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Learning About Liver Fibrosis

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What is Fibrosis / Cirrhosis?

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Fibrosis and Cirrhosis

Is liver fibrosis reversible?

Rate of Hepatitis C Liver Disease May Be More Rapid Than Previously Indicated

How Is the 'Fibrosis Rate' Determined?

FIBROSIS AND DISEASE PROGRESSION

LabCorp® Announces U.S. Launch Of Exclusive Liver Fibrosis Assay HCV Fibrosure™

A new non-invasive approach to help detect liver fibrosis

A new type of MRI of the liver developed at Mayo Clinic called MRE can reduce the need for liver biopsy in some patients with liver disease. Dr. Jayant Talwalkar, a hepatologist from the Mayo Clinic, discusses the types of patients that may benefit from this scan and how it may decrease the need for liver biopsy.

http://www.videomd.com/featured_video_category.aspx?cid=27

 

 

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Fibrosis and Cirrhosis

In a biopsy report, what does Stage mean, and what does Grade mean ?

“Stage” is the amount of fibrosis (scaring) detectable by biopsy…from stage one (mild) to four (cirrhosis). “Grade” is the amount of inflammation, which is caused by the activity of the virus. Generally speaking, inflammation is the precursor to fibrosis.

There is some emerging research indicating that both fibrosis and inflammation can in some cases be halted and even reversed with treatment.

 

As the hepatitis C virus affects the patient's liver, liver tissue is damaged. Two histological stages of chronic liver disease are fibrosis and cirrhosis.

Fibrosis is seen as scar formation in the patient's liver. The scars occur as the liver tries to repair damaged tissue. Cirrhosis is a condition where the liver becomes permanently scarred. Cirrhosis interferes with normal liver function, and many times, the patient is symptomatic.

Fibrosis is an accumulation of fibrous tissue resulting from an imbalance between several types of liver cells. As liver cell structures change, the function of the liver is altered. Fibrosis is common to several chronic liver diseases, as it is a sign of hepatic injury. A diagnosis of fibrosis is usually determined with a liver biopsy. The clinical feature that is most apparent with fibrosis is portal hypertension.

There is a spectrum of liver injury seen. Necrosis indicates that liver cells have been damaged and died. If there is substantial damage one may see scar tissue forming to replace the dead liver cells. The term for this finding is fibrosis. If there is really a lot of liver damage, these scars may alter the structure of the liver forming nodules. This severe form of fibrosis is called cirrhosis. It is often difficult to tell by clinical parameters how much fibrosis exists in a liver.

When the liver becomes permanently injured and scarred, the condition is called cirrhosis. This chronic (long-term) disease results from slow deterioration of the liver. Damage to the structure of the liver causes the flow of blood to be blocked and slows liver function so that the liver cannot regulate the content of the blood and process nutrients, hormones, drugs, and toxins (harmful substances) as well as it normally would.

Liver Fibrosis
by V. J. Smith, RN, BSN, MA	Article Date: 2/26/2004

Gut 2000;46:443-446 ( April )
 

Is liver fibrosis reversible?

Introduction

Liver fibrosis and cirrhosis result from the majority of chronic liver insults and represent a common and difficult clinical challenge of worldwide importance. At present, the only curative treatment for end stage cirrhosis is transplantation, but even in the developed world, the number of donor organs available and the clinical condition of the potential recipient limit the applicability of this technique. The alternative clinical course is one familiar to gastroenterologiststhat of a progressive damage limitation exercise in which the complications of fibrosis and cirrhosis are treated with greater or lesser success. The development of fibrosis, and particularly cirrhosis, is associated with a significant morbidity and mortality. Thus, there is a considerable imperative to develop antifibrotic strategies that are applicable to liver fibrosis. Such an approach is attractive precisely because it is aimed at the final common pathological pathway of chronic liver disease, regardless of aetiology. However, because fibrotic liver disease may not present clinically until an advanced or cirrhotic stage, the possibility of reversing the fibrosis is an essential issue for developing therapeutic approaches.

 

Liver fibrosis represents the wound healing response of the liver, as such it demonstrates generic aspects that characterise tissue healing elsewhere in the body  a wound healing response that is dynamic and has the potential to resolve without persistent scarring. This may seem at odds with the clinical impression that advanced fibrosis and cirrhosis are at best irreversible and at worst progressive. However, recent developments in our understanding of the process of hepatic fibrogenesis confirm that the process is dynamic with respect to both cell and extracellular matrix (ECM) turnover and suggest that a capacity for recovery from advanced cirrhosis and fibrosis is possible. Moreover, with the advent of effective antiviral therapies, biopsy documented examples of improvements in fibrosis and in some examples resolution, including that of cirrhotic change, are accumulating in the literature.^1-4 To utilise these observations and establish the attributes required of an effective antifibrotic therapy, we need to understand the nature and origin of the fibrotic ECM, the methods by which the ECM is degraded and the essential processes which occur when fibrosis undergoes recovery with restoration of the normal liver architecture.

Nature and origin of fibrosis

 

Development of liver fibrosis entails major alterations in the both quantity and quality of hepatic ECM and there is overwhelming evidence that activated hepatic stellate cells (HSC, Ito, fat storing cell, or lipocyte) are the major producers of the fibrotic neomatrix.^5 6 Hepatic stellate cells reside in the space of Disse and in normal liver are the major storage sites of vitamin A, stored in the cytoplasm as retinyl esters. Following chronic liver injury, HSC proliferate, lose their vitamin A and undergo a major phenotypical transformation to smooth muscle -actin positive myofibroblasts (activated HSC) which produce a wide variety of collagenous and non-collagenous ECM proteins. Cirrhotic liver contains approximately six times more ECM overall than normal liver, and in the space of Disse collagen types III and V and fibronectin accumulate in early injury.⁷ In chronic injury here is increasing deposition of collagen types I and IV, undulin, elastin, and laminin.⁸ Hyaluronan, normally a minor component of the space of Disse, is increased more than eightfold⁹ and dermatan and chondroitin sulphate and heparan sulphate proteoglycans also increase. Although collagen types I, III, and IV are all increased, type I increases most and its ratio to types III and IV therefore increases.^7 10-12 Culture studies have suggested that the neomatrix laid down in the space of Disse may itself contribute to the disease associated alterations in the phenotype of HSC, sinusoidal endothelial cells, and hepatocytes.^13-16 With progressive injury ECM spurs link the vascular structures, ultimately resulting in the architecturally abnormal nodules that characterise cirrhosis.

