Book on hepatitis from page 452 to 465

Book on hepatitis from page 452 to 465

452  Hepatology 2012
von Herbay A, de Groot H, Hegi U, Stremmel W, Strohmeyer G, Sies H. Low vitamine E
content in plasma of patients with alcoholic liver disease, hemochromatosis and
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Walshe JM. Copper chelation in patients with Wilson's disease. A comparison of penicillamine
and triethylene tetramine dihydrochloride. Q J Med 1973;42:441-52. (Abstract)
Walshe JM. The management of Wilson's disease with trienthylene tetramine 2HC1 (Trien
2HC1). Prog Clin Biol Res 1979;34:271-80. (Abstract)
Walshe JM. Treatment of Wilson's disease with trientine (triethylenetetramine) dihydrochloride.
Lancet 1982;1:643-7.
Walshe JM, Dixon AK. Dangers of non-compliance in Wilson's disease. Lancet 1986;1:845-7.
(Abstract)
Walshe JM. Diagnosis and treatment of presymptomatic Wilson's disease. Lancet 1988;2:435-7. (Abstract)
Walshe JM. Wilson's disease presenting with features of hepatic dysfunction: a clinical analysis
of eighty-seven patients. Q J Med 1989;70:253-63. (Abstract)
Walshe JM, Yealland M. Chelation treatment of neurological Wilson's disease. Q J Med
1993;86:197-204. (Abstract)
Walshe JM, Munro NA. Zinc-induced deterioration in Wilson's disease aborted by treatment
with penicillamine, dimercaprol, and a novel zero copper diet. Arch Neurol
1995;52:10-1. (Abstract)
Wilson SAK. Progressive lenticular degeneration: a familial nervous disease associated with
cirrhosis of the liver. Brain 1912;34:295-507.
Wilson DC, Phillips MJ, Cox DW, Roberts EA. Severe hepatic Wilson's disease in preschool-aged children. J Pediatr 2000;137:719-22. (Abstract)
Yamaguchi Y, Heiny ME, Gitlin JD. Isolation and characterization of a human liver cDNA as a
candidate gene for Wilson disease. Biochem Biophys Res Commun 1993;197:271-7.
(Abstract)
Autoimmune Liver Diseases: AIH, PBC and PSC  453
27. Autoimmune Liver Diseases: AIH, PBC
and PSC
Christian P. Strassburg
Autoimmune hepatitis (AIH)
Autoimmune hepatitis (AIH) is a chronic inflammatory disease, in which a loss of
tolerance against hepatic tissue is presumed. Autoimmune hepatitis (AIH) was first
described as a form of chronic hepatitis in young women showing jaundice, elevated
gamma globulins and amenorrhea, which eventually led to liver cirrhosis
(Waldenström 1950). He also first described a beneficial effect of steroids in the
patient cohort he reported on and thereby laid the groundwork for the first chronic
liver disease found to be curable by drug therapy. AIH was later recognized in
combination with other extrahepatic autoimmune syndromes, and the presence of
antinuclear antibodies (ANA) led to the term lupoid hepatitis (Mackay 1956).
Systematic evaluations of the cellular and molecular immunopathology, of the
clinical symptoms and of laboratory features has subsequently led to the
establishment of autoimmune hepatitis as a separate clinical entity which is
serologically heterogeneous, treated by a specific therapeutic strategy (Strassburg
2000). An established (Alvarez 1999a) and recently simplified (Hennes 2008b)
revised scoring system allows for a reproducible and standardized approach to
diagnosing AIH in a scientific context. The use  and interpretation of
seroimmunological and molecular biological tests permits a precise discrimination
of autoimmune hepatitis from other etiologies of chronic hepatitis, in particular
from chronic viral infection as the most common cause of chronic hepatitis
worldwide (Strassburg 2002). Today, AIH is a treatable chronic liver disease in the
majority of cases. Much of the same initial treatment strategies of
immunosuppression still represent the standard of care. The largest challenge
regarding treatment is the timely establishment of the correct diagnosis.
