Clinical Aspects of Liver Diseases 33 Autoimmune hepatitis

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33 Autoimmune hepatitis

Page:

1 Definition 678

2 Epidemiology 678

3 Aetiology 678

3.1 Immunologic tolerance 678

3.2 Immunogenetic susceptibility 678

3.3 Trigger factors 678

4 Pathogenesis 678

4.1 HLA system 678

4.2 Cellular immune reaction 679

4.3 Autoantibodies 679

5 Classification 680

5.1 Type 1 680

5.2 Type 2 680

5.3 Type 3 681

5.4 Drug-induced AIH 681

5.5 Overlap syndrome 681

5.6 Association with HV infection 681

5.7 Cryptogenic chronic hepatitis 682

6 Morphology 682

7 Clinical aspects 683

7.1 Clinical symptoms 683

7.2 Laboratory diagnostics 683

7.3 Liver histology 683

8 Course and prognosis 683

8.1 Course of disease 683

8.2 Associated diseases 684

8.3 Hepatocellular carcinoma 684

8.4 Prognosis 684

9 Therapy 684

9.1 Detailed diagnosis 684

9.2 Immunosuppressive therapy 685

9.2.1 Glucocorticoids 685

9.2.2 Glucocorticoids and azathioprine 685

9.2.3 Ursodeoxycholic acid 686

9.2.4 Monitoring therapy 686

9.2.5 Non-responders to therapy 686

9.2.6 Overlap syndrome 686

9.3 Liver transplantation 687

앫 References (1⫺107) 687

(Figures 33.1 ⫺33.4; tables 33.1⫺33.2)

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䉴 A particular form of chronic liver disease prevalent among young women with an excessive increase in protein andγ-globulin was first described by

S. A mberg (1942)

(1) and later by

J. W aldenström (1950)

, who used the name

“autoimmune hepati- tis”. (101). In 1951 ^{H. G. K} unkel et al.

termed this condition

“hypergammaglobulinaemic chronic hepatitis”. (47) This type of

disease was confirmed by

A. G. B earn et al. (1956)

(2) and, because of a positive LE-cell phenomenon in about 10% of cases

(R. A. J oske et al., 1955)

(43), was given the name

“lupoid hepatitis” by ^{I. R. M} acKay et al. (1956)

. (49)

•

During the following years, there were frequent reports of a particular form of active and necrotizing liver disease, which was assumed in many cases to be autoimmune due to the treatment success achieved with glucocorticoids and/or azathioprine. Laboratory parameters were characterized by increased transaminase values, GDH,γ-globulins and immunoglobulins as well as by distinct histological findings ⫺ there was no possibility of

obtaining immunologic evidence at that time.

1 Definition

The cause of autoimmune hepatitis (AIH) is unknown.

Autoimmune reactions lead to a chronic (rarely acute) inflammatory process (periportal piecemeal necrosis, infiltration of portal zones). AIH is frequently associ- ated with autoimmune diseases of other organs. It occurs predominantly among women, particularly in younger years. Hypergammaglobulinaemia is invari- ably in evidence. Various autoantibodies to compo- nents of the liver parenchyma are found. The presence and specificity of these antibodies, together with the respective clinical symptoms, facilitate differentiation between the various subtypes of AIH. Diagnosis is substantiated by the response to immunosuppressive therapy. If left untreated, AIH progresses rapidly with transition to cirrhosis and/or liver failure. If treated adequately, the course taken by the disease is favour- able.

2 Epidemiology

AIH is present worldwide. Some 15 ⫺20% of all patients with chronic hepatitis can be classified as AIH. Preva- lence and incidence differ in various geographic regions.

In Europe and North America, prevalence ranges between 3 ⫺17/100,000 inhabitants, whereby the lowest rates are found in southern countries. The incidence in Europe and North America is estimated to be between 0.1 ⫺1.9/100,000 inhabitants per year. Women are 4 to 5 times and children 7 to 9 times more frequently affec- ted. AIH can occur in all age groups.

(7)

3 Aetiology

3.1 Immunologic tolerance

The aetiology of autoimmune hepatitis is (as yet) unresolved. •

The immunologic tolerance of the body’s own cell structures can be disturbed as a result of (1.) immunogenetic abnormalities in the

MHC system (⫽ major histocompatibility complex, i.e. the main

complex in the HLA system, classes I and II), (2.)

clonal deletion

(⫽ removal of so-called “mobile” genes from plasmids) as well as suppressor defects, and (3.)

molecular mimicry (⫽ partial corres-

pondence of the molecular structure of a foreign antigen with a certain body-own protein structure). (s. p. 643)

3.2 Immunogenetic susceptibility

Genetic predisposition is paramount. •

The existence of such a genetic factor can be deduced from occasional familial occurrence (25, 37), gender and age specificity as well as a close correlation with the HLA system. (64) Women are affected in 85⫺90% of cases, mainly between the ages of 14⫺55 years (women: men ⫽ 4:1).

3.3 Trigger factors

AIH must be triggered by an antigen. •

Trigger factors include envi- ronmental noxae, medication, toxins, bacteria (e. g. salmonella antigen), hepatitis viruses HAV (72, 89, 95), HBV, HCV, Epstein- Barr (63, 96), lymphochoriomeningitis virus (39) and measles viruses (77, 97) as well as the Herpes simplex virus (type 1 of which is mainly responsible for AIH type 2). (48, 74) The development of AIH has also been precipitated by interferon therapy in chronic hepatitis B (13) and C (32, 66) even in children. (78)

•

The viral

trigger hypothesis has recently aroused great interest, since various

viruses (e. g. HAV, measles, Epstein-Barr) are known to persist

“unnoticed” for years, e. g. in lymphocytes.

4 Pathogenesis

4.1 HLA system

Immunogenetic susceptibility is substantiated by the close association between autoimmune hepatitis and the HLA system. (24, 50, 64, 81)

Ethnic differences are evident: an association with HLA-

DR4 is frequent in Japan and in the Euro-Caucasian population.

In patients with HLA-DR3 positivity, manifestation occurs in younger years, there is greater activity of disease and the outcome of therapy is less favourable (higher rate of non-responders and recurrences after ceasing immunosuppressive therapy, as well as more frequent indications for liver transplantation). In contrast, HLA-DR4 positivity correlates with manifestation at a more advanced age, a milder course of disease and a good response to immunosuppressives, albeit with the considerably more frequent occurrence of extrahepatic syndromes. The HLA markers DR3 and DR4 are hence characteristic of two different courses.

