Page 182 - Color Atlas Of Pathophysiology (S Silbernagl Et Al, Thieme 2000)

Fibrosis and Cirrhosis of the Liver
Liver cirrhosis is a disease in which necrosis, cytes, and monocytes). Diverse growth fac-
inflammation, fibrosis, nodular regeneration, tors and cytokines are then liberated from
and formation of vascular anastomoses de- the Kupffer cells and the recruited inflamma-
velop more or less simultaneously. It is tory cells. These growth factors and cytokines
usually caused by the long-term action of now
noxious factors, especially alcohol abuse, – transform the fat-storing Ito cells of the
which is the cause in 50% of cases world- liver into myofibroblasts
wide. While the probability of cirrhosis de- – transform the imigrated monocytes into
veloping after a cumulative uptake of 13 kg active macrophages
ethanol/kg body weight is only about 20%, it – trigger the proliferation of fibroblasts
Liver rises to over 90% after 40 kg. The substance The chemotactic action of transforming
that is most responsible for the development
growth factor β (TGF-β) and monocyte che-
Stomach, Intestines, metabolite acetaldehyde. Cirrhosis can also from the Ito cells (stimulated by tumor ne-
of fibrosis, and thus cirrhosis, is the ethanol
motactic protein 1 (MCP-1), whose release
crosis factor α [TNF-α], platelet-derived
be the final stage of viral hepatitis (20–40%
of cirrhosis cases in Europe). In acute fulmi-
growth factor [PDGF], and interleukins)
strengthens these processes, as do a number
nant disease it may develop in a matter of
of other signaling substances. As a result of
weeks; in chronic recurrent disease after
which are not yet entirely understood), the
struction to blood outflow (congestive liver;
→ p.170) or after other liver damage, for ex-
production of the extracellular matrix is in-
6 months or years. It can also occur after an ob- these numerous interactions (the details of
ample, as final stage of a storage disease (he- creased by myofibroblasts and fibroblasts,
mochromatosis, Wilson’s disease; → p. 252) i.e., leading to an increased deposition of col-
or genetically determined enzyme defi- lagens (Types I, III, and IV), proteoglycans
ciency. (decorin, biglycan, lumican, aggrecan), and
Factors involved in liver-cell damage are: glycoproteins (fibronectin, laminin, tenascin,
– ATP deficiency due to abnormal cellular undulin) in the Dissé space. Fibrosis of the
energy metabolism; latter impairs the exchange of substances be-
– increased formation of highly reactive tween sinusoid blood and hepatocytes, and
–
oxygen metabolites (·O 2 , ·HO 2 , H 2 O 2 ) with increases the flow resistance in the sinusoids
– concomitant deficiency of antioxidants (→ p.170).
(e.g., glutathione) and/or damage of pro- The excess amount of matrix can be bro-
tective enzymes (glutathione peroxidase, ken down (by metalloproteases, in the first
superoxide dismutase). instance), and the hepatocytes may regener-
The O 2 metabolites react with, for example, ate. If the necroses are limited to the centers
unsaturated fatty acids in phospholipids (lip- of the liver lobules (→ A, top left), full restitu-
id peroxidation). This contributes to damage tion of the liver’s structure is possible. How-
of plasma membranes and cell organelles ever, if the necroses have broken through the
(lysosomes, endoplasmic reticulum). As a re- peripheral parenchyma of the liver lobules,
sult, cytosolic Ca 2+ concentration rises, acti- connective tissue septa are formed (→ A,
vating proteases and other enzymes so that bottom). As a result, full functional regenera-
the cells are ultimately irreversibly damaged. tion is no longer possible and nodules are
Fibrosis of the liver develops in several formed (cirrhosis). The consequence of this
steps (→ A). When damaged hepatocytes is cholestasis (→ p.168), portal hypertension
die, lysosomal enzymes, among others, leak (→ p.170), and metabolic liver failure
out and release cytokines from the extracel- (→ p.174).
lular matrix. These cytokines and the debris
of the dead cells activate the Kupffer cells in
172 the liver sinusoids (→ A, center) and attract
inflammatory cells (granulocytes, lympho-
Silbernagl/Lang, Color Atlas of Pathophysiology © 2000 Thieme
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