The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD

Patients with nonalcoholic fatty liver disease (NAFLD) and advanced liver fibrosis are at the highest risk for progressing to end-stage liver disease. We constructed and validated a scoring system consisting of routinely measured and readily available clinical and laboratory data to separate NAFLD patients with and without advanced fibrosis. A total of 733 patients with NAFLD confirmed by liver biopsy were divided into 2 groups to construct (n = 480) and validate (n = 253) a scoring system. Routine demographic, clinical, and laboratory variables were analyzed by multivariate modeling to predict presence or absence of advanced fibrosis. Age, hyperglycemia, body mass index, platelet count, albumin, and AST/ALT ratio were independent indicators of advanced liver fibrosis. A scoring system with these 6 variables had an area under the receiver operating characteristic curve of 0.88 and 0.82 in the estimation and validation groups, respectively. By applying the low cutoff score (-1.455), advanced fibrosis could be excluded with high accuracy (negative predictive value of 93% and 88% in the estimation and validation groups, respectively). By applying the high cutoff score (0.676), the presence of advanced fibrosis could be diagnosed with high accuracy (positive predictive value of 90% and 82% in the estimation and validation groups, respectively). By applying this model, a liver biopsy would have been avoided in 549 (75%) of the 733 patients, with correct prediction in 496 (90%). CONCLUSION: a simple scoring system accurately separates patients with NAFLD with and without advanced fibrosis, rendering liver biopsy for identification of advanced fibrosis unnecessary in a substantial proportion of patients.     

Overlap of autoimmune hepatitis and primary biliary cirrhosis: long-term outcomes

BACKGROUND: The coexistence of primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) has been called "overlap syndrome," but diagnosis is challenging and the natural history of this syndrome has not been demonstrated. The importance of the diagnosis of PBC-AIH overlap is due to potential therapeutic options. Patients with PBC should receive ursodeoxycholic acid (UDCA); the role of and response to additional immunosuppressive therapy are unknown when AIH overlaps PBC. METHODS AND RESULTS: We reviewed 135 patients with PBC according to a revised scoring system proposed by the International Autoimmune Hepatitis Group (IAHG). Twenty-six patients had features of PBC-AIH overlap and 109 did not. Mean follow-up was 6.1 yr for overlap syndrome patients and 5.4 yr in PBC patients. There was a higher rate of portal hypertension (P=0.01), esophageal varices (P<0.01), gastrointestinal (GI) bleeding (P=0.02), ascites (P<0.01), and death and/or orthotopic liver transplantation (OLT) (P<0.05) in the overlap group. CONCLUSION: In conclusion, esophageal varices, GI bleeding, ascites, and death and/or OLT were more common in the overlap group. The higher risk of symptomatic portal hypertension and worse outcomes in patients with PBC overlap syndrome may justify the risks of immunosuppressive therapy. Large randomized studies are necessary to establish optimal therapeutic strategies.     

Sexual Function and Quality of Life for Women with Mild‐to‐Moderate Stress Urinary Incontinence

Introduction: Sexual function is affected by stress urinary incontinence with or without pelvic organ prolapse. The aim of the study was to describe the sexual function of women with mild‐to‐moderate stress urinary incontinence, with or without pelvic organ prolapse (up to stage 2) and examine correlations with symptoms and quality of life. This investigation was part of a large, randomized, clinical trial of women with stress urinary incontinence who participated in an exercise intervention. Methods: Women included in the study suffered from stress urinary incontinence as measured by a pad test and were interested in an exercise intervention. All participants underwent assessment for prolapse staging. Instruments included: the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ‐12), Incontinence Quality of Life Questionnaire (I‐QOL), and a health and urinary leakage questionnaire. Results: One hundred and eighty‐seven ambulatory women, aged 20 to 65 years, had a mean sexual function score of 36.9 (standard deviation [SD] 5.9). No significant correlation was found between the sexual function scores and quantity of urinary leakage. A significant correlation existed between the sexual function and I‐QOL scores (P < .001). An additional finding was that women with urgency symptoms were older (P= .04) and had significantly lower sexual function scores (mean 35.7; SD 6.4) than those who did not report urgency (mean 38.7; SD 4.6; P < .001). Discussion: Women with mild‐to‐moderate stress urinary incontinence, without or with lower stages of pelvic organ prolapse, demonstrated good sexual function, which correlated with physical and psychosocial factors. Health professionals need to perform multifaceted intake assessments on women with urinary leakage to customize their health promotion regimen.     

