Type 1 autoimmune hepatitis in a patient with microscopic

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Med Clin (Barc). 2011;136(8):345–348
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Clinical report
Type 1 autoimmune hepatitis in a patient with microscopic polyangiitis:
challenges in diagnosis and treatment
Sergio Prieto-González a,b, Francesc Cardellach b, Ramon Estruch b, Rosa Miquel c, Josep M. Grau b,
Maria Cinta Cid a,*
a
Vasculitis Research Unit, Department of Systemic Autoimmune Diseases, Hospital Clı´nic, University of Barcelona, Institut d’Investigacions Biomèdiques
August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
Department of Internal Medicine, Hospital Clı´nic, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
c
Department of Pathology, Hospital Clı´nic, Barcelona, Catalonia, Spain
b
ARTICLE INFO
A B S T R A C T
Article history:
Received 8 October 2010
Accepted 14 October 2010
Available online 4 February 2011
Background and objective: Autoimmune diseases/autoantibodies tend sometimes to cumulate in the
same individual, probably as a consequence of defects in immune regulation with breakdown of selftolerance. Autoimmune hepatitis and microscopic polyangiitis have been occasionally reported with
other autoimmune diseases, but the particular association of these both disorders has not been
previously reported in the English and Spanish medical literature.
Case report: A 72 year-old woman presented with symptoms suggesting giant cell arteritis and
polymyalgia rheumatica.
Results: A temporal artery biopsy disclosed a spared temporal artery, with vasculitis involving
surrounding small vessels. Anti-neutrophil cytoplasmic antibodies were positive, with myeloperoxidase
specificity. Increased liver enzymes led to a wider autoantibody determination. Anti-nuclear antibodies
and anti-smooth muscle cell antibodies with anti-f-actin specificity were also positive. A liver biopsy
showed changes consistent with autoimmune hepatitis.
Conclusions: Clues for the diagnosis of vasculitis and AIH in the context of this patient, challenges in its
classification among systemic vasculitides, and difficulties in the choice of a suitable therapeutic
management for this particular association are discussed.
ß 2010 Elsevier España, S.L. All rights reserved.
Keywords:
Microscopic polyangiitis
Autoimmune hepatitis
Giant-cell arteritis
Classification criteria
Immunosuppressive therapy
Hepatitis autoinmune tipo 1 en una paciente con poliangiı́tis microcópica:
desafı́os en el diagnóstico y tratamiento
R E S U M E N
Palabras clave:
Poliangiı́tis microscópica
Hepatitis autoinmune
Arteritis de células gigantes
Criterios de clasificación
Tratamiento inmunosupresor
Fundamento y objetivo: Las enfermedades autoinmunes/autoanticuerpos en ocasiones tienden a
presentarse en un mismo individuo, probablemente por defectos en la regulación inmune con pérdida
de la autotolerancia. La hepatitis autoinmune y la poliangiı́tis microscópica se han descrito
ocasionalmente asociadas a otras enfermedades autoinmunes, si bien la asociación particular de
ambas entidades no se ha descrito previamente en literatura médica inglesa o castellana.
Observación clı´nica: Mujer de 72 años que ingresó con sı́ntomas sugestivos de arteritis de células
gigantes y polimialgia reumática.
Resultados: Una biopsia de arteria temporal mostró una arteria indemne con presencia de vasculitis en
vasos de pequeño tamaño a su alrededor. Una biopsia muscular confirmó la existencia de una vasculitis
sistémica de pequeño vaso. Los anticuerpos anticitoplasma de neutrófilo fueron positivos, con
especificidad antimieloperoxidasa. Dada la presencia de elevación de las enzimas hepáticas y
anticuerpos antinucleares con especificidad anti-actina, se realizó una biopsia hepática que mostró
cambios compatibles con una hepatitis autoinmune.
* Corresponding author.
E-mail address: mccid@clinic.ub.es (M. Cinta Cid).
0025-7753/$ – see front matter ß 2010 Elsevier España, S.L. All rights reserved.
doi:10.1016/j.medcli.2010.10.015
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346
Conclusión: En el contexto de esta asociación insólita de enfermedades se discuten las claves del
diagnóstico, la dificultad en la clasificación dentro de las vasculitis sistémicas y la elección del
tratamiento más adecuado para la paciente.
