Notes by dr Claudio Italiano
Hepatic cirrhosis is a chronic progressive disease, affecting the liver parenchyma with the appearance of necrotic and regenerative phenomena, and in which fibrosis causes architectural subversion and changes in vascularization. There are several etiological factors. Now that there is a cure for viral hepatitis, at least in Western countries, if drug users are excluded, it is difficult to find patients with cirrhosis for previous chronic viral hepatitis. On the other hand, it is easy to come across alcoholic patients, with liver in cirrhosis and ascitic decompensation, at least in clinical practice, that is a liver destroyed by the use of alcohol that causes alcoholic hepatitis and finally transformation into cirrhosis. Other causes are determined by contact with toxic substances, especially in industrial workers. Finally, other causes are Wilson's M. and hemochromatosis. Here we talk about the liver damage represented by cirrhosis and how it is determined.
In the definition formulated by a Committee of the W.H.O. (Anthony et al., 1977)
cirrhosis is defined as "a widespread process, characterized by fibrosis and by
conversion from normal architecture into structurally abnormal nodules". This
definition takes into account the essential elements for the bioptic diagnosis
of cirrhosis (the widespread nature of lesions, fibrosis and nodules), while no
other important elements appear, such as necrosis, nodular regeneration and
abnormal vascularization. Although the latter are part of the cirrhotic process,
they are not easily confirmed in the hepatic needle biopsies and therefore are
not considered indispensable for the diagnosis.
The definition is useful for differentiating the true cirrhosis from the numerous other chronic hepatopathies that, although presenting some character in common with cirrhosis, differ in others, such as: focal nodular hyperplasia, diffuse nodular hyperplasia without cirrhosis, liver fibrosis congenital, nodular regenerative hyperplasia, hepatic sclerosis of inflammatory origin (tuberculosis, sarcoid, brucellosis, luetica), affections in which fibrosis, even when very extensive, is never such as to subvert the lobular architecture and where it lacks as a rule important outbreaks of hepatocellular regeneration.
Nodular appearance of the hepatic parenchyma,
under a greater magnification, in blue of the fibrous
septa
Cirrhosis is a disease of the middle or advanced age, with a maximum
frequency between 50 and 60 years (in the African and Asian populations,
individuals between 30 and 40 years are more affected). Infrequently struck, at
least in western countries, is the child's age, where the cirrhosis of the liver
often intervenes against the background of a congenital metabolic defect.
With regard to sex, men are affected at least twice as often as women, but there
are considerable differences in the various forms of cirrhosis. For example, in
alcoholic cirrhosis the male-female relationship varies, according to statistics,
from 2 to 10: 1, although the frequency in women appears to increase;
hemochromatosis cirrhosis prefers men with a ratio of 5 to 10: 1; also
postepatitic cirrhosis prevails in men. Primary biliary cirrhosis predominates
predominantly in women.
There is currently no satisfactory classification of cirrhosis, but the one
based on the etiology is the most followed.
The etiology of cirrhosis varies both geographically and socially; the following
is the approximate frequency of the etiological categories in the West:
Alcoholic liver disease 60-70%
Viral hepatitis 10%
Diseases of the biliary tract 5-10%
Hereditary hemochromatosis 5%
Rare Wilson disease
Rare a-1-antitrypsin deficiency
Cryptogenic cirrhosis 10-15%
The term crypt cirrhosis refers to those cases in which it is not possible to
identify a cause and its frequency demonstrates the difficulty of discerning the
various origins of cirrhosis. Once cirrhosis has developed, it is often
impossible to establish an etiological diagnosis based on morphological data
alone.
Macroscopic characters. The cirrhotic liver is mostly reduced in volume,
often more strongly in the left lobe (atrophic cirrhosis); but there are forms
in which the liver is enlarged and can even exceed 2 kg of weight (hypertrophic
cirrhosis), probably in relation to a greater intensity of the epa-tocellular
regenerative phenomena.