•

Fur- ther HLA types of importance include: HLA-A1, -B8, -DR4, -Bw54, -DR3, -DR13 (Brazil), -Dw3, -DR53, -C4AQO and -DQ4.

A close relationship was found between AIH and the CD 45 gene, which is considered quasi to be a “modifier gene of human auto-

immunity”. (99)

(3)

4.2 Cellular immune reaction

Cellular alteration of the immune response is characterized by T lymphocytes infiltrating liver tissue. The target antigens of the T lymphocytes are deemed to be cytochrome P450 II D6, mito- chondrial pyruvate dehydrogenase and asialoglycoprotein receptor proteins. (92) A loss of immune tolerance for autologous liver tissue can be attributed to the decrease in activity of T suppressor cells (with lymphocyte marker T8) and the preponderance of T helper cells (with lymphocyte marker T4) over the suppressor cells.

Any existing suppressor defect in autoimmune hepatitis is elimin- ated by glucocorticoids⫺ but not in cases of chronic viral hepatitis B. The suppressor T cell defect causes immunological hyperactivity against surface structures of the hepatocytes. T cells from the liver of autoimmune hepatitis patients are sensitized to asialoglycoprotein receptor proteins. (5, 53, 54, 65, 87, 93, 103)

4.3 Autoantibodies

䉴 There are various circulating autoantibodies to nuclear, cytoplasmatic and membranous antigens; they differ in their diagnostic and clinical significance. Auto- antibodies are deemed to be secondary immunological phenomena of liver cell lesions and have no pathoge- netic importance. Correlation of the antibody titres with AIH activity is unreliable. The antibodies may play a part in eliminating autoantigens. Their determination is essential for the diagnosis and classification of AIH as well as its overlap syndromes.

(6, 17, 20, 65, 86, 88)

(s. tabs.

5.19, 5.20; 33.1)

ANA: Antinuclear factors were described for the first time by

G. J. Friou et al.

in 1957. These antibodies are mainly directed against nucleoprotein DNA histone and cycline A. They show a predominantly homogeneous or

“speckled” pattern of fluorescence. ANA is not specific to the liver or to liver disease. (s. figs. 5.10, 5.11) (s.

p. 118)

SMA: Smooth muscle antibodies were first described by

G. D. Johnson et al. (1965)

. They mostly possess anti-actin (generally F-actin) specificity, predominantly of the IgG type. Antibodies against troponin and α-actin may also be present. There is great heterogeneity, and a mixture of different antibodies can almost always be found. Evi- dence of anti-actin antibodies has a high diagnostic value, particularly with a titre of > 1:640 and in the pres- ence of an IgG type. (s. fig. 5.12) (s. p. 119)

LKM: Anti-LKM 1 were detected by

^{M. R}izzetto et al.

and

W. B. Storch (86)

in 1973. As liver/kidney micro- somes, they are directed against an antigen of the ER (cytochrome P 450 II D 6) (anti-AER) as well as against proximal kidney tubuli. • There are also anti-LKM 2 (antigen: P 450 II C 8 ⫺II C 11 in tienilic acid-induced hepatitis) and anti-LKM 3 (antigen: part of the UDP glucuronyltransferase in chronic hepatitis D as well as in hydralazine and carbamazepine-induced hepatitis against P 450 I A2). LKM antibodies are directed against other microsomal antigens as well and conse- quently may be present in viral or toxic liver diseases.

They constitute a heterogeneous group.

(26, 38)

(s. p. 119)

LP/SLA: Anti-LP antibodies were described by

^{P. A.}

Berg et al.

in 1981.

(4)

They show a particularly strong reaction against soluble antigens from the liver and pan- creas. The specific antigen has not been identified. In autoimmune hepatitis, anti-LP antibodies are associated with ANA and/or SMA in > 60% of cases; even when detected on their own, they are of diagnostic import- ance.

(84)

• Soluble liver-antigen antibodies (SLA) were demonstrated for the first time by

M. P. Manns et al.

in 1987.

(51)

They seem to recognize cytokeratins as anti- gens and identify a target antigen of activated lympho- cytes. SLA are probably identical to LP and possibly even characterize the same patient group. Although they are indeed of diagnostic relevance in AIH, they are not specific. LP/SLA are detectable in AIH in 25% of cases.

(s. p. 120) • The postulated main antigen of cytosol anti- bodies has meanwhile been cloned.

(100, 104)

This group of cytosol antibodies was first described by

W. Storch

in 1975; they are probably identical to anti-LP and anti- SLA antibodies.

(86)

䉴 The autoantibodies ANA, SMA, LKM 1 and LP/

SLA are of diagnostic relevance in autoimmune hepa- titis. Moreover, they are usually detectable at a time when no clear diagnosis can be derived from clinical, laboratory or histological findings. This is most import- ant with regard to early immunosuppressive therapy.

Other autoantibodies (such as LMA, LC1, HHPM) are indeed often associated with AIH, yet have no diagnos- tic relevance.

LC: These liver-specific antibodies (LC1 and LC2) react with a soluble cytosolic antigen in the liver cells

(W.

Storch, 1975, 1979)

. This was confirmed by

E. Martini et al.

in 1982. They are frequently associated with anti- LKM 1 antibodies (60 ⫺70%). The hepatocytes around the central vein of the liver lobule are left out of the otherwise homogeneous cytoplasmatic fluorescence.

LC 1 antibodies are not present in chronic viral hepatitis C, and thus they are important in differentiating be- tween (LC1-positive) AIH and (LC1-negative) chronic HCV infection. LC1 is primarily found in young patients presenting with AIH type 2. Only rarely are LC2 antibodies found in AIH; they react with peripor- tal liver cells.

(35, 45)

LMA: The liver membrane antibodies were first iden- tified by

W. Storch

in 1973

(86)

and confirmed by

U. Hopf et al.

in 1976. They are directed against various epitopes of the liver cell membrane, e. g. the ASGPR receptor.

