S1727 Beyond Elevated Liver Enzymes: Recognizing Patterns of Liver Injury
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1 S1727 Beyond Elevated Liver Enzymes: Recognizing Patterns of Liver Injury Safia N. Salaria, MD, FCAP Mary Kay Washington, MD, PhD, FCAP
2 Objectives Identify patterns of liver injury caused by biliary disease, autoimmune disease, and chronic hepatitis Effectively diagnose and differentiate cirrhosis from hepatoportal sclerosis Recognize drug reaction (ie, cholestasis, bile duct injury) Integrate laboratory values and pathologic features to formulate a cohesive diagnosis 2
3 We noticed in our practice Disagreements with outside pathologists around diagnosis of: Autoimmune liver disease (PBC, PSC, AIH) Drug-induced liver injury Assessment of fibrosis (staging) Non-cirrhotic portal hypertension These disagreements are driven by missing clinical data (biopsies are at done at radiology offices), but using a pattern-based approach can help. 3
4 A confused 38 year old man presents to the emergency room complaining of severe abdominal pain for 48 hours. Review of his past medical records reveal a history of depression. Liver chemistries show marked elevations of transaminases with almost normal bilirubin: AST 1500 IU/L (normal range 5-40 IU/L) ALT 1100 IU/L (normal range 0-56 IU/L) ALP 120 IU/L (normal range IU/L) Total bilirubin 2.1 mg/dl (normal range mg/dl) Prothrombin time 21.7 (normal range seconds) INR 2.0 4
5 ACETAMINOPHEN RELATED LIVER TOXICITY 5
6 LIVER TESTS 6
7 Liver Tests: What do surgical pathologists need to know? Many liver biopsies are performed because of persistently abnormal liver test values: 1. Unclear etiology (e.g., patient is obese but there is a positive ANA) 2. Confirmation of diagnosis of medical liver disease 3. To evaluate fibrosis (stage) or to rule out cirrhosis Normal = mean value ±2 standard deviations in the reference, normal population. 7
8 The Basics: Liver Tests 101 Test Marker Elevated in Comments Transaminases (ALT, AST) Hepatocellular integrity Hepatitis Alkaline phosphatase Cholestasis Biliary obstruction, PBC, PSC, DILI Inducible enzyme made by biliary epithelium GGT Cholestasis Multiple conditions Confirms hepatic origin of alkaline phosphatase elevation Bilirubin Hepatic function Multiple conditions Direct versus indirect fractionation may be helpful INR Hepatic function Liver failure, cirrhosis Used in Childs-Pugh, MELD prognostic systems PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; DILI, drug induced liver injury MELD, model for end-stage liver disease. 8
9 Secrets of the Hepatologists AST/ALT ratio 1: Acute liver disease Chronic liver disease without advanced fibrosis 1: Cirrhosis Alcoholic liver disease Wilson s disease Extrahepatic causes of aminotransferase elevation Platelet count Decreased in chronic liver disease, especially cirrhosis (decreased production, sequestration, increased destruction) 9
10 More Secrets of the Hepatologists When you see: AST/ALT in thousands, low bilirubin Low platelets in patient with chronic liver disease Think: Acetaminophen toxicity Cirrhosis AST/ALT ratio >2 with increased mean corpuscular volume Isolated alkaline phosphatase in young man Isolated alkaline phosphatase in middle aged woman Alcoholic liver disease PSC PBC 10
11 LIVER TESTS: TAKE HOME POINTS Remember that, liver enzymes alterations can be due to extrahepatic diseases. A systematic approach classifying hepatic biochemical abnormalities as hepatocellular or cholestatic helps to narrow the etiology Acetaminophen associated liver injury has a very distinctive pattern of liver tests and is rarely biopsied. The degree and pattern of inflammation, assessment of fibrosis and/or a mentioning a specific or differential diagnosis are pertinent elements in the pathology report 11
12 Autoimmune Liver Disease What is it? Why does it occur? Who gets it? When to suspect it? How to diagnose it? 12
13 Key Points: Three main categories of autoimmune liver disease 1. Autoimmune hepatitis 2. Primary biliary cholangitis/cirrhosis 3. Primary sclerosing cholangitis Characteristic morphologic patterns of injury 13
14 Autoimmune Hepatitis: What and Why? Unresolving hepatitis Increased IgG levels Tissue directed autoantibodies with loss of self-tolerance Responds to immunosuppression Small heritable component; complex genetic trait 14
15 Autoimmune Hepatitis: Who Gets It? Prevalence of ~ 1 per 100,000 in North America ~20% of chronic hepatitis Associated with HLA A1-B8-DR3 in European populations and DR4 in Japan More common in women Wide age distribution ~50% will have other autoimmune disorders 15
16 Autoimmune Hepatitis: When to Suspect It Chronic hepatitis pattern of injury Moderately to severely active acute hepatitis, especially with zone 3 injury Prominent plasma cells at interface and in lobule Negative viral studies 16
