Clin J Gastroenterol (2012) 5:131–135 DOI 10.1007/s12328-012-0291-8
CASE REPORT
Autoimmune pancreatitis and primary sclerosing cholangitis in a 16-year-old boy with inflammatory bowel disease Alexander Huelsen • Wayne Bailey • Martin Whitehead • Teresa Chalmers-Watson
Received: 9 August 2011 / Accepted: 7 February 2012 / Published online: 7 March 2012 Ó Springer 2012
Abstract Autoimmune pancreatitis (AIP) is a rare systemic fibroinflammatory disorder. The disease usually occurs in elderly men and offers an excellent response to steroid treatment. AIP in childhood is exceedingly rare. We report the first case of AIP in a boy with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD). He presented with a six-year history of intermittent bloody diarrhoea. Colonoscopy revealed severe pancolitis and ileitis in keeping with IBD. Abnormal liver function tests and magnetic resonance cholangiopancreatography (MRCP) findings confirmed PSC and subsequent occurrence of renal lesions and pancreatic abnormalities on computed tomography imaging were suspicious for AIP. Immunoglobulin G4 (IgG4) serum levels were elevated and treatment with steroids led to complete resolution of renal lesions, pancreatic changes and normalization of IgG4 and liver function tests. Follow-up MRCP 6 months later revealed unchanged biliary abnormalities in keeping with PSC. The differentiation between PSC and extrapancreatic AIP affecting the biliary tree and liver is critical given the dramatic response of AIP to steroids. Recent recommendations therefore include IgG4 measurement in every adult with possible PSC. Our case documents for the first time that AIP has to be considered as a A. Huelsen (&) T. Chalmers-Watson Department of Gastroenterology, Christchurch Hospital, Private Bag 4710, Christchurch, 8140 Canterbury, South Island, New Zealand e-mail: [email protected]
differential diagnosis in childhood PSC. IgG4 measurement should be recommended universally in possible PSC. Keywords Autoimmune pancreatitis Inflammatory bowel disease Primary sclerosing cholangitis IgG4-associated cholangitis IgG4-related systemic disease
Introduction Autoimmune pancreatitis (AIP) is a rare fibroinflammatory disorder originally described in Japan but with increasing recognition worldwide [1]. Characteristic features include pancreatic enlargement or a mass, raised serum immunoglobulin G4 (IgG4) level, a lymphoplasmacytic infiltrate and fibrosis on biopsy, and a dramatic response to steroids. AIP may also affect extrapancreatic organs such as the biliary tree, salivary glands, lymph nodes and kidneys. The bile duct involvement also called IgG4-associated cholangitis (IAC) in recent terminology is one of the most common extrapancreatic manifestations of AIP occurring in 73 % of the cases [2]. The exact aetiology remains unknown but current understanding favours an autoimmune condition. AIP occurs predominately in men in their 60–70s and the exact prevalence is not known. The occurrence in childhood is exceedingly rare and to our best knowledge only twelve cases are reported in the literature [3]. Here we report the first case of AIP in childhood associated with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD).
