Visceral Leishmaniasis Mimicking Autoimmune Hepatitis, Primary Biliary Cirrhosis, and Systemic Lupus Erythematosus Overlap

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Abstract
Visceral leishmaniasis (VL) is a life-threatening infection caused by Leishmania species. In addition to typical clinical findings as fever, hepatosplenomegaly, and cachexia, VL is associated with autoimmune phenomena. To date, VL mimicking or exacerbating various autoimmune diseases have been described, including systemic lupus erythematosus (SLE), rheumatoid arthritis, and autoimmune hepatitis (AIH). Herein, we presented a patient with VL who had overlapping clinical features with SLE, AIH, as well as antimitochondrial antibody (AMA-M2) positive primary biliary cirrhosis.
133
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INTRODUCTION
Leishmaniasis is caused by Leishmania species and has vis-
ceral, cutaneous, and mucocutaneous forms in humans. Vis-
ceral leishmaniasis (VL), also known as kala-azar, a dissemi-
nated and potentially fatal form, is endemic in areas of the trop-
ics, subtropics, and Southern Europe [1,2]. The disease can be
observed sporadically at countries bordering Mediterranean
basin, including Turkey [3].
Classic clinical features of VL include high fever, anorexia,
hepatomegaly, marked splenomegaly, and pancytopenia due
to severe involvement of reticuloendothelial system (RES) or-
gans, particularly the liver, spleen, and bone marrow. Labora-
tory tests usually show elevated inflammatory markers, marked
eosinopenia, a relative lympho-monocytosis, hypergamma-
globulinemia with hypoalbuminemia, and occasionally evi-
dence of liver damage with raised liver enzymes [1,2].
Diagnosis of leishmaniasis is based on demographic, clini-
cal, and laboratory ndings. Definite diagnosis requires dem-
onstration of the parasite either histologically in relevant tis-
sues or with Leishmania-specific immunologic tests [1]. How-
ever, diagnosis could be challenging in sporadic cases and of-
ten delayed, as the main clinical presentation is often identical
to other infectious and non-infectious diseases. Furthermore,
some of VL manifestations are associated with immune respon-
ses of the host to Leishmania that mimic autoimmune diseases
like serum sickness [4].
Autoimmune phenomena are common in leishmaniasis
which could be related to polyclonal B-cell activation, molecu-
lar mimicry between microbial and host antigens, and altered-
reduced regulatory and suppressor T cell functions [4,5]. As a
consequence of these disturbances, several autoantibodies ap-
pear in the sera of patients with VL, albeit, in most cases ac-
companying clinical manifestations are lacking [5]. On the
other hand, there are several reports on concurrent or mas-
querading presentations with autoimmune diseases, particu-
larly systemic lupus erythematosus (SLE), rheumatoid arthritis,
and cryoglobulinemia in the literature [6-8]. Autoimmune
hepatitis (AIH) is also reported [9]. However, VL resembling
AIH and primary biliary cirrhosis (PBC) overlap hepatitis has
not been described before. Herein, we report a case of VL with
clinical and laboratory features mimicking AIH, PBC overlap
hepatitis, and SLE.
ISSN (Print) 0023-4001
ISSN (Online) 1738-0006
Korean J Parasitol Vol. 50, No. 2: 133-136, June 2012
http://dx.doi.org/
10.3347/kjp.2012.50.2.133
CASE REPORT
Visceral Leishmaniasis Mimicking Autoimmune Hepatitis,
Primary Biliary Cirrhosis, and Systemic Lupus
Erythematosus Overlap
Ozlem Guzel Tunccan
1,
*
, Abdurrahman Tufan
2
, Gülçin Telli
1
, Nalan Akyürek
3
, Merve Pamukçuo
ğ
lu
4
, Güldal lmaz
3
and Kenan Hızel
1
1
Department of Clinical Microbiology and Infectious Diseases,
2
Internal Medicine Department, Division of Rheumatology
3
Department of Pathology,
4
Department of Hematology, Gazi University Hospital Besevler, 06500, Ankara, Turkey
Abstract:
Visceral leishmaniasis (VL) is a life-threatening infection caused by Leishmania species. In addition to typical clin-
ical ndings as fever, hepatosplenomegaly, and cachexia, VL is associated with autoimmune phenomena. To date, VL
mimicking or exacerbating various autoimmune diseases have been described, including systemic lupus erythematosus
(SLE), rheumatoid arthritis, and autoimmune hepatitis (AIH). Herein, we presented a patient with VL who had overlapping
clinical features with SLE, AIH, as well as antimitochondrial antibody (AMA-M2) positive primary biliary cirrhosis.
