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Autoimmune pancreatitis: an adolescent case and review of literature
Journal of Pediatric Surgery (2008) 43, 1368–1372
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Autoimmune pancreatitis: an adolescent case and review of literature Javier Blejter⁎, Santiago Weller, Rosina Pace, Humberto Cusumano, Daniel Giambini Pediatric Surgery Service, Pedro de Elizalde Hospital, Buenos Aires, Argentina Received 20 November 2007; revised 13 February 2008; accepted 19 February 2008
Key words: Pancreatitis; Autoimmune; Chronic; Idiopathic
Abstract We present a case of a 16-year-old adolescent boy with autoimmune pancreatitis and a review of the related literature.The patient was sent from a peripheral medical center, presenting with jaundice, pruritus, weight loss, and hyperglycemia of 20 days' duration. At admission, the patient was icteric, choluric, and acholic. His abdomen was soft and nontender, and the patient felt no pain in his abdomen. He had skin lesions because of scratching. Laboratory findings showed a blood glucose level of 135 mg%; total serum bilirubin, 29.4 mg%; direct bilirubin, 23 mg%; and alkaline phosphatase, 1100 IU/L. Abdominal ultrasound showed an enlarged head of the pancreas that was 30 × 35 mm. The parenchyma was slightly heterogeneous. Abdominal computed tomography showed an enlarged head of the pancreas with a normal body and tail, thickened duodenal wall, and dilated intra- and extrahepatic biliary tract, and the distal choledochus was not visible. Magnetic resonance imaging showed dilated intra- and extrahepatic biliary tract. The choledochus was not visible, and the cystic duct ended abruptly. The pancreas head was enlarged and homogenous, and there were no changes with contrast. Wirsung's duct was not dilated. Laparotomy was performed with a presumed diagnosis of pancreatic head tumor. The pancreas was diffusely indurated and enlarged; biopsy and intraoperative cholangiography were performed. The biliary tract was dilated with no duodenal passage of contrast, and the Wirsung's duct was not observed. Cholecystectomy was performed, and a transcystic drain was positioned. The histopathology was compatible with autoimmune pancreatitis. Prednisone treatment was started with good response. Autoimmune pancreatitis is a very rare entity among children and adolescents. It should be suspected when characteristic clinical signs and radiographic images are associated with a higher level of IgG4. Autoimmune pancreatitis is confirmed by biopsy. Treatment with prednisone often alleviates all the symptoms, as what happened in this case. © 2008 Elsevier Inc. All rights reserved.
Autoimmune pancreatitis (AIP) is a rare syndrome especially in the pediatric and adolescent population. We present a case of a 16-year-old adolescent boy who was admitted with cholestatic syndrome, including pruritus and
⁎ Corresponding author. Tel.: +54 01115 55927015; fax: +54 0114 857 0546. E-mail address: [email protected] (J. Blejter). 0022-3468/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2008.02.064
weight loss of 20 days' duration. We accompany our presentation with a literature review.
1. Methods We reviewed the patient's chart and researched the related literature using the following key words: pancreatitis, autoimmune, chronic, and idiopathic.
Autoimmune pancreatitis
1369
2. Case 2.1. Case report A 16-year-old adolescent boy was transferred to our facility with a 20-day history of cholestatic syndrome, pruritus, and weight loss of 10 kg. Personal and family history was not available. At admission, the patient was icteric, acholic, and choluric. He had scratches on the abdomen and legs related to itching. His abdomen was soft and nontender, and he felt no pain in his abdomen. His laboratory results on the day of admission were as follows: blood glucose, 135 mg%; total serum bilirubin, 29.4 mg%; direct bilirubin (DB), 23 mg%; alkaline phosphatase, 1100 IU/L; aspartate amini transferase (AST), 110 IU/L; alanine amino tranferase (ALT), 160 IU/L; 5′ nucleotidase, 36.5 IU/L; serum amylase and lipase levels, normal. Abdominal ultrasound showed an enlarged pancreatic head (30 × 35 mm). The parenchyma was slightly heterogeneous. Abdominal computed tomography (CT) (Fig. 1) showed an enlarged head of the pancreas, thickened duodenal wall, and dilated intra- and extrahepatic biliary tract. The distal choledochus was not visible. The pancreatic body and tail were normal. The liver had a right posterior subcapsular hypodense image without clear boundaries. Magnetic resonance cholangiopancreatography (Fig. 2) showed dilated intra- and extrahepatic biliary tract. The common hepatic duct diameter was 14 mm. The choledochus was not visible, and the cystic duct ended abruptly. The pancreatic head was enlarged but homogeneous. There were no changes with contrast. Wirsung's duct was not dilated. Exploratory laparotomy was performed for suspected tumor in the head of the pancreas. The pancreas was diffusely enlarged and indurated. Cholangiography revealed dilated intra- and extrahepatic biliary tract (Fig. 3). There was no duodenal passage of contrast observed, and Wirsung's duct was not seen. Pancreatic biopsy and cholecystectomy were performed, and a transcystic drain was placed.
