Anti-nuclear matrix protein 2 antibody-positive dermatomyositis with gastrointestinal ulcers: A case report.

Gastrointestinal manifestations are a very rare complication of dermatomyositis (DM) and are much less frequent in adult cases than in juvenile cases. Only a few previous papers have reported adult patients who had DM with anti-nuclear matrix protein 2 (anti-NXP2) antibodies and who developed gastrointestinal ulcers. Herein, we report a similar case of a 50-year-old man who had DM with anti-NXP2 antibodies followed by relapsing multiple gastrointestinal ulcers. Even after the administration of prednisolone, his muscle weakness and myalgia deteriorated and gastrointestinal ulcers relapsed. In contrast, intravenous immunoglobulin and azathioprine improved his muscle weakness and gastrointestinal ulcers. Based on the parallel disease activity of the muscular and gastrointestinal symptoms, we considered that his gastrointestinal ulcers were a complication of DM with anti-NXP2 antibodies. We also propose that early intensive immunosuppressive therapy would be required for the muscular and gastrointestinal symptoms in DM with anti-NXP2 antibodies.

No increased risk of hepatocellular carcinoma after eradication of hepatitis C virus by direct-acting antivirals, compared with interferon-based therapy.

It is well-known that sustained virological response (SVR) by interferon (IFN)-based therapy against hepatitis C virus (HCV) infection reduced the incidence of hepatocellular carcinoma (HCC). However, whether IFN-free direct-acting antivirals reduce the risk of HCC is controversial. Therefore, this study aims to compare the incidence of HCC after the achievement of SVR between sofosbuvir combined with ledipasvir (SOF/LDV) and simeprevir with pegylated interferon plus ribavirin (Sim+IFN). Japanese patients with HCV infection (genotype 1) who achieved SVR between January 2013 and December 2014 by SOF/LDV (NCT01975675, n = 320) or Sim+IFN (000015933, n = 289) therapy in two nationwide, multicenter, phase III studies were prospectively monitored for the development of HCC by ultrasonography for 5 years after the end of treatment (EOT). No HCC was detected before the treatment. HCC was detected in 9 and 7 patients in the SOF/LDV and the Sim+IFN group in 5 years, respectively. The cumulative incidences of HCC rates 1, 3, and 5 years after EOT were similar between the two groups (1.5%, 2.7%, and 3.2% for the SOF/LDV and 1.8%, 2.8%, and 3.0% for the Sim+IFN group, respectively). No HCC was developed 3.5 years after EOT. Interestingly, a retrospective careful review of imaging taken before therapy revealed hepatic nodules in 50% of HCC patients, suggesting HCC was pre-existed before therapy. In conclusion, we could not find any differences in the incidence of HCC after the HCV eradication between the two therapeutic regimens, suggesting no enhancement of HCC development by DAA.

Risk factors of poor prognosis and impairment of activities of daily living in patients with hemorrhagic gastroduodenal ulcers.

BACKGROUND: Impairment of activities of daily living (ADL) due to hemorrhagic gastroduodenal ulcers (HGU) has rarely been evaluated. We analyzed the risk factors of poor prognosis, including mortality and impairment of ADL, in patients with HGU. METHODS: In total, 582 patients diagnosed with HGU were retrospectively analyzed. Admission to a care facility or the need for home adaptations during hospitalization were defined as ADL decline. The clinical factors were evaluated: endoscopic features, need for interventional endoscopic procedures, comorbidities, symptoms, and medications. The risk factors of outcomes were examined with multivariate analysis. RESULTS: Advanced age (> 75 years) was a significant predictor of poor prognosis, including impairment of ADL. Additional significant risk factors were renal disease (odds ratio [OR] 3.43; 95% confidence interval [CI] 1.44-8.14) for overall mortality, proton pump inhibitor (PPIs) usage prior to hemorrhage (OR 5.80; 95% CI 2.08-16.2), and heart disease (OR 3.05; 95% CI 1.11-8.43) for the impairment of ADL. Analysis of elderly (> 75 years) subjects alone also revealed that use of PPIs prior to hemorrhage was a significant predictor for the impairment of ADL (OR 8.24; 95% CI 2.36-28.7). CONCLUSION: In addition to advanced age, the presence of comorbidities was a risk of poor outcomes in patients with HGU. PPI use prior to hemorrhage was a significant risk factor for the impairment of ADL, both in overall HGU patients and in elderly patients alone. These findings suggest that the current strategy for PPI use needs reconsideration.