W. Bailey Department of Radiology, Christchurch Hospital, Christchurch, Canterbury, South Island, New Zealand
Case report
M. Whitehead Department of Anatomical Pathology, Christchurch Hospital, Christchurch, Canterbury, South Island, New Zealand
A 16-year-old Korean boy was referred to our Gastroenterology Department in 2009 with a 6-year history of
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132
intermittent bloody diarrhoea, abdominal pain, lethargy and recurrent iron deficiency anaemia. The patient was on no regular medication, did not drink alcohol and there was no significant family history. There were no abnormal findings on clinical examination. A colonoscopy revealed severe pancolitis with predominant proximal distribution and mild terminal ileitis. Histology of the colon showed mixed inflammation within the lamina propria, distortion of the crypt architecture with neutrophils extending into the crypt epithelium and Paneth cell metaplasia. There was also mild acute inflammation in the terminal ileum. There were no granulomata identified and changes in the colon appeared more severe proximally. These findings confirmed IBD of indeterminate type but with distribution favouring Crohn’s disease. Blood tests revealed haemoglobin 115 g/L (normal range 130–175 g/L), mean corpuscular volume 79 fl (normal range 80–99 fL), platelet count 458 9109/L (normal range 150–400 9 109/L), alkaline phosphatase 463 U/L (normal range 60–300 U/L),
Clin J Gastroenterol (2012) 5:131–135
Fig. 1 MRCP image showing narrowing of the central intrahepatic biliary ducts and dilation of the posterior sectoral ducts in keeping with a diagnosis of PSC
gamma-glutamyl transpeptidase 228 U/L (normal range 10–50 U/L), aspartate transaminase 69 U/L (normal range 10-50 U/L), alanine aminotransferase 132 U/L (normal range 0–40 U/L), C-reactive protein 11 mg/L (normal range \5 mg/L), ferritin 7 lg/L (normal range 20–350 lg/L), IgG 21.8 g/L (normal range 7–14 g/L), smooth muscle antibodies positive 1/20, and vitamin D 18 nmol/L (normal range 50–150 nmol/L). Further tests including hepatitis B and C serology, antinuclear antibodies, liver-kidney michrosomal antibodies, antimitochondrial antibodies, atypical perinuclear antineutrophil cytoplasmic antibodies and ceruloplasmin were negative. Treatment was started with mesalazine 2 g twice daily, oral iron and vitamin D. PSC was suspected because of the abnormal liver function tests and a magnetic resonance cholangiopancreatography (MRCP) was planned. However, he presented acutely to hospital after 3 weeks with severe central abdominal pain, worsening diarrhoea and fever. Investigations revealed acute pancreatitis with a raised pancreas specific amylase 366 U/L (normal range 8–53 U/L) and further elevation of liver function tests. Mesalazine was suspected as the causative drug for the pancreatitis once infection and metabolic disorders were excluded and the mesalazine was therefore discontinued. The patient improved with supportive treatment. MRCP demonstrated narrowing of the central intrahepatic biliary ducts and mild biliary mural thickening within the common hepatic duct and central branches of the posterior sectoral ducts in keeping with a diagnosis of PSC (Fig. 1). A liver biopsy 1 week later revealed bile duct inflammation with cytoplasmic vacuolation, occasional intraepithelial lymphocytes and patchy periductal concentric (‘onion skin’) fibrosis, as well as mild lymphoplasmacytic portal inflammation. The appearances within the liver were entirely in keeping with PSC with bridging fibrosis. After the acute episode, azathioprine 100 mg once daily was introduced, but the patient presented again with a further episode of acute pancreatitis 3 weeks later. A computed tomography (CT) of the abdomen was performed
Fig. 2 a CT image of a diffusely oedematous ‘sausage shaped’ pancreas with loss of fat lobulation and delayed enhancement. b CT arterial phase image prior to steroid treatment that shows two of the
three solid lesions in the right kidney (arrow). c CT image of common bile duct wall thickening (arrow) described as a typical feature of IgG4-associated cholangitis
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Clin J Gastroenterol (2012) 5:131–135
Fig. 3 a H&E stain at 920 objective showing a portal tract with inflammation and degenerate bile ducts with periductal ‘onion-skin’ fibrosis typical of PSC. b Immunohistochemical slide stained for
133
IgG4 at 940 objective showing portal tract with bile duct and occasional IgG4-positive plasma cells (\10 cells/high-power field)
Fig. 4 CT arterial phase images 4 weeks post-steroid treatment (and 4 weeks post-Fig. 2a–c) showing: a normal pancreatic size and enhancement and b complete resolution of all renal lesions
at that time, which showed a diffusely oedematous ‘sausage-shaped’ pancreas with loss of fat lobulation and delayed enhancement as well as three new solid lesions between 14 and 18 mm in the right kidney. The CT findings were characteristic of AIP (Fig. 2a, b). Additionally bile duct wall thickening was present which has been described as a typical finding in AIP (Fig. 2c) [4]. His serum IgG4 at that time was elevated at 2.1 g/L (normal range 0.06–1.86 g/L). In light of these findings the liver biopsy was reviewed to clarify whether PSC or IAC, a manifestation of extrapancreatic AIP, was the underlying liver pathology. The review confirmed PSC (Fig. 3a) and additional immunohistochemistry (also on colonic biopsies) revealed only scanty IgG4-positive plasma cells (\10 cells/high-power field; Fig. 3b). These changes were not of sufficient magnitude to confirm extrapancreatic AIP affecting the biliary system (IAC) as the cause of the liver disease.