The external surface has a granular appearance due to the presence of detected
nodules of variable size (Fig. 64). In relation to the size of the nodules there
are 3 forms of cirrhosis:
- Micronodular cirrhosis: the nodules are almost uniform in size, separated by
thin fibers, with a diameter of no more than 3 mm. Most of the cirrhosis of
alcohol, hemochromatosis cirrhosis, Indian infantile cirrhosis, some cases of
posterior cirrhosis, chronic biliary stasis and obstruction are micronodular;
venous outflow.
- Macronodular cirrhosis: the nodules are of variable size with a diameter of
more than 3 mm, separated by large irregular fibrous septa. There is not always
a reliable correlation between this type of cirrhosis and etiology. Cirrhosis
occurring on chronic viral or autoimmune hepatitis or cirrhosis of Wilson may be
of this aspect, but hemochromatosis and alcoholic cirrhosis may be macronodular
(especially after the suspension of alcohol abuse).
- Mixed cirrhosis: when macronodules and micronodules are present at the same
time.
The consistency of the organ in all cases is greatly increased, hard or even
wood. The section surface repeats the nodular appearance of the external surface;
the nodules detected and irregularly distributed, have a yellowish color, by
accumulation of lipids, or yellow-greenish by bile imbibition, and are separated
by more or less thick fibrous shoots and greyish-white color.
From the anatomopathological point of view, according to the etiopathogenetic
mechanisms, we can divide the cirrhosis into:
- Atrophic cirrhosis, classically that of Laennec, in alcoholism, in which the
mechanism of fibrogenesis prevails over that of nodular regeneration. atrophic
cirrhosis of drinkers or vulgar cirrhosis. It consists of a process with a
progressive course, which culminates in the shrinking or atrophy of the organ,
which can lose up to almost two thirds of its weight.
- Hypertrophic cirrhosis, in those forms in which the mechanism of regeneration
prevails
There are other forms of cirrhosis, equally producing ascites, although less
rapidly and less regularly, or sometimes decorrent without ascites, with less
severe symptoms of liver failure and therefore of a more benign prognosis, in
which the liver remains hypertrophic (hypertrophic cirrhosis) simple by Hanot
and Gilbert). Some authors also admit the dyspeptic hypertrophic cirrhosis (Budd
cirrhosis), due to toxic substances, originating from alterations of the
digestive processes. It should also be noted the form of malignant hypertrophic
cirrhosis of malignant Hutinel and Sabourin, which is noted above all in
tuberculosis subjects, and in which the malignancy of the process is due to the
profound degenerative changes of the parenchyma and therefore to the marked
degree of hepatic failure. Another variety has been isolated by Gilbert, Garnier
and Castaigne, under the name of diffuse hypertrophic cirrhosis.
For an overview, the fundamental histological finding is represented by the
subversion of the normal lobular structure, with a marked proliferation of the
connective tissue. In some cases the histological picture can be indicative of a
particular etiological form. This may occur in cirrhosis occurring on viral
hepatitis B or C, hemochromatosis, Wilson's disease, and a-1- antitrypsin
deficiency; also alcoholic cirrhosis and primary biliary cirrhosis can be
reasonably suspected in histological examination. The analysis of the structural
alterations of the hepatic parenchyma as well as suggesting an etiological
hypothesis may be indicative of the progression stage of cirrhosis.
In micronodular cirrhosis, the fibrous septa connect the small terminal portal
spaces to the hepatic venules by dissecting the grape in small nodular areas (subacine
nodules). In these nodules both portal spaces and terminal hepatic venules are
absent, which are instead included in the sclerosis areas. The disruption and
fragmentation of the grapes are therefore associated with alterations of the
hepatic circulation with the formation of an alternative blood flow to that of
the sinusoids, which occurs through the newly formed vascular structures present
in the septa. The association, more or less narrow, of micronodular cirrhosis
with some particular etiological agents seems to be explained by the homogeneous
and diffuse distribution of the damage caused by hepatic agents on the smaller
acinar morphofunctional units. In alcoholic hepatopathy e.g. every single grape
suffers the toxic action of alcohol and the fibrosis is distributed widely
around the terminal hepatic veins and along the perisinusoidal spaces of Disse.
