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47 Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. 2003;38:1008–17. 48 Laurin J, Lindor KD, Crippin JS, Gossard A et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcoholic-induced steatohepatitis: a pilot study. Hepatology 1996;23:1464–7. 49 Chalasani N, Aljadhey H, Kesterson J, Murray MD, Hall SD. Patients with elevated liver enzymes are not at higher risk for statin . 2004;126: 1287–92. Autoimmune 50 Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y et al. Angiotensin-II type 1 interac- tion is a major regulator for liver Stefan Lueth MD, Registrar any age between very early childhood development in rats. Hepatology 2001; Ansgar W Lohse MD, Professor of and the 80s and, like many other autoim- 34:745–50. Gastroenterology and Hepatology mune diseases, is more common in 51 Yokohama S, Yoneda M, Haneda M, Department of Medicine, University Medical women (3:1). AIH often presents sub- Okamoto S et al. Therapeutic efficacy of an 5 angiotensin II receptor antagonist in Centre Hamburg-Eppendorf, Hamburg, clinically leading to delayed diagnosis, patients with nonalcoholic steatohepatitis. Germany which explains why about a quarter of Hepatology 2004;40:1222–5. patients already show at presen- 52 Merat S, Malekzadeh R, Sohrabi MR, Clin Med 2006;6:25–8 tation.6 Up to one-third of patients may Sotoudeh M et al. Probucol in the treatment present with an disease, some even of non-alcoholic steatohepatitis: a double-blind randomized controlled study. with fulminant hepatic failure. Delay in J Hepatol 2003;38:414–8. Autoimmune hepatitis (AIH) is a diagnosis and initiating treatment in 53 Abdelmalek MF, Angulo P, Jorgensen RA, chronic inflammatory disorder of the such patients can be fatal. Sylvestre PB, Lindor KD. Betaine, a liver associated with hypergammaglobu- promising new agent for patients with non- linaemia and the occurrence of autoanti- alcoholic steatohepatitis: results of a pilot 1,2 Diagnosis study. Am J Gastroenterol 2001;96:2711–7. bodies. It was the first in 54 Lavine JE. Vitamin E treatment of nonalco- which controlled trials proved both the A diagnosis of AIH should be considered holic steatohepatitis in children: a pilot efficacy of a therapeutic intervention in any patient with elevated liver study. J Pediatr 2000;136:734–8. () and that timely diag- enzymes. The clinical picture only occa- 55 Harrison SA, Torgerson S, Hayashi P, Ward nosis and adequate therapy can change a sionally provides important clues to the J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with dismal prognosis into a normal life diagnosis. The typical patient has suba- nonalcoholic steatohepatitis. Am J Gastro- expectancy in the vast majority of cute disease, presenting with lethargy enterol 2003;98:2485–90. patients.3 AIH describes a complex dis- and often without a risk factor 56 Adams LA, Zein CO, Angulo P, Lindor KD. ease entity with a wide range of clinical for . Other clinical symp- A pilot trial of pentoxifylline in nonalco- presentations. toms may include and slight, holic steatohepatitis. Am J Gastroenterol 2004;99:2365–8. The prevalence of AIH is estimated as right upper quadrant pain. 4 57 Yuan M, Konstantopoulos N, Lee J, Hansen one in 5,000–10,000. It can manifest at With the possible exception of L et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted Table 1. Criteria for the diagnosis of autoimmune hepatitis (AIH). disruption of IKKbeta. Science 2001;293: 1673–7. Criteria 58 Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME et al. Ursodeoxycholic acid for Major Hypergammaglobulinaemia (with a preferential increase of IgG) treatment of nonalcoholic steatohepatitis: Demonstration of (ANA, SMA, SLA/LP, LKM) results of a randomized trial. Hepatology Absence of viral hepatitis 2004;39:770–8. Portal hepatitis (with lymphoplasmacellular infiltrates) on histology 59 Contos MJ, Cales W, Sterling RK, Luketic Minor* Personal or family history of other VA et al. Development of nonalcoholic fatty History of a spontaneously fluctuating course liver disease after orthotopic liver transplan- Arthralgia tation for cryptogenic cirrhosis. Liver Presence of HLA-DR3 or DR4 Transpl 2001;7:363–73. 60 Ong J, Younossi ZM, Reddy V, Price LL et al. * additional features may give further support to the diagnosis. Cryptogenic cirrhosis and posttransplanta- ANA = antinuclear ; IgG = ; LKM = liver-kidney microsomal antigen; SLA/LP = tion nonalcoholic . Liver soluble liver antigen; SMA = antigen. Transpl 2001;7:797–801.

