ResearchPad - liver https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Development and validation a nomogram for predicting the risk of severe COVID-19: A multi-center study in Sichuan, China]]> https://www.researchpad.co/article/elastic_article_15747 Since December 2019, coronavirus disease 2019 (COVID-19) emerged in Wuhan and spread across the globe. The objective of this study is to build and validate a practical nomogram for estimating the risk of severe COVID-19.MethodsA cohort of 366 patients with laboratory-confirmed COVID-19 was used to develop a prediction model using data collected from 47 locations in Sichuan province from January 2020 to February 2020. The primary outcome was the development of severe COVID-19 during hospitalization. The least absolute shrinkage and selection operator (LASSO) regression model was used to reduce data size and select relevant features. Multivariable logistic regression analysis was applied to build a prediction model incorporating the selected features. The performance of the nomogram regarding the C-index, calibration, discrimination, and clinical usefulness was assessed. Internal validation was assessed by bootstrapping.ResultsThe median age of the cohort was 43 years. Severe patients were older than mild patients by a median of 6 years. Fever, cough, and dyspnea were more common in severe patients. The individualized prediction nomogram included seven predictors: body temperature at admission, cough, dyspnea, hypertension, cardiovascular disease, chronic liver disease, and chronic kidney disease. The model had good discrimination with an area under the curve of 0.862, C-index of 0.863 (95% confidence interval, 0.801–0.925), and good calibration. A high C-index value of 0.839 was reached in the interval validation. Decision curve analysis showed that the prediction nomogram was clinically useful.ConclusionWe established an early warning model incorporating clinical characteristics that could be quickly obtained on admission. This model can be used to help predict severe COVID-19 and identify patients at risk of developing severe disease. ]]> <![CDATA[Serum glutamate dehydrogenase activity enables early detection of liver injury in subjects with underlying muscle impairments]]> https://www.researchpad.co/article/elastic_article_14604 Serum activities of alanine and aspartate aminotransferases (ALT and AST) are used as gold standard biomarkers for the diagnosis of hepatocellular injury. Since ALT and AST lack liver specificity, the diagnosis of the onset of hepatocellular injury in patients with underlying muscle impairments is severely limited. Thus, we evaluated the potential of glutamate dehydrogenase (GLDH) as a liver specific alternative biomarker of hepatocellular injury. In our study, serum GLDH in subjects with Duchene muscular dystrophy (DMD) was equivalent to serum GLDH in age matched healthy subjects, while serum ALT was increased 20-fold in DMD subjects. Furthermore, serum GLDH in 131 subjects with variety of muscle impairments was similar to serum GLDH of healthy subjects while serum ALT corelated with serum creatine kinase, a widely accepted biomarker of muscle impairment. In addition, significant elevations of ALT, AST, and CK were observed in a case of a patient with rhabdomyolysis, while serum GLDH stayed within the normal range until the onset of hypoxia-induced liver injury. In a mouse model of DMD (DMDmdx), serum GLDH but not serum ALT clearly correlated with the degree of acetaminophen-induced liver injury. Taken together, our data support the utility of serum GLDH as a liver-specific biomarker of liver injury that has a potential to improve diagnosis of hepatocellular injury in patients with underlying muscle impairments. In drug development, GLDH may have utility as a biomarker of drug induced liver injury in clinical trials of new therapies to treat muscle diseases such as DMD.