LMA are mostly associated with other (relevant) anti- bodies in AIH. (s. p. 119)

Asialoglycoprotein receptor: The antigen spectrum of

anti-LSP antibodies is a heterogeneous group. The asia-

loglycoprotein receptor protein (anti-ASGPR) is a spe-

cific antigen of this LSP mixture

(B. M. McFarlane et al., 1986)

. In AIH, 80 ⫺85% of cases displayed antibodies

against this purified protein. Yet, anti-ASGPR are also

(4)

ANA SMA LKM 1 SLA/LP ASGPR AMA pANCA AHA HCV anti- specific GOR nuclear antibody Autoimmune hepatitis

1a ⫹⫹ (⫹) ⫺ ⫺ (⫹)⫹ ⫺ (⫹) ⫺ (⫹) (⫹)

1b (⫹) ⫹⫹ ⫺ ⫺ (⫹)⫹ ⫺ (⫹) ⫺ (⫹) (⫹)

2a ⫺ ⫺ ⫹⫹ ⫺ (⫹)⫹ ⫺ ⫺ ⫺ ⫺ ⫺

2b ⫺ ⫺ ⫹⫹ ⫺ (⫹)⫹ ⫺ ⫺ ⫺ ⫹ ⫹

3 (⫹) (⫹)⫹ ⫺ ⫹⫹ (⫹)⫹ (⫹) ⫺ ⫺ ⫺ ⫺

Primary biliary cholangitis

앫 Primary biliary (⫹) ⫺ ⫺ ⫺ (⫹) ⫹⫹ (⫹) ⫺ ⫺ ⫺

cholangitis (PBC)

앫 Primary sclerosing (⫹) ⫺ ⫺ ⫺ ⫺ ⫺ ⫹⫹ ⫺ ⫺ ⫺

cholangitis (PSC)

Overlap syndrome

AIH/PBC ⫹ (⫹) ⫺ (⫹) (⫹) ⫹ ⫺ ⫺ ⫺ ⫺

AIH/PSC ⫹ (⫹) ⫺ (⫹) (⫹) ⫺ ⫹ ⫺ ⫺ ⫺

AIH/HCV (see type 2a) (⫹) (⫹) ⫹ (⫹) ⫹ ⫺ ⫺ ⫺ ⫺ (⫹)⫹

AIH/HCV (see type 2b) ⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ (⫹)⫹

AIH/alcohol (⫹) (⫹) ⫺ (⫹) (⫹) (⫹) ⫺ ⫹⫹ ⫺ ⫺

AIH/collagenosis ⫹⫹ ⫹⫹ ⫺ (⫹) (⫹) ⫺ ⫺ ⫺ ⫺ ⫺ ⫹⫹

Tab. 33.1: Differentiation of autoimmune liver diseases and their overlap syndromes (s. tab. 5.20) (s. p. 658). • (AHA

⫽ anti-histone antibody; anti-GOR⫽ anti-specific nuclear antigen in HCV) (see text for other abbreviations). ⫺/(⫹) ⫽ no or occasional slight increase

found in primary biliary cholangitis, primary sclerosing cholangitis and viral hepatitis.

(92)

5 Classification

Autoimmune hepatitis may be classified into three (sometimes four) types according to the different anti- body specificities in conjunction with the seromarkers of viral hepatitis. Further differentiation has also been made into subtypes (1a, 1b and 2a, 2b), although this remains controversial. In the future, it may well be pos- sible to derive therapeutic indications or prognostic indices from these subtypes; at the moment, they offer no guidance in this respect. It is, however, remarkable that ANA, SMA and LKM 1 are not primarily detect- able in 20% of patients with AIH, whereas other anti- bodies, such as LP/SLA and ASGPR antibodies, can often be identified.

(52)

• In this context, a more reliable definition of overlap syndromes might therefore be use- ful for therapy and prognosis. (s. tab. 33.1)

5.1 Type 1

This is the classical (formerly lupoid) form of autoim- mune hepatitis. It shows a markedly genetic predisposi- tion. Type 1 is the most frequently occurring form of AIH (70 ⫺80% of cases) and is mainly found in young women, especially between the ages of 20 and 40 years.

There is a marked increase in γ-globulins. ANA (40 ⫺70%), SMA (70⫺100%) (titre >1:80) and ASGPR

(70 ⫺80%) are commonly present. AMA and pANCA are also occasionally detected. ANA often only appears during the course of disease. Type 1 is highly responsive to immunosuppressive therapy. That is why cirrhosis develops in “only” 40 ⫺45% of cases. HCV antibodies of groups 1a and 1b are found with the same frequency (14%).

(16, 17, 36, 38, 60)

Subtype 1a: This subtype is ANA-positive; it can be found with or

without SMA. Its course is generally subclinical, so that the initial diagnosis can only be made later. Type 1a occurs more frequently in women than in men. Its frequency is distributed bimodally, with a peak between 10 and 30 years (⫽ association with HLA-DR3) and again after 30 years of age or following the menopause (⫽ association with HLA-DR4); occasionally, C4AQO is detectable.

Frequency is 25⫺30% of cases.

Subtype 1b: The SMA-positive subtype occurs particularly in chil-

dren of all ages and of both sexes. In later life, men are more often affected. This classification is, however, still disputed.

5.2 Type 2

The main criterion of this type is the detection of LKM 1 (titre > 1:80), which is exclusively found in AIH.

ASGPR and LC 1 are sometimes also present.

(26, 35, 45, 92, 107)

In contrast, ANA and SMA antibodies are

not detectable as a rule. Antithyroid and antiparietal cell

antibodies can be frequently identified. Type 2 is 5 ⫺6

times less frequent (5 ⫺10%) than type 1. It occurs early

in life (about 50% of cases involve children

(34, 56)

and

adolescents)

(68)

and is often associated with extrahepa-

tic manifestations. Type 2 usually commences like acute

viral hepatitis, and genetically determined IgA defi-

(5)

ciency is occasionally evident. Hypergammaglobulin- aemia is not, however, as obvious as in type 1. Anti- bodies against thyroid and parietal cell antigens are frequently detectable. Type 2 is less responsive to im- munosuppressive therapy than type 1. The prognosis is thus less favourable: cirrhosis develops frequently (approx. 80% of cases) and rapidly. Type 2 is associated in 10 ⫺15% of cases with the autoimmune polyen- docrine syndrome type 1. (s. p. 679) • Owing to a respec- tive HCV positivity of 20 ⫺60% or 35%, differentiation into subtypes 2a and 2b was proposed. This may, how- ever, not always be reliable.

