Three studies published in the October 2007 issue of the journal Clinical Gastroenterology and Hepatology discuss several novel noninvasive techniques for diagnosing fibrosis and cirrhosis of the liver. For people with hemophilia and hepatitis C, the question is whether these techniques are viable alternatives to liver biopsy, considered the gold standard for diagnosing the extent of liver disease.
Exposure to the hepatitis C virus (HCV) causes the cells in the liver, or hepatocytes, to become inflamed. Recurrent inflammation in the liver changes the liver’s structure, which slows its circulation, causes liver cells to die and creates scar tissue. The presence of scar tissue, or fibrosis, is an indication of liver damage. If fibrosis continues unabated, it can result in cirrhosis, when the scarring of the liver becomes irreversible. If enough of the liver is cirrhotic, it can lead to end-stage liver disease, or functional liver failure.
Types of Biopsies
Samples of the liver tissue can reveal pertinent information on the degree and severity of inflammation and injury. They can also be used to determine treatment options, particularly if there is co-infection with HIV. Liver biopsy is the method used to secure tissue specimens for evaluation; the two main types are transjugular and percutaneous.
“Transjugular biopsies are being performed on many of our hemophilia patients,” says Margaret Ragni, MD, MPH, director of the Hemophilia Center of Western Pennsylvania in Pittsburgh. Ragni is a member of the National Hemophilia Foundation’s (NHF) Medical and Scientific Advisory Council (MASAC). During the procedure, a guide wire with a core needle attached is threaded through a catheter in the external jugular vein in the neck down into the right hepatic vein of the liver, where the tissue sample is taken. It is performed under conscious sedation. “We cover them with factor beforehand and have not seen bleeding or infections as side effects,” Ragni says.
In percutaneous biopsy, a local anesthetic is given at the site where the liver tissue sample is obtained—on the right side between two of the right lower ribs. After a small incision is made, a needle is used to extract the specimen(s).
Postprocedure factor coverage depends on the patient’s diagnosis and other considerations, but typically the factor level is kept at 50% for up to three days. Most patients are followed in the hospital for one to three days, although outpatient transjugular biopsies have been successfully performed on people with hemophilia, according to a November 2004 study in the journal Haemophilia.
In a September 2004 study published in Haemophilia, Dickens Theodore, MD, MPH, from the University of North Carolina at Chapel Hill, and his co-authors compared the safety and efficacy of both procedures for people with coagulation disorders. Percutaneous liver biopsy was less costly and more accessible to most patients, and provided larger specimens that required fewer passes (the number of times the needle was inserted to obtain tissue samples). On the other hand, Dickens wrote that transjugular liver biopsy can be more costly, requiring the presence of a vascular interventional radiologist, but provides a better measure of hepatic venous wedge pressure—high blood pressure in the liver veins can indicate cirrhosis.
With more than 600 liver biopsies reported in the literature to date, the authors concluded that the risk of complications to patients with hemophilia was low, provided proper precautions were taken, including correcting factor levels to 100% immediately before starting the procedure. They also urged the patient’s hepatologist and hematologist to work closely prior to and throughout the procedure. This cooperation and coordination between experts in the field is consistent with NHF’s MASAC Recommendation #98, “MASAC Recommendations on Liver Biopsy in Individuals with Hemophilia,” issued in 2000. Dickens and his co-authors, however, added a note of caution: “What is clear is the need for an experienced pathologist to interpret the biopsy specimens.”
Staging and Grading Fibrosis
Liver tissue specimens give information on two aspects of fibrosis: its stage and grade. “The stage is the degree, or amount, of fibrosis (scar) within the liver that results from whatever disease process caused the liver injury,” says Kenneth Sherman, MD, PhD, Gould Professor of Medicine and director of the Division of Digestive Diseases at the University of Cincinnati College of Medicine. Sherman also is a member of NHF’s MASAC. “The grade is the activity of the disease as defined by the amount of inflammation and injury that are happening now.” He says the predictive value of a liver biopsy is based on determining both the grade and stage in a patient. As a general rule, the more inflammation and injury the liver has now, the greater the degree of scarring later. The stage of scar provides information about risk of decompensation, the inability of the liver to compensate for damage to it, and the likelihood of treatment response.