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<![CDATA[Ablation of <i>Iah1</i>, a candidate gene for diet-induced fatty liver, does not affect liver lipid accumulation in mice]]> https://www.researchpad.co/article/elastic_article_14595 Nonalcoholic fatty liver disease (NAFLD) is a pathological condition caused by excess triglyceride deposition in the liver. The SMXA-5 severe fatty liver mouse model has been established from the SM/J and A/J strains. To explore the genetic factors involved in fatty liver development in SMXA-5 mice, we had previously performed quantitative trait locus (QTL) analysis, using (SM/J×SMXA-5)F2 intercross mice, and identified Fl1sa on chromosome 12 (centromere-53.06 Mb) as a significant QTL for fatty liver. Furthermore, isoamyl acetate-hydrolyzing esterase 1 homolog (Iah1) was selected as the most likely candidate gene for Fl1sa. Iah1 gene expression in fatty liver-resistant A/J-12SM mice was significantly higher than in fatty liver-susceptible A/J mice. These data indicated that the Iah1 gene might be associated with fatty liver development. However, the function of murine Iah1 remains unknown. Therefore, in this study, we created Iah1 knockout (KO) mice with two different backgrounds [C57BL/6N (B6) and A/J-12SM (A12)] to investigate the relationship between Iah1 and liver lipid accumulation. Liver triglyceride accumulation in Iah1-KO mice of B6 or A12 background did not differ from their respective Iah1-wild type mice under a high-fat diet. These results indicated that loss of Iah1 did not contribute to fatty liver. On the other hands, adipose tissue dysfunction causes lipid accumulation in ectopic tissues (liver, skeletal muscle, and pancreas). To investigate the effect of Iah1 deficiency on white adipose tissue, we performed DNA microarray analysis of epididymal fat in Iah1-KO mice of A12 background. This result showed that Iah1 deficiency might decrease adipokines Sfrp4 and Metrnl gene expression in epididymal fat. This study demonstrated that Iah1 deficiency did not cause liver lipid accumulation and that Iah1 was not a suitable candidate gene for Fl1sa.

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<![CDATA[A pilot study of ex-vivo MRI-PDFF of donor livers for assessment of steatosis and predicting early graft dysfunction]]> https://www.researchpad.co/article/elastic_article_14544 The utility of ex vivo Magnetic resonance imaging proton density fat fraction (MRI-PDFF) in donor liver fat quantification is unknown.PurposeTo evaluate the diagnostic accuracy and utility in predicting early allograft dysfunction (EAD) of ex vivo MRI-PDFF measurement of fat in deceased donor livers using histology as the gold standard.MethodsWe performed Ex vivo, 1.5 Tesla MRI-PDFF on 33 human deceased donor livers before implantation, enroute to the operating room. After the exclusion of 4 images (technical errors), 29 MRI images were evaluable. Histology was evaluable in 27 of 29 patients. EAD was defined as a peak value of aminotransferase >2000 IU/mL during the first week or an INR of ≥1.6 or bilirubin ≥10 mg/dL at day 7.ResultsMRI-PDFF values showed a strong positive correlation (Pearson’s correlation coefficient) when histology (macro-steatosis) was included (r = 0.78, 95% confidence interval 0.57‐0.89, p<0.0001). The correlation appeared much stronger when macro plus micro-steatosis were included (r = 0.87, 95% confidence interval 0.72‐0.94, p<0.0001). EAD was noted in 7(25%) subjects. AUC (Area Under the Curve) for macro steatosis (histology) predicted EAD in 73% (95% CI: 48–99), micro plus macro steatosis in 76% (95% CI: 49–100). AUC for PDFF values predicted EAD in 67(35–98). Comparison of the ROC curves in a multivariate model revealed, adding MRI PDFF values to macro steatosis increased the ability of the model in predicting EAD (AUC: 79%, 95% CI: 59–99), and addition of macro plus micro steatosis based on histology predicted EAD even better (AUC: 90%: 79–100, P = 0.054).ConclusionIn this pilot study, MRI-PDFF imaging showed potential utility in quantifying hepatic steatosis ex-vivo donor liver evaluation and the ability to predict EAD related to severe allograft steatosis in the recipient. ]]> <![CDATA[Improvement of steatotic rat liver function with a defatting cocktail during <i>ex situ</i> normothermic machine perfusion is not directly related to liver fat content]]> https://www.researchpad.co/article/elastic_article_13803 There is a significant organ shortage in the field of liver transplantation, partly due to a high discard rate of steatotic livers from donors. These organs are known to function poorly if transplanted but make up a significant portion of the available pool of donated livers. This study demonstrates the ability to improve the function of steatotic rat livers using a combination of ex situ machine perfusion and a “defatting” drug cocktail. After 6 hours of perfusion, defatted livers demonstrated lower perfusate lactate levels and improved bile quality as demonstrated by higher bile bicarbonate and lower bile lactate. Furthermore, defatting was associated with decreased gene expression of pro-inflammatory cytokines and increased expression of enzymes involved in mitochondrial fatty acid oxidation. Rehabilitation of marginal or discarded steatotic livers using machine perfusion and tailored drug therapy can significantly increase the supply of donor livers for transplantation.

