Pancreatobiliary Maljunction-associated Gallbladder Cancer Is as Common in the West, Shows Distinct Clinicopathologic Characteristics and Offers an Invaluable Model for Anatomy-induced Reflux-associated Physio-chemical Carcinogenesis.

OBJECTIVE: To determine the associations of pancreatobiliary maljunction (PBM) in the West. BACKGROUND: PBM (anomalous union of common bile duct and pancreatic duct) is mostly regarded as an Asian-only disorder, with 200X risk of gallbladder cancer (GBc), attributed to reflux of pancreatic enzymes. Methods: Radiologic images of 840 patients in the US who underwent pancreatobiliary resections were reviewed for PBM and contrasted with 171 GBC cases from Japan. RESULTS: Eight % of the US GBCs (24/300) had PBM (similar to Japan; 15/ 171, 8.8%), in addition to 1/42 bile duct carcinomas and 5/33 choledochal cysts. None of the 30 PBM cases from the US had been diagnosed as PBM in the original work-up. PBM was not found in other pancreatobiliary disorders. Clinicopathologic features of the 39 PBM-associated GBCs (US:24, Japan:15) were similar; however, comparison with non-PBM GBCs revealed that they occurred predominantly in females (F/M = 3); at younger (<50-year-old) age (21% vs 6.5% in non-PBM GBCs; P = 0.01); were uncommonly associated with gallstones (14% vs 58%; P < 0.001); had higher rate of tumor-infiltrating lymphocytes (69% vs 44%; P = 0.04); arose more often through adenoma-carcinoma sequence (31% vs 12%; P = 0.02); and had a higher proportion of nonconventional carcinomas (21% vs 7%; P = 0.03). Conclusions: PBM accounts for 8% of GBCs also in the West but is typically undiagnosed. PBM-GBCs tend to manifest in younger age and often through adenoma-carcinoma sequence, leading to unusual carcinoma types. If PBM is encountered, cholecystectomy and surveillance of bile ducts is warranted. PBM-associated GBCs offer an invaluable model for variant anatomy-induced chemical (reflux-related) carcinogenesis.

Reduced Serum Phosphorus Levels Were Associated with Metabolic Syndrome in Men But Not in Women: A Cross-Sectional Study among the Japanese Population.

BACKGROUND: Reduced serum phosphorus (SP) levels are reported to be associated with insulin resistance and metabolic syndrome (MetS). However, there have been a few gender-specific studies although SP levels are substantially different between men and women. METHODS: This is a cross-sectional study. A total of 16,041 subjects (9,076 men and 6,965 women) were analyzed. The subjects were divided into 3 groups of gender-specific tertiles based on phosphorus levels: the lowest (T1), middle (T2), and the highest (T3). RESULTS: SP levels were significantly lower in subjects with MetS than in those without MetS in men but not in women. Waist circumference and fasting plasma glucose were negatively and high-density lipoprotein cholesterol was positively correlated with SP levels both in men and women. Blood pressure (BP) and triglycerides (TG) were negatively correlated with SP levels in men, while they were positively correlated with SP levels in women. Lower SP levels were associated with the prevalence of MetS in men (T1; 19.9%, T2; 16.9%, and T3; 14.3%; p < 0.001) but not in women (T1; 14.1%, T2; 16.6%, and T3; 15.3%; p = 0.282). CONCLUSION: BP and TG were unexpectedly positively correlated with SP levels in women. Reduced SP levels were associated with MetS in men but not in women.

Fasting Single-Spot Urine pH Is Associated with Metabolic Syndrome in the Japanese Population.

OBJECTIVE: To investigate the relationship between urine pH and metabolic syndrome (MetS) and its components, while controlling for covariates. SUBJECTS AND METHODS: This cross-sectional study was conducted on 5,430 Japanese subjects (4,691 without MetS; 739 with MetS) undergoing health assessments. Partial correlation analysis and analysis of covariance were used for controlling confounding parameters (age, gender, levels of serum uric acid and high-sensitivity C-reactive protein, estimated glomerular filtration rate, and smoking and drinking status). Using multiple logistic regression analyses, adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for MetS incidence were calculated across urine pH categories. Path analysis was used to determine the relationship between MetS and urine pH. RESULTS: Subjects with MetS had significantly lower urine pH (5.9 ± 0.7) than those without MetS (6.0 ± 0.7) (p < 0.001). Partial correlation analysis showed that systolic and diastolic blood pressure, and triglyceride and fasting plasma glucose levels were negatively correlated with urine pH, while high-density lipoprotein cholesterol was positively correlated with urine pH. Analysis of covariance indicated that urine pH decreased with an increasing number of metabolic abnormalities. Adjusted ORs (95% CI) for the presence of MetS in subjects with urine pH 5.5-6.0 and pH <5.5 were 1.34 (1.04-1.73) and 1.52 (1.09-2.13), respectively (reference: subjects with a urine pH >6.0). CONCLUSION: The MetS and its components were independently associated with lower urine pH.