Detection of circulating tumour DNA after neoadjuvant chemoradiotherapy in patients with locally advanced oesophageal cancer

Active surveillance instead of standard surgery after neoadjuvant chemoradiotherapy (nCRT) has been proposed for patients with oesophageal cancer. Circulating tumour DNA (ctDNA) may be used to facilitate selection of patients for surgery. We show that detection of ctDNA after nCRT seems highly suggestive of major residual disease. Tumour biopsies and blood samples were taken before, and 6 and 12 weeks after, nCRT. Biopsies were analysed with regular targeted next-generation sequencing (NGS). Circulating cell-free DNA (cfDNA) was analysed using targeted NGS with unique molecular identifiers and digital polymerase chain reaction. cfDNA mutations matching pre-treatment biopsy mutations confirmed the presence of ctDNA. In total, 31 patients were included, of whom 24 had a biopsy mutation that was potentially detectable in cfDNA (77%). Pre-treatment ctDNA was detected in nine of 24 patients (38%), four of whom had incurable disease progression before surgery. Pre-treatment ctDNA detection had a sensitivity of 47% (95% CI 24–71) (8/17), specificity of 85% (95% CI 42–99) (6/7), positive predictive value (PPV) of 89% (95% CI 51–99) (8/9), and negative predictive value (NPV) of 40% (95% CI 17–67) (6/15) for detecting major residual disease (>10% residue in the resection specimen or progression before surgery). After nCRT, ctDNA was detected in three patients, two of whom had disease progression. Post-nCRT ctDNA detection had a sensitivity of 21% (95% CI 6–51) (3/14), specificity of 100% (95% CI 56–100) (7/7), PPV of 100% (95% CI 31–100) (3/3), and NPV of 39% (95% CI 18–64) (7/18) for detecting major residual disease. The addition of ctDNA to the current set of diagnostics did not lead to more patients being clinically identified with residual disease. These results indicate that pre-treatment and post-nCRT ctDNA detection may be useful in identifying patients at high risk of disease progression. The addition of ctDNA analysis to the current set of diagnostic modalities may not improve detection of residual disease after nCRT. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.     

Optimizing therapy in primary biliary cholangitis: Alkaline phosphatase at six months identifies one-year non-responders and predicts survival

Background and Aims

Patients with primary biliary cholangitis (PBC) and insufficient response to ursodeoxycholic acid (UDCA), currently assessed after 1 year, are candidates for second-line therapy. The aims of this study are to assess biochemical response pattern and determine the utility of alkaline phosphatase (ALP) at six months as a predictor of insufficient response.

Methods

UDCA-treated patients in the GLOBAL PBC database with available liver biochemistries at one year were included. POISE criteria were used to assess response to treatment, defined as ALP <1.67 × upper limit of normal (ULN) and normal total bilirubin at one year. Various thresholds of ALP at six months were evaluated to predict insufficient response based on negative predictive value (NPV) and that with nearest to 90% NPV was selected.

Results

For the study, 1362 patients were included, 1232 (90.5%) female, mean age of 54 years. The POISE criteria were met by 56.4% (n = 768) of patients at one year. The median ALP (IQR) of those who met POISE criteria compared to those who did not was 1.05 × ULN (0.82–1.33) vs. 2.37 × ULN (1.72–3.69) at six months (p < .001). Of 235 patients with serum ALP >1.9 × ULN at six months, 89% did not achieve POISE criteria (NPV) after one year of UDCA. Of those with insufficient response by POISE criteria at one year, 210 (67%) had an ALP >1.9 × ULN at six months and thus would have been identified early.

Conclusions

We can identify patients for second-line therapy at six months using an ALP threshold of 1.9 × ULN, given that approximately 90% of these patients are non-responders according to POISE criteria.     