Subtype 2a: The criteria of this subtype are positivity of LKM 1

and LC 1 with negativity of anti-HCV and HCV RNA. It becomes manifest early in life, and the course of disease is severe. Women are mainly affected. HLA-DR3, -B14 and -C4AQO are present.

Subtype 2b: The criteria of this subtype are positivity of LKM1

and anti-HCV as well as HCV RNA. It becomes manifest at a more advanced age. Men in particular are affected. In 70% of cases, it was possible to detect antibodies to certain nuclear HCV antigens, so-called

anti-GOR. This is a fusion protein which is

derived from a cDNA clone (GOR 47-1). (55) (s. pp 121, 443)

䉴 The explanation of the term GOR is as follows:

^{S. M} ishiro et al.

were trying at that time (before the discovery of HCV) to detect a new virus which could be the cause of NANB hepatitis by immunoscreening cDNA libraries which were derived from chimpanzees infected with NANB hepatitis. One of these chimpanzees had the name “Gabriel” (“G”). Two cDNA libraries were made from Gabriel’s serum: one was primed with oligo- dT primer (“GO library”) and the other with random primer (“GR library”). These two libraries were mixed to a combined one, “GO” ⫹ “GR” 씮 GOR. Subsequently, an interesting clone was identified from the 47^th plate of the GOR library:

this was GOR 47-1. (Personal information from S. MISHIRO

)

5.3 Type 3

Type 3 is characterized by the positivity of LP/SLA.

These antibodies are the only type found in 25% of patients with AIH. • Sometimes, SMA, ANA and ASGPR can also be detected, but at low titre levels. The frequency is 5 ⫺10%. Women are affected five times more often than men. There is a high concentration of γ-globu- lin. HCV antibodies were found in 11% of patients.

(37)

The clinical course is similar to type 1; as a rule, it pro- gresses rapidly. The response to immunosuppressives is good. • Cryptogenic chronic hepatitis can often be diag- nosed with the help of LP/SLA. (s. tab. 33.1)

5.4 Drug-induced AIH

With a genetic or disease-related predisposition, the intake of medicaments and their subsequent catabolism in the biotransformatory system sometimes lead to the formation of reactive metabolites. (s. p. 55) (s. fig. 3.11) These can bind to components of the cytochrome sys- tem. After cytolysis, they may become the target anti- gens of antibodies. (s. p. 544) (s. fig. 29.1) This has been ascertained, for example, for carbamazepine (LMK 3),

halothane (LMK 2), hydralazine 1 (LMA, LMK 3) and ticrynafen (LKM 2) as well as for tienilic acid (LKM 2) and minocycline.

(33)

Other antibodies (ANA, LMA) may also be present.

5.5 Overlap syndrome

Primary biliary cholangitis: The overlap of PBC with AIH reveals positivity of AMA, ANA and ASGPR as well as lower titres of LP and SMA. In approx. 20% of cases, AMA can be found in AIH. The frequency of this overlap syndrome is 5 ⫺10% (⫺15%). It was first detected in a child (12-year-old girl).

(34)

IgG and IgM fractions are simultaneously elevated. Histological find- ings can comprise the criteria of both PBC and CAH.

Thus two different autoimmune diseases are present, whereby prognosis is determined by the degree of sever- ity of AIH. This provides the indication for immunosup- pressive therapy. (s. tab. 33.1) (s. p. 660)

Primary sclerosing cholangitis: An overlap of primary sclerosing

cholangitis with AIH is likewise possible; the latter also displayed pANCA in 13⫺16% of cases. (s. p. 657)

Collagenosis: An overlap of collagenosis with AIH is rare (0.2%).

Confirmation requires the determination of specific antinuclear antibodies (SSA, SSB, RNP, Sm, Scl70, ACA). (s. tab. 5.19)

Autoimmune polyendocrine syndrome: Approximately 20% of cases of the autosomal recessive APS type 1 are accompanied by autoimmune hepatitis. A loss of auto- immune regulator activity is considered to be the under- lying cause. There are autoimmune reactions in the skin, ovaries, suprarenal glands, parathyroid glands, intestinal tract, etc.; generalized candidiasis is also evident. Anti- bodies to LM (targeted against cytochrome P450 I A2) may be present. A combination of AIH and APS is more aggressive, with a tendency to an acute or subful- minant course, and shows a weak response to corti- costeroid therapy.

Alcohol-related liver disease: Approximately 80% of these patients display positive anti-histone 2 B anti- bodies. In alcoholic hepatitis, there is frequent evidence of LMA (60%) and LSP (30%) as well as ANA and/or SMA. In autoimmune hepatitis (15% of cases), high titres of IgA antibodies to histone 2 B can also be detected. • This autoimmune situation in alcoholic liver disease can indeed give rise to therapeutic problems if, despite absolute abstinence, there is self-perpetuation of the morphological findings (as we ourselves noticed in some cases).

5.6 Association with HV infection

In chronic hepatitis B, 5⫺10% of cases display ANA

and/or SMA. Due to the subtle differentiation achieved

with HBV markers, it is possible to classify each individ-

ual case reliably. Prognosis and therapy are determined

by chronic hepatitis B. Interferon therapy can trigger or

exacerbate autoimmune hepatitis.

(13, 66, 74, 78)

(6)

In chronic hepatitis D, 10⫺20% of cases displayed anti- bodies to LKM 3. The antigen is a part of UDP glucu- ronosyl transferase

(T. Philipp et al. 1994)

.

In chronic hepatitis C, there is a strikingly frequent asso- ciation with autoimmune hepatitis; this association, however, varies in different geographic regions. In ANA-positive AIH, HCV antibodies were detected in 40 ⫺50%, whereas in LKM-positive AIH, HCV markers were found in up to 88% of cases. Chronic hepatitis C showed ANA and/or SMA in 10 ⫺15% of patients, whereas 2 ⫺10% simultaneously displayed LKM 1 anti- bodies. This constellation, also classified as subtype 2b, has a relatively mild clinical course with relatively low LKM titres. Interferon therapy is indicated ⫺ yet cau- tion is called for, since this can trigger acute inflamma- tory episodes of chronic hepatitis C as well as the devel- opment of AIH.

(32, 66, 78)

In the event of replicative HCV infection, immunosuppressive therapy is not indi- cated. In this case, it is assumed that this is primarily a chronic hepatitis C with concurrent autoimmunity. It is necessary to clarify the HCV infection by PCR and to differentiate the autoantibodies further. In assessing such an overlap retrospectively, consideration must be given to the fact that (1.) the determination of HCV antibodies has often been false owing to the still unreli- able detection method, (2.) it has not yet been possible to verify HCV RNA by PCR, and (3.) hypergammaglo- bulinaemia produces higher false anti-HCV levels.

