ARCH
GASTROENTEROHEPATOLOGY 2002; 21 ( No 1 – 2 ):
Autoimmune
cholangitis - AMA-negative syndrome: Case report and
literature review
Autoimuni holangitis - AMA negativni sindrom: Prikaz slucaja i
pregled literature
( accepted
Rada Jesic, 1Ivan Boricic, Miodrag N. Krstic, Branka Nikolic, Dragan
Tomic, Aleksandra Pavlovic, Djordje Culafic, Vladislava Bulat, Tatjana Cvejic,
Radmila Kovac
Clinic for Gastroenterology and Hepatology, Institute
of Digestive Diseases, Clinical Centre of Serbia, Belgrade, 1Institute
of Pathology, School of Medicine, University of Belgrade.
Clinical Centre of
6 Koste Todorovica Str, YU-11000
………………….
………………………………
Autoimmune cholangitis – AMA-negative syndrome Gastroenteroloska sekcija SLD-
01726, 2002.
SUMMARY
Six females
and one male patient (mean age: 51 years; range, 27-67 years). with clinical
and laboratory signs of both primary biliary cirrhosis and autoimmune hepatitis
were reported. Mean follow-up was 34 months (range: 9-47 months). All but one
has been having overlap syndrome at presentation; one patient with PBC
subsequently developed AIH. All cases had clinical and laboratory evidence of
cholestatic liver disease. Liver biopsy demonstrated cirrhosis with significant
bile ductular changes of mixed type. In all patients ANA or ASMA, or both ANA
and ASMA, were positive. The treatment protocol consisted of prednisolone
and/or prednisolone and ursodeoxycholic acid. Follow-up liver function tests
demonstrated improvement of aminotransferases level. We conclude that our group
of patient may be classified as having overlapping syndrome or autoimmune
cholangitis, since they manifested with clinical, biochemical, immunological,
and histological characteristics of primary biliary cirrhosis and autoimmune
hepatitis type-1.
Key words:
overlapping syndrome, autoimmune cholangitis.
SAZETAK
U ovoj studiji je prikazano 7 pacijenata sa autoimunim holangitisom
(AIC)-PBC i AIH. Prosecna starosna dob je bila 51 godina (27-67godina).
Prosecno vreme pracenje bolesnika je bilo 34 meseca (9-47 meseci). Šest
pacijenata je imalo AIC - overlap
sindrom. Na pocetku pracenja jedan pacijent je imao PBC da bi docnije razvio
AIH. Laboratorijski i klinicki pokazatelji su ukazivali na holestatsku bolest
jetre u svih pacijenta. Biopsijske promene na jetri su pokazale cirozu sa znacajnim ostecenjima žučnih vodova
(pomešane dve slike, neke od njih su pokazivale više sliku AIH, dok je kod
drugih bila manifestnija PBC). U nasih pacijenata ANA i ASMA su bila pozitivna.
Pacijenti su lečeni prednisolonom ili prednisolonom i ursodeoksiholnom kiselinom
(UDCA). Prateći terapijske efekte uočeno je podoljšanje jetrinih funkcije u
svih bolesnika. S obzirom na kliničke, biohemijske, imunološke i histopatološke
karakteristike primarne bilijarne ciroze i autoimunog hepatitisa tip-1
zakljucili smo da su nasi pacijenti imali ima overlap sindrom ili autoimuni
holangitis.
Kljucne
reci: overlap sindrom, autoimuni holangitis.
INTRODUCTION
Autoimmune
cholangitis (AIC) is an idiopathic disorder with mixed hepatocellular and
cholestatic liver changes, lacking uniform diagnostic criteria. At present this
entity usually denotes overlap between AIH with AMA-negative bile ductular
lesions by histology (1).
Primary
biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) are two major autoimmune
liver diseases. Generally, they can be easily separated on the basis of
clinical, biochemical, serological, and histological findings. Occasionally,
otherwise distinctive features of both entities may overlap in the individual
case. First series of such patients with PBC -AIH overlap syndrome was reported
in 1970 (1-3).