Risk Factors for Acute Cholangitis Caused by Enterococcus faecalis and Enterococcus faecium.

Background/Aims: Acute cholangitis (AC) is a potentially life-threatening bacterial infection, and timely antimicrobial treatment, faster than that achieved with bacterial cultures, is recommended. Although the current guidelines refer to empirical antimicrobial treatment, various kinds of antimicrobial agents have been cited because of insufficient analyses on the spectrum of pathogens in AC. Enterococcus spp. is one of the most frequently isolated Gram-positive bacteria from the bile of patients with AC, but its risk factors have not been extensively studied. This study aimed to analyze the risk factors of AC caused by Enterococcus faecalis and Enterococcus faecium. Methods: Patients with AC who were hospitalized in a Japanese tertiary center between 2010 and 2015 were retrospectively analyzed. Patients' first AC episodes in the hospital were evaluated. Results: A total of 266 patients with AC were identified. E. faecalis and/or E. faecium was isolated in 56 (21%) episodes of AC. Prior endoscopic sphincterotomy (EST), the presence of a biliary stent, prior cholecystectomy, and past intensive care unit admission were more frequently observed in AC patients with E. faecalis and/or E. faecium than in those without such bacteria. Prior EST was identified as an independent risk factor for AC caused by E. faecalis and/or E. faecium in the multivariate analysis. Conclusions: Given the intrinsic resistance of E. faecalis and E. faecium to antibiotics, clinicians should consider empirical therapy with anti-enterococcal antibiotics for patients with prior EST.

Long-term survival after palliative argon plasma coagulation for intraductal papillary mucinous neoplasm of the bile duct.

Intraductal papillary mucinous neoplasm of the bile duct (IPNB) is an epithelial tumor that can cause obstructive jaundice and cholangitis due to mucin production. Although the effectiveness of argon plasma coagulation in IPNB treatment has been demonstrated, the long-term effect of the therapy is largely unknown. Here, we have presented a patient with IPNB who underwent argon plasma coagulation with a follow-up period of more than 2 years. A 74-year-old woman was referred to our department for treatment of obstructive jaundice. Endoscopic retrograde cholangiopancreatography revealed marked dilation of intrahepatic and extrahepatic bile ducts and thick mucin drainage from the ampulla of Vater. IPNB was diagnosed pathologically from biopsy specimens. Surgery was not recommended because of the extensive intrahepatic spread of the lesion. Endoscopic sphincterotomy, endoscopic papillary large balloon dilation, and insertion of a metallic stent could not resolve the obstructive jaundice. Finally, argon plasma coagulation with percutaneous cholangioscopy was performed 3 times over 1 month. After treatment, obstructive jaundice was resolved and the patient's clinical condition has been stable for more than 2 years, except for a single episode of transient cholangitis. In conclusion, argon plasma coagulation may be an alternative to surgery for the palliation of jaundice with IPNB.

Hepatitis C virus relapse after successful treatment with direct-acting antivirals, followed by sarcomatous changes in hepatocellular carcinoma: a case report.