ß 2010 Elsevier España, S.L. Todos los derechos reservados.
Introduction
Microscopic polyangiitis (MPA) is a systemic, non granulomatous, necrotizing vasculitis preferentially involving small vessels1,2. It is frequently associated with the presence of antineutrophil cytoplasmic antibodies (ANCA) with anti-myeloperoxidase (MPO) specificity1,2. MPA may be associated with other
conditions including interstitial lung disease and anti-glomerular
basement membrane glomerulonephritis. Association with other
autoimmune diseases, such as Sjögren’s syndrome, primary biliary
cirrhosis, systemic sclerosis, and mixed connective tissue disease,
has been sporadically reported3,4.
Autoimmune hepatitis (AIH) is a chronic inflammatory liver
disease predominantly affecting women of all ages. AIH shows a
highly variable, clinical presentation, ranging from asymptomatic
to fulminant5,6. The autoantibody pattern, along with clinical and
epidemiologic findings, defines 2 types of AIH. Type I AIH is
characterized by the presence of anti-smooth muscle cell
antibodies, particularly with anti-f-actin specificity and/or antinuclear antibodies, and type AIH II by the presence of anti liver and
kidney microsomal antibodies (LKM) or anti-liver cytosol (LC) I
antibodies5,6. AIH is frequently associated with other autoimmune
diseases, particularly thyroiditis, ulcerative colitis, celiac disease,
type I diabetes, systemic lupus erythematosus, and rheumatoid
arthritis5,6.
We describe a patient who was simultaneously diagnosed with
MPA and type I AIH. This association has not been previously
reported in the English or Spanish medical literature. Besides
raising awareness of this potential association and its clinical
consequences, this report addresses additional educative purposes
such as the diagnostic process of vasculitis and autoimmune
hepatitis in this clinical context, challenges in its classification
among systemic vasculitides, and difficulties in the choice of a
suitable immunosuppressive agent for this specific association on
the basis of current evidence-based recommendations.
Case report
A 72-year-old woman presented with a 3 month-history of
asthenia, malaise, 5-kilogram weight loss, frontal headache,
scapular girdle weakness and arthralgia in knees, elbows, and
wrists.
Generalized weakness was apparent at physical examination.
Muscle strength was 3/5 in the upper girdle and 4/5 in the lower
limbs. Osteomuscular reflexes and sensitivity examination were
normal. Temporal arteries were not enlarged or tender and had a
preserved pulse. No signs of inflammation were observed in the
affected joints.
Routine laboratory findings are depicted in table 1 table 1.
Increased acute-phase reactants and liver enzymes, with both
Table 1
Laboratory findings at baseline evaluation and after a follow-up period of 27 months.
Baseline
27 months
Reference values
C Reactive Protein
ESR
Creatinine
Urea nitrogen
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Gamma-glutamyltransferase (GGT)
Alkaline phosphatase (AP)
Total bilirubin
Albumin
Haemoglobin
Platelet count
WBC
Gamma-globulin
HBsAc
HBcAb
HCVAb
4.5 mg/dL
74 mm/hour
1.2 mg/dL
33 mg/dL
188 U/L
125 U/L
244 U/L
328 U/L
1.2 mg/dL
27 U/L
131 g/L
275 x 109/L
8.8 x 109/L
41 g/L
Negative
Negative
Negative
0.04 mg/dL
7 mm/hour
0.90 mg/dL
23 U/L
18 U/L
14 U/L
135 U/L
1.2 mg/dL
148 g/L
249 x 109/L
8.16 x 109/L
-
(0.001-0.90)
(1-20)
(0.30-1.30)
(10-25)
(5-40)
(5-40)
(5-40)
(90-290)
(0.2-1.2)
(37-53)
(120-170)
(130-400)
(4-11)
(9-17.5)
Antineutrophil cytoplasmic antibodies (ANCA)
ANCA specificiy
PR3
MPO
Positive perinuclear
Negative
0 U/mL
54 U/mL
0 U/mL
43 U/mL
Other ANCA specificitiesa
Negative
-
Antinuclear antibodies (ANA)
Anti-DNA antibodies
Anti-Crithidia lucilliae
Anti-smooth muscle antibodies (ASMA)
Anti-actin antibodies (AAA)
Anti-soluble liver antigen/liver pancreas antibodies (anti-SLA/LP)
Anti-liver-kidney microsomal-1 antibodies
Anti-liver cytosol antibody-1
Rheumatoid factor
Prothrombin time
640 URF
26 U/mL
Negative
1/160
Positive
Negative
Negative
Negative
913
16%c
113 URF
36 mUI/mL
Negative
Negative
403
-
a
b
c
Tested antibodies directed against: cathepsin G, lactoferrin, lysozym, bactericidal permeability inhibitor and elastase.
