Dawn-to-dusk dry fasting decreases circulating inflammatory cytokines in subjects with increased body mass index.

Background: The circadian rhythm involves numerous metabolic processes, including sleep/awakening, body temperature regulation, hormone secretion, hepatic function, cellular plasticity, and cytokine release (inflammation), that appear to have a dynamic relationship with all the processes above. Studies have linked various cytokines to the chronic state of low-grade inflammation and oxidative stress in obesity. Dawn-to-dusk dry fasting (DDDF) could alleviate the adverse effects of obesity by decreasing inflammation. This study examined the effects of DDDF on circulating inflammatory cytokines in subjects with increased body mass index (BMI). Methods: The current observational prospective study included adult subjects with a BMI equal to or greater than 25 kg/m2 who practiced the annual religious 30-day DDDF. Individuals with significant underlying medical conditions were excluded to limit confounding factors. All subjects were evaluated within two weeks before 30-day DDDF, within the fourth week of 30-day DDDF, and within two weeks after 30-day DDDF. Multiple cytokines and clinical health indicators were measured at each evaluation. Results: Thirteen subjects (10 men and three women) with a mean age of 32.9 years (SD = 9.7 years) and a mean BMI of 32 kg/m2 (SD = 4.6 kg/m2) were included. An overall associated decrease in the levels of multiple cytokines with DDDF was observed. A significant decrease in the mean interleukin 1 beta level was observed within the fourth week of 30-day DDDF (P = 0.045), which persisted even after the fasting period (P = 0.024). There was also a significant decrease in the mean levels of interleukin 15 (IL-15) (P = 0.014), interleukin 1 receptor antagonist (P = 0.041), macrophage-derived chemokine (MDC) (P = 0.013), and monokine induced by interferon gamma/chemokine (C-X-C motif) ligand 9 (P = 0.027) within the fourth week of 30-day DDDF and in the mean levels of fibroblast growth factor 2 (P = 0.010), interleukin 12 p40 subunit (P = 0.038), interleukin 22 (P = 0.025) and tumor necrosis factor alpha (P = 0.046) within two weeks after 30-DDDF. In terms of anthropometric parameters, there was a decrease in mean body weight (P = 0.032), BMI (P = 0.028), and hip circumference (P = 0.007) within the fourth week of 30-day DDDF and a decrease in mean weight (P = 0.026), BMI (P = 0.033) and hip circumference (P = 0.016) within two weeks after 30-day DDDF compared with the levels measured within two weeks before 30-day DDDF. Although there was no significant correlation between changes in weight and changes in circulating inflammatory cytokines, there was a significant positive correlation between changes in waist circumference and changes in specific inflammatory cytokines (e.g., IL-15, MDC, platelet-derived growth factor, soluble CD40L, vascular endothelial growth factor A) within the fourth week of 30-day DDDF and/or two weeks after 30-day DDDF. A significant decrease in mean average resting heart rate within the fourth week of 30-day DDDF was also observed (P = 0.023), and changes between average resting heart rate and changes in interleukin-8 levels within the fourth week of 30-day DDDF compared with baseline levels were positively correlated (r = 0.57, P = 0.042). Conclusion: DDDF appears to be a unique and potent treatment to reduce low-grade chronic inflammation caused by obesity and visceral adiposity. Further studies with more extended follow-up periods are warranted to investigate the long-term anti-inflammatory benefits of DDDF in individuals with increased BMI.

Evaluation of novel candidate filtration markers from a global metabolomic discovery for glomerular filtration rate estimation.

Creatinine and cystatin-C are recommended for estimating glomerular filtration rate (eGFR) but accuracy is suboptimal. Here, using untargeted metabolomics data, we sought to identify candidate filtration markers for a new targeted assay using a novel approach based on their maximal joint association with measured GFR (mGFR) and with flexibility to consider their biological properties. We analyzed metabolites measured in seven diverse studies encompasing 2,851 participants on the Metabolon H4 platform that had Pearson correlations with log mGFR and used a stepwise approach to develop models to < -0.5 estimate mGFR with and without inclusion of creatinine that enabled selection of candidate markers. In total, 456 identified metabolites were present in all studies, and 36 had correlations with mGFR < -0.5. A total of 2,225 models were developed that included these metabolites; all with lower root mean square errors and smaller coefficients for demographic variables compared to estimates using untargeted creatinine. Seventeen metabolites were chosen, including 12 new candidate filtration markers. The selected metabolites had strong associations with mGFR and little dependence on demographic factors. Candidate metabolites were identified with maximal joint association with mGFR and minimal dependence on demographic variables across many varied clinical settings. These metabolites are excreted in urine and represent diverse metabolic pathways and tubular handling. Thus, our data can be used to select metabolites for a multi-analyte eGFR determination assay using mass spectrometry that potentially offers better accuracy and is less prone to non-GFR determinants than the current eGFR biomarkers.

