Inhibition of IL-33 signaling ameliorate hepatic fibrosis with decreasing MCP-1 in a mouse model of diabetes and non-alcoholic steatohepatitis; comparison for luseogliflozin, an SGLT2 inhibitor.

Non-alcoholic fatty liver disease (NAFLD) is increasing globally, and seeking therapeutic molecule targets is urgent. Several studies have demonstrated that IL-33 plays an important role in the progression of Non-alcoholic steatohepatitis (NASH) with fibrosis and the proliferation of hepatocellular carcinoma (HCC). However, whether the inhibition of IL-33 signaling prevents NAFLD from progressing to NASH and HCC has not been clarified. We investigated the effects of a novel antibody, IL-33RAb, and luseogliflozin, a SGLT2 inhibitor, when administered to a model mouse for NASH and HCC, and their effects were compared to investigate the mechanisms of how IL-33 is involved in the pathogenesis of NASH progression. Compared with the positive control of luseogliflozin, inhibition of IL-33 signaling ameliorated decreasing hepatic fibrosis via decreasingαSMA and MCP-1, and also partially suppressed the progression of the HCC cell line in in vitro experiments. These findings suggest that inhibition of IL-33 possibly prevents progression from NASH to HCC, and their effect may be a newly arrived therapeutic agent.

Switching from the tablet to the powder formulation of levothyroxine corrects severe hypothyroidism in a patient with lactose intolerance.

We describe a case of a 38-year-old woman who, after radioactive iodine therapy for Graves' disease, developed severe hypothyroidism despite receiving a high dose of levothyroxine (L-T4) tablet as replacement therapy. Her thyroid stimulating hormone (TSH) remained to be high despite the dose of L-T4 tablets to 400 µg/day after treatment for hypothyroidism, and the patient complained of general malaise and edema of the legs. Reduced intestinal absorption of L-T4 is the most common cause of failure to achieve the therapeutic target in hypothyroid patients receiving replacement therapy. She was admitted to our hospital for severe hypothyroidism due to resistance to treatment with L-T4 tablet. Our patient was found to have lactose intolerance (LI) by a detailed examination during hospitalization. Therefore, we assumed that LI was impairing intestinal absorption of L-T4 tablet in our patient, leading to severe hypothyroidism. The patient was switched to the powder formulation of L-T4 at the same daily dose, and serum levels of thyroid-stimulating hormone and thyroid hormones normalized. This is the case in which hypothyroidism due to reduced absorption of L-T4 tablet in a patient with LI was resolved by switching to L-T4 powder formulation.

Acute Exacerbation of Anemia with Parvovirus B19 Infection One Year after Sleeve Gastrectomy for Severe Obesity.

Pancytopenia due to malnutrition sometimes occurs after gastric bypass but is rare after sleeve gastrectomy. A 35-year-old patient underwent sleeve gastrectomy for severe obesity. Twelve months after the operation, rapid progression of macrocytic anemia with leukopenia and thrombocytopenia occurred, and a decrease in some vitamins and trace elements due to an insufficient food intake was also detected. Haptoglobin decreased, suggesting the presence of hemolysis. In addition, IgM antibody against parvovirus B19 was detected, followed by IgG antibody. Parvovirus B19 infection was suggested to be involved in the rapid progression of anemia in this malnourished patient after bariatric surgery.

Serum levels of soluble dipeptidyl peptidase-4 in type 2 diabetes are associated with severity of liver fibrosis evaluated by transient elastography (FibroScan) and the FAST (FibroScan-AST) score, a novel index of non-alcoholic steatohepatitis with significant fibrosis.

