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Keywords:

  • autoimmune hepatitis;
  • autoimmune polyendocrinopathy–candiasis–ectodermal dystrophy syndrome;
  • liver–kidney microsomal autoantibodies;
  • primary sclerosing cholangitis;
  • primary biliary cirrhosis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Autoantibodies
  5. Subtypes of autoimmune hepatitis
  6. Diagnostic algorithm
  7. Natural course
  8. Therapy
  9. Transplantation
  10. Overlap syndromes
  11. Diagnosing overlap syndromes
  12. Antinuclear antibodies in overlap syndromes
  13. Treatment of overlap syndromes
  14. References

Abstract  Autoimmune hepatitis is a well-established chronic liver disease. It primarily affects women, is characterized by circulating autoantibodies and elevated gammaglobulins and is associated with extrahepatic immune-mediated syndromes. Treatment regimens have remained unchanged for a number of years because of the high efficacy of steroid monotherapy, or combination therapy of azathioprine and steroids. In approximately 90% of patients remission of the disease is reached by medical therapy, which is usually administered lifelong because long-term remission after drug withdrawal is achieved in only 17% of patients. In 10% of patients treatment failure is observed. The challenge of remission induction involves the use of transplant immunosuppressants such as cyclosporine, mycophenolate moffetil, and tacrolimus. The challenge of maintenance therapy minimizing steroid side-effects involves the evaluation of topical steroids and the use of azathioprine monotherapy. Overlap syndromes occur in approximately 20% of autoimmune liver diseases. The diagnosis is broadly based on serological, biochemical, clinical and histological parameters. Most common are the overlap of autoimmune hepatitis and primary biliary cirrhosis, as well as autoimmune hepatitis with primary sclerosing cholangitis. These yet incompletely defined syndromes are an important differential diagnosis in the diffcult-to-treat patient with autoimmune hepatitis.

© 2002 Blackwell Publishing Asia Pty Ltd


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Autoantibodies
  5. Subtypes of autoimmune hepatitis
  6. Diagnostic algorithm
  7. Natural course
  8. Therapy
  9. Transplantation
  10. Overlap syndromes
  11. Diagnosing overlap syndromes
  12. Antinuclear antibodies in overlap syndromes
  13. Treatment of overlap syndromes
  14. References

Autoimmune hepatitis (AIH) is a chronic inflamma-tory disease of the liver characterized by a loss of tolerance against hepatic tissue. Complex events determine immune-mediated liver diseases. In recent years it became evident that the tight balance between autoaggression and tolerance can be affected by several internal and external factors. Activation of autoreactive T cells is believed to be the central event in autoimmunity and to occur as a multistep process involving genetic susceptibility, environmental factors such as drugs, chemicals and nutrition, infections and the local tissue microenvironment (Fig. 1).

image

Figure 1. Activation of autoreactive T cells is believed to be the central event in autoimmune diseases and to occur as a multistep process involving genetic susceptibility, environmental factors and the local tissue microenvironment.

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Autoimmune hepatitis is a rare disease and the estimated prevalence in Northern Europe is approximately 170 cases per 1 million.1 In 1992 an international panel met in Brighton, UK, to establish diagnostic criteria for AIH because it was recognized that several features, including histological changes and clinical presentation, are also prevalent in other chronic liver disorders. In this and in a revised report the group noted that there is no single specific test for the diagnosis of AIH.2 In contrast, a set of diagnostic criteria was suggested in the form of a diagnostic scoring system designed to classify patients as having probable or definite AIH. According to this approach the diagnosis relies on a combination of indicative features of AIH and the exclusion of other causes of chronic liver diseases (Fig. 1). Autoimmune hepatitis predominantly affects women at any age and is characterized by marked elevation of serum globulins, in particular γ-globulins, and circulating autoantibodies.3 The clinical appearance ranges from an absence of symptoms, to a severe or fulminant presentation. An association with extrahepatic autoimmune diseases such as rheumatoid arthritis, autoimmune thyroiditis, ulcerative colitis and diabetes mellitus and a family history of autoimmune or allergic disorders has been reported.4,5

