IgG4-positive
Plasma Cell Infiltration in the Setting of Ulcerative Colitis
Sarah Alghamdi,
Jamie Barkin, Maykel Trotter, Dante Sorrentino, Antonio E Martinez
Sarah
Alghamdi, Antonio E Martinez, Department of
Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach,
Florida, Florida International University, 4300 Alton road, Miami Beach ,
Florida 33140, the United States
Jamie
Barkin, Department of
gastroenterology, Mount Sinai Medical Center, Miami Beach, Florida, Florida
International University, 4300 Alton road, Miami Beach , Florida 33140,
the United States
Maykel
Trotter, Department of
internal medicine, Mount Sinai Medical Center, Miami Beach, Florida, Florida
International University, 4300 Alton road, Miami Beach, Florida 33140, the
United States
Dante Sorrentino, Mount Sinai Medical Center. Miami
Beach, Florida, Florida International University College of Medcine, 4300 Alton road, Miami Beach, Florida 33140, the
United States
Correspondence to: Sarah Alghamdi, MD, Department of Pathology and Laboratory medicine, Mount
Sinai Medical Center, 4300 Alton road, Miami Beach, Florida 33140, the United
States. sarah.alghamdi@msmc.com
Telephone: +1-305-674-2277 Ext:2 Fax: +1-305-674-2999
Received: July 2, 2012
Revised: September 4, 2012
Accepted:
September 8, 2012
Published
online: December 21, 2012
ABSTRACT
AIM: IgG4 has gained
medical attention due to its role in IgG4- related sclerosing disease. Among
these, autoimmune pancreatitis (AIP) and sclerosing cholangitis have been well
documented. Several reports describe an association between IBD and chronic
pancreatitis. Primary sclerosing cholangitis (PSC) also has an established
association with IBD, particularly ulcerative colitis (UC). Because of the
aforementioned association between UC and sclerosing diseases, further studies
are in need to establish the presence and significance of IgG4 plasma cells in
UC.
METHOD: Herein, we
evaluate the significance of IgG4-positive plasma cells in 54 colonic biopsies
of UC patients. The medical records were reviewed for demographic and clinical
data including: the course of UC, the presence of any biliary symptoms or
diagnosis of PSC, liver enzymes, IgG4-related disease and IgG4 serum levels.
IgG4 positive plasma cells were recorded and categorized as follows: no=0,
rare=1-2, few=3-9, many=10 or more.
RESULTS: Four cases had
many IgG4 positive plasma cells, two of which had refractory UC course. Seven
UC patients had elevated liver enzymes. Two of the 54 patients had primary sclerosing
cholangitis. These patients had IgG4 labeling of none and rare.
CONCLUSION: In colonic
biopsies of UC patients, and a subset with PSC, significant IgG4 plasma cell
populations were not detected by immunohistochemistry. In a subset of UC
patients with many IgG4 positive plasma cells a more severe clinical course was
noted. Further studies are required to explore the significance of IgG4 in UC.
© 2012 Thomson research. All rights reserved.
Key words:
IgG4; Ulcerative
colitis; Sclerosing cholangitis
Alghamdi S, Barkin J, Trotter M, Sorrentino D, Martinez
AE. IgG4-positive Plasma Cell Infiltration in the Setting of Ulcerative
Colitis. Journal of Gastroenterology and Hepatology Research 2012; 1(11): 320-322 Available from: URL: http://www.ghrnet.org/index./joghr/
INTRODUCTION
Although normal function is not fully known, IgG4 has been shown to
play a significant role in allergic reactions, such as atopic eczema, bronchial
asthma, and bullous skin lesions, and has recently gained medical attention due
to its role in IgG4-related sclerosing disease[1]. Among these,
autoimmune pancreatitis (AIP) has been well characterized and subclassified
based on the presence of the IgG4-positive plasma cells[2]. This
unique subgroup, characterized by lymphoplasmacytic infiltrate and sclerosing
process, differs clinically, pathologically, and, unlike the other form,
responds to steroid therapy[3]. Increased levels of IgG4-positive
plasma cells have been identified in patients with other idiopathic-sclerosing
diseases of many sites of involvement including, but not limited to, the
hepatobiliary system, retroperitonium, mesentery, mediastinum, salivary glands
and lungs[4]. Some of the studies regarding AIP have shown a
significant increase in incidence of inflammatory bowel disease (IBD) in
patients with AIP[5]. Well-documented clinical case reports describe
an association between IBD and chronic pancreatitis[6-10]. Primary
sclerosing cholangitis (PSC) is a chronic progressive inflammatory process with
fibrosis and narrowing of the medium and large caliber hepatobiliary ducts. PSC
has an established association with IBD, particularly ulcerative colitis (UC).