Dawn-to-dusk dry fasting induces anti-atherosclerotic, anti-inflammatory, and anti-tumorigenic proteome in peripheral blood mononuclear cells in subjects with metabolic syndrome.

Background: Metabolic syndrome characterized by abdominal obesity, high blood pressure, elevated fasting glucose and triglyceride levels and low high-density lipoprotein cholesterol level is associated with pro-inflammatory state, increased risk for atherosclerosis, and multiple cancers. Our previous results on subjects with metabolic syndrome showed that 4-week dawn-to-dusk (sunset) dry fasting resulted in significant changes in the serum proteome and improvement in several metabolic risk factors. Peripheral blood mononuclear cells (PBMC) proteomics is a powerful tool that can provide mechanistic insights into how dawn-to-dusk dry fasting affects protein expression in metabolic pathways at cellular level. In this study, we determined whether dawn-to-dusk dry fasting would induce favorable changes in PBMC proteome in subjects with metabolic syndrome, similar to the changes induced by dawn-to-dusk dry fasting in the same subjects' serum proteome. Methods: We conducted a prospective study on subjects with metabolic syndrome and collected blood specimens before 4-week dawn-to-dusk dry fasting, at the end of 4-week dawn-to-dusk dry fasting, and one week after 4-week dawn-to-dusk dry fasting. We performed untargeted proteomics using nano ultra-high performance liquid chromatography-tandem mass spectrometry to assess the impact of 4-week dawn-to-dusk dry fasting on PBMC proteome. Results: There were 14 subjects with metabolic syndrome with a mean age of 59 who fasted from dawn to dusk (strict dry fasting without any liquid or food intake) for more than 14 h daily for 29 days. The quantitative proteome analysis showed that apolipoprotein B (APOB) gene protein products (GP) levels were downregulated and had the most statistical significance of the observed difference at the end of 4-week dawn-to-dusk dry fasting (P = 0.008) and one week after 4-week dawn-to-dusk dry fasting (P = 0.0004) compared with the levels before 4-week dawn-to-dusk dry fasting. The comparison between GP levels before and at the end of 4-week dawn-to-dusk dry fasting showed an alteration in the expression of genes associated with lipid and atherosclerosis pathway (P = 6.014e-4) and C-type lectin receptor signaling pathway (P = 1.064e-5). The genes that were differentially expressed in the lipid and atherosclerosis pathway were APOB (P = 0.008), CD36 (P = 0.040), CALM1, CALM2, CALM3 (P = 0.015), and HSPA8 (P = 0.047). One of the differentially expressed genes in the C-type lectin receptor signaling pathway was lymphocyte-specific protein 1 (LSP1), which showed an average of 19-fold increase at the end of 4-week dawn-to-dusk dry fasting compared with the GP levels before fasting (P = 0.004). Several GPs associated with tumor-suppressor effect (TUBB4B, LSP1, ACTR3B) were upregulated, and GPs associated with tumor-promoter effect (CD36, CALM1, CALM2, CALM3, FLOT2, PPIF) were downregulated at the end of 4-week dawn-to-dusk dry fasting or one week after 4-week dawn-to-dusk dry fasting compared with the GP levels before 4-week dawn-to-dusk dry fasting. Conclusion: Based on our results, we conclude that in subjects with metabolic syndrome, 4-week dawn-to-dusk dry fasting induced anti-atherosclerotic, anti-inflammatory, and anti-tumorigenic PMBC proteome. Randomized, controlled clinical trials are needed to further investigate the effect of dawn-to-dusk dry fasting on subjects with chronic metabolic diseases and metabolic syndrome-induced cancers.