Clinical Medicine Vol 6 No 1 January/February 2006 25 CME Liver Disease

anti-soluble liver antigen (SLA/LP) anti- and are helpful diagnostic markers. In sections. This will also detect bodies, there is no single test that proves AIH there is typically selective elevation antimitochondrial as the or disproves the diagnosis of AIH. of IgG, with normal levels of IgA and characteristic test for PBC. Diagnosis is therefore based on the com- IgM. Elevated IgA suggests a toxic cause, • For SLA/LP antibodies, which do bination of history, clinical examination particularly alcohol, while elevated IgM not show up on and several laboratory and serological is a feature of biliary disease, particularly immunofluorescence and are variables, the key features of which are primary biliary cirrhosis (PBC). Both therefore missed by routine testing, described in Table 1, together with liver PBC and primary sclerosing cholangitis specific immunoassays such as biopsy findings. The usually prompt (PSC) can be associated with AIH – ELISA and/or immunoblot should response to immunosuppression proves so-called overlap syndromes (see below). be used. the diagnosis. ANA, SMA and LKM can also be Autoantibodies found in some patients with other liver Screening tests disease and non-hepatic autoimmune At least 80% of AIH patients have patho- disease, but SLA/LP antibodies are highly logical titres of at least one . As a first step, viral hepatitis B and C specific for AIH and thus diagnostic in The most common are antinuclear anti- should be excluded by testing for patients in whom they can be demon- bodies (ANA) and antibodies to smooth hepatitis B surface antigen and anti- strated. This also seems to be true for muscle antigen (SMA); both are present virus. Alcohol consumption, antibodies to double-stranded DNA in 40–50% of cases, sometimes in combi- intake of hepatotoxic medication and (detectable in 15%), for which the only nation. Antibodies to SLA/LP are present hereditary liver diseases (Wilson disease, is systemic in about 20%, in half of whom they are haemochromatosis, alpha-1 antitrypsin erythematosus (SLE). deficiency) should be excluded. The first the only autoantibody demonstrable. hint to the presence of AIH is demonstra- Antibodies to liver-kidney microsomal tion of elevated gammaglobulins on antigen (LKM) are uncommon (1–3%) Histology serum electrophoresis. This is probably but delineate a separate disease subgroup The diagnosis of AIH should also be the cheapest screening test for AIH, but often called AIH type 2; this is more based on a . This is required 5–10% of AIH patients do not display prevalent in childhood where it may be a both to demonstrate the presence of a elevated gammaglobulins at initial severe disease. lymphocellular infiltrate and also to diagnosis. Serum lipids should be tested There are two methods for testing exclude important differential diagnoses as fatty liver disease is an important autoantibodies: such as drug-induced liver disease or differential diagnosis. ANA, SMA and antibodies to LKM • non-alcoholic steatohepatitis. About a Quantitative immunoglobulin (Ig) A, are best tested using quarter of patients with AIH already have IgG and IgM levels are also cheap to test immunofluorescence on tissue cirrhosis at the time of diagnosis.6 Cirrhosis is frequently macronodular; it may often be missed because of a sam- Key Points pling error in which biopsy of a large regenerative nodule misses the fibrous Autoimmune hepatitis (AIH) can occur in all age groups from earliest childhood septa. Some authors therefore favour until the ninth decade laparoscopy at initial diagnosis; this can AIH affects women more commonly than men (3:1) now be performed with minimal inva- siveness due to the availability of Clinical presentation may range from acute hepatitis to fulminant but mini-instruments. can also be

Diagnosis is based on a combination of elevated immunoglobulin (gammaglobulin) Treatment levels, autoantibodies and histological proof of hepatitis in the absence of active viral markers Immunosuppression dramatically im- proves the outcome in AIH. With indi- Response to immunosuppression is universal and prompt vidualised immunosuppression, patients Steroids are the drug of choice for remission induction and for now look forward to normal life maintenance of remission expectancy with a good quality of life. Prompt response to sufficient doses of Treatment should be maintained for a minimum of three years, but is often required lifelong corticosteroids is a universal feature of AIH, making it the most reliable final KEY WORDS: autoantibodies, cirrhosis, gammaglobulin, immunosuppression, diagnostic tool. Non-response to transaminases immunosuppression suggests another