 

Complete recovery from liver fibrosis would involve remodeling and breakdown of these multiple ECM components, with degradation of the predominant component, collagen I, being particularly important for recovery of normal liver histology. At present, the identities of the enzyme(s) that degrade the fibrillar collagens (collagens I and III) in the liver are unclear. The matrix metalloproteinases (MMP), a family of zinc dependent endoproteinases, have the capability to degrade these various ECM components and are expressed particularly by HSCs and Kupffer cells.¹⁷ The first discovered and best characterised interstitial collagenase in humans is MMP-1, which is widely expressed in human tissues including liver, but other human interstitial collagenases with a more limited cell expression include neutrophil collagenase (MMP-8) and collagenase 3 (MMP-13). The enzymes MMP-2 and MMP-14 have also recently been ascribed interstitial collagenolytic activity.^18 19 However, studies in animal models and human liver fibrosis indicate that interstitial collagenolytic activity decreases in liver extracts in advanced fibrosis,^20-24 which would promote net collagen deposition. There is increasing evidence that collagenase inhibition may arise from increased expression in fibrotic liver of endogenous MMP inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Expression of both TIMP-1 and -2 is increased in human and rat model fibrotic liver^25-31 and in human liver the degree of TIMP-1 expression correlates with extent of fibrosis²⁵ assessed by hydroxyproline content. Studies by our group and others^{25 27 31-33} indicate that activated HSC may be an important source of these TIMPs in injured liver. In rat models of liver fibrosis, TIMP-1 is expressed early in fibrogenesis before apparent collagen deposition.²⁶ In contrast to the TIMPs, mRNA for interstitial collagenase (MMP-1 in humans, MMP-13 in rats) remains unaltered in human and rat liver as fibrosis develops.^25 26 34 The resulting increase in TIMP:MMP ratio in liver may promote fibrosis by protecting deposited ECM from degradation by MMPs. However, other MMP inhibitory mechanisms might contribute to fibrosis. MMPs are released as inactive pro-enzymes, and an important regulatory step involves cleavage of the inhibitory N-terminal peptide to confer enzymatic activity.³⁵ The means of proenzyme activation varies between different MMPs, but the protease plasmin is required for efficient activation of proMMP-1.³⁶ Activated HSC may however inhibit plasmin synthesis in fibrotic liver through synthesis of plasminogen activator inhibitor-1 (PAI-1).^37 38 Plasmin may have an important antifibrotic role, as studies of fibrosis in lung and kidney utilising PAI-1 and urokinase plasminogen activator knockout mice suggest that an increased PAI-1:urokinase ratio in tissues promotes fibrogenesis.³⁹ In summary, activated HSC might produce a fibrogenic environment within the liver through a combination of ECM overproduction, diminished MMP activation and inhibition of active MMPs by TIMPs. The removal or inactivation of activated HSC from the liver is therefore likely to be a key process before recovery from fibrosis can occur.

Resolution of fibrosis

In clinical circumstances where an effective treatment for the underlying insult is available, remodeling of the scar tissue can occur and a return towards architectural normality has been documented even in advanced fibrosis and cirrhosis. This has been most clearly documented in autoimmune disease, but is paralleled by observations of haemochromatotic patients after venesection and patients with hepatitis B and C after successful interferon therapy.^1-4 These observations are highly encouraging and suggest that the liver has a capacity to remodel scar tissue which, if harnessed and manipulated, would offer a novel therapeutic approach to the treatment of liver fibrosis. It is difficult, if not impossible to follow the cellular mechanisms mediating recovery in humans, as ethical considerations prevent serial biopsy samples from being taken from patients with liver disease and fibrosis which seems to be resolving clinically. However, recovery from fibrosis has been studied in rat models, which permit frequent sampling and control over the chronology and extent of the fibrotic lesion. Abdel-Aziz and colleagues⁴⁰ examined reversibility of fibrosis in experimentally induced cholestasis in rats. Following bile duct ligation for three weeks, the typical features of bile duct proliferation and periportal fibrosis developed with a notable increase in hepatic mRNA for collagens I and IV. However, three weeks after relief of bile duct ligation (by reanastamosis of the bile duct to a jejunal loop), there was resorption of periportal fibrosis and the liver ECM returned virtually to normal, except for a persistence of collagen IV in sinusoids. Moreover mRNAs for collagen I and IV became virtually undetectable. We have recently examined spontaneous recovery from liver fibrosis in carbon tetrachloride treated rats.⁴¹ Rats treated for four weeks with intraperitoneal carbon tetrachloride developed established liver fibrosis with extensive intervascular bridging with collagen fibres. Carbon tetrachloride dosing then stopped and livers were examined at various times up to four weeks of recovery. After this time, histological analysis showed a noticeable dissolution of the collagenous fibrotic matrix and a return of liver structure to virtual normality. The hepatic mRNA content of TIMP-1 and -2 and procollagen I all dropped greatly in livers the first week of recovery which coincided with the most rapid phase of collagen degradation, as assessed by hydroxyproline content. A key finding was that interstitial collagenase activity increased in the liver homogenates during this time. The data support the hypothesis that TIMPs play a predominant role in regulating fibrosis by protecting fibrotic ECM from degradation by collagenase and possibly other MMPs. Another important observation was that there was prominent apoptosis of activated HSC during recovery, particularly in the first three days concomitant with the largest drop in hepatic TIMP and procollagen I mRNA. Apoptosis therefore effectively removed the activated HSC, which were overproducing ECM and TIMPs. This mechanism may also effect removal of "professional" ECM producing cells in other organs during wound healing and resolution of fibrosis. For example, Baker and colleagues⁴² showed that apoptosis removed surplus mesangial cells from glomeruli during resolution of mesangial proliferative nephritis and apoptosis also removes myofibroblasts during skin wound healing.^43 44 Our more recent studies suggest that during progressive fibrotic liver injury both HSC mitosis and apoptosis increasethat is, turnover of these cells is increased, although proliferation predominates such that there is net increase in HSC numbers. During recovery, apoptosis becomes the overriding process with resulting net HSC loss from the liver.