Safety and efficacy of estrogen therapy in preventing bone loss in primary biliary cirrhosis

OBJECTIVE: Estrogen therapy has been found to be useful in the treatment of postmenopausal osteoporosis. However, concern about its potential for worsening cholestasis has limited its use in postmenopausal women with primary biliary cirrhosis. The aim of the present study was to determine the safety as well as the efficacy of estrogen replacement therapy with respect to bone mass in postmenopausal women with primary biliary cirrhosis. METHODS: Bone mineral density of the lumbar spine (measured using dual energy x-ray absorptiometry) of 46 unselected postmenopausal women with primary biliary cirrhosis receiving estrogen replacement therapy was compared with 46 age-matched women with primary biliary cirrhosis not receiving estrogen replacement therapy, and with the expected normal bone mineral density adjusted for age and ethnic group. RESULTS: The mean duration of follow-up was 4.8 +/- 0.4 yr. Treatment with estrogens resulted in a significantly lower rate of bone loss (0.002 g/cm(2)/yr +/- 0.028 vs 0.009 g/cm(2)/yr +/- 0.020, p = 0.05). Worsening cholestasis attributable to estrogen replacement therapy did not occur in any patient. One patient (2%) discontinued therapy because of side effects. CONCLUSIONS: Estrogen replacement therapy in postmenopausal patients with primary biliary cirrhosis is safe and may be effective in decreasing the rate of bone loss.     

Primary sclerosing cholangitis

Primary sclerosing cholangitis is a chronic cholestatic disease characterized by periductal inflammation of intrahepatic and extrahepatic bile ducts with obliterative fibrosis and duct loss. Significant loss of bile ducts leads to interference with bile flow and ultimately results in cirrhosis of the biliary type. Aside from viral hepatitis and alcoholic liver disease, primary sclerosing cholangitis is one of the most common indications for liver transplantation. Although there is no known beneficial therapy for these patients, research aimed toward better understanding the pathogenetic mechanisms and clinical trials with promising new agents are ongoing.     

Fundamentals about onset and progressive disease character of type 2 diabetes mellitus

ResearchGate is a world wide web for scientists and researchers to share papers, ask and answer questions, and find collaborators. As one of the more than 15 million members, the author uploads research output and reads and responds to some of the questions raised, which are related to type 2 diabetes. In that way, he noticed a serious gap of knowledge of this disease among medical professionals over recent decades. The main aim of the current study is to remedy this situation through providing a comprehensive review on recent developments in biochemistry and molecular biology, which can be helpful for the scientific understanding of the molecular nature of type 2 diabetes. To fill up the shortcomings in the curricula of medical education, and to familiarize the medical community with a new concept of the onset of type 2 diabetes, items are discussed like: Insulin resistance, glucose effectiveness, insulin sensitivity, cell membranes, membrane flexibility, unsaturation index (UI; number of carbon-carbon double bonds per 100 acyl chains of membrane phospholipids), slow-down principle, effects of temperature acclimation on phospholipid membrane composition, free fatty acids, energy transport, onset of type 2 diabetes, metformin, and exercise. Based on the reviewed data, a new model is presented with proposed steps in the development of type 2 diabetes, a disease arising as a result of a hypothetical hereditary anomaly, which causes hyperthermia in and around the mitochondria. Hyperthermia is counterbalanced by the slow-down principle, which lowers the amount of carbon-carbon double bonds of membrane phospholipid acyl chains. The accompanying reduction in the UI lowers membrane flexibility, promotes a redistribution of the lateral pressure in cell membranes, and thereby reduces the glucose transporter protein pore diameter of the transmembrane glucose transport channel of all Class I GLUT proteins. These events will set up a reduction in transmembrane glucose transport. So, a new blood glucose regulation system, effective in type 2 diabetes and its prediabetic phase, is based on variations in the acyl composition of phospholipids and operates independent of changes in insulin and glucose concentration. UI assessment is currently arising as a promising analytical technology for a membrane flexibility analysis. An increase in mitochondrial heat production plays a pivotal role in the existence of this regulation system.