Azathioprine was halted and treatment was initiated with intravenous hydrocortisone (100 mg four times a day) to treat both his active IBD and AIP, including any component of his sclerosing cholangitis, which was caused by active IAC. He improved rapidly and was discharged 6 days later on a tapering course of prednisone. Current AIP treatment recommendations suggest a prolonged steroid course and he was therefore treated with a 6-month prednisone course (10 mg daily) to treat the AIP as well as his IBD. Mesalazine and thiopurines were not possible therapeutic options due to concerns they may have been the cause of the acute pancreatitis episodes. The patient felt well over that period and a follow-up CT abdomen 4 weeks later revealed normal pancreatic size and enhancement and complete resolution of all renal lesions (Fig. 4a, b). After 6 months his hepatobiliary system was reassessed with a repeat MRCP. This demonstrated an unchanged appearance in keeping with the diagnosis of
123
134
PSC; however, his IgG4 and liver function tests had normalized. Steroids were weaned resulting in a flare of his colitis, which was successfully treated with adalimumab with rapid resolution of symptoms. He has remained on adalimumab since that time and has been clinically well with normal bowel habit and normal liver function tests.
Discussion This case documents for the first time the presence of IBD, PSC and AIP together in childhood. The differentiation of PSC from the biliary changes of AIP is challenging and has significant importance given the excellent response to steroid treatment in AIP. The diagnosis of PSC requires characteristic findings on MRCP or endoscopic retrograde cholangiopancreatography as well as exclusion of secondary causes. Conversely there is no single pathognomonic finding in AIP and therefore various diagnostic criteria have been developed originating from Japan and Korea (Asian criteria) and the Mayo clinic in the USA (HISORt criteria) and more recently the International Consensus Diagnostic Criteria for AIP (ICDC) [5]. These require a combination of typical imaging findings, serology (IgG4 level), histology, other organ involvement and a response to steroid treatment and reflect differing diagnostic practice patterns worldwide. Furthermore current understanding of AIP recognizes two distinct disease patterns—type 1 and type 2 AIP. The differentiation of these types is based on clinical profile and/or pancreatic histology. Type 2 disease appears to be a pancreas-specific disorder that is less often associated with IgG4 serum elevations or other organ involvement. Its definite diagnosis therefore requires pancreatic histology revealing an idiopathic duct-centric pancreatitis. Conversely, type 1 AIP is a systemic IgG4 disease that frequently leads to extrapancreatic manifestations and elevated serum IgG4 with excellent response to steroid treatment [5]. The diagnosis of AIP in our case is robust and fulfils the criteria for a definitive type 1 AIP as suggested by the ICDC. The diagnosis here is based on imaging, serology, other organ involvement and response to steroid treatment. CT imaging revealed a characteristic ‘sausage-shaped’ enlarged pancreas with delayed enhancement and three solid mass lesions in the right kidney, which resolved completely following steroid treatment. Serum IgG4 level was raised and characteristically normalised following treatment. The question of whether our patient’s biliary changes are due to PSC or IAC therefore arises. A liver biopsy including immunohistochemistry is not required for the diagnosis of IAC but occurred in this case and did not confirm a
123
Clin J Gastroenterol (2012) 5:131–135
