Autoimmune Hepatitis. AIH: Clinical Features. Autoimmune Hepatitis (AIH) Core Curriculum In Hepatology And Liver Transplantation

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1 Core Curriculum In Hepatology And Liver Transplantation Autoimmune Liver Diseases: AIH, PBC, PSC November 20 th, 2012 Professor Suzanne Norris, PhD, FRCPI, Consultant Hepatologist, St. James Hospital, Trinity College Dublin Autoimmune Hepatitis Prevalence per 100,000 Europeans Females: Males= 3-4:1 Most cases no precipitant, but has occurred after infections: Hep A, EBV May be precipitated by drugs e.g. nitrofurantoin Dr. Raphael Merriman, SVUH Autoimmune Hepatitis (AIH) Hepatocellular inflammation of unknown cause characterised by interface hepatitis (periportal hepatitis, piecemeal necrosis), liver associated auto-antibodies hypergammaglobulinaemia All non specific and can make diagnosis challenging, hence use of several criteria taken together, including liver biopsy. Trigger unclear: autoantigen or antibody driven? HLA class II associations for disease susceptibility and severity described. Possibly an interaction between a drug or virus and environment in a genetically susceptible individual AIH: Clinical Features None in 25% cases, even cirrhotics Fatigue 85% Amenorrhoea, acne Rash, fever, Joint pains 30-60% Hepatomegaly 78%, jaundice 69% Splenomegaly without cirrhosis Spider naevi Other autoimmune diseases common 41% 30% cirrhosis at presentation Can present as acute liver failure (autoantibodies may be neg) AIH: Diagnostic Criteria For Diagnosis Revised/Modified IAIHG Female: +2 Alk phos:ast or ALT < >3.0-2 IgG >2.0: <1.0 0 ANA, SMA or Anti LKM >1: : :40 +1 < AMA Pos -4 Viral hepatitis markers Positive -3 Negative +3 Other etiologic factors: Drugs Yes -4 No +1 Alcohol consumption <25g/day +2 >60g/day -2 Seropositivity for other defined autoantibodies +2 Histological findings Interface hepatitis +3 Mainly lymphoplasmacytic infiltrate +1 Rosettes +1 None of the above -5 Biliary changes -3 Other features -3 Genetic Factors Other autoimmune diseases +2 HLA DR3 or DR4 +1 Treatment response Complete +2 Relapse +3 Interpretation of diagnostic scores Pre-treatment: Definite >15 Probable Post treatment: Definite >17 Probable Alvarez, J Hep 1999 AIH: Simplified Scoring System For Diagnosis >6 Probable, >7 Definite AIH PARAMETER VALUE SCORE ANA or SMA >1:40 +1 ANA or SMA >1:80 +2 Or LKM+ >1:40 +2 Or SLA + Any titre +2 (max 2 points for ALL autoabs) IgG level Histology (must have evidence of a hepatitis) > ULN >1.1 ULN Compatible with AIH Typical of AIH Absence of viral hepatitis Yes +2 88% sensitive, 97% specific using above cut offs However, - antibody testing not standardised across labs/institutions Hennes E et al. Hep