Autoantibodies are one of the distinguishing features of AIH and have led to a subclassification of AIH into three sero-immunological subgroups. According to this approach, AIH type 1 is characterized by the presence of antinuclear antibodies (ANA) and/or anti-smooth muscle antibodies (SMA) directed predominantly against smooth muscle actin.6,7 Autoimmune hepatitis type 2 is characterized by anti-liver–kidney microsomal autoantibodies (LKM-1) directed against cytochrome P450 (CYP) 2D68,9 and with lower frequency against UDP-glucuronosyltransferases (UGT).7 Autoimmune hepatitis type 3 is characterized by autoantibodies against soluble liver antigens (SLA/LP).10,11

Although the histological appearance of AIH is characteristic, there is no specific histological feature capable of proving the diagnosis. However, percutaneous liver biopsy should be performed for grading and staging, as well as for therapeutic monitoring. Histologic features usually include periportal hepatitis with lymphocytic infiltrates, plasma cells, and piecemeal necrosis, and, with advancing disease, bridging necrosis, panlobular and multilobular necrosis may occur ultimately leading to cirrhosis. The presence of copper deposits, granulomas and iron deposits argues against AIH and must be excluded before the diagnosis is made. Biliary changes can be found in one-fourth of AIH cases but they are not associated with distinctive clinical features or treatment response. Overlap syndromes must be considered if biliary changes are present.

Viral hepatitis should be excluded by the use of reliable, commercially available tests. The exclusion of ongoing hepatitis A, B and C virus infection is sufficient in most cases. The exclusion of other hepatotropic viruses such as cytomegalovirus, Epstein–Barr virus, herpes group viruses may be required only in cases suspicious of such infections or if the diagnosis of AIH based on the aforementioned criteria remains inconclusive.

Genetic factors appear to be involved in the pathogenesis of AIH.12 However, a conclusive role of a single genetic locus capable of explaining the etiology of AIH has not been identified thus far. Overall the genetic background of AIH must be considered to be polygenic. This is illustrated by a number of genetic associations that have been studied during the last years. Human leukocyte antigens (HLA) DRB1*0301 and DRB*0401 have been identified as independent determinants of susceptibility to AIH in northern European pa-tients.13,14 The course of AIH is influenced by the HLA antigen profile of the affected patients.13,15 Adult patients with HLA B8 have more severe inflammation at presentation and are more likely to relapse after therapy. The presence of HLA DR3 is associated with a lower probability of reaching remission, more frequent relapses and a higher frequency of liver transplantations. Patients with HLA DR4 are characterized by a higher age of onset, a more benign onset and a higher frequency of concurrent extrahepatic disease.16,17 In addition, tumor necrosis factor (TNF)-α and complement factor C4 alleles have been associated with AIH, despite the observation that both genes exhibit a strong linkage disequilibrium with the HLA A1-B8-DR3 haplotype.18,19 Polymorphisms of the cytotoxic T lymphocyte antigen 4 have been identified as non-major histocompatibility complex susceptibility determinant in AIH type 1.20–22 We have recently demonstrated an association of vitamin D receptor (VDR) polymorphisms with autoimmune liver diseases. The VDR polymorphisms were investigated by digestion of specific PCR products with four different enzymes (BsmI, TaqI, ApaI and Fok) in 127 patients suffering from AIH, 74 primary biliary cirrhosis (PBC) patients and 214 healthy controls (1). BsmI polymorphisms were associated with PBC while Fok polymorphisms were associated with AIH (15;16) (Fig. 2).22 In a recent analysis a lack of genetic association between idiopathic autoimmune liver diseases and hepatitis as part of the autoimmune polyendocrinopathy–candiasis–ectodermal dystrophy syndrome (APECED), which is associated with mutations of the autoimmune regulator gene, has been demonstrated.23

image

Figure 2. Association of vitamin D receptor polymorphisms with AIH. Analysis of allelic frequencies revealed a significant difference between AIH patients and controls for the Fok polymorphisms (X 2  = 9.71, P  = .008).