Definition and diagnosis of autoimmune hepatitis
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
(Johnson 1993). In this and in a revised report the group noted that there is no single
454  Hepatology 2012
test for the diagnosis of AIH. 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 (Table 1). 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. AIH predominantly affects women at any age, and is
characterized by a marked elevation of serum globulins, in particular
gammaglobulins, and circulating autoantibodies. It should be noted that AIH
regularly affects individuals older than 40 but should be considered in all age groups
(Strassburg 2006). The clinical appearance ranges from an absence of symptoms to
a severe or fulminant presentation (Stravitz 2011) and responds to
immunosuppressive treatment in most cases. 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 (Strassburg 1995).
Autoantibodies are one of the distinguishing features of AIH. The discovery of
autoantibodies directed against different cellular targets including endoplasmatic
reticulum membrane proteins, nuclear antigens and cytosolic antigens has led to a
suggested subclassification of AIH based upon the presence of 3 specific
autoantibody profiles. 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. AIH type 2 is
characterized by anti liver-kidney microsomal autoantibodies (LKM-1) directed
against cytochrome P450 CYP2D6 (Manns 1989, Manns 1991) (Figure 1) and with
lower frequency against UDP-glucuronosyltransferases (UGT) (Strassburg 1996).
AIH type 3 (Manns 1987, Stechemesser 1993) is characterized by autoantibodies
against a soluble liver antigen (SLA/LP) identified as UGA suppressor serine
tRNA-protein complex (Gelpi 1992, Wies 2000, Volkmann 2001, Volkmann 2010).
However, this serological heterogeneity does not influence the decision of whom to
treat or of what strategy to employ.
Figure 1: Indirect immunofluorescence showing LKM-1 autoantibodies on rat kidney and
liver cryostat sections. Serum of a patient with autoimmune hepatitis type 2. A. Using rat
hepatic cryostat sections a homogeneous cellular immunofluorescence staining is visualized
excluding the hepatocellular nuclei (LKM-1). B. Typical indirect immunofluorescence pattern of
LKM-1 autoantibodies detecting the proximal (cortical) renal tubules but excluding the distal
tubules located in the renal medulla, which corresponds to the tissue expression pattern of the
autoantigen CYP2D6.
Autoimmune Liver Diseases: AIH, PBC and PSC  455
Although the histological appearance of AIH is characteristic, there is no specific
histological feature  that  can be used to prove the diagnosis (Dienes 1989).
Percutaneous liver biopsy should be performed for grading and staging, as well as
for therapeutic monitoring. Histological features usually include periportal hepatitis
with lymphocytic infiltrates, plasma cells, and piecemeal necrosis. With advancing
disease, bridging necrosis, panlobular and multilobular necrosis may occur and
ultimately lead to cirrhosis. A lobular hepatitis can be present, but is only indicative
of AIH in the absence of copper deposits or biliary inflammation. In addition,
granulomas and iron deposits argue against AIH. A liver biopsy should be obtained
at first diagnosis before therapy for grading, staging and as confirmation of the
diagnosis.
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 and herpes group may only be required in cases suspicious of such
infections or if the diagnosis of AIH based on the above-mentioned criteria remains
inconclusive.
The probability of AIH decreases whenever signs of bile duct involvement are
present, such as elevation of alkaline phosphatase, histological signs of
cholangiopathy and detection of AMA. If one or more components of the scoring
system are not evaluated, merely a score pointing to a probable diagnosis can be
compiled (Table 1).
Epidemiology and clinical presentation
Based on limited epidemiological data, the prevalence is estimated to range between
50 and 200 cases per 1 million in Western Europe and North America among the
Caucasian population. The prevalence of AIH is similar to that of systemic lupus
erythematosus, primary biliary cirrhosis and myasthenia gravis, which also have an
autoimmune etiology (Nishioka 1997, Nishioka 1998). Among the North American
and Western European Caucasian population AIH accounts for up to 20% of cases
with chronic hepatitis (Cancado 2000). However, chronic viral hepatitis remains the
major cause of chronic hepatitis in most Western societies. In locales in which viral
hepatitis B and C are endemic, such as in Asia and Africa, the incidence of AIH
appears to be significantly lower. Additional epidemiological analyses are required
to comprehensively elucidate the prevalence and geographical distribution of AIH.