17 Autoimmune Hepatitis: How to Diagnose (Histologic Features) Chronic hepatitis pattern of injury Interface hepatitis Lobular activity Prominent plasma cells (IgG+, rarely IgM+) Hepatocyte rosette regeneration Centrilobular necroinflammatory activity in early disease Mild bile duct injury fairly common 17
18 Simplified Diagnostic Criteria for AIH Feature Cutoff Points ANA or SMA + >1:40 1 ANA or SMA + >1:80 2* OR LKM >1:40 OR SLM Positive IgG > Upper limit of normal 1 >1.1 x upper limit of normal 2 Liver histology Compatible with AIH 1 Typical AIH 2 Absence of viral hepatitis yes 2 *Addition of points achieved for all antibodies (max 2 points) >6: probable AIH >7 definite AIH 18
19 AUTOIMMUNE HEPATITIS 19
20 AUTOIMMUNE HEPATITIS 20
21 AUTOIMMUNE HEPATITIS 21
22 AUTOIMMUNE HEPATITIS 22
23 AUTOIMMUNE HEPATITIS 23
24 AUTOIMMUNE HEPATITIS 24
25 AUTOIMMUNE HEPATITIS TYPES I II Frequency 95% 5% Autoantibodies ANA, ASMA Anti LKM, Anti LC Demographics Adults Pediatrics Serum IgG levels Genetic predisposition (HLA) A1, B8, HLA-DR3 (DRB1*0301), DR4 (DRB1*0401) B14, DR3, C4AQ0 ANA, Antinuclear antibody; ASMA, anti-smooth muscle antibody; Anti-LKM, anti-liver-kidney microsomal antibody; Anti-LC, anti-liver cytosol antibody. 25
26 AUTOIMMUNE HEPATITIS: Treatment and Survival Immunosuppression Prednisone Azathioprine *10-year survival rate is up to 94% Liver transplantation for end-stage disease 96% survival at 5 years 30% recurrent disease, 3 years post transplant 26
27 AUTOIMMUNE HEPATITIS, TREATED 27
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30 Autoimmune Hepatitis: Diagnostic Difficulties Autoantibody negative patients Overlap with other autoimmune liver diseases Viral hepatitis DILI 30
31 AIH in the Elderly Over 20% are diagnosed after age 60 Often women with mild disease Responds to corticosteroid therapy, even in setting of cirrhosis HLA DR4 more common 31
32 Autoimmune Hepatitis and Viral Hepatitis True AIH, false positive anti-hcv Ab True HCV, autoantibodies at low titers True HCV and features of AIH Young women Extrahepatic autoimmune disorders High autoantibody titers Increased serum IgG 32
33 AIH: Differential Diagnosis Viral hepatitis Drug induced liver injury Serology Temporal relationship with use of drug Primary biliary cirrhosis Lack of definitive bile duct damage and florid duct lesions, hepatocyte necrosis is not prominent, Wilson s disease Alpha-1 antitrypsin Celiac disease Serum ceruloplasmin, 24 hour urine copper Intra-hepatocyte globules Clinical history; usual mild non-specific chronic hepatitis Chronic hepatitis of unclear etiology Reactive hepatopathy Spotty hepatocyte necrosis, no specific clinical features Mild non-specific chronic hepatitis in patients with other autoimmune diseases 33
34 Primary Biliary Cholangitis*: What and Who? Chronic cholestatic liver disease due to inflammatory destruction of intrahepatic bile ducts Serologic hallmark: circulating AMA Affects women (male-female ratio 1:9) Median age of onset 50 years (range 21-91) *The disease formerly known as primary biliary cirrhosis 34
35 PRIMARY BILIARY CHOLANGITIS/CIRRHOSIS 35
36 Pathogenesis of PBC: Why? Considered an autoimmune disorder Associated with Sjogren s disease, RA, autoimmune thyroiditis Multiple hit mechanism triggered by mimicry AMA directed against M2 antigen (E2 component of the pyruvate dehydrogenase complex) 36
37 PBC: Clinical Features 50-60% are asymptomatic at presentation Most common signs: pruritis and fatigue Elevated alkaline phosphatase Jaundice: in late stages Scleroderma, especially CREST syndrome, in 10% Gallstones in 50% 37
38 PBC: When to Suspect It alkaline phosphatase in middle-aged to elderly woman Bile duct injury and loss on biopsy No cholestasis in early stage disease Minimal lobular hepatitis 38
39 Pathology of PBC: How to Diagnose It Florid duct lesion: Inflammation Injury to bile duct epithelium Disruption of basement membrane 40 to 80 micron bile ducts Segmental destruction 39
40 PRIMARY BILIARY CIRRHOSIS 40
41 PRIMARY BILIARY CIRRHOSIS 41
42 Granulomas and PBC: Portal tracts Lobule Hilar lymph nodes Loose collection of epithelioid histiocytes Often found in earlier stages, ~50% of patients May portend better prognosis 42
43 Staging of PBC Stage Ludwig Scheuer 1 Portal Florid duct lesion 2 Periportal Ductular reaction 3 Septal Fibrosis 4 Cirrhosis Nodular cirrhosis Ludwig J, et al. Virchows Arch A 379: , Scheuer P. Proc Royal Soc Med 60: ,
44 Stage 1: Portal Florid duct lesion Portal inflammation Small portal tracts may lack bile ducts Kupffer cell aggregates, small granulomas in lobule; small collections of lymphocytes 44
45 Stage 2: Periportal Expansion Ductular reaction Portal tracts are enlarged Biliary piecemeal necrosis Lymphocytic interface hepatitis may predominate 45
46 Stage 3: Scarring Portal-portal fibrous septa Bile ductular reaction becomes less prominent Cholestasis and cholate stasis 46
47 Stage 4: Cirrhosis Profound loss of small and medium-sized ducts Usually no bile ductular reaction Cholate stasis with copper accumulation Mallory-Denk bodies 47
