etiologic designation there is little agreement,"55J because
different pattems may be seen in the same liver and these pattems are not
necessarily specific. Moreover, one anatomic form may change into an-
other during the course of the disease, e.g., in alcoholic liver disease
micronodular cirrhosis can become macronodular."O Steatosis, though
more frequentin some types, maysecondarily develop in any. Table 1 lists
some of the many terms in use. A simple anatomic classification based on
minimal criteria is recommended5 and lends itself also to morphologic
statistical analysis:'
1. Micronodular cirrhosis is characterized by nodules ofequal size, up
to 3 mm in diameter, associated with septa up to 2 mm in diameter and
Table 1-Examples of Synonyms Used for Anatomic Types of Cirrhosis
Recornmendedterm Mainlymicronodular Mainlymacronodular
Synonyms Laennec Podtnecrotic
Portal Irregular
Regular Extensivecollapse
"Nutltional" With Wthout
"postnecrotic" "posthepatitic"
JapaneseA JapaneseB
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usually of equal width. The pattern suggests a uniform process (Figure
IB).
2. In macronodular cirrhosis the size of the nodules varies; many are
more than 3 mm and some up to 3 cm in diameter. They are often
composed of many lobules. The irregular septa vary in width and are
often broad after collapse of multiple lobules and nodules (Figure IA).
The liver may be conspicuously deformed, particularly in the left lobe.
This pattern suggests either irregularity of the preceding injury or sus-
tained regeneration.
Either form may be found in an enlarged or in a small shrunken organ,
without significant correlation to the clinical picture, to the functional
parameters, or to the degree of regeneration reflected by the histologic
evidence. In addition, an incomplete septal cirrhosis is recognized in
which the regeneratory features are not conspicuous in large or smaller
nodules, but septa traversing the parenchyma are prominent. Some end
blindly and do not link central and portal canals (Figure 4B). The weak-
ness of anatomic classification is illustrated by the frequent use ofthe term
mixed macronodular and micronodular cirrhosis.
Functional Classification
A functional classification, useful in staging, should take into consid-
eration63'64 a) degree of development; b) activity indicating tendency
towards progression, which depends mostly on the activity of the atten-
dant chronic hepatitis as reflected by hypergammaglobulinemia, and by
inflammation and cell necrosis on the border of the parenchyma towards
portal tracts and septa (piecemeal necrosis); c) degree of hepatocytic
alterations (steatosis, hepatitis, cholestasis) as the basis of presenting
hepatic symptoms, indicated by liver function tests; and d) presence of
complications (portal hypertension and its sequelae, ascites, hemorrhagic
diathesis and encephalopathy). Liver biopsy is required for the evaluation
of the first three considerations, although its usefulness in prognosis is
limited.
Diagnosis of Cirrhosis by Liver Biopsy
This is important because of the unreliability of the clinical and labora-
tory manifestations and their absence in latent cirrhosis.65 Blind needle
liver biopsy is applied widely, particularly where laparoscopy is sparsely
used. Despite occasional sampling errors because of cylinders obtained
from large nodules with seemingly normal architecture or because of
deflection of the needle from portal and septal tissue, the diagnoses based
on or supported by liver biopsy have been found reliable in statistical
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studies." Sampling errors are more significant in the comparison ofrepeat
biopsy specimens during monitoring of therapy. Connective tissue stains
increase the diagnostic accuracy. The following criteria indicate cirrhosis
with decreasing certainty: 1) nodules surrounded by septawith orwithout
portal and central canals (in fibrosis a parenchymal portion near portal
tracts mav sometimes appear round); 2) hepatic vein tributaries incontact
with septa; 3) connective tissue septa linking central with portal canals,
particularlv when bent or zigzag; 4) fragmentation of specimens into
round pieces surrounded in more than half of their circumference by thin
layers of connective tissue; and 5) irregularity ofarchitecture including a)
circumscribed variations in size ofhepatocytes and thicknessofcell plates,
b) abnormal spacing of vascular channels, c) excess of hepatic vein tribu-
taries over portal tracts, especially if the latter are small, and d) in adults,
paucityofcentrolobular lipofuscin pigment in newly formed hepatocvtes.