BACKGROUND: Combination therapy of interferon and ribavirin has traditionally been used to eradicate hepatitis C virus. The sustained virologic response achieved with interferon-related therapy is persistent, and late relapses after achieving sustained virologic response at 24 weeks using this therapy are reportedly rare (< 1%). In 2014, interferon-free therapy with direct-acting antivirals was developed, and the rate of sustained virologic response was improved. However, the persistence thereof remains uncertain, and the appropriate follow-up period for hepatitis C virus-positive patients is under discussion. CASE PRESENTATION: A 74-year-old Japanese man who had hepatitis C virus-related hepatocellular carcinoma and was successfully treated with radiofrequency ablation four times underwent direct-acting antiviral therapy with daclatasvir and asunaprevir; sustained virologic response at 24 weeks was confirmed. However, although he had no high risk factors for reinfection, hepatitis C virus ribonucleic acid was detected again 6 months after achieving sustained virologic response at 24 weeks. Moreover, he developed active hepatitis with an increased viral load. Five months after development of hepatitis, recurrent hepatocellular carcinoma emerged in segment II, where we had performed radiofrequency ablation 17 months previously. The recurrent hepatocellular carcinoma enlarged quite rapidly and induced multiple peritoneal disseminations and lung metastases. He died 3 months after the abrupt recurrence. A sarcomatous change in the hepatocellular carcinoma was identified during the autopsy. CONCLUSIONS: Although sustained virologic response at 24 weeks has generally been regarded to denote complete eradication of hepatitis C virus, we present a patient in whom hepatitis C virus recurred 6 months after achieving sustained virologic response at 24 weeks with direct-acting antiviral therapy. In addition, a sarcomatous change in hepatocellular carcinoma emerged 5 months after active hepatitis developed due to late hepatitis C virus relapse in this case. The sarcomatous change in hepatocellular carcinoma is generally thought to be related to anticancer therapies, such as radiofrequency ablation. However, in this case, late viral relapse and active hepatitis in addition to the previous radiofrequency ablation could have been the trigger. There may be a need for follow-up of hepatitis C virus ribonucleic acid beyond sustained virologic response at 24 weeks with direct-acting antiviral therapy, owing to the possibility of late viral relapse and tumorigenesis.

Impact of the Sensitivity to Empiric Antibiotics on Clinical Outcomes after Biliary Drainage for Acute Cholangitis.

Background/Aims: Empiric antibiotics are given in combination with biliary drainage for acute cholangitis but sometimes turn out to be insensitive to microorganisms in blood and bile. Clinical outcomes were compared according to sensitivity to microorganisms detected in blood and bile culture to evaluate the impact of sensitivity to empiric antibiotics in cholangitis. Methods: Consecutive patients who underwent biliary drainage for acute cholangitis were retrospectively studied. Clinical outcomes such as 30-day mortality, length of hospital stay and high care unit stay, organ dysfunction and duration of fever were compared in three groups: group A (sensitive to both blood and bile culture), group B (sensitive to blood culture alone) and group C (insensitive to both blood and bile culture). Results: Eighty episodes of cholangitis were classified according to sensitivity results: 42, 32 and six in groups A, B and C. Escherichia coli and Klebsiella were two major pathogens. There were no significant differences in 30-day mortality rate (7%, 0%, and 0%, p=0.244), length of hospital stay (28.5, 21.0, and 20.5 days, p=0.369), organ dysfunction rate (14%, 25%, and 17%, p=0.500), duration of fever (4.3, 3.2, and 3.5 days, p=0.921) and length of high care unit stay (1.4, 1.2, and 1.7 days, p=0.070) in groups A, B and C. Empiric antibiotics were changed in 11 episodes but clinical outcomes appeared to be non-inferior even in 31 episodes of cholangitis who were on inadequate antibiotics throughout the course. Conclusions: Sensitivity of empiric antibiotics was not associated with clinical outcomes in acute cholangitis.

Incidence and risk factors of contrast-induced nephropathy after transcatheter arterial chemoembolization in hepatocellular carcinoma.