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Autoantibodies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Autoantibodies
  5. Subtypes of autoimmune hepatitis
  6. Diagnostic algorithm
  7. Natural course
  8. Therapy
  9. Transplantation
  10. Overlap syndromes
  11. Diagnosing overlap syndromes
  12. Antinuclear antibodies in overlap syndromes
  13. Treatment of overlap syndromes
  14. References

Autoantibodies are mainly used for the diagnosis of autoimmune liver diseases. For screening purposes, ANA, SMA, LKM and anti-mitochondrial antibodies (AMA) continue to be determined by indirect immunofluorscence on rodent liver, stomach, and kidney tissues. Autoantibody determinations are an integral part of the diagnosis of definite AIH.2 Perinuclear antineutrophil cytoplasmic antibodies (pANCA) are present in most patients with primary sclerosing cholangitis (PSC) or AIH.24,25 Antibodies against cytosolic antigens may be helpful to diagnose individuals with AIH, in whom the aforementioned antibodies are undetectable. Anti-SLA/LP antibodies characterize some of these patients and are detectable by radioimmunassay and enzyme-linked immunosorbent assays.11,26,27 In addition, many AIH patients exhibit autoantibodies with a reactivity toward the asialoglcyoprotein re-ceptor28,29 and some reactivity with the liver cytosolic antigen 1 (LC-1).30

Recent data indicate that autoantibodies might have prognostic values. Patients with antibodies against actin are reported to be younger than seronegative patients. Furthermore, antibodies against actin are associated with HLA B8 and DR3, and identify patients with a poor prognosis.31 Antibodies to dsDNA in ANA-positive type 1 AIH are associated with HLA DR4, and characterize patients who have a poorer immediate response to corticosteroid treatment.32 Antibodies to human asialoglycoprotein receptors may serve as diagnostic markers for inflammatory disease activity of AIH and are associated with reactivation of disease during treatment withdrawal.33,34 Similarly, antibodies to liver cytosol type 1 appear to fluctuate in parallel with aminotransferases, and may therefore reflect treatment response.35 However, these observations have to be corroborated in prospective studies.

Subtypes of autoimmune hepatitis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Autoantibodies
  5. Subtypes of autoimmune hepatitis
  6. Diagnostic algorithm
  7. Natural course
  8. Therapy
  9. Transplantation
  10. Overlap syndromes
  11. Diagnosing overlap syndromes
  12. Antinuclear antibodies in overlap syndromes
  13. Treatment of overlap syndromes
  14. References

There have been several suggestions to classify AIH according to different antibody profiles. AIH type 1 represents the most common form of AIH, whereas AIH type 3 and particularly AIH type 2 are rare entities.36,37 The International Autoimmune Hepatitis Group (IAIHG) has not recommended these subdivisions for other than research purposes, because autoantibodies do not define distinct therapeutic groups. However, they noted that the distinction between AIH type 1 and type 2 has already been widely adopted in clinical practise. Clinically, the subgroups do not differ fundamentally. The presentation of AIH type 3 resembles AIH type 1 with respect to clinical characteristics, immunogenetic markers, and treatment response.11,27,38 However, it is important to diagnose anti-SLA/LP-positive AIH, which occurs in 10% of AIH cases as the only serological markers. This may therefore decrease the likelihood of misclassification. The differences between AIH type 1 and AIH type 2 are more prominent. Autoimmune hepatitis displays a regionally variable prevalence, being only 4% in the USA and up to 20% in western Europe.36,39 Patients with AIH type 2 are younger at presentation, have a more severe course at onset and are more likely to progress to cirrhosis.4,39

Not only the prevalence but also the immunogenetic associations of AIH vary regionally.40–42 Whether this genetic heterogeneity is also present in the different subtypes of AIH is so far unclear, mainly because there are insufficient immunogenetic data concerning AIH type 2 and type 3. A recent study identified the CTLA-4 gene polymorphism as a non-HLA determinant that predisposes to AIH type 1 but not to AIH type 2 in children, suggesting pathogenic differences between both entities.21

Diagnostic algorithm

  1. Top of page
  2. Abstract
  3. Introduction
  4. Autoantibodies
  5. Subtypes of autoimmune hepatitis
  6. Diagnostic algorithm
  7. Natural course
  8. Therapy
  9. Transplantation
  10. Overlap syndromes
  11. Diagnosing overlap syndromes
  12. Antinuclear antibodies in overlap syndromes
  13. Treatment of overlap syndromes
  14. References