48 AMA Negative Primary Biliary Cirrhosis AMA absent in 10% of PBC patients Higher antibody & IgM levels Portal inflammation, less prominent Biochemical, clinical or histological feature, similar to AMA+ PBC Treatment and outcomes are similar to AMA+ PBC 48
49 PBC: Treatment and Survival Liver failure occurs in up to 20% of symptomatic patients and 5% of asymptomatic patients Ursodeoxycholic acid controls progression decreases liver enzymes Post transplant survival 80% at 2 years 70% at 7 years 49
50 PBC: Differential Diagnosis Primary sclerosing cholangitis (PSC) IBD, AMA -, abnormal cholangiography, extrahepatic ducts, periductal fibrosis of medium to large sized bile ducts, > ductular reaction Sarcoidosis AMA-, granulomas: larger, organized, greater in number, lobular and portal areas, no florid duct lesions, involves other organs e.g. lungs and skin Autoimmune hepatitis Drug induced liver injury Transaminases> alkaline phosphatase, IgG>IgM, lobular injury with hepatocyte damage is prominent, copper accumulation is not a feature AMA-, absence of florid duct lesions IBD, inflammatory bowel disease; AMA, anti-mitochondrial antibody; 50
51 Hepatic Sarcoidosis Almost 60% of cases of hepatic sarcoidosis showed evidence of cholestasis, usually chronic ~20% had bile duct lesions similar to those seen in PBC Granulomas of sarcoidosis are better formed and more numerous than PBC Devaney K, et al. Am J Surg Pathol 17: ,
52 Primary Sclerosing Cholangitis: What and Why? Chronic cholestatic liver disease, probably autoimmune in etiology (a-anca, p-anca, other autoantibodies) Affects extra- and intrahepatic biliary tree 52
53 Epidemiology of PSC: Who gets it? Male predominance (2:1 M/F) Median onset 30 years, range 1-90 yrs Prevalence in U.S. estimated as 2-7/100,000 70% of cases are associated with ulcerative colitis 53
54 PSC: When to Suspect it Young man with bile duct distortion or loss on biopsy Elevated alkaline phosphatase in young person, especially a young man Anyone with inflammatory bowel disease Liver biopsy may be virtually normal 54
55 PSC: Diagnosis Gold standard (MRCP) Multifocal stricturing and beading Involves both extra-and intrahepatic ducts in typical case Gallbladder and cystic duct are involved in ~15% 55
56 PSC: How to diagnosis it Concentric periductal fibrosis Rounded scars in portal tracts Distorted interlobular bile ducts Loss of small interlobular bile ducts (60% of cases) Superimposed changes of extrahepatic obstruction 56
57 PSC: Ductal lesions Periductal edema Periductal fibrosis Duct distortion Duct loss Often minimal inflammation 57
58 PSC: Ductal lesions 58
59 Biliary Cirrhosis in PSC 59
60 Primary Sclerosing Cholangitis: Natural History Clinical course is variable and unpredictable Obstructing strictures, bacterial cholangitis, biliary stone formation Cholangiocarcinoma Major cause of death in patients with ulcerative colitis Median survival from diagnosis 9-12 years Ursodeoxycholic acid Improves liver enzymes Limited effect on disease progression Transplantation Post-transplant frequency of recurrent PSC is estimated to be 20 25%. 60
61 SMALL DUCT PRIMARY SCLEROSING CHOLANGITIS Criteria: Chronic cholestatic liver disease of unknown etiology Histopathologic features suggestive of PSC Normal radiology studies i.e. endoscopic retrograde cholangiography, percutaneous cholangiography, magnetic resonance cholangiography [MRCP] Exclusion of other liver or biliary disease In some studies, diagnosis of IBD was required 61
62 SMALL DUCT PRIMARY SCLEROSING CHOLANGITIS 62
63 Liver transplantation free survival 63
64 PSC: Differential Diagnosis PBC Women, IgM, Antimitochondrial antibodies, normal radiology studies, portal granulomas and florid duct lesions IgG4 sclerosing cholangitis IgG4, pancreatic involvement typical, duct fibrosis and associated dense lymphoplasmacytic infiltrate, eosinophils are prominent, obliterative phlebitis, IgG4 positive plasma cells, involvement of peribiliary glands with sparing of bile duct epithelium. Secondary sclerosing cholangitis Diagnosis of exclusion Autoimmune hepatitis ASMA, ANA, IgG, normal radiology studies 64
65 Chronic Large Duct Obstruction May be difficult to distinguish from PSC Features common to both: periductal fibrosis bile ductular reaction cholestasis Bile duct loss does not occur in obstruction Finding numerous eosinophils favors PSC 65
66 PSC Obstruction 66
67 Demographics AIH PBC PSC More common in women 90% are female 70% are male (2:1 M:F) Wide age range ~20% of chronic hepatitis Middle aged or older; essentially never seen in children. Median age of onset 50 years (range 21-91) Wide age range, but generally young; median onset 30 years, range 1-90 yrs 67
68 Laboratory Tests AIH PBC PSC Increased AST, ALT, serum IgG, +/- bilirubin Increased alkaline phosphatase, serum IgM; bilirubin elevated late in disease Increased alkaline phosphatase; bilirubin, AST, ALT variable ANA, SMA + AMA + ANA, p-anca + 68