Autoimmune hepatitis is part of the syndrome of chronic hepatitis, which is
characterized by sustained hepatocellular inflammation of at least 6 months duration
and elevation of ALT and AST of 1.5 times the upper normal limit. In about 49% of
AIH patients an acute onset of AIH is observed and rare cases of fulminant AIH
have been reported. In most cases, however, the clinical presentation is not
spectacular and characterized by fatigue, right upper quadrant pain, jaundice and
occasionally also by palmar erythema and spider naevi. In later stages, the
consequences of portal hypertension dominate, including ascites, bleeding
esophageal varices and encephalopathy. A specific feature of AIH is the association
of extrahepatic immune-mediated syndromes including autoimmune thyroiditis,
vitiligo, alopecia, nail dystrophy, ulcerative colitis, rheumatoid arthritis, and also
diabetes mellitus and glomerulonephritis.
456  Hepatology 2012
Table 1. International criteria for the diagnosis of autoimmune hepatitis
(Alvarez 1999).
Parameter  Score
Gender
Female
Male
+ 2
0
Serum biochemistry
Ratio of elevation of serum alkaline phosphatase vs aminotransferase
>3.0
1.5-3
<1.5
- 2
0
+ 2
Total serum globulin, γ-globulin or IgG
(times upper limit of normal)
>2.0
1.5-2.0
1.0-1.5
<1.0
+ 3
+ 2
+ 1
0
Autoantibodies (titers by immunfluorescence on rodent tissues)
Adults
ANA, SMA or LKM-1
>1:80
1:80
1:40
<1:40
+ 3
+ 2
+ 1
0
Antimitochondrial antibody
Positive
Negative
- 4
0
Hepatitis viral markers
negative
positive
+ 3
- 3
History of drug use
Yes
No
- 4
+ 1
Alcohol (average consumption)
<25 gm/day
>60 gm/day
+ 2
- 2
Genetic factors: HLA-DR3 or -DR4  + 1
Other autoimmune diseases  + 2
Response to therapy
complete
relapse
+ 2
+ 3
Liver histology
interface hepatitis
predominant lymphoplasmacytic infiltrate
rosetting of liver cells
none of the above
biliary changes
other changes
+ 3
+ 1
+ 1
- 5
- 3
-3
Seropositivity for other defined autoantibodies  + 2
Interpretation of aggregate scores: definite AIH - greater than 15 before treatment
and greater than 17 after treatment; probable AIH - 10 to 15 before treatment and 12 to
17 after treatment.
Autoimmune Liver Diseases: AIH, PBC and PSC  457
Natural history and prognosis
Data describing the natural history of AIH are scarce. The last placebo-controlled
immunosuppressive treatment trial containing an untreated arm was published in
1980 (Kirk 1980). The value of these studies is limited considering that these
patients were only screened for epidemiological risk factors for viral hepatitis and
were not characterized by standardized diagnostic criteria and available virological
tests. Nevertheless, these studies reveal that untreated AIH had a very poor
prognosis and 5- and 10-year survival rates of 50% and 10% were reported. They
furthermore demonstrated that immunosuppressive treatment significantly improved
survival.
Data reveal 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 (86%) 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 and those
patients require a similarly aggressive treatment strategy (Geall 1968, Soloway
1972).
Almost half of the children with AIH already have cirrhosis at the time of
diagnosis. Long-term follow-up revealed that few children can completely stop all
treatment and about 70% of children receive long-term treatment (Homberg 1987,
Gregorio 1997). Most of these patients relapse when treatment is discontinued, or if
the dose of the immunosuppressive drug is reduced. About 15% of patients develop
chronic liver failure and are transplanted before the age of 18 years.
In elderly patients, a more severe initial histological grade has been reported
(Strassburg 2006). The risk of hepatocellular carcinoma varies considerably
between the different diseases PBC, PSC and AIH. Particular PCS can be
complicated by cholangiocarcinoma, gall bladder carcinoma and hepatocellular
carcinoma. In contrast, occurrence of HCC in patients with AIH is a rare event and
develops only in long-standing cirrhosis.
Who requires treatment?