There is no single specific test to confirm the diagnosis of AIH.2 If a patient presents with abnormal liver function tests, other frequent causes of liver disease have to be excluded first. Once viral hepatitis, drug-induced or alcoholic hepatitis have been ruled out, we then recommend to test for ANA, SMA, LKM and AMA. In parallel, Wilson's disease, hemochromatosis, α-1 antitrypsin deficiency and cholestatic liver diseases should be considered. A liver biopsy is mandatory unless contraindications such as clotting disorders are present. If diagnosis is still uncertain at this point, HLA-typing and screening for other defined autoantibodies might be helpful. Yet there is no other genetic marker improving the diagnosis of AIH that can be recommended for routine testing.

Natural course

  1. Top of page
  2. Abstract
  3. Introduction
  4. Autoantibodies
  5. Subtypes of autoimmune hepatitis
  6. Diagnostic algorithm
  7. Natural course
  8. Therapy
  9. Transplantation
  10. Overlap syndromes
  11. Diagnosing overlap syndromes
  12. Antinuclear antibodies in overlap syndromes
  13. Treatment of overlap syndromes
  14. References

Data describing the natural history of AIH are scare. The last placebo-controlled immunosuppressive treatment trial was published in 1980.43 The value of these studies is limited considering that these patients were screened only for epidemiological risk factors such as viral hepatitis and were not characterized by standardized diagnostic criteria. Nevertheless these studies revealed that untreated AIH had a very poor prognosis, and 5- and 10-year survival rates of 50% and 10% have been reported. They furthermore demonstrated that immunosuppressive treatment significantly improved survival.43,44

Recent data revealed that up to 30% of adult patients had histological features of cirrhosis at diagnosis. In 17% of patients with periportal hepatitis, cirrhosis developed within 5 years, but cirrhosis develops in 82% when bridging necrosis or necrosis of multiple lobules is present. The frequency of remission (80%) and treatment failure (14%) are comparable in patients with and without cirrhosis at presentation. Importantly, the presence of cirrhosis does not influence 10-year survival (90%) and those patients require a similarly aggressive treatment strategy.45,46

Almost half of the children with AIH already have cirrhosis at the time of diagnosis.4 Long-term follow up revealed that only few children can completely stop all treatment and approximately 70% of children receive long-term treatment.4,39 Most of these patients relapse when treatment is discontinued, or if the dose of immunosuppressive drug is reduced. Approximately 15% of patients develop chronic liver failure and undergo transplants before the age of 18 years.

In elderly patients a more severe initial histological grade has been reported, but the frequency of definite cirrhosis seems not to differ from younger patients.47,48 At follow up approximately 30% of patients develop cirrhosis. Response to immunosuppression is similar in older and younger patients and up to 90% of the older patients reach complete remission. However, in a study from the UK 41% of the elderly patients with AIH received no immunosuppressive therapy and the prognosis did not appear to be worse than in younger, usually treated, patients.

The risk of hepatocellular carcinoma varies considerably between the different diseases PBC, PSC and AIH. In particular PCS can be complicated by cholangiocarcinoma, gallbladder carcinoma and hepatocellular carcinoma.49 In contrast occurrence of HCC in patients with AIH is a rare event and develops only in long-standing cirrhosis.50,51

Therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Autoantibodies
  5. Subtypes of autoimmune hepatitis
  6. Diagnostic algorithm
  7. Natural course
  8. Therapy
  9. Transplantation
  10. Overlap syndromes
  11. Diagnosing overlap syndromes
  12. Antinuclear antibodies in overlap syndromes
  13. Treatment of overlap syndromes
  14. References

Autoimmune hepatitis is characterizd by a prompt response to immunosuppressive therapy. It was the first chronic liver disease in which medical therapy improved survival. Untreated patients with AIH of comparable disease severity have a 3-year and 10-year survival of 50% and 10%.43,52 Prospective studies described a mortality as high as 40% within 6 months.53 The 10-year survival of treated patients, with or without cirrhosis at presentation, is 93% and similar to that of an age-matched control group.45