Fig. 1 Computed tomography (with oral contrast) showing an enlarged pancreatic head compressing the duodenum.
Fig. 2 Magnetic resonance cholangiopancreatography shows intra- and extrahepatic biliary duct dilatation. The distal choledochus and Wirsung's duct are not visible.
The patient began feeding on the seventh postoperative (POP) day. There was up to 700 mL/d of drainage from the transcystic drain, which persisted until prednisone was administered. Subsequent sonograms demonstrated improvement of dilatation, but there was no change in the size of the pancreatic head. Abdominal ultrasound on the 13th POP day demonstrated intrahepatic biliary tract of 6 mm and extrahepatic duct of 9.7 mm; the pancreatic head was 50 × 34 mm. On the 14th POP day, laboratory tests showed improvement of cholestatic parameters: total serum bilirubin, 5.2 mg%; DB, 3.8 mg%; alkaline phosphatase, 480 IU/L; AST, 63 IU/L; ALT, 124 IU/L; amylase, 57 IU/L; and lipase, 12.3 IU/L, although acholia and hyperglycemia were still present. Fecal fat content was normal. On the 15th POP day, a cholangiography showed no changes. Transcystic drainage remained unchanged. A POP gastrointestinal contrast study showed slight dilatation of the duodenal bulb, unorganized folds in the second portion of the duodenum, and good passage of contrast material. Histopathology showed chronic pancreatitis with interstitial periductal lymphoplasmocytic infiltration. Immunosuppressant treatment with prednisone (40 mg/kg per day) was started 1 month after surgery. The condition of the patient with acholia improved, and his transcystic drainage progressively diminished. Hyperglycemia persisted; diabetes mellitus secondary to AIP was diagnosed and subsequently controlled by NPH insulin. Cholangiography on the 50th POP day (Fig. 4) showed good duodenal passage and smaller biliary tract diameter. An ultrasound demonstrated a nondilated biliary tract, and the pancreatic head diameter was 13 mm and appeared homo-
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Fig. 3 Intraoperative cholangiography demonstrating intra- and extrahepatic biliary duct dilatation. The distal choledochus and Wirsung's duct are not visible. Contrast does not pass into the duodenum.
J. Blejter et al. the head. Computed tomography scan may also show nodules or diffuse lesions in the cortex of the kidney, and their cause may be because of vasculitis or inflammatory pseudotumor [2,3]. These lesions usually regress with steroid treatment. Abdominal magnetic resonance imaging (MRI) shows the same pattern but has better definition. Endoscopic retrograde cholangiopancreatography (ERCP) usually demonstrates an irregular or narrowed Wirsung's duct as well as biliary tract stenosis at the entrance to the pancreas [4-7]. The possibility of making a differential diagnosis between primary sclerosing cholangitis (SC) and SC (secondary to AIP) using ERCP was studied in a series of 55 patients by Takahiro et al [8]. Their conclusion was that the ERCP findings were useful in differentiating between these 2 pathologies. This was verified by histologic analysis of all the cases. Imaging studies can be misleading and resemble pancreatic tumors as in our case, especially when serologies are negative [9]. However, there may be some findings on dual-phase CT, magnetic resonance cholangiopancreatography, and MRI that may support the diagnosis of AIP, such as “diffusely decreased enhancement of the pancreas, a capsule-like rim, bile duct enhancement, and renal involvement” [10] on the CT
geneous. In view of the above findings, the transcystic drain was closed. IgG4 level was normal (the patient was hypogammaglobulinemic), and autoimmune tracing serologies were negative. At discharge, the patient was anicteric and choluric, and feces were normal. A cholangiogram showed normal passage of contrast into the duodenum and normal biliary tract diameter. Then the drain was removed. Prednisone treatment was successfully tapered off; however, the patient still requires NPH insulin treatment of diabetes.
