Association between primary hypothyroidism and metabolic dysfunction-associated steatotic liver disease: an updated meta-analysis.

OBJECTIVE: Epidemiological studies have reported an association between primary hypothyroidism and metabolic dysfunction-associated steatotic liver disease (MASLD). However, the magnitude of the risk and whether this risk changes with the severity of MASLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between primary hypothyroidism and the risk of MASLD. DESIGN: We systematically searched PubMed, Scopus and Web of Science from database inception to 31 January 2024, using predefined keywords to identify observational studies in which MASLD was diagnosed by liver biopsy, imaging or International Classification of Diseases codes. A meta-analysis was performed using random-effects modelling. RESULTS: We identified 24 cross-sectional and 4 longitudinal studies with aggregate data on ~76.5 million individuals. Primary hypothyroidism (defined as levothyroxine replacement treatment, subclinical hypothyroidism or overt hypothyroidism) was associated with an increased risk of prevalent MASLD (n=24 studies; random-effects OR 1.43, 95% CI 1.23 to 1.66; I2=89%). Hypothyroidism was also associated with a substantially higher risk of metabolic dysfunction-associated steatohepatitis or advanced fibrosis (n=5 studies; random-effects OR 2.84, 95% CI 2.07 to 3.90; I2=0%). Meta-analysis of data from four longitudinal studies showed that there was a marginally non-significant association between hypothyroidism and risk of developing MASLD over a median 4.5-year follow-up (random-effects HR 1.39, 95% CI 0.98 to 1.97; I2=85%). Sensitivity analyses did not modify these findings. The funnel plot did not reveal any significant publication bias. CONCLUSION: This large and updated meta-analysis provides evidence that primary hypothyroidism is significantly associated with both an increased presence of and histological severity of MASLD.

Nonalcoholic fatty liver disease and hepatocellular carcinoma:Insights in epidemiology, pathogenesis, imaging, prevention and therapy.

Hepatocellular carcinoma (HCC) is estimated to be the third leading cause of cancer-related mortality and is characterized by low survival rates. Nonalcoholic fatty liver disease (NAFLD) is emerging as a leading cause of HCC, whose rates are increasing, owing to the increasing prevalence of NAFLD. The pathogenesis of NAFLD-associated HCC is multifactorial: insulin resistance, obesity, diabetes and the low-grade hepatic inflammation, which characterizes NAFLD, seem to play key roles in the development and progression of HCC. The diagnosis of NAFLD-associated HCC is based on imaging in the presence of liver cirrhosis, preferably computerized tomography or magnetic resonance imaging, but liver biopsy for histological confirmation is usually required in the absence of liver cirrhosis. Some preventive measures have been recommended for NAFLD-associated HCC, including weight loss, cessation of even moderate alcohol drinking and smoking, as well as the use of metformin, statins and aspirin. However, these preventive measures are mainly based on observational studies, thus they need validation in trials of different design before introducing in clinical practice. The treatment of NAFLD should be tailored on an individual basis and should be ideally determined by a multidisciplinary team. In the last two decades, new medications, including tyrosine kinase inhibitors and immune checkpoints inhibitors, have improved the survival of patients with advanced HCC, but trials specifically designed for patients with NAFLD-associated HCC are scarce. The aim of this review was to overview evidence on the epidemiology and pathophysiology of NAFLD-associated HCC, then to comment on imaging tools for its appropriate screening and diagnosis, and finally to critically summarize the currently available options for its prevention and treatment.

The relationship between length of denosumab treatment for postmenopausal osteoporosis and serum TRAcP5b measured six months after the last injection.

