Combined effect of histological findings and diabetes mellitus on liver-related events in patients with metabolic dysfunction-associated steatotic liver disease.

AIM: Advanced fibrosis has a strong influence on the occurrence of liver-related events in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), while diabetes mellitus (DM), which is often complicated by MASLD, is associated with the progression of MASLD. We stratified patients with MASLD according to the severity of liver pathological findings and the presence of DM, aiming to examine whether these indices could be used to accurately assess the risk of developing liver-related events. METHODS: A total of 282 patients with liver biopsy-proven MASLD were included. Liver-related events were defined as the occurrence of hepatocellular carcinoma (HCC) and complications of liver cirrhosis, such as ascites, hepatic encephalopathy, Child-Pugh class B and C, as well as treatment-eligible esophageal and gastric varices. RESULTS: Multivariate analysis adjusted for age, sex, body mass index, alanine aminotransferase, creatinine, hemoglobin A1c, smoking habits, dyslipidemia, hypertension, nonalcoholic fatty liver disease activity score (NAS), or fibrosis stage showed that advanced fibrosis with or without DM was a risk factor for liver-related events. The combined effect of DM and advanced fibrosis increased the risk of HCC onset. However, DM alone or in combination with NAS did not affect the development of liver-related events, including the occurrence of HCC and complications of liver cirrhosis. CONCLUSIONS: While the assessment of fibrosis in patients with MASLD is important for evaluating the risk of developing liver-related events, combining the assessment of DM may be possible to stratify groups at higher risk of developing HCC.

Association of abnormal glucose tolerance with liver-related disease and cardiovascular diseases in patients with chronic hepatitis C.

AIM: Hepatitis C complicated by diabetes mellitus (DM) is considered a risk factor for the progression of fibrosis and development of hepatocellular carcinoma (HCC) and cardiovascular diseases. However, several studies may have lacked appropriate diagnosis of glucose intolerance. We aimed to examine the risk associated with abnormal glucose intolerance in the development of liver-related diseases, including HCC and complications of liver cirrhosis, such as ascites, esophageal and gastric varices, and hepatic encephalopathy, and cardiovascular diseases in patients with hepatitis C accurately diagnosed with impaired glucose tolerance. METHODS: This longitudinal retrospective study included 365 patients with chronic hepatitis C admitted to Ehime University Hospital for anti-hepatitis C therapy between September 1991 and January 2015. Patients were classified into normal glucose tolerance (NGT), prediabetes, and DM groups based on 75-g oral glucose tolerance test results. RESULTS: Both univariate and multivariate (adjusted for potential confounders) analyses revealed a significantly higher risk of developing HCC and cardiovascular events in the DM group than in the NGT group. However, in multivariate analysis, liver-related events, particularly liver cirrhosis complications, revealed no significant association. In addition, the prediabetes group had no significant risk of any outcome. CONCLUSIONS: Patients with hepatitis C complicated by DM, compared with patients with hepatitis C with NGT or complicated with prediabetes, have a higher risk of HCC and cardiovascular disease events, but not liver-related events, particularly in not developing liver cirrhosis complications. Therefore, appropriate follow-up is required for patients with hepatitis C based on their glucose tolerance status.

Relationship between body composition and the histology of non-alcoholic fatty liver disease: a cross-sectional study.

