Long-term follow-up of autoimmune pancreatitis: characteristics of chronic disease and recurrence.

Autoimmune pancreatitis is a unique disease, characterized by lymphoplasmacytic inflammation in the acute stages. However, the active clinical features are unlikely to persist for long periods. Through long-term follow-up, we investigated the disease course in 51 patients with autoimmune pancreatitis. We found recurrence in 21 (41%) patients and pancreatic stone formation in 9 (18%) patients. Pancreatic stone formation was significantly more frequent in the recurrence group (7/21, 33%), compared with the nonrecurrence group (2/30, 7%). Moreover, we found high serum immunoglobulin G4 concentrations in 13 of 175 (7.4%) patients with ordinary chronic pancreatitis. This suggested that pancreatic stone formation is closely associated with recurrence and that autoimmune pancreatitis might transform into ordinary chronic pancreatitis after several recurrences. We found that the immune complex level, with a cutoff value of 10 microg/dL, served as a good predictor of recurrence, with high sensitivity (61.9%), specificity (70.0%), and efficacy (66.7%). We also confirmed that HLA and cytotoxic T-lymphocyte antigen-4 polymorphisms were useful predictors for AIP recurrence.

Efficacy of preoperative endoscopic nasobiliary drainage for hilar cholangiocarcinoma.

BACKGROUND/PURPOSE: Although percutaneous transhepatic biliary drainage has previously been recommended as a primary preoperative step, endoscopic nasobiliary drainage (ENBD) is prevalent as an alternative procedure. Few reports assess the efficacy and safety of ENBD in a substantial patient cohort. METHODS: Of 116 patients with hilar cholangiocarcinoma who underwent surgery, 62 (43 men and 19 women, median age 69 years) underwent preoperative ENBD. After classification of lesions according to Bismuth-Corlette (B-C) criteria, we evaluated efficacy and safety with respect to B-C type. RESULTS: Patients were classified as B-C types I (n = 5), II (n = 21), IIIa (n = 23), IIIb (n = 5), and IV (n = 8). Preoperative single ENBD was effective in 46/62 patients (74%) including 5/5 (100%) B-C type I, 20/21 (94%) type II, 16/23 (70%) type IIIa, 4/5 (80%) type IIIb, and 1/8 (13%) type IV. Sixteen cases (26%) required additional drainages with ENBD or endoscopic biliary stenting (EBS) in 8/16 (50%), and with PTBD in 8/16 (50%). Mild acute pancreatitis (n = 1, 2%), segmental cholangitis (n = 2, 3%), and acute cholangitis with catheter obstruction (n = 7, 11%) occurred with ENBD. CONCLUSIONS: Preoperative single ENBD in the future remnant lobe is effective treatment for B-C type I-III hilar cholangiocarcinoma. Preoperative ENBD was rarely complicated with segmental cholangitis.

Microsatellite scan identifies new candidate genes for susceptibility to alcoholic chronic pancreatitis in Japanese patients.

Alcohol abuse is one of the most common risk factor for chronic pancreatitis, but the underlying pathophysiological mechanisms remain unclear. The aim of this study was to identify genes that contribute to susceptibility or resistance for alcoholic chronic pancreatitis by screening the whole genome. Sixty-five patients with alcoholic chronic pancreatitis (63 men and 2 women, mean age 55.2 years) and 99 healthy Japanese controls were enrolled in this study. This was an association study using 400 polymorphic microsatellite markers with an average spacing of 10.8 cM distributed throughout the whole genome. This search revealed 10 candidate susceptibility regions and 5 candidate resistant regions throughout the genome. No specific microsatellite markers were detected in association with previously reported susceptibility genes for chronic pancreatitis, such as PRSS1, PRSS2, CTRC, SPINK1, CFTR, ALDH2, and CYP2E1. Among the statistically significant markers, D15S1007 on chromosome 15q14 showed strong evidence for disease susceptibility (70.8% vs. 35.1%, Pc = 0.0001). Within 500 kb of D15S1007, several genes were candidate genes for susceptibility, including FMN1, DKFZP686C2281, LOC440268, RYR3, and AVEN, This study identified 10 candidate susceptibility and 5 candidate resistant regions that may contain genes involved in ACP pathogenesis.

Differentiation of autoimmune pancreatitis from suspected pancreatic cancer by fluorine-18 fluorodeoxyglucose positron emission tomography.

