Journal of Pediatric Gastroenterology and Nutrition
44:401–406 # 2007 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and
North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition
Invited Review
Reversal of Liver Cirrhosis: A Desirable Clinical Outcome
and Its Pathogenic Background

Flavia Bortolotti and yMaria Guido

Clinica Medica 5, University of Padua, and {Pathology Department, Azienda Ospedale-University of Padua, Padova, Italy
ABSTRACT
Cirrhosis is the final stage of chronic liver damage of various
etiologies. It used to be considered an irreversible lesion, but
enormous advances in our understanding of hepatic cellular and
molecular biology in the past 2 decades have challenged this
view. There is now substantial evidence that cirrhosis can be a
reversible process. This concept is supported by an increasing
number of clinical reports showing the disappearance of cir-
rhotic lesions from liver biopsies taken from patients cured of
their liver disease. The reversal of cirrhosis usually occurs in
patients with short-lived liver disease, after the successful
treatment of the underlying liver damage. Recently, however,
we observed the spontaneous reversal of cirrhosis after the loss
INTRODUCTION
Cirrhosis is a pathological condition involving the
presence, throughout the liver, of fibrous septa dividing
the parenchyma into nodules (1). It represents the final
stage of chronic liver damage of various causes, which
may be viral, alcoholic, toxic, autoimmune, metabolic, or
ischemic. Its life-threatening complications include
refractory ascites, variceal bleeding, encephalopathy,
hyponatremia, and renal dysfunction, and it represents
a major health problem worldwide (2,3).
Until recently, cirrhosis was considered an irreversible
lesion (4), but in the past decade, both clinical reports and
advances in basic science have challenged this concept
(4–11). Reversal of cirrhosis has been described in a
wide range of liver diseases (12–22), and the results of
earlier studies, mainly concerning small series of
patients, are now supported by findings emerging from
large-scale trials in patients with chronic hepatitis C
treated with pegylated interferon (IFN) and ribavirin
(21–23). These biopsy-based studies have demonstrated
Received November 6, 2006; accepted December 13, 2006.
Address correspondence and reprint requests to: Dr. Flavia Bortolotti,
Clinica Medica 5, Via Giustiniani 2, 35100 Padova, Italy (e-mail:
flavia.bortolotti@unipd.it).
401
Copyright © 2007 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited.
of hepatitis B viremia in 2 men, 21 and 28 years old, who had
developed cirrhosis as young children. Several questions and
controversial issues concerning the definition of advanced
cirrhosis, the limitations of liver biopsy (eg, sampling, interpret-
ation error), and the applicability of noninvasive methods to the
assessment of fibrosis, are being addressed. Future prospects
include the possibility of antifibrotic therapy to prevent fibrosis
or favor its degradation. JPGN 44:401–406, 2007. Key Words:
Cirrhosis, reversible—Hepatitis—Fibrogenesis—Fibrolysis. #
2007 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for
Pediatric Gastroenterology, Hepatology, and Nutrition
the reversibility of cirrhosis after the clearance of viremia
in successfully treated patients, emphasizing that the
elimination of the underlying chronic injury is funda-
mental to the reversal of cirrhosis.
Key cellular and molecular mechanisms of liver fibro-
genesis that lead to cirrhosis have been extensively
investigated, focusing especially on the central role of
the hepatic stellate cells (HSC) in the production and
degradation of the extracellular matrix (ECM) (24).
There is now a substantial body of evidence to show
that liver fibrosis and cirrhosis are active, dynamic
processes that reflect the imbalance between the depo-
sition and degradation of connective tissue, and that ECM
deposition is far more reversible than was previously
believed (25,26).
This review focuses on the reversal of cirrhosis as a
clinical and histological event that has now been
described in a variety of liver disorders and on rational
scientific grounds.
PATHOGENESIS OF CIRRHOSIS
Three major mechanisms are central to the onset of
cirrhosis: cell death, ECM deposition, and vascular
modifications (27–29). The fibrotic process is charac-
terized by both quantitative and qualitative changes in the
 402 BORTOLOTTI AND GUIDO
composition of the hepatic ECM with excessive depo-
sition (of collagen, in particular) in the portal tracts and
the replacement of low-density type IV collagen with
high-density types I and III collagen in the space of
Disse, causing sinusoidal capillarization. The morpho-
genesis of cirrhosis is related to the underlying disease
and reflects the topographic distribution of the liver
damage and the contribution of different cells involved
in the fibrogenic process (30). In biliary diseases fibrosis
deposition involves the portal tracts and then progresses
to the formation of portal-portal septa. In chronic viral
hepatitis different mechanisms contribute to disrupting
the cellular architecture (ie, longstanding interface
hepatitis, responsible for the development of portal-
