Transcript
Page 1: Autoimmune Hepatitis or Drug Induced Liver Injury

Autoimmune Hepatitis or Drug Induced Liver Injury

Keith D. Lindor, M.D. Arizona State University

Tempe, AZ

Presenter
Presentation Notes
Thank you. Well, it's very nice to be here. My focus today is going to be trying to help, looking at a patient's perspective, using a clinician's viewpoint, how we might differentiate a drug-induced liver injury from autoimmune hepatitis. As Chris said, this is not an easy task. What I thought I'd do in this talk is first talk about autoimmune hepatitis, give you some background, some views of what it looks like as a clinical presentation, and then briefly talk about drug-induced liver injury, and show you really how difficult it can be to distinguish between the two, both on clinical, serologic and typical liver biochemical grounds. And then talk about the histology, and it is is largely drawn from a paper that we published last September, looking at histologic features of drug-induced liver injury versus autoimmune hepatitis.
Page 2: Autoimmune Hepatitis or Drug Induced Liver Injury

AUTOIMMUNE HEPATITIS 100,000 – 200,000 persons in USA Female>Male, all ages, occurs worldwide

Presenter
Presentation Notes
Autoimmune hepatitis is probably not quite as common as this slide says. We usually think in terms of 100 per million. So this would be somewhere around half as common as this would represent. It occurs more often in women than men, and it occurs really in all ages.
Page 3: Autoimmune Hepatitis or Drug Induced Liver Injury

Etiology

– Unknown – usually no trigger identified – Viruses, drugs (minocycline) and herbal

preparations can trigger – Disease can persist despite withdrawal of

trigger – ? Molecular mimicry between foreign and self

antigens – Associated with other AI diseases

Presenter
Presentation Notes
We don't know what causes autoimmune hepatitis. Something seems to trigger it in many cases. It could be a virus, a drug, herbal preparation. We oftentimes don't know. There's probably a genetic predisposition. HLA phenotyping helps us with this. One of the challenges has been that there can be what seems like an acute event, and then a long-lasting autoimmune process seems to occur. There may be -- part of this may be molecular mimicry between the inciting antigen and pieces of the liver in which the immune response then is perpetuated against. There is a strong association of autoimmune hepatitis with other autoimmune kinds of disease. I think helping suggest that there may be this genetic predisposition to an autoimmune process that becomes self-perpetuating and won't shut off.
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AUTOIMMUNE HEPATITIS Disease Spectrum

Classical chronic hepatitis + cirrhosis “Burned-out” cirrhosis Acute hepatitis Fulminant hepatitis Overlap syndrome with PSC or PBC

Presenter
Presentation Notes
The presentation for autoimmune hepatitis can be very varied. It can range from cirrhosis and patients recovering from liver transplantation, to a very mild, burnt out cirrhosis, which is oftentimes only discovered incidentally at the time of imaging or other testing. It could present acutely in about 20 percent or so of patients with autoimmune hepatitis having acute presentation. It can be fulminant. These patients can look like they're going to die if they don't require a transplant or steroid therapy. They may be deeply jaundiced. It could also be confused with other chronic liver diseases, such as primary biliary sclerosis or primary sclerosing cholangitis.
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AUTOIMMUNE HEPATITIS Diagnosis

International AIH scoring system Complicated

Histologic hallmark is interface hepatitis, but not specific Hypergammaglobulinemia and autoantibodies No cholestatic features No drug or viral cause, alcohol limit 25 g/d

Alvarez F, et al. J Hepatol 1999;31:929-38; Hennes EM, et al. Hepatology 2008;48:169-76

Presenter
Presentation Notes
So it's not a neat diagnostic category in and of itself, when we as clinicians see patients with this problem. There have been a variety of scoring systems that have been used to try and help identify these patients. These scoring systems are often useful in categorizing patients when we look at combined series. But their application amongst individuals with the disease is sometimes troublesome. So useful for broad categorization, but as clinical tools for individual diagnosis, they leave quite a bit to be desired.
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HISTOLOGY

