Fibrosis Stages in Hepatitis

Introduction and Source Material

The majority of this is taken from the SRU consensus document, which I think is a very good document, and a how to do a liver elastography, and I recommend that you review that document for additional information.

I do have several disclosures that are listed here.

Objective of the Talk

The objective of this talk is to provide an overview of diffuse liver disease and discuss how liver stiffness values can be affected by populations etiology and other factors, and review the best practices for ultrasound liver elastography.

Chronic Liver Disease Overview

Chronic liver disease is a substantial worldwide problem.

The inciting etiology of the chronic liver disease varies depending on which continents you're on.

So that in Europe, hepatitis C is the most prevalent.

In Asia we have both hepatitis B and hepatitis C.

And in the western world, non-alcoholic fat liver disease is the major disease that causes chronic liver disease.

Consequences of Chronic Liver Disease

The major consequence of all these diseases that cause chronic liver disease is increased deposition of fibrous tissue within the liver leading to the development of cirrhosis and its complications of portal hypertension, hepatic insufficiency, and hepatocellular carcinoma.

Importance of Staging Liver Fibrosis

The stage of liver fibrosis is important to determine the prognosis, surveillance prioritization for treatment, and the potential for reversibility.

Now that new drugs are available for several of the factors that can cause cirrhosis and have been shown to reverse the degree of fibrosis.

Liver elastography is becoming extremely important to be able to evaluate these patients and to monitor treatment.

The process of fibrosis is dynamic and regression of fibrosis is possible, again, with treatment of the underlying condition.

Limitations of Liver Biopsy

Previously, the only method of staging was of the degree of fibrosis was by liver biopsy.

And serial liver biopsies are not something that patients would like to do.

So using elastography, in a large portion of the world, liver biopsies are becoming significantly less frequent.

Liver biopsy is really an imperfect histological reference.

It is been used as the standard gold standard for assessment of liver fibrosis.

It also allows us to stage the amount of information and degrade the degree of stenosis, necrosis and inflammatory activity.

And, unfortunately a liver elastography is not able to distinguish all of these factors, but gives us an overall stiffness of the liver, which is a combination of fibrosis as well as inflammatory activity.

The liver biopsy is invasive and severe complications can occur in up to 1% of patients.

We really only biopsy about one 50,000 of the liver volume.

It is felt to be representative, but again, it there are some issues if the biopsy can be taken in one spot that just happens to be a little less than and another in the degree of fibrosis.

And actually, there's considerable inter observer variability by pathologists, and studies have shown that the kappa value can range from anywhere from 0.4 to 0.9 in these studies.

Fibrosis Progression

This is a slide showing you what happens with fibrosis.

So, normal or stage zero, we have our normal portal triads and hepatic veins.

And we then go through this area where we start to get fibrosis surrounding the portal triad.

And these then increase and then become bridging between adjacent sites and then more increased bridging, and then the development of nodules, and then a continued development of additional nodules.

Fibrosis Scoring Systems

There are three main scores that are used to grade these.

These are the, IS aq, the var, and the bats.

Ludwig and I have these shown here.

The majority of studies use the METAVERSE score, which is a five point score with zero is normal.

And four as cirrhosis in a lot of studies, they like to use the is Shaq because it does separate mild cirrhosis from severe fibrosis.

So it has actually a seven point score, zero to grade six cirrhosis is considered the end stage of chronic liver disease of any etiology and all result from progressive FibroGen fibrogenesis.

So any chronic liver disease, and some of examples are hepatitis C, hepatitis B, alcoholic liver disease, non-alcoholic steatohepatitis cholestatic disease, as well as autoimmune diseases can cause this increased fibrosis.

And again, it's a continual process that leads to fibrosis and then to cirrhosis.

Interest from Hepatology Colleagues

What our hepatology colleagues are very interested in is knowing at which stage of this process these patients are in, because it makes them know exactly how to treat the patient, how often to follow the patient, and to give some idea of the patient's prognosis.

So, as you can see here, we have our chronic liver disease that leads to fibrosis.