The impact of dawn to sunset fasting on immune system and its clinical significance in COVID-19 pandemic.

Dawn to sunset fasting, a type of intermittent fasting commonly practiced in the month of Ramadan, requires abstinence from food and drink from dawn to sunset. Dawn and dusk are two transition time zones of the day that play a critical role in the human circadian rhythm. Practicing dawn to sunset fasting requires the alignment of mealtimes and wake-sleep times with the human biological dawn and dusk. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs immune cell responses at multiple levels and leads to severe Coronavirus Disease 2019 (COVID-19). It generates high levels of pro-inflammatory cytokines and chemokines, also known as a cytokine storm, leads to mitochondrial dysfunction and generation of excessive amounts of mitochondrial reactive oxygen species, downregulates autophagy to escape detection for unchecked replication, and alters gut microbiome composition. Severe cases of COVID-19 have been associated with several comorbidities that impair immune responses (e.g., obesity, diabetes, malignancy) and blood laboratory abnormalities (e.g., elevated procalcitonin, C-reactive protein, interleukin-6, leukocytosis, lymphopenia). Several studies of dawn to sunset fasting showed anti-inflammatory effect by suppressing several pro-inflammatory cytokines, reducing oxidative stress, inducing a proteome response associated with increased autophagy, remodeling the gut microbiome, and improving the components of metabolic syndrome (e.g., obesity, blood glucose levels, blood pressure, lipids). In conclusion, dawn to sunset fasting has the potential to optimize the immune system function against SARS-CoV-2 during the COVID-19 pandemic as it suppresses chronic inflammation and oxidative stress, improves metabolic profile, and remodels the gut microbiome. This review presents scientific literature related to the effects of dawn to sunset fasting on the immune system. Studies are needed to assess and confirm the potential benefits of dawn to sunset fasting against SARS-CoV-2.

The role of zinc in the prevention and treatment of nonalcoholic fatty liver disease.

The zinc element is an essential nutrient for human health. Zinc is involved in the glucose, lipid, and protein metabolism and antioxidant processes in biological pathways. Zinc deficiency can lead to several chronic liver diseases. Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases where zinc deficiency plays a critical role in pathogenesis. Human and animal studies showed that both NAFLD risk factors (i.e., insulin resistance, diabetes mellitus, dyslipidemia, obesity, hypertension) and NAFLD itself are associated with decreased blood levels of zinc. Additionally, endoplasmic reticulum stress and inflammation due to unfolded protein response, inadequate dietary zinc intake, and decreased zinc absorption from the gastrointestinal tract can result in zinc deficiency leading to NAFLD. Herein, we reviewed the mechanistic links between zinc deficiency and NAFLD development and the role of zinc in the prevention and treatment of NAFLD.

The effect of four-week intermittent fasting from dawn to sunset on circulating brain-derived neurotrophic factor levels in subjects with metabolic syndrome and healthy subjects.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a key neurotrophin that regulates food intake and energy hemostasis. BDNF also promotes neurogenesis, neuroplasticity, and neuroprotection. There are conflicting reports regarding how intermittent fasting affects circulating BDNF levels. We tested the hypothesis that 4-week intermittent fasting from dawn to sunset (4-week-IF) would decrease circulating BDNF levels in subjects with metabolic syndrome and healthy subjects. METHODS: We conducted pilot studies in subjects with metabolic syndrome and healthy subjects who fasted from dawn to sunset for more than 14 h for four consecutive weeks. We measured serum BDNF levels and metabolic parameters before 4-week-IF, at the end of 4th week during 4-week-IF, and one week after 4-week-IF. RESULTS: We enrolled 28 subjects, 14 with metabolic syndrome (women/men:6/8) with a mean age of 59 years and 14 healthy subjects (women/men:1/13) with a mean age of 32 years. Overall, BDNF levels decreased at the end of 4th week during 4-week-IF compared with the levels before 4-week-IF (mean paired difference = -98.5 ng/ml, P = 0.0006). When subjects with metabolic syndrome were compared with healthy subjects, subjects with metabolic syndrome had a lower mean paired reduction in BDNF levels at the end of 4th week during 4-week-IF compared with the levels before 4-week-IF (BDNF mean paired difference = -27.6 ng/ml vs. -169.5 ng/ml, P = 0.003). Multivariate linear regression analysis showed a positive correlation between the change in tumor necrosis factor-alpha and change in BDNF levels at the end of 4th week during 4-week-IF compared with the levels before 4-week-IF in subjects with metabolic syndrome (P = 0.040) and healthy subjects (P = 0.007). The change in weight and body mass index independently predicted the change in BDNF levels 1 week after 4-week-IF compared with the levels before 4-week-IF in subjects with metabolic syndrome. CONCLUSION: Four-week-IF resulted in a reduction in the BDNF levels at the end of 4th week during 4-week-IF. Higher BDNF levels and a lower reduction in BDNF levels at the end of 4th week during 4-week-IF compared with the levels before 4-week-IF in subjects with metabolic syndrome than healthy subjects suggest a potential BDNF resistance similar to insulin and leptin resistance in metabolic syndrome. A positive correlation between the change in BDNF and change in tumor necrosis factor-alpha levels at the end of 4th week during 4-week-IF compared with the levels before 4-week-IF suggests that BDNF is a biomarker of inflammation and endothelial dysfunction in addition to its neurotrophic and anorexigenic features.