Interface Hepatitis Lympho-Plasmacytic

infiltrate Interface hepatitis Lympho-Plasmacytic

infiltrate

Presenter
Presentation Notes
All of the diagnoses for autoimmune hepatitis rely on histology. Primary biliary sclerosis, primary sclerosing cholangitis, hemochromatosis. We've moved away from in many chronic liver diseases from requiring a liver biopsy. Autoimmune hepatitis requires a liver biopsy for its diagnosis. These patients have evidence of a heightened immune response, with elevated gammaglobulin levels and auto-antibodies. They typically don't have cholestatic features. Some may have some bile duct injury, but that's not the typical feature, and usually we can't find a specific cause, including excess alcohol use. The characteristic histologic features, that of interface hepatitis. Interface hepatitis, when we think of the liver, we think of portal spaces where the vessels and the bile ducts flow, and then the liver parenchyma, where the hepatocytes reside. That limitation is called the limiting plate. If I was going to use this room as a model for the liver, I would probably call the tables the portal tracks, and the spaces in between the hepatocytes. So the edges of the table would be the limiting plate. So interface hepatitis is inflammation that extends from the portal space into the hepatic parenchyma, and that's characteristic of autoimmune hepatitis. But it also characterizes Stage 2 PBC, Stage 2 PSC, and so it isn't unique to this disease. Also, the types of cells that we see, we heard some of this discussion earlier in some of the models, is lymphocytoplasmic. It's not usually neutrophils; it's more of a chronic inflammatory condition, but again not unique. So the histologic features are suggested, but they're not unique to making this diagnosis.
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AUTOIMMUNE HEPATITIS Clinical Features

Patients, % Clinical features female 70 < 40 yrs old 50 acute onset 40 fatigue 85 jaundice 46 myalgias 30 hepatomegaly 78

Presenter
Presentation Notes
Now there are a variety of other clinical features that can help, but these are again fairly non-specific: muscle aches, large liver, tiredness are suggestive, but clearly don't make the diagnosis.
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AUTOIMMUNE HEPATITIS Subtypes

Type 1 Type 2

Characteristic autoAbs 75%ANA, SMA anti-LKM1

Associated autoAbs pANCA,SLA/LP anti-LC-1

Age at onset all ages 2-14 yrs

Associated diseases thyroiditis UC synovitis

vitiligo type 1 diabetes

Treatment steroids steroids

Tx failure uncommon common

Presenter
Presentation Notes
We do look at auto-antibodies. These could be helpful, and some who have been more interested in splitting different types have split one type that's uncommon in adults, LKM-1 Type 2 autoimmune hepatitis. Two to three percent maybe of the adult population have this. It's more common in children. LKM antibody characterizes this. Most people with autoimmune hepatitis have auto-nuclear or anti-nuclear antibodies or anti-smooth muscle antibodies. But again, this can be seen in drug-induced liver injury. They can have a variety of other associated diseases. I mentioned the autoimmune diseases. Thyroiditis is probably the most common of these, ulcerative colitis and a few diabetes and less. Fortunately autoimmune hepatitis has a treatment. It's cortical steroids with or without azathioprine, and this is effective in most people.
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AUTOIMMUNE HEPATITIS Genetic Predispositions

HLA-DR3 and HLA-DR4 present in most Caucasian North American and Northern European patients with type 1 autoimmune hepatitis

HLA-DR3 (DRB1*0301) associated with early-age onset, more treatment failure and frequent need for liver transplantation

HLA-DR4 (DRB1*401) associated with a good treatment result, older patients, and frequent concurrent immune diseases

Presenter
Presentation Notes
I mentioned the genetic background. These are some of the HLA associations that have been made with autoimmune hepatitis. Some are associated with earlier onset, more severe disease, whereas others, HLA-DR4, seem to be associated with a less severe course of the disease.
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NATURAL HISTORY