Treatment should be initiated in all patients with active AIH characterized by aminotransferase levels exceeding 5–10 times the upper normal level, and histological evidence of bridging or multilobular necrosis. Early initiation of therapy is important, especially in young patients. However, treatment is recommended in all patients, irrespective of age and weight. In patients 65 years and older with liver cirrhosis and low disease activity, the benefit–risk ratio of corticosteroids should be weighed carefully. Patients with liver failure or fulminant presentation, who fail to improve under im-munosuppressive therapy, should be considered as candidates for liver transplantation. In patients with mild hepatitis documented on histology, the decision to begin treatment depends on symptoms such as fatigue, upper right quadrant pain or associated immune-mediated symptoms. In patients without symptoms and only mild inflammation, the decision to treat must be weighted against the side-effects of immunosuppre-sive therapy.54,55 However, patients without treatment should be carefully monitored for disease progression. Treatment should generally follow predefined therapeutic regimes, but in individual patients therapy is best tailored to the patients presentation and response because individual maintenance doses of immunosuppressive drugs can vary considerably.

The goal of treatment is a complete biochemical and histological resolution of inflammation as well as the clinical remission of symptoms. This is achieved in approximately 80%.56 Usually, aminotransferase levels normalize within 3–6 months. It is important to note that histological remission can lag 3–6 months behind the normalization of biochemical markers. Early termination of treatment may therefore lead to frequent relapse episodes. Although there have been recent reports attesting the efficacy of other immunsuppressive agents, treatment with corticosteroids and azathioprine continues to remain the standard therapy.57 If standard treatment fails or drug intolerance occurs, alternative therapies such as cyclosporine A, tacrolimus, cyclophosphamide, mercaptopurine, mycophenolat mofetil can be considered, but is recommended only in the setting of controlled trials in hepatologically oriented centers.58

Calcium and vitamin D are recommended in patients with autoimmune liver diseases who require im-munosuppressive medication. We recommend life-long supplementation. Other requent side-effects of corticosteroids are obesity, diabetes mellitus and psychiatric disorders, which may require close follow up of the patients and additional treatment. In addition, patients with autoimmune liver diseases should be vaccinated against hepatitis B and, if necessary, also against hepatitis A.

Corticosteroids and azathioprine

Induction therapy of AIH with prednisone monotherapy or the combination of prednisone with azathioprine is equally effective.57 In our opinion combination therapy is to be preferred because of the reduction of unwanted steroid side-effects in this group. Common side-effects of corticosteroids are usually mild and include cosmetic changes such as facial rounding, acne, hirsutism, fluid retention, dorsal hump formation, and obesity. They are most often reversible with a decrease in dosage or the withdrawal of the drug. The decision for either strategy is based on the clinical patient pro-file: combination therapy is best suited for elderly, osteoporotic patients, patients with a metabolic syndrome (diabetes, hypertension, obesity), and with psychiatric lability. Conversely, monotherapy with steroids would be preferred in patients with hematological abnormalities, and in younger patients when fertility becomes an issue.

Budesonide

Budesonide is a synthetic steroid with high first-pass metabolism in the liver, which should limit systemic side-effects compared to conventional steroids. In a study treating 13 AIH patients with budesonide over a period of 9 months the drug was well tolerated and aminotransferase levels were normalized.59 Our own experiences have confirmed that budesonide is effective but does not offer an advantage over conventional steroids when cirrhosis and portosystemic shunts are present. However, in a recent study budesonide therapy was associated with a low frequency of remission and high occurrence of side-effects.60 The main advantage of budesonide for the future treatment of AIH may be to replace prednisone in long-term maintenance therapy to reduce steroid side-effects. The potential benefit of budenoside is currently evaluated in clinical trials.

Deflazacort

Deflazacort has been proposed as an alternative corticosteroid for immunosuppression with fewer side-effects than conventional glucocorticoids. In a recent study, 15 patients with AIH type I were treated with deflazacort, who previously had been treated with prednisone with or without azathioprine until biochemical remission was obtained.61 Remission was sustained during 2 years of follow up. However, the long-term role of second generation corticosteroids to sustain remission in AIH patients with reduced treatment-related side-effects requires further controlled studies.