Autoimmune hepatitis (AIH) is a remarkably treatable chronic liver disease (Manns
2001, Czaja 2010). Untreated, the prognosis of active AIH is dismal with 5- and 10-year survival rates between 50 and 10% and a well recognized therapeutic effect
exemplified by the last placebo-controlled treatment trials (Soloway 1972, Kirk
1980). For these reasons the indication for treatment is given in any patient who has
an established diagnosis of AIH, elevations of aminotransferase activities (ALT,
AST), an elevation of serum immunoglobulin G and histological evidence of
interface hepatitis or necroinflammatory activity. This has recently been discussed
in the newest version of the AIH guidelines for the American Association for the
Study of the Liver (AASLD) (Manns 2010a). These points indicate that an initial
liver biopsy specimen is desirable for confirmation of the diagnosis and for grading
and staging. Biopsies are also helpful for observation of aminotransferase activities
in serum reflecting inflammatory activity in the liver, which is not closely correlated
in all cases.
458  Hepatology 2012
Who does not require treatment?
Only very few patients with an established diagnosis of AIH should not be treated.
Rare cases, in which the initiation of standard therapy should be weighed against
potential side effects, are contraindications with steroids or azathioprine, or for
certain other immunosuppressants (see below). In decompensated liver cirrhosis of
patients on the waiting list for liver transplantation and in individuals with complete
cirrhosis and absent inflammatory activity treatment does not appear beneficial
(Manns 2010a).
Standard treatment strategy
Independent of clinically- or immunoserologically-defined type of AIH, standard
treatment is implemented with predniso(lo)ne alone or in combination with
azathioprine. Both strategies are just as effective (Manns 2001, Manns 2010a). The
basic strategy of this treatment is still based upon the findings of studies of almost 3
decades ago that indicated the effectiveness of steroids in AIH. Since that time no
single multicenter randomized treatment trial in AIH patients has been performed.
All advances of alternative treatment strategies are based on small cohorts and on
the need to develop strategies for difficult-to-treat patients. The use of prednisone or
its metabolite prednisolone, which is used more frequently in European countries, is
equally effective since chronic liver disease does not seem to have an effect on the
synthesis of prednisolone from prednisone. Important is the exact differentiation
between viral infection and autoimmune hepatitis. Treatment of replicative viral
hepatitis with corticosteroids must be prevented as well as administration of
interferon in AIH, which can lead to dramatic disease exacerbation.
Standard induction treatment and suggested follow-up examinations are
summarized in Table 2. Please note that there are differences in preferred regimen
in Europe and the US, which are delineated in the AASLD AIH Guideline (Manns
2010a). Therapy is usually administered over the course of 2 years. The decision
between monotherapy and combination therapy is guided principally by side effects.
Long-term steroid therapy leads to cushingoid side effects. Cosmetic side effects
decrease patient compliance considerably (Table 3). Serious complications such as
steroid diabetes, osteopenia, aseptic bone necrosis, psychiatric symptoms,
hypertension and cataract formation also have to be anticipated in long-term
treatment. Side effects are present in 44% of patients after 12 months and in 80% of
patients after 24 months of treatment. However, predniso(lo)ne monotherapy is
possible in pregnant patients. Azathioprine, on the other hand, leads to a decreased
dose of prednisone. It bears a theoretical risk of teratogenicity. In addition,
abdominal discomfort, nausea, cholestatic hepatitis, rashes and leukopenia can be
encountered. These side effects are seen in 10% of patients receiving a dose of 50
mg per day. From a general point of view, a postmenopausal woman with
osteoporosis, hypertension and elevated blood glucose would be a candidate for
combination therapy. In young women, pregnant women or patients with
hematological abnormalities, prednisone monotherapy may be the treatment of
choice.
Autoimmune Liver Diseases: AIH, PBC and PSC  459
Table 2. Treatment regimen and follow-up examinations of autoimmune hepatitis
regardless of autoantibody type.
Monotherapy  Combination therapy
Prednis(ol)one  60 mg
reduction by 10 mg/week to
maintenance of 20 mg/wk
reduction by 5 mg to 10 mg
find lowest dose in 2.5 mg
decrements
30-60 mg
reduction as in monotherapy
Azathioprine  n.a.