3. Discussion Autoimmune pancreatitis is a rare entity in the pediatric population, and its etiology is unknown. The signs and symptoms of AIP are variable. Jaundice, choluria, and acholia are present in 70% to 80% [1] of the patients. Mild to moderate pain usually located in the epigastrium or back, weight loss, and/or diabetes mellitus can also be present. Cholestasis caused by obstruction of the common bile duct is a characteristic of AIP. Ultrasound usually shows intraand extrahepatic biliary tract dilatation, sometimes with thickened walls. The pancreas is generally enlarged, heterogeneous, and hypoechoic [2]. Abdominal CT findings are similar and, in addition, sometimes demonstrate irregularities in the diameter of Wirsung's duct. Delayed contrast enhancement of pancreatic parenchyma and spherical hypodense areas are also frequently noted. In most cases, the enlargement of the pancreas is generalized, although there can be focal enlargements located mostly in
Fig. 4 Cholangiography on the 50th POP day shows improvement of biliary tract dilatation and contrast passing into the duodenum.
Autoimmune pancreatitis and “abnormal signal intensity on T1- and T2-weighted magnetic resonance images” [11] on the magnetic resonance cholangiopancreatography (MCP) and MRI. Hyperbilirubinemia with predominance of DB is the most prevalent finding. Hypergammaglobulinemia with elevated levels of IgG4 is also present in 68% of the cases [12], especially if AIP is associated with another autoimmune disorder. Thus, when IgG4 levels are elevated, autoimmune serologies must be performed, with positive results expected in 22% to 45% of cases. Kamisawa et al [12] also suggest that low IgG4 levels (b128 mg/dL) correlates closely with localized pancreas disease; when levels are high (N150 mg/dL), the disease may involve other organs as well. However, mild elevations of IgG4 levels were also seen in patients with pancreatic cancer, suggesting that those patients deserve further evaluation before assuming they have AIP [13,14]. In another study [15], IgG4 levels and immune complexes of IgG4 were measured before and after 4 weeks of treatment with prednisone. Statistically, significant lower IgG4 levels were found after treatment, suggesting that these complexes could be involved in the physiopathology of AIP. Autoimmune pancreatitis can be associated (as stated above) with other autoimmune pathologies such as Sjögren syndrome (the most prevalent), SC, inflammatory bowel disease, autoimmune thrombocytopenic purpura, retroperitoneal fibrosis, and Hashimoto thyroiditis [4,10,16,17]. Autoimmune pancreatitis can begin as SC. Unlike primary SC, AIP appears earlier in life, with obstructive jaundice and pancreatic abnormalities; IgG4 level can be elevated, and there is a good response to prednisone therapy [3]. Another entity, idiopathic fibrosing pancreatitis, unlike AIP, usually presents with jaundice because of obstruction and abdominal pain; however, the pathologic hallmark is fibrosis rather than lymphoplasmocytic infiltration as is the case in AIP. There are no reports associating idiopathic fibrosing pancreatitis to autoimmune diseases, although some AIP cases are also without such association [18]. Because the presentation of AIP is so variable and its signs and symptoms can be confused with malignancy, studies were initiated to find out whether CT or ultrasoundguided biopsies could help avoid unnecessary surgery. These procedures can theoretically differentiate pancreatic carcinoma from AIP; however, their sensitivity and specificity are “technical experience” dependent, resulting in a variable rate of false-positive and false-negative results, which often leads to surgery. Furthermore, sometimes, surgery is required to relieve obstructive symptoms [5]. On the other hand, AIP can be difficult to differentiate from biliary tract carcinoma [19], especially when pancreatic changes are not found, leading to unnecessary procedures when a biopsy would have been sufficient for diagnosis [20,21]. The characteristic pathologic findings are lymphoplasmocytic infiltrate (mostly CD8- and CD4-positive lymphocytes) and pericanalicular fibrosis. Positive IgG4 is also frequently