In macronodular cirrhosis, as a result of irregularly confluent necrosis
phenomena distributed in the berries, areas of irregularly contoured parenchyma
are surrounded by large bands of connective tissue that radiate from the
periportal areas and which contain arterial, venous and lymphatic vascular
structures, and often also an inflammatory infiltrator. Within the nodules, the
acinar structure appears distorted but not completely subverted. The macronodule
can incorporate elements of the complex berry or agglomerates of berries with
portal spaces and terminal venules, abnormally close to one another. In some
cases the macronodules can be buried in smaller units by thin fibrous septa,
often incomplete, which unite the terminal portal spaces; this can occur in
chronic hepatitis with marked activity where, as a final result, a micronodular
cirrhosis can be generated rather than macronodular. Within the macronodules,
through the fibrovascular septa, changes in blood flow occur that may involve a
direct intrahepatic shunt between portal space and terminal hepatic vein; from
the hemodynamic point of view this abnormal flow is accentuated by the formation
of arterio-venous anastomoses which involve a pressure gradient such that the
blood skips the sinusoidal system. Another element that involves a further
alteration of the blood flow is the regenerative activity of the hepatocytes
with the formation of an area of expansion within the nodules and compression
of the adjacent hepatocyte laminae and of the sinusoids.
Regenerative activity is responsible for the formation of true parenchyma
nodules surrounded by large fibrous bands containing newly formed portal spaces
or bile ducts. The hepatic laminae that make up the nodules are two or even
three cells thick, they have no radiated orientation but a circular course
without a relationship with a centrolobular vein. Within the nodule small portal
spaces may be present, with neoformed, hypoplastic and afferent veins, without
these structures having well-defined topographic relationships between them and
with the sinusoids; the latter also often have walls collapsed and only
partially resemble normal sinusoids.
Another constant, but not exclusive, aspect of cirrhosis is the newly formed
bile ducts.
It is documented by the presence, in the context of the connective tissue septa,
of numerous long-twisted, tortuous and branched cords, covered by epithelium
that delimits a mostly virtual lumen.
Inflammatory infiltration is often present, in a more or less conspicuous form,
in all forms of cirrhosis. Located in the harbor spaces and in the fibrous septa,
it consists predominantly of lymphocytes, plasma cells and histiocytes,
sometimes associated with low neutrophils and eosinophils granulocytes.
Generally, in inflammatory cirrhosis the inflammatory component is less
conspicuous with posphythritic cirrhosis. The term active cirrhosis indicates
the presence of "piecemeal" necrosis in the septum-parenchyma interface.
Hepatic cirrhosis is a dynamic process that is determined on the one hand by a
progressive fibrosis of the hepatic parenchyma and on the other by a severe
distortion of the normal lobular architecture for the subversion of the
parenchyma in nodular structures consisting of hepatocytes. The main processes
that, when combined with each other, are responsible for the cirrhotic
transformation of the hepatic parechima are: necrosis of the hepatocytes,
fibrosis and regeneration.
Necrosis. Hepatocytic necrosis is the most important initial lesion that
underlies every cirrhogenic process. Necrosis can be caused by a direct toxic
action (alcohol, hepatotoxic drugs), by accumulation in hepatocytes of iron (hemochromatosis)
or copper (Wilson's disease), by immune mechanisms (viral hepatitis) or
autoimmune or by cholestasis . It should also be emphasized that, to perform
cirrhogenic action, the necrosis must be repetitive or continuous, being
ascertained that an isolated episode of acute necrosis, even if extended, does
not lead to cirrhosis. However, not all forms of necrosis have an equal
potential for cirrhosis; the latter is mostly conditioned by the
morpho-pathogenic characteristics, by the extension and by the topographic
distribution of the necrosis in relation to the microvascular structures of the
liver.
The types of necrosis that most frequently evolve into cirrhosis are "piecemeal"
necrosis, necrotic lesions in alcoholic liver disease and necrosis secondary to
cholestasis.However, even anoxic necrosis and lithic necrosis, although more rarely, may be
responsible for a cirrhene process.
