PDF Handout

Fat, ballooning, plasma cells
and a +ANA. Yikes!
USCAP 2016
Evening Specialty Conference
Cynthia Guy
Goals
 Share an interesting case
 Important because it highlights a common problem that


we’re likely to see with increasing frequency
This situation can be a little frightening to a pathologist
who doesn’t frequently see a high volume of liver cases
Discuss a strategies for working through these type cases
Case History
 A 67 year old Caucasian woman presented to her local emergency

room with complaint of right upper quadrant abdominal pain and
subsequently underwent cholecystectomy. At the time of
cholecystectomy, the liver looked nodular and a needle core biopsy
was obtained.
Past medical history and physical exam
 Systemic hypertension and hyperlipidemia
 Height = 5’ 4”, weight = 155 lbs, BMI = 26
 The patient denied alcohol consumption
 There was no personal history or family history of autoimmune
disorders
Case History
 Laboratory values at presentation
 AST 75 [15 - 41 IU/L]
 ALT 46 [14 – 54 IU/L]
 Alkaline phosphatase 118 [24 – 110 IU/L]
 Total bilirubin 1.1 [0.4 – 1.5 mg/dL]
 Conjugated bilirubin 0.6 [0.1 – 0.6 mg/dL]
 Ceruloplasmin 21 [20 – 35 mg/dL]
 Platelets 89 [150 – 450]
 Anti-nuclear antibody (ANA) screen: Positive
 ANA titer 1:2560!
Case History






Anti-smooth muscle antibody (SMA) screen: Negative
Anti-mitochondrial antibody (AMA) screen: Negative
Immunoglobulin (Ig) G 1730 [588 – 1573 mg/dL]
IgA 457 [46 – 287 mg/dL]
IgM 114 [57 – 237 mg/dL]
Viral hepatitis markers: Negative
Rosettes anyone?
Does our patient have NASH
(nonalcoholic steatohepatitis)?
Does our patient have AIH
(autoimmune hepatitis)?
Does our patient have both NASH and AIH?
 Why does it matter?
 The etiology, natural history and therapies are very different.
 From the clinical setting and labs alone the hepatologist
can’t be certain which disease is
at play
 The biopsy interpretation is critical
Does our patient have NASH?
Does our patient have AIH?
Does our patient have both NASH and AIH?
 Why is this scary?
 Untreated AIH can be very serious and progressive; however, many

treated patients have sustained responses and can achieve
remission
But immunosuppressive therapy can have serious long term side
effects such as weight gain, worsening steatohepatitis, and
osteopenia
Does our patient have NASH?
 One of the most common definitions of NASH includes:
 steatosis
 ballooning +/- Mallory-Denk bodies
 lobular inflammation
 pericellular fibrosis
 Yes, the clinical setting is appropriate and the histological
findings are consistent with NASH
This woman has an ANA of 1:2560 and elevated
immunoglobulins including IgG and IgA, raising the question
of coexisting autoimmune hepatitis.
One of the key histologic features of AIH is interface hepatitis.
So a large part of the question becomes: Does our patient
have interface hepatitis? (Does our patient have chronic
hepatitis?)
How do we go about sorting this out?
Autoimmune hepatitis
 AIH is a chronic self-perpetuating inflammatory liver disease. It may



