Supplementary Table 1 | Selected features of diseases that are associated with gastrointestinal and hepatic granulomatous disorders
Etiology
Behçet's disease
Autoimmune
disorder with an
unclear etiology
Chronic
granulomatous
disease
X-linked and
autosomalrecessive forms
75% of patients
are diagnosed
before the age of
5 years
The majority of
patients are
males
Specific
granuloma
features
Symptoms
Examination findings
Diagnostic laboratory
tests/findings
Diagnostic
imaging
tests/findings
Miscellaneous
None
Genital
ulcerations
Oral ulcers
Visual disturbance
Skin rash
An acne-like
exanthem
Arthritis
Erythema nodosum
Folliculitis
Hypopyon
Iritis
Migratory
thrombophlebitis
Optic neuritis
Posterior uveitis
Recurrent oral and
genital ulcerations
Retinal vessel
occlusion
High ESR and CRP level
Leukocytosis
Nonspecific
CT: involved
bowel shows
concentric bowel
wall thickening or
polypoid masses
with marked
contrast
enhancement
In patients with no
complications,
perienteric or
pericolonic
infiltration is
absent or minimal
The presence of
severe infiltration
raises the
possibility of
complications
such as
microperforation
or localized
peritonitis
A positive
pathergy test is a
diagnostic test
where there is a
nonspecific
inflammatory skin
reaction to a
scratch or
intradermal
injection of saline
Epithelioid
granulomas
Granuloma
can involve
any part of the
gastrointestinal
tract and can
mimic Crohn’s
disease
Large
macrophages
Decreased growth
rates
Symptoms of
gastric outlet
obstruction (i.e.
early satiety,
bloating, nausea,
and vomiting) and
intestinal
obstruction
Symptoms related
Fever
Growth failure
Hepatosplenomegaly
Signs from recurrent
infections including
abscesses and
lymphadenopathy
Hypergammaglobulinemia
Hypoalbuminemia
Measurement of
superoxide production,
ferricytochrome c
reduction,
chemiluminescence,
nitroblue tetrazolium
reduction, or
dihydrorhodamine
oxidation
Thickening of the
mucosa
Areas of
narrowing
Prestenotic
dilatation
Cobblestone
pattern
Fistulas
Most common
infections in the
Western world:
Staphylococcus
aureus,
Burkholderia
cepacia, Serratia
marcescens,
Nocardia, and
Aspergillus.
In other parts of
1
Churg-Strauss
syndrome
A systematic
vasculitis
associated with
hypereosinophilia
and asthma
with brown
granular
cytoplasm or
pink
eosinophilic
crystalline
cytoplasmic
inclusions
to recurrent
infections of the
lung, skin, lymph
nodes, and liver
Osteomyelitis and
sepsis
the world:
Salmonella, BCG,
and tuberculosis
Necrotizing
vasculitis with
or without
extravascular
eosinophil
granulomas
and eosinophil
infiltration of
the vessel wall
Involves smallsized and
medium-sized
arteries and/or
venules
Abdominal pain
Arthralgia
Asthma
Cardiomyopathy
Cholecystitis
Fever
Gastrointestinal
bleeding, bowel
perforation
Mononeuritis
multiplex
Myalgia
Pancreatitis
Sinusitis
Weight loss
Eczema
Hypertension
Livedo reticularis
Palpable purpura
Rhinitis
Skin nodules
Urticaria
Eosinophilia >1,500 mm3
or >10%
Proteinuria 1 g/d
Microscopic hematuria
High ESR, fibrinogen, and
alpha-2 globulins
High ANCA titers
Paranasal
sinusitis
Pulmonary
infiltrates
CT or MRI might
show
disseminated
ischemic lesions
consistent with
small-vessel
vasculitis
Pericardial
effusion
Löffler syndrome
is pneumonitis
with pulmonary
infiltrates
associated with
eosinophilia
Histology
obtained in this
patient
population
usually lacks
plasma cells
and can
resemble that
of graft-versushost disease,
lymphoid
hyperplasia,
and celiac
disease
Recurrent lung
infections,
sinusitis, and otitis
Diarrhea
Hepatomegaly
Lymphadenopathy
Splenomegaly
Signs of infections
like sinusitis and
pneumonia
Hypogammaglobulinemia
(IgG, IgA and/or IgM)
Impaired antibody
response to vaccines
Flow-cytometry
Exclusion of other
diseases that have the
same presentation
Nonspecific
CT and
radiographic
changes
associated with
recurrent lung
infections, or
pneumonitis
Encapsulated and
atypical
organisms are
commonly
identified as
causing infections
Can have an
associated
autoimmune
disorder like
hemolytic anemia,
immune
thrombocytopenia,
and IBD
Only 40–60%
of surgical
Abdominal pain
Arthralgia
Abdominal mass
Ankylosing
High ESR and CRP
pANCA occasionally
Small bowel
follow through:
Rarely associated
with primary
Common variable
immunodeficiency
One of the most
common primary
immune
deficiencies
Has a multigenetic cause
Crohn’s disease
Genetic
susceptibility with
2
NOD2
(CARD15),
ATG16L1, and
IRGM as well as
other genetic
factors.