(3, 31, 48, 55, 60, 68, 91)

(s. p. 440)

5.7 Cryptogenic chronic hepatitis

Occasionally, forms of autoantibody-negative chronic hepatitis are found with no detectable cause. They resemble autoimmune hepatitis in every respect and respond well to corticosteroid therapy. This special group (10 ⫺15%) possibly comprises cases of autoim- mune hepatitis for which no immunoserologic markers are known as yet. In numerous cases of cryptogenic chronic hepatitis, AIH type 3 can be detected due to evidence of high-titric LP/LSA.

6 Morphology

Autoimmune hepatitis has no distinctive histology. The picture presented resembles that of chronic active hepa- titis: portal and periportal infiltration from some plasma cells as well as a high number of lymphocytes are in evidence. (s. figs. 33.1, 33.2) The lymphocytes are mainly of the T-cell type, whereby the ratio of subtypes CD4 : CD8 is about 1:1. The lymphocytes demonstrate emperipolesis ( ⫽ capable of infiltrating and surrounding other cells). (s. fig. 21.11) Hepatocytes often show

hydropic swelling and ballooning (s. fig. 21.4). Inflam- matory activity varies, whereby some areas are near nor- mal. In the lobule, there are infiltrates of lymphocytes with differing density together with activated Kupffer cells. As the degree of infiltration increases, with inflam- matory activity varying considerably from portal zone to portal zone, piecemeal necroses ( ⫽ interphase hepati- tis) and bridging necroses (between adjacent vascular structures) as well as liver cell rosettes become more and more distinctive histologically. Whereas lytic necrosis leaves a “blank” in the trabecular texture, acidophilic necrosis shows Councilman bodies as residues. Early on in this process, it may be possible to detect pronounced fibrosis. (s. figs. 33.3, 33.4) • Bile-duct lesions, granulo- mas and deposits of iron or copper are not present; their detection argues against AIH.

(11, 23, 58, 83, 90)

• Non- alcoholic steatohepatitis can resemble the picture of AIH.

Fig. 33.1: Acute AIH (ANCA

⫹) resembling acute hepatitis, with pronounced centrilobular parenchymal loss. Rapid therapy success (clinically, biochemically) with immunosuppressives (HE).

Fig. 33.2: So-called lupoid hepatitis. The left lobe of liver shows an

irregularly rippled surface (scattered light reflex) with salmon-pink and yellow colouring, patchy red marking due to highly inflammatory parenchymal zones; fine vascular multiplication and whitish scarred areas with diffuse fibrosis

(7)

Fig. 33.3: Autoimmune hepatitis in remission under treatment with

septal fibrosis and disarranged lobular structure

Fig. 33.4: Liver cirrhosis due to AIH: flat-nodular liver surface,

highly cicatrized furrows, local neovascularization, signs of mild inflammation

7 Clinical aspects

7.1 Clinical symptoms

Some 10 ⫺20% of patients with chronic active hepatitis can be categorized as autoimmune hepatitis cases. • Occasionally, the disease develops over a considerable period of time without being noticed subjectively.

(36)

This is why AIH is often not diagnosed before the stage of chronic hepatitis is reached. Non-specific complaints have been reported, such as fatigue, languor, inappe- tence, decreased performance and sometimes arthralgia as well as myalgia, frequently accompanied by slight fever. Clinical findings include hepato/splenomegaly, palmar erythema, facial teleangiectasia, hirsutism, amenorrhoea and spider naevi. (s. figs. 4.6, 4.7) • In 25 ⫺40% of cases, AIH can become manifest in the same manner as acute viral hepatitis, but it presents more dis- tinct subjective and clinical symptoms. At this point, scleral icterus or jaundice is usually present ⫺ as is gen- erally the case in active phases of a disease.

(31, 41, 65, 93, 98)

7.2 Laboratory diagnostics

Even at the subjective, asymptomatic stage, transami- nases are elevated to differing degrees. With the onset of symptomatic or acute hepatitis, high values can be de- tected for GPT, GOT and GDH (3 to 10 times, and more, above normal levels). The γ-GT value is only moderately or not at all increased; the same applies to bilirubin. Cho- linesterase is often decreased. • Cholestasis-indicating enzymes ( γ-GT, AP, LAP) are rarely elevated; clearly raised levels point to an overlap syndrome rather than to a (very infrequent) cholestatic form of autoimmune hepa- titis. • A sharp rise in γ-globulin (1.5 to 2 times above nor- mal) is a characteristic feature. This is almost solely due to an increase in the IgG fraction. IgA can be decreased.

Hyperproteinaemia (> 8g/dl) ensues. The blood sedi- mentation rate is greatly increased. • At this point, the serology of viral hepatitis (HBV, HCV, possibly HDV) has to be clarified. Autoantibodies (ANA, SMA, LKM, LP) and their titres are determined. When the presence of an overlap syndrome is suspected, the determination of specific autoantibodies is required (e. g. AMA with sub- types, LP, pANCA, anti-histone 2B, antinuclear anti- bodies). (s. tabs. 5.19, 5.20; 33.1) HLA typing (e. g. -A1, -B8, -DR3, -DR4) should then complete the diagnosis.

7.3 Liver histology

Histological examination of the liver and morphological clarification of the phase of disease (i.e. grading, staging) are imperative, although this does not facilitate the diagnosis of AIH.

(11, 90)

However, liver biopsy is recommended for the initial diagnosis; it should be car- ried out under laparoscopy to provide photodocumenta- tion of the surface structure of the liver and to obtain several specimens (including some from the left lobe of liver).

8 Course and prognosis

8.1 Course of disease

Autoimmune hepatitis displays a wide spectrum of clin- ical courses. Besides the subjective asymptomatic and insidious onset of the disease, acute manifestations simi- lar to acute viral hepatitis may occur. Severe courses have also been described, including acute liver failure and extreme atrophy of the right lobe of liver.

