LIVER SPECIALTY CONFERENCE USCAP 2016 Maha Guindi, M.D. Clinical Professor of Pathology Cedars-Sinai Medical Center Los Angeles, CA
Nothing to disclose
Case History 47-year-old male, long standing ileal Crohn's disease Small bowel resection 1998 and ileocecal resection in 2006 July 2015: malaise, fever of unclear etiology ALP 247, ALT 344, AST 234, and total bilirubin of 1.1 Piperacillin-tazobactam (ZOSYN), with continued fevers Liver tests peaked: ALP 379, ALT 496, AST 293, DBili 0.8 Doxycycline added. On 6-MP for over a year Hepatitis serology, CMV, and EBV PCR negative CMV seropositive, IgM neg MRCP - normal intra and extrahepatic bile ducts Transjugular liver biopsy
Diagnosis and Follow up Hypersensitivity reaction consistent with drug injury associated with purine analogues (Patient on 6-MP) 6-MP: recently increased, initially started on 50mg, increased to 125mg daily 6-MP held, with improvement in liver enzymes Repeat labs a month later: AST of 37; ALT of 53
1) Liver conditions as seen in the general population 2) Liver disease associated with IBD 3) Liver manifestations of IBD therapy
Liver conditions as seen in the general population
Liver disease associated with IBD Primary Sclerosing Cholangitis (PSC) Approx. 70-80% PSC patients have IBD Up to 7.5% IBD patients will develop PSC Chronic fibrosing disease of the intra- and extrahepatic bile ducts Multifocal strictures and dilatations in the intraand extrahepatic biliary tree Retrograde cholangiopancreatography (ERCP) and MRCP
Inflammation, fibrous obliteration of the bile ducts, fibrous knots
Heterogeneous distribution in the liver
Primary Sclerosing Cholangitis (PSC) Sampling: Early PSC: biopsy normal or subtle changes Late PSC: Duct lesion sampled in biopsy Duct lesion unsampled Severe duct loss - chronic biliary disease, no positive signs for PSC Liver biopsy in PSC: Small duct PSC Overlap with AIH suspected Fibrosis
Small duct variant of PSC Similar liver enzymes and liver biopsy abnormalities as large duct PSC No large duct findings on imaging studies Presence of IBD becomes important for the diagnosis Diagnosis difficult without biopsy
IgG4 Associated Cholangiopathy Biliary manifestation of systemic IgG4 disease Obstructive jaundice can be a first symptom; rare as a first symptom in PSC Preferentially affects large hilar/perihilar bile ducts Mass-like inflammatory infiltrate Radiologic ddx: PSC +/- cholangiocarcinoma
IgG4 Associated Cholangiopathy Histological features: Transmural inflammation of bile ducts Dense lymphoplasmacytic infiltration Obliterate phlebitis IgG4-positive cells IgG4-related inflammation in small portal tracts detected in liver biopsy, 25% of patients Liver biopsy indication: PSC vs. IgG4 related cholangiopathy Enough evidence to justify steroid therapy?
Bile duct biopsy IgG4
PSC IgG4 Hilum Affected Preferentially affected Peripheral Liver Duct lesions Peripheral Liver Inflammation IgG4 positive plasma cell inflammation >10/HPF PSC vs. IgG4 Periductal fibrosis, Ductopenia Not always seen Present Rare Liver biopsy findings: Inflammation, with increased numbers of IgG4-positive plasma cells, bile duct damage, portal-based fibroinflammatory nodules Variable and may not be conclusive Not Identified Present in 20% Serum IgG4 Elevated in 9% Elevated in 80-90%
Autoimmune hepatitis AIH/PSC overlap syndrome reported in IBD patients, especially UC Features of AIH and PSC present synchronously or sequentially Initial liver enzymes, serology and histologic features of AIH with normal cholangiography Pediatrics with AIH: 50% concurrent PSC Adults with AIH: 1.7 10% features of PSC
Autoimmune hepatitis International Autoimmune Hepatitis Group Criteria: demographic, histologic, laboratory Liver histology: Interface, lymphoplasmacytic infiltrate, rosetting Serum biochemistry Serum immunoglobulins Serum autoantibodies Viral serology Other etiologies, e.g. ETOH
Granulomatous hepatitis Rare complication of Crohn s disease Increased serum alkaline phosphatase Differential diagnosis: Granulomatous hepatitis related to DILI, infection, and malignancies
Portal vein thrombosis 1.3% of IBD cases Prothrombotic factors such as inflammation, immobilization, surgery, central catheters Hematological abnormalities: increased platelet counts, factor V and VIII levels, fibrinogen, decreased antithrombin III levels Liver biopsy: nonspecific changes, nodular regenerative hyperplasia, loss of small portal veins
Fatty liver disease Steatosis to steatohepatitis HTN and corticosteroids Up to 50% of abnormal liver bxs in IBD NAFLD in 8.2% IBD patients (vs. 33% of population) Older, fewer metabolic risk factors IBD impacts NAFLD (PNPLA3 148M allele carriers)
Liver manifestations of IBD therapy Misfits and Mavericks