Normal reference values.
Receiving acenocumarol for chronic atrial fibrillation..
< 25b
< 25b
< 10b
< 25b
(80-100)
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cytolysis and cholestasis, were the only abnormalities. A chest Xray showed no abnormalities and an abdominal ultrasound
disclosed a liver normal in size and structure.
Since one of the patient’s major complaints was headache, she
was older than 50 years, had arthralgia and proximal weakness
suggestive of polymyalgia rheumatica (PMR), and elevated acute
phase reactants, giant-cell arteritis (GCA) was considered and a
temporal artery biopsy was performed. Histopathologic examination showed mild mononuclear cell inflammation of a mediumsize artery in the vicinity of a spared temporal artery (fig. 1A). A
systemic vasculitis other than GCA was deemed and the patient
was re-evaluated. An electromyographic examination showed no
muscle or peripheral nerve abnormalities and a blind muscle
biopsy confirmed vasculitis involving small and medium-sized
vessels (fig. 1B). Immunologic studies are displayed in table 1.
ANCA were positive at immunofluorescence examination. AntiMPO specificity was confirmed by enzyme-linked immunoassay
(ELISA). The increase in liver enzymes led to a wider autoantibody
screening and anti-smooth muscle cell antibodies were positive
with anti-actin pattern and anti-f-actin specificity. Antinuclear
antibodies, anti-dsDNA and rheumatoid factor were also positive.
The abnormal liver tests and autoantibody profile led to the
performance of a liver biopsy which was consistent with AIH (fig.
1C and 1D). Combining clinical, analytical, immunologic and
histopathologic data she reached a definite diagnosis of AIH,
[()TD$FIG]
347
according to the International Autoimmune Hepatitis Group
criteria and a recently simplified version7.
The patient was treated with prednisone (60 mg/day) and
azathioprine (100 mg/day) for one month with subsequent
prednisone tapering. She quickly achieved clinical remission and
the liver enzymes completely normalized 6 weeks after the
beginning of treatment. Twenty-seven months after diagnosis the
patient remains asymptomatic under azathioprine 100 mg/day
and prednisone 2.5 mg/day.
Discussion
The patient reported had a biopsy-proven diagnosis of systemic
vasculitis that could be classified as MPA on the basis of the size of
involved vessels and positive pANCA with anti-MPO specificity2. She
also had a definite diagnosis of AIH according to the International
Autoimmune Hepatitis Group-scoring system and a recently revised
version7. This patient illustrates how autoimmune diseases/autoantibodies tend sometimes to cumulate in the same individuals,
probably as a consequence of defects in immune regulation with
breakdown of self-tolerance. However, this particular association is
unusual and this is the first case published in the English or Spanish
medical literature. Two possible additional cases have been reported
in Japanese journals8,9.
A
B
C
D
Figure 1. A: Vasculitis involving small arteries in the scalp. Temporal artery biopsy disclosing a normal temporal artery and an inflamed and occluded small sized artery in the
vicinity (hematoxylin and eosin staining). A higher magnification of the involved artery (inset) shows infiltration of the artery wall by a mixed inflammatory infiltrate. B:
Vasculitis involving small arteries in skeletal muscle. Vasculitis involving a small sized artery in a muscle biopsy (trichromic acid staining). In both specimens, inflammatory
infiltrates are predominantly mononuclear and no fibrinoid necrosis can be observed, possibly indicating chronicity. C: Chronic hepatitis. Liver biopsy disclosing slight
periportal necrosis and moderate-intense inflammatory infiltrates with predominance of lymphocytes. Plasma cells (x100 magnification inset) and scarce eosinophils can
also be seen. Mild erosive periportal and portal necrosis, mild sinusoid inflammation and hepatocellular necrosis are also observed (hematoxylin and eosin staining). D:
Chronic hepatitis. Trichromic acid staining shows porto-septal fibrosis and incipient nodular formation (x10).
