Clinical characteristics of autoimmune pancreatitis with IgG4 related kidney disease.

PURPOSE: To clarify the clinical characteristics of autoimmune pancreatitis (AIP) in immunoglobulin (Ig)G4-related kidney disease (IgG4-RKD). PATIENTS AND METHODS: A total of 92 patients with AIP were divided into an IgG4-RKD-positive group (RKD-P group, n = 13) and an IgG4-RKD-negative group (RKD-N group, n = 79) on the basis of the diagnostic criteria for IgG4-RKD. Clinical characteristics, including: age; sex; the presence of extrapancreatic lesions other than renal lesions, proteinuria, and hematuria; serum concentrations of IgG, IgG4, IgE, and creatinine; and urinary concentrations of liver-type fatty acid binding protein, α1-microglobulin, ß2-microglobulin, and N-acetyl-ß-d-glucosaminidase were compared between the RKD-P and RKD-N groups. The clinical course of the RKD-P group was also characterized. RESULTS: The prevalence of extrapancreatic lesions other than renal lesions was significantly higher in the RKD-P group (84.6% vs 43.0%,p < 0.01). Serum creatinine (1.19 mg/dl versus 0.74 mg/dl, p < 0.05), urinary ß2-microglobulin (6609.8 µg/l vs 265.8 µg/l, p < 0.05), and the prevalence of proteinuria (30.7% vs 7.6%, p < 0.05) were significantly higher in the RKD-P group. Nine out of thirteen patients in the RKD-P group had multiple low-density renal lesions on enhanced computed tomography, 3 patients had multiple high-intensity lesions on diffusion-weighted magnetic resonance images, and 1 patient had diffuse thickening of the renal wall, with a smooth intra-luminal surface. CONCLUSIONS: Patients who had AIP with IgG4-RKD were more likely to have extrapancreatic lesions other than those in the kidney, and their serum creatinine and urinary ß2-microglobulin concentrations were significantly higher than in those without IgG4-RKD.

Hypothyroidism in patients with autoimmune pancreatitis.

AIM: To examine thyroid function and clinical features of hypothyroidism in autoimmune pancreatitis (AIP) patients. METHODS: We examined thyroid function in 77 patients with type 1 AIP (50 males, 27 females; median age 68 years, range 33-85) diagnosed according to the Japanese diagnostic criteria for AIP 2011. We compared clinical and serological findings between patients with and without various categories of hypothyroidism. The change in hypothyroidism after steroid therapy was also examined. RESULTS: Eight patients (10%) had hypothyroidism of 6 patients had subclinical hypothyroidism with a normal serum free thyroxine (FT4) and high thyroid stimulating hormone (TSH) level, and 2 patients had central hypothyroidism with low serum free triiodothyronine (FT3), FT4 and TSH levels. A significant goiter of the thyroid was not observed in any patient. There were no significant differences in age; male to female ratio; serum concentrations of IgG and IgG4-related disease (IgG4-RD); presence of anti-thyroglobulin antibody, antinuclear antigen or rheumatoid factor; or presence of extrapancreatic lesions between the 6 patients with subclinical hypothyroidism and patients with euthyroidism. After steroid therapy, both subclinical and central hypothyroidism improved with improvement of the AIP. CONCLUSION: Hypothyroidism was observed in 8 (10%) of 77 AIP patients and was subclinical in 6 patients and central in 2 patients. Further studies are necessary to clarify whether this subclinical hypothyroidism is another manifestation of IgG4-RD.

Tumor development in Japanese patients with Lynch syndrome.