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<![CDATA[EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks]]> https://www.researchpad.co/article/elastic_article_13744 Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long‐term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients.Approach and ResultsEXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0‐52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0‐37.0]). Elevated levels of hepatic δ‐aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ‐aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization.ConclusionsPatients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day‐to‐day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. ]]> <![CDATA[Improvement in Quality of Life and Decrease in Large‐Volume Paracentesis Requirements With the Automated Low‐Flow Ascites Pump]]> https://www.researchpad.co/article/elastic_article_6848 The automated low‐flow ascites pump (alfapump) is an implantable device that drains ascites directly into the urinary bladder. We studied its safety (absence of serious complications) and efficacy (decreased large‐volume paracentesis [LVP] requirement and improved quality of life [QoL]) in the management of ascites in a cohort of North American patients with cirrhosis and recurrent ascites ineligible for transjugular intrahepatic portosystemic shunt (TIPS). QoL was measured by the Chronic Liver Disease Questionnaire (CLDQ) and Ascites Questionnaire (Ascites Q). Following alfapump implantation, patients were monitored for ascites control, laboratory abnormalities, QoL, adverse events, and survival at 12 months. A total of 30 patients (60.0 ± 9.9 years; 57% male; Model for End‐Stage Liver Disease score, 11.4 ± 2.7) received an alfapump, mostly by an interventional radiology approach (97%), followed by longterm prophylactic antibiotics. The alfapump removed a mean ascites volume of 230.6 ± 148.9 L/patient at 12 months, dramatically reducing the mean LVP frequency from 2.4 ± 1.4/patient/month before pump implantation to 0.2 ± 0.4/patient/month after pump implantation. All surviving patients had improved QoL (baseline versus 3 months; CLDQ, 3.9 ± 1.21 versus 5.0 ± 1.0; Ascites Q, 51.7 ± 21.9 versus 26.7 ± 18.6; P < 0.001 for both) and a better biochemical index of nutritional status (prealbumin 87.8 ± 37.5 versus 102.9 ± 45.3 mg/L at 3 months; P = 0.04). Bacterial infections (15 events in 13 patients), electrolyte abnormalities (11 events in 6 patients), and renal complications (11 events in 9 patients) were the most common severe adverse events. By 12 months, 4 patients died from complications of cirrhosis. Alfapump insertion may be a definitive treatment for refractory ascites in cirrhosis, especially in patients who are not TIPS candidates.

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<![CDATA[Serum levels of bone sialoprotein correlate with portal pressure in patients with liver cirrhosis]]> https://www.researchpad.co/article/Nd170950f-0b0f-46af-a42d-6b06a3bc49ed

Liver cirrhosis represents the common end-stage of chronic liver diseases regardless of its etiology. Patients with compensated disease are mostly asymptomatic, however, progression to a decompensated disease stage is common. The available stratification strategies are often unsuitable to identify patients with a higher risk for disease progression and a limited prognosis. SIBLINGs, soluble glycophosphoproteins, are secreted into the blood by immune-cells. While osteopontin, the most prominent member of the SIBLINGs family, has been repeatedly associated with liver cirrhosis, data on the diagnostic and/or prognostic value of bone sialoprotein (BSP) are scarce and partly inconclusive. In this study, we analyzed the diagnostic and prognostic potential of circulating BSP in comparison to other standard laboratory markers in a large cohort of patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt (TIPS). Serum levels of BSP were similar in patients with different disease stages and were not indicative for prognosis. Interestingly, BSP serum levels did correlate inversely with portal pressure, as well as its surrogates such as platelet count, the portal vein cross-sectional area and correlated positively with the portal venous velocity. In summary, our data highlight that BSP might represent a previously unrecognized marker for portal hypertension in patients with liver cirrhosis.