26 Clinical Medicine Vol 6 No 1 January/February 2006 CME Liver Disease diagnosis, provided that the patient is Maintenance regimen should be reinstituted immedi- compliant and the dose adequate. ately. When transaminases rise, steroid In most patients, treatment moni- Steroids are the drug of choice for the dosage should be increased briefly. The toring can be based solely on laboratory induction of remission but azathioprine exact dose and duration of the increase investigations (eg aminotransferases and (AZT) is the drug of choice for mainte- depend on when a relapse is detected: if gammaglobulins). Liver biopsy on nance of remission. Its effect takes several the intervention is early in the relapse, an follow-up is required only in special weeks to develop fully, so AZT should be increase for only a limited time is situations. started as soon as the diagnosis of AIH required (eg 20 mg for 1 week, 15 mg for has been established; it may then allow 1week, 10 mg for 2 weeks), returning to the dose of corticosteroids to be reduced. Remission the original maintenance dose thereafter. The usual dose of azathioprine is 1 mg/kg (considerably lower than in Induction Treatment withdrawal inflammatory bowel disease) and tolera- Different experts recommend different bility is very good in most patients. Most patients will require long-term doses. We strongly recommend a starting If the diagnosis has not been con- (mostly lifelong) immunosuppression, dose of 1 mg/kg for all firmed at the time of initiating treat- many being maintained on 50–100 mg patients except those with mild disease. ment, the response to steroids should be AZT daily. AZT should be continued for Severe icteric disease may cause malab- evaluated before adding AZT. In icteric a minimum of three years in all patients sorption of corticosteroids so intra- patients the pharmacodynamics of AZT before complete treatment withdrawal is venous (iv) administration is best. and its metabolites may be considerably considered, otherwise relapse rates are Transaminase levels usually fall within a altered, increasing the danger of toxicity. high (>80% within 18 months).8 few days and the prednisolone dose can In these patients a fall of bilirubin below Treatment withdrawal should be consid- soon be tapered. A typical treatment 150 microgram/ml should normally first ered in patients who have been schedule for a patient with a body weight be achieved before adding AZT, using a relapse-free for three years in whom liver of 75 kg is given in Table 2. lower starting dose and gradually biopsy has demonstrated absence of sig- The dose can be tapered more quickly increasing to the desired dose. nificant inflammation. The strongest in patients who have a prompt response An idiosyncratic reaction may occur in predictor of relapse after treatment with- and in milder disease. However, it should about 3% of patients causing abdominal drawal is the presence of histological not be reduced too quickly because rapid pain, and . In addition, bone signs of continued inflammation.9 tapering often results in early relapse, thus marrow toxicity is possible so regular Compliance may become a problem in requiring higher overall steroid doses. blood counts are required, initially every some long-term patients. It may occa- Administration of vitamin D and calcium 1–2 weeks then slowly decreasing to once sionally be justified to attempt treatment prevents development of osteoporosis. every three months. The superiority of withdrawal despite negative predictors AZT over corticosteroids in maintaining for stable remission, as only proof of remission has been convincingly demon- relapse will convince these patients to strated by the King’s College group.7 take a potentially toxic drug for many Table 2. Stepwise reduction of steroids Combination therapy should be given and combined azathioprine (AZT) years. immunosuppressive therapy in a for the first 12 months, then corticos- Patients must be closely observed for 70–80 kg patient. AZT, at a constant teroids should be tapered slowly for all the first 1–2 years after treatment with- dose of 75 mg/day, should be added as patients in biochemical remission drawal in order to detect relapse which soon as the diagnosis of AIH is (normal transaminases and normal IgG). may be delayed by many months. It is considered definite. Some groups recommend increasing the important to emphasise the risk of late Week Corticosteroids dose of AZT at this stage up to 2 mg/kg relapse to patients and their caregivers (mg/day) to avoid relapse on steroid withdrawal, so that they are not misled by a stable others (including our group) prefer to situation early after treatment withdrawal. 175 continue low-dose steroids (5 mg) and 260low-dose azathioprine (1 mg/kg) because 350of worries about oncogenic effects of Difficult-to-treat patients 440 long-term high-dose AZT. Trans- Fulminant autoimmune hepatitis 530aminases and IgG should be monitored 625closely each time immunosuppression A few patients, more commonly children 720is significantly decreased as relapse upon and young adults, present with fulmi- 8 & 9 15 dose reduction is not uncommon. nant hepatic failure. Unfortunately, 10 & 11 12.5 Relapse may often be preceded by an immunosuppression may be too late for 12 ... 10 increase in IgG well before the transami- some of them. The standard criteria for nases increase; if this occurs, the original emergency should