69 Major Histologic Features AIH PBC PSC Hepatitis, often chronic, of variable severity Less bile duct injury Florid duct lesion and bile duct loss Variable interface hepatitis; less lobular hepatitis Periductal fibrosis and bile duct loss with nodular scars Variable interface hepatitis 69
70 Treatment AIH PBC PSC Immunosuppression; recurs on withdrawal Ursodeoxycholic acid Ursodeoxycholic acid not recommended in AASLD 2014 guidelines Overlap syndromes: Treated with ursodeoxycholic acid + immunosuppression 70
71 Overlap Syndromes of Autoimmune Hepatopathies 8-14% AIH 6-8% PBC PSC Based on combined clinical, serologic, histologic features 71
72 OVERLAP SYNDROMES patients with autoimmune liver disease should be categorized according to the predominating feature(s) as AIH, PBC, and PSC/small duct PSC, respectively, and that those with overlapping features are not considered as being distinct diagnostic entities. The IAIHG scoring system should not be used to establish subgroups of patients 72
73 Autoimmune hepatitis + PBC PARIS CRITERIA AIH PBC ALT >5 x ULN Alkaline phosphatase >2 x ULN or GGT >5 x ULN IgG levels >2 x ULN or + SMA Positive AMA Liver biopsy with periportal interface hepatitis Liver biopsy with florid duct lesions Chazouillères O. et al. Hepatology 1998;28:
74 Autoimmune hepatitis + PBC 74
75 Autoimmune hepatitis + PBC 75
76 Autoimmune hepatitis + PSC (Autoimmune sclerosing cholangitis) Frequency of 6-11% Children -Teenage years -Intrahepatic disease predominates -50% IBD, 15% immunodeficiency -Langerhans cell histiocytosis The prevalence of IBD in overlap PSC AIH has been reported to be higher than in patients with AIH only UDCA + immunosuppressive/corticosteroid therapy Consider Autoimmune hepatitis + primary sclerosing overlap in patients with cholestatic liver chemistries, biliary damage on biopsy, and a poor response to AIH treatment. 76
77 Autoimmune hepatitis + PSC 77
78 Autoimmune hepatitis + PSC 78
79 Pearls of Pathology: Overlap Syndromes Classify autoimmune liver disease according to the dominant pattern Don t overinterpret Minor bile duct injury in AIH Interface hepatitis and plasma cells in PBC Remember Low titer AMA can be found in AIH 79 PSC may present in children with a hepatitic pattern PBC does not typically have prominent lobular hepatitis When possible, use published or standard criteria Paris criteria for AIH-PBC overlap syndrome is a good starting point 79
80 A 42 year old woman, with a history of rheumatoid arthritis for which she takes prednisone, presents with 9 months of persistently abnormal liver chemistries. Viral serologic studies are negative. The patient denies any over or off counter drug use. Liver tests show low grade elevation of transaminases with normal alkaline phosphatase and bilirubin. AST 80 IU/L (normal range 5-40 IU/L) ALT 100 IU/L (normal range 0-56 IU/L) ALP 50 IU/L (normal range IU/L) Total bilirubin 0.5 mg/dl (normal range mg/dl) ANA titer 1:640 ASMA titer 1:80 A liver biopsy is performed. 80
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84 An 12 year old female presents with a 3 year history of ulcerative colitis presents with elevated liver enzymes. Liver tests show a mixed cholestatic/hepatitis pattern of injury with elevated alkaline phosphatase, GGT, and transaminases with normal bilirubin. AST 210 IU/L (normal range 5-40 IU/L) ALT 170 IU/L (normal range 0-56 IU/L) ALP 520 IU/L (normal range IU/L) GGT 64 IU/L (normal range 2-40 IU/L) Total bilirubin 0.9 mg/dl (normal range mg/dl) ANA titer: 1:80 ASMA titer 1:80 A liver biopsy is performed. 84
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88 Drug Induced Liver Injury: Rounding up the Usual Suspects Clues to cholestatic DILI and bile duct injury Drug-induced AIH 88
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90 Hepatology Volume 59, Issue 2, pages , 18 DEC 2013 DOI: /hep
91 Drug-Associated Cholestasis Pattern Bland hepatocellular cholestasis Cholestatic hepatitis Small duct cholangiopathy Causative Agents Estrogens, anabolic steroids (almost pathognomonic) Antibiotics Anticonvulsants, antibiotics, neuroleptics Sclerosing ischemic lesions of large bile ducts Intrahepatic artery chemotherapy (rarely used) 91
92 Bland Cholestasis 92
93 Drug-Induced Bland Acute Cholestasis Bile in canaliculi, Kupffer cells, hepatocytes Predominantly zone 3 No significant portal inflammation or bile ductular reaction Minimal hepatocyte necrosis Most commonly associated with estrogen, androgenic steroids 93
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96 Portal Tract in Bland Cholestasis 96
97 Bland Cholestasis- Clinical Features Jaundice may be prolonged Minimal elevation of AST, ALT, alkaline phosphatase Almost pathognomonic for androgenic steroids (men) or estrogen therapy (women) Women with a history of cholestasis of pregnancy are more susceptible May be seen with OCPs, typically in first cycle May be due to variant of bile salt transporter proteins 97
