Cirrhosis: new research provides a basis

liver411

[B]for rational and targeted treatments[/B]

BMJ  2003;327:143-147 (19 July)
[B]Science, medicine, and the future[/B]

John P Iredale, professor1

1 Division of Infection, Inflammation and Repair, University of Southampton,
Southampton General Hospital, Southampton SO16 6YD [email protected]

Liver transplantation and antiviral treatments for hepatitis have improved
the outlook for many patients with liver disease. For patients with
cirrhosis, new developments herald targeted treatments

    Introduction
It is an exciting time to be working in hepatology. The success of liver
transplantation and the advances in the radiological and endoscopic
management of portal hypertension have improved the longevity and quality of
life of patients with liver cirrhosis. Additionally, the development of
effective antiviral treatments means that disease can be cured in many
patients infected with hepatitis B and hepatitis C. However, these
interventions also serve to highlight our current impotence in altering the
underlying fibrotic process in many patients with liver disease. This rather
depressing perspective may soon change: data from clinical and laboratory
based research are showing that cirrhosis may be reversible. By highlighting
the attributes required of an effective antifibrotic, a new dynamic model is
likely to lead to the development of targeted treatment for liver cirrhosis.

    Methods
This article is based on knowledge accrued over 13 years of work
investigating the mechanisms of fibrosis and aspects of hepatic stellate
cell biology and on regular Medline searches of the peer reviewed scientific
literature during that time. The field has benefited from the recognition
that certain mechanisms are common to hepatic, renal, and pulmonary
fibrosis, and I have reviewed models of these processes while preparing this
article. My examples highlight how laboratory based studies of the biology
of hepatic fibrosis may inform the design of future treatments.

    Clinical impact of cirrhosis
Liver fibrosis and its end stage, cirrhosis, represent enormous worldwide
healthcare problems. In the United Kingdom, more than two thirds of the 4000
people who died of cirrhosis in 1999 were under 65, and the incidence of
cirrhosis related death is increasing.1 Worldwide, the common causes of
liver fibrosis and cirrhosis include hepatitis B and hepatitis C and
alcohol. Other causes include immune mediated damage, genetic abnormalities,
and non-alcoholic steatohepatitis, which is associated with diabetes and the
metabolic syndrome.2 Changing patterns of alcohol consumption in the West
and the increasing rates of obesity and diabetes mean that advances in
preventing and treating viral hepatitis may be offset by an increasing
burden of fibrosis and cirrhosis related to alcohol and non-alcoholic
steatohepatitis.1-3

Summary points
Fibrosis, the liver's wound healing response, is bi-directional and
potentially reversible

Antiviral treatments provide increasing evidence for reversibility of
fibrosis and cirrhosis

Excess fibrillar (scar) matrix can be degraded even in advanced cirrhosis
but is held in check by protease inhibitors termed TIMPs

Antifibrotic treatments are likely to be developed in the next decade, on
the basis of a better understanding of the pathogenesis of fibrosis

Hepatic stellate cells have been shown to contribute to portal hypertension
by dynamic contractile activity; this could lead to the design of specific
agents to reduce portal hypertension

Current treatments for cirrhosis are limited to removing the underlying
injurious stimulus (where possible); eradicating viruses using interferon,
ribavirin, and lamivudine in viral hepatitis; and liver transplantation.
Transplantation is a highly successful treatment for end stage cirrhosis,
with a 75% five year survival rate. But limited availability of organs,
growing lists of patients needing a transplant, issues of compatibility, and
comorbid factors mean that not everyone is eligible for transplantation. As
a result, effective antifibrotic treatments are needed urgently.

    Inflammation and repair
Liver fibrosis and cirrhosis represent a continuous disease spectrum
characterised by an increase in total liver collagen and other matrix
proteins which disrupt the architecture of the liver and impair liver
function.4 5 Fibrosis results from sustained wound healing in the liver in
response to chronic or iterative injury. The wound healing response is an
integral part of the overall process of inflammation and repair: it is
dynamic and has the potential to resolve without scarring (fig 1).

Pathogenesis of fibrosis
High quality experimental evidence supports the hypothesis that the final
common pathway of fibrosis is mediated by the hepatic stellate cells.4-7
Hepatic stellate cells in normal liver store retinoids and reside in the
spaces of Disse (fig 2). In injured areas of the liver, hepatic stellate
cells undergo a remarkable transformation: they resemble myofibroblasts and
express contractile proteins. In this "activated" phenotype, hepatic
stellate cells proliferate and are known to be the major source of the
fibrillar collagens that characterise fibrosis and cirrhosis (fig 2). The
mechanisms mediating activation of hepatic stellate cells are a major
subject of research.