•
•
•
•
start with an episode of acute hepatitis and can lead to cirrhosis.
Female predominance
The standard of care includes immunosuppression with
corticosteroids alone or in combination with azathioprine
The classic histopathologic lesions include:
interface necrosis and inflammation (interface hepatitis)
rich in plasma cells and lymphocytes
hepatocyte rosetting
lobular (centrivenular) hepatitis with necrosis
AIH
Interface plate
Making the diagnosis of
autoimmune hepatitis
The diagnosis of AIH is based on the clinical setting, laboratory findings
and the histological features.
The International Autoimmune Hepatitis Group (IAIHG) created a
diagnostic scoring system developed in 1993 that was revised in 1999
• IAIHG scoring system guides clinical decision making
• It’s perceived as “objective”! It’s based on numbers.
• Therefore pathologists should be aware of this scoring system as well
as it’s limitations
Manns MP et al. J Hepatology. 2015 62(1);S100-S111
Revised International Autoimmune Hepatitis
Group Modified Scoring System
Manns MP et al. J Hepatology. 2015 62(1);S100-S111
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Manns MP et al. J Hepatology. 2015 62(1);S100-S111
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Manns MP et al. J Hepatology. 2015 62(1);S100-S111
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Manns MP et al. J Hepatology. 2015 62(1);S100-S111
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Manns MP et al. J Hepatology. 2015 62(1);S100-S111
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Manns MP et al. J Hepatology. 2015 62(1);S100-S111
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Manns MP et al. J Hepatology. 2015 62(1);S100-S111
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Manns MP et al. J Hepatology. 2015 62(1);S100-S111
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Manns MP et al. J Hepatology. 2015 62(1);S100-S111
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Manns MP et al. J Hepatology. 2015 62(1);S100-S111.
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Total score
so far =
14
10-15 = Probable AIH
>15 = Definite AIH
Manns MP et al. J Hepatology. 2015 62(1);S100-S111
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Manns MP et al. J Hepatology. 2015 62(1);S100-S111
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Liver histology
Score
Interface hepatitis
+3
Lymphoplasmacytic
infiltrate
+1
Hepatocyte rosette
pattern of regeneration
+1
None of the above
-5
Biliary changes
-3
Biliary changes include
feature of bile duct injury
and/or inflammation (PBC or
PSC-like changes)
Other features
-3
Features suggesting any other
etiology (e.g., NAFLD)
Manns MP et al. J Hepatology. 2015 62(1);S100-S111.
Comments
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Liver histology
Score
Interface hepatitis
+3
Lymphoplasmacytic
infiltrate
+1
Hepatocyte rosette
pattern of regeneration
+1
None of the above
-5
Biliary changes
-3
Biliary changes include
feature of bile duct injury
and/or inflammation (PBC or
PSC-like changes)
Other features
-3
Features suggesting any other
etiology (e.g., NAFLD)
Manns MP et al. J Hepatology. 2015 62(1);S100-S111.
Comments
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Liver histology
Score
Interface hepatitis
+3
Lymphoplasmacytic
infiltrate
+1
Hepatocyte rosette
pattern of regeneration
+1
None of the above
-5
Biliary changes
-3
Biliary changes include
feature of bile duct injury
and/or inflammation (PBC or
PSC-like changes)
Other features
-3
Features suggesting any other
etiology (e.g., NAFLD)
Manns MP et al. J Hepatology. 2015 62(1);S100-S111.
Comments
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Liver histology
Score
Interface hepatitis
+3
Lymphoplasmacytic
infiltrate
+1
Hepatocyte rosette
pattern of regeneration
+1
None of the above
-5
Biliary changes
-3
Biliary changes include
feature of bile duct injury
and/or inflammation (PBC or
PSC-like changes)
Other features
-3
Features suggesting any other
etiology (e.g., NAFLD)
Manns MP et al. J Hepatology. 2015 62(1);S100-S111.
Comments
?
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Liver histology
Score
Interface hepatitis
+3
Lymphoplasmacytic
infiltrate
+1
Hepatocyte rosette
pattern of regeneration
+1
None of the above
-5
Biliary changes
-3
Biliary changes include
feature of bile duct injury
and/or inflammation (PBC or
PSC-like changes)
Other features
-3
Features suggesting any other
etiology (e.g., NAFLD)
Manns MP et al. J Hepatology. 2015 62(1);S100-S111.
Comments
Revised International Autoimmune Hepatitis Group
Modified Scoring System
Liver histology
Score
Interface hepatitis
+3
Lymphoplasmacytic
infiltrate
+1
Hepatocyte rosette
pattern of regeneration
+1
None of the above
-5
Biliary changes
-3
Biliary changes include
feature of bile duct injury
and/or inflammation (PBC or
PSC-like changes)
Other features
-3
Features suggesting any other
etiology (e.g., NAFLD)
Manns MP et al. J Hepatology. 2015 62(1);S100-S111.
Comments
110-15 = Probable AIH
>15 = Definite AIH
The main findings of this study were:
(1) the AIH score without liver biopsy results was not useful for diagnosis
of AIH in NAFLD patients
(2) patients with NAFLD had a higher prevalence of ANA positivity than did
patients with other chronic liver disease
(3) ANA positivity was significantly higher in female patients than in male patients,
while obesity was significantly associated with a high ANA titer (≥1:80) in NAFLD patients
(4) the presence of ANA did not have prognostic clinicopathological significance
In patients who have both elevated ANA titers and risk factors for NAFLD,
these findings underscore the importance of performing a liver biopsy to make a
definitive diagnosis [of AIH] before starting corticosteroid therapy.
High prevalence of NAFLD
PubMed/MEDLINE search
Discussion: This meta-analysis included 86 studies from 22 countries.
From the available data, “we estimate that 25% of the adult
population in the world has NAFLD.”
The current world population is 7.4 billion people x 25% =
1.8 billion people with NAFLD
USA 80 million people have NAFLD
Younossi ZM et al. Hepatology. 2015 Dec 28 [Epub ahead of print].
Corey KE and Rinella ME. Dig Dis Sci March 2016
Autoimmune antibodies
in NAFLD
Can be seen at
high titers
Adams LA et al. Am J Gastroenterology 2004
Vuppalanchi R et al. Hepatol International 2012
Yatsuji S et al. J Gastroenterology 2005
Comparison case
 29 year old female with an established history of AIH for the