BACKGROUND: Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has been widely used for the diagnosis of pancreatic cancer. Because autoimmune pancreatitis is easily misdiagnosed as pancreatic cancer and can be tested for by FDG-PET analysis based on the presence of suspected pancreatic cancer, we attempted to clarify the differences in FDG-PET findings between the two conditions. METHODS: We compared FDG-PET findings between 15 patients with autoimmune pancreatitis and 26 patients with pancreatic cancer. The findings were evaluated visually or semiquantitatively using the maximum standardized uptake value and the accumulation pattern of FDG. RESULTS: FDG uptake was found in all 15 patients with autoimmune pancreatitis, whereas it was found in 19 of 26 patients (73.1%) with pancreatic cancer. An accumulation pattern characterized by nodular shapes was significantly more frequent in pancreatic cancer, whereas a longitudinal shape indicated autoimmune pancreatitis. Heterogeneous accumulation was found in almost all cases of autoimmune pancreatitis, whereas homogeneous accumulation was found in pancreatic cancer. Significantly more cases of pancreatic cancer showed solitary localization, whereas multiple localization in the pancreas favored the presence of autoimmune pancreatitis. FDG uptake by the hilar lymph node was significantly more frequent in autoimmune pancreatitis than in pancreatic cancer, and uptake by the lachrymal gland, salivary gland, biliary duct, retroperitoneal space, and prostate were seen only in autoimmune pancreatitis. CONCLUSIONS: FDG-PET is a useful tool for differentiating autoimmune pancreatitis from suspected pancreatic cancer, if the accumulation pattern and extrapancreatic involvement are considered. IgG4 measurement and other current image tests can further confirm the diagnosis.

Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis.

BACKGROUND: Autoimmune pancreatitis is a unique form of chronic pancreatitis characterized by high serum IgG4 concentrations and abundant IgG4-bearing plasma cell infiltration in the pancreatic lesion, and it has been reported to be associated with a variety of extrapancreatic lesions, leading us to postulate the concept of a systemic inflammatory disease. To confirm this, we clarified the exact distribution of these extrapancreatic lesions and provide a panoramic view of them. METHODS: The frequency, distribution, clinical characteristics, and pathology of five extrapancreatic lesions were determined in 64 patients with autoimmune pancreatitis by examining clinical and laboratory findings. RESULTS: The most frequent extrapancreatic lesion was hilar lymphadenopathy (80.4%), followed by extrapancreatic bile duct lesions (73.9%), lachrymal and salivary gland lesions (39.1%), hypothyroidism (22.2%), and retroperitoneal fibrosis (12.5%). No patients had all five types of lesions. Patients with hilar lymphadenopathy or lachrymal and salivary gland lesions were found to have significantly higher IgG4 levels than those without (P = 0.0042 and 0.0227, respectively). Patients with three lesions were found to have significantly higher IgG4 levels than those with no lesion, suggesting that patients with multiple extrapancreatic lesions have active disease. Similar to pancreatic lesions, extrapancreatic lesions have a characteristic histological finding of abundant IgG4-bearing plasma cell infiltration, and they respond favorably to corticosteroid therapy. CONCLUSIONS: Autoimmune pancreatitis was recognized as a systemic inflammatory disease. Furthermore, recognition of these characteristic findings will aid in the correct diagnosis of this disease.

Autoimmune pancreatitis can develop into chronic pancreatitis.

Autoimmune pancreatitis (AIP) has been recognized as a distinct type of pancreatitis that is possibly caused by autoimmune mechanisms. AIP is characterized by high serum IgG4 and IgG4-positive plasma cell infiltration in affected pancreatic tissue. Acute phase AIP responds favorably to corticosteroid therapy and results in the amelioration of clinical findings. However, the long-term prognosis and outcome of AIP remain unclear. We have proposed a working hypothesis that AIP can develop into ordinary chronic pancreatitis resembling alcoholic pancreatitis over a long-term course based on several clinical findings, most notably frequent pancreatic stone formation. In this review article, we describe a series of study results to confirm our hypothesis and clarify that: 1) pancreatic calcification in AIP is closely associated with disease recurrence; 2) advanced stage AIP might have earlier been included in ordinary chronic pancreatitis; 3) approximately 40% of AIP patients experience pancreatic stone formation over a long-term course, for which a primary risk factor is narrowing of both Wirsung's and Santorini's ducts; and 4) nearly 20% of AIP patients progress to confirmed chronic pancreatitis according to the revised Japanese Clinical Diagnostic Criteria, with independent risk factors being pancreatic head swelling and non-narrowing of the pancreatic body duct.