Reply to Fujimoto, T. Comment on "Okaniwa, S. How Can We Manage Gallbladder Lesions by Transabdominal Ultrasound? Diagnostics 2021, 11, 784".

Thank you for your interesting comments [...].

Cutaneous sarcoidosis in a chronic hepatitis C patient receiving pegylated interferon and ribavirin therapy.

A 61-year-old Japanese woman suffered from a small, painful, subcutaneous nodule on the sole of her foot that was 10 mm across in diameter during pegylated interferon (PEG IFN) and ribavirin (RBV) combination therapy for chronic hepatitis C. Skin biopsy revealed multiple non-caseating granulomas composed of epithelioid histiocytes with multinucleate giant cells, which was consistent with sarcoidosis. Ophthalmologic examination revealed uveitis. Thoracic computed tomography (CT) showed multiple bilateral hilar lymphadenopathies and a diffuse micronodular interstitial pattern of the lungs. Genetic analysis indicated a probable homozygous haplotype of A*02:01-C*15:02-B*51:01-DRB1*16:02-DQB1*05:02 in human leukocyte antigen regions. The patient was observed carefully without any additional medication because no significant systemic symptoms were noted. Combination therapy was continued for 2 months afterwards. She was asymptomatic for over 3 years of follow up, and repeated hematological and biological investigations and chest CT showed improvement. In conclusion, clinicians should bear sarcoidosis in mind as a complication during PEG IFN and RBV combination therapy. They should also be aware of the usually good prognosis of PEG IFN-induced cutaneous sarcoidosis in order not to prematurely discontinue a treatment necessary for liver disease; maintenance of PEG IFN treatment may be advised with careful follow up.

Humoral hypercalcemia associated with gastric carcinoma secreting parathyroid hormone: a case report and review of the literature.

Hypercalcemia with concomitant elevation of serum parathyroid hormone (PTH) and PTH-related protein (PTHrP) levels was found in a patient with advanced gastric carcinoma and multiple liver metastases. The most common features are hypercalcemia associated with hypersecretion of PTHrP and physiological suppression of PTH secretion in the syndrome of humoral hypercalcemia of malignancy (HHM). Although we initially made a diagnosis of primary hyperparathyroidism concomitant with HHM due to gastric cancer, diagnostic imaging studies, such as echography, CT, sestamibi scintigraphy, and autopsy findings, did not reveal evidence of any parathyroid tumors or ectopic parathyroid glands in the mediastinum. Both primary and metastatic tumor cells showed positive staining with PTH-specific antibody as well as PTHrP-specific antibody on immunohistochemical examination. PTH concentration in the cytosolic fraction of the metastatic tumor was elevated compared to that from a control patient with no calcium metabolic disorders in vitro. These findings indicated that PTH secreted ectopically by gastric cancer cells, not by parathyroid glands, caused hypercalcemia in this patient. To our knowledge, this is the first case report of PTH-secreting gastric carcinoma cells. We report the case and a review of the previous reported PTH-secreting non-parathyroid tumors along with the mechanisms of secretion.

Endoscopic pancreatic duct stents reduce the incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis in high-risk patients.

BACKGROUND & AIMS: Pancreatitis is the most common and potentially serious complication of post-endoscopic retrograde cholangiopancreatography (ERCP). Post-ERCP pancreatitis (PEP) is caused mostly by postprocedural papillary edema and retention of pancreatic juice. We conducted a randomized controlled trial to determine whether placement of a temporary-type, pancreatic duct stent prevents PEP and to identify risk factors for PEP. METHODS: We analyzed data from 426 consecutive patients who underwent ERCP-related procedures at 37 endoscopic units. The patients were assigned randomly to groups that received stents (S group, n = 213) or did not (nS group, n = 213). The stent used was temporary, 5F in diameter, 3 cm long, and straight with an unflanged inner end. RESULTS: The overall frequency of PEP was 11.3%. The frequencies of PEP in the S and nS groups were 7.9% and 15.2%, respectively; the lower incidence of PEP in the S group was statistically significant based on the full analysis set (P = .021), although there was no statistically significant differences in an intention-to-treat analysis (P = .076). There were significant differences in PEP incidence between groups in multivariate analysis for the following risk factors: pancreatography first, nonplacement of a pancreatic duct stent after ERCP, procedure time of 30 minutes or more, sampling of pancreatic tissue by any method, intraductal ultrasonography, and difficulty of cannulation (≥15 min). Patients with more than 3 risk factors had a significantly greater incidence of pancreatitis. CONCLUSIONS: Placement of a pancreatic duct stent reduces the incidence of PEP. Several risk factors are associated with PEP.