portal septa, and more extensive necroinflammatory
lesions, such as portal-central bridging necrosis, leading
to the onset of portal-central vein fibrous septa). Central-
central septa are usually associated with outflow
disorders. In both alcoholic and nonalcoholic steatohe-
patitis, fibrosis surrounding groups of hepatocytes—the
so-called chicken-wire pattern—in the area around
the central veins is a key step in the development of
cirrhosis (31).
Regardless of the cause, sinusoidal capillarization is
an early event with remarkable effects on the metabolic
exchanges between hepatocytes and blood circulation.
Further impairment in liver function stems from the
formation of novel intrahepatic vessels, via porto-portal
and porto-central collaterals, that shunt the blood away
from the hepatocytes.
Fully developed cirrhosis has diverse morphological
features, with more or less numerous, slender or broad
septa and parenchymal nodules of varying sizes and
shapes. It has been suggested that the severity of cirrhosis
be classified according to the characteristics of the septa
(32). More recently, a combination of nodule size and
septal thickness has been proposed for staging the sever-
ity of portal hypertension. Basing the severity of cirrhosis
on histological criteria (33) may help us to predict its
potential for reversal.
The anatomic classification distinguishes between
micronodular cirrhosis, typically associated with alcohol
abuse and characterized by small uniform nodules a few
millimeters in size; macronodular, or posthepatitis,
cirrhosis, with large bulging nodules of varying sizes;
and mixed cirrhosis, typical of primary biliary cirrhosis
and primary sclerosing cholangitis. Most cases of
advanced cirrhosis acquire a mixed pattern, however,
because of the ongoing regenerative and fibrogenic
process. Incomplete septal cirrhosis, characterized by
slender fibrous septa that do not connect portal tracts to
portal tracts and/or central veins, is regarded as a histo-
logical feature of regression of cirrhosis (34). The practical
value of the above classification is to remind pathologists
that it may be difficult to recognize macronodular and
incomplete septal cirrhosis in liver biopsy specimens (35).
J Pediatr Gastroenterol Nutr, Vol. 44, No. 4, April 2007
Copyright © 2007 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited.
Cellular Effectors of Fibrogenesis
The HSC have been considered the key cellular source
of collagen (36–38). In the normal liver, HSC reside in a
quiescent status in the space of Disse, between hepato-
cytes and sinusoidal endothelial cells, and they store
vitamin A and other retinoids. In response to liver injury
and the related production of cytokines, HSC undergo a
phenotypic transformation into proliferative, fibrogenic,
and contractile myofibroblasts (cells not found in the
normal liver). The proliferation of myofibroblasts, stimu-
lated especially by platelet-derived growth factor-b,
amplifies the number of fibrogenic cells. The direct
fibrogenic activity of the myofibroblasts, stimulated
particularly by transforming growth factor-b-1, gives
rise to a dramatic increase in the synthesis and deposition
of ECM. Myofibroblast contractility, primarily in
response to endothelin-1, leads to increased portal
resistance by constricting individual sinusoids and con-
tracting the liver as a whole. In addition, HSC produce
tissue inhibitor of matrix metalloproteinases (TIMPs),
which inhibits collagen-degrading matrix metallo-
proteinases and tips the balance between ECM synthe-
sis and degradation in favor of ECM synthesis and
fibrogenesis.
Hepatic cell types other than HSC may also have
fibrogenic potential (39–41). In an experimental model
of bile duct ligation, fibroblasts normally residing around
vessels and bile ducts may acquire a myofibroblastic
phenotype and start depositing collagen in the portal
zones. Together with vascular smooth muscle cells,
fibroblasts around centrilobular veins or in the liver
capsule may also change into myofibroblasts, thus con-
tributing to fibrogenesis. More recent studies in humans
have suggested that mesenchymal cells in the portal tract
have a significant role in the development of liver fibrosis
and cirrhosis.
Hepatic fibrosis pathways are largely similar, regard-
less of the cause of the liver injury, but some disease-
specific fibrogenic mechanisms are under investigation,
including the direct stimulation of HSC by viral infection
in hepatitis C, high leptin levels, and increased leptin
signaling by HSC in nonalcoholic steatohepatitis.
Factors Interfering With Fibrogenesis
The rate of progression of fibrosis can vary consider-
ably. Progression tends to be rapid in some cases, as in
infants with congenital hepatic fibrosis, patients coin-
fected with hepatitis C virus (HCV) and HIV, and patients
with recurrent hepatitis C after liver transplantation.
Risk factors such as alcohol consumption, a high body
mass index, or immunosuppressive therapy may also
accelerate progression (42). Genetic factors are likely
to influence the deposition and elimination of fibrosis,
but the complex mechanisms of fibrogenesis, involving
 REVERSAL OF LIVER CIRRHOSIS 403