Type 1 autoimmune pancreatitis can transform into chronic pancreatitis: a long-term follow-up study of 73 Japanese patients.

Some patients with autoimmune pancreatitis (AIP) form pancreatic stones suggestive of transformation into chronic pancreatitis (CP). The present study examined the underlying risk factors and mechanism of AIP progression to confirmed CP. We compared the clinical and laboratory parameters of subjects who progressed to confirmed CP with those of the subjucts who did not in a cohort of 73 type 1 AIP patients. A total of 16 (22%) AIP patients progressed to CP. Univariate analysis revealed that relapse was significantly more frequent in the progression group, and multivariate analysis indicated that pancreatic head swelling (OR 12.7, P = 0.023) and nonnarrowing of the main pancreatic duct in the pancreatic body (OR 12.6, P = 0.001) were significant independent risk factors for progression to CP. Kaplan-Meier testing showed that the progression rate to CP was approximately 10% at 3 years and 30% at 10 years in total AIP patients and 30% at 3 years and 60% at 10 years in subjects with both risk factors. AIP with pancreatic head swelling and a history of relapse may cause pancreatic juice stagnation and nonnarrowing of the main pancreatic duct in the pancreatic body, which can progress to advanced stage chronic pancreatitis.

Risk factors for pancreatic stone formation in autoimmune pancreatitis over a long-term course.

BACKGROUND: Autoimmune pancreatitis (AIP) has the potential to progress to a chronic state that forms pancreatic stones. The aim of this study was to clarify the risk factors underlying pancreatic stone formation in AIP. METHODS: Sixty-nine patients with AIP who had been followed for at least 3 years were enrolled for evaluation of clinical and laboratory factors as well as computed tomography and endoscopic retrograde cholangiopancreatography findings. RESULTS: During the course of this study, increased or de novo stone formation was seen in 28 patients, who were defined as the stone-forming group. No stones were observed in 32 patients, who were defined as the non-stone-forming group. Nine patients who had stones at diagnosis but showed no change during the course of this study were excluded from our cohort. Univariate analysis revealed no significant differences in clinical or laboratory factors associated with AIP-specific inflammation between the two groups. However, pancreatic head swelling (P = 0.006) and narrowing of both Wirsung's and Santorini's ducts in the pancreatic head region (P = 0.010) were significantly more frequent in the stone-forming group. Furthermore, multivariate analysis identified Wirsung and Santorini duct narrowing at diagnosis as a significant independent risk factor for pancreatic stone formation (OR 4.4, P = 0.019). CONCLUSIONS: A primary risk factor for pancreatic stone formation in AIP was narrowing of both Wirsung's and Santorini's ducts, which most presumably led to pancreatic juice stasis and stone development.

[A case of unilocular serous cystic neoplasm mimicking mucinous cystic neoplasm].

A 40's woman had a cystic lesion in the tail of the pancreas that had grown over a 1.5-year period. Endoscopic ultrasound revealed a partition structure and "cyst-in-cyst" like lesion, and a diagnosis of mucinous cystic neoplasm was made. The patient underwent distal pancreatectomy with splenectomy. Following histological examination, our final diagnosis was revised to unilocular serous cystic neoplasm since the increase in cysts was due to hemorrhage and the partition structure was in fact granulation tissue. We here discuss this rare case with reference to previous published reports.

Pancreaticobiliary fistula evident after ESWL treatment of pancreatolithiasis.

Here we report a patient with a pancreaticobiliary fistula that was possibly associated with pancreatolithiasis. He was admitted due to mild pancreatitis. Pancreatolithiasis was revealed in the parenchyma of the head region and in the main pancreatic duct of the pancreas body with distal dilatation. Extracorporeal shock wave lithotripsy (ESWL) effectively eliminated the pancreatic stones; however, an apparent internal fistula from the middle portion of the common bile duct (CBD) to the main pancreatic duct was revealed where the parenchymal stones had been located. The patient was considered to be in the same condition as pancreato-biliary malunion without CBD dilatation, and was treated with laparoscopic cholecystectomy.

Abscess of the round ligament of the liver associated with acute obstructive cholangitis and septic thrombosis.

A man with abscess of the round ligament of the liver associated with acute obstructive suppurative cholangitis and portal thrombosis is reported. A 63-year-old man was admitted with epigastralgia and high fever. Blood tests showed elevation of hepato-biliary enzymes and coagulopathy consistent with acute obstructive suppurative cholangitis and disseminated intravascular coagulation. Computed tomography revealed a small abscess of the round ligament of the liver and left portal thrombosis. After endoscopic biliary stenting, antibiotics and thrombolytic therapy, the high fever, disseminated intravascular coagulation and portal thrombosis rapidly improved, and the round ligament abscess was also later resolved.