BACKGROUND: Lynch syndrome (LS) patients have a high risk of developing various tumors. This study aimed to clarify the characteristics of tumors developing in LS patients. METHODS: This is a retrospective review of 55 LS patients treated at Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital. RESULTS: The median age at the diagnosis of the first malignant tumor and first LS-related tumor was 44 (range, 19-65) and 44 (range, 24-66) years, respectively. Of the 55 LS patients with developing malignant tumors, 45 (93.8%) developed an LS-related tumor as the first malignant tumor. Colorectal cancer (CRC) developed in 47 patients (85.4%), followed by endometrial cancer (n = 13, 56.5%) in females and gastric cancer (n = 10, 18.1%). In 6 gastric cancer patients, Helicobacter pylori was detected in resected specimens. Twenty-nine patients (52.7%) developed CRC and extra-colonic tumors; of these, 15 patients (48.3%) had mutations in MLH1, 10 (58.8%) in MSH2, and 4 (57.1%) in MSH6. At the age of 50, the cumulative incidence was 50.9% [95% confidence interval (CI), 36.9-63.3%] for CRC, 17.4% (95% CI, 5.2-35.6%) for endometrial cancer, and 5.5% (95% CI, 1.4-13.8%) for gastric cancer. Eight gastric cancer, one breast cancer patient, five bladder cancer patients, and one prostate cancer patient demonstrated loss of expression of the mismatch repair (MMR) protein; patients with thyroid cancer, spindle cell sarcoma, and giant cell tumors did not demonstrate this. CONCLUSION: Gastric cancer incidence was high in Japanese patients with LS and associated with H. pylori infection. MMR protein deficiency caused the development of malignant tumors in LS patients.

Fracture of a Colonic Self-expandable Metallic Stent in Malignant Colonic Obstruction.

Self-expandable metallic stents (SEMSs) are used for the management of malignant colorectal obstruction. A patient who underwent colonic uncovered SEMS insertion for extraluminal stenosis in the splenic flexure of the transverse colon due to advanced gastric cancer is herein reported. The patient presented with a fracture of the colonic SEMS 494 days after SEMS insertion. Although various complications of stenting have previously been reported, the details of fractures of colonic SEMSs have not yet been reported. Because the improvement in the prognosis for patients who undergo palliative SEMS insertion leads to long-term SEMS placement, diverse complications can thus be expected, and new events like stent fracture are expected to increase in the future.

A case of annular pancreas with Wirsung's duct encircling the duodenum: embryological hypothesis based on cholangiopancreatographic and immunohistochemical findings.

We present a resected case of annular pancreas in which Wirsung's duct encircled the duodenum and continued directly to the main pancreatic duct in the body and tail. Furthermore, Wirsung's duct coursed along the right side of the lower bile duct near the major duodenal papilla. Histologically, the islets of Langerhans in the annular pancreas were irregular in shape and were characterized by a striking abundance of pancreatic polypeptide (PP)-positive cells. The PP-rich area that encircled the duodenum was fused with the PP-poor area in the head of the pancreas. The following embryological hypothesis is proposed. The tip of the ventral pancreatic anlage adhered to the duodenal wall and stretched to form a ring during clockwise rotation. The rotation was incomplete, and the pancreatic duct did not cross over the lower bile duct. Since there was adequate ventral anlage in the lower part of the head of the pancreas, fusion between the ducts of the ventral and dorsal anlagen did not occur. The tip of the ventral anlage overgrew and adhered to the dorsal anlage, and the annular duct fused with the main duct of the dorsal anlage.

A case of pancreaticobiliary maljunction with a connecting duct without a long common channel.

Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic and bile ducts join anatomically outside the duodenal wall, usually forming an abnormally long common channel. In PBM, since the long common channel defeats the effect of the sphincter of Oddi, pancreatobiliary reflux frequently occurs, resulting in high rates of biliary tract cancers. We present the case of a 68-year-old female with advanced gallbladder cancer concomitant with bile duct cancer associated with PBM without biliary dilatation that had an extremely rare configuration showing a connecting duct without a long common channel. Pancreatography in the selectively cannulated main pancreatic duct showed the terminal portion of the common bile duct via an abnormal connecting duct. Cholangiography in the selectively cannulated lower bile duct showed the main and accessory pancreatic ducts via the connecting duct. The bile amylase level was markedly elevated. This case of a rare configuration of PBM with a connecting duct without a long common channel is the first such reported case in the English literature.

Biliary carcinogenesis in pancreaticobiliary maljunction.

Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic and bile ducts join anatomically outside the duodenal wall. Because of the excessive length of the common channel in PBM, sphincter action does not directly affect the pancreaticobiliary junction, which allows pancreatic juice to reflux into the biliary tract. According to the results of a nationwide survey, bile duct and gallbladder cancers were found in 6.9 and 13.4 % of adult patients with congenital biliary dilatation, respectively, and in 3.1 and 37.4 % of those with PBM without biliary dilatation, respectively. Biliary tract cancers develop about 15-20 years earlier in patients with PBM than in individuals without PBM; they sometimes develop as double cancers. Carcinogenesis is strongly associated with stasis of bile intermingled with refluxed pancreatic juice. Epithelial cells in the biliary tract of PBM patients are under constant attack from activated pancreatic enzymes, increased secondary bile acids, or other mutagens. This can result in hyperplastic change with increased cell proliferation activity, and in turn, oncogene and/or tumor suppressor gene mutations in the epithelia, leading to the biliary tract carcinogenesis. The carcinogenesis of biliary tract cancer accompanying PBM is considered to involve a hyperplasia-dysplasia-carcinoma sequence induced by chronic inflammation caused by the reflux of pancreatic juice into the biliary tract, which differs from the adenoma-carcinoma sequence or the de novo carcinogenesis associated with biliary tract cancers in the population without PBM. Patients with a relatively long common channel have a similar, albeit slightly lower, risk for gallbladder cancer compared with PBM patients.

Immune-related pancreatitis secondary to nivolumab in a patient with recurrent lung adenocarcinoma: A case report.

Immune checkpoint inhibitor is a verified standard of care as a second-line chemotherapy for non-small cell lung cancer. Management of immune-related adverse effects (irAEs) is crucial for ensuring patient safety. However, less frequent irAEs may result in complications. Here, we report a patient with recurrent lung adenocarcinoma who was treated with nivolumab and developed immune-related pancreatitis. A 66-year-old Japanese female with recurrent lung adenocarcinoma and metastatic lymph nodes presented with anorexia, vomiting, and back pain on day 18 of two cycles of nivolumab. Laboratory data demonstrated a grade 3 elevation of serum amylase and lipase levels. Initially, no abnormality could be detected on computed tomography (CT), magnetic resonance cholangiopancreatography (MRCP), or the Gallium scan. The patient was treated with high-dose prednisone, resulting in gradual improvement of symptoms and laboratory data. A follow-up MRCP revealed a swollen pancreas and pancreatic inflammation. Immune-related pancreatitis is a rare type of nivolumab-induced irAE that shows no significant changes on radiologic imaging, except for a swollen pancreas on CT, and can be suppressed using high-dose prednisone.

[A case of hemorrhagic cholecystitis associated with Churg-Strauss syndrome].

A woman in her 70s with Churg-Strauss syndrome presented with epigastric pain. She was being treated with steroids at the time of admission. Computed tomography showed swelling of the gallbladder, and percutaneous transhepatic cholangiography revealed bloody secretion. On duodenoscopy, bleeding was observed from the orifice of the major duodenal papilla. Emergency cholecystectomy was performed under a diagnosis of hemorrhagic cholecystitis;intraoperatively, extensive hematoma was detected in the thickened wall of the gallbladder. Subsequent histopathological examination revealed mucosal ulceration with infiltration of inflammatory cells, torn small vessels, and extensive transmural bleeding and abscess formation in the thickened wall of the gallbladder. We considered that the hemorrhagic cholecystitis was induced by either vasculitis or corticosteroid therapy. To the best of our knowledge, this is the first report of hemorrhagic cholecystitis associated with Churg-Strauss syndrome.

A case of IgG4-related mesenteritis.