(maintenance with azathioprine:
monotherapy: 2 mg/kg body weight)
1 mg/kg of body weight (Europe)
50 mg (US)
Examination  Before
therapy
During
therapy
before
remission
q 4 weeks
Remission
on therapy
q 3-6
months
Cessation
of therapy
q 3 weeks
(x 4)
Remission
post-therapy
q 3-6
months
Evaluation of
relapse
Physical  +    +  +  +  +
Liver biopsy  +    (+/-)      +
Blood count  +  +  +  +  +
Aminotransferases  +  +  +  +  +  +
Gamma
glutamyltransferase
+  +  +   
Gammaglobulin  +  +  +  +  +  +
Bilirubin  +  +  +  +  +  +
Coagulation studies  +  +  +  +  +
Autoantibodies   +  +/-        +
Thyroid function
tests
+  +/-        +
Table 3. Side effects.
Prednis(ol)one  acne
moon-shaped face
striae rubra
dorsal hump
obesity
weight gain
diabetes mellitus
cataracts
hypertension
Azathioprine  nausea
vomiting
abdominal discomforts
hepatotoxicity
rash
leukocytopenia
teratogenicity (?)
oncogenicity (?)
460  Hepatology 2012
One of the most important variables for treatment success is adherence. The
administration of treatment is essential since most cases of relapse are the result of
erratic changes of medication and/or dose. Dose reduction is aimed at finding the
individually appropriate maintenance dose. Since histology lags 3 to 6 months
behind the normalization of serum parameters, therapy has to be continued beyond
the normalization of aminotransferase levels. Usually, maintenance doses of
predniso(lo)ne range between 10 and 2.5 mg. After 12-24 months of therapy
predniso(lo)ne can be tapered over the course of 4-6 weeks to test whether a
sustained remission has been achieved. Tapering regimens aiming at withdrawal
should be attempted with great caution and only after obtaining a liver biopsy that
demonstrates a complete resolution of inflammatory activity. Relapse of AIH and
risk of progression to fibrosis is almost universal when immunosuppression is
tapered in the presence of residual histological inflammation. Withdrawal should be
attempted with caution to prevent recurrence and subsequent fibrosis progression
and should be discussed with the patient and closely monitored.
Outcomes of standard therapy can be classified into four categories: remission,
relapse, treatment failure and stabilization.
Remission is a complete normalization of all inflammatory parameters including
histology. This is ideally the goal of all treatment regimens and ensures the best
prognosis. Remission can be achieved in 65-75% of patients after 24 months of
treatment. Remission can be sustained with azathioprine monotherapy of 2 mg/kg
bodyweight (Johnson 1995). This prevents cushingoid side effects. However, side
effects such as arthralgia (53%), myalgia (14%), lymphopenia (57%) and
myelosuppression (6%) have been observed. Complete remission is not achieved in
about 20% of patients and these patients continue to carry a risk of progressive liver
injury.
Relapse  is characterized by an increase  in aminotransferase levels and the
reccurrence of clinical symptoms either while on treatment, following tapering of
steroid doses to determine the minimally required dose, or, after a complete
withdrawal of therapy. Relapse can be found in 50% of patients within 6 months of
treatment withdrawal and in 80% after 3 years. Relapse is associated with
progression to cirrhosis in 38% and liver failure in 14%. Relapse requires
reinitiation of standard therapy, consideration of dosing as well as diagnosis, and
perhaps a long-term maintenance dose with predniso(lo)ne or azathioprine
monotherapy.
Treatment failure characterizes a progression of clinical, serological and
histological parameters during standard therapy. This is seen in about 10% of
patients. In these cases the diagnosis of AIH has to be carefully reconsidered to
exclude other etiologies of chronic hepatitis. In these patients experimental
regimens can be administered or ultimately liver transplantation becomes necessary.
Stabilization is the achievement of a partial remission. Since 90% of patients
reach remission within 3 years, the benefit of standard therapy has to be reevaluated
in this subgroup of patients. Ultimately, liver transplantation provides a definitive
treatment option.