To test the hypothesis that during treatment with denosumab osteomorphs and precursors recycle to higher number of osteoclasts with time, we measured TRAcP5b in serum taken 6 months after the last injection in postmenopausal women treated for 1-10 years. Serum TRAcP5b values were not related to time of exposure to denosumab. PURPOSE: In women with postmenopausal osteoporosis the aetiology of the observed inverse relationship between duration of denosumab (Dmab) therapy and bone loss after its discontinuation is currently unknown. In studies in mice inhibition of RANKL is associated with an increase in osteomorphs and osteoclast precursors that recycle into osteoclasts and may accumulate with time. We hypothesized that longer inhibition of RANKL by Dmab will be followed by the synchronous formation of a larger number of osteoclasts after stopping treatment. To test this hypothesis, we measured serum TRAcP5b, a marker of osteoclast numbers, in postmenopausal women treated with Dmab for different periods of time up to 10 years. METHODS: TRAcP5b, C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at 6.0 months ± 15 days after last Dmab injection in 59 women who had received Dmab for 4.0 ± 2.3 years (range 1-10 years). Of these, 38 were treatment naïve (group 1) and 21 had received other treatments prior Dmab (group 2). RESULTS: Duration of Dmab treatment was not related to serum TRAcP5b values or to TRAcP5b/CTX ratio either in the whole cohort or in each of the two groups separately. In contrast, serum TRAcP5b values were significantly correlated with serum CTX values (rs = 0.619; p < 0.001), but not with serum P1NP values or BMD at all skeletal sites. CONCLUSION: Our observations indicate that serum TRAcP5b, measured at 6 months after a Dmab injection, is not a useful early marker for time-dependent increased accumulation of osteoclasts in humans and for identification of patients at risk for a higher rebound increase in bone resorption.

Circulating leptin in patients with nonalcoholic fatty liver disease-related liver fibrosis: a systematic review and a meta-analysis.

BACKGROUND AND AIM: Clinical data on the association between leptin levels and nonalcoholic fatty liver disease (NAFLD)-related liver fibrosis are conflicting. This meta-analysis aimed to compare circulating leptin between NAFLD patients with versus without liver fibrosis or non-NAFLD controls. METHODS: A systematic search was conducted in PubMed, Scopus, and the Cochrane Library. Fifteen studies were included, reporting data from 964 individuals (422 NAFLD patients with fibrosis, 297 NAFLD patients without fibrosis, 245 no-NAFLD controls). RESULTS: Leptin standardized mean difference (SMD) was higher in NAFLD patients with fibrosis (F1-F4) than in controls (SMD: 2.27; 95% confidence interval [CI]: 0.81-3.73); however, this association did not remain robust after the exclusion of studies with morbidly obese individuals. No difference was observed in leptin SMD between NAFLD patients with fibrosis and those without fibrosis (F0), and NAFLD patients without fibrosis versus controls. Heterogeneity was high (I2: 66-98%) among studies. Meta-regression analysis revealed a positive association of leptin SMD with homeostasis model assessment-insulin resistance, when comparing NAFLD patients with fibrosis versus NAFLD patients without fibrosis (beta: 0.53; 95% CI: 0.04-1.03), and a negative association of leptin SMD with age, when comparing NAFLD patients with fibrosis versus controls (beta: -0.29; 95% CI: -0.53 to -0.05). CONCLUSION: Circulating leptin was higher in NAFLD patients with liver fibrosis than non-NAFLD controls, an association, however, attenuated after the exclusion of a study with morbidly obese individuals. Circulating leptin was not different between NAFLD patients with and without fibrosis, or NAFLD patients without fibrosis and controls.

Potential impact of trained innate immunity on the pathophysiology of metabolic dysfunction-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) occurs in a low-grade inflammatory milieu dependent on highly complex networks that span well-beyond the hepatic tissue injury. Dysfunctional systemic metabolism that characterizes the disease, is further induced in response to environmental cues that modify energy and metabolic cellular demands, thereby altering the availability of specific substrates that profoundly regulate, through epigenetic mechanisms, the phenotypic heterogeneity of immune cells and influence hematopoietic stem cell differentiation fate. This immuno-metabolic signaling drives the initiation of downstream effector pathways and results in the decompensation of hepatic homeostasis that precedes pro-fibrotic events. Recent evidence suggests that innate immune cells reside in different tissues in a memory effector state, a phenomenon termed trained immunity, that may be activated by subsequent exogenous (e.g., microbial, dietary) or endogenous (e.g., metabolic, apoptotic) stmuli. This process leads to long-term modifications in the epigenetic landscape that ultimately precondition the cells towards enhanced transcription of inflammatory mediators that accelerates MAFLD development and/or progression. In this mini review we aimed to present current evidence on the potential impact of trained immunity on the pathophysiology of MAFLD, shedding light on the complex immunobiology of the disease and providing novel potential therapeutic strategies to restrain the burden of the disease.