In injured areas, soluble factors (cytokines) are released by the incoming
inflammatory cells, the damaged and regenerating hepatocytes, and other
liver cells that target the hepatic stellate cells, activating them so they
become the central mediators of wound healing.5 Because of the key role of
inflammation, removing the causative agent and treating the patient with
immunosuppressive drugs are effective interventions for some diseases (box).
Greater understanding of the specific cytokine and chemokine messengers that
mediate the inflammatory process in liver disease is informing the design of
future treatments. This is exemplified by the identification of
interleukin-10 as a downregulator of the inflammatory response and tumour
necrosis factor  as a pro-inflammatory mediator.8 9 Studies using
interleukin-10 knockout mice have identified this cytokine as a major
anti-inflammatory effector in fibrotic liver injury. A pilot study suggested
that interleukin-10 may be valuable clinically in the context of hepatitis C
virus infection,10 but definitive evidence of efficacy has yet to be
produced in a large scale clinical trial. Antagonising tumour necrosis
factor  would also be expected to downregulate hepatic inflammation.
Reagents to neutralise tumour necrosis factor  are available for clinical
use, and this approach is likely to be investigated further in the clinic.11

Another approach to chronic liver fibrosis is to block the signals which
promote transition of hepatic stellate cells from a quiescent to an
activated phenotype and promote collagen secretion. Foremost among the
soluble mediators promoting the fibrogenic response from hepatic stellate
cells is transforming growth factor -1 (box). This cytokine also has a role
in the development of fibrosis in other organs, including the lung and
kidney.12 13 The activated hepatic stellate cells respond to it by
increasing production of collagen and decreasing its breakdown (see below).
Models in other internal organs suggest that modifying the secretion or
activity of transforming growth factor -1 can attenuate fibrosis, which
indicates that this is a possible antifibrotic target in the liver.14 Recent
studies of experimental liver fibrosis have shown the potential of this
approach.15


    Matrix synthesis and turnover in fibrosis and cirrhosis
Activated stellate cells proliferate, with the result that increases in
numbers of hepatic stellate cells, in addition to increases in secretion of
the fibrillar (or scarring) collagens, result in the deposition of excess
fibrotic matrix. Collagen synthesis is therefore clearly a target for
therapeutic intervention.16 Because fibrosis is advanced when most patients
present, understanding the processes regulating matrix degradation is likely
to be pivotal to the development of effective anti-fibrotic treatments.
Effective treatment will require breakdown of the pre-existing matrix.

Stellate cells and other cells involved in the fibrotic process, including
macrophages and Kupffer cells, secrete a repertoire of matrix degrading
metalloproteinase enzymes (MMPs).17 These enzymes degrade collagen and other
matrix molecules, and their presence in the fibrotic liver highlights the
potential dynamic nature of scarring within the liver. Molecular studies of
the expression of mRNA for these enzymes (including those with
collagenolytic activity) have shown that they are expressed in the liver
even in cirrhosis, but their activity is held in check by powerful
inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) 1 and 2.18
The potential for matrix degradation is present, even in advanced
cirrhosis-but it is held in check by concurrently secreted TIMPs (fig 3). It
should be possible to unharness the latent matrix degrading capacity of a
fibrotic or cirrhotic liver and to facilitate matrix degradation, resulting
in a return to normal or near normal architecture.19