a large number of cytokines, make the study of gene TABLE 1. Cirrhosis reversal in relation to cause and
polymorphisms rather difficult. treatment: data published in the past decade
Cirrhosis
Mechanisms of Fibrolysis Reversal
Study Cause Treatment (n)
Experimental models in rats and transgenic mice and
cell culture studies have enhanced our knowledge of the Dufour et al (12) Autoimmune Steroids þ azathioprine 8
Kaplan et al (14) PBC Methotrexate 3
critical events and processes in fibrosis and cirrhosis Cotler et al (16) HDV IFN 1
reversal. In the normal liver the ECM accumulation Muretto et al (17) Thalassemia Bone marrow transplant 6
produced by HSC and other fibrogenic cells is balanced Kweon et al (18) HBV IFN  ribavirin 5
by a proportional increase in its degradation. Our knowl- Lau et al (19) Autoimmune Steroids 1
Farci et al (20) HDV IFN 4
edge of the cell types and of enzymes that degrade Poynard et al (22) HCV IFN  ribavirin 75


collagen in the liver is still limited. Matrix metallopro- Pol et al (23) HCV IFN  ribavirin 7
teinases are zinc-dependent enzymes expressed mainly Bortolotti et al (50) HBVy None 2
by HSC and Kupffer cells; they are capable of degrading PBC ¼ primary biliary cirrhosis; HDV, hepatitis D virus; HBV,
different matrix components (43). In the damaged liver hepatitis B virus; HCV, hepatitis C virus.


increased mitochondrial processing peptidase activity is Normal liver in 3 cases.
y
the major mechanism behind the regression of fibrosis. Acquired in childhood.
This activity is regulated by TIMPs. Recent data support
the hypothesis that TIMPs play a predominant part in
regulating fibrosis by protecting fibrotic ECM against
degradation by collagenase (43,44). In rodents the regimens. Using the METAVIR scoring system, they
reversal of fibrosis is accompanied by an increase in found that the extent of liver fibrosis had improved in
the apoptosis of activated HSC, which simultaneously 75 (49%) patients: from stage 4 to stage 3 in 23 patients,
reduces ECM and tissue inhibitors of metalloproteinases. to stage 2 in 26 patients, to stage 1 in 23 patients, and to a
Apoptotic mechanisms, however, would be different virtually normal histological appearance in 3 patients. No
between rodent and human cells, and fully activated such improvements were recorded in the control group
human HSC proved resistant to proapoptotic stimuli of patients treated with IFN monotherapy. Reversal of
(45,46). Clearly, at some point (probably coinciding with cirrhosis was more common among younger patients.
the onset of the clinical symptoms of cirrhosis), fibrosis In the above-mentioned studies the favorable out-
come of liver disease always followed some kind of
becomes irreversible. Animal models suggest that this
event coincides with a significant collagen cross-linking treatment, whereas we have recently reported on the
by tissue transglutaminase, leading to the production of spontaneous reversal of cirrhosis in 2 young patients in
an insoluble matrix (47). a cohort of 99 Italian children with chronic hepatitis B
(50,51). In these 2 patients biopsy-proven micronodular
cirrhosis had developed by the time they were 2 and
CIRRHOSIS REVERSAL IN CLINICAL 8 years old, respectively. The source of infection was
PRACTICE vertical in 1 case and unknown in the other. They had a
short-lived hepatitis Be antigen (HBeAg) antigen-
Regression of fibrosis and cirrhosis in humans is not a positive phase with active cytolysis but without any
novel concept. Anecdotal reports published more than clinical or biochemical features of liver failure. After e
30 years ago recorded an improvement in patients with antibody 10 HBeAg seroconversion, they became
cirrhosis treated for hemochromatosis and Wilson dis- hepatitis B virus DNA negative by conventional
ease (48,49). More recently, regression of fibrosis and hybridization techniques, and 1 eventually cleared
cirrhosis (Table 1) has been documented in the entire HBsAg. Further liver biopsies performed during their
spectrum of chronic liver diseases (11–21) (ie, in auto- childhood confirmed the histological diagnosis, but
immune hepatitis and primary biliary cirrhosis after liver biopsy specimens obtained at the ages of 21 and
effective immunosuppressive therapy, in biliary obstruc- 28 years, respectively, showed only mild periportal
tion after surgical decompression, in thalassemia after fibrosis. Liver histology was reviewed by the same
iron depletion, in hepatitis B after lamivudine therapy, expert pathologist on adequate bioptic samples. The
and in hepatitis D during long-term follow-up after IFN results of biochemical tests and ultrasound were con-
treatment). Larger studies have been conducted in sistent with a normal liver. In these patients initial active
patients with HCV-related cirrhosis. Poynard et al (21) liver damage may have caused the early evolution to
examined liver biopsy specimens taken before and after cirrhosis, whereas a subsequent spontaneous cessation
therapy from 153 patients with HCV-related cirrhosis of virus replication, before the onset of clinical com-
treated with different pegylated IFN and ribavirin plications, probably enabled the reversal of cirrhosis.