BACKGROUND: Transcatheter arterial chemoembolization (TACE) is widely used for unresectable hepatocellular carcinoma (HCC). The purpose of this study was to investigate incidence and risk factors of contrast-induced nephropathy (CIN) after TACE in patients with HCC. METHODS: In this single-center retrospective study, we examined 461 consecutive TACE sessions in 260 patients between January 2003 and October 2015. CIN was defined as an increase in serum creatinine levels by ≥ 0.5 mg/dl or ≥ 25% from baseline within 72 h after TACE. We calculated incidence rate of CIN and tried to identify its risk factors by logistic regression analysis. RESULTS: Twenty-one cases of CIN (5%) were observed in 461 TACE sessions. One patient required subsequent hemodialysis transiently. In univariate analysis, tumor size > 5 cm [odds ratio (OR) 5.76, 95% confidence interval (CI) 2.34-14.14, p < 0.001], chronic kidney disease (OR 2.54, 95% CI 1.05-6.14, p = 0.04), serum hemoglobin level [OR 0.79 (per 1 g/dl increase), 95% CI 0.64-0.98, p = 0.03] and serum albumin level [OR 0.44 (per 1 g/dl increase), 95% CI 0.19-1.02, p = 0.05] were associated with the development of CIN. Stepwise logistic regression methods showed that tumor size > 5 cm (OR 7.81, 95% CI 2.99-20.46, p < 0.001) and serum albumin [OR 0.29 (per 1 g/dl increase), 95% CI 0.11-0.75, p = 0.01] were risk factors of CIN. CONCLUSIONS: In this study, HCC tumor size and lower serum albumin level were independent predictors of CIN after TACE.

Paraneoplastic dermatomyositis appearing after nivolumab therapy for gastric cancer: a case report.

BACKGROUND: While dermatomyositis is often associated with malignancy, several autoimmune diseases like myositis can be caused by immune checkpoint inhibitors. Differentially diagnosing malignancy-associated dermatomyositis or myositis caused by immune checkpoint inhibitors is sometimes difficult, particularly when a patient with malignancy shows the symptoms of myositis after checkpoint inhibitor administration. We experienced such a case in which we had difficulties in diagnosing paraneoplastic dermatomyositis or drug-associated myositis. In this case, all of our team initially assumed that the diagnosis was myositis caused by immune checkpoint inhibitors. However, it turned out finally that the diagnosis was paraneoplastic dermatomyositis. Because the diagnosis was unexpected, we report here. CASE PRESENTATION: We report the case of a 71-year-old Japanese man who developed clinical symptoms of myositis, such as muscle aches and weakness, after initiation of nivolumab therapy for his gastric cancer. He was initially diagnosed with nivolumab-induced myositis, because the myositis symptoms appeared after nivolumab administration, and nivolumab is known to trigger various drug-associated autoimmune diseases. However, according to his characteristic skin lesions, the type of muscle weakness, his serum marker profiles, electromyography of his deltoid muscle, and magnetic resonance imaging, he was finally diagnosed as having paraneoplastic dermatomyositis. Accordingly, treatment with intravenously administered corticosteroid pulse treatment, immunoglobulin injection, and tacrolimus was applied; his symptoms subsequently improved. However, to our regret, at day 142 after administration, he died due to rapid worsening of his gastric cancer. CONCLUSION: Differentially diagnosing paraneoplastic dermatomyositis or drug-associated myositis caused by immune checkpoint inhibitors is difficult in some cases. The differential diagnosis is crucial because it influences the decision regarding the appropriateness of the use of immunosuppressive treatment against the autoimmune diseases as well as the decision regarding the appropriateness of the continuous use of immune checkpoint inhibitors against the primary cancers. Because subclinical autoimmune disease may become overt after administering immune checkpoint inhibitors, non-apparent autoimmune diseases, which have already existed, should also be considered to avoid the delay of appropriate treatment, when symptoms of autoimmune diseases are recognized.

Pancreaticoduodenectomy for an Ampullary Region Carcinoma Occurred in Annular Pancreas Coexistent with Replaced Common Hepatic Artery.