We eventually get to compensated cirrhosis, and by compensated cirrhosis, I mean the patient now has cirrhosis, metaverse stage four, but this is not easily diagnosed clinically.

These patients do not have very many presenting symptoms that the hepatologist will be able to do a clinical exam and determine that they have cirrhosis.

They have a median survival of greater than 12 years.

Also at this stage, they may or may not have varice and having varice tripled their mortality in one year.

So these are other in things that the hepatologist very interested as This patient with compensated cirrhosis progresses, they eventually develop variceal hemorrhage, ascites, encephalopathy, or jaundice.

And at that point we call these decompensated cirrhosis patients.

This is an easy diagnosis and usually the hepatologist can tell when the patient's walking in the room that they have decompensated and their mean survival is approximately two years.

So there's a huge difference between those patients that have compensated cirrhosis and decompensated cirrhosis in terms of morbidity and mortality.

And one of our goals using elastography is to try to find these patients in fibrosis or compensated cirrhosis so they can be triaged to treatment to prevent them from going to do decompensated cirrhosis.

Portal Hypertension and Fibrosis

Fibrosis also increases the portal hypertension so that using the metaverse score, you can see that we have normal pressures that have zero and they increase as we go to cirrhosis.

And again, one of the complicating features that is going to determine that the patient decompensates is going to be if they have bleeding varice.

So the safest and most reliable method of measuring hepatic venous pressure is the hepatic venous pressure gradient.

And it's defined here and it's usually three to five millimeters.

A hepatic venous gradient of greater than 10 millimeters per mercury is the strongest predictor of the development of varice.

Patients with a hepatic venous pressure of less than 10 millimeters of mercury having 90% chance of not developing clinically decompensation in a four year period in patients with compensated cirrhosis, a reduction in the portal venous pressures of greater than 10% at one year protects against the development of varice and significantly improves outcome.

Non-Invasive Assessment Goals

The non-invasive assessment of patients with chronic liver disease that our hepatology colleagues would like us to do, is there cirrhosis, is there not cirrhosis?

If there is compensated cirrhosis, does that patient have clinically significant portal hypertension or not?

If compensated cirrhosis is present or gastroesophageal vari is present or absent, and if they are treating this patient, is there improvement in therapy?

So when we design our report and our examinations, these are the things that are hepatologists would like us to address.

Spleen Stiffness

I do wanna mention that there is some early work on spleen stiffness as opposed to liver stiffness.

And the spleen stiffness appears to correlate with portal hypertension.

And here's a paper that again shows that the spleen stiffness actually correlates with increased hepatic venous pressures more than the liver stiffness does.

In another paper, they were able to actually predict which patients could decompensate by looking at the splenic stiffness.

And again, these studies are relatively early and have not been reproduced.

But I think in the future, we may also be doing spleen stiffness for those patients with advanced fibrosis or cirrhosis to again, help to characterize where on the spectrum of disease the patients lie to triage them to appropriate treatment.

Treatment Advances and Role of Elastography

I just wanted to include these slides that just show that now that we have some medications, this zero for hepatitis C, that when these patients are treated with this therapy, they actually regress.

And the newer drugs coming out have shown a greater than 95% complete regression of disease and Hepatitis C the unfortunate problem is that these drugs are extremely expensive, and we need to triage who is the most appropriate to get these.

And at least in the United States, insurance companies have come up with one of the indications is a liver stiffness of a specific value to determine which patients should receive this therapy.

New drugs for hepatitis B as well as non-alcoholic fat liver disease are also coming out.

And again, so I think for the three major causes of cirrhosis, we will have treatment.

And again, I think these tests are gonna be extremely helpful in using liver stiffness to number one, decide which patients need treatment and to be able to follow treatment.

Importance of Staging in Disease Management

Why is staging important in the management of disease?

It's very prognostic.

So again, we can assign which patients are more needed in terms of urgency for the treatment and those that can wait given the cost, surveillance.

All these diseases lead to hepatocellular carcinoma and varice if they progress.

So we want to determine where they're at so we can again decide how the management will be given.

Again, we can use this for baseline monitoring of treatment deficiency, and we can tailor the treatment algorithms.