98 Drug-induced Cholestatic Hepatitis Cholestasis is associated with liver cell necrosis and inflammatory infiltrate Bile ductular reaction usually not prominent Some degree of damage to small bile ducts is common but may be subtle Numerous agents: anticonvulsants, antibiotics, antirheumatics, antidepressants 98
99 Drug-Induced Cholestatic Hepatitis 99
100 Cholestatic Hepatitis 100
101 Morphologic Features: DILI-associated Small Duct Cholangiopathy Early stages: bile duct epithelial cells are swollen; degenerative changes and mitoses may be seen. Portal infiltrate is variable, often contains eosinophils Zone 3 cholestasis Bile duct loss is seen as early as 10 days Ductopenia may persist for months 101
102 Bile Duct Injury: Erythromycin 102
103 Itraconazole 103
104 Bile Duct Injury- Amoxicillin/Clavulanate 104
105 105
106 Drugs associated with VBDS/Prolonged Cholestasis Persistence of jaundice for more than 6 months or biochemical abnormalities for more than one year after drug-induced cholestatic hepatitis Withdrawal of drug No past history of chronic liver or biliary disease More common Rare Single case reports Amoxicillin/clavulanate Allopurinol Omeprazole Azithromycin Thalidomide Lansoprazole Lanalidomide Enalapril Montelukast Cephalosporins Bonkovsky et al. Hepatology 56(4): ,
107 Late stage bile duct injury: Tetracycline 107
108 Drug-Induced Prolonged Cholestasis 108
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111 Pathogenesis of Bile Duct Injury Biotransformation to toxic intermediates results in direct cellular injury Immune response targeting bile duct epithelial cells: many of the drugs associated this pattern of injury are thought to cause cholestatic hepatitis through a hypersensitivity mechanism Shared epithelial antigen in TEN cases 111
112 Differential Diagnosis PBC PSC Large duct obstruction 112
113 Drug-Induced Ductopenia: A Practical Approach Condition Helpful Features Cholestasis DILI-related bland cholestasis Portal tracts almost normal; no ductular reaction Intense, zone 3 DILI-related bile duct injury and loss Bile duct injury without ductular reaction Present before bile duct loss PBC Florid duct lesion None in early stages PSC Periductal fibrosis Usually not seen in early stages Large duct obstruction Portal edema and prominent ductular reaction Zone 3 113
114 Drug-Induced Ductopenia: Pearls Biopsy may be done late after withdrawal of drug, to rule out other causes of cholestasis Look for acute onset of cholestasis, appropriate drug history, prolonged jaundice Look for bile duct loss with empty portal tracts without bile ductular reaction 114
115 Take home points Bile duct loss due to DILI has a poor prognosis, especially if >50% of portal tracts lack bile ducts Requires adequate biopsy with careful counting of portal tracts and bile ducts Bile duct loss is mostly seen with drugs causing acute cholestatic or mixed hepatitis with immunoallergenic features. 115
116 AIH versus Drug-Induced Liver Injury Feature Favors AIH Favors DILI Severe portal inflammation Prominent lobular lymphocytes (hepatitic form) Prominent lobular eosinophils but NS Canalicular cholestasis Portal plasma cells Rosette formation Fibrosis Prominent portal PMNs Hepatocellular cholestasis Severe focal necrosis Suzuki et al. Hepatology 2011;54:
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120 Self-perpetuating Drug-induced AIH Serologic profile may resemble either Type 1 AIH or Type 2 AIH Commonly implicated drugs include Alpha methyldopa Minocycline Nitrofurantoin Interferon Hydralazine Anti-TNF alpha therapies (infliximab, adalimumab) 120
121 Associations with AIH Hepatitis A infection Hepatitis vaccine Twinrix (HAV + HBV vaccine) Interferon tx for HCV, MS Terbinafine in HBV Atomoxetine Phenylpropyluracil Masitinib Black cohosh Imatinib Infliximab Methylphenidate Statins Kava & St Johns wort Minocycline Risperidone 121
122 Pearls for Pathologists: AIH versus DILI-AIH Cannot distinguish on morphologic grounds Injury persists after withdrawal of drug- self-perpetuating injury Responds to immunosuppressive therapy Usually does not relapse Have a high degree of suspicion if patient is taking minocycline 122
123 Approach to the Nodular Liver Extensive Fibrosis Regenerative Nodules Consideration Yes Yes Cirrhosis No Yes Nodular regenerative hyperplasia Yes No Congenital hepatic fibrosis Biliary cirrhosis 123
124 Cirrhosis: Evolving Clinical Concepts Simple binary approach is not sufficient Interventions can arrest progression Assessment of severity needed for treatment decisions Need better endpoints to assess new treatments 124
125 Cirrhosis: Evolving Clinical Concepts Major clinical distinction: Compensated cirrhosis Varices yes/no Decompensated cirrhosis Clinically evident complications of portal hypertension ascites variceal bleed encephalopathy liver insufficiency (jaundice) 125
126 Clinical Approach to Assessment of Chronic Liver Disease Non-invasive testing: transient elastography (Fibroscan) Clinical scoring systems Childs-Pugh (total bilirubin, albumin, INR, ascites, hepatic encephalopathy) MELD (total bilirubin, creatinine, INR) Serum biomarkers Fibrotest, Hepascore, FibroSpect, ELF score, AAR, APRI, etc PPVs from NPVs from Hepatic venous pressure gradient Motola DM, et al. Curr Pathobiol Rep 2(4):245-56,