manifestation of extrapancreatic AIP. However, patchy organ infiltration has been reported and IAC cannot be ruled out on the basis of a negative liver core biopsy [6]. The unchanged appearance on follow-up MRCP favours PSC as the main hepatobiliary pathology; however, the normalized liver function tests may suggest a component of IAC that responded to steroid treatment [7]. Further speculative options are that the aetiology is longstanding IAC with established and therefore non-reversible fibrotic strictures mimicking PSC or that the PSC in our case represents a steroid responsive subgroup of PSC. At the present time it is not known if PSC and IAC actually represent a spectrum of the same disease or different conditions, though the latter is favoured by current evidence [8]. Since the description of IgG4 disease, studies have retrospectively reviewed previous PSC cases. Takikawa et al. [9] found that 7% would now meet criteria for AIP whereas Mendes et al. [10] showed isolated elevated IgG4 serum levels in 9% of their established PSC cases. The authors therefore speculated that IgG4 serum-positive PSC cases might form a steroid responsive subgroup of PSC. Of concern is that the subgroup of IgG4-positive PSC cases in this study appeared to have a more severe disease course with shorter time to liver transplantation. The differentiation of these conditions is clearly of upmost significance given the dramatic response of AIP and its extrapancreatic manifestations to steroids. For this reason the 2010 guideline of the American Association for the Study of Liver Diseases suggests serum IgG4 measurements in all new PSC cases to identify a potentially treatable subgroup [11]. This guideline addresses the adult patient; however, our case shows that AIP has to be considered now also as a differential diagnosis in childhood PSC. We suggest therefore the universal recommendation of IgG4 measurement in possible PSC. In conclusion this case documents for the first time the presence of IBD, PSC and type 1 AIP together in childhood. The diagnostic criteria for AIP are currently not unified; however, it responds dramatically to steroid treatment and therefore should be considered as a differential diagnosis in possible PSC in childhood. Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Kim KP, Kim MH, Lee SS, Seo DW, Lee SK. Autoimmune pancreatitis: it may be a worldwide entity. Gastroenterology. 2004;126(4):1214. 2. Hamano H, Arakura N, Muraki T, Ozaki Y, Kiyosawa K, Kawa S. Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis. J Gastroenterol. 2006;41(12): 1197–205.
Clin J Gastroenterol (2012) 5:131–135 3. Mannion M, Cron RQ. Successful treatment of pediatric IgG4 related systemic disease with mycophenolate mofetil: case report and a review of the pediatric autoimmune pancreatitis literature. Pediatr Rheumatol Online J. 2011;9(1):1. 4. Nishino T, Toki F, Oyama H, Oi I, Kobayashi M, Takasaki K, et al. Biliary tract involvement in autoimmune pancreatitis. Pancreas. 2005;30(1):76–82. 5. Shimosegawa T, Chari ST, Frulloni L, Kamisawa T, Kawa S, Mino-Kenudson M, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40(3):352–8. 6. Deshpande V, Sainani NI, Chung RT, Pratt DS, Mentha G, Rubbia-Brandt L, et al. IgG4-associated cholangitis: a comparative histological and immunophenotypic study with primary sclerosing cholangitis on liver biopsy material. Mod Pathol. 2009;22(10):1287–95. 7. Ghazale A, Chari ST, Zhang L, Smyrk TC, Takahashi N, Levy MJ, et al. Immunoglobulin G4-associated cholangitis: clinical
135
8.
9.
10.
11.
profile and response to therapy. Gastroenterology. 2008;134: 706–15. Webster GJ, Pereira SP, Chapman RW. Autoimmune pancreatitis/IgG4-associated cholangitis and primary sclerosing cholangitis—overlapping or separate diseases? J Hepatol. 2009;51(2): 398–402. Takikawa H, Takamori Y, Tanaka A, Kurihara H, Nakanuma Y. Analysis of 388 cases of primary sclerosing cholangitis in Japan: presence of a subgroup without pancreatic involvement in older patients. Hepatol Res. 2004;29:153–9. Mendes FD, Jorgensen R, Keach J, Katzmann JA, Smyrk T, Donlinger J, et al. Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol. 2006;101:2070–5. Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51(2):660–78.