past several years
The patient remains on azathioprine 100 mg per day
LFTs were all within normal limits including ALT 18, AST 22
Interval 6 month follow up
Liver biopsy was performed to determine whether
immunosuppression can be discontinued
The liver biopsy was 23 mm long with 13 portal triads
 The comparison case highlights the need to understand
the complete clinical setting.
 A subtle finding in one biopsy may have different
implications in another setting.
 Communicating with the hepatologist is always a good idea.
 Reviewing cases together is often the best.
In Summary:
Lessons Learned And Suggested
Approach to Such Cases
 The prevalence of NAFLD is high around the globe
 NAFLD patients with elevated autoantibodies (possibly high

titers) and immunoglobulins will likely be commonly
encountered and this ≠ co-existing AIH (“chronic hepatitis”)
Don’t use the “C” word (chronic hepatitis) or the “I” word
(interface hepatitis) unless you mean it
In Summary:
Lessons Learned And Suggested
Approach to Such Cases
 Our patient has NASH. It’s important to say that.
 If you cannot be certain about interface necrosis, say that.
You could make a comment in which you describe what you
see and say that rare foci of interface inflammation are
present and minimal interface hepatitis cannot be excluded
although it is not favored.
 Don’t be afraid. You’ve got this!
Thank you!
Boberg KM et al. J Hepatology 2011;54:374-385
Boberg KM et al. J Hepatology 2011;54:374-385
Overlap syndromes
Co-existing diseases
Dunlap Syndromes?
Urban Dictionary:
A condition in which the person’s stomach folds over
their pants and past their belt. Origin probably with
"That guy's gut has "done lap"ed
over his belt. Hence the name "Dunlap Disease".
NAFLD co-existing with another
liver disease
AIH
PBC
PSC
With the high prevalence of NAFLD are we going to start
seeing larger numbers of cases with co-existing
diseases?
The co-existence of NAFLD with another form of liver disease?
Modern Pathol. 2003;16(1):49-56
93 liver biopsies from 1997-2000.
NASH + HCV, or AIH, or PBC
7.9 -1.6%