Fibrosis-4 Index Predicts Long-Term All-Cause, Cardiovascular and Liver-Related Mortality in the Adult Korean Population.

BACKGROUND & AIMS: Associations between hepatic fibrosis and mortality remain to be fully elucidated in large population-based studies. This study aimed to evaluate the associations of the fibrosis-4 index (FIB-4) with all-cause, cardiovascular, cancer, and liver-related mortality in the adult Korean population without viral hepatitis. METHODS: Baseline data were retrieved from the Korea National Health and Nutrition Examination Survey, and mortality data were retrieved from the Korean Cause of Death data registry. Adults (age, ≥19 y) without viral hepatitis B or C, liver cirrhosis, any cancer, stroke, myocardial infarction, angina pectoris, or renal failure at baseline were eligible. Presumed hepatic fibrosis was evaluated with FIB-4. Hazard ratios (HRs) and 95% CIs were calculated using multivariable Cox regression analysis, and Kaplan-Meier estimates of the cumulative mortality were evaluated. RESULTS: There were 46,456 individuals with a median follow-up period of 8.6 years (interquartile range, 6.3-10.6 y). Kaplan-Meier curves for cumulative mortality showed that participants with a FIB-4 of ≥2.67 (vs FIB-4, <2.67) had higher cumulative all-cause, cardiovascular, cancer, and liver-related mortality. In the fully adjusted model, Cox regression analysis revealed that presumed advanced hepatic fibrosis (FIB-4, ≥2.67) remained associated with all-cause mortality (HR, 1.64; 95% CI, 1.23-2.18), cardiovascular mortality (HR, 2.96; 95% CI, 1.60-5.46), and liver-related mortality (HR, 10.50; 95% CI, 4.70-23.44), but not cancer mortality, after adjusting for confounders including central obesity and insulin resistance. Excluding participants with an estimated alcohol intake of 30 grams or more for men and 20 grams or more for women did not affect the results. CONCLUSIONS: At the population level, liver fibrosis estimated by FIB-4 was associated with increased cumulative all-cause, cardiovascular, and liver-related mortality.

The Five-Year Effect of a Single Zoledronate Infusion on Bone Mineral Density Following Denosumab Discontinuation in Women with Postmenopausal Osteoporosis.

The long-term effects of zoledronate treatment in women with postmenopausal osteoporosis who stop denosumab therapy when they become osteopenic are not known. In a prospective, randomized, controlled clinical trial we previously reported that a single intravenous infusion of zoledronate 5 mg given to such patients 6 months after the last denosumab injection effectively prevents bone loss in the majority of them for up to 3 years. The study was extended for an additional 2 years and included all 19 patients from one Trial Site of the total 27 patients originally randomized in the zoledronate arm. Baseline characteristics of this cohort treated with denosumab for 2.4 ± 0.2 years were not different from those of the whole initial cohort or from the patients who did not participate in this extension. At the end of 5 years 7 patients had become again osteoporotic requiring additional treatment, 9 remained osteopenic while 3 did not complete the study extension. Thus, more than half of the osteoporotic women who became osteopenic with denosumab treatment and stopped it, maintained the BMD gains 5 years after a single zoledronate infusion with no additional treatment. Whether these results are also applicable to patients treated with denosumab for longer periods remains to be established.

Controlling the Impact of Helicobacter pylori-Related Hyperhomocysteinemia on Neurodegeneration.