BACKGROUND: Causes of non-alcoholic fatty liver disease and its progression include visceral fat accumulation and loss of muscle mass; however, which of the two phenomena is more critical is unclear. Therefore, we intended to examine the relationship between body composition and non-alcoholic fatty liver disease progression as indicated by fibrosis and the non-alcoholic fatty liver disease activity score. METHODS: This cross-sectional study comprised 149 patients (55 men; age, 20-76 years) treated for non-alcoholic fatty liver disease between December 2010 and January 2020. Body composition measurements, histological examinations of liver samples, and comprehensive blood chemistry tests were performed. The relationship between body composition and non-alcoholic fatty liver disease histology findings was analyzed using the logistic regression model. RESULTS: Fibrosis was significantly and inversely correlated with muscle mass and appendicular skeletal muscle mass and significantly and positively correlated with fat mass, fat mass/height squared, visceral fat area, and waist-hip ratio (P < 0.05). After adjustment for sex, blood chemistry measurements, and body composition indices, fibrosis remained associated with appendicular skeletal muscle mass, fat mass, fat mass/height squared, and visceral fat area (P < 0.05). Non-alcoholic fatty liver disease activity score ≥ 5 significantly correlated with fat mass and fat mass/height squared in a univariate but not multivariate analysis. CONCLUSIONS: Fibrosis in non-alcoholic fatty liver disease, an indicator of unfavorable long-term outcomes, is associated with more indices of fat mass than of those of muscle mass. Hence, fat mass should be controlled to prevent non-alcoholic fatty liver disease progression.

Tricks and traps of ICG endoscopy for effectively applying endoscopic transsphenoidal surgery to pituitary adenoma.

Differentiating tumor from normal pituitary gland is very important for achieving complete resection without complications in endoscopic endonasal transsphenoidal surgery (ETSS) for pituitary adenoma. To facilitate such surgery, we investigated the utility of indocyanine green (ICG) fluorescence endoscopy as a tool in ETSS. Twenty-four patients with pituitary adenoma were enrolled in the study and underwent ETSS using ICG endoscopy. After administering 12.5 mg of ICG twice an operation with an interval > 30 min, times from ICG administration to appearance of fluorescence on vital structures besides the tumor were measured. ICG endoscopy identified vital structures by the phasic appearance of fluorescent signals emitted at specific consecutive elapsed times. Elapsed times for internal carotid arteries did not differ according to tumor size. Conversely, as tumor size increased, elapsed times for normal pituitary gland were prolonged but those for the tumor were reduced. ICG endoscopy revealed a clear boundary between tumors and normal pituitary gland and enabled confirmation of no more tumor. ICG endoscopy could provide a useful tool for differentiating tumor from normal pituitary gland by evaluating elapsed times to fluorescence in each structure. This method enabled identification of the boundary between tumor and normal pituitary gland under conditions of a low-fluorescence background, resulting in complete tumor resection with ETSS. ICG endoscopy will contribute to improve the resection rate while preserving endocrinological functions in ETSS for pituitary adenoma.

Association between serum remnant cholesterol level and metabolic dysfunction-associated steatotic liver histology.

CONTEXT: Estimated remnant cholesterol (Rem-C) level, a risk factor for cardiovascular disease (CVD), is associated with metabolic dysfunction-associated steatotic liver disease (MASLD) diagnosed via ultrasonography. However, the relationship between accurate serum Rem-C level measurements and histological findings of MASLD remains unclear. OBJECTIVE: We aimed to elucidate the relationship between accurately measured serum Rem-C levels and histological findings of MASLD. DESIGN: Cross-sectional single-center observational study. METHODS: We assessed 222 patients (94 men and 128 women; age 20-80) who were diagnosed with MASLD via liver biopsy with available medical history, physical examination, and biochemical measurement data. Serum ester-type cholesterol and free cholesterol contents in the remnant lipoproteins were measured using an enzymatic method. RESULTS: Serum Rem-C levels were significantly higher in patients with NAFLD activity score (NAS) 5-8, ＞66% steatosis grade, lobular inflammation with ≥5 foci, and many cells/prominent ballooning cells (a contiguous patch of hepatocytes showing prominent ballooning injury) than in patients with NAS 1-4, <33% steatosis grade, lobular inflammation with <2 foci, and few ballooning cells (several scattered balloon cells), respectively. While univariate analysis revealed no significant association between Rem-C levels and advanced fibrosis, a significant association between Rem-C levels and NAS was evident. This relationship remained significant in multivariate analysis adjusted for confounders. Furthermore, in the analysis by sex, these relationships were significant for men but not for women. CONCLUSION: High serum Rem-C levels were associated with high NAS, but not with fibrosis stage, particularly in men. Controlling serum Rem-C level may improve MASLD activity.