And I think this is going to be more and more important as we gain more experience in evaluating treatment of drugs with these applications to determine what is the most appropriate timing for follow-up examinations.

And again, this many of the insurance companies are now requiring that we have a liver stiffness value above a certain value before they will agree to pay for treatment.

Monitoring Frequency

How often should treatment be monitored?

Again, we don't know the answer to that because this is still in the learning phase, it may depend on what as the underlying disease.

So in other words, the response time may be different for patients with hepatitis C versus non-alcoholic fat liver disease.

It may vary with disease disease severity.

So patients that have an F three maybe need to monitor it more or less than those patients that are starting with a metaverse F four.

It may depend on which type of therapy the patients are getting.

It may depend on what phase.

So is this on the induction of remission, or is this at maintenance?

After the patient has completed their treatment, we may be able to look at the toxicity and efficacy of treatment.

So it may be that instead of a normal 12 week course, some patients may be able to use an eight week course of drug saving a significant amount of cost.

And again, we may be able to use liver stiffness to help decide which of those patients can go to a shorter therapy.

And again, we can see the end points of where this is.

And again, some patients may be different than other patients depending on their phenotype.

So there we know that there are some patients that have a slow progression of disease where others have very rapid progression of disease.

So in general, if we had to guess at this point, elastography at one year intervals is probably not an inappropriate first guess as to what we want to do when the patient is being treated.

These may need to be a little bit shorter in time and patients on maintenance that have been cured, and maybe we need to do this at a longer time.

And again, I think research in the next coming years will help us decide and be able to give a better idea of what is the most appropriate for patient treatment.

Report Summary for Hepatology Colleagues

What I wanna do is summarize what the hep our hepatology colleagues actually would like us to include in the report.

So to them, they really put people in several boxes, and I think the three main boxes are the patient has no, or minimal fibrosis.

These are patients that probably need no immediate treatment, and the follow up would be based on their initial disease and other clinical factors.

Those that have mild to moderate fibrosis.

In this case, the patients would be treated or follow up again based on other clinical factors.

So those patients that have a somewhere between an F two and an F three that may be appropriate for hepatitis C treatment, if that's their initial etiology, those patients would fall in this category and would be then triaged appropriately.

And then the third group are those that already have severe fibrosis or cirrhosis, and this now triggers regardless of their initial etiology, of why they've got cirrhosis, that the patients need to be screened for hepatocellular carcinoma.

And in addition, it to put them in the appropriate treatment arm, we need to decide if the patient has compensated or decompensated cirrhosis.

And in those patients that have compensated cirrhosis, do they have normal hepato venous pressures or are they abnormal?

And again, by placing patients in these different categories, it allows the hepatologist to determine how fast they need to treat the patients, what their prognosis is, and what their appropriate follow up would be.

Liver Stiffness Calculations

So let's now move on to liver stiffness calculations.

Most of these techniques, if not all these techniques use sheer wave speed estimation.

So a sheer wave is just like other ultrasound waves as it goes through tissue.

Its speed is changed based on the stiffness of the tissue.

So the sound the sheer wave will propagate faster in stiffer tissue and slower and softer tissue.

And to generate sheer waves in ultrasound, we use what's called an RFI, A RFI or push pulse, which is a long duration high intensity ultrasound push that's made to cause tissue to move.

And then we use tracking tissue displacement, our standard beam mode ultrasound perpendicular to that beam where we monitor how the tissue moves.

And what you'll see is for a typical thing, this is the distance from the RV pulse, these are what happens to the tissue displacement.

And you can see closer to the this is the distance from the RV pulse closer we are to the RV pulse.

We get a quicker time to peak, and the peak is much higher.

And as we move away, the wave goes through at a later time, and we have some attenuation of the pulse.

If we take the peak time of displacement, and we plot that, we can then get the slope of this line corresponds to the ShearWave speed in meters per second.

This movie clip is a visual of what happens.

We're starting here now where we got our RV pulse, and you can see that this is the tissue displacement moves across the scan elastography for liver fibrosis.

Methods of Elastography

There are several methods that have been used.

Strain is one method.