IgG4-related disease is a newly recognized fibroinflammatory condition characterized by tumefaction consisting of fibrosis with dense infiltration of IgG4-positive plasma cells; affecting various organs. A case of IgG4-related sclerosing mesenteritis is reported. A 64-year-old man was admitted to our hospital with a suspected tumor of the small intestine. Abdominal computed tomography demonstrated a 6-cm soft tissue mass in the right lower mesentery compressing the jejunum, which also showed accumulation of fluorodeoxyglucose uptake on fluorine-18 fluorodeoxyglucose positron emission tomography. With a preoperative diagnosis of suspected malignant lymphoma with lymphadenopathy in the mesentery, partial small bowel resection was performed. Macroscopically, a hard mass, including several swollen lymph nodes, was detected in the mesentery. Microscopically, marked fibrosis showing partially storiform pattern, obstructive phlebitis, follicular hyperplasia, and abundant infiltration of IgG4-positive plasma cells were detected. IgG4-related mesenteritis was diagnosed histopathologically, but the serum IgG4 level was 81 mg/dl postoperatively. Five months after the surgery, an 11-cm soft tissue mass involving the left ureter appeared. Histological examination of a biopsy specimen from the retroperitoneal mass showed fibrosis with inflammatory infiltration. Although IgG4-related retroperitoneal fibrosis could not be confirmed histologically, the tumor responded well to steroid therapy.

Organ Correlation in IgG4-Related Diseases.

IgG4-related disease (IgG4-RD) is a potentially multiorgan disorder. In this study, clinical and serological features from 132 IgG4-RD patients were compared about organ correlations. Underlying pathologies comprised autoimmune pancreatitis (AIP) in 85 cases, IgG4-related sclerosing cholangitis (IgG4-SC) in 12, IgG4-related sialadenitis (IgG4-SIA) in 56, IgG4-related dacryoadenitis (IgG4-DAC) in 38, IgG4-related lymphadenopathy (IgG4-LYM) in 20, IgG4-related retroperitoneal fibrosis (IgG4-RF) in 19, IgG4-related kidney disease (IgG4-KD) in 6, IgG4-related pseudotumor (IgG4-PT) in 3. Sixty-five patients (49%) had multiple IgG4-RD (two affected organs in 36 patients, three in 19, four in 8, five in 1, and six in 1). Serum IgG4 levels were significantly higher with multiple lesions than with a single lesion (P<0.001). The proportion of association with other IgG4-RD was 42% in AIP, the lowest of all IgG4-RDs. Serum IgG4 level was lower in AIP than in other IgG4-RDs. Frequently associated IgG4-RDs were SIA (25%) and DAC (12%) for AIP; AIP (75%) for IgG4-SC; DAC (57%), AIP (38%) and LYM (27%) for IgG4-SIA; AIP (26%) and LYM (26%) for IgG4-DAC; SIA (75%), DAC (50%) and AIP (45%) for IgG4-LYM; SIA (58%), AIP (42%) and LYM (32%) for IgG4-RF; AIP (100%) and SIA (67%) for IgG4-KID; and DAC (67%) and SIA (67%) for IgG4-PT. Most associated IgG4-RD lesions were diagnosed simultaneously, but IgG4-SIA and IgG4-DAC were sometimes identified before other lesions. About half of IgG4-RD patients had multiple IgG4-RD lesions, and some associations were seen between specific organs.

Preoperative detection and handling of aberrant right posterior sectoral hepatic duct during laparoscopic cholecystectomy.

BACKGROUND: An aberrant right posterior sectoral hepatic duct (PHD) draining into extrahepatic bile duct, gallbladder or cystic duct directly is a common and critical anomaly during cholecystectomy. This study aimed to investigate the frequency of aberrant PHD and describe why PHD is critical. METHODS: In 753 consecutive patients who underwent laparoscopic cholecystectomy (LC) using our standardized procedure over 9 years, we reinvestigated whether an aberrant PHD was present using preoperative images. A PHD joining the common bile duct through the cranial side of the hilar plate was defined as the supraportal type, and one passing through the caudal side of the right portal vein was defined as the infraportal type. RESULTS: Fifty-one (6.8%) patients had aberrant PHD. All of them had the infraportal type, and the cystic duct drained into aberrant PHD in 10 (1.3%) and aberrant PHD drained into the cystic duct in six (0.8%). These 16 most dangerous anomalies were diagnosed before surgery. In all patients with aberrant PHD, LC was completed without any complications. CONCLUSIONS: It seems possible to identify most aberrant PHD by attention to the infraportal-type PHD, and injury to them can be avoided by exposing a critical view using an appropriate procedure.

Assessment in steroid trial for IgG4-related sclerosing cholangitis.