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<![CDATA[Severe hyperbilirubinemia is associated with higher risk of contrast-related acute kidney injury following contrast-enhanced computed tomography]]> https://www.researchpad.co/article/N624c57d4-8983-4ece-aecc-e0e7860066cf

Introduction

Contrast-induced acute kidney injury (CI-AKI) is associated with high risks of morbidity and mortality. Hyperbilirubinemia might have some renal protection but with no clear cutoff value for protection. Related studies are typically on limited numbers of patients and only in conditions of vascular intervention.

Methods

We performed this study to elucidate CI-AKI in patients after contrast-enhanced computed tomography (CCT). The outcomes were CI-AKI, dialysis and mortality. Patients were divided to three groups based on their serum levels of total bilirubin: ≤1.2 mg/dl, 1.3–2.0 mg/dl, and >2.0 mg/dl.

Results

We enrolled a total of 9,496 patients who had received CCT. Patients with serum total bilirubin >2.0 mg/dl were associated with CI-AKI. Those undergoing dialysis had the highest incidence of PC-AKI (p<0.001). No difference was found between the two groups of total bilirubin ≤1.2 and 1.3–2.0 mg/dl. Patients with total bilirubin >2mg/dl were associated with CI-AKI (OR = 1.89, 1.53–2.33 of 95% CI), dialysis (OR = 1.40, 1.01–1.95 of 95% CI) and mortality (OR = 1.63, 1.38–1.93 of 95% CI) after adjusting for laboratory data and all comorbidities (i.e., cerebrovascular disease, coronary artery disease, peripheral arterial disease, and acute myocardial infarction, diabetes mellitus, hypertension, gastrointestinal bleeding, cirrhosis, peritonitis, ascites, hepatoma, shock lung and colon cancer). We concluded that total bilirubin level >2 mg/dl is an independent risk factor for CI-AKI, dialysis and mortality after CCT. These patients also had high risks for cirrhosis or hepatoma.

Conclusion

This is the first study providing evidence that hyperbilirubinemia (total bilirubin >2.0 mg/dl) being an independent risk factor for CI-AKI, dialysis and mortality after receiving CCT. Most patients with total bilirubin >2.0mg/dl had cirrhosis or hepatoma.

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<![CDATA[Toward precision prescribing for methadone: Determinants of methadone deposition]]> https://www.researchpad.co/article/N51499fe4-a854-40f2-ac0e-5bd2b114360f

Background

Despite the World Health Organization listing methadone as an essential medication, effective dose selection is challenging, especially in racial and ethnic minority populations. Subtherapeutic doses can result in withdrawal symptoms while supratherapeutic doses can result in overdose and death. Although CYP3A4 was conventionally considered the principal methadone metabolizing enzyme, more recent data have identified CYP2B6 as the principal enzyme. CYP2B6 has ethnically-associated polymorphisms that affect the metabolic rate. Our objective was to investigate the effects of genetic and nongenetic factors on methadone metabolism.

Methods

We measured trough plasma methadone levels in 100 participants with opioid use disorder. We assessed methadone metabolism by calculating the metabolite ratio (major metabolite: 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine [EDDP] divided by methadone concentration). We assessed hepatic fibrosis and steatosis by transient elastography and CYP2B6 alleles, principally responsible for methadone metabolism. Mixed effects models modeled the data in 97 participants.

Results

Participants were largely male (58%), minority (61% African American) and non-Hispanic (68%). Forty percent were HCV mono-infected, 40% were uninfected, and 20% were HCV/HIV co-infected. Female sex had significant effects on (R)- and (S)-methadone metabolism (p = 0.016 and p = 0.044, respectively). CYP2B6 loss of function (LOF) alleles significantly affected (S)-methadone metabolism (p = 0.012). Body mass index (BMI) significantly affected (R)-methadone metabolism (p = 0.034). Methadone metabolism appeared to be lower in males, in individuals with LOF alleles, and elevated BMI.

Conclusions

Genetic analysis, especially in minority populations, is essential to delivering individualized treatments. Although the principal methadone metabolizing enzyme remains controversial, our results suggest that sex, CYP2B6 genotype, and BMI should be incorporated into multivariate models to create methadone dosing algorithms. Methadone dosing algorithms should facilitate medication delivery, improve patient satisfaction, and diminish overdose potential.