In some
cases the diagnosis of autoimmune hepatitis (AIH) or primary biliary cirrhosis
(PBC) is difficult because some patients may have characteristics common to PBC
and AIH. This may account for 5 – 10% of all cases of AIH (3). Until recently this AMA-negative
syndromes has been classified as autoimmune cholangitis/cholangiopathy (3).
The
diagnosis of autoimmune cholangitis/cholangiopathy (AIC) is based on the
clinical and biochemical evidence of chronic cholestatic liver disease,
histological changes of chronic non-suppurative cholangitis, positivity of
antibodies other than AMA, and elevation of gamma-globulin (4). Liver biopsy usually demonstrates mixed
microscopic changes, some typical for AIH and others of PBC. In some cases
typical changes of PBC and AIH were present in the same biopsy specimen (5).
Generally, response to steroid therapy helps to distinguish one from another
disease. The diagnosis of AIC is often confirmed by ALT/AST decrease after the initiation
of steroid treatment, what is found in almost 80% of AIH patients. There is
evidence that AIC resistance to steroids or UDCA acid may occur (1).
The
objectives of this study were to describe the clinical features of our group of
patients with AMA-negative AIC overlap syndrome and to analyze its response to
therapy: immunosuppressive medication and UDCA.
PATIENTS
AND METHODS
From
February 1996 to February 2002, 7 patients (6 females and 1 male) with PBC-AIH
overlap syndrome and AIC were treated at the Clinic for Gastroenterology and
Hepatology,
The
criteria for diagnosis of AIC were: 1) laboratory evidence of autoimmunity,
including ANA and/or SMA seropositivity and/or hypergammaglobulinemia, 2)
absence of AMA, 3) clinical, laboratory and/or histological changes of chronic
cholestatic liver disease in addition to biochemical features of active
hepatocellular inflammation, 4) negativity to HBV and HCV infection, 5) an absence of other aetiologies of
chronic liver disease.
All
patients underwent liver and biliary tract ultrasonography and ERCP. The signs
of biliary obstruction and biliary tract
disease were absent in any case.
In this
series the main patient, s complaint was fatigue. Three cases had
jaundice and 2 pruritus. Moderate hepatosplenomegaly was documented in 4 cases.
Four patients (1,2,5,7) had extrahepatic disorders (Sjogren’s syndrome,
Raynaud’s phenomenon, and arthropathies). Normal serum albumin, PT, and PTT
time had all patients except Case 5. One had positive AMA (ASMA appeared later
on, while AMA became negative). Five patients had positive ASMA, while positive
ANA were found in 4. Table 1.
Liver
biopsies in all 7 patients demonstrated cholestatic changes in general. But
there were some differences in microscopic changes in the studied group. The
portal tracts were enlarged with slight periportal fibrosis in 3 cases,
porto-portal fibrous septa in 3, and biliary cirrhosis in 1 case. Lymphocyte
piece-meal necroses were seen in 1 case, as were biliary ones. Bile ductules were increased in number in 4
cases. More or less pronounced disappearance (vanishing) of biliary ducts was present
in 4 cases. Larger interlobular bile duct demonstrated damage to their lining
cells in 1 case.
In the
liver parenchyma, single cell necrosis and acidophil bodies were found in 3
cases. Slight periportal cellular and canalicular cholestasis was noticeable in
4 cases. In one patient small, round megamitochondriae were seen. The deposits
of copper binding protein and copper were found in periportal hepatocytes in
one case. Haemosiderin was present (grade 1) in periportal hepatocytes in one
case. The number of Kupffer cells was increased in all 7 cases and in 1 patient
the cytoplasm of the macrophages contains biliary pigment.
All
patients were treated with UDCA (10 mg/kg/24h) and prednisolone (30 mg/24h).
After 6-12 months of such treatment prednisolone maintenance dose of 10mg/kg
was instituted.
Table 1.
