Fibrosis of the Liver: A Commonly Used Term with
Great Misunderstanding for the Patient
Joseph S. Galati, M.D.
Liver Specialists of
A day does not go by where I find myself sitting with a patient explaining what fibrosis of the liver is. In most situations, patients have a hint of what fibrosis is, but they are unfamiliar with the other words that can be substituted for fibrosis, which might include scarring, scar tissue, collagen, connective tissue, or lastly, cirrhosis. Amongst patients, there is the general sense that fibrosis of the liver is a bad thing to have, though they are not quite sure why. Generally speaking, they are right.
Most everyone understands what a “scar” is. We have them all over our bodies, from accidental or intentional injury to our skin. Cuts and bruises leave visible scars, as does the symmetrical scar left by a steady surgeons’ hand. Internally, out of sight, scar tissue can develop in any organ or tissue, the end result of chronic injury and inflammation to that tissue. The same process can take place in the liver. Understanding how scar tissue and fibrosis develops in the liver is an extremely complex subject, with a number of brilliant clinicians and researchers dedicating themselves to understanding the convoluted series of events that take place in the liver and throughout the body, leading to liver damage. The goal of all of this attention and research is to attempt to control the progression of fibrosis and possibly reverse what was once thought irreversible. Most forms of chronic liver disease, including hepatitis B, chronic hepatitis C, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, autoimmune hepatitis, and disorders of the bile duct, have the potential to cause fibrosis in the liver. The common thread in all of these conditions is inflammation in the liver. The development of fibrosis in the liver, and its later complications, cirrhosis, should be considered a spectrum taking many years or decades to develop. Think of cirrhosis of the liver as the end-stage complication of fibrosis, a situation where the majority of healthy liver tissue is replaced with non-functioning scar tissue. This leaves the liver severely handicapped in its ability to perform the multitude of metabolic functions that is required of it. One of the great mysteries in hepatology is trying to determine which patients are at risk for the development of fibrosis and cirrhosis. It does appear that there is a genetic and environmental predisposition. These exact risk factors are still being firmly defined, which in turn, can be developed into screening tests for those at highest risk.
There are several reasons fibrosis is looked down upon in the liver. The presence of fibrosis, or scar tissue, in a sense, displaces healthy, functioning liver tissue for non-functioning tissue. This results in a loss in the hepatic synthetic function, which we rely on the liver for. The over 200 metabolic activities the liver is involved in gradually slow down due to a lack of viable liver tissue, leading to increased symptoms and complications. The second major complication of scar tissue in the liver is the disruption of normal blood flow through the liver. Once cirrhosis sets in, portal hypertension develops. Normally, blood is carried to the liver by a major blood vessel called the portal vein. If blood cannot flow easily through the liver because of cirrhosis, the blood gets slowed down in this vein, and the pressure surrounding these vessels increases. This higher blood pressure in the portal vein is called portal hypertension. If blood can’t flow normally through the portal vein, and thus through the liver, it must return to the heart using other blood vessels. These vessels, typically in the esophagus and stomach, become swollen due to the increased amount of blood flowing through them. These distended veins are called varices. Varices, which are thin-walled veins called upon to carry this diverted blood away from the liver, can easily rupture leading to a torrential life-threatening hemorrhage. Bleeding from esophageal or gastric varices is a true medical emergency, which can lead to a number of unwarranted complications. Other complications of portal hypertension include the development of ascites, a visible buildup of fluid in the abdomen. Hepatic encephalopathy, a confusional state that develops in patients with liver disease, is also related to portal hypertension and the abnormal blood flow through the liver noted above.
The presence of fibrosis is generally determined at the time of pathologic review of a liver biopsy. At this time, liver biopsy and pathologic evaluation has been the gold standard in determining the presence of fibrosis as well as its extent. There are a number of noninvasive technologies that are currently in development and will be discussed below.
Once a biopsy of the liver is obtained either through a needle biopsy or a surgically obtained wedge biopsy, the pathologist uses a number of special stains, which highlight the presence of scar tissue, when examined under a microscope. The two common stains used include Masson’s trichrome that demonstrates the presence of type 1 collagen and the Reticulin stain, which identifies type 3 collagen, that can identify the presence of early fibrosis with the presence of liver cell collapse and nodule formation.