AIM: To investigate the relationship in people with type 2 diabetes between serum soluble dipeptidyl peptidase-4 (sDDP-4) and degree of liver fibrosis assessed as the liver stiffness measurement (LSM) and FAST (FibroScan-AST) score, both of which were measured by transient elastography (FibroScan). SUBJECTS AND METHODS: In this cross-sectional study, we examined 115 patients with type 2 diabetes. With transient elastography (FibroScan), we assessed the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) as measures of hepatic steatosis and liver fibrosis, respectively. We calculated the FAST score, which identifies progressive non-alcoholic steatohepatitis (NASH), from CAP, LSM, and the serum aspartate aminotransferase level. Significant hepatic steatosis was defined as CAP ≥280 dB/m; and significant liver fibrosis, as LSM ≥ 8.0 kPa. LSM was divided into 3 severity levels: significant fibrosis (8.0 to <9.7 kPa); advanced fibrosis, (9.7 to <13.0 kPa); and liver cirrhosis (≥ 13.0 kPa). RESULTS: Serum sDPP-4 correlated positively with liver enzymes, CAP, LSM, and FAST score. Multivariate analysis showed that LSM remained to be an independent factor for serum sDDP-4. Serum sDPP-4 was significantly higher in patients with LSM ≥ 8.0 kPa than in those with LSM <8.0 kPa and was significantly elevated in patients who are at risk for non-alcoholic steatohepatitis (NASH) with fibrosis (FAST score ≥ 035 or 0.67). Patients with both hepatic steatosis and liver fibrosis had the highest serum sDPP-4. CONCLUSION: Serum sDPP-4 was strongly associated with severity of liver fibrosis evaluated by LSM and the FAST score and was markedly elevated in diabetic patients with LSM ≥ 13.0 kPa indicating probable cirrhosis.

Genetic alteration of ARMC5 in a patient diagnosed with meningioma and primary macronodular adrenal hyperplasia: a case report.

A monoallelic germline alteration of ARMC5 causes primary bilateral macronodular adrenal hyperplasia (PBMAH) with Cushing's syndrome via its subsequent somatic alteration on the other allele as the second hit. PBMAH is sometimes complicated with meningioma. Dependency of such a multi-organ disease on the second hit mechanism was reported before, but this finding has not been confirmed yet. We describe a case of a 65-year-old female with PBMAH, carrying a heterozygous germline alteration of ARMC5, p.R267*, complicated with meningioma associated with somatic loss of heterozygosity (LOH) of the unaffected allele. Pathogenic alterations of ARMC5 may also contribute to the development of meningioma by the two-hit mechanism.

Teneligliptin, a DPP-4 Inhibitor, Decreases Plasma Levels of Inflammatory Chemokines During a Standard Meal Test in Patients With Type 2 Diabetes.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) rapidly inactivates incretin hormones and several chemokines, thus influencing chemokine function. There have recently been several reports that DPP-4 inhibitor therapy is associated with an increased risk of bullous pemphigoid (BP), an autoimmune skin disease. Previous studies have demonstrated an increase of CCL11/Eotaxin, a DPP-4 substrate, in serum and blister fluid from patients with BP. Serum levels of CCL22/macrophage-derived chemokine (MDC) and CXCL10/IP-10, other DPP-4 substrates, are also elevated in BP patients. MATERIALS AND METHODS: In patients with type 2 diabetes, we investigated the effect of treatment with teneligliptin (a DPP-4 inhibitor) for 24 weeks on plasma levels of CCL11/Eotaxin, CCL22/MDC and CXCL10/IP-10 during a meal test. Ten consecutive patients with type 2 diabetes who showed inadequate glycemic control by metformin and/or sulfonylureas were recruited. A standard meal test was performed at baseline and after 24 weeks of treatment with teneligliptin at 20 mg/day. Blood samples were collected at 0, 30, 60 and 120 minutes after ingestion of the meal. In addition to plasma levels of the 3 chemokine, plasma DPP-4 enzyme activity and soluble DPP-4 antigen were measured. RESULTS: Treatment with teneligliptin decreased hemoglobin A1c and reduced fasting plasma DPP-4 activity by 90.1% compared with baseline. Unexpectedly, plasma levels of all 3 chemokines (including CCL11/Eotaxin) were not increased after teneligliptin treatment, and instead were significantly lower at every point during the meal test. CONCLUSIONS: Teneligliptin reduced the plasma concentrations of 3 chemokines (DPP-4 substrates) that may be related to the occurrence of DPP4 inhibitor-associated BP (UMIN000012508).

Denosumab improves clinical manifestations of hypophosphatemic osteomalacia by adefovir-induced Fanconi syndrome: a case report.