INTRODUCTION: Annular pancreas is a rare congenital abnormality characterized by a ring of pancreatic tissue surrounding the descending portion of the duodenum. Annular pancreas coexisting with replaced common hepatic artery which is also a rare anatomical variation has not been reported previously. CASE PRESENTATION: A 53-year-old man visited our hospital complaining of epigastric pain. Based on radiological examinations, he was diagnosed as having pancreatitis, annular pancreas, and hepatomesenteric trunk. One month later, obstructive jaundice developed. Endoscopic examination revealed ampullary region carcinoma. We performed pancreaticoduodenectomy using the "artery-first" approach. DISCUSSION: Both annular pancreas and common hepatic artery anomaly are rare. High-quality preoperative imaging and awareness of such rare conditions are necessary for operative safety. Although the embryological relationship between these anomalies is uncertain, the present case may suggest some relevance between the two. CONCLUSION: The "artery-first" approach may be a useful method for pancreaticoduodenectomy in patients who have an anatomical abnormality.

Multicenter study of endoscopic preoperative biliary drainage for malignant hilar biliary obstruction: E-POD hilar study.

BACKGROUND AND AIM: Endoscopic nasobiliary drainage (ENBD) is often recommended in preoperative biliary drainage (PBD) for hilar malignant biliary obstruction (MBO), but endoscopic biliary stent (EBS) is also used in the clinical practice. We conducted this large-scale multicenter study to compare ENBD and EBS in this setting. METHODS: A total of 374 cases undergoing PBD including 281 ENBD and 76 EBS for hilar MBO in 29 centers were retrospectively studied. RESULTS: Extrahepatic cholangiocarcinoma (ECC) accounted for 69.8% and Bismuth-Corlette classification was III or more in 58.8% of the study population. Endoscopic PBD was technically successful in 94.6%, and adverse event rate was 21.9%. The rate of post-endoscopic retrograde cholangiopancreatography pancreatitis was 16.0%, and non-endoscopic sphincterotomy was the only risk factor (odds ratio [OR] 2.51). Preoperative re-intervention was performed in 61.5%: planned re-interventions in 48.4% and unplanned re-interventions in 31.0%. Percutaneous transhepatic biliary drainage was placed in 6.4% at the time of surgery. The risk factors for unplanned procedures were ECC (OR 2.64) and total bilirubin ≥ 10 mg/dL (OR 2.18). In surgically resected cases, prognostic factors were ECC (hazard ratio [HR] 0.57), predraiange magnetic resonance cholangiopancreatography (HR 1.62) and unplanned re-interventions (HR 1.81). EBS was not associated with increased adverse events, unplanned re-interventions, or a poor prognosis. CONCLUSIONS: Our retrospective analysis did not demonstrate the advantage of ENBD over EBS as the initial PBD for resectable hilar MBO. Although the technical success rate of endoscopic PBD was high, its re-intervention rate was not negligible, and unplanned re-intervention was associated with a poor prognosis in resected hilar MBO.

Evaluation of the Efficacy of Sorafenib on Overall Survival in Patients with Hepatocellular Carcinoma using FT Rate: A Devised Index.

INTRODUCTION: Transcatheter arterial chemoembolization (TACE) is the first-line treatment for intermediate stage hepatocellular carcinoma (HCC) and prolongs survival in HCC patients. However, repeated TACE results in diminished therapeutic response. In addition, the superiority of sorafenib to TACE monotherapy or combined therapy in patients with HCC is still controversial. The prognosis of HCC has many variables and, thus, the effect of a specific treatment is difficult to evaluate. The frequency of treatments per year (FT rate) used in this study was obtained by dividing the total number of radiofrequency ablations and TACE or transcatheter arterial infusion treatments by the years of survival. The aim of this study was to evaluate the overall survival (OS) of TACE versus sorafenib using the FT rate. METHODS: We compared the OS of patients with recurrence of HCC receiving repeated TACE monotherapy (CON) with those receiving therapy switched from TACE to sorafenib (SOR). In addition, a one-to-one FT rate matching cohort consisting of matched SOR (mSOR) and matched CON (mCON) was determined using the propensity score matching method, and OS in the cohort was evaluated. Factors influencing survival were evaluated using Cox proportional hazard regression analysis in all patients and the FT rate matched cohort. RESULTS: In the FT rate matched cohort, the cumulative survival rate was significantly higher in the mSOR group compared with the mCON group. Multivariate regression analysis of the FT rate matched cohort showed the FT rate and sorafenib to be significant variables for survival with a hazard ratio (HR) of 2.86 (p < 0.001) and 0.42 (p = 0.008), respectively. CONCLUSION: Early switching from TACE to sorafenib therapy may prolong OS in HCC patients unresponsive to TACE. The present study indicates that the FT rate is potentially a useful index in evaluating the outcome for patients at various stages and treatment regimens. FUNDING: Bayer Yakuhin, Ltd.