There's really a limited amount of things in the literature.

This has mostly been promoted by Hitachi, and they have very specific software that they use to calculate the liver stiffness.

Most of the guidelines do not recommend this be done at this time until further literature validates its use.

Then we have 1D ShearWave elastography, transient elastography by fiber scan, which is a one dimensional meaning we don't have an image but the system monitors the ShearWave image.

Then we have point ShearWave elastography or PSWE.

In this situation, we use that RV pulse and we have a small ROI that we use to calculate the ShearWave speed in that small ROI.

We also have 2D ShearWave elastography, where we take many, many, many point ShearWave elastography in a very large field of view, usually color coding the results over that larger field of view.

And then you can take a smaller ROI and place it within that to get the ShearWave speed at that point of the image.

There's also magnetic residency elastography, which uses a device that causes vibration.

And we look at the shear waves as they go through the liver.

We're using a specific mr sequence, and we'll discuss these at a little bit more at length.

Stiffness Measurement Considerations

I think you have to remember the elastography measures stiffness.

It does not measure fibrosis only, and we'll talk about this at length as we go along here.

So that stiffness is influenced both by fibrosis as well as increased hepatic pressures, including the portal hypertension, hepatic congestion, or increased blood flow from food digestion and also from inflammation.

So you need to be aware of that, and these are things you need to evaluate the patient for to determine if you're getting or cutoffs that are for fibrosis will be accurate.

Transient Elastography

If we look at transient elastography, it's been around for a long time.

There are a large number of studies and meta-analysis available, and these studies show that the area under the curve in indeed diagnosing cirrhosis is quite high a range of about 0.9 and classifies cirrhosis correctly in 85 to 94% of patients.

If we look at significant fibrosis it does a little bit less accurate with an area under the curve of 0.75 2.93 with a correct classification of 57 to 90% in the there is substantial overlap between stages of hepatic fibrosis, particularly at lower stages.

And most of this work has been formed performed on hepatitis C, although more literature is now coming out for Hepatitis B and for nash, the advantages of using transient elastography, it's very easy to use.

The disadvantages are, it cannot be used if ascites is present, and you cannot determine where the measurements are taken.

So you don't know if the patient has a large HCC if you're actually taking the measurements of the HCC and not the underlying liver, or that you're also taking a measurement over a large vein, which will give you inaccurate measurements.

The probe that's used is a mechanical device that causes the thump.

And these need to be recalibrated every six to 12 months point.

Point ShearWave Elastography

ShearWave Elastography uses this RFI pulse to generate cheer waves in a small approximately one cc region of interest.

This is a real-time imaging technique, so you can use the real-time imaging to localize where you're taking the measurements so no masses or large vessels can be identified and avoided where we take the measurement.

You can s systemically, I'm sorry, systematically select different parts of the liver to do samples.

This is a newer technique than transient elastography and there are fewer studies available, but the studies do show that this is a highly reproducible technique and meta-analysis have found that point.

ShearWave shows a higher rate of reliable measurements and a similar predictive value to transient elastography for both significant fibrosis and cirrhosis.

This is just an example.

And in this case, again, we've got our standard B mode image of the liver, and then we can place our box in the liver and hit our button and we will get a readout as to what the liver stiffness is, and we'll talk about where we should be placing the box and how many measurements we should take in as we progress with this talk.

2D ShearWave Elastography

2D Sheray Elastography is basically doing multiple measurements using the RV technology over a large field of view.

This can be done as a single image or performed in real time.

The realtime imaging is again used on B mode, so we can determine where we're doing the lo the positioning of the box so we know where masses or large vessels are identified and avoid these so that we get more accurate measurement in general.

All these 2D techniques use a color coating that color codes the stiffness over the large field of view, and then allows you to place your region of interest.

It also allows you to vary that area of region of interest, so you can do averaging over a larger area of the liver.

Again, this is newer technique and there's less studies out, but there are a couple studies that demonstrate that there is higher accuracy than transient elastography in assessing mild and intermediate stages of fibrosis using this technique and other studies that show that the 2D ShearWave was more accurate than transient elastography in assessing significant fibrosis.