Autoimmune Liver Diseases: AIH, PBC and PSC  461
Treatment of elderly patients
The presentation of acute hepatitis, clinical symptoms of jaundice, abdominal pain
and malaise have a high likelihood of attracting medical attention and subsequently
leading to the diagnosis of AIH (Nikias 1994). More subtle courses of AIH may not
lead to clinically relevant signs and may develop unnoticed other than via routine
work-up for other problems or via screening programs. The question of disease
onset in terms of initiation of immune-mediated liver disease versus the clinical
consequences that become noticeable after an unknown period of disease
progression is not easily resolved. Thus, “late onset” AIH may just simply reflect a
less severe course of the disease with a slower progression to cirrhosis. While
LKM-positive patients display a tendency towards an earlier presentation, both
acute and subtle (earlier and late presentation) variants appear to exist in ANA-positive AIH. In practice, the diagnostic dilemma is that AIH is still perceived by
many as a disease of younger individuals and that therefore this differential
diagnosis is less frequently considered in elderly patients with “cryptogenic”
hepatitis or cirrhosis. Another relevant question resulting from these considerations
is the issue of treatment. Standard therapy in AIH consists of steroids alone or a
combination with azathioprine. In maintenance therapy azathioprine monotherapy
can also be administered but induction with azathioprine alone is not effective.
From a general standpoint most internists will use caution when administering
steroids to elderly patients, especially in women in whom osteopenia or diabetes
may be present.
Recommendations for the treatment of AIH suggest that the steroid side effects be
weighed against the potential benefit of therapy, and that not all patients with AIH
are good candidates for steroid treatment (Manns 2001). Controversy exists
surrounding the benefit of therapy in this group of elderly patients. One cohort
reported on 12 patients over 65 out of a total of 54 AIH patients. Cirrhosis
developed after follow-up in 26% irrespective of age although the histological grade
of AIH activity was more severe in the elderly group. 42% of the patients over 65
did not receive therapy and yet deaths were reported only in the younger group
(Newton 1997). In another cohort of 20 patients aged >65 years, a longer time to
establishment of the diagnosis (8.5 vs. 3.5 months) was reported, patients presented
mainly with jaundice and acute onset AIH and showed a response rate to
immunosuppression comparable to that of younger patients (Schramm 2001). The
authors also noted that the prevalence of the HLA-A1-B8 allotype was less frequent
in older patients suggesting a role for immunogenetics.
This point was further elaborated by a recent report analyzing 47 patients with
ANA-positive AIH 60 years and older, as well as 31 patients 30 years and younger
in whom DR4+/DR3- prevalence was 47% (older) versus 13% (younger) patients
(Czaja 2006). In the older patients steroid responsiveness was better, which is in line
with previous findings in the same collective (Czaja 1993). Cirrhosis and
extrahepatic immune-mediated syndromes including thyroid and rheumatologic
disease (47% vs. 26%) were more prevalent in older AIH patients. However,
although more treatment failures were observed in the younger patients (24% vs
5%) the rates of remission, sustained remission and relapse were similar.
Interestingly, an assessment of age-stratified prevalence showed an increase after
the age of 40 from 15% to over 20%.
462  Hepatology 2012
From all this data, AIH in elderly patients appears to be characterized by a distinct
clinical feature, a distinct immunogenetic profile, favourable response rates and
higher rates of cirrhosis present at diagnosis, all of which contribute to the
heterogeneity of AIH. In a  cohort of 164 patients from the UK including 43
individuals 60 years and older AIH was looked at (Al-Chalabi 2006). The age
groups showed no significant differences regarding serum biochemistry,
autoantibody titers, time to establishment of diagnosis, and mode of presentation.
The authors provided a substratification of patients below and above 40 years of age
and reported that older patients had a higher median histological stage and a
comparable median grade but younger patients had more median relapse episodes
and a higher median stage at follow-up biopsy. The most distinguishing clinical sign
was a higher prevalence of ascites in the older group. However, rates of complete,
partial and failed response were similar, and the median number of relapses was
higher in younger patients, which nevertheless did not lead to differences in liver-related deaths in either group (12% vs. 15%). In comparison to the study of ANA-positive AIH patients from the US (Czaja 2006) the differing findings regarding
HLA association are notewothy. In the UK study there was no differential
distribution of HLA-DR3 and -DR4 and this questions the suggested hypothesis of a
primary influence of immunogenetics on the observed clinical distinctions. The
reasons for the clinical differences of AIH in older and younger patients are unclear.
They may include differences in hepatic blood flow and alterations involving the
regulation of cellular immunity during aging (Talor 1991, Prelog 2006). In
summary, these data suggest that AIH in elderly patients should be considered and
treated (Strassburg 2006).