There are relatively few studies of how apoptosis of HSC is controlled in the liver. HSC activated in culture undergo spontaneous apoptosis in vitro, which can be greatly increased by serum deprivation and fas ligand.^41 45 46 Our recent studies show that a further cytokine present in injured liver, nerve growth factor, induces HSC apoptosis in culture. Mast cells, which become more abundant in fibrotic liver, are a rich source of nerve growth factor.⁴⁷ The proapoptotic receptor fas and its ligand are also expressed by activated HSC.⁴⁵ It is possible that persistence of HSC in fibrotic liver might therefore require undefined survival factors to offset the effects of these apoptotic stimuli, and removal of survival factors when liver injury ceases would then allow relatively rapid removal of HSC. Apoptotic signals in the liver might not be confined to soluble factors and the fibrotic neomatrix itself might render activated HSC susceptible to apoptosis. The role of cell-matrix interactions in regulating cell survival has most extensively been studied in epithelial cells in which absolute deprivation of contact with the ECM is a potent proapoptotic mechanism, a process that has been termed anoikis.⁴⁸ A recent study has shown that blocking HSC attachment to plastic induces apoptosis,⁴⁹ whereas data from our laboratory show that HSC cultured on plastic or collagen I are more susceptible to apoptosis induced by serum deprivation than HSC cultured on Matrigel, a basement membrane-like matrix which reduces HSC proliferation and activation. These final data raise the interesting idea that ECM degradation may result in HSC apoptosis rather than HSC apoptosis facilitating ECM degradation.

Although liver fibrosis in rats is reversible, the implications for recovery from cirrhosis in humans remain to be clarified. In our studies⁴¹ and those of Abdel-Aziz and coworkers,⁴⁰ liver cirrhosis had not been achieved before recovery was initiated. Clearly a key question which can be tackled using rat models is: does liver fibrosis reach a point where it becomes irreversible, and if so what are the qualitative and quantitative differences in the liver structure compared with recoverable fibrosis? Several factors might dictate whether liver fibrosis can recover. Firstly, it is clear that recovery requires degradation of the existing ibrotic matrix, but this matrix may be modified to resist degradation as fibrosis progresses. Newly secreted collagen fibrils can be cross-linked by both tissue transglutaminase and lysyl oxidase pathways; the activity of both pathways is increased during liver fibrogenesis.^50-52 Such cross-linking during maturation of collagen might reduce its susceptibility to collagenase.⁵³ A recent report also suggests that tissue transglutaminase can be released onto ECM from apoptotic hepatocytes which are found in increased numbers in fibrotic liver.⁵⁴ Mature ECM is also relatively rich in elastin; to date there are very limited data on the turnover of this important matrix protein in fibrosis. Secondly, recovery is unlikely if collagenolytic enzymes remain inactive following cessation of liver injury. The full range of enzymes having interstitial collagenase activities in liver still require identification. However, interstitial collagenase mRNA expression (MMP-1 in humans, MMP-13 in rats) is similar in normal compared with cirrhotic livers, and does not change during recovery in the rat model, even in the face of overt ECM degradation.^25 26 41 Previous studies suggest that collagenase activity becomes deficient during evolution of liver fibrosis in animal models and in humans,^20-24 and the studies described earlier suggest that this may be caused by TIMP overexpression. Continued inhibition of ECM degradation by TIMPs may block the ability to recover from fibrosis, even after removal of the injury. As activated hepatic stellate cells are an important source of both ECM and TIMPs, recovery from fibrosis might require either removal of the activated HSC population, as shown in rat models, or possibly the phenotypical reversal of stellate cell activation, a process yet to be observed in vivo. In non-recovering liver fibrosis activated HSC might persist as a result of a "memory" effect, possibly mediated by collagenous and non-collagenous components of the deposited fibrotic neomatrix, which either promote HSC activation or protect them from apoptotic stimuli.^{16 48 49 55}

In summary, accumulating evidence suggests that liver fibrosis is reversible and that recovery from cirrhosis may be possible. Moreover, the application of cell and molecular techniques to models of reversible fibrosis are helping to establish the events and processes that are critical to recovery. It is anticipated that ultimately these approaches will lead to the development of effective antifibrotics, which harness or mimic the liver's capacity for reversal of fibrosis with resolution to a normal architecture.

Acknowledgments

 

JPI gratefully acknowledges the support of the Medical Research Council. JPI and RCB are in receipt of grant funding from the Wessex Medical Trust and Bayer AG.

R C BENYON J P IREDALE
Liver Fibrosis Group, Division of Cell and Molecular Medicine, Southampton University, Mail point 811, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK

 

Correspondence to: Dr Iredale (email jpi@soton.ac.uk)

 

Footnotes

Leading articles express the views of the author and not those of the editor and editorial board.

Abbreviations

Abbreviations used in this article:
ECM, extracellular matrix; HSC, hepatic stellate cell; MMP, metalloproteinase; PAI, plasminogen activator inhibitor; TIMP, tissue inhibitor of metalloproteinases.

References

 

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© 2000 by Gut

Rate of Hepatitis C Liver Disease May Be More Rapid Than Previously Indicated

By Brian Boyle, MD

http://www.hivandhepatitis.com/hep_c/news/052301a.html

The rate of progression of liver disease caused by hepatitis C virus (HCV) infection varies remarkably from person-to-person and from study-to-study.

Studies evaluating the natural history of HCV have reported rates of progression to cirrhosis from 2% to 20% over 20 years of infection. To provide more information regarding the natural course of HIV infection, researchers evaluated the clinical, biochemical and histological manifestations of liver disease in HCV patients presenting to primary care clinics in the University of Michigan health system.