Key words:
Leishmania, visceral leishmaniasis, systemic lupus erythematosus, autoimmune hepatitis, primary biliary cirrhosis
Received 30 January 2012, revised 3 March 2012, accepted 3 March 2012.
*
Corresponding author (oguzel@gazi.edu.tr)
134
Korean J Parasitol
Vol. 50, No. 2: 133-136, June 2012
CASE RECORD
A 26-year-old female patient referred to the rheumatology
department with complaints of anorexia, malaise, weight loss,
joint swelling, and low grade fever. She was living in a Mediter-
ranean region of Turkey. Her past history was notable for pho-
tosensitivity, oral ulcers, and possible thalassemia trait. On ad-
mission, her physical examination was significant for erythema
and symmetrical arthritis at ankles, wrists, and hand joints. The
spleen was palpated 10 cm below the costal margin, and the
liver had a longitudinal size of 15 cm. Erythrocyst sedimenta-
tion rate (ESR) and C- reactive protein was 65 and 19.9 mg/L,
respectively. Complete blood count revealed hemoglobin 10.2
gr/dl, mean corpuscular volume 69 fl, leukocyte 4,000/mm
3
,
and platelet 157,000/mm
3
. Other pertinent laboratory data
was as follows: creatinine 0.7 mg/dl (Normal
=
0.5-1.2), ala-
nine aminotransferase 46 U/L (ALT, Normal
<
40), aspartate
aminotransferase 51 U/L (AST, Normal
<
40), alkaline phos-
phatase 67 U/L (ALP, N
=
53-141), gama-glutamyl transferase
17 U/L (GGT, N
=
0-50), albumin 3.2 g/dl, globulin 6.9 g/dl,
and lactate dehydrogenase 236 U/L (N
=
125-243). Her labo-
ratory investigation was positive for anti-nuclear antibody im-
munofluorescence (ANA-IFA), anti-smooth muscle antibody
(ASMA), and Coombs tests on previous referral center. Repeat-
ed ANA was strongly positive as well as antimitochondrial
(AMA-M2) antibodies and Coombs tests. Rheumatoid factor
(RF) was 123 IU/ml (N
<
20). Liver kidney microsomal (anti-
LKM), anti-cytosolic liver (LC-1), antisoluble liver/liver-pan-
creas (SLA/LP), ASMA, anti-ENA, ds-DNA tests were negative.
Serum C3 and C4 were within normal limits. IgG was 5,810
mg/dl (N
=
751-1,560) with a polyclonal pattern. A liver biop-
sy was performed to rule out autoimmune hepatitis. Histologi-
cal examination of the liver biopsy revealed robust plasma cell
and lymphocyte infiltrations in the sinusoidal areas, and peri-
ductal and portal small granuloma formation. Histochemical-
ly, plasma cells, which were stained for Methyl Grün Pyronine
(MGP), were found to act as a dominant feature among the in-
ammatory inltrates in the liver. This finding also supported
and raised the suspicion of autoimmune hepatitis-PBC over-
lap (Fig. 1A, B).
Prednisone was started at a dose of 1 mg/kg under a pre-
sumptive diagnosis of SLE/AIH with a rapid clinical improve-
ment on arthritis, fever, malaise and general condition, liver
function tests, acute phase response, and hypergammaglobu-
linemia. Therefore, azathioprine 50 mg b.i.d. was added to the
therapy with tapering steroid dose. A few weeks after the im-
munosuppression, her leukocyte and platelet counts began to
fall gradually, reaching 1,000/mm
3
and 14,000/mm
3
, respec-
tively. Azathiopurine was discontinued. The patient was trans-
ferred to the infectious diseases department with the diagnosis
of neutropenic fever. An empirical therapy with cefoperazone
sulbactam was started. After 4 days, teicoplanin and flucon-
azole were added to the treatment because of urinary infection
caused by enterococci and Candida albicans. Although, against
this appropriate treatment, her condition got worse, fever con-
tinued, and neutropenia and thrombocytopenia persisted. A
bone marrow aspiration and biopsy were performed to rule
out possible bone marrow pathology.
The bone marrow smears revealed macrophages with nu-
merous Leishmania amastigotes (Fig. 2). The bone marrow bi-
Fig. 1. (A) Indirect cholestatic features with lobular confluent ne-
crosis (H&E stain, × 200). (B) Plasma cells as a dominant com-
ponent of inflammation in the liver (MGP, × 400)
A B
Fig. 2. A bone marrow smear showing macrophages containing
numerous Leishmania amastigotes (May-Grunwald/Giemsa stain,
× 100).