123
CASE REPORT
Autoimmune pancreatitis and primary sclerosing cholangitis in a 16-year-old boy with inflammatory bowel disease Alexander Huelsen • Wayne Bailey • Martin Whitehead • Teresa Chalmers-Watson
Received: 9 August 2011 / Accepted: 7 February 2012 / Published online: 7 March 2012 Ó Springer 2012
Abstract Autoimmune pancreatitis (AIP) is a rare systemic fibroinflammatory disorder. The disease usually occurs in elderly men and offers an excellent response to steroid treatment. AIP in childhood is exceedingly rare. We report the first case of AIP in a boy with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD). He presented with a six-year history of intermittent bloody diarrhoea. Colonoscopy revealed severe pancolitis and ileitis in keeping with IBD. Abnormal liver function tests and magnetic resonance cholangiopancreatography (MRCP) findings confirmed PSC and subsequent occurrence of renal lesions and pancreatic abnormalities on computed tomography imaging were suspicious for AIP. Immunoglobulin G4 (IgG4) serum levels were elevated and treatment with steroids led to complete resolution of renal lesions, pancreatic changes and normalization of IgG4 and liver function tests. Follow-up MRCP 6 months later revealed unchanged biliary abnormalities in keeping with PSC. The differentiation between PSC and extrapancreatic AIP affecting the biliary tree and liver is critical given the dramatic response of AIP to steroids. Recent recommendations therefore include IgG4 measurement in every adult with possible PSC. Our case documents for the first time that AIP has to be considered as a A. Huelsen (&) T. Chalmers-Watson Department of Gastroenterology, Christchurch Hospital, Private Bag 4710, Christchurch, 8140 Canterbury, South Island, New Zealand e-mail: [email protected]
differential diagnosis in childhood PSC. IgG4 measurement should be recommended universally in possible PSC. Keywords Autoimmune pancreatitis Inflammatory bowel disease Primary sclerosing cholangitis IgG4-associated cholangitis IgG4-related systemic disease
Introduction Autoimmune pancreatitis (AIP) is a rare fibroinflammatory disorder originally described in Japan but with increasing recognition worldwide [1]. Characteristic features include pancreatic enlargement or a mass, raised serum immunoglobulin G4 (IgG4) level, a lymphoplasmacytic infiltrate and fibrosis on biopsy, and a dramatic response to steroids. AIP may also affect extrapancreatic organs such as the biliary tree, salivary glands, lymph nodes and kidneys. The bile duct involvement also called IgG4-associated cholangitis (IAC) in recent terminology is one of the most common extrapancreatic manifestations of AIP occurring in 73 % of the cases [2]. The exact aetiology remains unknown but current understanding favours an autoimmune condition. AIP occurs predominately in men in their 60–70s and the exact prevalence is not known. The occurrence in childhood is exceedingly rare and to our best knowledge only twelve cases are reported in the literature [3]. Here we report the first case of AIP in childhood associated with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD).