Alternative Treatments
When standard treatment fails or drug intolerance occurs, alternative therapies such
as cyclosporin, tacrolimus, cyclophosphamide, mycophenolate mofetil, rapamycin,
UDCA, and budesonide can be considered (Table 4). The efficacy of most of these
options has not yet been definitively decided and is only reported in small case
studies.
Table 4. Alternative drugs in autoimmune hepatitis.
Compound  Advantage  Disadvantage
Budesonide  High first pass effect
Immunosuppressive action
Inactive metabolites
Cirrhosis (portosystemic
shunts) and side effects
Cyclosporine  Satisfactory experience
Potent immunosuppressant
Transplant immunosuppressant
Renal toxicity
Tacrolimus  Potent immunosuppressant
Transplant immunosuppressant
Renal toxicity
Mycophenolic acid  Favourable toxicity profile
Transplant immunosuppressant
Disappointing
effectiveness
Cyclophosphamide  Effective  Continuous therapy
Hematological side effects
Autoimmune Liver Diseases: AIH, PBC and PSC  463
Budesonide
Budesonide is a synthetic steroid with high first-pass metabolism in the liver, in
principle with limited systemic side effects compared to conventional steroids. In
comparison to prednisone the absolute bioavailability of budesonide is less than 6-fold lower (Thalen 1979) but it has an almost 90% first-pass metabolism in the liver,
a higher affinity to the glucocorticoid receptor, acts as an anti-inflammatory and
immunosuppressive drug and leads to inactive metabolites (6-OH-budesonide, 16-OH-prednisolone). In a pilot study treating 13 AIH patients with budesonide over a
period of 9 months the drug was well tolerated and aminotransferase levels were
normalized (Danielson 1994). However, in a second study budesonide therapy was
associated with a low frequency of remission and high occurrence of side effects
(Czaja 2000). In that study, 10 patients were treated who had previously been
treated with azathioprine and steroids and had not reached a satisfactory remission.
The conclusion of the authors was that budesonide was not a good treatment option
in those patients. A third study with 12 previously untreated patients was published
(Wiegand 2005). In this study remission was induced with budesonide combination
therapy. The authors performed kinetic analyses and reported that in those with high
inflammatory activity and cirrhosis the area under the curve (AUC) of budesonide
was increased. This finding plausibly demonstrates that in patients with
portosystemic shunts in portal hypertension the effect of high hepatic first-pass
metabolism that would limit typical steroid side effects is reduced.
The main advantage of budesonide for the future  treatment of autoimmune
hepatitis would therefore be to replace prednisone in long-term maintenance therapy
and induction therapy to reduce steroid side effects. To this end the first multicenter
placebo-controlled randomised AIH treatment trial in 3 decades was performed with
a total of 207 non-cirrhotic patients from 30 centres in 9 European countries and
Israel (Manns 2010b). In this trial 40 mg prednisone (reduction regimen) and
azathioprine was compared to 3 mg budesonide (TID initially, reduced to BID) in
combination with azathioprine. The data was recently published and shows that
budesonide in combination with azathioprine is efficient in inducing stable
remission, is superior in comparison to a standard prednisone tapering regimen
beginning with 40 mg per day (Manns 2010b) and leads to a substantially superior
profile of steroid-specific side effects. From these data budesonide is emerging as an
alternative first-line treatment strategy for non-cirrhotic patients with AIH (Manns
2010b).
Deflazacort
This alternative corticosteroid has also been studied for immunosuppression in AIH
because of its feature of fewer side effects than conventional glucocorticoids. In a
pilot study 15 patients with AIH type I were treated with deflazacort, who had been
previously treated with prednisone with or without azathioprine until they reached a
biochemical remission. Remission was sustained for 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 (Rebollo Bernardez 1999).
464  Hepatology 2012
Cyclosporine A
Cyclosporine A (CyA) 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 (Strassburg 2008). Out of the alternative AIH
drugs considerable experience has been reported with CyA. In these studies CyA
was successfully used for AIH treatment and was well tolerated (Alvarez 1999b,
Debray 1999). The principal difficulty in advocating widespread use of CyA 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)  (Alvarez 1999b, Debray 1999, Fernandez 1999,
Heneghan 2002).