Helicobacter pylori infection consists a high global burden affecting more than 50% of the world's population. It is implicated, beyond substantiated local gastric pathologies, i.e., peptic ulcers and gastric cancer, in the pathophysiology of several neurodegenerative disorders, mainly by inducing hyperhomocysteinemia-related brain cortical thinning (BCT). BCT has been advocated as a possible biomarker associated with neurodegenerative central nervous system disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and/or glaucoma, termed as "ocular Alzheimer's disease". According to the infection hypothesis in relation to neurodegeneration, Helicobacter pylori as non-commensal gut microbiome has been advocated as trigger and/or mediator of neurodegenerative diseases, such as the development of Alzheimer's disease. Among others, Helicobacter pylori-related inflammatory mediators, defensins, autophagy, vitamin D, dietary factors, role of probiotics, and some pathogenetic considerations including relevant involved genes are discussed within this opinion article. In conclusion, by controlling the impact of Helicobacter pylori-related hyperhomocysteinemia on neurodegenerative disorders might offer benefits, and additional research is warranted to clarify this crucial topic currently representing a major worldwide burden.

Nonalcoholic fatty liver disease and osteoporosis: A potential association with therapeutic implications.

Nonalcoholic fatty liver disease (NAFLD) and osteoporosis are two highly prevalent metabolic diseases. Increasing experimental evidence supports a pathophysiological link between NAFLD and osteoporosis. A key feature could be chronic, low-grade inflammation, which characterizes NAFLD and possibly affects bone metabolism. In this context, several factors, including but not limited to receptor activator of nuclear factor kappa-B ligand, osteoprotegerin, osteopontin and osteocalcin, may serve as mediators. In the clinical setting, most but not all epidemiological evidence indicates that NAFLD is associated with lower bone mineral density or osteoporosis in adults. Although an association between NAFLD and osteoporosis has not yet been established, and thus remains speculative, pharmacological considerations already exist. Some of the current and emerging pharmacological options for NAFLD have shown possible anti-osteoporotic properties (eg, vitamin E, obeticholic acid, semaglutide), while others (eg, pioglitazone, canagliflozin) have been associated with increased risk of fractures and may be avoided in patients with NAFLD and concomitant osteoporosis, especially those at high fracture risk. Conversely, some anti-osteoporotic medications (denosumab) might benefit NAFLD, while others (raloxifene) might adversely affect it and, consequently, may be avoided in patients with osteoporosis and NAFLD. If an association between NAFLD and osteoporosis is established, a medication that could target both diseases would be a great advancement. This review summarizes the main experimental and clinical evidence on the potential association between NAFLD and osteoporosis and focuses on treatment considerations derived from this potential association.

Circulating adiponectin in patients with nonalcoholic fatty liver disease-related liver fibrosis: A systematic review and a meta-analysis.

BACKGROUND AND AIM: There are conflicting data on adiponectin concentrations in nonalcoholic fatty liver disease (NAFLD). The main aim was to compare circulating total adiponectin concentrations in NAFLD patients with versus without liver fibrosis. METHODS: A systematic search was performed in PubMed, Scopus, and Cochrane Library. Twenty-two studies comprising 1753 biopsy-proven NAFLD individuals (1290 with and 463 without fibrosis) were included in the meta-analysis. RESULTS: There was no difference in adiponectin concentration between NAFLD patients with versus without fibrosis (standardized mean difference [SMD]: -0.15; 95% confidence interval [95% CI]: -0.35 to 0.05). Heterogeneity was moderate among studies (Ι2 : 60%, P < 0.001); no risk of publication bias was observed (Egger's test; P = 0.37). The sensitivity analysis, performed after the exclusion of studies with (i) children/adolescents and morbidly obese patients (n = 3) and (ii) adiponectin measurement with other methods than enzyme-linked immunosorbent assay (ELISA) (n = 9), revealed significantly lower adiponectin concentrations in NAFLD patients with fibrosis (i) SMD: -0.23, 95% CI: -0.41 to -0.04; (ii) SMD: -0.30, 95% CI: -0.55 to -0.04, respectively). Meta-regression analysis revealed no significant association of adiponectin SMD with age, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl-transferase, homeostasis model assessment insulin resistance and the proportion of men. CONCLUSIONS: Overall, patients with NAFLD and fibrosis had similar adiponectin concentrations with patients with NAFLD without fibrosis. However, adiponectin concentration was lower in NAFLD patients with fibrosis than those without fibrosis within the adult patients without morbid obesity and in studies in which adiponectin was measured with the same method (ELISA).