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348
S. Prieto-González et al / Med Clin (Barc). 2011;136(8):345–348
The diagnosis and classification of vasculitis in this patient was
not easy. Interestingly, our patient presented with symptoms
suggestive of GCA and fulfilled 4 ACR classification criteria: age
older than 50 years, new headache, elevated ESR and an abnormal
temporal artery biopsy disclosing mononuclear cell inflammation10. In addition, although she lacked some typical PMR
symptoms such as proximal stiffness, she had generalized
arthralgia and proximal muscle weakness, which may have
suggested PMR. However, the temporal artery itself was not
involved and inflammatory infiltrates were restricted to a smallsized artery nearby. Involvement of small/medium-sized vessels
surrounding a spared temporal artery may be an incomplete
picture of GCA but may also occur in systemic necrotizing
vasculitis11. Consequently, patients with inflammation of vessels
surrounding a spared temporal artery should be subjected to an
extensive evaluation to rule out systemic necrotizing vasculitis,
even fulfilling ACR criteria for GCA11. Clearly illustrating this
concept, this patient was classified as having MPA on the basis of
the size of affected vessels, widespread involvement beyond small
cranial arteries, lack of granulomatous inflammation, and ANCAMPO positivity2.
Elevation of alkaline-phosphatase can be observed in 30-50% of
patients with GCA or other systemic vasculitis12. However, with
the exception of hepatitis B-related polyarteritis nodosa or
hepatitis B or C-associated cryoglobulinemia, cytolisis is highly
uncommon in systemic vasculitis. Elevated transaminases were an
important clue for the diagnosis of AIH in our patient, leading to an
extension of the immunologic study.
Interestingly, 40-96% of patients with AIH have positive
ANCA5,6. However, in AIH, ANCA exhibit an atypical perinuclear
pattern, and specificities are highly variable including lactoferrin,
cathepsin G, a-enolase, and bactericidal/permeability increasing
protein, among others5,6. Our patient’s ANCA had a typical
perinuclear pattern and confirmed specificity against MPO. Other
specificities were excluded by ELISA (table 1).
The importance of recognizing the presence of AIH in the
context of MPA has prognostic and therapeutic implications.
Although both diseases are responsive to immunosuppressive
therapy, the treatment choice needs to be adapted to their coexistence. Moreover, since AIH is a recurrent and chronic disease,
an inadequate monitoring of hepatic activity during follow-up,
adjusting treatment to vasculitis activity indexes only, may lead to
irreversible liver damage. Current evidence-based therapeutic
recommendations advise that patients with systemic vasculitis
involving small and medium-sized vessels should be treated with
prednisone and an immunosuppressive agent13. Cyclophosphamide is the gold-standard for inducing remission in systemic
necrotizing vasculitis but increasing awareness of its toxicity
advises the use of less harmful drugs for patients without severe
compromise of vital organs, such as the patient reported13.
Methotrexate has been also demonstrated to be effective in
inducing remission in a randomized clinical trial14; however, this
study mainly included patients with Wegener’s granulomatosis. A
recent prospective, randomized clinical trial has demonstrated
that about 50% of patients with MPA with no involvement of vital
organs (five factor score of zero) can be induced to remission with
glucocorticosteroids alone. For those unable to achieve/maintain
remission with glucocorticosteroids alone, azathioprine has been
equally effective than cyclophosphamide in inducing remission15.
Azathioprine is currently the gold-standard for the treatment of
AIH and experience with other drugs is anecdotal5,6. Although not
exempt of potential hepatotoxicity, the hepatic profile of
azathioprine is safer than that of other drugs effective for systemic
vasculitis. Azathioprine was, then, the adjuvant therapy chosen for
our patient, with such uncommon, perhaps underrecognized,
combination of diseases. Treatment was effective and she
successfully achieved remission with no recurrences or adverse
events during 27-month follow-up.
Financing
Supported by Ministerio de Ciencia e Innovación SAF 08/04328
and SGR 0300/2005.
S. Prieto-González was a post-residency research award
recipient form Hospital Clı́nic. M.C. Cid and G. Espı́gol-Frigolé
were supported by Instituto de Salud Carlos III. R. Estruch was
supported by CIBER 06/03.
Conflict of interest
The authors declare no conflicts of interest.
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