Gemcitabine and S-1 versus gemcitabine and cisplatin treatment in patients with advanced biliary tract cancer: a multicenter retrospective study.

Objective This study aimed to compare the safety and efficacy of the combination therapy of gemcitabine and S-1 (GS) versus gemcitabine and cisplatin (GC) in patients with advanced biliary tract cancer (BTC). Methods In this multicenter retrospective cohort study, a total of 212 patients with advanced BTC receiving GS (n = 125) or GC (n = 87) between July 2006 and August 2015 were analyzed. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective tumor response, and safety. Results Patient characteristics were well balanced between the two groups, except for tumor size (the baseline sum of the largest diameter of the tumor: 6.3 cm in the GS group vs. 8.6 cm in the GC group, p = 0.01). Although the response rate was higher in the GS group than in the GC group (28.8% vs. 10.3%, p = 0.01), the median PFS and OS were comparable between the two groups (PFS of 5.6 vs. 7.6 months, p = 0.74; OS of 12.4 vs. 9.2 months, p = 0.20, respectively). Stomatitis and skin rash were more frequently observed in the GS group, whereas anemia, thrombocytopenia, nausea, and renal toxicity were more commonly observed in the GC group. Conclusion This study demonstrates that GS and GC are similar with regard to their safety and efficacy in patients with advanced BTC. GS could serve as an alternative treatment for advanced BTC as a first-line chemotherapy.

Potential Effectiveness of Tolvaptan to Improve Ascites Unresponsive to Standard Diuretics and Overall Survival in Patients with Decompensated Liver Cirrhosis.

BACKGROUND AND OBJECTIVE: After tolvaptan was approved for the treatment of cirrhosis patients with ascites, only a few studies have reported its efficacy in the real clinical setting, and no studies have reported its contribution to overall survival. This study clarified the clinical outcomes of tolvaptan treatment in terms of improving ascites unresponsive to standard diuretics (AUS) and overall survival. METHODS: We retrospectively enrolled 80 decompensated cirrhosis patients with AUS who were administered tolvaptan from October 2012 to December 2014. The patients were divided into two groups according to ascites improvement. We compared laboratory results and overall survival and analyzed factors that affected overall survival. RESULTS: Of the 80 patients, 59 (73.8 %) were male and the median age was 70 years. Thirty-nine (48.8 %) patients were Child-Pugh class C, and 36 (45.0 %) had advanced hepatocellular carcinoma (HCC). Tolvaptan was effective in 48 (60.0 %) patients with an average 3.8 kg weight reduction and ineffective in 32 (40.0 %) patients. The cumulative survival rate differed significantly between the two groups (p < 0.0001), with 87.5 and 68.0 % survival at 30 and 90 days, respectively, in the effective group, and 50.0 and 30.5 % survival, respectively, in the ineffective group. Multivariate analysis showed that improvement in AUS, advanced HCC, total bilirubin level, blood urea nitrogen level, and the presence of hyponatremia were independent predictors of overall survival. CONCLUSIONS: Tolvaptan could possibly improve overall survival in decompensated cirrhosis patients with AUS as long as it was demonstrated to be effective in these patients.

Multicenter study of endoscopic preoperative biliary drainage for malignant distal biliary obstruction.