This is an example of 2D one where the liver stiffness is very soft.

And again, you can see here's our large field of view where we have measurements of the ShearWave stiffness and then they're color coded based on this color scale.

And in this image I've used kilopascals and this image I've used meters per second as the method that we're going to measure and we'll talk about which to use.

They actually are equivalent.

And again here we put our little dotted circle is our region of interest, and here is our read out of the mean maximum mean standard deviation of that value.

In this case, you can see we have an area that's red or very stiff liver and much higher stiffness of the liver magnetic resonant imaging.

Magnetic Resonance Elastography

Again, a device placed on the patient to generate sheer waves.

Special MR sequences is used to image these mechanical waves and there's specific software that's used to color code, the image stiffness.

It actually is a relatively short exam taking about a minute for the acquisition.

And the results are displayed as the shear modulus.

And in all the ultrasound techniques, it's the young modulus that's displayed.

And the conversion from Young's modulus to sheer modulus is the sheer modulus is three times the Young's modulus.

And the technique allows for evaluation over a large volume of tissue.

So its advantages are that it evaluates a large area.

The disadvantages are obviously the cost of an MR is significantly more than that of ultrasound, and there's limited access to this technology.

Performing the Examination

So how do we perform the examination?

An intercostal approach to the right lobe of the liver is preferred.

The patient should rise their right hand above their head.

To increase the intercostal space, you should use your beam mode imaging to find the best acoustical window.

That's where the beam mode signals are the best.

And there's no shadowing because if you're getting the mode ultrasound wave in, you're also going to be getting in the rv, push pulse with less artifacts, and that's going to give you better signal to noise.

The measurement should be taken in in a breath hold, in a neutral breathing position.

This technique is very sensitive, and as you do a val Salva or take a breath in, you increase your hepatic venous pressure, which also increases the stiffness of the liver.

So we will talk about this a little bit more later in the talk in more detail.

The measurement should be taken in the right lobe of the liver, as has been found that in many studies that the left lobe of the liver measurements are often unreliable.

And this is found to be that the motion from the heart significantly interferes with the ability to get an accurate measurement in the left lobe of the liver.

You also want to avoid the first one and a half to two centimeters from the liver capsule.

And the reason for this is there's reverberation of the aphy push pulse and the B mode pulses.

And again, we'll give you artificially elevated numbers.

So you should take your measurements approximately two centimeters deep to the liver capsule, not the skin, the liver capsule, to optimize that aphy displacement that's used to calculate the sheer wave speed and give us better signal to noise.

You wanna avoid large blood vessels and bile ducts, not only because there's stiffness is different, but again, there may be reverberation of the sound waves from these vessels that cause an interference pattern and may give you inaccurate measurements.

You should also be concerned that it's not only vessels in that 2D view, but vessels that may be in or out of the plane.

So in addition to avoiding them in the plane scan a little bit above and below these to make sure that there's no large vessels near the volume that you're going to be evaluating.

And I believe that it's really important to get that aphy pulse perpendicular to the liver capsule because if you have an angle, then you're going to get refraction of that RFI pulse, which again decrease your signal to noise and provide you with less accurate measurements.

Examination Examples and Tips

So here's just some examples.

What we want to do is I prefer the patient obli.

Some people like to have them supine.

There's no difference.

I like the oly technique because I can rest my wrist on the patient because not only do I want the patient to hold still, I wanna make sure that I'm holding the probe very still.

You want to be parallel to the rib space so that again, we're getting a B mode image without any artifacts or any rib shadowing.

So you want to avoid doing measurements at depth.

And the reason for that is that again, the RV pulse is attenuated, and the deeper you go, the less signal to noise you have, the less accurate your measurements are going to be.

In general at this time.

All of the vendors probably will not allow you to get a measurement at less than eight centimeters from the skin surface because there's just not enough RV pulse left at those points.

To get a reasonable measurement, you wanna avoid imaging add vessels as well as adjacent to vessels because one, the vessel stiffness is different than the liver stiffness.

And two, you can get a refraction and reflection off the walls of the vessels that may cause interference with the measurement you want to avoid doing.