Conditions Resembling Cirrhosis
The proposed criteria exclude some conditions often designated as
cirrhosis. They include:
A. Precirrhotic stages: 1) precursor stages in biliary cirrhosis, either
primaryv or obstructive," in both of which cirrhosis only develops in the
latest stages and is thus seen at autopsy, 2) congestive fibrosis before
nodule formation and hnking septa have developed," 3) fibrosis from
sarcoidosis,70 and 4) central hyaline sclerosis in alcoholic liver injury.71 In
the first three, presinusoidal portal hypertension may be a problem, but
ascites, if present, is not hepatic. The fourth has sinusoidal portal hvper-
tension with tendencv to ascites before nodules appear.19
B. Hepatic fibrosis with portal hypertension on presinusoidal basis (in
most the flow in the portal vein tributaries is compromised and possibly
arterial flow is augmented): 1) Schistosomiasis producing portal lesions
on immunologic basis." (In somecountries this, the mostcommon form of
portal hvpertension in the world, is associated with cirrhosis, possible due
to additional causes.) 2) Biliarv dvsplasias, encompassing hamartomatous
lesions involving biliarv ductal epithelium, with manv transitions between
them, include Meyenberg complexes, hepatic cysts, focal dilatation ofthe
intrahepatic bile ducts (Caroli's disease), choledochal cysts, and con-
genital hepatic fibrosis. (The last73 resembles cirrhosis because of the
excessive portal fibrosis separating nodular portions of normal pa-
renchvma. The uniform separation of hepatic vein tributaries from the
fibrotic areas, excess arteries, and bile precipitates in abundant ductules
lined by cuboidal regular epithelium in the absence of jaundice are
diagnostic criteria.) 3) Hepatic fibrosis associated with exposure to envi-
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ronmental agents such as Thorotrast, inorganic arsenicals, and vinyl chlo-
ride leads only exceptionally to cirrhosis. (Both portal and hepatic vein
pressure may be elevated. The fibrosis proceeding to angiosarcoma is
associated with nodules in which both hepatocytes and sinusoidal cells are
hyperplastic but which are not demarcated by connective tissue.74) 4)
Reversible pericellular fibrosis from hypervitaminosis A.75 5) Radiation
fibrosis. 6) Gaucher's disease.76 and 7) Partial nodular transformation.77
Presinusoidal portal hypertension may cause additional hepatic fibrosis
(Banti's syndrome). This is also true for other causes of presinusoidal
portal hypertension such as myeloproliferative diseases with spleno-
megaly, arteriovenous fistulae, and extrahepatic portal vein thrombosis, as
well as those designated as idiopathic portal hypertension.
C. Acute submassive necrotic hepatitis exhibits, following collapse of
necrotic parenchyma, bridges which by dissecting the lobules create a
resemblance to cirrhosis, particularly in autopsy specimens. The absence
of a roundness of the nodules and, more important, thesharpdemarcation
of portal tracts seen with connective tissue stains should prevent mis-
diagnosis (Figure 5A). This is important in legal/medical problems when
preexisting disease is claimed in fatal acute hepatic insufficiency.
Etiology
In many forms of cirrhosis the etiology can be established or is strongly
suspected. But since the same etiologic factor may not cause cirrhosis in
another person, additional contributing, mostly host, factors are required.
This is similar to the situation in infectious diseases, where doubts about
etiology are not as frequently raised. The etiologic features, primarily in
the precursor lesions, are the key to an etiologic classification and there-
fore will here receive emphasis for morphologic differential diagnosis.
Treatment by corticosteroids and other antiinflammatory agents may
obscure inflammatory features of diagnostic significance; moreover, at
autopsy the inflammatory reaction may be subdued.
Alcoholic Cirrhosis
It is estimated that only 10 to 30% of alcoholics develop cirrhosis.78
Recently, dose and time dependence was described.79 Studies in baboons
have established that ethanol intake even with adequate diet produces
cirrhosis.80 This resolves the long-standing argument about the cirrho-
genous potential of ethanol. In the early stages, a large micronodular
cirrhosis with steatosis prevails, whereas later, large nodules and broad
septa predominate.59 The most useful diagnostic feature is the alcoholic