Fat, ballooning, plasma cells and a +ANA. Yikes! USCAP 2016 Evening Specialty Conference Cynthia Guy

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1 Fat, ballooning, plasma cells and a +ANA. Yikes! USCAP 2016 Evening Specialty Conference Cynthia Guy

2 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

3 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

4 Case History Laboratory values at presentation AST 75 [15-41 IU/L] ALT 46 [14 54 IU/L] Alkaline phosphatase 118 [ IU/L] Total bilirubin 1.1 [ mg/dl] Conjugated bilirubin 0.6 [ mg/dl] Ceruloplasmin 21 [20 35 mg/dl] Platelets 89 [ ] Anti-nuclear antibody (ANA) screen: Positive ANA titer 1:2560!

5 Case History Anti-smooth muscle antibody (SMA) screen: Negative Anti-mitochondrial antibody (AMA) screen: Negative Immunoglobulin (Ig) G 1730 [ mg/dl] IgA 457 [ mg/dl] IgM 114 [ mg/dl] Viral hepatitis markers: Negative

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12 Rosettes anyone?

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19 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

20 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

21 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

22 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?

23 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

24 Interface plate AIH

25 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 (1);S100-S111

26 Revised International Autoimmune Hepatitis Group Modified Scoring System Manns MP et al. J Hepatology (1);S100-S111

27 Revised International Autoimmune Hepatitis Group Modified Scoring System Manns MP et al. J Hepatology (1);S100-S111

28 Revised International Autoimmune Hepatitis Group Modified Scoring System Manns MP et al. J Hepatology (1);S100-S111

29 Revised International Autoimmune Hepatitis Group Modified Scoring System Manns MP et al. J Hepatology (1);S100-S111

30 Revised International Autoimmune Hepatitis Group Modified Scoring System Manns MP et al. J Hepatology (1);S100-S111

31 Revised International Autoimmune Hepatitis Group Modified Scoring System Manns MP et al. J Hepatology (1);S100-S111

32 Revised International Autoimmune Hepatitis Group Modified Scoring System Manns MP et al. J Hepatology (1);S100-S111

33 Revised International Autoimmune Hepatitis Group Modified Scoring System Manns MP et al. J Hepatology (1);S100-S111

34 Revised International Autoimmune Hepatitis Group Modified Scoring System Manns MP et al. J Hepatology (1);S100-S111

35 Revised International Autoimmune Hepatitis Group Modified Scoring System Manns MP et al. J Hepatology (1);S100-S111.

36 Revised International Autoimmune Hepatitis Group Modified Scoring System Total score so far = = Probable AIH >15 = Definite AIH Manns MP et al. J Hepatology (1);S100-S111

37 Revised International Autoimmune Hepatitis Group Modified Scoring System Manns MP et al. J Hepatology (1);S100-S111

38 Revised International Autoimmune Hepatitis Group Modified Scoring System Liver histology Score Comments Interface hepatitis +3 Lymphoplasmacytic infiltrate Hepatocyte rosette pattern of regeneration 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 (1);S100-S111.

39 Revised International Autoimmune Hepatitis Group Modified Scoring System Liver histology Score Comments Interface hepatitis +3 Lymphoplasmacytic infiltrate Hepatocyte rosette pattern of regeneration 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 (1);S100-S111.

40 Revised International Autoimmune Hepatitis Group Modified Scoring System Liver histology Score Comments Interface hepatitis +3 Lymphoplasmacytic infiltrate Hepatocyte rosette pattern of regeneration 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 (1);S100-S111.

41 Revised International Autoimmune Hepatitis Group Modified Scoring System Liver histology Score Comments Interface hepatitis +3 Lymphoplasmacytic infiltrate Hepatocyte rosette pattern of regeneration 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 (1);S100-S111.

42 Revised International Autoimmune Hepatitis Group Modified Scoring System Liver histology Score Comments Interface hepatitis +3 Lymphoplasmacytic infiltrate Hepatocyte rosette pattern of regeneration 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 (1);S100-S111.

43 Revised International Autoimmune Hepatitis Group Modified Scoring System Liver histology Score Comments Interface hepatitis +3 Lymphoplasmacytic infiltrate Hepatocyte rosette pattern of regeneration 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 (1);S100-S = Probable AIH >15 = Definite AIH

44 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.

45 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 Dec 28 [Epub ahead of print]. Corey KE and Rinella ME. Dig Dis Sci March 2016

46 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

47 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

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52 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.

53 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

54 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!

55 Thank you!

56 Boberg KM et al. J Hepatology 2011;54:

57 Boberg KM et al. J Hepatology 2011;54:

58 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

59 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): liver biopsies from NASH + HCV, or AIH, or PBC %

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