Role of transabdominal ultrasound in the diagnosis of autoimmune pancreatitis.

The most important thing in the diagnosis of autoimmune pancreatitis (AIP) is to suspect the possibility of AIP. In the acute phase, diffuse pancreatic enlargement is a highly specific finding of AIP compared to focal enlargement. Though the sensitivity is low, high-frequency transducers can detect the capsule-like rim sign and penetrating duct sign. Those findings are characteristic of AIP and useful for differential diagnosis with pancreatic carcinoma. In focal AIP, both contrast-enhanced US showing iso/hypervascularity and elastography showing increased stiffness not only in the focal enlargement but also in the surrounding parenchyma are also useful for differential diagnosis. Furthermore, changes over time after the two-week steroid trial, such as resolution or measurable reduction in parenchymal enlargement and a decrease in the mean shear-wave velocity on elastography, are also cardinal features of AIP. Since AIP is a pancreatic manifestation in immunoglobulin G4-related disease, evaluation of other organs, including the biliary tract and salivary glands, is particularly useful in focal AIP. A characteristic US finding of bile ducts is three-layered (high-low-high pattern) wall thickening with a markedly thickened middle layer. US can also detect wall thickening of bile ducts, which show no abnormalities on cholangiography. These findings are useful for differential diagnosis with cholangiocarcinoma. Multiple hypoechoic areas in submandibular glands are characteristic US findings of sialadenitis in type 1 AIP, and the sensitivity is higher than that of physical examination. US can further contribute to the diagnosis of AIP by employing elastography and contrast-enhanced US in addition to high-frequency transducers.

Role of conventional ultrasonography in the diagnosis of gallbladder polypoid lesions.

The major role of conventional ultrasonography (US) can be divided into three processes: cancer screening, differential diagnosis, and assessment of the depth of tumor invasion. As US is a simple and minimally invasive modality, it is widely used for cancer screening and health checkups. Both gallbladder (GB) polyps and thickened wall of the GB are common US findings. On the contrary, US is prone to interference from gas echoes, and its diagnostic accuracy depends on both the US technology and the ability of sonographers. It is also important to be well acquainted with characteristic artifacts and how to manage their influence. Furthermore, magnified images acquired using high-resolution US (HRUS) are strongly helpful to pick up small lesions. As for differential diagnosis, classification of GB polypoid lesions (GPLs) into pedunculated or sessile (broad-based) types is very important. Cholesterol polyps in pedunculated lesions and localized adenomyomatosis (ADM) in sessile lesions are the most important targets to be differentiated. Furthermore, significant findings including number, size, growth rate, shape, internal echo, surface contour, and internal structure should be evaluated and judged as a whole. Usually, US delineates the GB wall as a two- or three-layer structure. However, as the inner hypoechoic layer includes not only the mucosa and muscularis propria but also the fibrous layer of subserosa, the differentiation between T1 (confined to the mucosa or muscularis propria) and T2 (invading the subserosa) based on the layer structure is difficult. Shape, size, and internal echo structure may be helpful for further assessment.

How Can We Manage Gallbladder Lesions by Transabdominal Ultrasound?

The most important role of ultrasound (US) in the management of gallbladder (GB) lesions is to detect lesions earlier and differentiate them from GB carcinoma (GBC). To avoid overlooking lesions, postural changes and high-frequency transducers with magnified images should be employed. GB lesions are divided into polypoid lesions (GPLs) and wall thickening (GWT). For GPLs, classification into pedunculated and sessile types should be done first. This classification is useful not only for the differential diagnosis but also for the depth diagnosis, as pedunculated carcinomas are confined to the mucosa. Both rapid GB wall blood flow (GWBF) and the irregularity of color signal patterns on Doppler imaging, and heterogeneous enhancement in the venous phase on contrast-enhanced ultrasound (CEUS) suggest GBC. Since GWT occurs in various conditions, subdividing into diffuse and focal forms is important. Unlike diffuse GWT, focal GWT is specific for GB and has a higher incidence of GBC. The discontinuity and irregularity of the innermost hyperechoic layer and irregular or disrupted GB wall layer structure suggest GBC. Rapid GWBF is also useful for the diagnosis of wall-thickened type GBC and pancreaticobiliary maljunction. Detailed B-mode evaluation using high-frequency transducers, combined with Doppler imaging and CEUS, enables a more accurate diagnosis.