(36, 61)

The course of disease is often characterized by acute

intermittent phases. Other patients, however, experience

uncharacteristic complaints over long periods of time as

well as aetiologically unexplained increases in trans-

aminases. The effect of pregnancy on the course of AIH

varies: deterioration, unchanged status and remission

have been reported. Long-lasting spontaneous remis-

sions were observed in up to 20% of cases (e. g. in pla-

cebo groups), but there were also cases of rapid transi-

tion into cirrhosis.

(9, 29, 41, 45, 93)

(8)

8.2 Associated diseases

A variety of immunopathies and diseases have been associated with autoimmune hepatitis (20 ⫺30%). These association factors can render it more difficult to estab- lish a diagnosis or differential diagnosis; as a result, therapy is more problematic, and the prognosis deteri- orates. (s. tab. 33.2)

CREST Panniculitis

Diabetes insipidus Pericarditis Diabetes mellitus (type I) Polyarthritis Glomerulonephritis Polymyositis Haemolytic anaemia Pulmonary fibrosis Hypereosinophilic syndrome Sjögren’s syndrome Hyperthyroidosis Thrombocytopenia

Iridocyclitis Thyroidism

Lupus erythematodes Ulcerative colitis Mixed collagenoses Vasculitis Myasthenia gravis Vitiligo Myocarditis

Tab. 33.2: Diseases or immunopathies which may be associated

with autoimmune hepatitis (s. tabs. 22.2, 22.7, 22.8; 32.3, 32.6)

8.3 Hepatocellular carcinoma

Hepatocellular carcinoma is a rare occurrence (5 ⫺7%).

(67, 79, 106)

It may not be due to AIH or related medica- tion, but to concurrent HBV or HCV infection. An association of HCC with corticosteroid therapy is unu- sual

(102)

; the same study group, however, reported an association of HCC with azathioprine therapy.

8.4 Prognosis

Prognosis depends on the time when the diagnosis is established and therapy initiated. Risk factors are consid- ered to be manifestation in early years, severe hepatic inflammatory reactions with bridging necroses and the presence of HLA-DR3. Type 2 develops more rapidly into cirrhosis (up to 82% within 3 years).

(38)

If the condi- tion is not treated, prognosis is poor; in such cases, cirrho- sis inevitably develops. Approximately 50% of patients die after 3 ⫺5 years, and some 90% within 10 years; mor- tality is highest during the first 2 years. Obviously, prog- nosis is worst in those patients who have already reached the cirrhotic stage at the time of initial diagnosis. • The prognosis of the overlap syndrome is presumably deter- mined by the stage and degree of activity of primary bili- ary cholangitis or primary sclerosing cholangitis.

(46)

When immunosuppression is properly administered at an early stage, prognosis is good; such patients can anticipate normal life expectancy. It is even possible for liver fibrosis to recede.

(19, 28)

In general, a therapy-

related remission rate of 80 ⫺90% can be achieved. • Relapse occurs in some two-thirds of successfully treated patients, yet this usually responds well to re- administration of the initial therapy at an adequately high dosage. So-called non-responders (approximately 15% of cases) should be critically reviewed in terms of detailed diagnosis, while additional exogenous or endo- genous risk factors as well as patient compliance should be investigated anew. • The survival rate of treated patients (excluding cirrhosis and severe, well-advanced CAH at the time of initial diagnosis) is ca. 90% and 80% after 5 and 10 years, respectively. In cases of cirrho- sis, despite properly administered therapy, the 10-year survival rate is reduced to < 65% (relapse risk is 90%).

9 Therapy

Hardly any other autoimmunopathy responds so well to immunosuppressive treatment as does autoim- mune hepatitis. Most patients can reckon with nor- mal life expectancy. • However, this calls for the following prerequisites: (1.) early detailed diagnosis, (2.) appropriate, continuous therapy, and (3.) elimin- ation and prevention of exogenous risk factors.

9.1 Detailed diagnosis

The diagnosis of autoimmune disease is in itself not difficult. • Nevertheless, the wide variety of autoim- munopathies and their multiple facets, their unpre- dictable preference for certain tissue, cellular or organ systems and the fact that they frequently overlap with a multitude of associated partners to differing degrees often give rise to problems which cannot be solved when setting up a detailed diagnosis. For this reason, depending on the respective level of knowledge, it is inevitable that “similar” immunopathies will be clas- sified either as “identical” forms or possibly even as

“entities” in their own right.

The occurrence of an autoimmunopathy is invariably

based on a genetic predisposition with an inducibility that

differs in intensity from case to case. • However, it is pos-

sible with great subtlety to detect the biochemical/bio-

molecular products of the cascade from the comple-

ment system, HLA system, antigen-antibody reactions,

helper and suppressor cell functions, etc. (which in

point of fact come “at the end of the successful reac-

tion”). Furthermore, it is also possible to assess the

respective interrelations of these products and to pre-

dict their immunopathogenetic significance. • Al-

though the endocrine-autonomic-central nervous sys-

tems (in evidence “at the beginning of humoral / cellular

tolerance or defence”) are generally accepted as a matter

of course, they are still inadequately quantifiable.

(9)

The multiple reactions invoked “on the biochemical pathway” (i. e. between the beginning and the end of an autoimmunopathy) are definitely involved in the accumulation of other unknown intermediary prod- ucts, which can in turn influence and manipulate a state of autoimmunopathy.

䉴 see

^{D. B} itter

-

S uermann

(1983) and particularly „Immunologie und Psychoneuroendokrinium“ (

W. P. K aschka

) in „Medizini- sche Immunologie“ (

H. W. B aenkler

, editor) (1996)

From their own experience, many clinicians are familiar with that often rapid and even insidious deterioration of an autoimmune disease as a result of extreme over- burdening of the endocrine or mental systems. The cases of two patients, whose fate touched my staff and me deeply at the time, are briefly outlined below; as we experienced them, these were not merely post hoc, but propter hoc events, i. e. the one directly caused the other.

䉴 A female patient between 35 and 40 years of age with confirmed

(in line with the methods of the time, including laparoscopy and biopsy) autoimmune hepatitis (ANA

⫹⫹, SMA⫹, LMA⫹, LE

factor

⫹, IgG ⫹⫹, γ-globulin⫹⫹, GPT, GOT 80⫺100 U/l, GDH ca.