Glycemic Control Is Associated with Histological Findings of Nonalcoholic Fatty Liver Disease.

BACKGRUOUND: Poor lifestyle habits may worsen nonalcoholic fatty liver disease (NAFLD), with progression to nonalcoholic steatohepatitis (NASH) and cirrhosis. This study investigated the association between glycemic control status and hepatic histological findings to elucidate the effect of glycemic control on NAFLD. METHODS: This observational study included 331 patients diagnosed with NAFLD by liver biopsy. Effects of the glycemic control status on histological findings of NAFLD were evaluated by comparing the following four glycemic status groups defined by the glycosylated hemoglobin (HbA1c) level at the time of NAFLD diagnosis: ≤5.4%, 5.5%-6.4%, 6.5%-7.4%, and ≥7.5%. RESULTS: Compared with the lowest HbA1c group (≤5.4%), the higher HbA1c groups (5.5%-6.4%, 6.5%-7.4%, and ≥7.5%) were associated with advanced liver fibrosis and high NAFLD activity score (NAS). On multivariate analysis, an HbA1c level of 6.5%- 7.4% group was significantly associated with advanced fibrosis compared with the lowest HbA1c group after adjusting for age, sex, hemoglobin, alanine aminotransferase, and creatinine levels. When further controlling for body mass index and uric acid, total cholesterol, and triglyceride levels, the higher HbA1c groups were significantly associated with advanced fibrosis compared with the lowest HbA1c group. On the other hand, compared with the lowest HbA1c group, the higher HbA1c groups were also associated with a high NAS in both multivariate analyses. CONCLUSION: Glycemic control is associated with NAFLD exacerbation, with even a mild deterioration in glycemic control, especially a HbA1c level of 6.5%-7.4%, contributing to NAFLD progression.

Clinical utility of spoiled-gradient echo 3D-T1 sequence in deciding appropriate treatment strategy for ACTH-producing pituitary adenoma; a case report and review of the literature.

INTRODUCTION AND IMPORTANCE: When treating adrenocorticotropic hormone (ACTH)-producing adenoma, accurate tumor localization is critical. We report a case of Cushing's disease in which MRI with a spoiled-gradient echo 3D T1-weighted sequence was useful in precise localization of an ACTH-producing adenoma and deciding appropriate treatment strategy. CASE PRESENTATION: A 47-year-old woman was admitted to our hospital with signs and symptoms of Cushing's disease. Laboratory findings showed hypercortisolemia and suggested Cushing's disease. However, neuroimaging on conventional pituitary MRI using a spin-echo (SE) protocol did not confirm pituitary adenoma in the sella turcica. Inferior petrosal sinus sampling suggested a higher central/peripheral ratio of ACTH after corticotropin-releasing hormone (CRH) administration on the right side. Reviewing the dynamic MRI using an SE protocol from that perspective, we vaguely identified a 5.0 mm area of gradual contrast on the right side of the pituitary gland. In addition, pituitary MRI with a spoiled-gradient echo 3D T1-weighted sequence, a 2.0 mm hypo-enhancing region was identified on the right side within the anterior pituitary gland. The tumor was resected completely removing the right pituitary gland including the tumor. The histological diagnosis was ACTH-producing pituitary adenoma. Symptoms of Cushing's disease gradually improved and endocrinological function normalized. Follow-up neuroimaging after 1 year showed no signs of recurrence. CLINICAL DISCUSSION: In the treatment of Cushing's disease, accurate detection of ACTH-producing pituitary adenoma is crucial to maximizing curative rates. However, exact confirmation of the tumor location is very difficult. CONCLUSION: MRI with a spoiled-gradient echo 3D T1-weighted sequence may facilitate accurate tumor localization and appropriate treatment strategy.

Simultaneous combined endoscopic endonasal and transcranial surgery for giant pituitary adenomas: Tips and traps in operative indication and procedure.