How Does Ultrasound Manage Pancreatic Diseases? Ultrasound Findings and Scanning Maneuvers.

As ultrasound (US) is simple and less invasive than other imaging modalities, this technique is widely used for mass screening. However, visualizing the entire pancreas due to complicated anatomy, obesity and overlying gas can be difficult. US plays a key role in the diagnosis of pancreatic carcinoma (PC), of which tumors smaller than 10 mm (TS1a) and pancreatic carcinoma in situ are expected to have good prognosis. To detect these forms of PC, main pancreatic duct (MPD) dilatation (3 mm or more) and pancreatic cysts (5 mm or larger) are US findings of high-risk individuals (HRIs), and these subjects should be observed periodically. Scanning maneuvers are also important for both screening for PC and follow-up of HRIs. As lesions in the groove area and ventral pancreas do not affect the MPD or extrahepatic bile duct, we should pay attention to these areas. Visualization of the tail is also challenging due to gas and stool in the alimentary tract. As the position of the pancreas changes depending on the body posture, and several different body positions should be employed, such as the right lateral decubitus, sitting, and upright positions, rather than only applying strong compression with the transducer. In cases with poor visualization, the liquid-filled stomach method is highly recommended.

Efficacy and safety of addition of minor bloodletting (petit phlebotomy) in hepatitis C virus-infected patients receiving regular glycyrrhizin injections.

BACKGROUND: Hepatoprotective therapies that include regular glycyrrhizin injections (GIs) are beneficial for chronic hepatitis C patients, but are sometimes insufficient for normalizing serum alanine aminotransferase (ALT) levels. Here, we evaluated whether the addition of minor bloodletting, named petit phlebotomy (PP), prior to each GI could further reduce serum ALT concentrations in such patients. METHODS: Seventy-six hepatitis C virus (HCV)-infected patients receiving regular GI, with persistently abnormal serum ALT levels, were randomly divided into GI + PP and GI groups and monitored for 12 months. PP was performed before every GI to a total 60 ml of blood a week. The primary PP endpoint was a serum ferritin level of less than 20 ng/ml. PP was suspended upon reaching the endpoint, but was resumed as needed. The efficacy of the addition of PP was evaluated by measuring changes in serum ALT levels. RESULTS: Two patients in each group dropped out because of the appearance of hepatocellular carcinoma. The remainder completed the 12-month treatment with no serious adverse events. Serum ALT and ferritin levels were significantly decreased in the GI + PP group (from 67 +/- 34 to 44 +/- 14 U/l and from 163 +/- 127 to 25 +/- 21 ng/ml, respectively, both P < 0.001), but these changes were not seen in the GI group. Although 20 patients in the GI + PP group had compensated cirrhosis, no significant reductions in serum albumin concentrations were observed. CONCLUSIONS: The addition of PP is effective and safe for improving serum aminotransferase levels in HCV-infected patients receiving regular GI, even in those with compensated cirrhosis.

Association of Low Urine pH with Insulin Resistance in Non-Diabetic Japanese Subjects.

BACKGROUND: Epidemiology studies have revealed that patients with obesity, hyperglycemia, or hypertension are associated with a decreased urine pH. These metabolic disorders are related to insulin resistance; however, the association between urine pH and insulin resistance remains unclear. METHODS: To evaluate this association while controlling for covariates, the present study was conducted in 1084 non-diabetic Japanese subjects undergoing health examination. Fasting urine pH was analyzed using an automated urine dipstick analyzer. The subjects were divided into five groups according to urine pH: those with pH <5.5, 5.5, 6.0, 6.5, and >6.5. Insulin resistance was determined using the homeostatic model assessment of insulin resistance (HOMA-IR) and divided into three categories: lower, middle, and higher tertiles of HOMA-IR. Analysis of covariance and multivariate logistic regression analysis were used to control confounding factors including serum uric acid. RESULTS: Analysis of covariance showed an increase in the mean HOMA-IR from 1.26, 1.46, 1.69, and 1.75 to 1.89 with a decrease in urine pH (p<0.001). Subjects with urine pH ≤5.5 had a significantly higher HOMA-IR than those with urine pH>6.5. Furthermore, multivariate logistic regression analysis showed that urine pH had an inverse and independent association with HOMA-IR. In subjects with urine pH 5.5 and <5.5, adjusted odds ratio (95% confidence interval) for the incidence of higher tertile of HOMA-IR was 1.34 (1.04-1.73) and 1.52 (1.09-2.13), respectively (reference, subjects with a urine pH>6.5). CONCLUSION: Insulin resistance is independently associated with a lower urine pH, possibly via lower formation of ammonium in the kidneys.