12 U/l, no cholestasis) had been undergoing treatment with predni- solone / azathioprine and had been in constant remission for over 3 years (maintenance dose of 4

⫺6 mg prednisolone and 50 mg aza-

thioprine for over 2 years). Physically and mentally stable, engaged in her profession, she had placed great confidence in us. Approxi- mately 3 days after a sudden, severe emotional trauma with mental breakdown, the AIH deteriorated on a massive scale, and about 3 weeks later, the patient died in a coma hepaticum from acute liver failure.

䉴 A female patient of approx. 45 years of age with autoimmune

hepatitis and Sjögren’s syndrome was in constant remission, having undergone treatment with prednisolone / azathioprine for more than 6 years. Physically and mentally stable, she was active at home, with her family and in her profession; compliance was excellent. The maintenance dose was 4

⫺6 mg prednisolone and 50 mg azathioprine.

A sudden, severe emotional trauma triggered an excessive and, despite all medication, progressive deterioration of her condition within a few days. A 2-year period of suffering followed with pro- gression of CAH, confirmed by laparoscopy and two biopsies, to florid complete cirrhosis, from which the patient died.

The methods applied today allow precise differenti- ation of autoimmune hepatitis, thus providing the ne- cessary early diagnosis. • Besides the “classical” or

“pure” forms of autoimmune hepatitis and autoim- mune cholangitis (s. p. 659), HBV-positive and HCV- positive individuals and possibly PCR-confirmed car- riers should be strictly excluded from types 1 ⫺3 with their respective subgroups and classified in their own overlap groups. (s. tab. 33.1) (s. p. 660)

9.2 Immunosuppressive therapy

The primary target in treating autoimmune disease, espe- cially autoimmune hepatitis, is to restore the immune bal- ance. • When correctly administered, immunosuppres- sion can effect the remission of autoimmune hepatitis and improve the survival rate ⫺ and even normalize

individual life expectancy. However, this requires an early detailed diagnosis and the widest possible differen- tiation of the immunological and serological profiles as well as a histological investigation of the liver.

(18, 53, 73, 93, 98)

9.2.1 Glucocorticoids

䉴 Treatment of autoimmune hepatitis with glucocorti- coids has been successfully carried out for about 45 years

(A. R. Page et al., 1960)

. Fundamentally, predniso- lone brings about remission of the condition in approx.

80% of patients. A survival rate of 10 years has been observed in over 90% of precirrhotic patients under prednisolone therapy

(G. L. Davies et al., 1989)

. A course of glucocorticoid monotherapy is indicated in (1.) young patients, (2.) minimal inflammatory activity in the initial phase, (3.) relevant bone-marrow depression, (4.) chole- stasis under azathioprine therapy (very rare), and (5.) women contemplating pregnancy, but who have to avoid using azathioprine.

(15, 19, 69, 80, 85)

Dosage: Initial dose of approx. 1mg/kg BW/day for about 1 week

(until an obvious reduction in transaminase values has been achieved), ca. 40 mg/day for 1 week, ca. 30 mg/day for a further 2 weeks and then ca. 20 mg/day, depending on the decrease in activity and onset of remission. With continued acceptance of a lower dose, a further reduction should be made in steps of 2.5⫺5 mg at intervals of 5⫺10 days until the desired maintenance dose of 4⫺8 mg is reached. A mean duration of treatment of 2⫺3 years is generally recommended.

•

Basically, we continued to administer the achieved maintenance dose (“only as much as required”) as a life-

long prednisolone therapy unless, for any reason, it became neces-

sary to stop treatment. In such cases, therapy should be phased out at a rate of 1 mg per week (!). On the principle of “having

respect for, but no fear of prednisolone”, osteoporosis prophylaxis is

of the utmost importance. Besides the administration of, for example, a combination of calcium and sodium fluorophosphates together with vitamin D, it is essential for the patients to exercise their muscles regularly every day. (s. p. 650)

• We also can confirm that the maintenance dose differs greatly for each individual patient

⫺ some patients remain in remission with 2⫺4 mg glucocorticoids.

9.2.2 Glucocorticoids and azathioprine

䉴 Azathioprine should not be used initially as mono- therapy. However, remission attained with prednisolone and azathioprine can be maintained by azathioprine on its own (some 100 ⫺200 mg/day).

^{(42, 85)}

• The combin- ation of prednisolone with azathioprine

(I. R. MacKay, 1968)

is just as effective as monotherapy with predniso- lone. Moreover, with the above-mentioned initial dose of prednisolone (together with azathioprine), any subse- quent dosage of prednisolone can be reduced more rapidly to a maintenance dose of 4 ⫺6 (⫺8) mg/day.

Dosage: An initial dose of azathioprine of 1⫺2 mg/kg BW/day

(rounded off to the nearest 25 mg or 50 mg tablet) is recommended. A maintenance dose of 50⫺75 (⫺100) mg/day is sufficient.

•

We always administered the combination therapy from the outset and thereby did not observe any side effects from azathioprine⫺ minor fluctuations in bone-marrow depression reverted to normal values spontaneously or after a short period of reduced dosage (25 mg).

•

With this maintenance dose, we retained a

(10)

number of female patients in remission for over 16 years (!)⫺ see the patient group treated with prednisolone and azathioprine for primary biliary cholangitis. (s. p. 650)

As a criterion of successful therapy, the following remission figures are given in the relevant literature:

50 ⫺60% after 6 months, 70⫺80% after 12 months and 80 ⫺90% after 24 months. The corresponding success figures in terms of liver histology are 10%, 30 ⫺40%

and 50 ⫺60%, respectively. At the end of successful ther- apy with a cessation of medication, ca. 50% of patients suffered a relapse, so that a new “initial dose” had to be applied ⫺ sometimes with less positive results, however.

• Thus we consider a lifelong maintenance dose to be preferable. We have repeatedly noted that continued administration of the combination therapy eventually achieved a stabilized remission, even after a period of 2 ⫺3 (⫺4) years. Particularly in immunopathies, patience is called for, while attention must focus on the current state of disease and on the patient “in his/her entirety”.

䉴 Should cirrhosis be present at the time of initial diag- nosis in the wake of confirmed “pure” autoimmune hepatitis (i. e. without HBV or HCV replication mark- ers), it is advisable to implement combined immunosup- pression ⫺ which is often successful in relatively low but sufficient dosage. Even if the morphological end-stage has already been reached, inflammatory activity can be repressed and clinical improvement achieved. • The question of whether (and when) a liver transplantation should be planned always has to be considered.

Budesonide: Initial results with the oral “topical” steroid budesonide have also proved remarkable in AIH.