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<![CDATA[Infections in Cirrhosis]]> https://www.researchpad.co/article/N27bf446b-75f2-4fec-9088-50eed8d89708

Purpose of review

Patients with cirrhosis are at high risk of developing serious infections. Bacterial infections remain the most common cause of morbidity and mortality in these patients. This review is focused on the prevalence of infections in those with cirrhosis, including multidrug-resistant (MDR) pathogens, pathogenesis of infection-related acute-on-chronic liver failure (ACLF), current treatment recommendations, and prophylactic strategies in patients with cirrhosis.

Recent findings

Recent epidemiological studies have noted an emerging prevalence of MDR bacterial infections and associated with poor prognosis, and a high rate of treatment failure and mortality. Therefore, new recommendations on empirical antibiotic use based on epidemiological data have been developed in order to improve outcomes.

Summary

Spontaneous bacterial peritonitis (SBP) and urinary tract infection (UTI) are the most frequent infections followed by pneumonia, cellulitis, and bacteremia, while pneumonia carries the highest risk of mortality. The incidence of MDR bacterial infections has been increasing, especially in healthcare-associated settings. Second infections that develop during hospitalization, multiple organ failures, and high MELD score are associated with poor survival. Preventive measures, early diagnosis, and adequate treatment of infections are essential key concepts in minimizing morbidity and mortality in patients with cirrhosis.

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<![CDATA[Application of the optimized carbon monoxide rebreathing method for the measurement of total haemoglobin mass in chronic liver disease]]> https://www.researchpad.co/article/N1b279fe6-eed3-405d-ba58-fd7f8c7afc00

Abstract

Background

Anemia is common in liver cirrhosis. This generally infers a fall in total hemoglobin mass (tHb‐mass). However, hemoglobin concentration ([Hb]) may fall due to an expansion in plasma volume (PV). The “optimized carbon monoxide rebreathing method” (oCOR) measures tHb‐mass directly and PV (indirectly using hematocrit). It relies upon carboxyhemoglobin (COHb) distribution throughout the entire circulation. In healthy subjects, such distribution is complete within 6–8 min. Given the altered circulatory dynamics in cirrhosis, we sought in this pilot study, to assess whether this was true in cirrhosis. The primary aim was to ascertain if the standard timings for the oCOR were applicable to patients with chronic liver disease and cirrhosis. The secondary aim was to explore the applicability of standard CO dosing methodologies to this patient population.

Methods

Sixteen patients with chronic liver parenchymal disease were studied. However, tHb‐mass was determined using the standard oCOR technique before elective paracentesis. Three subjects had an inadequate COHb% rise. In the remaining 13 (11 male), mean ± standard deviation (SD) age was 52 ± 13.8 years, body mass 79.1 ± 11.4 kg, height 175 ± 6.8 cm. To these, mean ± SD dose of carbon monoxide (CO) gas administered was 0.73 ± 0.13 ml/kg COHb values at baseline, 6 and 8 min (and “7‐min value”) were compared to those at 10, 12, 15 and 20 min after CO rebreathing.

Results

The “7‐min value” for median COHb% (IQR) of 6.30% (6.21%–7.47%) did not differ significantly from those at subsequent time points (8 min: 6.30% (6.21%–7.47%), 10 min: 6.33% (6.00%–7.50%), 12 min: 6.33% (5.90%–7.40%), 15 min: 6.37% (5.80%–7.33%), 20 min: 6.27% (5.70%–7.20%)). Mean difference in calculated tHb‐mass between minute 7 and minute 20 was only 4.1 g, or 0.6%, p = .68. No subjects reported any adverse effects.

Conclusions

The oCOR method can be safely used to measure tHb‐mass in patients with chronic liver disease and ascites, without adjustment of blood sample timings. Further work might refine and validate appropriate dosing regimens.

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<![CDATA[Split chimeric antigen receptor-modified T cells targeting glypican-3 suppress hepatocellular carcinoma growth with reduced cytokine release]]> https://www.researchpad.co/article/N50bfc0b6-929a-44e1-b893-d1beb5be9a7a

Background:

Human glypican-3 (hGPC3) is a protein highly expressed in hepatocellular carcinoma (HCC) but limited in normal tissues, making it an ideal target for immunotherapy. The adoptive transfer of hGPC3-specific chimeric antigen receptor T (CAR-T) cells for HCC treatment has been conducted in clinical trials. Due to the rigid construction, conventional CAR-T cells have some intrinsic limitations, like uncontrollable overactivation and inducing severe cytokine release syndrome.