Micro-Ultrasound-Guided vs Multiparametric Magnetic Resonance Imaging-Targeted Biopsy in the Detection of Prostate Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: Micro-ultrasound is a novel high resolution ultrasound technology aiming to improve prostate imaging and, consequently, the diagnostic accuracy of ultrasound-guided prostate biopsy. Micro-ultrasound-guided prostate biopsy may present comparable detection rates to the standard of care multiparametric magnetic resonance imaging-targeted prostate biopsy for the diagnosis of clinically significant prostate cancer. We aimed to compare the detection rate of micro-ultrasound vs multiparametric magnetic resonance imaging-targeted prostate biopsy for prostate cancer diagnosis. MATERIALS AND METHODS: We performed a systematic review and meta-analysis of diagnostic accuracy studies comparing micro-ultrasound-guided prostate biopsy to multiparametric magnetic resonance imaging-targeted prostate biopsy as a reference standard test (PROSPERO ID: CRD42020198326). Records were identified by searching in PubMed®, Scopus® and Cochrane Library databases, as well as in potential sources of gray literature until November 30th, 2020. RESULTS: We included 18 studies in the qualitative and 13 in the quantitative synthesis. In the quantitative synthesis, 1,125 participants received micro-ultrasound-guided followed by multiparametric magnetic resonance imaging-targeted and systematic prostate biopsy. Micro-ultrasound and multiparametric magnetic resonance imaging-targeted prostate biopsies displayed similar detection rates across all prostate cancer grades. The pooled detection ratio for International Society of Urological Pathology Grade Group ≥2 prostate cancer was 1.05 (95% CI 0.93-1.19, I2=0%), 1.25 (95% CI 0.95-1.64, I2=0%) for Grade Group ≥3 and 0.94 (95% CI 0.73-1.22, I2=0%) for clinically insignificant (Grade Group 1) prostate cancer. The overall detection ratio for prostate cancer was 0.99 (95% CI 0.89-1.11, I2=0%). CONCLUSIONS: Micro-ultrasound-guided prostate biopsy provides comparable detection rates for prostate cancer diagnosis with the multiparametric magnetic resonance imaging-guided prostate biopsy. Therefore, it could be considered as an attractive alternative to multiparametric magnetic resonance imaging-targeted prostate biopsy. Nevertheless, high quality randomized trials are warranted to corroborate our findings.

Comparative Effect of Zoledronate at 6 Versus 18 Months Following Denosumab Discontinuation.

Discontinuation of denosumab treatment is associated with rapid bone loss that could be prevented in many patients by zoledronate (ZOL) infusion given 6 months after the last denosumab injection. The effects, however, of zoledronate administration at a later time point are unknown. We aimed to compare the 1-year effect of ZOL infusion given 6 versus 18 months following the last Dmab injection. In this extension of a previously reported 2-year randomized clinical trial, we included initially treatment-naive postmenopausal women, who became osteopenic after approximately 2.5 years of denosumab therapy, and were subjected to a single ZOL infusion at 6 months (early-ZOL, n = 27) versus 18 months (late-ZOL, n = 15) after the last Dmab injection. Annual changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), and markers of bone turnover (P1NP, CTx) at 6 and 12 months following ZOL infusion were assessed. LS BMD was maintained in both early-ZOL (+ 1.7%) and late-ZOL (+ 1.8%) infusion with no difference between groups (p = 0.949). FN BMD was maintained in early-ZOL (+ 0.1%) and increased in late-ZOL (+ 3.4%) infusion with no difference between groups (p = 0.182). Compared to 6 months after last Dmab injection, the overall LS BMD change of the late-ZOL group (- 3.5%) was significantly different (p = 0.007) from that of the early-ZOL group (+ 1.7%). P1NP and CTx gradually increased in the early-ZOL group, while profoundly decreased and remained suppressed in the late-ZOL infusion. A ZOL infusion 18 months following the last Dmab injection is still useful in terms of BMD maintenance and BTM suppression. However, there is no clear clinical benefit compared to the early infusion, while any theoretical advantage is counterbalanced from the expected bone loss, especially at the LS, and the risk of rebound-associated fractures.Trial Registration: NCT02499237; July 16, 2015.