Tacrolimus
Tacrolimus is a macrolide lactone compound with immunosuppressive qualities
exceeding those of CyA. The mechanism of action is similar to that of CyA but it
binds to a different immunophilin (Strassburg 2008). 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 BUN and creatinine levels (Van
Thiel 1995). In a second study with 11 steroid refractory patients improvement of
inflammation was also observed (Aqel 2004). Although tacrolimus represents a
promising immunosuppressive candidate drug, larger randomized trials are required
to assess its role in the therapy of AIH.
Mycophenolic acid
Mycophenolate has attracted attention as a transplant immunosuppressant with an
important role in the steroid-free immunosuppressive therapy of patients
transplanted for chronic hepatitis C infection. Mycophenolate is a noncompetitive
inhibitor 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 pilot study 7 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 addition to steroids.
In 5 out of 7 patients normalization of aminotransferase levels was achieved within
3 months. These preliminary data suggested that mycophenolate may represent a
promising treatment strategy of AIH (Richardson 2000). In a recent retrospective
study 37 patients with AIH and azathioprine failure or intolerance were treated with
mycophenolate (Hennes 2008a). There was no statistically significant benefit for
mycophenolate treatment. Less than 50% reached remission and in the azathioprine
non-responders failure was 75%. Although the toxicity profile of mycophenolate
would suggest its use, the retrospective study data does not indicate an effective
second line therapeutic option.
Cyclophosphamide
The induction of remission with 1-1.5 mg per kg per day of cyclophosphamide in
combination with steroids has been reported. However the dependency of continued
application of cyclophosphamide with its potentially severe hematological side
effects renders it a highly experimental treatment option (Kanzler 1996).
Autoimmune Liver Diseases: AIH, PBC and PSC  465
Anti-TNF α antibodies
There is some emerging evidence that anti-TNF antibodies are capable of inducing
remission in AIH patients in whom standard or alternative therapeutic options have
been exhausted (Efe 2010, Umekita 2011). However, the development of AIH has
also been observed under treatment with anti-TNF antibodies (Ramos-Casals 2008).
Future studies will have to define the role of this therapeutic option in difficult-to-treat cases of AIH.
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. Uncontrolled trials have
shown a reduction in histological abnormalities, clinical and biochemical
improvement but not a reduction of fibrosis in 4 patients with AIH type 1 (Calmus
1990, Nakamura 1998, Czaja 1999). However, its role in AIH therapy or in
combination with immunosuppressive therapy is still unclear.
Other alternative treatment strategies include methotrexate, anti-TNF a antibodies,
and rituximab, but there is currently insufficient data on any of these.
Overlap syndromes and treatment
The term overlap syndrome describes a disease condition that is only incompletely
defined (Strassburg 2006). A valid definition is difficult (Boberg 2011). It is
characterized by the coexistence of clinical, biochemical or serological features of
autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing
cholangitis (PSC), and depending on the definition, also viral hepatitis C (Ben-Ari
1993, Colombato 1994, Duclos-Vallee 1995, Chazouilleres 1998, Angulo 2001,
Rust 2008). In adult patients an overlap of PBC and AIH is most frequently
encountered although it is unclear whether this is true co-existence of both diseases
or an immunoserological overlap characterized by the presence of antinuclear
(ANA) as well as antimitochondrial (AMA) antibodies (Poupon 2006, Gossard
2007, Silveira 2007, Al-Chalabi 2008). In many AMA-negative patients with a
cholestatic liver enzyme profile ANA are present. This has been termed
autoimmune cholangiopathy or AMA-negative PBC (Michieletti 1994).
Apart from coexisting, autoimmune liver diseases can also develop into each
other, i.e., the sequential manifestation of PBC and autoimmune hepatitis. The true
coexistence of AIH and PSC has only been conclusively shown in pediatric patients
(Gregorio 2001). It can be hypothesized whether a general predisposition toward
liver autoimmunity exists which has a cholestatic, a hepatitic and a bile duct facet,
which may be variable depending upon unknown host factors. The diagnosis of an
overlap syndrome relies on the biochemical profile (either cholestatic with elevated
alkaline phosphatase, gamma glutamyltransferase and bilirubin, or hepatitic with
elevated aspartate aminotransferase and alanine aminotransferase levels in addition
to elevated gamma globulins), the histology showing portal inflammation with or
without the involvement of bile ducts, and the autoantibody profile showing AMA
or autoantibodies associated primarily with AIH such as liver-kidney microsomal