Clinical guidelines for primary sclerosing cholangitis 2017.

BACKGROUND: Primary sclerosing cholangitis (PSC) is relatively rare disease and pathogenesis and methods of treatments were still not established. Then, we had conducted the making clinical guidelines to manage patients with PSC based on the literature review and expert opinions. These clinical guidelines were made for the medical doctors on the management of PSC, except child case of PSC. METHODS: We had employed modified Delphi method. The production committee decided guidelines, strength of recommendations and evidence level after reviewed literatures systematically, and The Expert panel evaluated those. The Scientific Committee of the Japan Biliary Association (JBA) evaluated revised guidelines, and the Public comments were collected on web site of JBA. RESULTS: We had made 16 guidelines about epidemiology/pathophysiology, diagnostics, therapy and prognosis. Also, we had made both diagnostic and therapeutic flow chart. CONCLUSIONS: We hope that these guidelines will contribute to the improvement and development of the medical care of PSC.

Corrigendum to "Optimal Hemoglobin A1c Levels for Screening of Diabetes and Prediabetes in the Japanese Population".

[This corrects the article DOI: 10.1155/2015/932057.].

A Patency Capsule Remained Intact in the Colon over 210 Hours.

We present an unusual case of a 35-year-old male patient whom a patency capsule stayed in his gut without breaking. He has a history of Peutz-Jeghers syndrome and multiple abdominal surgeries. Prestudy was performed for abdominal searching, but a patency capsule remained in the colon over 9 days. He displayed neither abdominal nor obstructive symptoms in that period. We collected the patency capsule using colonoscopy after dilating a postoperative stricture at an anastomotic site of the rectum. Clinicians should bear in mind that patency capsules may become retained as distally as the colon in patients with a surgical history of the large intestine.

Reflux-Associated Cholecystopathy: Analysis of 76 Gallbladders From Patients With Supra-Oddi Union of the Pancreatic Duct and Common Bile Duct (Pancreatobiliary Maljunction) Elucidates a Specific Diagnostic Pattern of Mucosal Hyperplasia as a Prelude to Carcinoma.

Pancreaticobiliary maljunction (PBM) is the anomalous union of the main pancreatic duct and common bile duct outside the Oddi-sphincter, allowing the reflux of pancreatic juice to the gallbladder. There is only limited awareness and understanding of the pathologic correlates of this condition, mostly from Japan; this entity is largely unrecognized in the West. In this study, 76 gallbladders from patients with PBM (64 from Japan; 12 from the United States) were analyzed and contrasted with 66 from non-PBM patients. These were predominantly females (54 vs. 22), mean age, 53 (range: 14 to 81). Cholelithiasis was uncommon (16% vs. 80% in non-PBM, P<0.01) whereas cholesterolosis was more common (49% vs. 29%, P=0.02) suggesting an altered chemical milieu. There was a distinctive diffuse mucosal hyperplasia (82% vs. 42%, P<0.01) with markedly elongated folds (mean: 1.1 vs. 0.7 mm, P<0.01) composed of compact villoglandular proliferation, often showing broad-based pushing into muscle, accompanied by prominent and more complex Rokitansky-Aschoff sinus formation (2.0 vs. 1.0/cm, P<0.01) at the base. At the tips, this villiform hyperplasia displayed frequent horizontal bridging of the folds (68% vs. 47%, P=0.01), bulbous dilatation (52% vs. 21%, P<0.01) as well as deposition of a peculiar amyloid-like hyaline material (56% vs. 15%, P<0.01). Despite paucity of inflammation and gallstones, findings attributed to mucosal injury were common including: pyloric gland metaplasia (70% vs. 48%, P=0.01) and intestinal metaplasia (24% vs. 6%, P<0.01). Invasive gallbladder carcinoma was present in 22 (29%) of the cases with 6 of these (27%) arising in association with intracholecystic papillary tubular neoplasm. Five cases had bile duct carcinoma at the time of cholecystectomy and 1 developed it 4 years after. In conclusion, gallbladders with patients with PBM display a distinctive pattern of mucosal hyperplasia with distinguishing features, which in constellation render it a microscopically diagnosable specific entity. We propose to refer to this entity as "reflux-associated cholecystopathy." Recognition of the pathologic characteristics of this entity is important so that investigation for, as well as treatment and prevention of, PBM-associated complications (biliary tract cancers and pancreatitis) can be instituted. This group also offers a distinct model of carcinogenesis (chemical rather than inflammatory) in the gallbladder for cancer researchers to scrutinize.