Drug-Induced Liver Injury Associated With Alpha Bolic (RAD-140) and Alpha Elite (RAD-140 and LGD-4033).

We report a 52-year-old man who developed drug-induced liver injury after taking Alpha Bolic (contains RAD-140) and Alpha Elite (contains both RAD-140 and LGD-4033) supplements. Liver biopsy demonstrated diffuse centrilobular canalicular cholestasis, prominent ductular reaction, and mild lobular inflammation with rare non-necrotizing epithelioid granuloma suggestive of drug-induced liver injury. Liver enzymes returned to normal levels approximately 3 months after the patient stopped both supplements. We present the mechanism of drug-induced liver injury associated with 2 selective androgen receptor modulators, including RAD-140 and LGD 4033.

Intermittent fasting from dawn to sunset for four consecutive weeks induces anticancer serum proteome response and improves metabolic syndrome.

Metabolic syndrome is characterized by central obesity, insulin resistance, elevated blood pressure, and dyslipidemia. Metabolic syndrome is a significant risk factor for several common cancers (e.g., liver, colorectal, breast, pancreas). Pharmacologic treatments used for the components of the metabolic syndrome appear to be insufficient to control cancer development in subjects with metabolic syndrome. Murine models showed that cancer has the slowest progression when there is no food consumption during the daily activity phase. Intermittent fasting from dawn to sunset is a form of fasting practiced during human activity hours. To test the anticancer effect of intermittent fasting from dawn to sunset in metabolic syndrome, we conducted a pilot study in 14 subjects with metabolic syndrome who fasted (no eating or drinking) from dawn to sunset for more than 14 h daily for four consecutive weeks. We collected serum samples before 4-week intermittent fasting, at the end of 4th week during 4-week intermittent fasting and 1 week after 4-week intermittent fasting. We performed serum proteomic analysis using nano ultra-high performance liquid chromatography-tandem mass spectrometry. We found a significant fold increase in the levels of several tumor suppressor and DNA repair gene protein products (GP)s at the end of 4th week during 4-week intermittent fasting (CALU, INTS6, KIT, CROCC, PIGR), and 1 week after 4-week intermittent fasting (CALU, CALR, IGFBP4, SEMA4B) compared with the levels before 4-week intermittent fasting. We also found a significant reduction in the levels of tumor promoter GPs at the end of 4th week during 4-week intermittent fasting (POLK, CD109, CAMP, NIFK, SRGN), and 1 week after 4-week intermittent fasting (CAMP, PLAC1) compared with the levels before 4-week intermittent fasting. Fasting from dawn to sunset for four weeks also induced an anti-diabetes proteome response by upregulating the key regulatory proteins of insulin signaling at the end of 4th week during 4-week intermittent fasting (VPS8, POLRMT, IGFBP-5) and 1 week after 4-week intermittent fasting (PRKCSH), and an anti-aging proteome response by upregulating H2B histone proteins 1 week after 4-week intermittent fasting. Subjects had a significant reduction in body mass index, waist circumference, and improvement in blood pressure that co-occurred with the anticancer, anti-diabetes, and anti-aging serum proteome response. These findings suggest that intermittent fasting from dawn to sunset actively modulates the respective genes and can be an adjunct treatment in metabolic syndrome. Further studies are needed to test the intermittent fasting from dawn to sunset in the prevention and treatment of metabolic syndrome-induced cancers.