Liver manifestations of IBD therapy 5- aminosalycilic acid Sulfasalazine = Sulfapyridine + 5-ASA Efficacy: 5-ASA - anti-inflammatory effects Mainly used in UC Incidence of liver toxicity: 0.4-2.9% Mostly mild Severe hepatotoxicity from Sulfasalazine; part of a systemic hypersensitivity reaction Granulomatous hepatitis
Azathioprine (AZA) 6-Mercaptopurine (6=MP) Thioguanine modulators Maintain remission in CD and UC induced by steroids AZA 6-MP 6-thioguanine (therapeutic properties) 6-methylmercaptopurine (hepatoctoxicity)
Azathioprine (AZA) 6-Mercaptopurine (6=MP) Incidence of hepatotoxicity: 4% Incidence of elevated liver tests: 7%/patient year Patterns of injury: Hepatocellular injury Cholestatic hepatitis Vascular injury: veno-occlusive disease and nodular regenerative hyperplasia Dose dependent, endothelial cell injury Onset later than that of hypersensitivity reaction, 3 months - 3 years after treatment initiation
Methotrexate Structural analogue of folate Inhibits production folinic acid and synthesis of purines & pyrimidines Used for treatment of CD but not UC Fatty liver disease/nash; potential to develop fibrosis & cirrhosis Rate of progression of fibrosis related to the cumulative dose
Methotrexate 6.7% fibrosis progressing by at least one stage fibrosis/gm Liver biopsy prior to MTX therapy: American College of Gastroenterology guidelines: Elevated liver tests at baseline Suspected chronic liver disease Risk factors for hepatoctoxicity Liver biopsy after MTX therapy: No data from CD patients The American Rheumatology association guidelines used Patients with AST rise in 5 out of 9 blood samples in one year or if serum albumin is decreased
Anti-Tumor Necrosis Factor α TNFα - proinflammatory cytokine Anti-TNFα monoclonal antibodies: Infliximab and Adalimumab Infliximab Adalimumab Chimeric Fully humnan 6.7% DILI < often Mild AST, ALT rise Mild AST, ALT rise Latency 29 weeks Latency 10-12 weeks AIH latency 16 weeks Few cases Cholestatic injury: case reports (bland cholestasis, severe cholestatic hepatitis)
Antibiotics Treat IBD complications (abscesses in CD, pouchitis) Metronidazole, ciprofloxacin most commonly used Metronidazole: DILI - rare, hepatocellular, immune-mediated injury Ciprofloxacin (a fluoroquinolone): Minor transaminase elevations Severe hepatocellular, cholestatic or a mixed pattern of injury
How to approach these overlapping issues (not just overlap syndromes ) Primary Liver Disease impacted by IBD Reactivation of HBV (Corticosteroids and anti-tnfα antibodies) NASH (PNPLA3 148M allele carriers, anti-tnfα) Patterns of liver injury that may be primary liver disease or drug induced Autoimmune hepatitis, overlap syndrome with PSC Granulomatous hepatitis NASH (Methotrexate) Duct injury/loss
Conclusions. Patterns of liver injury in IBD are diverse Need to divide them somehow in order to have an approach to differential diagnosis IBD patients, like transplant patients, have multiple coexistent processes and are on multiple drugs Clinical pathological correlation and communication are important Proving causality of drug induced liver injury LiverTox website is invaluable
Nothing to disclose
1) Liver conditions as seen in the general population 2) Liver disease associated with IBD 3) Liver manifestations of IBD therapy
Primary Sclerosing Cholangitis (PSC) Chronic fibrosing disease of the intra- and extrahepatic bile ducts. Approx. 70-80% PSC patients have IBD Up to7.5% IBD patients will develop PSC Cholestatic enzyme pattern Multifocal strictures and dilatations in the intra- and extrahepatic biliary tree Retrograde cholangiopancreatography (ERCP) and MRCP
Fibrous obliteration of the bile ducts, fibrous knots Periductal concentric fibrosis; onion skin pattern Heterogeneous distribution in the liver Sampling: Early PSC: bx may be almost normal Late PSC: a) Duct lesion present in biopsy b) Unsampled, severe duct loss - chronic biliary disease, no positive signs for PSC
Similar liver enzyme and liver biopsy abnormalities as large duct PSC No large duct features on imaging studies Diagnosis difficult Presence of IBD becomes important for the diagnosis
Biliary manifestation of systemic IgG4- related disease Described in UC Obstructive jaundice can be a first symptom but is rare as a first symptom in PSC Preferentially affects large hilar perihilar bile ducts Mass-like inflammatory infiltrate Radiologic ddx: PSC with cholangiocarcinoma
Histological features: transmural inflammation obliterative phlebitis heavy lymphoplasmacytic infiltration predominance of IgG4-positive cells IgG4-related inflammation in small portal tracts detected by liver biopsy, 25% of patients Liver biopsy may be done to distinguish between IgG4 related cholangiopathy and PSC Enough evidence to attempt steroid therapy?