The investigators reviewed the medical records of 229 adult, HVC antibody positive patients who were seen at he University of Michigan between January 1998 and December, 1999. Of these patients, 56% were men, 77% were Caucasian and the mean age was 44 years. The identifiable risk factors for HCV infection included a previous history of IVDU (25%), transfusion prior to 1992 (11%), and a history of cocaine use, tattoos, occupational exposure or a sexually transmitted disease (18%). At the time of their evaluations, none of the patients had symptoms or signs of hepatic decompensation.

The investigators found that 192 of the 229 patients had been tested for HCV RNA and that of those patients tested 78% were positive. They found no correlation between having a positive HCV RNA and the gender, age or race of the patient or the risk factor for HCV infection. Of the HCV RNA positive patients, 73% had an elevated ALT, 19% had a normal ALT, and 8% were not tested. Among the 43 patients who were HCV RNA negative, 14% had elevated and 61% had normal ALT levels, and 25% were not tested. Of the 37 patients not tested for HCV RNA, 76% had elevated and 24% had normal ALT.

Of the patients involved in this study, 57% were evaluated in a gastroenterology/liver clinic. Of the 109 patients who were HCV RNA positive with elevated ALT, 43% underwent liver biopsy, revealing no fibrosis in 12, minimal/portal fibrosis in 14, septate/bridging fibrosis in 12, cirrhosis in 8 and hepatocellular carcinoma in 1. Among the 40 patients who were HCV RNA positive with normal ALT, 25% underwent liver biopsy, showing no fibrosis in 5, minimal/portal fibrosis in 3, septate/bridging fibrosis in 1, and cirrhosis in 1. The mean age of the 27 patients found to have septate/bridging fibrosis or cirrhosis on liver biopsy was 44.6 years compared to 41.5 years for patients with no or minimal portal fibrosis (p<0.05).

The authors conclude, "The majority (78%) of anti-HCV positive patients presenting to primary care clinics were viremic, 70% had elevated ALT and 47% of those
biopsied had significant fibrosis/cirrhosis. Overall, the spectrum of HCV related liver disease seen in primary care clinics appears to be more severe than expected." This conclusion, and the fact that many patients that had an indication for liver biopsy did not obtain one, should be of concern to clinicians treating HCV. Now that more effective and better tolerated treatments for HCV are available, increased vigilance for HCV and the pursuit of appropriate diagnostic evaluations may improve the management and outcomes of this insidious disease.

5/23/01

Reference
T Shehab and others. Spectrum of liver disease in hepatitis C patients presenting to primary care clinics. Abstract 1881. Digestive Disease Week 2001. May 20-23, 2001. Atlanta, Georgia.

How Is the 'Fibrosis Rate' Determined?

Dr. Thierry Poynard

The Fibrosis Progression Model

In dealing with patients with HCV infections, predicting the future is both
crucial and difficult. Patients want to know whether they will have months,
years, or decades before developing complications: clinicians want to know
whether a given patient should be treated now, soon, or never.

A valuable tool for helping with these decisions was described by Dr.
Thierry Poynard, an eminent French researcher. The fibrosis progression
model relies on the degree of fibrosis, quantitated using the METAVIR scale,
to estimate a patient's chance of progression. The METAVIR scale, which
grades fibrosis from F0 (no fibrosis) to F4 (cirrhosis), is a widely used
scale that has excellent interobserver reliability.

Three methods have been described for assessing the rate of progression of
fibrosis: observation, estimation, and simulation. Observed rates are the
most straightforward, as they are based on two biopsies performed several
years apart in the same patient. The calculation is simply the second F
stage minus the first, divided by the number of years between the two
biopsies. The observed rate is easy to understand, but this method has
several shortcomings. Often the time between biopsies is short, compared
with the mean time of transition between fibrosis stages, seven years.
Sampling error, and interpretation error, are important issues. As well,
many patients do not want a second biopsy.

An estimated rate can be calculated by dividing the current fibrosis stage
by the number of years since infection. This method requires just one
biopsy, but has the disadvantage that at least 40% of patients do not know
when their infection was acquired. This method also assumes that patients
had no fibrosis at the time of infection, which may not always be true.

The third method of examining the rate of fibrosis progression, simulation,
does not require biopsy. Instead, a regression function is used to suggest a
rate, based on age, duration of infection, gender, and alcohol intake, all
of which are major factors predicting progression. The simulated model has
the advantage of not subjecting patients to biopsy, but is very reliant on
underlying assumptions that only explain 30% of the variance in fibrosis
progression.

Figure 7 shows the widely disparate rates of fibrosis progression that were
found in a large study by Dr. Poynard, based on gender, age, and alcohol
intake.11 The figure shows time from infection to cirrhosis ranging from
less than 20 years, to more than 50 years.

Several other factors that have an impact on fibrosis progression can be
examined. For instance, progression is obviously much faster in
HIV-coinfected patients, with a marked increase in progression rates in
patients with CD4 counts less than 200 µcells/L.

Some patients with established disease still have normal ALT levels. These
patients, when compared with other patients with high ALT, matched for age
at infection, age at biopsy, gender, and alcohol intake, have much lower
progression rates.

An exciting and clinically relevant point made by

Dr. Poynard was that antiviral treatment with interferon alfa-2b and
ribavirin causes regression of fibrosis (that is, a negative progression
rate) in responders. Recently published data show that even nonresponders
have lower rates of fibrosis than controls.12 Given the crucial importance
of fibrosis as a predictor of cirrhosis and death, this information suggests
even more strongly that combination therapy with interferon alfa-2b and
ribavirin will benefit patients with hepatitis C infections. The Influence
of Host Factors on the Outcome of HCV Infections

Clinicians treating patients with hepatitis C viral infections are well
aware of the huge variability in disease progression. Some patients develop
cirrhosis within a decade of infection: others are free of clinical
complications after 30 years. Viral factors, such as genotype, quasispecies,
and viral load, have very little role in the variable clinical progression.
In his lecture, Dr. Gerry Minuk examined the crucial importance of host
factors in disease outcome in hepatitis C.

Many host factors have not been clearly proven, with different researchers
finding conflicting evidence of association. For instance, smoking,
geographic factors, diabetes, HLA phenotypes, and hemochromatosis have all
been suggested as factors affecting outcomes, but remain unproven or
controversial. No controversy exists, however, concerning the three most
important host factors: age, gender, and alcohol intake.