Measuring the degree of fibrosis provides information on the rate at which hepatitis is progressing in the liver. Although there are several systems used by pathologists to score fibrosis, the Metavir system is the simplest.
“We’re using the Metavir score in our National Institutes of Health-funded study of hepatitis C in biopsies from patients with hemophilia,” Ragni says. “It provides a way of distinguishing severity of fibrosis. It has well-defined criteria that are consistent from examiner to examiner.”
The Metavir scoring system has five categories: F0, no scarring; F1, minimal scarring; F2, scarring that extends outside the areas in the liver that contain blood vessels; F3, bridging fibrosis—scarring that extends among newly formed septa, or segmented sections; and F4, cirrhosis.
Novel Noninvasive Tests
The new tests involve techniques that do not require the invasiveness of biopsy—no needles are used. Their purpose and prowess when compared to liver biopsy, however, are under scrutiny by experts.
One of the new tests uses ultrasound waves to measure elastography, or the stiffness of the liver, a determining trait of fibrosis. “Elastography sends a sound wave into the liver with a probe,” Sherman says. “Like sonar, it measures the wave that bounces back.”
Although it sounds like an elegant technique, Sherman has tested the equipment in France and is withholding his stamp of approval for now. “There are a number of problems with it,” he says. “The machine to perform it is not approved in the US, and no studies have been done on patients with hemophilia.” The results to date have been highly variable. “They had a high rate of error in some studies,” Sherman says. “They were wrong 30% to 40% of the time.”
Further, the study was a meta-analysis—it combined data from 18 previous studies. “The problem is that the information was not controlled for age, gender or sex,” Ragni says. “Were they looking at young men or older men? Were they looking at all males? What race(s) were they including? Whom were they using for their controls? Pooling data may not be helpful for people who want to know, ‘What about me?’ ”
Another test measured blood flow in the spleen using a splenic artery pulsatility index. “The results show that the test is not 100% sensitive and specific,” Ragni says. She adds that the test also appears to be less accurate in diagnosing fibrosis in its earlier stages; results depend on which group of individuals the test was validated.
A second test used magnetic resonance elastography instead of ultrasound. Its main flaw was the number of research participants involved. “They used a relatively small group,” Sherman says. In addition, he states the tests don’t provide enough accuracy or information in the mid-ranges of fibrosis. They can predict mild fibrosis well enough and late cirrhosis well enough, but not the middle stages. “The real question is, What do you need the test to tell you?” Sherman says. “If you don’t set the bar very high, then it’s not very hard to find something that works.”
Blood Tests
A number of blood tests also provide alternative noninvasive tests to predict fibrosis. “There are a variety of blood test indices, combining both common and uncommon lab markers,” Sherman says. “Many are pretty good at very advanced stages of disease, but are not so good at the in-between stages. These tests do not add a lot to our clinical armamentarium.” He says that often a routine physical exam and standard blood tests provide the information he is seeking. “With them we can often tell who has cirrhosis without ever looking at any special panel or index. For example, a mild decrease in the platelet count often suggests the early stages of advanced scarring in the liver.”
Not Ready for Prime Time
“These techniques are not ready for ‘prime time,’ ” Ragni says. She believes that some day they may be used in tandem with liver biopsy to correlate fibrosis staging and grading. Before they become standard tests, however, more information is needed, she says. “We still need to evaluate the tests, look at the reasons that the sensitivity and specificity are low, and determine what they really measure.”
The first step for patients with hemophilia and hepatitis C, Sherman says, is to be evaluated by expert hematologists and hepatologists. He stands by liver biopsy as an information-gathering tool that is safe and effective. “It provides a great deal of information. The most recent consensus statement by experts in the field suggests that liver biopsy should be applied widely in patients with hemophilia.”
As for the new techniques, Sherman, like Ragni, is cautiously optimistic. “There are some very promising noninvasive methodologies under evaluation,” he says. But he does not foresee the day when they will supplant biopsies. “I think they will provide an adjunct, not a replacement.”