PURPOSE: Response to steroids is included in the diagnostic criteria for IgG4-related sclerosing cholangitis (IgG4-SC). To assess how to appropriately conduct steroid trials for IgG4-related SC, we examined the clinical pictures of steroid responsiveness in IgG4-SC patients. MATERIAL AND METHODS: A total of 29 patients with IgG4-SC (lower bile duct involvement, n=29; hilar/intrahepatic bile duct involvement, n=6) initially treated with steroids were enrolled in this study. Blood biochemistry was examined at about 5, 10 and 15 days after commencing steroid therapy. Endoscopic retrograde cholangiography (ERC) and magnetic resonance cholangiopancreatography (MRCP) were performed after steroid administration in 18 and 25 patients, respectively. RESULTS: In 19 patients without biliary drainage, elevated serum levels of total bilirubin, alanine aminotransferase, and alkaline phosphatase were halved in 50%, 25%, and 44% of patients at about 5 days after starting steroids, and in 17%, 38%, and 44% at about 10 days. Responsiveness to steroids could be evaluated at 1-2 weeks on ERC or MRCP, but response was lower in the hilar/intrahepatic bile duct than in the lower bile duct. CONCLUSIONS: Steroid responsiveness of IgG4-SC is recommended to be assessed by blood biochemistry at 5 and 10 days and on MRCP and/or ERC at 1-2 weeks after starting steroid.

[A case of MALT lymphoma of the colon, stomach, and small intestine].

An 85-year-old man was diagnosed with mucosa-associated lymphoid tissue (MALT) lymphoma of the colon in 20XX. Although Helicobacter pylori eradication was performed as part of the treatment, it was ineffective. He was followed-up by colonoscopy for 4 years without additional treatment and there was no interval change;however, he was lost to follow-up 6 years after the first visit. Nine years after the initial diagnosis, he presented with new MALT lymphoma lesions in the stomach and small intestine. Genetic analysis showed that a biopsy specimen was positive for API2/MALT1 fusion gene, and IgH rearrangement showed monoclonal banding between colon and stomach. This suggested disseminated monoclonal API2/MALT1-positive MALT lymphoma of the colon, stomach, and small intestine. Careful attention should be paid to the appearance of multiple lesions in MALT lymphoma.

Characteristic findings of endoscopic retrograde cholangiopancreatography in autoimmune pancreatitis.

BACKGROUND/AIMS: Diffuse or segmental irregular narrowing of the main pancreatic duct (MPD), as observed by endoscopic retrograde cholangiopancreatography (ERCP), is a characteristic feature of autoimmune pancreatitis (AIP). METHODS: ERCP findings were retrospectively examined in 40 patients with AIP in whom irregular narrowing of the MPD was detected near the orifice. The MPD opening sign was defined as the MPD within 1.5 cm from the orifice being maintained. The distal common bile duct (CBD) sign was defined as the distal CBD within 1.5 cm from the orifice being maintained. Endoscopic findings of a swollen major papilla and histological findings of specimens obtained from the major papilla were examined in 26 and 21 patients, respectively. RESULTS: The MPD opening sign was detected in 26 of the 40 patients (65%). The distal CBD sign was detected in 25 of the 32 patients (78%), which showed stenosis of the lower bile duct. The patients who showed the MPD opening sign frequently showed the distal CBD sign (p=0.018). Lymphoplasmacytic infiltration, but not dense fibrosis, was histologically detected in biopsy specimens obtained from the major papilla. CONCLUSIONS: On ERCP, the MPD and CBD adjacent to the major papilla are frequently maintained in patients with AIP involving the pancreatic head. These signs are useful for diagnosing AIP on ERCP. (Gut Liver 2015;9113-117).

Pancreaticobiliary maljunction and biliary cancer.

Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic and bile ducts join anatomically outside the duodenal wall. Japanese clinical practice guidelines on how to deal with PBM were made in 2012, representing a world first. According to the 2013 revision to the diagnostic criteria for PBM, in addition to direct cholangiography, diagnosis can be made by magnetic resonance cholangiopancreatography (MRCP), 3-dimensional drip infusion cholangiography computed tomography, endoscopic ultrasonography (US), or multiplanar reconstruction images by multidetector row computed tomography. In PBM, the common channel is so long that sphincter action does not affect the pancreaticobiliary junction, and pancreatic juice frequently refluxes into the biliary tract. Persistence of refluxed pancreatic juice injures epithelium of the biliary tract and promotes cancer development, resulting in higher rates of carcinogenesis in the biliary tract. In a nationwide survey, biliary cancer was detected in 21.6% of adult patients with congenital biliary dilatation (bile duct cancer, 32.1% vs. gallbladder cancer, 62.3%) and in 42.4% of PBM patients without biliary dilatation (bile duct cancer, 7.3% vs. gallbladder cancer, 88.1%). Pathophysiological conditions due to pancreatobiliary reflux occur in patients with high confluence of pancreaticobiliary ducts, a common channel ≥6 mm long, and occlusion of communication during contraction of the sphincter. Once the diagnosis of PBM is established, immediate prophylactic surgery is recommended. However, the surgical strategy for PBM without biliary dilatation remains controversial. To detect PBM without biliary dilatation early, MRCP is recommended for patients showing gallbladder wall thickening on screening US under suspicion of PBM.

[A case of Lynch syndrome with advanced jejunal cancer].

A woman in her 80s had two episodes of ileus, which led to the diagnosis of advanced jejunal cancer. She was diagnosed with Lynch syndrome when she was in her 60s, for which she underwent annual follow-up with computed tomography for 8 years. Unfortunately, she died from the recurrence of jejunal cancer and liver metastases. Jejunal cancer is relatively rare in Lynch syndrome, and no surveillance strategy has been established for small bowel cancer. In patients with unexplained abdominal complaints, small bowel cancer should be considered.

Major and minor duodenal papillae in autoimmune pancreatitis.

OBJECTIVE: The objective of this study was to evaluate picture of the major and minor duodenal papillae in patients with autoimmune pancreatitis (AIP). METHODS: Endoscopic features of the major and minor papillae were examined in 59 and 13 patients with AIP. After steroid therapy, changes of the major and minor papillae were observed in 5 and 6 patients. The major and minor papillae were observed with narrow band imaging in 24 and 6 patients. Biopsy specimens from the major (n = 50) and minor (n = 13) papillae were immunostained using an anti-IgG4 antibody. RESULTS: Endoscopic features of the major and minor papillae were abnormal in 26 patients (44%; swelling [n = 20] and redness [n = 14]) and 5 patients (38%; swelling [n = 5]). Swelling of the pancreatic head, irregular narrowing of the main pancreatic duct of the pancreatic head, stenosis of the lower bile duct, and abundant infiltration of IgG4-positive plasma cells were more frequent in the patients with an abnormal major papilla compared with those with a normal major papilla. On narrow band imaging, dilated vessels were observed in abnormal papillae. After therapy, swelling of the major and minor papillae improved in all 4 and 2 patients. CONCLUSIONS: Endoscopic features of the major and minor papillae were abnormal in 44% and 38% of the patients with AIP.

Allergen-specific IgE antibody serologic assays in patients with autoimmune pancreatitis.

OBJECTIVE: To clarify the allergic manifestations in patients with autoimmune pancreatitis (AIP). METHODS: We assessed 67 AIP patients, before they received steroid therapy, for a past history of allergic disease, the peripheral eosinophil count (n=62) and the serum IgE level (n=53). Allergen-specific IgE antibody serologic assays were performed in 15 patients. RESULTS: A positive past history and/or the presence of active allergic disease were found in 24 AIP patients (36%), including 15 patients with acute allergic rhinitis and eight patients with bronchial asthma. Peripheral eosinophilia and elevation of the serum IgE level were detected in 16% (10/62) and 60% (32/53) of the patients, respectively. Allergen-specific IgE antibody serologic assays were positive in 13 patients (87%). There were no differences between the assay-positive and -negative patients regarding the clinical profiles. CONCLUSION: In conclusion, 87% of the 15 AIP patients tested had positive allergen-specific IgE antibody serologic assays. Allergic mechanisms may be related to the occurrence of AIP.