Cyclosporine A

Cyclosporine A is a lipophylic cyclic peptide of 11 residues produced by Tolypocladium inflatum that acts on calcium-dependent signaling and inhibits T-cell function via the interleukin 2 gene. Of all alternative agents, the greatest experience to date has been with cyclosporine A.62–66 In these studies cyclosporine A was succesfully used for the treatment of AIH and was well tolerated.64,65 The principal difficulty in advocating widespread use of the drug as first-line therapy relates to its toxicity profile, particularly with long-term use (increased risk of hypertension, renal insufficiency, hyperlipidemia, hirsutism, infection, and malignancy).

Tacrolimus

Tacrolimus is a macrolide lactone compound with immunosuppressive capabilities exceeding those of cyclosporine A. The mechanism of action is similar to that of cyclosporine A but it binds to a different immunophilin. The application of tacrolimus in 21 patients treated for 1 year led to an improvement of aminotransferase and bilirubin levels with a minor increase in serum blood urea nitrogen (BUN) and creatinine levels.67 Although tacrolimus represents a promising immunosuppressive candidate drug, larger randomized trials are required to assess its role in the therapy of AIH.

Mycophenolate

Mycophenolate has attracted attention as a transplant immunosuppressant with an important role in the steroid-free immunosuppressive therapy of patients undergoing transplantation for chronic hepatitis C infection. Mycophenolate is a non-competitive inhi-bitor of inosine monophosphate dehydrogenase, which blocks the rate-limiting enzymatic step in de novo purine synthesis. Mycophenolate has a selective action on lymphocyte activation, with marked reduction of both T and B lymphocyte proliferation. In a recent pilot study seven patients with AIH type 1 who either did not tolerate azathioprine or did not respond to standard therapy with a complete normalization of aminotransferase levels were treated with mycophenolate in ad-dition to steroids.68 In five out of seven patients normalization of aminotransferase levels was achieved within 3 months. These preliminary data suggest that mycophenolate may represent another promising treatment strategy of AIH.

Cyclophosphamide

The induction of remission with 1–1.5 mg/kg per day in combination with steroids has been reported.69 However, the dependency of continued application of cyclophosphamide with its potentially severe hematological side-effects render it a highly experimental treatment option.

Ursodeoxycholic acid

Ursodeoxycholic acid is a hydrophilic bile acid with putative immunomodulatory capabilities. It is presumed to alter HLA class I antigen expression on cellular surfaces and to suppress immunoglobulin production.70 Uncontrolled trials have shown a reduction in histological abnormalities, clinical and biochemical improvement but not a reduction of fibrosis in four patients with AIH type 1.71 However, its role in AIH therapy or in combination with immunosuppressive therapy is still unclear.72

Transplantation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Autoantibodies
  5. Subtypes of autoimmune hepatitis
  6. Diagnostic algorithm
  7. Natural course
  8. Therapy
  9. Transplantation
  10. Overlap syndromes
  11. Diagnosing overlap syndromes
  12. Antinuclear antibodies in overlap syndromes
  13. Treatment of overlap syndromes
  14. References

Liver transplantation represents the ultimate therapeutic option for most chronic liver diseases when irreversible and life-threatening complications ensue, or their development becomes apparent.73 In Europe, AIH accounted for 4% of all 20 539 liver transplants performed between January 1988 and December 2000. The indication for liver transplantation in AIH is similar to that in other chronic liver diseases and includes clinical deterioration, development of cirrhosis, bleeding esophageal varices and coagulation abnormalities despite adequate immunosuppressive therapy.73 Candidates for liver transplantation are usually patients who do not reach remission within 4 years of continuous therapy.3,74 The long-term results of liver transplantation for AIH are excellent and well within the range of other indications for liver transplantation. Acute rejection episodes are more frequent in AIH, but usually respond to immunosuppressive therapy with steroids, and do not influence the long-term outcome of the graft.75–80 It is meanwhile accepted that the recurrence of AIH is a serious complication, which may be as high as 15–68% after 5 years of follow up76,78,81–83 and should be diagnosed by serum biochemistry, histology and autoantibody titer determinations. Although the available data have not been validated the reduction of steroids after liver transplantation for AIH should be performed with great caution to prevent or control recurrence of AIH.