At least 75% of PSC patients have coexisting UC, however, only 5% of UC
patients develop PSC[11]. One of the many forms of IgG4 sclerosing
diseases is sclerosing cholangitis, an entity similar to PSC with few
differences[12]. Because of the aforementioned association between
UC and sclerosing diseases, namely PSC and AIP, further studies are in need to
establish the possible role of IgG4 plasma cells in UC.
Herein, we
evaluate the presence and the significance of IgG4-positive plasma cells in 54
colonic biopsies of patients with established diagnosis of ulcerative colitis.
METHODS
The study was approved by the institutional review
board at Mount Sinai Medical Center.
A COPATH database was searched for colonic biopsies in patients with an
established diagnosis of ulcerative colitis exhibiting chronic active colitis.
Fifty-four cases were identified. Two concurring pathologists reviewed the H
& E slides of the biopsies retrospectively. These cases were selected based
on the presence of chronic active colitis. The criterion for activity was the
presence of neutrophilic infiltration of the epithelium with cryptitis or crypt
abscesses and chronicity was defined by architectural distortion and increased
plasma cells in the lamina propria (Figure 1). Ten biopsy samples of normal
colonic mucosa were selected for use as controls.
The medical
records of the patients were reviewed for demographic and clinical data
including: the onset and duration of UC, the presence of any biliary symptoms
or diagnosis of PSC, abnormal liver enzymes (AST/ALT/protein/albumin/total
bilirubin/direct bilirubin/alkaline phosphatase), IgG4-related disease and IgG4
serum levels.
The paraffin
blocks of the 54 cases were available. Re-cut sections were immunostained
utilizing monoclonal IgG4 antibody (MRQ-44, Cell Marque, Rockein, CA) on
Ventana Ultraview using standard immunohisochemical techniques. The number of
immunohisochemically identified IgG4 ¨C positive plasma cells per high power
field (40¡Á HPF) was counted
in each specimen. IgG4 positive plasma cells were scored as an average number
of the total count of three high power fields (40¡Á, 20 mm field of view ocular). The
average IgG4 positive cell counts were recorded and categorized as follows:
no=0, rare=1-2, few=3-9, many=10 or more.
RESULTS
The mean age of our patient population was 55 years with slight male
predominance (male 54%, female 46%).
The mean duration of the disease was 13 years. Among the cases,
thirty-four of the biopsies of UC showed no to rare IgG4 positive plasma cell
labeling. Sixteen UC cases had few IgG4 positive plasma cells. Four cases had
many IgG4 positive plasma cells (Figure 2). The 10 control normal colonic
biopsies showed none to rare IgG4 positive plasma cells.
Seven UC
patients (13%) had elevated liver enzymes. Of these, six had elevated AST,
three had elevated ALT, five had elevated direct bilirubin, and three showed
elevated alkaline phosphatase. One patient with elevated AST, ALT, direct
bilirubin had 10 IgG4 positive plasma calls; however, this patient did not have
evidence of PSC and the information about his clinical course was limited. The
other patients with elevated liver enzymes had none to few IgG4 labeling. Two
of the four patients with 10 or more IgG4 labeling had refractory UC course.
Two of the 54
patients (4%) had primary sclerosing cholangitis. These patients had IgG4
labeling of none and rare (2 IgG4 positive plasma cells on average),
respectively. Of the remaining patients, none had biliary symptoms. No serum
IgG4 levels were measured.
DISCUSSION
IgG4-related sclerosing disease is a relatively
recently described clinical entity of unknown etiology with male predilection
which generally responds well to steroids. While many organs can be involved,
the most well characterized form of IgG4-sclerosing diseases is autoimmune
pancreatitis[4]. Another form of IgG4-sclerosing disease is IgG4-related
sclerosing cholangitis, an entity that differs from PSC in that patients with
IgG4-related sclerosing cholangitis are older at diagnosis and they present
more abruptly with obstructive jaundice. IgG4 related sclerosing cholangitis
has known association with autoimmune pancreatitis and other complex autoimmune
IgG4 syndromes, but the association with IBD has not been fully explored in the
literature. Histologically, IgG4 sclerosing cholangitis has similar features to
PSC but differs in that the biliary epithelium is usually intact, while PSC
shows mucosal erosions. In addition, neutrophilic infiltrates of the biliary
epithelium, commonly seen in PSC, are generally not a feature of IgG4
sclerosing cholangitis. Immunohistochemically, abundant IgG4-positive plasma
cells are detected in the bile ducts, in contrast to PSC[4,12]. In
recent series of cases of PSC, elevated IgG4 levels were found in 9% of
patients. This group also had significantly lower frequency of IBD, with only
50% of patients with elevated IgG4 showing history of IBD compared to 85% with
normal IgG4 levels[13]. In a recent study, Ravi et al concluded
that approximately 6% of patients with proven AIP carried a diagnosis of
IBD(Crohn¡¯s Disease or Ulcerative Colitis), compared to a prevalence of
0.4-0.5% in the general population. The same study showed that patients with
both AIP and IBD had a more severe clinical course of IBD[5].