127 Cirrhosis: Clinical Correlates Portal hypertension is an early and important consequence of cirrhosis Hepatic venous pressure gradient is an indirect measure of portal pressure. Normal HVPG: 3-5 mm Hg >10: risk of varices and clinical decompensation >20: marker for poor outcome in setting of variceal hemorrhage Elevation is also related to risk of HCC 127
128 Measurement of wedged hepatic venous pressure Bosch, J. et al. (2009) The clinical use of HVPG measurements in chronic liver disease Nat. Rev. Gastroenterol. Hepatol. doi: /nrgastro
129 Thickness of fibrous septa correlates with HVPG Collagen in space of Disse and micronodularity independent predictors of high portal pressure Hepatology 51 (4):1445-9,
130 Major Patterns of Cirrhosis Morphology is related to underlying liver disease because of injury location and activation of specific cell types Portal versus central bridging Biliary versus non-biliary Nodule morphology Micronodular (<3 mm)- alcohol, Wilson s disease, hemochromatosis Macronodular- viral hepatitis Pattern can change over time, with remodeling/regression/progression 130
131 Patterns of Fibrosis: 2 Major Distinctions 1. Portal-based fibrosis Chronic hepatitis (HBV, HCV, AIH) Biliary disease (PBC, PSC, chronic obstruction) Hemochromatosis Wilson s disease and Alpha-1-Antitrypsin deficiency 2. Central-based fibrosis NASH Alcohol Outflow obstruction (Budd-Chiari, congestive hepatopathy) 131
132 Biliary cirrhosis Viral hepatitis 132
133 Commonly Used Staging Systems: Chronic Hepatitis Batts-Ludwig Stage 0-4 Widely used in US METAVIR Ishak Fibrosis scale 0-4 (F0-F4) Widely used in Europe Stage 0-6 Used in clinical trials 133
134 Batts-Ludwig Staging Stage Description 0 No fibrosis 1 Fibrous portal expansion 2 Periportal fibrosis with rare bridges 3 Septal fibrosis with architectural distortion 4 Cirrhosis 134
135 Theise ND. Modern Pathology 2007, 20(suppl 1):S
136 Centrilobular Fibrosis Pattern Often produces a micronodular cirrhosis Major associated lesions: Steatohepatitis NASH Alcoholic hepatitis Chronic venous outflow obstruction Chronic Budd-Chiari syndrome Cardiac hepatopathy 136
137 137
138 Nonalcoholic Steatohepatitis Clinical Research Network Histologic Scoring System for Fibrosis Score Description 0 No fibrosis 1 Perisinusoidal/pericellular OR periportal fibrosis 1a: Mild, zone 3 (requires special stain) 1b: Moderate, zone 3 1c: Portal/periportal 2 Perisinuoidal/pericellular AND periportal fibrosis 3 Bridging fibrosis 4 Cirrhosis Kleiner DE, Brunt EM, Van Natta M, et al. Hepatology 41: ,
139 Chronic Budd-Chiari Syndrome 139
140 Cardiac Hepatopathy 140
141 Modified Laennec System Stage Description Criteria Score 0 No fibrosis No definite fibrosis 0 1 Minimal fibrosis No septa or rare thin septum; may have portal expansion of mild sinusoidal fibrosis 2 Mild fibrosis Occasional thin septa; may have portal expansion or mild sinusoidal fibrosis 3 Moderate fibrosis Moderate thin septa, up to incomplete cirrhosis A Cirrhosis, mild definite or probable Marked septation with rounded contours or visible nodules. Most septa are thin; one broad septum allowed. 4B Cirrhosis, moderate At least 2 broad septa, but no very broad septa and <1/2 of biopsy length composed of micronodules 4 5 4C Cirrhosis, severe At least 1 very broad septum or >1/2 of biopsy length composed of micronodules 6 141
142 Mixed Lesions: Which system to use? Usually viral hepatitis with NASH Stage zone 3 and portal fibrosis separately for earlier stages Viral hepatitis component: do not include zone 3 fibrosis in staging NASH component: Must decide if periportal fibrosis is due to viral hepatitis or NASH Periportal and zone 3 fibrosis due to NASH: Stage 2 If periportal is due to chronic hepatitis: Stage 1 NASH 142
143 Hot Topics: Can fibrosis regress? (Yes, in some circumstances) Wound healing response in the liver Dynamic, bi-directional process Evidence from large scale HBV, HCV trials, with regression defined as a decrease in fibrosis scores on biopsy over time Can cirrhosis regress? (Less amenable) Wide, paucicellular septa Collagen cross-linking and elastin deposition Vascular abnormalities in scar May remodel, with micronodular cirrhosis becoming macronodular or incomplete 143
144 Features of Progression vs. Regression Feature Progression Regression Portal tracts Enlarged, with chronic inflammation and fibrosis. Normal or enlarged, but with fibrosis only. No active interface hepatitis. Bile ducts Preserved or absent, depending on etiology Usually preserved Hepatic arteries May be prominent due to formation of shunts Prominence persists Portal veins May be obscured Obscuring persists Fibrous septa Thickness variable; active interface; inflamed, depending on etiology Thinned and delicate; may be discontinuous (perforated) Parenchyma Variable, depending on etiology Generally quiescent Quaglia A, et al. (2016) Histopathology 68,