Clinical Medicine Vol 6 No 1 January/February 2006 27 CME Liver Disease

be used for these patients, despite the prednisolone and ≤2 mg/kg/day AZT). of primary biliary cirrhosis, primary presence of an underlying condition Only exceptional patients will con- sclerosing cholangitis, and autoimmune which, in principle, is responsive to med- tinue to show high inflammatory activity hepatitis in a Norwegian population. Scand J Gastroenterol 1998;33:99–103. ical treatment. Some patients rapidly despite such a treatment schedule. It is 5Kogan J, Safadi R, Ashur Y, Shouval D, Ilan deteriorate on steroids in this situation important to re-examine the diagnosis Y. Prognosis of symptomatic versus asymp- and any delay in transplantation will and to exclude drug-induced hepatotoxi- tomatic hepatitis: a study of 68 patients. increase the risk of potentially fatal infec- city; a second opinion, both clinically J Clin Gastroenterol 2002;35:75–81. tion. Patients without encephalopathy, and on the histology, may also be helpful. 6Roberts SK, Therneau TM, Czaja AJ. Prognosis of histological cirrhosis in type 1 however, should undergo an intensive Various experimental protocols have autoimmune hepatitis. Gastroenterology trial of immunosuppression with up to been used; our personal preference is 1996;110:848–57. 250 mg prednisolone iv for the first few again cyclophosphamide. In order to give 7King’s College group. days. specialist centres the chance to evaluate 8Kanzler S, Löhr H, Gerken G, Galle PR, More intensive immunosuppression, novel therapeutic approaches in such Lohse AW. Long-term management and prognosis of autoimmune hepatitis (AIH): a including AZT, is recommended fol- patients, they should be referred to single center experience. Z Gastroenterol lowing liver transplantation as relapse of experts with a special interest in AIH. 2001;39:339-41,344–8. AIH is observed in up to a fifth of organ Discussion of these exceptional cases 9Kanzler S, Gerken G, Löhr H, Galle PR et al. recipients.10 should not distract from the fact that Duration of immunosuppressive therapy in AIH is a condition that can be managed autoimmune hepatitis. J Hepatol 2001;34: 354–5. Patients intolerant of azathioprine extremely successfully by medical 10 Neuberger J, Portmann B, Calne R, therapy which, however, needs to be Williams R. Recurrence of autoimmune About 3% of patients are intolerant to individually tailored. With such careful chronic active hepatitis following ortho- AZT and a similar proportion will management, both survival and quality topic liver grafting. Transplantation 1984; develop side effects later (myelosuppres- of life are excellent. 37:363–5. 11 Gohlke F, Lohse AW, Dienes HP, Lohr H sion, hepatotoxicity, ) et al. Evidence for an requiring either dose reduction or drug Overlap syndromes of autoimmune hepatitis and primary withdrawal. Some of these patients can sclerosing cholangitis. J Hepatol 1996;24: be managed with steroid monotherapy, Some 10–20% of patients will have over- 699–705. but most will require another second- lapping features with either PSC11 or 12 Lohse AW, zum Buschenfelde KH, Franz B, 12 Kanzler S et al. Characterization of the line drug. Mycophenolate mofetil (more commonly) PBC. Management overlap syndrome of primary biliary cir- (MMF) has emerged as the standard should be primarily directed by the AIH rhosis (PBC) and autoimmune hepatitis: second-choice drug, primarily because of component of their disease. This is the evidence for it being a hepatitic form of its low toxicity. There are only limited part of the syndrome which drives more PBC in genetically susceptible individuals. data but the overall experience is that rapid liver damage and progression to Hepatology 1999;29:1078–84. about two-thirds of patients fare well on cirrhosis and which can be treated effec- MMF 1–2 g/day. tively. In overlap patients it appears sen- In the one-third who fail to benefit sible to add ursodeoxycholic acid to the from MMF the choice of drug is more treatment schedule, even though the evi- difficult. Our preference (in descending dence for this approach is weak. Patients order) is cyclophosphamide, metho- with AIH/PSC overlap seem to run a less trexate or cyclosporin. Cyclophos- favourable course than those with AIH phamide can be given orally (100 mg/day only, while AIH/PBC overlap patients initially) or as a bolus infusion as in SLE. seem to have a similarly good prognosis These patients should be treated in spe- to that of AIH alone. cialised centres as side effects of the drug need to be closely weighed against the References dangers of progressive disease. 1Mackay IR, Weiden S, Ungar B. Treatment of active chronic hepatitis and lupoid Poor responders to standard hepatitis with 6-mercaptopurine and aza- immunosuppression thioprine. Lancet 1964;42:899–902. 2O’Brien EN, Goble AJ, Mackay IR. Plasma- Few patients fail to reach remission using transaminase activity as an index of the the schedule of high-dose steroids in the effectiveness of cortisone in chronic initiation of treatment. The best choice hepatitis. Lancet 1958;i:1245–9. 3Krawitt EL. Autoimmune hepatitis. Review. of management in some of the N Engl J Med1996;334:897–903. non-responders may be higher than 4Boberg KM, Aadland E, Jahnsen J, usual maintenance doses (10–20 mg/day Raknerud N et al. Incidence and prevalence

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