The initial characteristics of 7 patients with PBC-AIH overlap syndrome
|
Patiens |
Age |
Sex |
Pruritus/ |
bilirubin |
AF |
GGT |
ALT |
AST |
IgG |
IgM |
AMA/ ASMA /ANA |
|
|
|
|
Jaundice |
mmol/l |
IU/L |
IU/L |
IU/L |
IU/L |
g/L |
g/L |
|
|
1 |
31 |
F |
+/- |
19 |
165 |
254 |
95 |
58 |
22,3 |
5,8 |
-/ +
/- |
|
2 |
27 |
F |
-
/ - |
15 |
283 |
378 |
87 |
69 |
19,6 |
3,0 |
-
/ + / - |
|
3 |
42 |
F |
+
/+ |
47 |
372 |
486 |
254 |
203 |
28,2 |
4,9 |
-
/ - / + |
|
4 |
67 |
F |
+
/ + |
187 |
198 |
285 |
202 |
176 |
31,2 |
3,1 |
-
/ + / |
|
5 |
34 |
M |
-
/ - |
16 |
325 |
753 |
187 |
196 |
25,6 |
2,1 |
-/
+ / + |
|
6 |
52 |
F |
-
/ + |
20 |
236 |
564 |
98 |
48 |
34,5 |
7,4 |
- / -
/ + |
|
7 |
61 |
F |
- /- |
14 |
256 |
587 |
137 |
78 |
34 |
6,7 |
+/ + /+ |
DISCUSSION
Differential
diagnosis between AIH and other chronic autoimmune liver diseases of different
aetiology is of particular interest. Their management strategy differs
significantly. It is considered that about 20% of AIH patients initially
present with biochemical evidence of cholestasis, 20% are or may become
AMA-positive during disease course, and some AIH patients may have significant
histological evidence of small bile ducts damage (3). Therefore cholestatic
syndromes overlapping with AIH may occur in the individual patients. The most
common overlaps are AIH/PBC, AMA-negative PBC, AMA- positive AIH, cholestatic
AIH, and AIH/PSC (24).
AIC is used
to determine overlap between AIH and AMA-negative bile ductular changes by
histology. Typically this AMA-negative patients are ANA and/or ASMA positive
with clinical, laboratory, and/or histological cholestatic hepatic changes, and
normal biliary tree by cholangiography. On the contrary to PBC, patients with
AIC have higher AST and lower serum IgM. They are also characterized by the
presence of antibodies to carbonic anhydrase. HLA risk factors are different
from PBC with clonal expansion of liver-infiltrating lymphocytes expressing Vb 5.1 T-cell receptor (2).
Overlap
between AIH with AMA-negative bile ductular changes by histology, AIC is
sometimes called AMA-negative PBC (6,24). Recently, Czaja and associates
considered this disease as variant of PBC or AIH, hybrid of both conditions, or
separated entity (6). They suggested that AIC is the most probably the
heterogeneous condition with features of atypical PBC, small-duct PSC, or
transitory disease. In fact, this syndrome may represent different stages of
the same process, variant expression of established diverse autoimmune
diseases, transitory state between one autoimmune disease to another, or a
single disorder with varying manifestations (1,2). Alternatively, it may be a
separate disease entity with different histological manifestations of PBC, PSC
or AIH (1,2,7,8). On the contrary, there is evidence that there are no substantial
differences in the clinical spectrum or disease course between AMA-positive PBC
and AMA-negative PBC (9,10). Further on, some patients with so-called
AMA-negative PBC are in fact AMA positive when rigorously tested for a series
of mitochondria antigens reacting with each of three main immunoglobulin
isotypes (11). If one consider that AMA positivity (and particularly M2 subtype that reacts with
2-oxo acid dehydrogenase complexes) is pathognomonic for PBC and that,
accordingly, patients with AMA are not considered to have AIH, then
"AMA-positive AIH” is a contradictory term. Therefore it seems likely that
some patients suffer from PBC and that failure to find histological evidence of
PBC is due to an early stage of the disease and/or liver biopsy sampling error.