2 Type 1 AIH (75%) ANA and/or SMA Anti SLA/LP specific 10-30%, helpful if above neg, (Type 3) Any age, bimodal yrs and 45-70yrs F:M 3:1 Extrahepatic immunological disease 41% Acute onset 40% (FLF) Types of AIH Type 2 AIH Anti-LKM 1 or anti-liver cytosolic (LC-1) Mainly (80%) children 2-14 yrs F:M 10:1 Commonly concurrent immune disorders and antibodies Generally advanced at presentation, treatment failure more common, relapse more common, virtually all require long term therapy Can also get panca and AMA pos cases Up to 25% high AFP at presentation, reflects hepatocyte regeneration Overlaps/Variants Even title is controversial! Nomenclature/diagnostic criteria not standardised Can change pattern from one autoimmune disease to another, sequential syndromes Well documented that can have features of both 7% with AIH/PBC 6% with AIH/PSC 11% with AIH/AIC (autoimmune cholangitis/ cholangiopathy) Overlaps/Variants Variant Features Therapy Overlap with PBC Overlap with PSC Autoimmune sclerosing cholangitis (Children>>adults) Overlap with viral hepatitis AMA pos, histology features of AIH AMA neg, ANA or SMA pos Histology like PBC Some label as AMA negative PBC IBD Cholestatic LFTs, Cholangitis and Int hepatitis on biopsy, Abnormal cholangiogram (except small duct PSC) Antibodies present, IgG high Resistance to steroids Hep C Ab and PCR pos ANA or SMA present Predominant disease determined by serology and histology Very similar to AIH, treat the same Respond poorly to steroids, Give trial, and/or Urso May have worse prognosis than either alone, follow up biopsies??? Respond poorly to steroids Empiric therapy with Urso Or combination Pred, aza and Urso Treat AIH first if predominant as antiviral therapy can precipitate AIH Overlaps/Variants Variant Features Therapy Autoimmune cholangitis Cryptogenic chronic hepatitis ANA and/or SMA Cholestatic LFTs No AMA Cholangitis on biopsy Normal cholangiogram Autoimmune hepatitis but no antibodies present Behave the same otherwise Steroids Urso As for AIH Prognosis of AIH Severity of Inflammation Biochemical: AST and IgG levels 3 yr mortality of 50% and 10 yr of 90% with sustained AST level greater than 10 N or greater than 5 times N and IgG at least twice normal Lower mortality and progression to cirrhosis if biochemistry less severe 13-20% spontaneously resolve regardless of severity Mild cases may do as well without treatment (10 yr survival 90%), but 10% can develop symptoms, so need follow up HLA status HLA B8 and DR3: less responsive, more require LT HLA DR4, do better, often older females ABSOLUTE *Clear survival benefits Treatment RELATIVE NONE Incapacitating symptoms Mild or no symptoms Asymptomatic with mild lab changes Relentless clinical progression AST > 10 fold N AST > 5 times N and IgG > 2N Bridging or multilobular necrosis Children with AIH Cirrhotics with any degree of inflammation BSG recommend treating if ALT, AST or IgG >2N & if symptomatic or have interface hepatitis as many will progress without Previous intolerance of Pred and/or Azathioprine Inactive cirrhosis Severe cytopenia (check TPMT before giving Aza) Need to be monitored regularly if not treated, =+/- repeat liver biopsy (BSG suggest at 2 yrs) Needs to be individualised and Guidelines vary on exact cut offs for levels of ALT, Take symptoms, LFTs, histology and pre morbid conditions into consideration 2

3 Treatment AIM: To achieve biochemical and ultimately histological remission, if normalise ALT more likely to achieve remission (absence of interface hepatitis), 65% and 80% after 18/12 and 3 years respectively, (average months), chances decrease after 2 years 1. Combination therapy (fewer side effects) Pred 30mg and Aza 50mg or 1-2 mg/kg 2. Prednisolone alone Pred 60mg/day 1 and 2. Improve LFTs, histology and survival. Both better than Placebo or aza alone. 80% on either achieve ALT <2N within 6/12 Histological remission lags behind, 75% within 18/12, IgG level may be predictive of remission with ALT Regimes Many would delay introduction of Azathioprine To see response to steroids Awaiting TPMT levels (not mandatory in all groups, should be done in those with cytopenia) Tolerance by patients, nausea etc Can cause hepatitis and confuse matters Monitor bloods: Weekly x 1/12, then 1-3 monthly until remission reached As ALT drops decrease Pred by 5mg/week to 10mgs. Continue on pred 5-10mg and Aza 50mg for at least 2 years or at least 12 months after LFTs normalise (until histological remission likely) 3. Budesonide (non cirrhotics) with Aza 9mg/day and Aza 1-2mg/kg/d Treatment Options Non responders Increase Pred to 1mg/kg/day or IV Methylpred and/or aza 2mg/kg/day No improvement or severe disease,?olt Will also be difficult to control after OLT Tacrolimus/MMF as rescue Incomplete response Continue long term therapy (can try other agents) and aim to keep asymptomatic with labs as stable as possible Can repeat liver biopsy after months Sustained Remission Decision Time MAINTAIN THERAPY Younger patients Anti-LKM or anti SLA Anticipated steroid side effects if required retreatment Severity of initial presenatation Cirrhosis or decompensation WITHDRAW THERAPY Absence cirrhosis or decompensation Absence LKM or SLA Good tolerance of initial steroids Potential precipitant drug or viral Hx of malignancy In practice this is often determined by patient choice about repeat biopsy and their preference for continuing therapy/monitoring frequency Aza alone at dose of 2mg/kg as good as combination in maintaining remission. Sustained remission off therapy achieved in only 10-40% Relapse If decide to withdraw medications, do slowly and monitor indefinitely, as 50-90% relapse and can happen at any time If histological remission achieved, relapse rate only 30%, without its 75-90% Treat as for initial presentation Maintenance therapy recommended (combination if previously relapsed on aza alone) Aza 2mg/kg as effective as combination in long term Other Considerations Hep B vaccine Pneumococcal and Flu Calcium and vit d to all on steroids Baseline DEXA scan Screen for glaucoma and cataracts after 1 yr on steroids Safe to treat in pregnancy (except MMF) HCC screening if cirrhotic, 4-6% overall, 10-20% over 20 yrs 3