1371 found. In some cases, among the CD4 cell population, Th1 type predominates over Th2, for example, in Sjögren syndrome. CD4 carrying HLA-DRB1*04/05 or DQB1*04/ 01 has been found in pancreatic tissue and blood tests in patients with AIP. These findings confirm an autoimmune basis for this disease [4,22]. The treatment of choice for AIP is steroid administration. Normally, patients respond well to this plan of treatment. Sometimes, in patients with associated autoimmune diseases or elevated levels of IgG4, it is necessary to continue prednisone therapy for a long period [23]. In most cases, 4 weeks of treatment improve symptoms and laboratory values. There was one case with histologic improvement [24] under this same treatment and another case with improvement in the state of diabetes mellitus [25]. Patients who are seronegative for IgG4, have no obstructive jaundice, are not diabetic, have no swelling of the duodenal papilla, have a negative staining result of the duodenal papilla for IgG4, and have focal pancreatic swelling have better chance of spontaneous remission. On the other hand, patients with diffuse pancreatic swelling and AIP have an increased risk of relapse [26]. Another study concluded that substitution of aspartic acid to nonaspartic acid at HLA-DQβ157 correlated with higher relapse rates [27]. When pancreatic failure occurs, appropriate treatment must be provided. Our patient presented with cholestatic signs, pruritus, weight loss, and diabetes mellitus. He had an enlarged pancreatic head, dilated biliary tract, and a normal IgG4 level, although his total γ-globulin level was diminished. Histopathology demonstrated interstitial fibrosis and a dense periductal lymphoplasmocytic infiltration. The patient responded well to prednisone treatment, as manifested by an improvement of laboratory values, and rapid relief of symptoms, although he still requires continuous insulin treatment by NPH for diabetes. Although the patient did not present with an elevated IgG4 level or Wirsung's duct pathology, he most likely had AIP because he had 7 of the 11 characteristics proposed by Yoshida et al [28]: (1) diffuse pancreas enlargement, (2) fibrotic changes with lymphoplasmocytic infiltration, (3) absence of symptoms of acute pancreatitis, (4) constriction of common bile duct with proximal dilatation, (5) no pancreatic calcification, (6) no pancreatic cyst, and (7) effective steroid therapy. The characteristics that were not met in this case were the following: (1) increased IgG levels, (2) presence of antibodies, (3) diffuse narrowing of the main pancreatic duct on ERCP (although we did not perform this test, MRI was negative), and (4) no association with other autoimmune diseases. The presentation and evolution of this case did not differ much from an adult case, but to our knowledge, this is the youngest patient who had AIP and the only pediatric case reported in the literature.
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Acknowledgment The authors thank D Navacchia, MD, for the pictures of the anatomical pathologic samples and A Palti, LLM, for helping in the translation of the manuscript.
References [1] Okazaki K, Uchida K, Chiba T. Recent concept of autoimmune-related pancreatitis. J Gastroenterol 2001;36:293. [2] Takahashi N, Kawashima A, Fletcher JG, et al. Renal involvement in patients with autoimmune pancreatitis: CT and MR imaging findings. Radiology 2007;242(3):791-801. [3] Khalili K, Doyle DJ, Chawla TP, et al. Renal cortical lesions in patients with autoimmune pancreatitis: a clue to differentiation from pancreatic malignancy. Eur J Radiol 2007 [Epub ahead of print]. [4] Günter K, Jutta L, Matthias L, et al. Autoimmune pancreatitis: pathological, clinical, and immunological features. Pancreas 2003;27 (1):14-9. [5] Wolfson D, Barkin J, Chari S, et al. Management of pancreatic masses. Pancreas 2005;31(3):203-17. [6] Takahiro N, Hirotaka O, Hitoshi S, et al. Clinical differences between primary sclerosing cholangitis and sclerosing cholangitis with autoimmune pancreatitis. Pancreas 2005;30:20-5. [7] Deshpande V, Mino-Kenudson M, Brugge W, et al. Autoimmune pancreatitis: more than just a pancreatic disease? A contemporary review of its pathology. Arch Pathol Lab Medicine 2005;129(9): 1148-54. [8] Takahiro N, Hirotaka O, Hitoshi S, et al. Cholangiography can discriminate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis. Gastrointest Endosc 2004;60(6): 937-44. [9] Shimoda M, Kubota K, Sawada T, et al. Autoimmune pancreatitis diagnosed on the basis of immunohistology alone. A case report. JOP 2006 10;7(5):478-81. [10] Takahashi N, Fletcher JG, Fidler JL, et al. Dual phase CT of autoimmune pancreatitis a multireader study. AJR Am J Roentgenol 2008;190(2):280-6. [11] Kamisawa T, Chen PY, Tu Y, et al. MRCP and MRI findings in 9 patients with autoimmune pancreatitis. World J Gastroenterol 2006;4 (12(18)):2919-22. [12] Kamisawa T, Okamoto A, Funata N. Clinicopathological features of autoimmune pancreatitis in relation of elevation of serum Ig G4. Pancreas 2005;31:28-31.