PSC IgG4 Hilum Affected Preferentially affected Peripheral Liver Periductal Fibrosis Ductopenia Rare Inflammation Lymphocytes Inflammation, with increased numbers of IgG4-positive plasma cells, bile duct damage, a portal-based fibroinflammatory nodules IgG4 positive plasma cell inflammation >10/hPF PSC vs. IgG4 Not Identified Present Serum IgG4 Elevated in 9% Elevated in 80-90%
AIH/PSC overlap syndrome reported in IBD patients, especially UC. Features of AIH and PSC present synchronously or sequentially Initial liver enzymes, serology and histologic features of AIH with normal cholangiography, may develop pathologic features of PSC during the follow-up
International Autoimmune Hepatitis Group Criteria: demographic, histologic, and laboratory markers
Rare complication of Crohn s disease Increased serum alkliane phosphatase Differential diagnosis: Granulomatous hepatitis related to DILI, infection, and malignancies
1.3% of IBD cases Prothrombotic factors such as inflammation, immobilization, surgery, central catheters Hematological abnormalities: increased platelet counts, factor V and VIII levels, fibrinogen, decreased antithrombin III levels Liver biopsy: nonspecific changes, nodular regenerative hyperplasia, loss of small portal veins
Common finding in liver bxs of IBD patients, up to 50% Steatosis to steatohepatitis Presumed secondary to nutritional disturbances, steroids NAFLD in 8.2% IBD patients (vs. 33% of population) Older, fewer metabolic risk factors IBD impacts NAFLD (PNPLA3 148M allele carriers)
Misfits and Mavericks
Sulfasalazine and 5- aminisalycilic acid (5-ASA) Sulfapyridine + 5-ASA Efficacy from 5-ASA - anti-inflammatory effects on reactive oxygen species, nuclear factor kappa and cytokines Mainly used in UC Incidence of liver toxicity: 4-2.9%. Severe hepatotoxicity can occur as part of a systemic hypersensitivity reaction Granulomatous hepatitis
Thioguanine modulators Maintain remission in CD and UC induced by steroids AZA 6-MP 6-thioguanine (therapeutic properties) 6-methylmercaptopurine (hepatoctoxicity)
Incidence of hepatotoxicity: 4% Incidence of elevated liver tests: 7% per patient year Patterns of injury: Hepatocellular injury and cholestatic hepatitis Vascular injury: veno-occlusive disease and nodular regenerative hyperplasia Dose dependent, endothelial cell injury Onset later than that of hypersensitivity reaction, 3 months - 3 years after treatment initiation
Structural analogue of folate Inhibits production folinic acid and synthesis of purines & pyrimidines Used for treatment of CD but not UC Hepatotoxicity mechanism not clear Fatty liver disease/nash; potential to develop fibrosis & cirrhosis Rate of progression of fibrosis related to the cumulative dose 6.7% chance of progressing by at least one stage of fibrosis per gram of MTX American College of Gastroenterology guidelines: Liver biopsy prior to MTX therapy in patients with elevated liver tests at baseline Patients with suspected chronic liver disease Risk factors for hepatoctoxicity Indication for liver biopsy after starting MTX therapy: No data from CD patients The American Rheumatology association guidelines are used Liver biopsy in patients with AST rise in 5 out of 9 blood samples in one year or if serum albumin is decreased
Anti-Tumor necrosis factor α TNFα - proinflammatory cytokine Anti-TNFα monoclonal antibodies: Infliximab and Adalimumab Infliximab: Chimeric monoclonal anti TNF-α antibody 6.7 % develop hepatocellular injury, mild elevations of AST and ALT, latency 29 weeks Autoimmune hepatitis: increasingly reported with TNF-α; latency: 16 weeks Histologic features: similar to non-drug related autoimmune hepatitis Cholestatic injury: case reports (bland cholestasis, severe cholestatic hepatitis)
Anti-Tumor necrosis factor α Adalimumab: Fully human monoclonal anti TNF-α antibody Less often associated with DILI than Infliximab Mild elevation of ALT and AST Few cases of drug induced autoimmune hepatitis, autoantibodies, latency 10-12 weeks
Reactivation of HBV (Corticosteroids and Anti TNF α antibodies) NASH (PNL carriers, anti-tnfα)
Autoimmune hepatitis Granulomatous hepatitis NASH (Methotrexate)
Autoimmune hepatitis alone Autoimmune hepatitis overlap syndrome with PSC Autoimmune hepatitis-like DILI
PSC impacts IBD phenotype PSC pre or post IBD IBD post liver transplant for PSC