Circulating tumor necrosis factor-α levels in non-alcoholic fatty liver disease: A systematic review and a meta-analysis.

BACKGROUND AND AIM: To synthesize data on circulating tumor necrosis factor (TNF)-α levels between patients with histologically confirmed non-alcoholic fatty liver disease (NAFLD) (simple steatosis or non-alcoholic fatty liver [NAFL] and/or non-alcoholic steatohepatitis [NASH]) and controls. METHODS: We performed a systematic search in PubMed, Scopus, and Cochrane Library. Fifty-six studies, published between 2003 and 2019, were finally included, reporting data from 5848 individuals (1634 controls and 4214 NAFLD patients). RESULTS: Higher circulating TNF-α levels were observed in NAFLD patients than controls (standardized mean difference [SMD] 0.84; 95% confidence interval [95% CI] 0.59-1.09), NAFL patients than controls (SMD 0.56; 95% CI 0.27-0.85), NASH patients than controls (SMD 0.93; 95% CI 0.64-1.22), and NASH than NAFL patients (SMD 0.31; 95% CI 0.16-0.46). There were only minimal changes in the comparisons between groups after excluding studies with morbidly obese populations (n = 11), or pediatric/adolescent populations (n = 6), or other than enzyme-linked immunosorbent assay method of TNF-α measurement (n = 8). There was high heterogeneity among studies in all comparisons, which was not essentially affected after sensitivity analyses. The meta-regression analysis revealed that the male ratio was positively associated with TNF-α SMD in the comparison between patients with NASH and NAFL (beta = 0.809; 95% CI 0.052-1.566) and accounted for 36% (P = 0.037) of the heterogeneity in this pair of comparison. TNF-α SMD was not associated with age, body mass index, and alanine aminotransferase in any pair of comparisons. CONCLUSIONS: Circulating TNF-α levels were higher in patients with NAFLD compared with controls. Higher levels of circulating TNF-α were also associated with the severity of NAFLD.

Efficacy of Antiosteoporotic Medications in Patients With Rebound-Associated Fractures After Denosumab Discontinuation.

Denosumab discontinuation results in rapid bone loss and increased risk of multiple rebound-associated vertebral fractures (RAVFs). The optimal treatment for patients who have sustained such fractures is currently unknown. We aimed to investigate the bone mineral density (BMD) changes achieved with various regimens in postmenopausal women who had sustained RAVFs after denosumab discontinuation in everyday clinical practice. In this multicenter, retrospective observational study, 39 Greek postmenopausal women from six regional bone centers throughout Greece with RAVFs after denosumab discontinuation were included. We collected BMD and fracture data before and 1 year after treatment with denosumab (n = 20), teriparatide (n = 8), zoledronate (n = 8) or teriparatide/denosumab combination (n = 3). Both lumbar spine (LS)-- and femoral neck (FN)-BMD were preserved with all regimens used. With the exception of zoledronate, a trend towards increase was observed with all regimens in LS-BMD. Three patients sustained additional fractures despite treatment reinstitution (2 with zoledronate and 1 with teriparatide). Among patients with RAVFs following denosumab discontinuation both antiresorptive (zoledronate and denosumab) and anabolic (teriparatide) treatment as well as the combination of denosumab with teriparatide seem to be effective in terms of BMD response.

Progression of Rebound-Associated Vertebral Fractures Following Denosumab Discontinuation Despite Reinstitution of Treatment: Suppressing Increased Bone Turnover May Not Be Enough.