OBJECTIVES: This retrospective analysis of patients treated with endoscopic endonasal transsphenoidal surgery (ETSS) alone or simultaneous combined surgery investigated imaging features suitable for surgical methods and pitfalls in simultaneous combined surgery for giant pituitary adenoma. PATIENTS AND METHODS: Ten patients with giant pituitary adenoma treated by ETSS alone or simultaneous combined endoscopic endonasal and transcranial surgery were enrolled. By analyzing tumor imaging features on magnetic resonance imaging (MRI), operative findings and clinical outcomes, we examined types of imaging features suitable for each surgical method. RESULTS: Four patients received ETSS alone and six patients underwent simultaneous combined endonasal and transcranial surgery. Four patients treated by ETSS alone and three patients treated by combined surgery had high resection rates and good outcomes. The remaining three patients with combined surgery achieved partial resection and visual deterioration in one patient. MRI features suitable for ETSS included an enlarged sella, upward tumor extension, and round surface, whereas those for combined surgery included normal/enlarged sella, anterior and/or unilateral tumor extension, and a multilobulated surface. Tumors extending extensively bilaterally or upward and encasing neurovascular structures could not be effectively resected even under combined surgery. CONCLUSION: Both ETSS alone and simultaneous combined endonasal and transcranial surgery showed good results for giant pituitary adenoma when the surgical methods matched suitable imaging features. Tumors with unilateral or anterior extension and a multilobulated surface were maximally resected without neurological deficit by combined surgery, but tumors showing extensive multi-directional extension and full encasement of neurovascular structures were not effectively resected even with combined surgery.

Plasma Fatty Acid Composition Is Associated with Histological Findings of Nonalcoholic Steatohepatitis.

The relationship between advanced nonalcoholic steatohepatitis (NASH) and plasma fatty acid composition remains unknown. We aimed to examine the plasma fatty acid composition in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) and evaluate the relationship between histological findings and fatty acid composition. Overall, 235 patients (134 women) with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. Multivariate analyses adjusted for age, sex, body mass index, alanine aminotransferase, hemoglobin A1c, creatinine, total cholesterol, triglyceride, and NAFLD Activity Score values showed that lower levels of arachidic, behenic, α-linolenic, eicosatetraenoic, docosapentaenoic, and docosahexaenoic acids and higher levels of mead acid were associated with fibrosis stage 3-4. Furthermore, higher lauric acid, myristic acid, and palmitic acid levels and monounsaturated fatty acids such as palmitoleic acid and oleic acid were significantly associated with high NAS in analyses adjusted for the same factors and fibrosis stage. The plasma fatty acid composition was associated with the histological evidence of NASH. Increased synthesis of fatty acids is associated with NASH; insufficient intake of n-3 essential fatty acids and reduced elongation of fatty acids are associated with fibrosis in NASH. These features may help clinicians to understand and treat advanced NASH cases.

Combined evaluation of Fibrosis-4 index and fatty liver for stratifying the risk for diabetes mellitus.

AIMS/INTRODUCTION: To investigate whether the Fibrosis-4 index can help stratify the risk of diabetes mellitus in patients with fatty liver disease. MATERIALS AND METHODS: Based on fatty liver disease and Fibrosis-4 index (cut-off value 1.3), we retrospectively divided 9,449 individuals, who underwent at least two annual health checkups, into four groups stratified by sex: normal; high Fibrosis-4 index without fatty liver disease; low Fibrosis-4 index with fatty liver disease; and high Fibrosis-4 index with fatty liver disease. RESULTS: Onset rates for diabetes mellitus in the normal, high Fibrosis-4 index without fatty liver disease, low Fibrosis-4 index with fatty liver disease and high Fibrosis-4 index with fatty liver disease groups were 1.6%, 4.3%, 6.8% and 10.2%, respectively, in men, and 0.6%, 0.9%, 5.3% and 7.0%, respectively, in women. Compared with the normal group, the high Fibrosis-4 index without fatty liver disease, low Fibrosis-4 index with fatty liver disease and high Fibrosis-4 index with fatty liver disease groups were at a significant risk for diabetes mellitus onset in both male and female participants. Furthermore, in both sexes, high Fibrosis-4 index with fatty liver disease remained a significant risk factor on multivariate analysis (high fibrosis-4 index with fatty liver disease group: adjusted hazard ratio 4.03, 95% confidence interval 2.19-7.42 [men] and adjusted hazard ratio 6.40, 95% confidence interval 1.77-23.14 [women]). CONCLUSIONS: Individuals with fatty liver disease and high Fibrosis-4 index had a higher risk of diabetes mellitus onset. Therefore, Fibrosis-4 index can help stratify the risk of diabetes mellitus in patients with fatty liver disease and identify patients requiring intervention.