145 Progression vs. Regression 145
146 Practical Approach to Assessing Fibrosis Etiology Determine underlying disease Viral hepatitis, NASH, alcohol, biliary Staging Choose relevant staging system Batts-Ludwig, NASH CRN, METAVIR Details Consider providing additional information for Stage 4 Nodule size, septal width, inflammation/activity 146
147 Portal hypertension with nodular liver but, no fibrosis! Is biopsy adequate (sampling)? Think about conditions causing non-cirrhotic portal hypertension Nodular regenerative hyperplasia Reticulin stain can help Hepatoportal sclerosis Look carefully at small portal vein branches Regressed cirrhosis- are there delicate incomplete septa? 147
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149 Nodular Regenerative Hyperplasia 149
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152 152
153 Nodular Regenerative Hyperplasia Up to ~ 2.5% in some autopsy series Regenerating parenchymal nodules with minimal fibrosis Associated with autoimmune conditions and some medications Azathioprine, thioguanine, mercaptopurine, didanosine, stavudine, isoplatin, vitamin A and possibly methotrexate Cystic fibrosis, CVID, chronic granulomatous disease, and after solid organ transplantation May be seen after chemotherapy but usually not associated with portal hypertension in that setting Associated with heterogeneous blood flow in the liver (regenerative response to vascular injury) 153
154 Hepatoportal sclerosis Portal hypertension, usually with hypersplenism Obliteration of portal vein radicles Underlying etiology unclear? Previous portal inflammatory condition? Exposure to toxins (arsenic) Prothrombotic states Does not evolve into cirrhosis; morbidity is due to portal hypertension Dense fibrosis of portal tracts with obliteration of portal vein branches (should be largest structure in portal tract) 154
155 Hepatoportal Sclerosis Normal 155
156 Small Portal Tracts in HPS Minute portal tracts without portal vein branches 156
157 Fibrosis, but No Regeneration? Consider biliary etiology such as PSC or PBC Regeneration may be less prominent in biliary cirrhosis Congenital hepatic fibrosis (ductal plate malformation) 157
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161 Pearls of Pathology: Assessment of Fibrosis Look for patterns of fibrosis (nodule size and shape) Choice of staging system depends on etiology In cirrhosis, providing additional information (activity, septal width) may be helpful clinically 161
162 Summary Hepatic fibrosis is a dynamic process Better therapies mean that pathologists will be called upon to assess more than simple stage 0-4 Severity of portal hypertension correlates roughly with histology Remember nodular regenerative hyperplasia and hepatoportal sclerosis 162
163 References (Liver tests) 1. Giannini EG,Testa R,Vincenzo Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ Feb 1; 172(3): Agrawal S, Dhiman RK, Limdi JK. Evaluation of abnormal liver function tests. Postgrad Med J Apr;92(1086): Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzymes results in asymptomatic patients. N Engl J Med 2000;342: Ruhl CE, Eerhart JE. Upper limits of normal for alanine aminotransferase activity the United States population. Hepatology 2012;55: Yoon E, Babar A, Choudhary M et al. Acetaminophen-induced hepatotoxicity: a comprehensive update. J Clin Transl Hepatol 2016 Jun 28; 4(2):
164 References (Liver tests) 6. Björnsson E, Davidsdottir L. The long-term follow-up after idiosyncratic druginduced liver injury with jaundice. J Hepatol.2009;50(3): Fontana J. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology. 2014; 146(4): Badrick T, Turner P. Review and Recommendations for the Component Tests in the Liver Function Test Profile. Indian J Clin Biochem Mar;31(1): Botros M, Sikaris KA. The De Ritis Ratio: The Test of Time. Clin Biochem Rev Nov; 34(3):
165 Reference ( Chronic liver injury) 1. Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010; 51: Pena Polanco NA, Levy C, Martin EF. Cholestatic Liver Diseases After Liver Transplant. Clin Liver Dis May;21(2): Montano-Loza AJ, Bhanji RA, Wasilenko S, et al. Systematic review: recurrent autoimmune liver diseases after liver transplantation. Aliment Pharmacol Ther Feb;45(4): Moreira RK, Revetta F, Koehler E, Washington MK. Diagnostic utility of IgG and IgM immunohistochemistry in autoimmune liver disease. World J Gastroenterol Jan 28;16(4): Lohse AW, Herkel J, Weiler-Normann C. Can Understanding the Pathogenesis of Autoimmune Hepatitis Lead to Rational Therapy? Dig Dis. 2017;35(4): Sebode M, Hartl J, Vergani D, et al. Autoimmune hepatitis: From current knowledge and clinical practice to future research agenda. Liver Int Apr Cropley A, Weltman M. The use of immunosuppression in autoimmune hepatitis: A current literature review. Clin Mol Hepatol Mar;23(1):