Rebound-associated vertebral fractures (RAVFs) could occur in a minority of the patients who discontinue denosumab. In such patients, denosumab is often reinstituted to rapidly suppress bone turnover and avert the risk of additional fractures. Herein we report the cases of 2 patients who sustained RAVFs, and in whom resuming denosumab treatment did not avert the occurrence of new RAVFs a few months later, despite the suppression of bone turnover markers. It seems that denosumab reinstitution cannot completely eliminate the risk of new RAVFs and that the rebound of bone turnover may not be the sole mechanism to explain this phenomenon.

Adult hypophosphatasia treated with reduced frequency of teriparatide dosing.

We report a 41-year-old man diagnosed with the adult form of hypophosphatasia (HPP) and treated for 4 years with less frequent than conventional daily doses of teriparatide (TPTD). He presented with a history of three low-energy fractures and low bone mineral density (BMD) ineffectively treated with bisphosphonate. We identified within ALPL, the gene that encodes the homodimeric "tissue-nonspecific" isoenzyme of alkaline phosphatase (ALP) and underlies HPP, a heterozygous missense mutation (c.455 G>A→R135H). Characteristic painful periarticular calcification removed at a shoulder did not recur. However, access to medical treatment with asfotase alfa (AA) was denied. After he sustained a low-energy metatarsal fracture, we administered TPTD subcutaneously "off-label" at 20 µg/d. An elbow fracture occurred two months later. Five months afterwards, due to his limited number of approved TPTD doses, TPTD treatment was extended using alternate-day dosing. Although his serum ALP activity did not increase (33-48 U/l; reference range 40-120) with 4 years of TPTD treatment, his BMD improved 15% in the lumbar spine and 6% in the femoral neck with no further fractures. Our experience represents success overcoming two prescription deadlocks; AA was denied for adult HPP, and TPTD was not to be administered daily for more than two years.

Alzheimer's disease and gastrointestinal microbiota; impact of Helicobacter pylori infection involvement.

Background: Alzheimer disease (AD) is a leading cause of global burden with great impact on societies. Although research is working intensively on promising therapy, the problem remains up-to-date. Among the various proposed hypotheses regarding causality and therapy, emerging evidence supports the hypothesis that gastrointestinal microbiota through the so-called 'gut-brain axis' interacts with immune system and brain and shape the balance between homeostasis and disease; the involvement of gastrointestinal microbiota in the pathophysiology of AD is less defined, even though the role of 'gut-brain axis' has been well verified for other neurodegenerative conditions.Methods: We performed a systematic review of PubMed/MEDLINE database from 1st January 1990 to 17th October 2018, to investigate the accessible literature regarding possible association between AD and gastrointestinal microbiota. Inclusion criteria were available full text in English language, original clinical papers implicating AD patients and any sort of gastrointestinal microbiota.Results: Through our query, an initial number of 241 papers has been identified. After removing duplicates and through an additional manual search, twenty-four papers met our inclusion criteria. The great majority of eligible publications supported a possible connection between AD and gastrointestinal microbiota. The most common investigated microorganism was Helicobacter pylori.Conclusion: Our own systematic review, showed a possible association between AD and gastrointestinal microbiota mainly including Helicobacter pylori, and thus further research is required for substantiation of causality as well as for the establishment of promising novel therapies.

Similar late effects of a 7-week orthodox religious fasting and a time restricted eating pattern on anthropometric and metabolic profiles of overweight adults.

A hypocaloric diet, based on Orthodox fasting (OF) was followed by 29 overweight adults. A low-calorie, 16/8, time restricted eating (TRE) pattern was followed by 16 age- and weight-matched participants. Anthropometric, lipid, glycaemic and inflammation markers were assessed at baseline, at the end of the intervention (7 weeks from baseline) and 6 weeks after the cessation of diets (13 weeks from baseline). There was a trend of weight loss in both groups, which was evident at week 7 (TRE: -2.1 ± 1.0; OF: -2.0 ± 0.5 kg, p < 0.001 from baseline) and remained significant at week 13 (TRE: -2.9 ± 0.7; OF: -2.6 ± 0.3 kg, p < 0.001 from baseline). In the OF group, lipid concentrations declined at week 7 compared with baseline, increasing at week 13 compared with week 7. Our findings suggest that OF promotes a decrease in lipid concentrations, which however, is not evident 6 weeks after its end.