(21)

In precirrhotic patients without collateral shunts, this substance achieves a first-pass effect in the liver of up to 90%, resulting in a satisfactory anti-inflammatory steroid impact with only minor side effects.

9.2.3 Ursodeoxycholic acid

If cholestasis is not present, the additional application of ursodeoxycholic acid (UDCA) is worth considering because of its pharmacological properties and lack of side effects or interactions. • Initial results on the treat- ment of chronic hepatitis with UDCA were reported by

F. Ichida (1961)

,

T. Nakahara et al. (1975)

and

K. Miyaji (1976)

. (s. p. 705) • In 1988 our study group also noted obvious and permanent effects of UDCA on the course of disease in terms of clinical and laboratory indices in severe acute viral hepatitis B. (s. p. 437) Such observa- tions were confirmed by

A. Jorge

in 1993. • Owing to the multiple mechanisms of action of UDCA, in par- ticular its immunomodulatory effect, adjuvant thera- peutic efficacy can be anticipated in autoimmune hepa- titis, as reported by

^{P. J}anowitz et al.

in 1996. In autoimmune-associated chronic hepatitis C, UDCA proved to be a successful therapeutic agent

(K. Nakamura et al., 1999)

.

9.2.4 Monitoring therapy

GPT is the leading parameter for regular monitoring of laboratory indices ⫺ initially at intervals of 4⫺8 days and subsequently every 2 ⫺4 weeks (depending on the activity status). GDH is a good complementary value, possibly together with GOT (for the concurrent deter- mination of the respective quotient). (s. tabs. 5.6, 5.7) • The γ-globulin value is a further important parameter.

With these results, it is possible to assess the course of AIH reliably and to monitor the success of therapy.

(14)

9.2.5 Non-responders to therapy

䉴 Patients in whom initial treatment was devoid of suc- cess (though a detailed diagnosis had been made) and increased dosage in a renewed course of therapy failed or in whom relapse therapy was not efficacious were administered cyclosporin (3⫺5mg/kg BW). However, there are divergent reports regarding the success rate of this treatment.

(30, 40, 59, 68, 70, 82)

• In individual cases, good results have been achieved with cyclophosphamide (100 mg and subsequently 50 mg/day).

(44)

• New, effect- ive substances that have been successfully used in AIH type 1 include tacrolimus

⁽⁹⁴⁾

and mycophenolate mofetil.

(8, 76)

• In the case of treatment failure (prednisolone ⫹ azathioprine), the administration of methotrexate (7.5 mg/week) proved successful in type 1.

(10)

Good thera- peutic efficacy could also be achieved with 6-mercapto- purine after failure with azathioprine.

⁽⁷¹⁾

Boswellinic acids are seen as selective non-redox inhibitors of leu-

kotriene biosynthesis. Leukotrienes are mediators of inflammation.

Boswellic acids proved to be antiphlogistic, hepatoprotective and immunosuppressive in their impact

(H. P. T. A mmon et al., 1991)

.

•

Although there has been no therapeutic application in hepatology up to now, it is likely that future discussion will focus on this pharmacologically interesting group of substances. (s. pp 652, 659)

A small percentage (5 ⫺15%) of patients can be defined at an early stage as non-responders; their condition and the laboratory parameters show no improvement within the first 2 ⫺4 weeks. Should histological investigation reveal bridging necroses that are already dilated as well as multilobular liver cell necroses, conservative therapy does not usually prove successful ⫺ such patients are candidates for liver transplantation.

9.2.6 Overlap syndrome

Present-day immunological examination techniques facilitate a detailed differential diagnosis of the pre- senting overlap syndrome. They also provide informa- tion which is useful for the pathogenetic, clinical and prognostic assessment of the associated diseases.

Whether or not such immunological diagnostics will

result in further divergent therapeutic measures cannot

(as yet) be foreseen ⫺ but this is feasible in view of the

anticipated development and testing of new immuno-

suppressive substances (such as mycophenolate mofetil,

monoclonal anti-CD4 antibodies, T-cell vaccines, T-cell

(11)

receptor antibodies, HLA-blocking peptides, anti-HLA antibodies, etc.).

UDCA: The administration of UDCA offers the least risk due to

its relative lack of side effects or interactions. It is the therapy of choice in all overlap syndromes with PBC or PSC features and also in cases with autoimmune cholangitis phenomenology.

•

In view of the above-mentioned positive effects on chronic and acute viral hepatitis as well as in AIH, UDCA is both pharmacologically and clinically plausible as adjuvant therapy.

Interferon: The occurrence of AIH during the treatment of chronic

hepatitis B with interferon has already been described (13), as have manifestations and new episodes of inflammation caused by interferon in patients with AIH and chronic hepatitis C. (32, 66, 78) The indication for interferon therapy has to be considered with caution in cases of chronic viral hepatitis with concurrent AIH or autoimmune cholangitis; it should also be monitored with great care. In replicative chronic hepatitis B, B/D or C, the chronic viral hepatitis constitutes the major factor⫺ whereas AIH is seen as a concomitant phenomenon. Immunosuppressive therapy is not indicated.

•

In addition, as recent studies show, there are also differences within the HCV infection itself; for example, 90% of HCV carriers in Japan and 20% of those in the USA and Germany are at the same time HGV carriers (GB-C). The GB-C and HGV hepatitis viruses are designated “defective” because they require

“completion” by the helper virus HCV. (s. p. 450)

This recently acquired knowledge gives new impetus to our suggestion of removing all patients with repli- cative HBV, HBV/HDV and HCV infections from their respective groups (1a, 1b, 2b, 3); they can then be redefined and treated as separate overlap groups.

• These patients have “another immunology” ⫺ and indeed “other statistics”.

9.3 Liver transplantation

Liver transplantation is indicated in the terminal stage of cirrhosis, in acute liver failure and, above all, for non- responders to long-term therapy. The 5-year survival rate is 85 ⫺90%. Determining the right time for trans- plantation is problematical, however. All possibilities of medication should have been exploited first. It is remark- able that AIH reoccurs in the transplanted liver: in 7 ⫺10% of cases after 1 year and in 65⫺70% of cases after 5 years. In patients with HLA-DR3, there was no evidence of recurrence anymore.

(13)

Following trans- plantation, the autoantibodies may disappear from the serum.

(12, 22, 27, 57, 62, 75, 80, 105)

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(12)

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