Drugs
Up to 60 different
drugs associated
with hepatic
granuloma
Intestinal
tuberculosis
Caused by
Mycobacterium
tuberculosis and
to a lesser extent
by M. bovis
resection
specimens and
15–36% of
biopsy
samples
exhibit
granulomas
Diarrhea
Hematochezia
Obstructive
symptoms
Perianal disease
Tenesmus
spondylitis
Arthritis
Clubbing
Perianal abscesses
and fistula
Erythema nodosum
Pyoderma
gangrenosum
Sacroiliitis
Sweet syndrome
Metastatic Crohn’s
disease
detected in the serum
ASCA (More than 50%)
could be
nodularity of the
mucosa, loss of
mucosal folds,
linear ulcers,
strictures, or
fistulas
CT: increased
bowel wall
thickness, with
mesenteric fat
wrapping and
mesenteric lymph
nodes, and
possible
abscesses
sclerosing
cholangitis
Granuloma in
hepatic portal
areas and acini
Epiltheliod
multinucleated
giant cells
Eosinophilic
infiltrate
predominates
May remain
asymptomatic
Fever
Rash
Lymphadenopathy
is rare
Hepatomegaly
Eosinophilia
Predominant
transaminase elevation,
moderate alkaline
phosphatase elevation
Trial of drug
discontinuation
Non-contributory
N/A
Large,
confluent
granulomas
with caseous
necrosis
At times the
Mycobacterium
organism can
be identified
Diarrhea
Fistulas
Fever
Rectal bleeding
Symptoms of
pulmonary
tuberculosis can
be present
Abdominal mass
Ascites
Clubbing
Findings of
pulmonary
tuberculosis can be
present
Perianal fistulas
(uncommon)
Biopsy culture for M.
tuberculosis
Tuberculosis PCR assay
on either endoscopic or
surgical sections has a
sensitivity of 64.1%
QFT has a 67%
sensitivity, 90%
specificity, 87% positive
predictive value, and 73%
negative predictive value
CT: symmetrical
bowel wall
thickening <6 mm
Separation of
bowel loops by
lymphadenopathy,
lymph nodes can
be larger than
1 cm with a
necrotic center
Associated
parietal peritoneal
thickening and
ascites
The TST has a
false positive rate
of 8.5% if the
BCG vaccine is
administered in
infancy
Polyarteritis
3
nodosa
Necrotizing, focal
segmental
vasculitis
affecting
medium-sized
arteries
Primary biliary
cirrhosis
Chronic
idiopathic
autoimmune liver
disease that
primarily affects
females
Triggered by an
environmental
factor in a
genetically
susceptible host
Sarcoidosis
Unknown
etiology but
thought to be
due to exposure
of genetically
susceptible
individuals to
specific
environmental
agents
Inflammation
consisting of
monocytes,
lymphocytes,
PMN, and
necrotizing
angiitis
Fibrinoid
necrosis of the
medial layer of
medium-sized
arteries
Arthralgia
Fever
Gastrointestinal
bleeding or
perforation
Malaise
Myalgias or
weakness
Postprandial
abdominal pain
Testicular pain
Weight loss
Arthritis of the large
joints
Diastolic blood
pressure greater
than 90 mmHg
Livedo reticularis,
splinter
hemorrhages, and
palpable purpura
Mononeuropathy or
polyneuropathy
Testicular
tenderness
Weakness
Elevated blood urea
nitrogen or serum
creatinine
Hepatitis B serology
(HBsAg and anti-HBs)
Mild increase in hepatic
transaminases
Abnormalities on
arteriography
including saccular
and fusiform
aneurysms as
well as stenosis
and occlusion of
medium-sized
arteries
CT: bowel wall
thickening with a
target sign
N/A
N/A
Fatigue
Pruritis
Sicca Syndrome
Signs of portal
hypertension in
advanced cases with
cirrhosis
Elevated alkaline
phosphatase
High AMA titer
Osteoporosis in
up to one third of
patients
Normal ultrasound
in early disease;
findings of portal
hypertension and
cirrhosis in
advanced disease
N/A
Noncaseating
epithelioid cell
granuloma
Radially
arranged
epithelioid
cells,
surrounded by
a lymphocytic
infiltration
Multinucleate
Langhans
giant cells are
present and
Commonly
asymptomatic
Cough
Shortness of
breath
Constitutional
symptoms
including fever
and weight loss
Symptoms related
to specific organ
involvement
Erythema nodosum
Lupus pernio
Lymphadenopathy
Splenomegaly
Uveitis
Pulmonary function tests
with carbon monoxide
diffusion capacity
Serum calcium can be
elevated
Chest
radiography:
Hilar
lymphadenopathy
Pulmonary
infiltration
Löfgren’s
Syndrome:
Bilateral hilar
lymphadenopathy
Ankle arthritis
Erythema
nodosum
Fever, myalgia,
malaise, and
weight loss
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may contain
Schaumann
and asteroid
bodies
Schistosomiasis
Parasitic
infection caused
by different
species but
commonly
Schistosoma.