BACKGROUND: Adefovir dipivoxil is a nucleotide analogue that is approved for treatment of chronic hepatitis B. Adefovir dipivoxil is associated with proximal tubular dysfunction, resulting in Fanconi syndrome, which can cause secondary hypophosphatemic osteomalacia. We describe a case of a patient with hypophosphatemic osteomalacia secondary to Fanconi syndrome induced by adefovir dipivoxil concomitantly with osteoporosis in whom clinical symptoms were improved by adding denosumab (a human monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand) to preceding administration of vitamin D3. CASE PRESENTATION: A 60-year-old Japanese man had been receiving low-dose adefovir dipivoxil (10 mg/day) to treat chronic hepatitis B for approximately 5 years. He presented to an orthopedic surgeon with severe pain of the right hip and no trauma history, and fracture of the neck of the right femur was identified. In addition, 99mTc-hydroxymethylene diphosphate scintigraphy revealed significantly abnormal uptake in the bilateral ribs, hips, and knees, and he was therefore referred to our university hospital for evaluation of multiple pathological fractures. We diagnosed hypophosphatemic osteomalacia due to Fanconi syndrome induced by adefovir dipivoxil therapy. Although we reduced the patient's adefovir dipivoxil dose and added calcitriol (active vitamin D3), he did not respond and continued to complain of bone pain. Several bone resorption markers and bone-specific alkaline phosphatase were also persistently elevated. Therefore, we added denosumab to vitamin D3 supplementation for treatment of excessive bone resorption. Two months after initiation of denosumab, his hip and knee pain was relieved, along with a decrease in serum alkaline phosphatase and some bone resorption markers. CONCLUSIONS: Although denosumab is not generally an appropriate treatment for acquired Fanconi syndrome, it may be useful for patients who have hypophosphatemic osteomalacia due to adefovir dipivoxil-induced Fanconi syndrome associated with excessive bone resorption. However, clinicians should keep in mind that if denosumab is administered to patients with hypophosphatemic osteomalacia accompanied by excessive bone resorption, adequate vitamin D and/or phosphate supplementation should be done before administration of denosumab.

Impact of dapagliflozin, an SGLT2 inhibitor, on serum levels of soluble dipeptidyl peptidase-4 in patients with type 2 diabetes and non-alcoholic fatty liver disease.

AIMS: Soluble dipeptidyl peptidase-4 (sDPP-4) is secreted by hepatocytes and induces adipose tissue inflammation and insulin resistance. Sodium-glucose co-transporter-2 (SGLT2) inhibitors can improve hepatic steatosis by inhibiting hepatic de novo lipogenesis. We investigated the effects of dapagliflozin (an SGLT2 inhibitor) on serum levels of sDPP-4 in patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). METHODS: Fifty-seven patients with type 2 diabetes and NAFLD were randomized to a dapagliflozin group (5 mg/d for 24 weeks) (n = 33) or the control group (n = 24). Serum levels of sDPP-4 were measured with a commercial ELISA kit. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured by dual bioelectrical impedance analysis. RESULTS: In a total of 57 patients, baseline serum sDPP-4 was positively correlated with aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transferase (GGT) and HOMA-IR Both VAT and SAT areas decreased significantly in the dapagliflozin group alone. Liver enzymes were decreased at 24 weeks in the dapagliflozin group, but were unchanged in the control group. Although both groups showed significant reduction of serum sDPP-4 after 24 weeks of treatment, the magnitude of decrease was significantly larger in the dapagliflozin group. Changes in liver enzymes during treatment with dapagliflozin were positively correlated with the change in serum sDPP-4, but not with changes in VAT volume or HbA1c. CONCLUSIONS: Improvement of liver dysfunction after treatment with dapagliflozin was associated with a decrease in serum sDPP-4, suggesting that reduction of serum sDPP-4 by SGLT2 inhibitors may be a therapeutic strategy for NAFLD/NASH in patients with type 2 diabetes that is independent of glucose lowering or weight loss.

[Oculomotor nerve compression on MRI in a 56-year-old man with pituitary apoplexy due to panhypophisitis].