Additional Effect of Luseogliflozin on Semaglutide in Nonalcoholic Steatohepatitis Complicated by Type 2 Diabetes Mellitus: An Open-Label, Randomized, Parallel-Group Study.

INTRODUCTION: Untreated nonalcoholic fatty liver may progress to nonalcoholic steatohepatitis (NASH) and cirrhosis and induce hepatocellular carcinoma and liver failure. Type 2 diabetes mellitus (T2DM), often complicated with nonalcoholic fatty liver disease (NAFLD), is a driver of NAFLD progression. Thus, efficacious treatment strategies for patients with coexisting NAFLD and T2DM are important for preventing NAFLD progression. Although previous studies have demonstrated that either sodium-glucose transporter 2 inhibitors (SGLT2is) or glucagon-like peptide 1 receptor agonists (GLP-1 RAs) benefit NASH patients with T2DM, the rate of NASH resolution has not sufficiently improved. Therefore, we developed a protocol for a randomized controlled trial to examine whether the addition of an SGLT2i to the treatment regimen of patients receving a GLP-1 RA (combination therapy), within the therapeutic dose range for T2DM, increases the rate of NASH resolution in patients with coexisting NASH and T2DM. METHODS: This open-label, randomized, parallel-group study commenced in June 2021, will conclude recruitment in May 2023, and will end by March 2025. Sixty patients with NASH complicated by T2DM are enrolled at the Ehime University Hospital in Toon, Japan. Participants will be randomized into: (1) an intervention group receiving combination therapy with the SGLT2i luseogliflozin 2.5 mg, once daily (Taisho Pharmaceutical, Tokyo, Japan) and the GLP-1 RA semaglutide 0.5 mg, once per week (Novonordisk, Copenhagen, Denmark); and (2) a control group receiving monotherapy with the GLP-1 analog semaglutide. The primary endpoints, which will be ascertained by liver biopsy, are: (1) NASH resolution rate from baseline without worsening of liver fibrosis after 52 weeks of intervention; (2) rate of improvement from baseline of at least 1 point in the NAFLD activity score without worsening of liver fibrosis after 52 weeks of intervention; and (3) rate of improvement from baseline of at least one fibrosis stage without worsening of NASH after 52 weeks of intervention. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) number: UMIN000045003. Japan Registry of Clinical Trials registration number: jRCTs061210009.

Fatty liver with metabolic disorder, such as metabolic dysfunction-associated fatty liver disease, indicates high risk for developing diabetes mellitus.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is diagnosed after excluding other liver diseases. The pathogenesis of NAFLD when complicated by other liver diseases has not been established completely. Metabolic dysfunction-associated fatty liver disease (MAFLD) involves more metabolic factors than NAFLD, regardless of complications with other diseases. This study aimed to clarify the effects of fatty liver occurring with metabolic disorders, such as MAFLD without diabetes mellitus (DM), on the development of DM. MATERIALS AND METHODS: We retrospectively assessed 9,459 participants who underwent two or more annual health check-ups. The participants were divided into the MAFLD group (fatty liver disease with overweight/obesity or non-overweight/obesity complicated by metabolic disorders), simple fatty liver group (fatty liver disease other than MAFLD group), metabolic disorder group (metabolic disorder without fatty liver disease), and normal group (all other participants). RESULTS: The DM onset rates in the normal, simple fatty liver, metabolic disorder, and MAFLD groups were 0.51, 1.85, 2.52, and 7.36%, respectively. In the multivariate analysis, the MAFLD group showed a significantly higher risk of DM onset compared with other three groups (P < 0.01). Additionally, the risk of DM onset was significantly increased in fatty liver disease with overweight/obesity or pre-diabetes (P < 0.01). CONCLUSIONS: Fatty liver with metabolic disorders, such as MAFLD, can be used to identify patients with fatty liver disease who are at high risk of developing DM. Additionally, patients with fatty liver disease complicated with overweight/obesity or prediabetes are at an increased risk of DM onset and should receive more attention.