166 Reference (Chronic liver injury) 8. Balitzer D, Shafizadeh N, Peters MG, et al. Autoimmune hepatitis: review of histologic features included in the simplified criteria proposed by the international autoimmune hepatitis group and proposal for new histologic criteria. Mod Pathol May;30(5): R. Liberal, M.S. Longhi, G. Mieli-Vergani, et al. Pathogenesis of autoimmune hepatitisbest. Pract. Res. Clin. Gastroenterol., 25 (2011), pp Y.S. de Boer, N.M. van Gerven, A. Zwiers, et al. Genome-wide association study identifies variants associated with autoimmune hepatitis type-1gastroenterology, 147 (2014), pp D.P. Bogdanos, K. Choudhuri, D. Vergani. Molecular mimicry and autoimmune liver disease: virtuous intentions, malign consequences. Liver, 21 (2001), pp R.T. Stravitz, J.H. Lefkowitch, R.J. Fontana et al. Autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology, 53 (2011), pp Invernizzi P, Floreani A, Carbone M. Primary Biliary Cholangitis: advances in management and treatment of the disease. Dig Liver Dis May 8. pii: S (17)
167 Reference (Chronic liver injury) 14. Chascsa D, Carey EJ, Lindor KD. Old and new treatments for primary biliary cholangitis. Liver Int Apr;37(4): Tanaka A, Takikawa H, Mochida S, et al. Changing nomenclature for PBC from "Primary Biliary Cirrhosis" to "Primary Biliary Cholangitis". Nihon Shokakibyo Gakkai Zasshi Jul;113(7): Gulamhusein AF, Juran BD, Lazaridis KN. Genome-Wide Association Studies in Primary Biliary Cirrhosis. Semin Liver Dis Nov;35(4): Parés A. Therapy of Primary Biliary Cirrhosis: Novel Approaches for Patients with Suboptimal Response to Ursodeoxycholic Acid. Dig Dis. 2015;33 Suppl 2: Sclair SN, Little E, Levy C. Current Concepts in Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis. Clin Transl Gastroenterol Aug 27;6:e Yamagiwa S, Kamimura H, Takamura M. Autoantibodies in primary biliary cirrhosis: recent progress in research on the pathogenetic and clinical significance. World J Gastroenterol Mar 14;20(10): Muratori P, Muratori L, Ferrari R, et al. Characterization and clinical impact of antinuclear antibodies in primary biliary cirrhosis. Am J Gastroenterol. 2003;98:
168 Reference (Chronic liver injury) 21. Das KM. Immunopathogenesis of primary sclerosing cholangitis: Possible role of a shared colonic and biliary epithelial antigen. J Gastrol Hepatol. 2004;19:S Patel A, Seetharam A. Primary Biliary Cholangitis: Disease Pathogenesis and Implications for Established and Novel Therapeutics. J Clin Exp Hepatol Dec;6(4): Zen Y, Kawakami H, Kim JH. IgG4-related sclerosing cholangitis: all we need to know. J Gastroenterol Apr;51(4): Restellini S, Chazouillères O, Frossard JL. Hepatic manifestations of inflammatory bowel diseases. Liver Int Apr;37(4): Gidwaney NG, Pawa S, Das KM. Pathogenesis and clinical spectrum of primary sclerosing cholangitis. World J Gastroenterol Apr 18;23(14): Björnsson E, Olsson R, Bergquist A et al. The natural history of small-duct primary sclerosing cholangitis.gastroenterology Apr;134(4): Vierling JM. Autoimmune Hepatitis and Overlap Syndromes: Diagnosis and Management. Clin Gastroenterol Hepatol Nov;13(12):
169 Reference (Chronic liver injury) 28. Tiniakos DG, Brain JG, Bury YA. Role of Histopathology in Autoimmune Hepatitis. Dig Dis. 2015;33 Suppl 2: KM Boberg, RW Chapman, GM Hirschfield et al. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol Feb;54(2): Rossi RE, Conte D, Massironi S. Primary sclerosing cholangitis associated with inflammatory bowel disease: an update. Eur J Gastroenterol Hepatol Feb;28(2): Chazouilleres O,Wendum D, Serfaty L. et al. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology, 28 (1998), pp Hennes EM, Zeniya M, Czaja AJ et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology Jul;48(1): Levy C, Naik J, Giordano C et al. Hispanics with primary biliary cirrhosis are more likely to have features of autoimmune hepatitis and reduced response to ursodeoxycholic acid than non- Hispanics. Clin Gastroenterol Hepatol Aug;12(8): Gregorio GV, Portmann B, Karani J et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology Mar;33(3):
170 References: Drug Reactions and Fibrosis 1. Bonkovsky HL, Kleiner DE, Gu J, Odin JA, et al. Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements. Hepatology 2017;65: Kleiner DE. The histopathological evaluation of drug-induced liver injury. Histopathology 2017;70: Kim MY, Cho MY, Baik SK, Park HJ, Jeon HK, et al. Histological subclassification of cirrhosis using the Laennec fibrosis scoring system correlates with clinical stage and grade of portal hypertension. J Hepatol 2011; 55: Motola DL, Caravan P, Chung RT, Fuchs BC. Noninvasive biomarkers of liver fibrosis: Clinical applications and future directions. Curr Pathobiol Rep. 2014; 2: Quaglia A, Alves VA, Balabaud C, Bhathal PS, et al. Role of aetiology in the progression, regression, and parenchymal remodeling of liver disease: implications for liver biopsy interpretation. Histopathology 2016; 68:
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Autoimmune Liver Diseases
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