W. Bailey Department of Radiology, Christchurch Hospital, Christchurch, Canterbury, South Island, New Zealand
Case report
M. Whitehead Department of Anatomical Pathology, Christchurch Hospital, Christchurch, Canterbury, South Island, New Zealand
A 16-year-old Korean boy was referred to our Gastroenterology Department in 2009 with a 6-year history of
123
132
intermittent bloody diarrhoea, abdominal pain, lethargy and recurrent iron deficiency anaemia. The patient was on no regular medication, did not drink alcohol and there was no significant family history. There were no abnormal findings on clinical examination. A colonoscopy revealed severe pancolitis with predominant proximal distribution and mild terminal ileitis. Histology of the colon showed mixed inflammation within the lamina propria, distortion of the crypt architecture with neutrophils extending into the crypt epithelium and Paneth cell metaplasia. There was also mild acute inflammation in the terminal ileum. There were no granulomata identified and changes in the colon appeared more severe proximally. These findings confirmed IBD of indeterminate type but with distribution favouring Crohn’s disease. Blood tests revealed haemoglobin 115 g/L (normal range 130–175 g/L), mean corpuscular volume 79 fl (normal range 80–99 fL), platelet count 458 9109/L (normal range 150–400 9 109/L), alkaline phosphatase 463 U/L (normal range 60–300 U/L),
Clin J Gastroenterol (2012) 5:131–135
Fig. 1 MRCP image showing narrowing of the central intrahepatic biliary ducts and dilation of the posterior sectoral ducts in keeping with a diagnosis of PSC
gamma-glutamyl transpeptidase 228 U/L (normal range 10–50 U/L), aspartate transaminase 69 U/L (normal range 10-50 U/L), alanine aminotransferase 132 U/L (normal range 0–40 U/L), C-reactive protein 11 mg/L (normal range \5 mg/L), ferritin 7 lg/L (normal range 20–350 lg/L), IgG 21.8 g/L (normal range 7–14 g/L), smooth muscle antibodies positive 1/20, and vitamin D 18 nmol/L (normal range 50–150 nmol/L). Further tests including hepatitis B and C serology, antinuclear antibodies, liver-kidney michrosomal antibodies, antimitochondrial antibodies, atypical perinuclear antineutrophil cytoplasmic antibodies and ceruloplasmin were negative. Treatment was started with mesalazine 2 g twice daily, oral iron and vitamin D. PSC was suspected because of the abnormal liver function tests and a magnetic resonance cholangiopancreatography (MRCP) was planned. However, he presented acutely to hospital after 3 weeks with severe central abdominal pain, worsening diarrhoea and fever. Investigations revealed acute pancreatitis with a raised pancreas specific amylase 366 U/L (normal range 8–53 U/L) and further elevation of liver function tests. Mesalazine was suspected as the causative drug for the pancreatitis once infection and metabolic disorders were excluded and the mesalazine was therefore discontinued. The patient improved with supportive treatment. MRCP demonstrated narrowing of the central intrahepatic biliary ducts and mild biliary mural thickening within the common hepatic duct and central branches of the posterior sectoral ducts in keeping with a diagnosis of PSC (Fig. 1). A liver biopsy 1 week later revealed bile duct inflammation with cytoplasmic vacuolation, occasional intraepithelial lymphocytes and patchy periductal concentric (‘onion skin’) fibrosis, as well as mild lymphoplasmacytic portal inflammation. The appearances within the liver were entirely in keeping with PSC with bridging fibrosis. After the acute episode, azathioprine 100 mg once daily was introduced, but the patient presented again with a further episode of acute pancreatitis 3 weeks later. A computed tomography (CT) of the abdomen was performed
Fig. 2 a CT image of a diffusely oedematous ‘sausage shaped’ pancreas with loss of fat lobulation and delayed enhancement. b CT arterial phase image prior to steroid treatment that shows two of the
three solid lesions in the right kidney (arrow). c CT image of common bile duct wall thickening (arrow) described as a typical feature of IgG4-associated cholangitis
123
Clin J Gastroenterol (2012) 5:131–135
Fig. 3 a H&E stain at 920 objective showing a portal tract with inflammation and degenerate bile ducts with periductal ‘onion-skin’ fibrosis typical of PSC. b Immunohistochemical slide stained for
133
IgG4 at 940 objective showing portal tract with bile duct and occasional IgG4-positive plasma cells (\10 cells/high-power field)
Fig. 4 CT arterial phase images 4 weeks post-steroid treatment (and 4 weeks post-Fig. 2a–c) showing: a normal pancreatic size and enhancement and b complete resolution of all renal lesions
at that time, which showed a diffusely oedematous ‘sausage-shaped’ pancreas with loss of fat lobulation and delayed enhancement as well as three new solid lesions between 14 and 18 mm in the right kidney. The CT findings were characteristic of AIP (Fig. 2a, b). Additionally bile duct wall thickening was present which has been described as a typical finding in AIP (Fig. 2c) [4]. His serum IgG4 at that time was elevated at 2.1 g/L (normal range 0.06–1.86 g/L). In light of these findings the liver biopsy was reviewed to clarify whether PSC or IAC, a manifestation of extrapancreatic AIP, was the underlying liver pathology. The review confirmed PSC (Fig. 3a) and additional immunohistochemistry (also on colonic biopsies) revealed only scanty IgG4-positive plasma cells (\10 cells/high-power field; Fig. 3b). These changes were not of sufficient magnitude to confirm extrapancreatic AIP affecting the biliary system (IAC) as the cause of the liver disease.