Nonalcoholic fatty liver disease is a risk factor for glucose intolerance onset in men regardless of alanine aminotransferase status.

INTRODUCTION: Fatty liver disease (FLD) is a surrogate condition for glucose intolerance development. FLD may involve normal or abnormal liver enzyme levels. Whether FLD is a risk factor for glucose intolerance, regardless of liver enzyme levels, remains unknown. We assessed relationships between the development of impaired fasting glucose (IFG) and FLD, liver enzyme abnormalities, and alcohol consumption. MATERIALS AND METHODS: We retrospectively evaluated 8,664 participants with more than two annual health check-ups. Participants were classified according to sex, alcohol consumption, alanine aminotransferase (ALT) levels, and fatty liver status. RESULTS: In univariate analyses, IFG onset among men was related to normal or high ALT levels with FLD in the nonalcoholic and alcoholic groups (P-trend < 0.01). In multivariate analyses, IFG onset among nonalcoholic men was associated with normal or high ALT levels with FLD, independent of potential confounding factors (P-trend < 0.01). However, IFG onset was non-independently associated with any condition among alcoholic men. In univariate analyses, IFG onset among women was related to normal or high ALT levels with FLD in the nonalcoholic group (P-trend < 0.01) and high ALT levels with FLD in the alcoholic group (P-trend < 0.05). In multivariate analyses, IFG onset was independently associated with only normal ALT levels in nonalcoholic FLD women. CONCLUSIONS: Among nonalcoholic men and women, FLD was a risk factor for IFG onset, including normal ALT concentrations. Care is needed for individuals with nonalcoholic FLD, regardless of liver injury, possibly helping reduce glucose intolerance risk.

Advanced fibrosis of non-alcoholic steatohepatitis affects the significance of lipoprotein(a) as a cardiovascular risk factor.

BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is an important independent cardiovascular risk factor. However, Lp(a) levels are lower in patients with chronic liver disease than in healthy subjects. Furthermore, Lp(a) levels decrease as residual liver function declines. Although non-alcoholic fatty liver disease (NAFLD), especially advanced non-alcoholic steatohepatitis (NASH), increases the risk of cardiovascular diseases, the relationship between serum Lp(a) level and NASH is unknown. Thus, we examined the relationship between serum Lp(a) levels and biopsy-proved NAFLD and clarified the significance of Lp(a) measurements for cardiovascular disease screening in patients with NAFLD. METHODS: A total of 176 patients with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. The relationship between serum Lp(a) levels and NAFLD was analyzed. RESULTS: Serum Lp(a) levels in advanced fibrosis (stage 3-4) were lower than those in non-advanced fibrosis (stage 0-2) (p < 0.05). After adjustment for age, sex, body mass index, alanine aminotransferase (ALT), creatinine (Cre), HbA1c level, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and the use of lipid-lowering agents, the significant inverse association between advanced fibrosis and serum Lp(a) levels remained (p < 0.01). Although the Lp(a) level was inversely associated with an NAFLD Activity Score (NAS) of 5-8, there was no significant association between Lp(a) levels and NAS adjusted for age, sex, body mass index, ALT, Cre, HbA1c level, HDL-C, LDL-C, TG, and the use of lipid-lowering agents. CONCLUSIONS: Advanced NASH is associated with low serum Lp(a) levels; therefore, Lp(a) levels may not be useful in evaluating cardiovascular risk.