Methods:

We redesigned the hGPC3-specific CAR by splitting the traditional CAR into two parts. By using coculturing assays and a xenograft mouse model, the in vitro and in vivo cytotoxicity and cytokine release of the split anti-hGPC3 CAR-T cells were evaluated against various HCC cell lines and compared with conventional CAR-T cells.

Results:

In vitro data demonstrated that split anti-hGPC3 CAR-T cells could recognize and lyse hGPC3+ HepG2 and Huh7 cells in a dose-dependent manner. Impressively, split anti-hGPC3 CAR-T cells produced and released a significantly lower amount of proinflammatory cytokines, including IFN-γ, TNF-α, IL-6, and GM-CSF, than conventional CAR-T cells. When injected into immunodeficient mice inoculated subcutaneously with HepG2 cells, our split anti-hGPC3 CAR-T cells could suppress HCC tumor growth, but released significantly lower levels of cytokines than conventional CAR-T cells.

Conclusions:

We describe here for the first time the use of split anti-hGPC3 CAR-T cells to treat HCC; split anti-hGPC3 CAR-T cells could suppress tumor growth and reduce cytokine release, and represent a more versatile and safer alternative to conventional CAR-T cells treatment.

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<![CDATA[Genetic variants of innate immunity receptors are associated with mortality in cirrhotic patients with bacterial infection]]> https://www.researchpad.co/article/N1d76945c-b9a9-4bd1-9df9-825045fb85ce

Abstract

Background & Aims

Acute‐on‐chronic liver failure (ACLF) is characterized by acute decompensation of cirrhosis (AD), organ failure(s) and high risk of short‐term mortality with bacterial infection frequently as precipitating event. Innate immune pattern recognition receptors and members of the lectin pathway of complement activation are crucial to the innate immune response to pathogens. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) of innate immune components are associated with the occurrence of bacterial infections or mortality in patients with cirrhosis hospitalized for AD or ACLF.

Methods

Twenty‐one innate immunity SNPs with known functional implications were genotyped in 826 AD/ACLF patients included in the CANONIC study. Associations between baseline characteristics of the patients, the occurrence of bacterial infections and survival rate at 90 days of follow‐up in relation to the innate immunity genetic variants were analysed.

Results

The NOD2‐G908R genetic variant was associated with mortality (HR 2.25, P = .004) independently of age and MELD Score. This association was also found in a predefined subgroup analysis in patients with bacterial infections (HR 2.78, P < .001) along with MBL_Yx (HR 1.72, P = .008) and MASP2_371 (HR 1.67, P = .012) genetic variants. None of the analysed SNPs were significantly associated with the occurrence of acute bacterial infections or spontaneous bacterial peritonitis in particular.

Conclusions

Innate immune system‐specific NOD2‐G908R, MBL_Yx and MASP2_371 genetic variants were independently associated with increased risk of short‐term mortality in AD/ACLF patients with bacterial infection.

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<![CDATA[In‐field evaluation of Xpert® HCV viral load Fingerstick assay in people who inject drugs in Tanzania]]> https://www.researchpad.co/article/N990559a7-6596-4c3e-be09-fab6c189de61

Abstract

Background

Although novel hepatitis C virus (HCV) RNA point‐of‐care technology has the potential to enhance the diagnosis in resource‐limited settings, very little real‐world validation of their utility exists. We evaluate the performance of HCV RNA quantification using the Xpert® HCV viral load Fingerstick assay (Xpert® HCV VL Fingerstick assay) as compared to the World Health Organisation pre‐qualified plasma Xpert® HCV VL assay among people who inject drugs (PWID) attending an opioid agonist therapy (OAT) clinic in Dar‐es‐Salaam, Tanzania.

Methods

Between December 2018 and February 2019, consecutive HCV seropositive PWID attending the OAT clinic provided paired venous and Fingerstick samples for HCV RNA quantification. These were processed onsite using the GeneXpert® platform located at the Central tuberculosis reference laboratory.