AIM: To determine the optimal method of endoscopic preoperative biliary drainage for malignant distal biliary obstruction. METHODS: Multicenter retrospective study was conducted in patients who underwent plastic stent (PS) or nasobiliary catheter (NBC) placement for resectable malignant distal biliary obstruction followed by surgery between January 2010 and March 2012. Procedure-related adverse events, stent/catheter dysfunction (occlusion or migration of PS/NBC, development of cholangitis, or other conditions that required repeat endoscopic biliary intervention), and jaundice resolution (bilirubin level < 3.0 mg/dL) were evaluated. Cumulative incidence of jaundice resolution and dysfunction of PS/NBC were estimated using competing risk analysis. Patient characteristics and preoperative biliary drainage were also evaluated for association with the time to jaundice resolution and PS/NBC dysfunction using competing risk regression analysis. RESULTS: In total, 419 patients were included in the study (PS, 253 and NBC, 166). Primary cancers included pancreatic cancer in 194 patients (46%), bile duct cancer in 172 (41%), gallbladder cancer in three (1%), and ampullary cancer in 50 (12%). The median serum total bilirubin was 7.8 mg/dL and 324 patients (77%) had ≥ 3.0 mg/dL. During the median time to surgery of 29 d [interquartile range (IQR), 30-39 d]. PS/NBC dysfunction rate was 35% for PS and 18% for NBC [Subdistribution hazard ratio (SHR) = 4.76; 95%CI: 2.44-10.0, P < 0.001]; the pig-tailed tip was a risk factor for PS dysfunction. Jaundice resolution was achieved in 85% of patients and did not depend on the drainage method (PS or NBC). CONCLUSION: PS has insufficient patency for preoperative biliary drainage. Given the drawbacks of external drainage via NBC, an alternative method of internal drainage should be explored.

Effectiveness of Ipragliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor, as a Second-line Treatment for Non-Alcoholic Fatty Liver Disease Patients with Type 2 Diabetes Mellitus Who Do Not Respond to Incretin-Based Therapies Including Glucagon-like Peptide-1 Analogs and Dipeptidyl Peptidase-4 Inhibitors.

BACKGROUND: We previously reported that incretin-based drugs, such as dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon-like peptide-1 (GLP-1) analogs, improved glycemic control and liver inflammation in non-alcoholic fatty liver disease (NAFLD) patients with type 2 diabetes mellitus (T2DM). However, the effect on alanine aminotransferase (ALT) normalization was still limited. AIMS: The aim of this study is to elucidate the effectiveness of sodium-glucose co-transporter 2 (SGLT-2) inhibitors as second-line treatments for NAFLD patients with T2DM who do not respond to incretin-based therapy. METHODS: We retrospectively enrolled 130 consecutive Japanese NAFLD patients with T2DM who were treated with GLP-1 analogs or DPP-4 inhibitors. Among them, 70 patients (53.8 %) had normal ALT levels. Of the remaining 60 patients (46.2 %) who did not have normal ALT levels, 24 (40.0 %) were enrolled in our study and were administered SGLT-2 inhibitors in addition to GLP-1 analogs or DPP-4 inhibitors. We compared changes in laboratory data including ALT levels and body weight at the end of the follow-up. RESULTS: Thirteen patients were administered a combination of SGLT-2 inhibitors with DPP-4 inhibitors, and the remaining 11 patients were administered a combination of SGLT-2 inhibitors with GLP-1 analogs. The median dosing period was 320 days. At the end of the follow-up, body weight (from 84.8 to 81.7 kg, p < 0.01) and glycosylated hemoglobin levels (from 8.4 to 7.6 %, p < 0.01) decreased significantly. Serum ALT levels also decreased significantly (from 62 to 38 IU/L, p < 0.01) with an improvement in the FIB-4 index (from 1.75 to 1.39, p = 0.04). Finally, 14 patients (58.3 %) achieved normalization of serum ALT levels. CONCLUSIONS: Administration of SGLT-2 inhibitors led to not only good glycemic control, but also to a reduction in body weight, normalization of ALT levels, and a reduction in the FIB-4 index even in patients who did not respond to incretin-based therapy.