In our cohort of 54 patients, four (7%) had significant IgG4 labeling of
10 or more per high power field; however, none of these had biliary disease. Of
interest, half of the patients with 10 or more IgG4 labeling had a refractory
UC course. The two patients with both UC and PSC in our cohort showed no
significant IgG4 positive plasma cell populations (none to rare per high power
field) in their colonic biopsies.
CONCLUSION
In colonic biopsies in patients with UC, and a subset with PSC,
significant IgG4 plasma cell populations were not detected by
immunohistochemistry. In a subset of UC patients with many IgG4 positive plasma
cells a more severe clinical course was noted. Further studies are required to
explore the role and possible clinical significance of IgG4 in patients with
UC.
REFERENCES
1 Shakib F. The IgG subclass in
milk intolerance . Monogr Allergy 1986; 19: 218-22
2 SARLES H, SARLES JC, MURATORE R, GUIEN C.
Chronic inflammatory sclerosis of the pancreas--an autonomous pancreatic
disease? Am J Dig Dis 1961; 6: 688-698
3 Ketikoglou I, Moulakakis A.
Autoimmune pancreatitis. Dig Liver Dis 2005; 37: 211-215
4 Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of
IgG4-related sclerosing disease. J Gastroenterol 2006; 41:
613-625
5 Ravi K, Chari ST, Vege SS,
Sandborn WJ, Smyrk TC, Loftus EV. Inflammatory bowel disease in the setting of
autoimmune pancreatitis. Inflamm Bowel Dis 2009; 15: 1326-1330
6 Bhatt SP, Makharia GK. An
unusual association between chronic pancreatitis and ulcerative colitis. JOP
2008; 9: 74-75
7 Barthet M, Hastier P,
Bernard JP, Bordes G, Frederick J, Allio S, Mambrini P, Saint-Paul MC, Delmont
JP, Salducci J, Grimaud JC, Sahel J. Chronic pancreatitis and inflammatory
bowel disease: true or coincidental association? Am J Gastroenterol
1999; 94: 2141-2148
8 S¨¢ez J, Mart¨ªnez J, Garc¨ªa C, Griñ¨® P,
P¨¦rez-Mateo M. Idiopathic pancreatitis associated with ulcerative colitis. 2000; 95: 3004-3005
9 Inoue
H, Shiraki K, Okano H, Deguchi M, Yamanaka T, Sakai T, Ohmori S,
Yoshimura H, Nakano T. Acute pancreatitis in patients with ulcerative colitis. Dig
Dis Sci 2005; 50: 1064-1067
10 Okano A, Takakuwa H, Nishio A.
Idiopathic pancreatitis may be associated with ulcerative colitis. Intern
Med 2003; 42: 125-126
11 Levine J, Burakoff R. Extraintestinal
Manifestations of Inflammatory Bowel Disease. Gastroenterology and
Hepatology 2011; 7: 235-241
12 Cheuk W, Chan JK. IgG4-related
sclerosing disease: a critical appraisal of an evolving clinicopathologic
entity. Adv Anat Pathol 2010; 17: 303-332
13 Mendes FD, Jorgensen R, Keach J,
Katzmann JA, Smyrk T, Donlinger J, Chari S, Lindor KD. Elevated serum IgG4
concentration in patients with primary sclerosing cholangitis. Am J
Gastroenterol 2006; 101: 2070-2075
Peer reviewers: Maha Maher Shehata, Professor,
Internal Medicine Department, Gastroenterology and Hepatology Unit, Mansoura
University, Specialized Medical hospital, 35516, Mansoura, Egypt; Jeffry Adam Katz, Division of Gastroenterology and
Liver Disease, 11100 Euclid Avenue, Cleveland, OH
44106-5066, the United States.
Refbacks
- There are currently no refbacks.
This work is licensed under a Creative Commons Attribution 3.0 License.