Tunccan et al.: Visceral leishmaniasis mimicking autoimmune hepatitis, cirrhosis, and SLE 135
opsy also showed Leishmania parasites within macrophages.
The amastigote tissue forms were seen when her liver biopsy
was re-evaluated (Fig. 3). Leishmania IgG was found positive at
a 1/1,280 titer in her serum specimen by indirect immunoflu-
orescent assay. High dose (4 mg/kg/day) intravenous liposo-
mal amphotericin B was given on days 1 to 5 and 10, 17, 24,
31, and 38 days [10]. Then, her fever resolved, and general con-
ditions greatly improved with the exception of neutropenia.
After a dose of granulocyte colony-stimulating factor, her neu-
trophil count also reached to a normal level. No other compli-
cations were observed in the duration of the treatment.
On her follow-up examination at 6 months after amphoter-
icin therapy, she was in good clinical condition with free of any
complaints and had normal blood counts, biochemical ana-
lyzes, and normal gammaglobulin levels. ASMA become nega-
tive, and ANA and AMA-M3 tests remained weak and strong
positives, respectively.
DISCUSSION
Leishmaniasis is a parasitic disease, which is transmitted to
humans by sandflies in endemic areas. VL is considered en-
demic in tropical and subtropical regions (Bangladesh, India,
Nepal, Sudan, and Brazil) in the world. However, in other coun-
tries, it is detected in a few cases. In Turkey, VL is seen mainly
in the Aegean, Mediterranean, and Central Anatolia regions,
and Leishmania infantum is the most responsible agent for the
human diasese. Children were at a higher risk of infection, and
only a few adult cases of VL were reported from Turkey [9,11-
13].
Our patient was living in an endemic region. VL is a dissem-
inated intracellular infection with a fatality rate of as high as
90%, unless treated. Classic clinical features include high fever,
severe anorexia, and marked hepatosplenomegaly. Laboratory
tests frequently show pancytopenia, marked eosinopenia, a
relative lympho-monocytosis and hypergammaglobulinemia
with hypoalbuminemia, and occasionally evidence of liver
damages with raised liver enzymes. The diagnosis is based on
a combination of demographic, clinical, laboratory findings,
and confirmation of the disease via demonstration of amasti-
gote tissue forms of parasites or Leishmania-specific immuno-
logical tests [1,2]. VL remains asymptomatic or subclinical in
many cases, or can follow an acute, subacute, or chronic course.
Chronic VL results in delays in diagnosis due to subtle or atyp-
ical presentations [1].
Autoimmune phenomena are common in Leishmania infec-
tions. This might be due to a release of high amounts of self
antigens as a result of tissue destruction caused by the parasite.
Release of tissue antigens may stimulate the autoreactivity and
autoantibody production. Another possible mechanism is al-
tered host immune responses caused by Leishmania parasites.
Both T and B cells are affected by VL [14]. VL causes polyclonal
B cell activation independent of T cells through mitogen acti-
vation or stimulation of cytokines by other immune cells [4,5].
B cell hyperactivation results in severe hypergammaglobuline-
mia observed in VL. Finally, as demonstrated previously, there
are some molecular mimicry between Leishmania antigens and
host antigens such as ribosomal phosphoproteins expressed
on parasites, causing cross-reactivity [5,14].
Reported autoimmune diseases that were mimicked or exac-
erbated by leishmaniasis are SLE, AIH, rheumatoid arthritis,
polyarteritis nodosa, cryoglobulinemic vasculitis, autoimmune
hemolytic anemia, and Ewan
s syndrome [6-9,11,12]. All of
them, particularly SLE and AIH have clinical and laboratory
features undistinguishable from VL that makes confusion. More-
over, many autoantibodies are formed in VL, even disease spe-
cific ones, including RF, anticitrulline, ANA, ds-DNA, ASMA,
anti-Ro, anti-La, anti-Sm, anti-cardiolipin, and anti-platelet an-
tibodies [4,5,14,15]. Positivity of one or more of these tests
with vague clinical presentations may be misinterpreted as au-
toimmune disorders.