Ligandrol (LGD-4033)-Induced Liver Injury.

We described a 32-year-old man who developed severe drug-induced liver injury after using Ligandrol (LGD-4033). The diagnosis was confirmed by a liver biopsy that showed cholestatic hepatitis with a mild portal, periportal, and perisinusoidal fibrosis. Ligandrol is a selective androgen receptor modulator that is available over the counter and via the internet.

Intermittent fasting from dawn to sunset for 30 consecutive days is associated with anticancer proteomic signature and upregulates key regulatory proteins of glucose and lipid metabolism, circadian clock, DNA repair, cytoskeleton remodeling, immune system and cognitive function in healthy subjects.

Murine studies showed that disruption of circadian clock rhythmicity could lead to cancer and metabolic syndrome. Time-restricted feeding can reset the disrupted clock rhythm, protect against cancer and metabolic syndrome. Based on these observations, we hypothesized that intermittent fasting for several consecutive days without calorie restriction in humans would induce an anticarcinogenic proteome and the key regulatory proteins of glucose and lipid metabolism. Fourteen healthy subjects fasted from dawn to sunset for over 14 h daily. Fasting duration was 30 consecutive days. Serum samples were collected before 30-day intermittent fasting, at the end of 4th week during 30-day intermittent fasting, and one week after 30-day intermittent fasting. An untargeted serum proteomic profiling was performed using ultra high-performance liquid chromatography/tandem mass spectrometry. Our results showed that 30-day intermittent fasting was associated with an anticancer serum proteomic signature, upregulated key regulatory proteins of glucose and lipid metabolism, circadian clock, DNA repair, cytoskeleton remodeling, immune system, and cognitive function, and resulted in a serum proteome protective against cancer, metabolic syndrome, inflammation, Alzheimer's disease, and several neuropsychiatric disorders. These findings suggest that fasting from dawn to sunset for 30 consecutive days can be preventive and adjunct therapy in cancer, metabolic syndrome, and several cognitive and neuropsychiatric diseases. SIGNIFICANCE: Our study has important clinical implications. Our results showed that intermittent fasting from dawn to sunset for over 14 h daily for 30 consecutive days was associated with an anticancer serum proteomic signature and upregulated key regulatory proteins of glucose and lipid metabolism, insulin signaling, circadian clock, DNA repair, cytoskeleton remodeling, immune system, and cognitive function, and resulted in a serum proteome protective against cancer, obesity, diabetes, metabolic syndrome, inflammation, Alzheimer's disease, and several neuropsychiatric disorders. Importantly, these findings occurred in the absence of any calorie restriction and significant weight loss. These findings suggest that intermittent fasting from dawn to sunset can be a preventive and adjunct therapy in cancer, metabolic syndrome and Alzheimer's disease and several neuropsychiatric diseases.

Renal Trajectory Patterns Are Associated With Postdischarge Mortality in Patients With Cirrhosis and Acute Kidney Injury.

BACKGROUND & AIMS: Little is known about long-term outcomes of acute kidney injury (AKI) in patients with cirrhosis. Outcomes can vary with stage of AKI, chronic kidney disease, and trajectory of renal function. METHODS: We collected data from the Department of Veterans Affairs and identified 6917 patients with cirrhosis who developed AKI during hospitalization at any of its 127 hospitals, from 2004 through 2014. We used latent class analysis of serial creatinine measurements during the index hospitalization to determine trajectories of renal function. RESULTS: Overall, 32% of patients died within 90 days of discharge from the hospital and 48% of patients died within 1 year. We identified 5 distinct in-hospital renal trajectories: mild AKI with full improvement (24.8% of patients died 90 within days), severe AKI with rapid improvement (24.7% of patients died within 90 days), moderate AKI with partial improvement (33.7% of patients died within 90 days), moderate to severe AKI with partial improvement (42.0% of patients died within 90 days), and severe AKI with minimal improvement (48.0% of patients died within 90 days). Trajectories were associated significantly with mortality within 90 days and 1 year of mortality. Patients with severe AKI with minimal improvement had the highest risk of death within 90 days (adjusted odds ratio, 3.08; 95% CI, 2.54-3.72) and within 1 year (adjusted odds ratio, 2.71; 95% CI, 2.25-3.27) compared with patients with mild AKI with full improvement. The highest 90-day postdischarge mortality (65.2%) was observed in patients with normal or near-normal prehospitalization renal function who developed severe AKI with minimal improvement during hospitalization. CONCLUSIONS: In an analysis of almost 7000 veterans with cirrhosis who were hospitalized for AKI, we found the pattern of renal trajectory to be associated with mortality after discharge. Renal trajectory patterns can be used to identify subgroups of patients with cirrhosis and AKI who should receive intensive postdischarge management.