J. Blejter et al. [13] Raina A, Krasinskas AM, Greer JB, et al. Serum immunoglobulin G fraction 4 levels in pancreatic cancer elevations not associated with autoimmune pancreatitis. Arch Pathol Lab Med 2008;132(1):48-53. [14] Ghazale A, Chari ST, Smyrk TC, et al. Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer. Am J Gastroenterol 2007;102(8):1646-53. [15] Hideaki H, Shigeyuki K, Akira H, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001;344:732-8. [16] Dooreck B, Katz P, Barkin J. Autoimmune pancreatitis in the spectrum of autoimmune exocrinopathy associated with sialoadenitis and anosmia. Pancreas 2004;28(1):105-7. [17] Hirotaka O, Takahiro N, Hitoshi S, et al. Systemic extrapancreatic lesions associated with autoimmune pancreatitis. Pancreas 2005;31: 232-7. [18] Cartmell M, Cusick E, Ashworth M, et al. Idiopathic fibrosing pancreatitis and spontaneous resolution of pancreatic masses in children. Pediatr Surg Int 2007;23(9):897-901. [19] Hideaki H, Shigeyuki K, Takeshi U. Immunoglobulin G4-related lymphoplasmacytic sclerosing cholangitis that mimics infiltrating hilar cholangiocarcinoma: part of a spectrum of autoimmune pancreatitis? Gastrointest Endosc 2005;62(1):152-7. [20] Levy MJ, Reddy RP, Wiersema MJ, et al. EUS guided trucut biopsy in establishing autoimmune pancreatitis as the cause of obstructive jaundice. Gastrointest Endosc 2005;61(3):467-72. [21] Bang SJ, Kim MH, Kim do H, et al. Is pancreatic core biopsy sufficient to diagnose autoimmune chronic pancreatitis? Páncreas 2008;36(1): 84-9. [22] Pearson R, Longnecker D, Chari S, et al. Controversies in clinical pancreatology. Pancreas 2003;27(1):1-13. [23] Wakabayashi T, Kawaura Y, Satomura Y, et al. Long-term prognosis of duct-narrowing chronic pancreatitis: strategy for steroid treatment. Pancreas 2005;30(1):31-9. [24] Takeshi S, Shigeki T, Hitoshi Y, et al. A case of autoimmune pancreatitis responding to steroid therapy evidence of histologic recovery. Pancreatology 2002;2:550-6. [25] Ioannis G, Ketikoglou, Ioannis S, et al. Diabetes mellitus responsive to corticosteroids in autoimmune pancreatitis. J Clin Gastroenterol 2004; 38(10):910. [26] Kubota K, Iida H, Fujisawa T, et al. Clinical factors predictive of spontaneous remission or relapse in cases of autoimmune pancreatitis. Gastrointest Endosc 2007;66(6):1142-51. [27] Park DH, Kim MH, Oh HB, et al. Substitution of aspartic acid at position 57 of the DQbeta1 affects relapse of autoimmune pancreatitis. Gastroenterology 2007 [electronic publication ahead of print]. [28] Yoshida K, Toki F, Takeuchi T, et al. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci 1995;40:1561-8.
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Autoimmune pancreatitis: an adolescent case and review of literature Javier Blejter⁎, Santiago Weller, Rosina Pace, Humberto Cusumano, Daniel Giambini Pediatric Surgery Service, Pedro de Elizalde Hospital, Buenos Aires, Argentina Received 20 November 2007; revised 13 February 2008; accepted 19 February 2008
Key words: Pancreatitis; Autoimmune; Chronic; Idiopathic
Abstract We present a case of a 16-year-old adolescent boy with autoimmune pancreatitis and a review of the related literature.The patient was sent from a peripheral medical center, presenting with jaundice, pruritus, weight loss, and hyperglycemia of 20 days' duration. At admission, the patient was icteric, choluric, and acholic. His abdomen was soft and nontender, and the patient felt no pain in his abdomen. He had skin lesions because of scratching. Laboratory findings showed a blood glucose level of 135 mg%; total serum bilirubin, 29.4 mg%; direct bilirubin, 23 mg%; and alkaline phosphatase, 1100 IU/L. Abdominal ultrasound showed an enlarged head of the pancreas that was 30 × 35 mm. The parenchyma was slightly heterogeneous. Abdominal computed tomography showed an enlarged head of the pancreas with a normal body and tail, thickened duodenal wall, and dilated intra- and extrahepatic biliary tract, and the distal choledochus was not visible. Magnetic resonance imaging showed dilated intra- and extrahepatic biliary tract. The choledochus was not visible, and the cystic duct ended abruptly. The pancreas head was enlarged and homogenous, and there were no changes with contrast. Wirsung's duct was not dilated. Laparotomy was performed with a presumed diagnosis of pancreatic head tumor. The pancreas was diffusely indurated and enlarged; biopsy and intraoperative cholangiography were performed. The biliary tract was dilated with no duodenal passage of contrast, and the Wirsung's duct was not observed. Cholecystectomy was performed, and a transcystic drain was positioned. The histopathology was compatible with autoimmune pancreatitis. Prednisone treatment was started with good response. Autoimmune pancreatitis is a very rare entity among children and adolescents. It should be suspected when characteristic clinical signs and radiographic images are associated with a higher level of IgG4. Autoimmune pancreatitis is confirmed by biopsy. Treatment with prednisone often alleviates all the symptoms, as what happened in this case. © 2008 Elsevier Inc. All rights reserved.