A correct diagnosis of VL was tricky in our patient because
of presentation which was very similar to the autoimmune liv-
er disease and SLE. Though the liver enzymes are frequently
elevated in leishmaniasis, positive autoimmune laboratory tests
and liver biopsy reported as consistent with AIH-PBC overlap
Fig. 3. Clusters of leishmanias within the cytoplasm of Kupffer
cells in the liver (H&E stain, × 1,000)
136
Korean J Parasitol
Vol. 50, No. 2: 133-136, June 2012
led us to consider autoimmune overlap hepatitis and SLE as
the cause. Rapid response to prednisone further supported
AIH/SLE diagnosis. Hematological manifestations appeared
later in the clinical course and that was thought as an azathio-
prine side-effect. However, discontinuation of this drug and
escalating prednisone dose did not improve clinical pictures,
and the patient was re-evaluated revealing VL diagnosis.
PBS or its serological marker AMA-M2 positivity has not
been reported in patients with VL, to the best of our knowl-
edge. Persistently high titers of AMA-M2 even 6 months after
the appropriate treatment could be consistent with true diag-
nosis of PBS in our patient which might be concurrent with
VL. However, re-biopsy was refused by the patient.
Leishmaniasis is characterized by multiple immunological
abnormalities and protean clinical manifestations that may be
misinterpreted as various autoimmune diseases. Moreover,
early responses to immunosuppressives may masquerade clin-
ical pictures of VL. Treatment of autoimmune diseases may
worsen the disease and even cause a fatal outcome in VL pa-
tients. Therefore, in case of atypical presentations or treatment
failure in autoimmune diseases, leishmaniasis should be con-
sidered and ruled out.
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    • "The second theory claims that polyclonal B-cell activation and the altered function of regulatory and suppressor T-cells lead to the formation of autoantibodies. The last theory claims that molecular mimicry of the host antigens by antigens of Leishmania can cause a cross-reactivity [5, 7, 13]. The gold standard of VL diagnosis still remains the detection of parasites in the bone marrow aspiration or splenic tissue by smear or culture [17]. "
    [Show abstract] [Hide abstract] ABSTRACT: Visceral leishmaniasis (VL), a life-threatening parasitic infection, is endemic in the Mediterranean region. Diagnosis of VL is based on epidemiologic, clinical, and laboratory findings. However, sometimes, clinical features and laboratory findings overlap with those of autoimmune diseases. In some cases, autoantibodies are detected in patients with VL and this could be a potential diagnostic pitfall. In this study, we have reported on a three-year-old girl from a VL-endemic area in Iran, who presented with prolonged fever and splenomegaly. Bone marrow examination, serologic tests, and the molecular PCR assay were performed; however, results were inconclusive. The levels of anti-double stranded DNA, cytoplasmic antineutrophil cytoplasmic autoantibody, and perinuclear antineutrophil cytoplasmic autoantibody were elevated and, at the end, splenic biopsy was performed. The splenic tissue PCR test detected the DNA of Leishmania infantum . The patient’s condition improved with anti- Leishmania therapy, and the autoantibodies disappeared within the following four months. Clinical presentations and laboratory findings of VL and autoimmune diseases may overlap in some patients.
    Full-text · Article · Jun 2016
    • "Different regimens of Ambisome® have been recommended for treatment of kala-azar121314. The regimen which is usually administered in immunocompetent pediatric patients was scheduled for our patient [14,15]. In conclusion, medical practitioners especially in endemic areas should be aware of and consider VL among differential diagnosis of afebrile unexplained anemia. "
    [Show abstract] [Hide abstract] ABSTRACT: Visceral leishmaniasis or kala-azar is an endemic parasitic disease in some parts of the world which is characterized by fever, splenomegaly, and pancytopenia in most of the cases. Herein we report an 11 month-old male infant with diagnosis of kala-azar who presented with pallor, hepatosplenomegaly, failure to gain weight, and no history of fever. Surprisingly, fever started after beginning of meglumine antimoniate treatment in this patient. As far as we are aware of, this is a rare presentation of visceral leishmaniasis. Therefore, clinicians especially in endemic areas are highly recommended to include kala-azar among differential diagnosis of unexplained anemia without fever to prevent misdiagnosis of this potentially fatal, but treatable condition.
    Full-text · Article · Apr 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Intestinal parasites infections caused by a variety of worms are very common in low-income people without access to sewage and treated water. Contamination occurs in various forms and the main one is the intake of contaminated food or water and through the skin by small wounds. The host response will be different according to the place of parasite replication: intra or extracellular. Usually the musculoskeletal symptom develops within a period of a few days after the intestinal infection. And the clinical manifestations are more likely similar to those seems in Spondiloarthropathies. It is more frequent in children and adolescent, and a slight prevalence for female. Many parasites are able to bypass the host’s immune system, and parasitic disease is the prototype of chronic infection in humans. Persistent parasites have the capacity to release large quantities of antigens, inducing a variety of immunologic reactions.
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