There have been a number of scoring systems developed to carefully measure the degree of fibrosis noted on a biopsy specimen. By having a uniform scoring system, it allows both pathologists as well as clinicians to compare not only one patient to another, but also on follow-up biopsies on the same patient, it provides insight into the progression of fibrosis formation and their ultimate risk of cirrhosis and more serious complications. In 1981, R. G. Knodell introduced the histology activity index, resulting in a reproducible histologic score for liver biopsies. This histology activity index commented on not only the fibrosis in the specimen, but also the degree of inflammation. Very simply, fibrosis was scored on a 0-4 scheme (see Table). With this strategy, a score of 0 was associated with no fibrosis noted on the Masson trichrome stain. A score of 1 was associated with localized fibrosis around the portal tract. A score of 3 revealed expanding fibrosis with portal-to-portal linkage, also known as bridging fibrosis. The presence of cirrhosis resulted in a score of 4. Other scoring systems developed over the years, including those described by Scheuer, Ishak, Metavir, and Ludwig, despite the unique nuances of each scoring system, allow for the accurate and systematic measurement of fibrosis in a uniform fashion. While obtaining a liver biopsy and direct examination under a microscope is the “gold standard” for assessing both the presence and type of fibrosis, as well as the distribution and severity, there are a number of laboratory tests that are noninvasive methods for objective measurement of hepatic fibrosis and for monitoring therapy that may be aimed at arresting or reversing fibrosis. While a detailed discussion of these various biochemical assays are far beyond the scope of this discussion now, measurement of serum hyaluronate has been reported to correlate with the progression of fibrosis and the ultimate development of cirrhosis in patients with alcoholic liver disease, though there are still further studies required to validate this testing method. The most thoroughly evaluated biomarker is the FibroTest (FT). The FibroTest is computed by the patient’s age, sex, and result of analysis of serum haptoglobin, alpha 2-microglobulin, apolipoprotein A1, GGT, and bilirubin levels. In studies looking at the reliability and reproducibility of FT, in one particular study, 81% of patients could be correctly staged and liver biopsy avoided. While a number of these studies looking at FT are promising, they is still general discussion amongst hepatologists that more data may be required before it becomes the standard of care and replaces the liver biopsy.
One step beyond biochemical markers to determine the presence of fibrosis is a new, noninvasive and reproducible technique that measures tissue stiffness. Transient elastography (Fibro Scan) has been demonstrated to be a reliable tool for assessing hepatic fibrosis and cirrhosis, mainly in patients with chronic hepatitis C. This system is equipped with a probe consisting of an ultrasonic transducer mounted on the axis of a vibrator. A vibration of mild amplitude and low frequency is transmitted from the vibrator to the tissue by the transducer itself. This vibration induces an elastic shear wave, which propagates through the tissue, in this situation, the liver. The propagation of this shear wave is measured, which is directly related to tissue stiffness and its elasticity. The harder and denser the tissue, corresponding to more fibrosis, the faster the shear wave propagates. Reports have shown that liver stiffness measurement using Fibro Scan allowed accurate prediction of hepatic fibrosis in patients with hepatitis C.
Whether or not the presence of hepatic fibrosis is a reversible process will require additional research. While the liver is endowed with the capacity to regenerate itself, there is data to support the reversal of fibrosis in specific cases. Whether or not this reversal phenomenon is a process that can take place spontaneously or with intervention and treatment of the underlying inflammatory process, will keep investigators busy for the next 50 years. It has been recommended by experts in the area of fibrosis that the better term to describe this “reversal of fibrosis” would be to use the descriptive term “regression”, which would imply less fibrosis than earlier. We have all had patients with autoimmune hepatitis who on initial presentation have advanced fibrosis on their original liver biopsy, and on follow-up specimens two or three years later, after intense immunosuppressive therapy, there is a miraculous improvement in the degree of fibrosis noted. There is tremendous interest growing in the role that interferon plays in the control and regression of fibrosis in patients with chronic type C hepatitis. Preliminary findings from the CO-PILOT study using PEG-interferon alpha-2 maintenance therapy for advanced hepatitis C fibrosis indicates a reduced incidence of clinical events related to complications of portal hypertension. Gene therapy, which appears to have a role in just about every disease process, may also have a role in hepatic fibrosis. During stress and injury to the liver, a number of growth factors are released, which in turn lead to an increase in fibrosis formation. Transforming growth factor-beta (TGF-b) is a cytokine produced in large quantities during liver injury stimulating hepatic fibrosis. Investigators have been able to attenuate its activity, and in theory, can control the development of fibrosis. This exciting area of gene research therapy is shedding greater understanding in the entire process, but still is a number of years away before we fully understand how it can universally prevent hepatic fibrosis.
In summary, the presence of hepatic fibrosis, and its more advanced kin, cirrhosis, is the end-stage complication of uncontrolled hepatic inflammation. Our basic understanding of why this occurs has improved greatly over the past 25 years. Developing strategies to intervene remain a challenge, though rest assured that progress is being made.
While a liver biopsy and direct examination under a microscope remains the gold standard, noninvasive tests are becoming available, which would allow greater monitoring of those patients that are on therapy, which hopefully will arrest or regress the degree of fibrosis noted. The rationale with these noninvasive studies is to alleviate the need for frequently performed liver biopsies.
Of course, probably the most unstated message to all those with chronic liver disease, of any variety, is to seek treatment and learn about risk factors that would result in continued inflammation in the liver.