Azathioprine was halted and treatment was initiated with intravenous hydrocortisone (100 mg four times a day) to treat both his active IBD and AIP, including any component of his sclerosing cholangitis, which was caused by active IAC. He improved rapidly and was discharged 6 days later on a tapering course of prednisone. Current AIP treatment recommendations suggest a prolonged steroid course and he was therefore treated with a 6-month prednisone course (10 mg daily) to treat the AIP as well as his IBD. Mesalazine and thiopurines were not possible therapeutic options due to concerns they may have been the cause of the acute pancreatitis episodes. The patient felt well over that period and a follow-up CT abdomen 4 weeks later revealed normal pancreatic size and enhancement and complete resolution of all renal lesions (Fig. 4a, b). After 6 months his hepatobiliary system was reassessed with a repeat MRCP. This demonstrated an unchanged appearance in keeping with the diagnosis of
123
134
PSC; however, his IgG4 and liver function tests had normalized. Steroids were weaned resulting in a flare of his colitis, which was successfully treated with adalimumab with rapid resolution of symptoms. He has remained on adalimumab since that time and has been clinically well with normal bowel habit and normal liver function tests.
Discussion This case documents for the first time the presence of IBD, PSC and AIP together in childhood. The differentiation of PSC from the biliary changes of AIP is challenging and has significant importance given the excellent response to steroid treatment in AIP. The diagnosis of PSC requires characteristic findings on MRCP or endoscopic retrograde cholangiopancreatography as well as exclusion of secondary causes. Conversely there is no single pathognomonic finding in AIP and therefore various diagnostic criteria have been developed originating from Japan and Korea (Asian criteria) and the Mayo clinic in the USA (HISORt criteria) and more recently the International Consensus Diagnostic Criteria for AIP (ICDC) [5]. These require a combination of typical imaging findings, serology (IgG4 level), histology, other organ involvement and a response to steroid treatment and reflect differing diagnostic practice patterns worldwide. Furthermore current understanding of AIP recognizes two distinct disease patterns—type 1 and type 2 AIP. The differentiation of these types is based on clinical profile and/or pancreatic histology. Type 2 disease appears to be a pancreas-specific disorder that is less often associated with IgG4 serum elevations or other organ involvement. Its definite diagnosis therefore requires pancreatic histology revealing an idiopathic duct-centric pancreatitis. Conversely, type 1 AIP is a systemic IgG4 disease that frequently leads to extrapancreatic manifestations and elevated serum IgG4 with excellent response to steroid treatment [5]. The diagnosis of AIP in our case is robust and fulfils the criteria for a definitive type 1 AIP as suggested by the ICDC. The diagnosis here is based on imaging, serology, other organ involvement and response to steroid treatment. CT imaging revealed a characteristic ‘sausage-shaped’ enlarged pancreas with delayed enhancement and three solid mass lesions in the right kidney, which resolved completely following steroid treatment. Serum IgG4 level was raised and characteristically normalised following treatment. The question of whether our patient’s biliary changes are due to PSC or IAC therefore arises. A liver biopsy including immunohistochemistry is not required for the diagnosis of IAC but occurred in this case and did not confirm a
123
Clin J Gastroenterol (2012) 5:131–135