Czaja A. Atlas Liver Disease 2005

Presenter
Presentation Notes
So a little prognostic information, but again, diagnostically these have not been that helpful. Now the natural history, you may have trouble seeing this slide, really ranges from initial portal hypertension all the way through increased fibrosis to cirrhosis, which isolates the normal parts of the liver leading to portal hypertension, and possibly end stage liver disease. So there can be a broad spectrum of ways that this disease presents. Many times we see patients early on in the course of the disease.
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INDICATIONS FOR THERAPY Defined Not well defined

AST > 10 times ULN Mild disease

AST > 5 times ULN + IgG > 2 times ULN

Severe fulminant disease

Bridging or multilobular necrosis

Seronegative chronic hepatitis

Relative – symptoms, interface hepatitis, AST lower than absolute criteria

Asymptomatic patients may not required therapy

Feld JJ, et al; Hepatology 2005;42:53-62

Presenter
Presentation Notes
If they're effectively treated, they may have a normal life expectancy. If they aren't effectively treated, they will go on, in many cases, to develop cirrhosis and the need for liver transplantation. This is not a common reason for liver transplantation, but it is still an important cause for transplants in adults. There have been some well defined studies, now 40 years old, that talk about the criteria for treating patients. Those with most severe inflammation, whether it's measured by elevated transaminases or more severe hepatic histologic features are those that respond best to therapy. There's a gray zone. Some patients have very mild disease. We don't know whether in those the side effects from the prednisone azathioprine outweigh the potential benefits. The patients with very minimal inflammation may have a very, very long natural history, oftentimes undefined. So it's a matter of weighing the risk versus the benefit. I think what we've seen over the years is more and more people with less severe disease undergoing treatment, particularly as we've had more experience with use of azathioprine, sometimes as monotherapy after remission has been induced.
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Drug Induced Liver Injury (DILI) Vs. Autoimmune Hepatitis (AIH) AIH DILI Distinguishing features in histology

Presenter
Presentation Notes
Now to try and make a distinction between these two can be challenging. I'll focus mostly on histology, but let me try to put drug-induced liver injury into a little bit of a perspective.
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DILI – not common

1:10000 to 1:100000 treated >1000 drugs Risk - >50 mg/day hepatic metabolism,

mitochondrial dysfunction (diabetes)

Presenter
Presentation Notes
It's in the same range of frequency as autoimmune liver disease. So when a patient presents, the odds are about the same that it could be drug-induced liver injury or autoimmune hepatitis. So many drugs cause this that it's really -- and so many patients are on multiple drugs that just the drug history itself doesn't help distinguish it. Most of the people who -- many people who come with autoimmune hepatitis are going to be on a drug that has been known to be associated with drug-induced liver injury. We talked about the dose. Patients who have mitochondrial dysfunction, particularly diabetics, which we're seeing increasingly now as a wave of obesity passes through the nation, seems to predispose people to drug-induced liver injury.
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Clinical Manifestations

Minor liver abnormalities Autoimmune hepatitis Fulminant hepatitis

Presenter
Presentation Notes
As you know, this can present from minor liver injuries to autoimmune hepatitis to fulminant, the same spectrum that autoimmune hepatitis can have.
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DILI or AIH

Can be impossible to differentiate by Clinical presentation auto antibodies Histology may help but not perfect

Presenter
Presentation Notes
The clinical presentation does not distinguish drug-induced disease from autoimmune hepatitis. Auto-antibodies can't necessarily distinguish these. You all are aware of patients with drug-induced liver injury who have auto-antibodies that are induced. The auto-antibodies are probably more commonly seen in patients than autoimmune hepatitis, but there's not a clear distinction. So a patient who you are suspecting has drug-induced liver injury, and has auto-antibodies, cannot be classified as autoimmune hepatitis. I think the reason that John asked me to give this talk for this group had to do with this paper that was published in Hepatology this past September. Einar Bjornsson from then Sweden now Iceland, was with us for a sabbatical year, and was sort of the driving force behind this study. So we've looked at patients from Mayo Clinic, who we thought had well-characterized autoimmune hepatitis, and then a similar number of patients from the Spanish registry of drug-induced liver injury.
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Histology of DILI vs. AIH 35 DILI (19 hepatocellular 16 cholestasis) 28 AIH 4 pathologists