The decreasing predictive power of MELD in an era of changing etiology of liver disease.

The field of liver transplantation has shifted considerably in the MELD era, including changing allocation, immunosuppression, and liver failure etiologies, as well as better supportive therapies. Our aim was to evaluate the predictive accuracy of the MELD score over time. The United Network for Organ Sharing provided de-identified data on 120 156 patients listed for liver transplant from 2002-2016. The ability of the MELD score to predict 90-day mortality was evaluated by a concordance (C-) statistic and corroborated with competing risk analysis. The MELD score's concordance with 90-day mortality has downtrended from 0.80 in 2003 to 0.70 in 2015. While lab MELD scores at listing and transplant climbed in that interval, score at waitlist death remained steady near 35. Listing age increased from 50 to 54 years. HCV-positive status at listing dropped from 33 to 17%. The concordance of MELD and mortality does not differ with age (>60 = 0.73, <60 = 0.74), but is lower in diseases that are increasing most rapidly-alcoholic liver disease and non-alcoholic fatty liver disease-and higher in those that are declining, particularly in HCV-positive patients (HCV positive = 0.77; negative = 0.73). While MELD still predicts mortality, its accuracy has decreased; changing etiology of disease may contribute.

No Gains in Long-term Survival After Liver Transplantation Over the Past Three Decades.

OBJECTIVE: The aim of this study was to assess improvements in long-term survival after liver transplant by analyzing outcomes in transplant recipients who survived beyond 1 year. SUMMARY OF BACKGROUND DATA: Gains in short-term survival following liver transplantation have been gratifying. One-year survival in 1986 was 66% improved to over 92% in 2015. However, little is known about why long-term has not seen similar success. METHODS: We analyzed 111,568 recipients from 1987 to 2016 using the Kaplan-Meier method for time-to-event analysis and multivariable Cox regression. RESULTS: There were no significant gains in unadjusted long-term outcomes among 1-year survivors over the past 30 years. Only the time periods of 1987 to 1990 [hazard ratio (HR) 1.35, confidence interval CI) 1.28-1.42] and 1991 to 1995 (HR 1.17, CI 1.13-1.21) had a minor increase in risk compared with the period 2011 to 2016. Cause of death analysis suggests malignancy after transplantation is a growing problem and preventing recurrent hepatitis C with direct-acting antivirals (DDAs) may only have a limited impact. Furthermore, rejection leading to graft failure and death had a rare occurrence (1.7% of long-term deaths) especially when compared with the sequelae of long-term immunosuppression: malignancy (16.4%), nonrejection graft failure (9.8%), and infection (10.5%) (P < 0.001). CONCLUSION: In stark contrast to short-term survival, there have been no appreciable improvements in long-term survival following liver transplantation among 1-year survivors. Long-term sequelae of immunosuppression, including malignancy and infection, are the most common causes of death. This study highlights the need for better long-term immunosuppression management.

Metabolomic biomarkers are associated with mortality in patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis.

AIM: To assess the ability of signature metabolites alone, or in combination with the model for end-stage liver disease-Na (MELD-Na) score to predict mortality in patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis. MATERIALS & METHODS: Plasma metabolites were detected using ultrahigh-performance liquid chromatography/tandem mass spectrometry in 39 patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis. Mortality was predicted using Cox proportional hazards regression and time-dependent receiver operating characteristic curve analyses. RESULTS: The top five metabolites with significantly greater accuracy than the MELD-Na score (area under the receiver operating characteristic curve [AUROC] = 0.7591) to predict 1-year mortality were myo-inositol (AUROC = 0.9537), N-acetylputrescine (AUROC = 0.9018), trans-aconitate (AUROC = 0.8880), erythronate (AUROC = 0.8345) and N6-carbamoylthreonyladenosine (AUROC = 0.8055). Several combined MELD-Na-metabolite models increased the accuracy of predicted 1-year mortality substantially (AUROC increased from 0.7591 up to 0.9392). CONCLUSION: Plasma metabolites have the potential to enhance the accuracy of mortality predictions, minimize underestimates of mortality in patients with cirrhosis and low MELD-Na scores, and promote equitable allocation of donor livers.