4 Re-Biopsy? Can repeat after 2-3 years Guide maintenance therapy to prevent relapse (may need to increase meds eg Aza to 2mg/kg if not in remission) See fibrosis progression (25%, can develop cirrhosis) or regression (50%) Predict relapse if meds withdrawn Predict long term survival If not repeated, aim for normal LFTs Tacrolimus Other Agents Effective rescue in acute Cyclosporin Used in children at diagnosis to avoid steroids Mycophenolate mofetil (MMF) Best if intolerant to aza rather than unresponsive, 2gm/day, CI in Pregnancy Budesonide (but not cirrhotics, as 90% first pass metabolism by liver and may get shunting)? better than Pred and Aza, need more data Lack of long term follow up with above compared to Pred and Aza Liver Transplantation Indications as for other groups: FLF Decompensated HCC AIH can recur, 20% differential ACR Rx: Pred and Aza Can get de novo AIH in other transplant groups esp HCV AIH with DILI Drug-induced AIH Drugs: AIH and DILI Can be impossible to distinguish histologically, may be useful to divide into these categories, Ref: J of Hep 2011;55: Immunemedicated DILI Known AIH, probable chance association,? More prone to DILI, often advanced fibrosis on histology Unrecognised or predisposed patient with AIH unmasked or induced by drug eg. Statin (may be chance), good response to steroids +/- Eosinophilia, rash, fever, lymphadenopathy Usually no advanced fibrosis Good response to steroids and remission maintained when therapy stopped Nitrofurantoin, minocycline, HLA association for some e.g. fluclox and coamoxiclav 57 year old Jaundiced female 22 nd Dec: 3 day history of painless jaundice GI symptoms nausea, dark urine, pale stools Husband noticed jaundice History No travel Transfused 30 years previously after PPH No IVDA, Tattoos Alcohol 1 unit per night Meds: Deltacortril 5mg Calvepan 333mg bd Tegretol 200mgs tds 4

5 Past Medical History SLE x 30 years Thrombocytopenia Splenectomy for same Epilepsy, no seizures in 20 years PE Jaundiced No stigmata of CLD Non-tender liver edge Investigations Ultrasound: Hepatomegaly with 2 echogenic lesions CT scan advised: Multiple hyperdense lesions in R lobe,? Metastatic, thickened greater curve of stomach, enlarged coeliac lymph node, 2cm Sent for OGD: 3 rd Jan Gastritis and oesophagitis, gastric biopsies taken. MRI recommended: 5 th Jan Right lobe nodular, no discrete lesions,? Hepatitis, cirrhosis, atypical hepatoma Asked to review 6 th Jan No herbals/otcs o/e Jaundice, palmar erythema Spontaneous improvement in LFTs since admission INR 1.8 to 1.3 ALT 3,619 to 984 Bili 273 to 147 Testing Results Hep A, B, C Neg CMV, EBV, Lepto Neg Ferritin = 8,385, Iron saturations = 88.2% IgG = 20.1, ANA 1:2,560, ds DNA-POS, SMA-Neg, anti-ro Pos FP 15.1 Proceeded to liver biopsy 9 th Jan LOW POWER Zones of pallor LOW POWER Bridging necrosis 5

6 Bridging necrosis Acidophil bodies Interface hepatitis with pigmented macrophages Masson trichrome, established minimal fibrosis Histopath findings Progress Bridging necrosis moderate to severe, interface hepatitis, lobular inflammation, portal tract minimal increase in fibrosis, bile duct inflammation, no excess iron, 1AT globules Neg? Autoimmune,? Drug,? Viral?? Bile duct process CT reviewed Portal vein thrombosis Commenced on LMWH, warfarinised LFTs continued to settle, commenced on azathioprine 50mg, reducing dose steroids Rheumatology review: SLE and Sjogrens 6

7 Follow-up Last reviewed Oct 2012 LFTs: ALL NORMAL since and remains well Meds: Aza 75 mg bd, Pred 5 mg Platelets : Normal Lessons from this case Don t base diagnosis on imaging alone Review imaging if story doesn t fit Note very high ferritin and also high FP that can be seen in acute setting doesn t necessarily imply HH and HCC Primary Cholestatic Disorders Primary Biliary Cirrhosis (PBC) Primary Sclerosing Cholangitis (PSC) Primary Biliary Cirrhosis (PBC) 90% female, increasing incidence Chronic, non-suppurative, granulomatous cholangitis Elevated Alk Phos >6/12 and AMA (>1:40) diagnostic - don t need liver biopsy AMA pos only, normal LFTs: most go on to develop PBC eventually-follow annually - Intrahepatic bile duct destruction - Extrahepatic (+/- intrahepatic) bile duct injury High IgM, cholesterol, +ANA 30%. Many now asymptomatic at diagnosis; can have fatigue, hyperpigmentation, Sjogrens, arthritis Pruritus - may predate increased AP and disproportionate to disease severity PBC Onset ~ 50 y/o Autoimmune disease HLA-DR8W association GRANULOMA Immunologic target terminal bile ducts Lymphocytic inflammation, lymphoid granulomas 50 cases/million Histology: Stages I-IV (florid duct lesion, bile duct destruction and proliferation and loss, cirrhosis) Xanthelasma in PBC 7