mansoni.
S. japonicum.
and S. mekongi.
Ulcerative colitis
Interplay exists
between genetic
and
environmental
factors with at
least 21
susceptibility loci
confirmed in
ulcerative colitis
alone
Viral hepatitis
Chronic infection
with HBV or HCV
Wegener’s
granulomatosis
Autoimmune
Granulomas
develop at
areas where
the eggs are
deposited
Granulomas
result in
destruction of
the eggs but
cause fibrosis
Abdominal pain
Diarrhea (can be
bloody)
Loss of appetite
Hepatomegaly
Splenomegaly and
signs of portal
hypertension in
advanced disease
Detection of schistosome
eggs in the feces or urine
is diagnostic
In suspected cases but
with negative urine and
feces specimens, a
biopsy of the rectal
mucosa can be performed
Periportal fibrosis
can be seen on
ultrasound, CT, or
MRI and is
characteristic of
schistosomiasis
Acute
schistosomiasis is
also known as
Katayama fever:
constitutes a
fever, headache,
myalgia,
abdominal pain,
and bloody
diarrhea
Cryptassociated
giant cells and
clusters of
histiocytic and
multinucleate
giant cells can
be present at
the point of
rupture of
crypts and
abscesses;
therefore,
granulomas
can occur in
ulcerative
colitis
Abdominal pain
Arthralgia
Diarrhea
Hematochezia
Tenesmus
Arthritis
Ankylosing
spondylitis
Clubbing
Erythema nodosum
Iritis, uveitis, and
episcleritis
Pyoderma
gangrenosum
Sacroiliitis
High ESR and CRP
pANCA (about 70%)
ASCA occasional
Leukocytosis
Anemia
Rare small bowel
involvement
(back-wash ileitis)
Moderate
increase in bowel
wall thickness,
infrequently
mesenteric lymph
node enlargement
Occasionally
associated with
primary sclerosing
cholangitis
Non-necrotic
granuloma
Nonspecific
lymphocytepredominant
infiltrate
Mostly
asymptomatic
Splenomegaly and
signs of portal
hypertension in
advanced disease
Serum transaminase
elevation in majority of
patients
Positive serological tests
Positive PCR assays
Normal ultrasound
in early disease;
findings of portal
hypertension and
cirrhosis in
advanced disease
Granuloma may
occur in response
to interferonbased antiviral
therapy
Mixed
Fever
Cutaneous findings
cANCA positive
CT: nonspecific
N/A
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disorder that
causes small
vessel vasculitis
Predominantly
affects the upper
and lower
respiratory tract
and the kidneys
inflammatory
infiltrate
associated
with
necrotizing and
granulomatous
vasculitis of
small-sized
and mediumsized vessels
Hearing loss
Malaise
Recurrent otitis
medi, mastoiditis,
and sinusitis
Recurrent
epistaxis
Weight loss
of vasculitis
Nasal septum
perforation
Polyarthritis
Saddle nose
deformity
Signs of peritonitis in
case of perforation
Subglottic stenosis
Findings of
glomerulonephritis (red
blood cell casts)
findings including
diffuse or
multifocal bowel
wall thickening,
abnormal
enhancement
pattern of bowel
wall, dilatation of
bowel segments,
mesenteric vessel
engorgement and
ascites
Chest
radiography: lung
infiltrates and
parenchymal
nodules and/or
cavitation
Abbreviations: AMA, Anti mitochondrial antibodies; ANCA, antineutrophil cytoplasmic antibodies; ASCA, Anti-Saccharomyces cerevisiae antibodies;
BCG, Bacille Calmette–Guérin; c-ANCA, classical antineutrophil cytoplasmic antibodies; CRP, C-reactive protein; ESR, Erythrocyte sedimentation rate;
HBsAg, Hepatitis B surface antigen; N/A, not applicable; p-ANCA, protoplasmic-staining antineutrophil cytoplasmic antibodies; PMN, Polymorphonuclear
neutrophils; QFT, QuantiFERON®-TB (Cellestis Ltd, Victoria, Australia); TST, Tuberculin skin test
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