Evidence from many studies, and many countries, confirms that men show more
rapid progression of disease than women, and that faster progression is seen
in patients who acquire their infection at an older age (age > 50).
Excessive alcohol intake is, possibly, the most important single risk
factor - however, Dr. Gerry Minuk presented some new animal data suggesting
that limited alcohol intake may actually increase the rate of hepatic
regeneration, compared with controls.

Four mechanisms can be suggested to explain how a host factor can increase
the rate of progression. These mechanisms are increased viral load,
increased hepatocyte injury, decreased liver regeneration, or increased
liver fibrosis. Table 3 illustrates how these mechanisms relate to the major
host factors, age, gender, and alcohol intake.

The table shows that each of the host factors influences progression through
different combinations of mechanisms. This finding is unfortunate from a
clinical point of view, as it means that on mechanistic grounds, no single
therapeutic breakthrough will provide the answer to slowing progression.
<snipTable 3>: Host Factors: Mechanisms of Increased Disease Progression


The fibrosis (scarring) progression rate (FPR) was measured by using the following formula. The mean baseline liver fibrosis score * (scale of 0-4) was divided by the estimated duration of HCV infection. For example, if someone had a fibrosis score of F2 and had been infected with HCV for 8 years, then the FPR would be 2 / 8 = 0.25 fibrosis units per year.

Then, different patients could be compared in terms of how fast they develop liver disease-this correlates with liver illness symptoms and death from liver disease. This method was first described by one of the report's co-authors, Thierry Poynard, MD in 1997 in the journal Lancet. If there are two liver biopsies in different years, then the fibrosis score used is the score from the first biopsy subtracted from the score on the second biopsy.

Then, that score is divided by the duration of HCV infection. This latter method is considered to be more accurate than the first one with only one biopsy. However, many patients prefer not to have multiple liver biopsies. In the current study, 12 of the HCV/HIV co-infected patients had two liver biopsies.

1/28/00
 

Can Liver Fibrosis Be Reversed? Still A Widely Debated Topic
 

Alan Franciscus
Editor-in-Chief

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Cirrhosis is a result of late stage scarring in chronic liver disease. Cirrhosis occurs as a result of progressive damage to the liver tissue starting with subendothelial or pericentral fibrosis (hepatic fibrosis) and progresses to panlobular fibrosis with nodule formation (cirrhosis). Up until now it has been generally thought that once fibrosis is established it is irreversible. Until recently the clinical diagnosis of cirrhosis was made based upon the signs and symptoms of end stage liver disease. Such symptoms include variceal bleeding, jaundice, ascites, muscle wasting and encephalopathy. Clinically these symptoms continue to indicate a poor prognosis in the absence of liver transplantation and are used to classify severity for patients waiting transplantation. However, due to advances in the management of liver disease and the impact that hepatitis C disease management is having, liver biopsies have led to fibrosis and cirrhosis being diagnosed at an earlier stage. It has been demonstrated in some studies that early stage fibrosis, and even advanced cases of cirrhosis can regress during treatment of hepatitis C even without the benefit of a sustained virological response (SVR) to treatment with interferon.

Basically, treatment gives the liver a vacation or rest from inflammation caused by HCV. Providing that the cirrhosis is not at such an advanced stage that treatment is not an option, treatment is often used to improve the health of the liver even if the disease cannot be eradicated.

In February 2001 issue of the New England Journal of Medicine, Hammel et al discussed a group of patients with liver fibrosis who had surgery to decompress an obstructed biliary system. In this patient population, some patients had their liver fibrosis regress significantly after decompression, which was confirmed by pre and post liver biopsy. Until this publication the natural history of histologic changes after biliary decompression had not been discussed in humans. This study certainly implies that fibrosis caused by biliary obstruction is reversible in some cases, but studies similar to this one need to duplicate results to rule out variations in sampling on liver biopsy. As well, this study was criticized for not having a control arm or strict selection criteria. Regardless of the criticism, the apparent improvement in fibrosis after biliary decompression adds another example to a growing list of specific interventions, which result in histologic improvements including fibrosis regression.

There have been consistent reports on the reversibility of liver fibrosis in humans when the cause of the underlying liver disease is eliminated. These include abstinence from alcohol, surgical reversal of jejunoileal (removal of a portion of the small intestine) bypass, immunosuppressive therapy for autoimmune hepatitis, long term treatment with lamivudine for chronic hepatitis B, treatment of hepatitis C and hepatitis D with interferon and, finally, treatment of primary biliary cirrhosis with methotrexate plus ursodiol.

Over the past decade or so there has been major progress in understanding the cellular and molecular regulation of hepatic fibrosis. It has been determined that the build up of scarring in fibrotic diseases of the liver is not static or a unidirectional event but a dynamic and regulated process that works well with intervention.

The growing amounts of clinical and scientific data provide us with the knowledge that extensive fibrosis or cirrhosis in patients that still have compensated liver function should no longer be considered untreatable. Both currently available as well as future therapies have the potential for preventing the progression of disease by regression of fibrosis.

Despite growing knowledge on whether liver fibrosis is reversible, there are still some unanswered questions. Liver fibrosis does not develop at the same rate in all patients and the fibrotic responses to therapy will vary from patient to patient. What are the host or disease specific factors that are linked to both a slower progression of fibrosis and a positive response to treatment? In addition, should treatment strategies be better designed to reverse fibrosis and improve liver health, rather than to only treat when there’s a good probability of a cure? For example, long-term therapy with alpha interferon may improve fibrosis in patients with chronic hepatitis C even in those patients who do not experience a virologic response. With that finding wouldn’t long-term alpha interferon therapy be well justified in patients that do not gain a virologic response to treatment? It certainly seems to make a case for physicians to partner with patients to make these important treatment decisions.

http://www.hcvadvocate.org/
 

FIBROSIS AND DISEASE PROGRESSION

 

Chronic infection with HCV is associated with the typical histological features of chronic hepatitis including hepatocellular necrosis and inflammation (activity or grade) and fibrosis (stage). While the activity of the chronic liver disease can fluctuate over time, the stage of fibrosis is believed to be progressive and largely irreversible. In chronic hepatitis C, the rate at which fibrosis progresses varies markedly. In some individuals, fibrosis ultimately leads to cirrhosis, which is associated with the major complications of the liver disease: portal hypertension, liver failure, and hepatocellular carcinoma. In others, fibrosis does not appear to progress even after decades of infection. For these reasons, assessment of the stage and rapidity of progression of fibrosis can be helpful in determining the prognosis and the need for therapy in the individual patient. Factors associated with fibrosis progression are not well defined and the role of necroinflammatory activity is still controversial.