Trimebutine Maleate Monotherapy for Functional Dyspepsia: A Multicenter, Randomized, Double-Blind Placebo Controlled Prospective Trial.

Background and Objectives: Functional dyspepsia (FD) is one of the most common functional gastrointestinal disorders; it has a great impact on patient quality of life and is difficult to treat satisfactorily. This study evaluates the efficacy and safety of trimebutine maleate (TM) in patients with FD. Materials and Methods: Α multicenter, randomized, double-blind, placebo controlled, prospective study was conducted, including 211 patients with FD. Participants were randomized to receive TM 300 mg twice per day (BID, 108 patients) or placebo BID (103 patients) for 4 weeks. The Glasgow Dyspepsia Severity Score (GDSS) was used to evaluate the relief of dyspepsia symptoms. Moreover, as a pilot secondary endpoint, a substudy (eight participants on TM and eight on placebo) was conducted in to evaluate gastric emptying (GE), estimated using a 99mTc-Tin Colloid Semi Solid Meal Scintigraphy test. Results: Of the 211 patients enrolled, 185 (87.7%) (97 (52.4%) in the TM group and 88 (47.6%) in the placebo group) completed the study and were analyzed. The groups did not differ in their demographic and medical history data. Regarding symptom relief, being the primary endpoint, a statistically significant reduction in GDSS for the TM group was revealed between the first (2-week) and final (4-week) visit (p-value = 0.02). The 99 mTc-Tin Colloid Semi Solid Meal Scintigraphy testing showed that TM significantly accelerated GE obtained at 50 min (median emptying 75.5% in the TM group vs. 66.6% in the placebo group, p = 0.036). Adverse effects of low to moderate severity were reported in 12.3% of the patients on TM. Conclusion: TM monotherapy appears to be an effective and safe approach to treating FD, although the findings presented here warrant further confirmation.

Noninvasive Liver Fibrosis Tests in Patients with Nonalcoholic Fatty Liver Disease: An External Validation Cohort.

The main aim of this study was the comparative evaluation of nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS), fibrosis 4 index (FIB-4), AST-to-Platelet Ratio Index (APRI), and enhanced liver fibrosis (ELF) test in distinguishing none/early (F0/F1) from significant/advanced (F2/F3) fibrosis in NAFLD patients, thereby providing an external validation cohort. Thirty-one patients with biopsy-proven NAFLD and 10 matched controls without NAFLD were prospectively enrolled. Serum hyaluronic acid (HA), aminoterminal propeptide of type III procollagen (PIIINP), tissue inhibitor of metallo-proteinases (TIMP)-1, and biochemical tests were measured. NFS, FIB-4, APRI, and ELF were calculated. ELF, FIB-4, and APRI, but not NFS, were higher in F2/F3 than F0/F1 group. Specifically, ELF [area under the ROC curve (AUROC): 0.86±0.10; p=0.004) and APRI (AUROC: 0.86±0.07; p=0.005], but not NFS (AUROC: 0.68±0.12; p=0.16), and FIB-4 (AUROC: 0.71±0.11; p=0.10), could similarly discriminate F0/F1 from F2/F3 stage. The sensitivity, specificity, positive predicted value (PPV), and negative predicted value (NPV) were: a) for cut-off of APRI=0.5, 85.7%, 70.8%, 46.2%, and 94.4%, respectively, and b) for cut-off of ELF=9.0, 85.7%, 83.3%, 60.0%, and 95.2%, respectively. When ln(PIIINP) or TIMP-1 were combined with APRI, the combined AUROCs could distinguish F2/F3 from F0/F1, but without significantly higher accuracy compared with APRI alone. APRI could also distinguish patients with simple steatosis from nonalcoholic steatohepatitis, and those with from those without lobular inflammation and ballooning, findings warranting further research. In conclusions: The application of ELF test and APRI can distinguish F0/F1 from F2/F3 fibrosis stages in NAFLD patients.