Pancreaticobiliary fistula associated with pancreatolithiasis.

We report here a case of pancreaticobiliary fistula associated with pancreatolithiasis. A 47-year-old female without a habit of alcohol drinking was admitted by her family physician after suffering from mild acute pancreatitis. Computed tomography revealed mild acute pancreatitis with pancreatolithiasis at the head of the pancreas. The pancreatolithiasis was exposed to the inner surface of the common bile duct and possibly compressed and narrowed the Wirsung and Santorini ducts, resulting in the pancreatitis attack. We used extracorporeal shock wave lithotripsy to treat the pancreatolithiasis. After complete elimination of stones by extracorporeal shock wave lithotripsy, endoscopic retrograde cholangiography showed an apparent pancreaticobiliary fistula between a branch of the Santorini duct and the lower portion of the common bile duct. There was no communication between the bile duct and the Wirsung duct or its branches; therefore, the diagnosis was not pancreaticobiliary maljunction. There have only been a few reports of pancreaticobiliary fistula without an association with pancreatic pseudocysts or intraductal papillary-mucinous pancreatic neoplasm, and there have only been few reports of pancreaticobiliary fistula with pancreatolithiasis.

Small cell carcinoma of the extrahepatic bile duct diagnosed with EUS-FNA and effectively treated with chemoradiation.

Small cell carcinoma of the bile duct system is extremely rare, and surgical procedures have been complicated by early hematogenous dissemination. In this study, we report a patient with small cell carcinoma of the bile duct system presenting with jaundice. The diagnosis was made early by endoscopic ultrasonography-guided fine needle aspiration biopsy (EUS-FNA). We performed radiation therapy of a total of 30 Gy, resulting in a marked decrease of serum neuron specific enolase levels and amelioration of jaundice, which had been resistant to drainage procedures. The patient was then treated with combined chemotherapy of cisplatin and CPT-11, which resulted in the disappearance of the tumor mass by image tests.

A novel immunoglobulin-immunoglobulin interaction in autoimmunity.

Well over six decades since its first description, the Rheumatoid Factor (RF)-autoantibodies recognizing Fc (constant) portion of IgG through their own Fab (antigen binding variable segments)-is believed to have come of age. Autoimmune pancreatitis is a unique form of pancreatitis, biologically characterized by an elevated serum IgG4 concentration. Given the fact that IgG4 myeloma proteins can act as RF, we initially hypothesized that IgG4 in autoimmune pancreatitis might do likewise, hence potentially contributing to disease pathogenesis. Indeed Western blotting clearly showed that IgG4 binds to IgG1 kappa, IgG2 kappa, IgG3 kappa myeloma proteins, as well as to IgG Fc, in line with a typical RF activity. Further experiments however unraveled the unexpected fact that unlike hitherto known RF, IgG4 does not engage IgG Fc through its Fab, but its very own Fc. These data therefore collectively describe a Novel RF (NRF) in autoimmune pancreatitis. In the future, the relevance of NRF, beyond autoimmune pancreatitis, in both diagnosis/prognosis as well as pathophysiology of autoimmune and other systemic diseases where IgG4's role seems paramount, needs to be systematically assessed.

Lymphoproliferative disease of granular lymphocytes with T-cell receptor gamma delta-positive phenotype: restricted usage of T-cell receptor gamma and delta subunit genes.

Lymphoproliferative disease of granular lymphocytes (LDGL) is characterized by more than 0.5 x 109/L of proliferating granular lymphocytes in the peripheral blood. Because of its rarity, the characteristics of LDGL with T-cell receptor (TCR) gammadelta phenotype (gammadeltaT-LDGL) have not yet been identified. This report describes the clinical, hematological, and immunological findings of four patients with this disease. In two cases, the clinical course was indolent and the other two patients required various therapies. The cells had a common immunophenotype: CD3+, CD4-, CD16+, CD56-, CD57-, CD122-, TCR-gammadelta+, and three were CD8-positive. The immunopurified TCR-gammadelta cells from the patients expressed only Vgamma9 and Vdelta1. Spectratyping and sequencing showed mono- or oligoclonality for TCRgamma and TCRdelta subunit genes. Soluble Fas ligand in sera was significantly elevated in all patients. These findings suggest that gammadeltaT-LDGL qualifies as a distinct disease entity.