Assessment of the Stage of Fibrosis

Liver biopsy remains the gold standard to assess fibrosis. Several systems for scoring liver fibrosis have been proposed, each based upon visual assessment of portal and periportal fibrosis. The more frequently used systems are the Histology Activity Index (HAI: Knodell score), the Ishak modification of the HAI score, and the METAVIR. The HAI scoring system ranges from 0 to 22 and fibrosis is staged as 0, 1, 3, and 4. This discontinous scale was developed to allow for clear separation of mild (1+) from extensive (3+) fibrosis which has important prognostic value. The HAI system is simple and has been widely used, particularly in the large multicenter trials of interferon and ribavirin therapy of chronic hepatitis C. However, the intra- and inter-observer reproducibility of the HAI is not very good and distinction between stages 1 and 3 may be difficult. In addition, its discontinous scale complicates statistical analysis in clinical trials.

The modification of the HAI scoring system proposed by Ishak et al. is more sensitive in assessing fibrosis. Fibrosis stage is scored continuously from 0 to 6, which permits a better assessment of the effect of therapy on fibrosis. The Ishak score is better validated and gives a more accurate assessment of fibrosis. The METAVIR scoring system is simple; fibrosis stages are scored continuously from 0 to 4. This system has been carefully validated in large groups of patients with chronic hepatitis C and has shown good intra- and inter-observer reproducibility. Important limitations of these scoring systems should be emphasized. Hepatic fibrosis may not be homogenous throughout the liver and the liver specimen obtained by needle biopsy may not accurately reflect the overall average degree of fibrosis. The reliability of the assessment of fibrosis stage increases with the size of the liver sample. In most studies, a minimum length of 10 mm is required. Regardless of biopsy length, however, fibrosis may be underestimated and cirrhosis missed in some patients.

Factors Associated With the Stage of Fibrosis

Most cross-sectional studies of large numbers of liver biopsies have shown that the stage of fibrosis is associated with patient age, the age at onset of infection, male sex, a history of heavy alcohol consumption, and the presence of immune deficiency, such as HIV co-infection or immunosuppressive therapy. The mechanisms by which age and sex affect the degree of fibrosis are not known. Alcohol, which by itself can cause liver disease and fibrosis, may worsen fibrosis in hepatitis C at amounts that are not injurious in non-infected persons, but the amount of alcohol beyond which the progression of fibrosis is increased is unknown.

Serum biochemical tests do not reliably predict the stage of fibrosis. Currently available, indirect serum markers of fibrosis are not reliable, particularly in discriminating between mild and moderate degrees of fibrosis. In cross-sectional studies, serum alanine and aspartate aminotransferase (ALT and AST) levels do not correlate well with fibrosis. However, patients with documented, persistently normal ALT levels usually have mild degrees of hepatitis and either no or mild stages of fibrosis. The association between fibrosis stage and the necroinflammatory activity scores on liver biopsy is controversial. Necroinflammatory activity is a dynamic process in chronic hepatitis C and may fluctuate over time. Therefore, the activity score reflects the severity of necrosis and inflammation at a given point.

Factors Associated With Progression of Fibrosis

From retrospective studies and from some prospective studies done in patients infected by blood transfusion at a relatively older age, it is estimated that 20 percent of patients with chronic hepatitis C develop cirrhosis within 20 years of onset. In contrast, studies of cohorts of women who did not drink alcohol and who were infected by Rh immune globulin at a young age indicated that fewer than 5 percent developed cirrhosis within 20 years. These natural history studies validate the importance of age, sex, and alcohol intake in progression of fibrosis. Cross-sectional studies using mathematical modelling performed on cohorts of patients with a single liver biopsy suggest that the average rate of progression of fibrosis in chronic hepatitis C is 0.133 METAVIR points per year. Based on this rate, the estimate is that cirrhosis develops in the average patient after 30 years. The average delay to the development of cirrhosis ranges from 13 years in infected men aged 40 or more years who drink more than 50 g of alcohol to 42 years in infected women under 40 years of age who do not drink alcohol. Furthermore, the progression of fibrosis is probably not linear. For instance, the time required to progress from stage 0 to 2 may be far longer than the time required to progress from stage 3 to 4. Moreover, fibrosis progression may accelerate with age (particularly after the age of 50). Finally, fibrosismay remain mild and stable for decades and may even regress spontaneously in some patients.

The progression of fibrosis is difficult to predict in the individual patient particularly based upon assessment at one point in time.  High serum ALT levels have been associated with more active liver disease and more rapid progression of fibrosis in some prospective studies, which supports the use of monitoring of ALT levels in assessing prognosis and need for therapy. However, the validity of this approach and the level above which the ALT elevations are predictive of more rapid progression is not known. Virological factors such as serum HCV RNA level and HCV genotype are not predictive of fibrosis. Genotype 3 is associated with more liver steatosis than other genotypes, and steatosis itself, as well as other metabolic factors (such as lipid disorders, obesity, insulin resistance, and diabetes) may also predispose to more rapid progression of fibrosis.

Repeat liver biopsy is the only reliable means of assessing the progression of fibrosis and is commonly recommended every 3 to 5 years in untreated patients. A second liver biopsy can distinguish patients with rapidly progressive fibrosis, but may also merely indicate that the initial biopsy underestimated the degree of fibrosis. Overall, the risk of progression of fibrosis of more than one point in a 3 to 5 year period is low. In patients with factors associated with a higher risk of progression such as age beyond 50 years, alcohol consumption, or high serum ALT levels, liver biopsy may be recommended more frequently (2 to 3 years); in contrast, in the younger patient with no other risk factors, liver biopsies may be performed less frequently (every 5 to 6 years).
 