There is
group of hepatologist who argue about the possibility of simultaneous
occurrence of AIH and PBC (14). They suggest that in some patients
differentiation between AIH and PBC is not easy because in 5-10% PBC of cases
are AMA-negative and their liver biopsy demonstrate piece-meal necrosis. In
these patients ANA and SMA can be positive but their titers are low.
Patients
with AIH type-1 share some features with PBC such as female preponderance and
age of presentation (fifth decade). Their biochemical indices of hepatocellular
necrosis, AST and ALT increase, are more pronounced than in PBC. They also
usually have higher SMA and/or ANA
titers. Commonly, liver biopsy reveals more intense piece-meal necrosis and
interacinar focal inflammation than in PBC. Clinical and biochemical response
to steroids is generally good, though somewhat different to that in PBC cases
(15).
To
distinguish AIH from PBC, pANCA, antibody assay may help because pANCA, which
are frequently positive in AIH, are relatively rare in PBC. Therefore, this
autoantibody may be useful to differentiate between the genuine cases of AIH
and PBC patients with features overlapping AIH. Some studies have documented
the improvement of parenchymal inflammation indices with steroid therapy in
patients with AMA-negative PBC (although the biliary damage persisted), but
others found that steroids are ineffective (12). In some patients the
characteristics seem to change over the years. Colombato reported a case of AMA
positive PBC patient, who had had a good response to UDCA and subsequently
developed a clinical picture of AIH with negative AMA (13).
"Cholestatic
AIH" is a term that has been used to describe approximately 10% of AIH
patients manifesting markedly elevated serum ALP and g-glutamyl transferase (GGT)
but without histological evidence of biliary tract disease (16,17). Our two
female patients with such biochemical and histological characteristics
responded well to combined therapy prednisolone and UDCA.
Overlap
between AIH and PSC are well recognized, particularly in children. The
comprehensive study of PSC in adults by Boberg et al. demonstrated that in
adult patients with AIH, features of PSC: hyper-IgG and indefinite hepatitis
liver histology may occur frequently. But very few patients have combination of
these laboratory and microscopic changes of sufficient severity to qualify them
as having definite AIH (18). Their differential diagnosis from AIH can be
difficult in the presence of histological evidence of biliary changes and in the
absence of cholangiographic changes of PSC especially because the serum ALP in
PSC is not oftenly markedly elevated.
However,
due to the fact that very few series of such cases are described, an optimal
clinical management is still undefined. Several case reports have documented a
good response to steroids in terms of improved parenchymal necroinflamatory
indices and normalization of serum aminotransferases but others have noted less
marked positive response. Gohlke and colleagues suggested the treatment
protocol, which combined steroids, azathioprine, and UDCA. The efficacy of such
regimen has to be determined yet (19). This syndrome may represent an important
and unrecognized cause of resistance to UDCA in patients with PBC (18).
The
recognition of autoimmune overlap syndrome - AIC is not only important from
classification point of view, but it may have important therapeutic
implications. Late Dame S.Sherlock suggests that AIC may represent a subgroup
of AIH, ANA positive/AMA negative cholestatic autoimmune liver disease with
significant small bile ductular changes. She suggested elective therapy with
steroids (20,23). UDCA is also recommended although this drug is less efficient
in PBC (20,21). On the contrary Ishak considered AIC as variant of PBC without
indication for steroid treatment (16). Masumoto et al indicated that the type
of response to steroids indicates the final diagnosis in AIC (22). Czaja et al
found no positive responses to the same therapy in his series of patients (1).
In
conclusion, we presented our 7 patients with AMA-negative overlap syndrome with
bile ductular changes of so-called AIC. In spite of verified liver cirrhosis at
the beginning of therapy, after the initiation of combined steroid-UDCA therapy
the clinical course in 4 patients was favorable, without any episode of further
decompensation of liver function tests. The similar situation occurred with our
female patient, who initially presented with clinical picture of PBC, and
subsequently developed AIH verified by repeated liver biopsy. After 3 years,
ASMA appeared, while test to AMA turned to be negative. Prednisolone was
introduced in the therapy and the remission occurred in this patient too.
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