Overlap syndromes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Autoantibodies
  5. Subtypes of autoimmune hepatitis
  6. Diagnostic algorithm
  7. Natural course
  8. Therapy
  9. Transplantation
  10. Overlap syndromes
  11. Diagnosing overlap syndromes
  12. Antinuclear antibodies in overlap syndromes
  13. Treatment of overlap syndromes
  14. References

Clinical practise has shown that in approximately 20% of all patients with autoimmune liver diseases a clinical or serological overlap between the different subentities exists (Fig. 3).84 This situation has been termed ‘autoimmune overlap syndrome’ but a clear definition of the syndrome in question has not been provided. In approximately 5% of patients with a primary diagnosis of AIH, signs and symptoms of PBC (bilirubin and alkaline phosphatase elevation, liver biopsy) exist. In contrast, 19% of patients with a primary diagnosis of PBC also have signs of AIH. Because the etiology of all three classical autoimmune diseases of the liver (AIH, PBC and PSC) is unknown, a definition of their overlap based on etiological parameters is not possible. All considerations are therefore based upon the characterization of the immunoserological profile, the biochemical profile and the clinical presentation. In principle, three situations can be differentiated: (i) the coexistence of two autoimmune diseases simultaneously (e.g. AIH and PBC, or AIH and PBC); (ii) the presence of a dominating autoimmune disease that has additional features of a second autoimmune liver disease; and (iii) the consecutive development of two autoimmune diseases with a change of diagnosis and therapy. For the first situation evidence is scarce and it is doubtful whether the true simultaneous coexistence of two autoimmune diseases ever occurs in adults. The only evidence so far has been provided by the analysis of pediatric patients in whom serological, immunological and histological findings of AIH have been seen together with typical findings of PSC detected by ERCP. The second situation is more frequent and mostly diagnosed based on immunoserological and biochemical parameters. However, it should be emphasized that the diagnosis of overlap syndromes should be broadly based not only on the immunoserology, but also on the clinical presentation and a very careful assessment of liver histology. The third situation is infrequent but has led to the realization that autoimmune liver diseases are variable and can develop into a clinically distinct pattern. A recent case report has illustrated this scenario. In this report a 56-year-old Caucasian woman was treated for AMA-positive disease with ursodeoxycholic acid which led to the normalization of her elevated serum alkaline phosphatase.85 After 18 months of treatment, alkaline phosphatase and aspartate aminotransferase levels increased, AMA titers disappeared, and previously negative ANA titers were detectable. All parameters normalized after treatment with corticosteroids. This case not only demonstrates a switch of serological markers (AMA to ANA) but also a switch of the required treatment regimen. Treatment based on the autoantibody profile proved to be effective in this setting, and demonstrated the validity of autoantibody testing in overlapping syndromes of autoimmune liver diseases.

image

Figure 3. In up to 20% of patients with AIH additional markers and symptoms point to other liver diseases. In principle, overlap syndromes may occur in three settings: (I) the coexistence of two diseases simultaneously, (II) the presence of a dominating disease with additional features of a second disease, and (III) the consecutive development of two diseases with a change of diagnosis and therapy.

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Diagnosing overlap syndromes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Autoantibodies
  5. Subtypes of autoimmune hepatitis
  6. Diagnostic algorithm
  7. Natural course
  8. Therapy
  9. Transplantation
  10. Overlap syndromes
  11. Diagnosing overlap syndromes
  12. Antinuclear antibodies in overlap syndromes
  13. Treatment of overlap syndromes
  14. References