 

Alternatives to a biopsy: non-invasive biomarkers of liver disease

New research is looking at whether results from laboratory tests can be used in place of a biopsy. This could easily change the way that hepatitis C (HCV) is managed in the future.

Studies using combinations of these lab results suggest they are useful for identifying serious liver damage, but it remains controversial whether they are a reliable substitute for a liver biopsy.

Battle of the New, Non-invasive Measures of Fibrosis: FibroScan versus FibroTest

New Index for Assessing Liver Fibrosis

Predicting the degree of hepatic fibrosis through blood tests.
06/28/2002

Hepatic fibrogenesis (scar tissue formation) occurs in response to liver injury. It represents the body's attempt at healing the damaged liver. With recurrent bouts of inflammation, the liver's normal architecture can be replaced by fibrous scar tissue, ultimately resulting in the advanced liver disease known as cirrhosis. The only proven method for assessing hepatic fibrosis is liver biopsy. The procedure is usually safe but on rare occasions significant complications, such as massive bleeding and even death can occur. In addition, some clinicians believe that since liver biopsies sample only 1/50,000 of the entire liver mass, sampling errors are bound to occur. As a result, researchers have begun to look at non-invasive ways of estimating the degree of liver fibrosis.

One avenue that has received some attention is the estimation of serum levels of the break down products of scar tissue, known as the "extracellular matrix." The rationale is that since there is extensive deposition of fibrous tissue, serum levels of the constituents of fibrous tissue will increase as a result of remodeling and recurrent scarring. Thus, components of the extracellular matrix such as laminin, hyaluronic acid, collagen VI and many of their breakdown products are under investigation. The limitations have been that no single component appears to be adequate for estimating fibrosis. But a combination of these molecules in a single assay may yet yield valuable information on fibrosis.

A second approach looks at markers that are not components of scar tissue but are biochemical markers often used to gauge the functional ability of the liver. As in the case of extracellular matrix components, no single biochemical marker appears to approach the accuracy of liver biopsy. In one study, performed on patients infected with chronic hepatitis C, researchers found that evaluation using a combination of biochemical markers (alpha2 macroglobulin, haptoglobulin, GGT, gamma-globulin, total bilirubin and apolipoprotein A) compared favorably with liver biopsies in predicting fibrosis. These observations are in their infancy and extensive research needs to be done to corroborate the early findings. Regardless, there is optimism that serum evaluation may some day replace liver biopsies in most cases where the desire is only to evaluate the degree of hepatic scarring.

References:

Imbert-Bismut F et al.(2001). Biochemical markers of liver fibrosis in patients with hepatitis C infection: a prospective study. Lancet; 357:1069-1074

Alabanis E and Friedman SL. (2001). Hepatic fibrosis: pathogenesis and principles of therapy. Clin Liver Dis;5:315-334.

Hayasaka A and Saisho H. (1998). Serum markers as tools to monitor liver fibrosis. Digestion; 59:381-384  
 

By: Chinweike Ukomadu, M.D., Ph.D.