– 65 % agreement in clinical diagnoses – 46% agreement in 4 pathologist

Table 3. Agreement Between Clinical and Histological Diagnosis for AIH, DILI (HC), and DILI (CS)

Histological Diagnosis

Clinicopathologic Diagnosis

N

AIH (%)

DILI (%)

Indeterminate (%)

AIH 28 71.4 (20) 0.0 (0) 28.6 (8) DILI (HC) 19 15.8 (3) 57.9 (11) 26.3 (5) DILI (CS) 16 12.5 (2) 62.5 (10) 25.0 (4) DI-AIH* 7 57.1 (4) 28.6 (2) 14.3 (1)

Presenter
Presentation Notes
We had a group of really top notch pathologists. Paul asked if David Kleiner was here. I have kept a very close eye on whether David was here or not. He was one of the pathologists. I told him this morning I felt very uncomfortable discussing the histology when he was sitting right there. He had another meeting this afternoon. So we have a group of several hepatologists who characterize the patient's clinical features, and five pathologists who reviewed the material. I think one of the things that I wanted to point out is even with a very robust group of pathologists with dedicated time to spend doing this, we had only about 65 percent agreement on a clinical diagnosis, and that was amongst the hepatologists. When we looked at the pathologists, there was about 46 percent agreement. So that's one of the challenges as we look at histologic features, is that it can be tough. This slide, this table from the paper shows where some of the challenges occurred. So in the patients that we thought had autoimmune hepatitis, usually the pathologist thought it was or indeterminate in about a quarter of the case. If we thought it was drug-induced liver disease, the pathologist agreed about 60 percent of the time. So the clinicians are on the left; the pathologists are the along the top. So this is again one of the challenges. So these are experienced clinicians, experienced pathologists with time to do this study, and this is one of the shortcomings of the pathologists, of the histologic differentiation.
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AIH vs. DILI More severe in AIH

– Interface hepatitis – Focal necrosis – Portal inflammation

AIH proven by – Portal and intra-acinar plasma cells – Rosette formation – Emperiopolesis

Presenter
Presentation Notes
Now in autoimmune hepatitis. The interface hepatitis, which I talked about, is usually more prominent. That's a characteristic feature of that condition. We might see more focal necrosis areas, where there's focal inflammation in the liver parenchyma, and much of the autoimmune hepatitis is around the portal tracks. In the model of this room, that would be inflammation on top of your table. There are other things that help show this, some unusual features. Rosetting, where cells group together. But these are not common. Some of these findings are not perfect.
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(A) Plasma cell (B) Plasma cells with apoptotic body (C) Canalicular cholestasis (D) Rosettes (white arrow)

Drug-induced Liver Injury

Presenter
Presentation Notes
So this is showing drug-induced liver injury, and you'll see that the next slide shows autoimmune liver injury, and you'll see how similar they look. Both have plasmacytic infiltrates. They have some element of interface hepatitis and both have drug-induced liver injuries as well as autoimmune hepatitis can show the hepatic rosettes. In the drug-induced liver injury panel C, difficult to see as it projects. Easier to see on the original paper. There's a little bit of cholestasis, so some bile staining.
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Autoimmune hepatitis

(A) Interface hepatitis (B) An expanded portal tract (white arrows) (C) As above eosinophils (D) plasma cells

Presenter
Presentation Notes
This is now autoimmune hepatitis. Perhaps one is struck by more inflammation. It looks like it's more an inflammatory condition. Some of it relates to the power of magnification. See the interface hepatitis, which is a little bit more prominent in some of the plasmacytic cells. But in general, I think you can see, from this to this, if you're a pathologist looking at this, how they're not clearly separate features, and this is one of the challenges with the histologic approach.
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AIH vs. DILI