Current Applications of Metabolomics in Cirrhosis.

Metabolomics is the identification and quantification of all or specified metabolites in a living system under a specific condition or disease. Metabolomics in cirrhosis can be used in diagnosing complications, determining prognosis and assessment of response to therapy. In this review, we summarized representative applications of metabolomics in cirrhosis and significant metabolites associated with cirrhosis and its complications.

Predicting Liver Allograft Discard: The Discard Risk Index.

BACKGROUND: An index that predicts liver allograft discard can effectively grade allografts and can be used to preferentially allocate marginal allografts to aggressive centers. The aim of this study is to devise an index to predict liver allograft discard using only risk factors available at the time of initial DonorNet offer. METHODS: Using univariate and multivariate analyses on a training set of 72 297 deceased donors, we identified independent risk factors for liver allograft discard. Multiple imputation was used to account for missing variables. RESULTS: We identified 15 factors as significant predictors of liver allograft discard; the most significant risk factors were: total bilirubin > 10 mg/dL (odds ratio [OR], 25.23; confidence interval [CI], 17.32-36.77), donation after circulatory death (OR, 14.13; CI, 13.30-15.01), and total bilirubin 5 to 10 mg/dL (OR, 7.57; 95% CI, 6.32-9.05). The resulting Discard Risk Index (DSRI) accurately predicted the risk of liver discard with a C statistic of 0.80. We internally validated the model with a validation set of 37 243 deceased donors and also achieved a 0.80 C statistic. At a DSRI at the 90th percentile, the discard rate was 50% (OR, 32.34; CI, 28.63-36.53), whereas at a DSRI at 10th percentile, only 3% of livers were discarded. CONCLUSIONS: The use of the DSRI can help predict liver allograft discard. The DSRI can be used to effectively grade allografts and preferentially allocate marginal allografts to aggressive centers to maximize the donor yield and expedite allocation.

Cystatin C Is a Gender-Neutral Glomerular Filtration Rate Biomarker in Patients with Cirrhosis.

BACKGROUND: Lower serum Cr levels in women as compared to men result in underestimation of renal dysfunction and lower model for end-stage liver disease-sodium scores leading to reduced access to liver transplantation in women compared to men with comparable hepatic dysfunction. AIM: The aim of this study was to determine the gender differences in serum Cr, cystatin C, and other endogenous glomerular filtration rate (GFR) biomarkers, measured and estimated GFR, Cr clearance, and Cr production rates. METHODS: We measured GFR by iothalamate plasma clearance in 103 patients with cirrhosis and assessed gender differences in GFR, Cr clearance and production rate, serum Cr, cystatin C and other endogenous GFR biomarkers including beta-trace protein, beta-2 microglobulin, and dimethylarginines. RESULTS: Comparison of men and women showed significantly lower values for mean serum Cr (0.97 vs. 0.82 mg/dl, P = 0.023), and Cr production rate (13.37 vs. 11.02 mg/kg/day, P = 0.022). In contrast to the serum Cr and Cr production rate, men and women exhibited no significant differences in the means of serum cystatin C and other GFR biomarkers, measured GFR, GFR estimated using Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearances. After controlling for age, race, weight, height, and GFR, female gender remained associated with lower serum Cr levels (P = 0.003). Serum cystatin C levels were not associated with gender, age, race, weight, height, C-reactive protein, and history of hypothyroidism. CONCLUSIONS: Our results suggest that cystatin C and endogenous GFR biomarkers other than Cr, measured GFR, GFR estimated by Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearance minimized between-gender biases in accounting for renal function in patients with cirrhosis. Therefore, serum cystatin C should be measured as a complementary test to serum Cr when renal function is assessed in patients with cirrhosis, particularly in women and those with sarcopenia.