Regarding the importance of the topographic distribution of necrosis in
morpho-genesis of cirrhosis, it can be said that the isolated perivenular
necrosis of simple berry (zone 3) is never practically responsible for
cirrhogenic processes, while it becomes the necrosis that affects the zones 3 of
adjacent simple berries (necrosis of the periphery of the complex berry), or
zones 3 and 2 of the simple berry (periacinare necrosis) or the peri-portal
acinar area, with the characters of the "piecemeal" necrosis.
Progressive fibrosis is the central pato-genetic process of cirrhosis. In the normal liver interstitial collagen is concentrated
in the portal spaces, around the centrolobular veins and, in small quantities,
in the Disse spaces. In cirrhosis too much collagen is deposited not only in the
portal spaces, but also inside the lobules forming septal structures. The
sinudoids in turn are transformed into capillaries for the formation of a
basement membrane that seriously compromises the interchanges between
hepatocytes and blood.
The main source of excess collagen in cirrhosis are the perisinusoidal stellate
cells of Ito and sinusoidal endothelial cells. Although Ito stellate cells
normally have the function of storing vit. A, during the pathogenetic process of
cirrhosis, following the release of cytokines from activated Kupffer cells and
other inflammatory cells, they are activated and transformed into
myofibroblast-like cells capable of producing extracellular collagen matrix.
However, the synthesis and deposition of collagen can be the consequence of a
variety of stimuli:
• Chronic inflammation with the production of inflammatory cytokines.
• Cytokines produced by damaged cells (Kupffer cells, endothelial cells,
hepatocytes and bile duct epithelial cells).
• Destruction of the extracellular matrix.
• Direct stimulation of stellate cells by toxins.
The prevalently portal and periportal fibrosis, on a "star" enlargement of the
portal spaces, is realized in the areas of periportal necrosis and of the
limiting amine and is characterized by the formation of the active septa which
wedge themselves in the parenchyma by dissociating them. Intracinated fibrosis
is usually the consequence of confluent necrosis and therefore traces the
topography of the latter with the realization of perivenular fibrosis and with
the formation of central-central fibrous bridges, central-port and port-portals.
Hepatocytes, epithelial cells of the bile ducts and undifferentiated progenitor cells retain the potential to multiply during adulthood and are carried out in each of its destructive processes, but which reaches its highest expression in cirrhosis. In relation to the type of etiological agent, the nature and extent of hepatocyte damage, regeneration can occur through at least two mechanisms involving either differentiated adult hepatocytes that may undergo division (or multiplication) or through the stimulation of cell proliferation. progenitor. In the liver small "oval cells" have been identified that are able to differentiate into hepatocytes and into the epithelial cells of the bile ducts. The proliferation of these cells initially gives rise to "ductular hepatocytes" that can differentiate into both hepatocytes and epithelial cells organized into bile ductules. It has been observed that following massive hepatic necrosis appears a proliferation of ductular structures connecting to the Hering channels and then to the terminal bile ducts within the portal spaces.
The structural subversion of the hepatic parenchyma is responsible for
evident changes in intrahepatic microcirculation. However, it is debated whether
the resulting portal hypertension represents the consequence of fibrosis or
nodular regeneration, as well as if it results from the strangulation or
occlusion of the small intrahepatic portal branches by the retracting
cicatricial fibrous tissue, or the compression exerted by the regenerative
nodules. on the roots of the suprahepatic veins. However, it is certain that in
cirrhosis of the liver there is always a considerable reduction of the terminal
portal network (with a decrease in the volume of blood that passes through the
liver), associated with the obliteration of numerous centrilobar veins and the
frequent distortion and compression of the veins underneath. lobular. It is
therefore probable that there are many phenomena contributing to the genesis of
portal hypertension, although it must be recognized that, in most cases,
pre-eminent pathogenic importance is due to occlusion of the afferent venous
vessels rather than the efferent vessels.
The increase in the anastomosis between the thin branches of the hepatic artery
and those of the portal vein certainly contributes to the increase in portal
vein pressure. These arterio-venous plexuses that originate from the portal
spaces make contact with those that originate around the terminal hepatic vein,
thus coming to form arterio-venous and veno-venous anastomoses. The formation of
these plexuses is accompanied by a relative increase in the flow from the
hepatic artery; in this way the high arterial pressure is transmitted to the
venous vessels increasing the portal pressure.
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