Model for hepatocellular vs AIH

Table 5. Models to Predict DILI (HC) Versus AIH and DILI (CS) Versus AIH

A. Model for DILI (HC) Versus

AIH

AUROC 0.90 Estimates SE P Value

Intercept 1.304 1.510 0.388 Portal inflammation* -0.939 1.080 0.384 Prominent intra-acinar lymphocytes 1.832 1.116 0.101 Prominent intra-acinar eosinophils -1.871 1.358 0.168 Cholestasis canalicular 1.700 1.051 0.106 Prominent portal-plasma cells -2.177 0.891 0.015 Rosette formation -1.659 0.895 0.064

Presenter
Presentation Notes
In this study, we were able to ask the pathologists to look at various components, and they were able to look at -- there are two kinds of drug-induced liver injury. One was hepatocellular, and then in this series about half are cholestatic. These are the features, so portal inflammation, intra-acinar lymphocytes or eosinophils, cholestasis and a rosette formation, while pieces of the predictor, to try and differentiate autoimmune hepatitis from drug-induced liver injury. The other end of the curve was good at 0.9.
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Model for cholestatic DILI or AIH

B. Models for DILI (CS) Versus AIH

AUROC 0.90

Model 1

Estimates SE P Value

Intercept 2.193 1.510 0.147 Portal inflammation* -1.773 1.112 0.111 Fibrosis† -1.951 1.270 0.124 Prominent portal-neutrophils 2.291 1.388 0.099 CS-intracellular 2.709 1.490 0.069 Focal necrosis‡ -1.738 1.233 0.159

Presenter
Presentation Notes
A slightly different model was used for cholestatic, the CS, the cholestatic variant, and again it's inflammation. This time it was fibrosis. Neutrophils, which didn't appear in the other one, but oftentimes is a sign of bile duct injury, the cholestasis again and focal necrosis. So I'm showing the two models. Not exactly the same features, but using these features, the pathologists were able to construct a model that led to pretty good differentiation. The other end of the curve was again 0.9. But complicated, and when you think about their intra-observer agreement, in all of these various components if their agreement on each one of these was running at that rate, there's some limits to the use of models such as this. So these are some of the things that they had pointed out, as features that support drug-induced liver injury.
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Table 6. Histologic Features Favoring AIH Versus DILI

Favoring

Histologic Features AIH DILI

Severe portal inflammation (2:grade 2) Prominent intra-acinar lymphocytes

* *h

Prominent intra-acinar eosinophils * Cholestasis canalicular *h, *c Prominent portal plasma cells * Rosette formation * Any levels of fibrosis (2:grade 1) Prominent port neutrophils

* *c

Hepatocellular cholestasis *c Several focal necrosis (2:grade 4) *

Presenter
Presentation Notes
You can see this will be in your handout. I won't go through all of this. But it shows that there are specific features that may favor one or the other, but again, it's not going to be a totally clear-cut differentiation.
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Conclusion

There is overlap histologically Problems with inter-observer agreement Patterns of injury can be useful

Presenter
Presentation Notes
When we try to use histology to differentiate, there really is substantial overlap histologically in the patterns of injury that we see with autoimmune hepatitis. There are other challenges with inter-observer agreement, not only with the clinicians looking at the material but also with the pathologists. There are some patterns that can be suggestive, but they're not going to be definitive. Someone earlier had mentioned the Spanish registry study that was recently published in Journal of Hepatology, in which they had nine out of 700-some patients who had a recurrence of drug-induced liver injury to a different drug. Of that nine, four in retrospect were thought to have autoimmune hepatitis. So it may be that the presence of recurrent drug-induced liver injury, two different agents, is simply a sign for underlying but uncovered autoimmune hepatitis. Thank you for the attention.

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