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Asking the Right Questions

At a Glance

  • A patient’s clinical history is essential for the diagnosis of liver pathologies
  • Whenever there is any doubt, pathologists should not hesitate to consult subspecialty experts
  • Most diagnostic “errors” stem from being either too specific or not specific enough
  • The number of routine liver biopsies may decrease in the future, but the complexity of the remaining ones will likely increase

“I like to think of the liver as being a microcosm of the human body’s pathology as a whole,” says Robert M. Najarian, consultant in gastrointestinal and liver pathology at Beth Israel Deaconess Medical Center. The detoxifying organ doesn’t directly recapitulate the body’s physiological diversity; rather, it allows an immunological glimpse into the body’s processes. “We see a whole spectrum of conditions, from infections to autoimmune diseases to a host of primary and metastatic neoplasms in the liver,” Najarian says. “As a liver pathologist, you really do end up seeing everything – inflammatory, neoplastic, and other surprises.” With the array of diseases expressed in the liver, the tools and techniques used for diagnosis are especially vital to differentiate between them – but, according to Najarian, one particular aspect stands above all others. “The most important tool we have is the availability of clinical history (something that, hopefully, is available at our fingertips), followed closely by a high-quality H&E-stained slide. This is the fundamental basis of what we do in liver pathology – and really all pathology – because they allow us to diagnose a pattern of injury first, then supplement what we see under the microscope with the clinical history to truly inform what’s happening to the patient.”

Modern, high-tech tools are great additions to a pathologist’s roster from a technical perspective, but using them without a strong foundation from clinical history and H&E is like building a house on an unstable foundation. And in an era where efficiency and cost-saving measures are becoming increasingly predominant, those two pillars cost relatively little and contribute a lot.

The most important tool we have is the availability of clinical history, followed closely by a high-quality H&E-stained slide.
A generalist specialist

Once you’ve firmly established the two main building blocks and you actually dive into the biopsy itself, what are the next steps? “A pathologist should ask themselves, ‘What am I seeing in terms of the organization of the sample? Am I seeing reasonably normal liver architecture with intact portal triads and lobules?’” After determining the presence of abnormal inflammatory or neoplastic cells, Najarian says you should also keep an eye out for what isn’t there. “Have intact native bile ducts been lost for some reason – possibly due to prolonged damage? Is there steatosis (irregular fat retention) where normal hepatocytes should be? Next, once abnormalities are identified, it’s important to then ask yourself, ‘Can I attribute these changes to a single pattern of liver injury, or is this perhaps illustrating features of multiple patterns and thus multiple causes of damage?’ Once you’ve done that, as a pathologist, that’s more than half the battle.” From that point on, all the pathologist must do is narrow down the options and specify what diseases fit the patient’s individual patterns or combinations – but this isn’t a straightforward task.

Najarian emphasizes the need to question the possibilities and, in cases where you cannot make a conclusive diagnosis, seek the knowledge of an experienced expert. “The ‘long story short’ is to be aware of what you, as a well-educated pathologist, do and do not know – and to know when it’s time to ask for consultative assistance,” says Najarian. “You shouldn’t allow your years of experience or your familiarity with a particular type of tissue to limit your willingness to call on others who might be able to give you a unique perspective or share their experience with you. Liver pathology can be quite complex.” And with that complexity comes the potential for inaccuracy.

Two sides of an erroneous coin

“I think errors come in two different flavors. One is on the part of the pathologist who, feeling the need to be too specific with a histologic diagnosis, may attribute a pattern of injury to a specific disease when there isn’t sufficient evidence to support it,” says Najarian. The second aspect deals with the opposite end of the spectrum. “If you have an injury pattern that makes sense in the context of several different diseases, failing to mention the specific entities in what may be a broad differential diagnosis, and which one you might favor, is an issue that may mislead the liver specialist and affect what confirmatory laboratory tests they order.”

The way to avoid these pitfalls is to have the plethora of information necessary for an accurate diagnosis. And what’s the best way to provide that information? “I may sound a bit repetitive, but it starts with clinical history, combined with laboratory testing, and with imaging tests in certain situations. They make up the most important pieces of the puzzle,” Najarian says. “The second most important piece is having more eyes in the game. It’s vital to have more consultative opinions available to you, and to feel comfortable asking for those opinions.” After all, two heads are better than one – and nowhere more so than in patient care.

Voracious variability

Despite taking precautions to avoid pitfalls, there’s one tricky aspect of medicine that has the potential to affect all pathology tests: sampling variability. Its effect on blood tests is well-known (1) but, when dealing with tissue sampling, the solutions that work for blood don’t necessarily apply. “By nature, most of what pathologists see in terms of liver samples are needle core biopsies taken via a percutaneous, transvenous, or even endoscopic route – the ideal sample of which is about 2.5 cm in length and 1–2 mm in thickness, depicting about 1/50,000 of the whole organ. That’s going to bring about variability issues and raise questions as to whether or not we’re truly seeing a representation of the whole liver,” warns Najarian. “With that in mind, I would encourage my fellow pathologists to first evaluate the adequacy of the samples they are assessing. Often, what we receive isn’t sufficient in the first place, and we shouldn’t be afraid of describing the limitations that might come with a diagnosis we render from an inadequate sample.” He encourages pathologists to ask for more tissue or supplementary information if they need it – because having all of the information necessary for diagnostic accuracy is the key. “Consult your friendly expert liver pathologist often, if needed, in those circumstances where your own eyes may not be 100 percent certain,” suggests Najarian. “H&E appearance is simple, but the differential diagnosis and the rendering of a specific diagnosis can be complex – so have no fear; consultants are here!”

Steatohepatitis in a 74-year-old woman with amiodarone-induced liver injury. This high-power magnification H&E-stained image demonstrates prominent macrovesicular steatosis, ballooning degeneration of hepatocytes with intracytoplasmic hyaline, and lobular neutrophils – all histologic features more commonly associated with alcohol-induced steatohepatitis.

Hepatic outlook

If these are the tools and techniques most essential in liver pathology right now, what does the future hold? Najarian believes that the field is going to become increasingly complex, so biopsy-based diagnosis isn’t going to get any easier. “With the advent of new therapies to cure diseases such as chronic viral hepatitis C, I know that the number of routine liver biopsies most practices will see may decrease,” he says. “But that doesn’t necessarily mean that the amount of time we’re going to spend on biopsies will decrease, because the biopsies we do see are going to reflect more complex and evolving disease processes (such as non-alcoholic fatty liver disease/steatohepatitis), multiple disease processes, injuries resulting from certain treatments – and, sometimes, all of those superimposed on top of each other.” If this shift in complexity does occur, then the need for clarity becomes even more important – as does the need for the clinical history and collaborative aspects stressed by Najarian.

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  1. J Nichols, “Variations on a drop”, The Pathologist, 17, 44–45 (2016). Available at:
About the Author
Robert M. Najarian

Robert M. Najarian is Consultant in Gastrointestinal and Liver Pathology at Beth Israel Deaconess Medical Center.

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