8 PBC: Treatment URSODEOXYCHOLIC ACID 13-15MG/KG/D Improves LFTs, histology, Reduction in likelihood of transplant and death seen in long term studies Decrease in A Phos by >40% or normalisation associated with 95% transplant free survival at 14 yrs (Barcelona criteria) Several other meds tried, including colchicine, MTX, steroids, not as good as Urso Urso not helpful for itch or fatigue Transplantation PBC: Treatment Indications as for other diseases Should refer when Bili >100 umol/l or MELD >12. Survival excellent AMA stays positive PBC can recur (18%) but rarely associated with graft failure Primary Sclerosing Cholangitis Inflammation with fibrosis and strictures of medium and large bile ducts Cause unknown, genetic susceptible? Recurrent cholangitis (triad of RUQ pain, jaundice, fever), M:F is 2:1 IBD in 80%, usually UC (85%) MRCP or ERCP usually diagnostic: multifocal strictures and beading chain of lakes Intrahepatic and extrahepatic biliary tree 87% Intrahepatic biliary tree alone 11% Extrahepatic biliary tree alone 2% Often positive panca, ANA and SMA Liver biopsy non specific, disease patchy, may even be normal PSC Chronic, progressive fibrosing bile duct inflammation - onion-skinning lesion M:F 2:1, onset ~ y/o Bile duct strictures, dilation and superinfection Autoimmune, HLA-B8/DR3 Extrahepatic > intrahepatic Hepatocyte injury occurs late PSC Ultrasound may show changes and GB abnormalities or enlargement ERCP may have better accuracy for early disease Cholangiogram normal in small duct PSC,? Require presence of IBD for diagnosis here,? better prognosis, but may evolve to classical PSC Differential with secondary SC: Post surgical changes, cholangiocarcinoma, stone disease, IgG4 - associated cholangitis/ai Pancreatitis, AIDs cholangiopathy Prognosis: median survival after diagnosis years, worse if symptoms at diagnosis 8

9 PSC IBD 80% and risk of colon cancer UC 80%, Crohns 10%, Indeterminate 10% Usually precedes diagnosis of PSC but can occur at any time, so colonoscopy should be done in all with PSC (and after OLT) to look for IBD More often pancolitis, rectal sparing Risk of CRC x4 times higher than UC alone (?increased risk with CD) therefore both groups should have annual colonoscopy PSC: Hepatobiliary Malignancy x161 times normal population Cholangiocarcinoma, HCC and GB cancer in 13.3% Cholangiocarcinoma life time risk 10-15%, HCC 2%, GB 2% 50% CCA diagnosed within first year of PSC diagnosis, thereafter 0.5 to 1.5% per year Notoriously difficult to diagnose, consider in any PSC patient with deterioration: Ca19.9 levels, imaging, ERCP with brushings =/1 FISH, PET scanning all used, biopsy very difficult and often unhelpful 10% survival at 2 years following diagnosis OLT using Mayo protocol (hilar lcoation, chemorad, staging ex-lap)? Annual US recommended to see GB and/or MRCP and CA19.9 levels - no proven impact on survival PSC: Medical Treatment No proven treatment to slow progression of disease Urso 15-20mg/kg doses improve biochemistry in some, no firm evidence it slows progression Higher doses 20-30mg/kg/d may be harmful: studies were more deaths, need for LT AASLD now recommend against its use and to stop in those on it (can recommence if deteriorate) Maintain bile duct patency (ERCP), antibiotics, early transplantation (LDLT?) Urso and colon cancer in those with IBD Lower doses seen to decrease risk of dysplasia and CRC Higher doses may increase risk of CRC Again AASLD recommend against its use Cholangiocarcinoma PSC Treatment ERCP if required to dilate (and stent if necessary) dominant strictures, take brushings Antibiotic cover for all with PSC, high risk of cholangitis even with this Prophylactic long term antibiotics may be necessary in those that get recurrent cholangitis despite biliary drainage at ERCP LT for late stage disease, may find incidental CCA in explant (10%) Roux-en Y choledochojejunostomy standard to remove risk of cancer in native biliary tree PSC can recur post LT 9

10 FFIB: Fatigue, Fat-soluble vitamin deficiency Itch And Bones And Other Disease Consequences Of Cholestasis Fatigue! Exclude other causes, eg TFTs etc Supportive therapy Modafenil Fat-soluble vitamin (ADEK) deficiency Itch: Cholestyramine, Rifampicin, Naltrexone, Sertraline, Liver Transplant Osteoporosis, assess individuals for risks, recommended all get Ca and Vit D, regular DEXAs 10