Autoimmune pancreatitis (AIP) is a rare syndrome especially in the pediatric and adolescent population. We present a case of a 16-year-old adolescent boy who was admitted with cholestatic syndrome, including pruritus and
⁎ Corresponding author. Tel.: +54 01115 55927015; fax: +54 0114 857 0546. E-mail address: [email protected] (J. Blejter). 0022-3468/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2008.02.064
weight loss of 20 days' duration. We accompany our presentation with a literature review.
1. Methods We reviewed the patient's chart and researched the related literature using the following key words: pancreatitis, autoimmune, chronic, and idiopathic.
Autoimmune pancreatitis
1369
2. Case 2.1. Case report A 16-year-old adolescent boy was transferred to our facility with a 20-day history of cholestatic syndrome, pruritus, and weight loss of 10 kg. Personal and family history was not available. At admission, the patient was icteric, acholic, and choluric. He had scratches on the abdomen and legs related to itching. His abdomen was soft and nontender, and he felt no pain in his abdomen. His laboratory results on the day of admission were as follows: blood glucose, 135 mg%; total serum bilirubin, 29.4 mg%; direct bilirubin (DB), 23 mg%; alkaline phosphatase, 1100 IU/L; aspartate amini transferase (AST), 110 IU/L; alanine amino tranferase (ALT), 160 IU/L; 5′ nucleotidase, 36.5 IU/L; serum amylase and lipase levels, normal. Abdominal ultrasound showed an enlarged pancreatic head (30 × 35 mm). The parenchyma was slightly heterogeneous. Abdominal computed tomography (CT) (Fig. 1) showed an enlarged head of the pancreas, thickened duodenal wall, and dilated intra- and extrahepatic biliary tract. The distal choledochus was not visible. The pancreatic body and tail were normal. The liver had a right posterior subcapsular hypodense image without clear boundaries. Magnetic resonance cholangiopancreatography (Fig. 2) showed dilated intra- and extrahepatic biliary tract. The common hepatic duct diameter was 14 mm. The choledochus was not visible, and the cystic duct ended abruptly. The pancreatic head was enlarged but homogeneous. There were no changes with contrast. Wirsung's duct was not dilated. Exploratory laparotomy was performed for suspected tumor in the head of the pancreas. The pancreas was diffusely enlarged and indurated. Cholangiography revealed dilated intra- and extrahepatic biliary tract (Fig. 3). There was no duodenal passage of contrast observed, and Wirsung's duct was not seen. Pancreatic biopsy and cholecystectomy were performed, and a transcystic drain was placed.
Fig. 1 Computed tomography (with oral contrast) showing an enlarged pancreatic head compressing the duodenum.
Fig. 2 Magnetic resonance cholangiopancreatography shows intra- and extrahepatic biliary duct dilatation. The distal choledochus and Wirsung's duct are not visible.
The patient began feeding on the seventh postoperative (POP) day. There was up to 700 mL/d of drainage from the transcystic drain, which persisted until prednisone was administered. Subsequent sonograms demonstrated improvement of dilatation, but there was no change in the size of the pancreatic head. Abdominal ultrasound on the 13th POP day demonstrated intrahepatic biliary tract of 6 mm and extrahepatic duct of 9.7 mm; the pancreatic head was 50 × 34 mm. On the 14th POP day, laboratory tests showed improvement of cholestatic parameters: total serum bilirubin, 5.2 mg%; DB, 3.8 mg%; alkaline phosphatase, 480 IU/L; AST, 63 IU/L; ALT, 124 IU/L; amylase, 57 IU/L; and lipase, 12.3 IU/L, although acholia and hyperglycemia were still present. Fecal fat content was normal. On the 15th POP day, a cholangiography showed no changes. Transcystic drainage remained unchanged. A POP gastrointestinal contrast study showed slight dilatation of the duodenal bulb, unorganized folds in the second portion of the duodenum, and good passage of contrast material. Histopathology showed chronic pancreatitis with interstitial periductal lymphoplasmocytic infiltration. Immunosuppressant treatment with prednisone (40 mg/kg per day) was started 1 month after surgery. The condition of the patient with acholia improved, and his transcystic drainage progressively diminished. Hyperglycemia persisted; diabetes mellitus secondary to AIP was diagnosed and subsequently controlled by NPH insulin. Cholangiography on the 50th POP day (Fig. 4) showed good duodenal passage and smaller biliary tract diameter. An ultrasound demonstrated a nondilated biliary tract, and the pancreatic head diameter was 13 mm and appeared homo-
1370
Fig. 3 Intraoperative cholangiography demonstrating intra- and extrahepatic biliary duct dilatation. The distal choledochus and Wirsung's duct are not visible. Contrast does not pass into the duodenum.