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(continued) Models of resolution of liver fibrosis Studies that used pathological specimens and paired biopsies from trials of antiviral treatments in chronic hepatitis have shown that matrix degradation occurs in advanced human cirrhosis. In parallel, rodent models in which spontaneous recovery from liver fibrosis and cirrhosis occurs have allowed the frequent sampling that is needed to identify the critical features of the process.19-21 In recovery, expression of TIMPs 1 and 2 decreases rapidly while matrix degrading metalloproteinases continue to be expressed, resulting in increased collagenase activity and consequent matrix degradation within the liver (see fig 1). Together with these changes, apoptosis of the hepatic stellate cells occurs. Apoptosis, in effect the suicide of a cell, fulfils a function in mammalian tissue, removing unwanted cells when they become too numerous or redundant. During progressive liver injury, when stellate cells are activated in the normal wound healing response, stellate cell apoptosis is forestalled, probably through signals from soluble factors and changes in the matrix. When the injurious stimulus is withdrawn and remodelling of matrix is required, the loss of these survival factors causes the activated stellate cell to default into apoptosis, which facilitates the remodelling process by removing the major cellular source of collagen and TIMPs. Logically, therefore, manipulating matrix degradation or enhancing hepatic stellate cell apoptosis might be expected to reduce fibrosis and promote a return to normal liver architecture. Studies in this area are currently limited to experimental models but show promise that liver fibrosis can be attenuated by manipulating the TIMP-MMP balance or enhancing hepatic stellate cell apoptosis.22 23 Possible therapeutic interventions in liver fibrosis In progressive or established fibrosis Inflammation Removal of injurious agent Interleukin-10-anti-inflammatory effect Tumour necrosis factor inhibitors-anti-inflammatory effect Antioxidants-suppress fibrotic response to oxidative damage Stellate cell activation Interferon gamma (or interferon alfa)-inhibits activation of hepatic stellate cells Hepatocyte growth factor-inhibits activation of hepatic stellate cells Peroxisome proliferator-activated receptor ligand-reduces activation of hepatic stellate cells Perpetuation of stellate cell activation Transforming growth factor -1 antagonists-reduce matrix synthesis and enhance matrix degradation Platelet derived growth factor antagonists-reduce proliferation of hepatic stellate cells Nitric oxide-inhibits proliferation of hepatic stellate cells Angiotensin-converting-enzyme inhibitors-inhibit proliferation of hepatic stellate cells Stellate cell secretion of collagen rich matrix Angiotensin converting enzyme inhibitors-reduce fibrosis Polyhydroxylase inhibitors-reduce experimental fibrosis Interferon gamma-reduces fibrosis Endothelin receptor antagonists-reduce fibrosis and portal hypertension To enhance or initiate resolution of fibrosis Stellate cell apoptosis Gilotoxin-causes apoptosis of hepatic stellate cells Nerve growth factor-causes apoptosis of hepatic stellate cells Degradation of collagen rich matrix Metalloproteinases-enhance activity of metalloproteinases Tissue inhibitor of matrix (TIMP) antagonists-enhance activity of metalloproteinases Transforming growth factor -1 antagonists-downregulate TIMPs and increases activity of metalloproteinases Relaxin-downregulates TIMPs and increases activity of metalloproteinases Stellate cells as mediators of portal hypertension A major and life threatening consequence of cirrhosis is the development of portal hypertension. Studies of isolated hepatic stellate cells have revolutionised our view of the mechanisms underlying portal hypertension and point to a role for these cells. Activation of hepatic stellate cells is associated with the expression of contractile intracellular proteins such as smooth muscle actin, and activated cells become sensitive to the potent vasoactive substance endothelin. Endothelin concentrations increase after fibrotic liver injury, promoting contraction of hepatic stellate cells. In parallel, injury results in a reduction in nitric oxide derived from hepatic endothelial cells, which antagonises the effect of endothelin (fig 4). The net result of this imbalance is that stellate cell contraction is stimulated, and the consequent increases in intrahepatic sinusoidal resistance contribute to portal hypertension. The observation that this process is dynamic and might be manipulated has led to the exciting concept that effective endothelin antagonism might reduce portal hypertension in cirrhosis.24 Educational resources The August 2001 edition of Seminars in Liver Diseases is devoted to the hepatic stellate cell and reviews of hepatic stellate cell biology. Chapters of particular interest are: Rockey DC. Hepatic blood flow regulation by stellate cells in normal and injured liver. (pp 337-50) Schuppan D, Ruehl M, Somasundaram R, Hahn EG. Matrix as a modulator of hepatic fibrogenesis. (pp 351-72) Benyon RC. Arthur MJP. Extracellular matrix degradation and the role of hepatic stellate cells. (pp 373-84) Pinzani M, Marra, F. Cytokine receptors and signalling in hepatic stellate cells. (pp 397-416) Maher JJ. Interactions between hepatic stellate cells and the immune system. (pp 417-26) Iredale JP. Hepatic stellate cell behaviour during resolution of liver injury. (pp 427-37) Design of anti-fibrotic treatments: Bataller R, Brenner DA. Hepatic stellate cells as a target for the treatment of liver fibrosis. Seminars in Liver Disease 2001;21: 437-51. Murphy F, Arthur M, Iredale J. Developing strategies for liver fibrosis treatment. Expert Opin Investig Drugs 2002;11: 1575-85. Friedman SL. Liver fibrosis-from bench to bedside. J Hepatol 2003;38(suppl): S38-53. For information on the incidence and epidemiology of liver disease, the addresses of patient support groups, and information for patients: British Liver Trust (www.britishlivertrust.org.uk) Children's Liver Disease Foundation (http://childliverdisease.org) Serum markers of fibrosis At present, the clinical assessment of antifibrotic interventions relies on serial liver biopsies. Liver biopsy remains associated with a (small) morbidity and mortality, and even though effective fibrosis scoring systems have been introduced, liver biopsy is prone to sampling error. It may not be an appropriate way of monitoring in a dynamic situation such as a clinical trial of an antifibrotic agent. A further likely development is the identification of a panel of serum fibrosis markers which can be used to predict the stage of fibrosis and monitor disease progression or resolution without recourse to repeated liver biopsies.25 The future In future, patients with cirrhosis are likely to be treated simultaneously with a targeted anti-inflammatory agent, an agent to lower portal pressure, and an antifibrotic or fibrolytic agent, and the effectiveness of the treatment may well be monitored by using a panel of serum markers. The development of effective targeted treatments and the tools to monitor their effectiveness non-invasively will change the way we view and treat cirrhosis. ------------------------------------------------------------------------------- I gratefully acknowledge the support of the MRC(UK), the Wellcome Trust, the British Liver Trust, the Children's Liver Disease Foundation, and the Wessex Medical Trust and thank Christothea Constandinou, Catriona J Gunn, and Chris Shepherd for their help in compiling the manuscript. Competing interests: JPI has received research grant funding from Bayer AG. References http://bmj.com/cgi/content/full/327/7407/143?etoc

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