Although a complete clinical work up and careful histological assessment are crucial, immunoserological tests provide important diagnostic parameters that contribute to the definition of autoimmune overlap syndromes. Before considering an overlap syndrome the definition of the predominant autoimmune diseases is required. As described in the previous section, the diagnosis of AIH is reached by a scoring system established by the IAIHG in 1992.86 According to this diagnostic score, AIH is defined through the exclusion of viral, genetic, metabolic or toxic liver disease in addition to the exclusion of biliary inflammation or portal hepatitis. Consequently, the presence of autoantibodies, the absence of viral infection and biliary inflammation, the absence of alcoholic disease, as well as the presence of the immune HLA haplotypes DR3 and DR4 result in a high probability score of AIH. The scoring system therefore provides parameters that describe the strength of the diagnosis AIH. The presence of AMA for example decreases the probability of AIH. The presence of ANA and AMA represents a situation in which the probability of genuine AIH is reduced and an overlap syndrome with PBC is likely. Recently, a revised version of the AIH diagnostic score has been suggested that leads to a higher specificity of the discrimination of overlap syndromes and genuine AIH.2 In contrast to AIH, the diagnosis of PBC is reached by the detection of AMA directed against the E2 subunit of pyruvate dehydrogenase (PDH-E2) in cholestatic patients who do not show bile duct obstruction upon ultrasound examination.87 The biopsy shows bile duct infiltration in contrast to the findings in AIH. AMA against PHD-E2 are present in 95% of patients with PBC and have a high disease specificity.

Antinuclear antibodies in overlap syndromes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Autoantibodies
  5. Subtypes of autoimmune hepatitis
  6. Diagnostic algorithm
  7. Natural course
  8. Therapy
  9. Transplantation
  10. Overlap syndromes
  11. Diagnosing overlap syndromes
  12. Antinuclear antibodies in overlap syndromes
  13. Treatment of overlap syndromes
  14. References

The overlap of PBC and AIH is characterized by the presence of ANA in 67% and antibodies against SMA in 67%. Because it has been reported that patients with an overlap of PBC and AIH can respond to corticosteroid treatment equally well as patients with primary AIH, the diagnostic identification of this variant group by autoantibody characterization is required and contributes to the establishment of a safe and efficacious therapeutic strategy. Overlap syndromes share a number of common features including hypergammaglobulinemia, the presence of ANA and interface hepatitis in the histological examination. A specific test to identify and classify overlap syndromes has not yet been established, but the autoantibody profile allows for a subclassification, in particular the presence or absence of PBC-specific AMA.

The definition of another overlapping syndrome, autoimmune cholangiopathy, is diagnostically and clinically not precisely established. It is a matter of perspective whether autoimmune cholangiopathy is viewed as a subentity of AIH type 1,88 or as an AMA-negative form of PBC.89

Treatment of overlap syndromes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Autoantibodies
  5. Subtypes of autoimmune hepatitis
  6. Diagnostic algorithm
  7. Natural course
  8. Therapy
  9. Transplantation
  10. Overlap syndromes
  11. Diagnosing overlap syndromes
  12. Antinuclear antibodies in overlap syndromes
  13. Treatment of overlap syndromes
  14. References

Standardized treatment protocols for overlapping autoimmune syndromes have not yet been established or validated. A practical approach is the treatment of the dominating autoimmune disease, usually AIH or PBC. When clinical features of the other disease increase or become a problem, therapy should be expanded to include either ursodeoxycholic acid or, after careful consideration of contraindications, steroid therapy.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Autoantibodies
  5. Subtypes of autoimmune hepatitis
  6. Diagnostic algorithm
  7. Natural course
  8. Therapy
  9. Transplantation
  10. Overlap syndromes
  11. Diagnosing overlap syndromes
  12. Antinuclear antibodies in overlap syndromes
  13. Treatment of overlap syndromes
  14. References
  • 1
    Boberg KM, Aadland E, Jahnsen J, Raknerud N, Stiris M, Bell H. Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand. J. Gastroenterol. 1998; 33: 99103.
  • 2
    Alvarez F, Berg PA, Bianchi FB et al. International Autoimmune Hepatitis Group Report: Review of criteria for diagnosis of autoimmune hepatitis. J. Hepatol. 1999; 31: 92938.
  • 3
    Manns MP, Strassburg CP. Autoimmune hepatitis: Clinical challenges. Gastroenterology 2001; 120: 150217.
  • 4
    Gregorio GV, Portman B, Reid F et al. Autoimmune hepatitis in childhood: A 20-year experience. Hepatology 1997; 25: 5417.
  • 5
    Benten D, Widjaja A, Von Depka M et al. Autoimmune hepatitis associated with coagulation disorders and immunethyreopathy. Z. Gastroenterol. 2001; 39: 83740.
  • 6
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