J. Blejter et al. the head. Computed tomography scan may also show nodules or diffuse lesions in the cortex of the kidney, and their cause may be because of vasculitis or inflammatory pseudotumor [2,3]. These lesions usually regress with steroid treatment. Abdominal magnetic resonance imaging (MRI) shows the same pattern but has better definition. Endoscopic retrograde cholangiopancreatography (ERCP) usually demonstrates an irregular or narrowed Wirsung's duct as well as biliary tract stenosis at the entrance to the pancreas [4-7]. The possibility of making a differential diagnosis between primary sclerosing cholangitis (SC) and SC (secondary to AIP) using ERCP was studied in a series of 55 patients by Takahiro et al [8]. Their conclusion was that the ERCP findings were useful in differentiating between these 2 pathologies. This was verified by histologic analysis of all the cases. Imaging studies can be misleading and resemble pancreatic tumors as in our case, especially when serologies are negative [9]. However, there may be some findings on dual-phase CT, magnetic resonance cholangiopancreatography, and MRI that may support the diagnosis of AIP, such as “diffusely decreased enhancement of the pancreas, a capsule-like rim, bile duct enhancement, and renal involvement” [10] on the CT
geneous. In view of the above findings, the transcystic drain was closed. IgG4 level was normal (the patient was hypogammaglobulinemic), and autoimmune tracing serologies were negative. At discharge, the patient was anicteric and choluric, and feces were normal. A cholangiogram showed normal passage of contrast into the duodenum and normal biliary tract diameter. Then the drain was removed. Prednisone treatment was successfully tapered off; however, the patient still requires NPH insulin treatment of diabetes.
3. Discussion Autoimmune pancreatitis is a rare entity in the pediatric population, and its etiology is unknown. The signs and symptoms of AIP are variable. Jaundice, choluria, and acholia are present in 70% to 80% [1] of the patients. Mild to moderate pain usually located in the epigastrium or back, weight loss, and/or diabetes mellitus can also be present. Cholestasis caused by obstruction of the common bile duct is a characteristic of AIP. Ultrasound usually shows intraand extrahepatic biliary tract dilatation, sometimes with thickened walls. The pancreas is generally enlarged, heterogeneous, and hypoechoic [2]. Abdominal CT findings are similar and, in addition, sometimes demonstrate irregularities in the diameter of Wirsung's duct. Delayed contrast enhancement of pancreatic parenchyma and spherical hypodense areas are also frequently noted. In most cases, the enlargement of the pancreas is generalized, although there can be focal enlargements located mostly in
Fig. 4 Cholangiography on the 50th POP day shows improvement of biliary tract dilatation and contrast passing into the duodenum.