http://www.veritasmedicine.com/d_home.cfm?type=WU&did=7&cid=72576

Prometheus Laboratories Introduces FIBROSpect(SM) II

1/20/2004 @ 4:32 PM

Prometheus Laboratories Inc., a specialty pharmaceutical company, announced today the introduction of FIBROSpect II, a unique non-invasive diagnostic panel to aid in the detection of liver fibrosis in patients with chronic hepatitis C. This simple blood test helps physicians differentiate the presence of no/mild from significant liver fibrosis without the pain, anxiety and risk associated with liver biopsy.        "In chronic hepatitis C infection, liver biopsy has been the favored approach to evaluate the extent of liver fibrosis and help guide treatment decisions; however, it is expensive, associated with possible complications, and limited by sampling error and observer variability," stated Dr. F. Fred Poordad, Associate Director, Hepatology and Liver Transplant at Cedars Sinai Medical Center. "Non-invasive methods to aid in assessing liver disease severity, such as FIBROSpect II, provide additional diagnostic options."        FIBROSpect II, an enhanced version of the original FIBROSpect test, eliminates indeterminate test results that were occasionally reported with the first generation test, and improves the ability to accurately differentiate patients with and without significant liver fibrosis. FIBROSpect II is based on three extracellular matrix remodeling proteins utilizing a new algorithm and unique index, thereby providing physicians with even more clinically useful information.        According to the most recent estimates by the Centers for Disease Control and Prevention, 3.9 million people are currently infected with hepatitis C in the U.S., with 2.7 million being chronically infected. Worldwide, over 170 million are infected. Chronic hepatitis C varies in its cause and outcome. At one end of the spectrum are patients who have no sign of liver disease and for whom the overall prognosis may be good. At the other end of the spectrum are patients with chronic hepatitis C and advanced fibrosis that may ultimately develop end-stage liver disease. The major consequence of liver disease is the progression to fibrosis and cirrhosis, which can lead to liver cancer or the need for a liver transplant. Therefore, early and accurate diagnoses and staging are critical for proper patient management.        Prometheus Laboratories Inc. is a specialty pharmaceutical company committed to developing new ways to help physicians individualize patient care. The Company focuses on the treatment, diagnosis and detection of gastrointestinal, autoimmune and inflammatory diseases and disorders. The Company's strategy includes the marketing and delivery of pharmaceutical products complemented by its proprietary, high-value diagnostic testing services. By integrating these therapeutic, diagnostic and treatment monitoring services, Prometheus addresses the full continuum of care, thereby providing physicians with a comprehensive solution to treat chronic diseases. Prometheus' corporate offices are located in San Diego, California. Additional information about Prometheus Laboratories Inc. can be found at www.prometheuslabs.com .   A new non-invasive approach to help detect liver fibrosis FIBROSpect provides non-invasive serodiagnostic information to aid in diagnostic triage. Aids in evaluating liver fibrosis without biopsy-associated limitations.59,60,61 Sampling error Patient discomfort Interpretation subjectivity Morbidity and mortality May be useful when biopsy is contraindicated. May aid in counseling patients on biopsy considerations. Detect the difference with FIBROSpect   Helps to distinguish no/mild fibrosis (METAVIR F0-F1) from significant fibrosis (METAVIR F2-F4).62 Assists in treatment decisions for patients with hepatitis C. Click here to review supporting publications. Disclaimer: Prometheus Laboratories diagnostic services provide important information to aid in the diagnosis and management of certain diseases and conditions. How this information is used to guide patient care is the responsibility of the physician. The performance characteristics of FIBROSpect were established in a study population of 294 patients with a 52% prevalence of liver fibrosis, METAVIR F2-F4. Overall sensitivity and specificity were 72% and 95%, respectively, with an indeterminate rate of 32%. Predictive values for negative results (NPV), positive results (PPV), test accuracy, and projected indeterminate rates are modeled for a 5-60% prevalence of liver fibrosis, METAVIR F2-F4.    LabCorp® Announces U.S. Launch Of Exclusive Liver Fibrosis Assay HCV Fibrosure™ Noninvasive Blood Test Provides Alternative to Liver Biopsy for Assessing Status of Hepatitis C Patients Burlington, NC, March 17, 2004 - Laboratory Corporation of America® Holdings (LabCorp®) (NYSE: LH) today announced the availability of HCV FIBROSURE™, a noninvasive blood test for assessing liver status in hepatitis C virus (HCV) patients. Developed by leading hepatologists at the Pitie-Salpetriere Hospital and BioPredictive in France, HCV FIBROSURE™ is only available in the United States through LabCorp. HCV FIBROSURE™ provides an easily accessible alternative to liver biopsy, which physicians use to assess liver fibrosis and necroinflammatory activity in HCV patients. While liver biopsy has long been considered the gold standard to monitor the status of HCV and determine therapy options, it is an invasive procedure that carries a risk of serious complications. HCV FIBROSURE™ uses a combination of six serum biochemical markers plus age and gender in a patented algorithm to determine the degree of liver fibrosis and the level of ongoing necroinflammatory activity. The test, which has been clinically available in Europe for the past two years, has been shown in several studies to enable quantitative, reproducible assessment of fibrogenic and necrotic activity in the liver of HCV patients. "The launch of this important new test once again validates LabCorp's strategy of creating a world-class national laboratory with the best and broadest array of diagnostic testing services," said Myla P. Lai-Goldman, M.D., executive vice president, chief scientific officer and medical director at LabCorp. "Our focus on bringing forth innovative new technologies and tests, coupled with our scientific expertise and national scope, helps us broadly deliver vital new tools like BioPredictive's liver fibrosis assay to U.S. physicians managing HCV patients." BioPredictive is currently researching clinical use of this test for other disease populations, including hepatitis B, HIV-HCV, and alcoholic and non-alcoholic steato hepatitis (NASH). "We anticipate that HCV FIBROSURE™ will prove to be just the first in a family of innovative, noninvasive diagnostic testing products aimed at hepatitis and non-hepatitis-related conditions," said Dr. Thierry Poynard, a world-renowned hepatologist, head of Hepato-Gastrotroenterology department in Pitie-Salpetriere Hospital in Paris, and researcher and founder of BioPredictive. "We look forward to continuing our relationship with LabCorp and building upon their expertise in the world of hepatitis testing for future products." HCV FIBROSURE™ is recommended for use to assess liver status following a diagnosis of HCV, as a baseline determination of liver status before initiating HCV therapy, as post-treatment assessment of liver status six months after therapy completion, and for noninvasive assessment of liver status in patients at risk of complications from a liver biopsy. The blood sample for HCV FIBROSURE™ can be collected in minutes and results can be returned to the physician within days. The test uses six biochemical markers that are routine and considered standard of care in the United States. About BioPredictive Founded at Paris University in 2002, BioPredictive is focused on the study, design and development of medically important biological tests. At the center of the company's scientific efforts is the desire to improve disease management by replacing invasive strategies with noninvasive alternatives. BioPredictive has developed two noninvasive tests for chronic liver disease - FibroTest and ActiTest. FibroTest is a biochemical marker of liver fibrosis and ActiTest is a biochemical marker of inflammation and necrosis of the liver. BioPredictive licenses the FibroTest and ActiTest technology from Assistance Public-HTMpitaux de Paris (AP-HP). The company performs more than 2,000 tests per month, and services 150 private and 12 public hospital laboratories in France, Switzerland, Portugal, Morocco and Mexico. To learn more about BioPredictive, visit the company Web site at: www.BioPredictive.com. FibroTest and ActiTest are available in the U.S. exclusively through Laboratory Corporation of America® Holdings (LabCorp) under the name HCV FIBROSURE™. About LabCorp Laboratory Corporation of America® Holdings is a pioneer in commercializing new diagnostic technologies and the first in its industry to embrace genomic testing. With annual revenues of $2.9 billion in 2003, approximately 23,000 employees nationwide, and more than 220,000 clients, LabCorp offers over 4,400 clinical assays ranging from blood analyses to HIV and genomic testing. LabCorp combines its expertise in innovative clinical testing technology with its Centers of Excellence: The Center for Molecular Biology and Pathology, in Research Triangle Park, NC; National Genetics Institute, Inc. in Los Angeles, CA; ViroMed Laboratories, Inc. based in Minneapolis, MN; The Center for Esoteric Testing in Burlington, NC; and DIANON Systems, Inc. based in Stratford, CT. LabCorp clients include physicians, government agencies, managed care organizations, hospitals, clinical labs, and pharmaceutical companies. To learn more about our growing organization, visit our Web site at: www.LabCorp.com. Each of the above forward-looking statements is subject to change based on various important factors, including without limitation, competitive actions in the marketplace and adverse actions of governmental and other third-party payors. Actual results could differ materially from those suggested by these forward-looking statements. Further information on potential factors that could affect LabCorp's financial results is included in the Company's Form 10-K for the year ended December 31, 2003, and subsequent SEC filings.