A 56-year-old man noted sudden onset of headache, fever, right pupil-spared oculomotor nerve palsy and consciousness disturbance. Swelling of pituitary with T1 high intensity on brain MRI suggested the diagnosis of pituitary apoplexy. Considering significant decrease of pituitary anterior lobe hormone and central diabetes insipidus, high dose of hydrocortisone was administered. Eight days after onset, consciousness level and headache improved. On day 30, brain MRI revealed the reduction of mass size, and on day 46, photophobia and double vision disappeared. Following the rapid response to steroid and disappearance of pituitary lesion, pituitary apoplexy was probably caused by panhypophisitis. Thin-slice brain MRI confirmed the compression of oculomotor nerve at inlet zone of cavernous sinus, suggesting the mechanism of oculomotor palsy was perfusion impairment of feeding artery.

Modified esophagogastrostomy in laparoscopy-assisted proximal gastrectomy: A reverse-Tornado anastomosis.

INTRODUCTION: The aim of this study was to introduce and examine a modified mechanical end-to-side esophagogastrostomy method ("reverse-Tornado" anastomosis) in laparoscopy-assisted proximal gastrectomy. METHODS: Five patients with gastric cancer who underwent laparoscopy-assisted proximal gastrectomy were analyzed retrospectively. Esophagogastrostomy in the anterior wall was performed in three patients, and esophagogastrostomy in the posterior wall was performed in two patients. Clinicopathological features, operative outcomes (operative time, operative blood loss), and postoperative outcomes (complications, postoperative hospital stay, reflux esophagitis) were evaluated. RESULTS: Operative time was normal (278 min). There was no marked operative blood loss, postoperative complications, prolonged hospital stay, or reflux esophagitis. CONCLUSION: Esophagogastrostomy was completed in a normal time with reverse-Tornado anastomosis. This method can be safe and can enable good postoperative quality of life.

Pre-operative diagnosis and successful surgery of a strangulated internal hernia through a defect in the falciform ligament: a case report.

INTRODUCTION: Internal hernia within the falciform ligament is exceedingly rare. A literature search revealed only 14 cases of internal herniation of the small bowel through a congenital defect of the falciform ligament, most of which were found intra-operatively. CASE PRESENTATION: A 77-year-old Japanese woman presented to our emergency department with sudden hematemesis, occurring at least four to five times over a 12-hour period. No ulcer or gastrointestinal bleeding was detected on gastroendoscopy. A 40mm mass in the inferior lobe of the right lung was found on a chest X-ray, and our patient's symptoms were therefore initially ascribed to aspirated blood from lung tumor-associated hemoptysis. However, our patient continued to show signs of severe abdominal pain and decreased urine output despite aggressive hydration, leading her examining physicians to search for a possibly severe, occult abdominal pathology. On emergent computed tomography imaging, we found an acute strangulated internal hernia within the falciform ligament. Diagnosis was made by helical computed tomography, permitting rapid surgical intervention. CONCLUSIONS: Our findings on computed tomography imaging assisted with the pre-operative diagnosis and enabled us to make a rapid surgical intervention. Early diagnosis may help preclude significant strangulation with unnecessary resection.

Solitary hepatic lymphangioma: report of a case.

A 52-year-old woman presented with upper abdominal pain. Abdominal ultrasonography showed a 4-cm well-defined mass containing solid and cystic components in segment IV of the liver, and contrast-enhanced T1-weighted magnetic resonance imaging revealed heterogeneous enhancement within the tumor, indicating a solid or fibrous component. There were no cystic lesions in any other organs. A partial hepatectomy was performed, based on a preoperative diagnosis of sclerosing hemangioma and biliary cystadenoma or cystadenocarcinoma. Pathologically, the tumor appeared to be a multilocular and cystic lesion lined by attenuated endothelial- like cells with no atypia. Immunohistochemistry demonstrated the endothelial-like cells to be positive for the lymphatic-specific markers D2-40, LYVE-1, and Prox-1, which proved helpful for confirming the diagnosis as solitary hepatic lymphangioma. This case is presented with details of the pathologic and radiologic findings, because solitary hepatic lymphangioma is an extremely rare tumor and no previous reports have provided details of the immunohistochemical characteristics.