Autoimmune pancreatitis and “abnormal signal intensity on T1- and T2-weighted magnetic resonance images” [11] on the magnetic resonance cholangiopancreatography (MCP) and MRI. Hyperbilirubinemia with predominance of DB is the most prevalent finding. Hypergammaglobulinemia with elevated levels of IgG4 is also present in 68% of the cases [12], especially if AIP is associated with another autoimmune disorder. Thus, when IgG4 levels are elevated, autoimmune serologies must be performed, with positive results expected in 22% to 45% of cases. Kamisawa et al [12] also suggest that low IgG4 levels (b128 mg/dL) correlates closely with localized pancreas disease; when levels are high (N150 mg/dL), the disease may involve other organs as well. However, mild elevations of IgG4 levels were also seen in patients with pancreatic cancer, suggesting that those patients deserve further evaluation before assuming they have AIP [13,14]. In another study [15], IgG4 levels and immune complexes of IgG4 were measured before and after 4 weeks of treatment with prednisone. Statistically, significant lower IgG4 levels were found after treatment, suggesting that these complexes could be involved in the physiopathology of AIP. Autoimmune pancreatitis can be associated (as stated above) with other autoimmune pathologies such as Sjögren syndrome (the most prevalent), SC, inflammatory bowel disease, autoimmune thrombocytopenic purpura, retroperitoneal fibrosis, and Hashimoto thyroiditis [4,10,16,17]. Autoimmune pancreatitis can begin as SC. Unlike primary SC, AIP appears earlier in life, with obstructive jaundice and pancreatic abnormalities; IgG4 level can be elevated, and there is a good response to prednisone therapy [3]. Another entity, idiopathic fibrosing pancreatitis, unlike AIP, usually presents with jaundice because of obstruction and abdominal pain; however, the pathologic hallmark is fibrosis rather than lymphoplasmocytic infiltration as is the case in AIP. There are no reports associating idiopathic fibrosing pancreatitis to autoimmune diseases, although some AIP cases are also without such association [18]. Because the presentation of AIP is so variable and its signs and symptoms can be confused with malignancy, studies were initiated to find out whether CT or ultrasoundguided biopsies could help avoid unnecessary surgery. These procedures can theoretically differentiate pancreatic carcinoma from AIP; however, their sensitivity and specificity are “technical experience” dependent, resulting in a variable rate of false-positive and false-negative results, which often leads to surgery. Furthermore, sometimes, surgery is required to relieve obstructive symptoms [5]. On the other hand, AIP can be difficult to differentiate from biliary tract carcinoma [19], especially when pancreatic changes are not found, leading to unnecessary procedures when a biopsy would have been sufficient for diagnosis [20,21]. The characteristic pathologic findings are lymphoplasmocytic infiltrate (mostly CD8- and CD4-positive lymphocytes) and pericanalicular fibrosis. Positive IgG4 is also frequently
1371 found. In some cases, among the CD4 cell population, Th1 type predominates over Th2, for example, in Sjögren syndrome. CD4 carrying HLA-DRB1*04/05 or DQB1*04/ 01 has been found in pancreatic tissue and blood tests in patients with AIP. These findings confirm an autoimmune basis for this disease [4,22]. The treatment of choice for AIP is steroid administration. Normally, patients respond well to this plan of treatment. Sometimes, in patients with associated autoimmune diseases or elevated levels of IgG4, it is necessary to continue prednisone therapy for a long period [23]. In most cases, 4 weeks of treatment improve symptoms and laboratory values. There was one case with histologic improvement [24] under this same treatment and another case with improvement in the state of diabetes mellitus [25]. Patients who are seronegative for IgG4, have no obstructive jaundice, are not diabetic, have no swelling of the duodenal papilla, have a negative staining result of the duodenal papilla for IgG4, and have focal pancreatic swelling have better chance of spontaneous remission. On the other hand, patients with diffuse pancreatic swelling and AIP have an increased risk of relapse [26]. Another study concluded that substitution of aspartic acid to nonaspartic acid at HLA-DQβ157 correlated with higher relapse rates [27]. When pancreatic failure occurs, appropriate treatment must be provided. Our patient presented with cholestatic signs, pruritus, weight loss, and diabetes mellitus. He had an enlarged pancreatic head, dilated biliary tract, and a normal IgG4 level, although his total γ-globulin level was diminished. Histopathology demonstrated interstitial fibrosis and a dense periductal lymphoplasmocytic infiltration. The patient responded well to prednisone treatment, as manifested by an improvement of laboratory values, and rapid relief of symptoms, although he still requires continuous insulin treatment by NPH for diabetes. Although the patient did not present with an elevated IgG4 level or Wirsung's duct pathology, he most likely had AIP because he had 7 of the 11 characteristics proposed by Yoshida et al [28]: (1) diffuse pancreas enlargement, (2) fibrotic changes with lymphoplasmocytic infiltration, (3) absence of symptoms of acute pancreatitis, (4) constriction of common bile duct with proximal dilatation, (5) no pancreatic calcification, (6) no pancreatic cyst, and (7) effective steroid therapy. The characteristics that were not met in this case were the following: (1) increased IgG levels, (2) presence of antibodies, (3) diffuse narrowing of the main pancreatic duct on ERCP (although we did not perform this test, MRI was negative), and (4) no association with other autoimmune diseases. The presentation and evolution of this case did not differ much from an adult case, but to our knowledge, this is the youngest patient who had AIP and the only pediatric case reported in the literature.
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Acknowledgment The authors thank D Navacchia, MD, for the pictures of the anatomical pathologic samples and A Palti, LLM, for helping in the translation of the manuscript.
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