manifestation of extrapancreatic AIP. However, patchy organ infiltration has been reported and IAC cannot be ruled out on the basis of a negative liver core biopsy [6]. The unchanged appearance on follow-up MRCP favours PSC as the main hepatobiliary pathology; however, the normalized liver function tests may suggest a component of IAC that responded to steroid treatment [7]. Further speculative options are that the aetiology is longstanding IAC with established and therefore non-reversible fibrotic strictures mimicking PSC or that the PSC in our case represents a steroid responsive subgroup of PSC. At the present time it is not known if PSC and IAC actually represent a spectrum of the same disease or different conditions, though the latter is favoured by current evidence [8]. Since the description of IgG4 disease, studies have retrospectively reviewed previous PSC cases. Takikawa et al. [9] found that 7% would now meet criteria for AIP whereas Mendes et al. [10] showed isolated elevated IgG4 serum levels in 9% of their established PSC cases. The authors therefore speculated that IgG4 serum-positive PSC cases might form a steroid responsive subgroup of PSC. Of concern is that the subgroup of IgG4-positive PSC cases in this study appeared to have a more severe disease course with shorter time to liver transplantation. The differentiation of these conditions is clearly of upmost significance given the dramatic response of AIP and its extrapancreatic manifestations to steroids. For this reason the 2010 guideline of the American Association for the Study of Liver Diseases suggests serum IgG4 measurements in all new PSC cases to identify a potentially treatable subgroup [11]. This guideline addresses the adult patient; however, our case shows that AIP has to be considered now also as a differential diagnosis in childhood PSC. We suggest therefore the universal recommendation of IgG4 measurement in possible PSC. In conclusion this case documents for the first time the presence of IBD, PSC and type 1 AIP together in childhood. The diagnostic criteria for AIP are currently not unified; however, it responds dramatically to steroid treatment and therefore should be considered as a differential diagnosis in possible PSC in childhood. Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Kim KP, Kim MH, Lee SS, Seo DW, Lee SK. Autoimmune pancreatitis: it may be a worldwide entity. Gastroenterology. 2004;126(4):1214. 2. Hamano H, Arakura N, Muraki T, Ozaki Y, Kiyosawa K, Kawa S. Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis. J Gastroenterol. 2006;41(12): 1197–205.
Clin J Gastroenterol (2012) 5:131–135 3. Mannion M, Cron RQ. Successful treatment of pediatric IgG4 related systemic disease with mycophenolate mofetil: case report and a review of the pediatric autoimmune pancreatitis literature. Pediatr Rheumatol Online J. 2011;9(1):1. 4. Nishino T, Toki F, Oyama H, Oi I, Kobayashi M, Takasaki K, et al. Biliary tract involvement in autoimmune pancreatitis. Pancreas. 2005;30(1):76–82. 5. Shimosegawa T, Chari ST, Frulloni L, Kamisawa T, Kawa S, Mino-Kenudson M, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40(3):352–8. 6. Deshpande V, Sainani NI, Chung RT, Pratt DS, Mentha G, Rubbia-Brandt L, et al. IgG4-associated cholangitis: a comparative histological and immunophenotypic study with primary sclerosing cholangitis on liver biopsy material. Mod Pathol. 2009;22(10):1287–95. 7. Ghazale A, Chari ST, Zhang L, Smyrk TC, Takahashi N, Levy MJ, et al. Immunoglobulin G4-associated cholangitis: clinical
135
8.
9.
10.
11.
profile and response to therapy. Gastroenterology. 2008;134: 706–15. Webster GJ, Pereira SP, Chapman RW. Autoimmune pancreatitis/IgG4-associated cholangitis and primary sclerosing cholangitis—overlapping or separate diseases? J Hepatol. 2009;51(2): 398–402. Takikawa H, Takamori Y, Tanaka A, Kurihara H, Nakanuma Y. Analysis of 388 cases of primary sclerosing cholangitis in Japan: presence of a subgroup without pancreatic involvement in older patients. Hepatol Res. 2004;29:153–9. Mendes FD, Jorgensen R, Keach J, Katzmann JA, Smyrk T, Donlinger J, et al. Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol. 2006;101:2070–5. Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51(2):660–78.
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