J Pediatr Gastroenterol Nutr, Vol. 44, No. 4, April 2007

Copyright © 2007 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited.
 404
OPEN QUESTIONS AND CONTROVERSIES
Despite the mounting clinical evidence, the potential
for the reversal of cirrhosis remains a debated issue, the
methods used in the clinical studies are still criticized,
and even the terminology is a matter of controversy. In
their recent review (11), Friedman and Bansal proposed
standardizing the use of the terms ‘‘reversal’’ and
‘‘regression’’ in this context: ‘‘reversal’’ would prefer-
ably indicate the complete restoration of normal liver
architecture after recovery from liver damage, whereas
‘‘regression’’ would simply indicate a reduction in the
amount of fibrosis, irrespective of its initial extent.
Sampling Error
Sampling error, defined as the deviation of a sample
from the tissue from which it was taken, is an issue in the
diagnosis of cirrhosis, in particular of the macronodular
and incomplete septal types. A needle biopsy covers a
small portion of the whole liver, representing approxi-
mately 1/50,000 of the organ. The available data con-
sistently indicate the risk of underestimating fibrosis on
the basis of semiquantitative assessments on excessively
small samples (52–55). The sampling error issue has
been reviewed in detail elsewhere (52). The strategy
for reducing the risk of sampling error is to obtain
‘‘adequate’’ samples, which should contain no less than
11 complete portal tracts for the staging of chronic
hepatitis (56). Caution is consequently needed when a
reversal (or regression) of fibrosis/cirrhosis is diagnosed
on substandard biopsy samples. It is also important to
emphasize that a histological diagnosis of cirrhosis relies
both on the extent of fibrosis and on the detection of
architectural derangement. In the hands of an expert
pathologist, various subtle histological changes reflect-
ing architectural disruption may point to a confident
diagnosis of cirrhosis even in small samples and/or in
the macronodular type.
Scoring Systems and Intra- and Inter-observer
Variation
At least 3 scoring methods are commonly used in the
staging of liver fibrosis. They are based on the collagen
staining of biopsy samples and take into account the
typical progression of fibrosis from periportal to septal,
and ultimately to nodule formation. In the Knodell and
METAVIR scores (57,58) fibrosis is staged as 0 to 4,
where 4 indicates cirrhosis. The Ishak (59) system scores
fibrosis on a scale from 0 to 6, where 5 means incomplete
or early cirrhosis and 6 means established cirrhosis.
Recent studies have found good intra- and interobserver
reproducibility for the staging of fibrosis regardless of the
scoring system used (54). All of these systems are
semiquantitative and nonlinear, however, and have been
J Pediatr Gastroenterol Nutr, Vol. 44, No. 4, April 2007
Copyright © 2007 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited.
BORTOLOTTI AND GUIDO
designed to stage the deposition of fibrosis rather than its
regression, which is likely to be a dynamic process taking
months or years to complete, so a biopsy taken shortly
after treatment of the liver disease may fail to show any
significant improvement. By contrast, the invasiveness of
liver biopsy makes a close histological monitoring of
fibrosis unfeasible, especially in pediatric patients,
hence, the investigations into noninvasive methods for
assessing liver fibrosis. Several putative serological
markers of fibrosis have been studied in adults, and
encouraging results have been obtained by combining
different markers. Several recent reviews are available,
and many studies in progress are attempting to validate
such noninvasive methods for clinical practice (60).
CONCLUSIONS AND FUTURE DIRECTIONS
Some messages seem to emerge unequivocally from
the literature:
1. Reversal of cirrhosis is more likely to occur in
patients with a relatively short-lived history of
disease and well-preserved liver function.
2. An improvement in, or the disappearance of, the
underlying chronic liver injury is a necessary
condition for the reversal of cirrhosis.
3. Reversion of cirrhosis usually follows specific
treatment but may also be a spontaneous event.
4. Reversal is probably a slow process, which starts
soon after the liver injury has been overcome and
may take several years; a short-lived liver disease and
stronger regenerative activity could accelerate the
reversal of cirrhosis in some pediatric subgroups.
Several aspects of the reversal of cirrhosis deserve
further discussion and clarification, particularly concern-
ing the definition of irreversible cirrhosis based on cli-
nical signs and symptoms, and the concept of histological
severity of cirrhosis. The identification of reliable non-
invasive markers for assessing liver fibrosis is highly
desirable to overcome the drawbacks of liver biopsy,
especially in children.
Removing the cause of liver damage remains the best
treatment for cirrhosis (61,62), but it is anticipated that
pinpointing efficient targets for antifibrotic therapy,
identified amidst the cascade of events leading to the
progression of fibrosis, will definitely change the prog-
nosis of chronic liver disease in the future.
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