Given the option of a diagnostic procedure that is invasive, even with a small risk of death, over a noninvasive equivalent, the choice seems obvious. As an analogy, why in 2016 would a patient with ulcerative colitis, a raised alkaline phosphatase level and suspected primary sclerosing cholangitis undergo ERCP first and not magnetic resonance cholangiopancreatography Now two decades after subjecting our hepatitis C (HCV) patients to liver biopsy (because it is the gold standard) before starting treatment, gastroenterologists are realizing that biopsy may not always be “the way to go.”
In 1958, Menghini’s “one-second liver biopsy” ushered in a new era;1 at one point 30,000 liver biopsies were done in the U.S. annually. It is worth recalling that in order for the first oral hepatitis B (HBV) drugs to gain FDA approval, there was an insistence on tangible evidence of “liver improvement,” (i.e., histological evidence of reduction in hepatic inflammation. Viral levels were relatively immaterial). Later, the initial hepatitis C therapies also required both pre- and post-treatment liver biopsies in order for these agents to gain approval. But lately, the numbers of HCV-staging biopsies have plummeted and many centers are reporting steep declines in the use of this procedure.
The use of biopsy in order to stage liver disease, in retrospect, probably contributed to a vast underdiagnosis of HCV-related cirrhosis in the U.S. Physicians were reluctant to order or perform the test, and patients were even more reluctant to proceed. Often pathologists could not visualize complete nodules and render the diagnosis, and cirrhosis was frequently diagnosed only once decompensation occurred, when it was too late. Up to 25 percent of HCV patients today have cirrhosis but most are still not aware of their diagnosis. Several very useful and validated noninvasive biomarkers are available (FibroTest, aspartate aminotransferase/platelet ratio index, Fibrosis-4 and others) but are relatively underutilized. Finally, U.S. clinicians are catching up with their European and Asian counterparts and can instantly, cheaply and noninvasively utilize elastography to assess their patients’ “liver stiffness” to help gauge if cirrhosis is likely, and if present, determine how to proceed.
In many ways the advent of transient elastography has paved a new pathway in HCV diagnostic testing. Stiffness scores are visualized, and it represents a simplistic and understandable concept both for physicians and patients. In addition to the most popular transient (vibration-controlled) elastography, there are ultrasound-based, acoustic radiation force impulse and magnetic-resonance-based elastography platforms. Each has their respective strengths and weaknesses, but each is also noninvasive. Moreover, the ability to provide a numerical “degree” of liver stiffness that correlates both with diagnosis of cirrhosis and with translation to clinical outcomes (hepatocellular carcinoma and hepatic decompensation) offers a giant leap forward in staging liver fibrosis measurement. Thus the potential ability to provide a tangible parameter of “how much” cirrhosis is present, not just that it exists.
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Therefore, transient elastography not only obviates the need for invasive and often inaccurate liver biopsies, but the actual stiffness score provides us with our first glimpse of “staging” cirrhosis on a continuum: the higher the score, the stiffer the liver, the worse the prognosis. On the other hand, even the most successful percutaneous liver biopsy, no matter how large a specimen, that actually rendered the diagnosis of cirrhosis could provide a “METAVIR IV” score or an “Ishak 6” score, but no additional assessment of degree of fibrosis.
As with any diagnostic medical test, caveat emptor, or “let the buyer beware.” For elastography, caveats abound. The stiffness score represents a risk stratification; it does not stage fibrosis and this fact bears repeating. State Medicaid groups and third-party insurance companies dangerously use these scores as a means by which to deny curative antiviral HCV therapy. We have seen the patient with a non-cirrhotic stiffness score who subsequently, one year later, was found to have hepatocellular carcinoma and, alas, a cirrhotic liver. Stiffness scores correlate very well with fibrosis, but confounders can affect results. Scores depend upon user experience and competence, comorbid conditions, obesity and a host of other factors. Although very low and very high scores are helpful, in-between scores are by definition ambiguous.
There is also now the exciting option of longitudinal follow up and assessment of fibrosis progression over time. Previously, serial liver biopsy studies were few and far between, fraught with confounders and low patient numbers. As the elastography field is refined, one can envision a “delta score” over time as a means by which to assess fibrosis progression or regression.
This truly represents a refinement in liver disease assessment that was not heretofore possible.
In many ways, the archaic days of mandated liver biopsies, are alive and well: the new NAFLD drugs in development, like HBV and HCV in the past, still require pre- and post-treatment liver biopsies, including the stipulation for large liver sample size, length and width, to document changes in fibrosis as the pathway toward drug registration.
For nonalcoholic fatty liver disease, biopsy remains king, with noninvasive elastography not yet ready for prime time for fibrosis staging. Nevertheless, the reality is that gastroenterologists and hepatologists are largely abandoning doing the procedure themselves (too much risk, too little reimbursement). Radiologists rarely use the 16-gauge cutting needle that allows for adequate sampling. So where does that leave us — and is liver biopsy becoming a dying art?
The revelations at liver biopsy can help establish many unexpected diagnoses including infiltrative disorders, neoplasms, unusual infections, vascular conditions and cellular rejection. For those hepatologists and liver pathologists who appreciate the clinical and academic value of each liver biopsy specimen, the advent of elastography will serve to augment but never replace biopsies. Yet for simply staging fibrosis in patients with chronic hepatitis C, the era of liver biopsy is fading fast, because primum non nocere, or “first, do no harm.”
Dr. Gordon receives grant/research support from AbbVie, Bristol-Myers Squibb, Conatus, CymaBay, Exalenz, Gilead, Intercept and Merck. He also consults for Abbie, Bristol-Myers Squibb, Intercept, CVS Caremark, Gilead and Merck, and has received speaking fees from Gilead and Intercept.
1. Menghini G. One-second needle biopsy of the liver. Gastroenterology 1958; 35; 190-199