Results

A total of 208 out of 220 anti‐HCV‐positive participants recruited (94.5%) had a valid Xpert® HCV VL result available; 126 (61%; 95% CI 53.8‐67.0) had detectable and quantifiable HCV RNA. About 188 (85%) participants had paired plasma and Fingerstick whole blood samples; the sensitivity and specificity for the quantification of HCV RNA levels were 99.1% and 98.7% respectively. There was an excellent correlation (R 2 = .95) and concordance (mean difference 0.13 IU/mL, (95% CI −0.9 to 0.16 IU/mL) in HCV RNA levels between plasma samples and Fingerstick samples.

Conclusion

This study found excellent performance of the Xpert® HCV VL Fingerstick assay for HCV RNA detection and quantification in an African‐field setting. Its clinical utility represents an important watershed in overcoming existing challenges to HCV diagnosis, which should play a crucial role in HCV elimination in Africa.

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<![CDATA[Model‐based data analysis of individual human postprandial plasma bile acid responses indicates a major role for the gallbladder and intestine]]> https://www.researchpad.co/article/Ndad3d676-77e0-4ed8-b6fc-053ede7bb5c4

Abstract

Background

Bile acids are multifaceted metabolic compounds that signal to cholesterol, glucose, and lipid homeostasis via receptors like the Farnesoid X Receptor (FXR) and transmembrane Takeda G protein‐coupled receptor 5 (TGR5). The postprandial increase in plasma bile acid concentrations is therefore a potential metabolic signal. However, this postprandial response has a high interindividual variability. Such variability may affect bile acid receptor activation.

Methods

In this study, we analyzed the inter‐ and intraindividual variability of fasting and postprandial bile acid concentrations during three identical meals on separate days in eight healthy lean male subjects using a statistical and mathematical approach.

Main findings

The postprandial bile acid responses exhibited large interindividual and intraindividual variability. The individual mathematical models, which represent the enterohepatic circulation of bile acids in each subject, suggest that interindividual variability results from quantitative and qualitative differences of distal active uptake, colon transit, and microbial bile acid transformation. Conversely, intraindividual variations in gallbladder kinetics can explain intraindividual differences in the postprandial responses.

Conclusions

We conclude that there is considerable inter‐ and intraindividual variation in postprandial plasma bile acid levels. The presented personalized approach is a promising tool to identify unique characteristics of underlying physiological processes and can be applied to investigate bile acid metabolism in pathophysiological conditions.

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<![CDATA[Development and implementation of a commissioned pathway for the identification and stratification of liver disease in the community]]> https://www.researchpad.co/article/N83b2d7d3-223f-49fd-abf0-670e9477fc5e

Objective

To describe the development of the Nottingham liver disease stratification pathway, present a 12-month evaluation of uptake and stratification results, and compare the pathway with current British Society of Gastroenterology (BSG) guidelines.

Design

A referral pathway between primary and secondary care for the detection and risk stratification of liver disease.

Setting

Four Nottinghamshire clinical commissioning groups (700 000 population).

Patients

Patients are referred to the pathway with (1) raised aspartate aminotransferase to alanine aminotransferase (AST:ALT) ratio, (2) harmful alcohol use or (3) risk or presence of non-alcoholic fatty liver disease (NAFLD).

Interventions

We report on clinic attendance within secondary care for transient elastography (TE) and brief lifestyle intervention. The TE result is reported back to the general practitioner with advice on interpretation and referral guidance.

Main outcome measures

Pathway uptake, patient characteristics, liver disease stratification results and stakeholder feedback.

Results

Over the first 12 months 968 patients attended a TE clinic appointment, with raised AST:ALT ratio being the most common single reason for referral (36.9%). Of the total, 222 (22.9%) patients had an elevated liver stiffness (≥8 kPa), in whom 57 (25.7%) had a liver stiffness which was indicative of advanced chronic liver disease. If a traditional approach based on raised liver enzymes (BSG guidance) had been followed, 38.7% of those with significant liver disease (≥8 kPa) would have gone undetected among those referred for either NAFLD or raised AST:ALT ratio.

Conclusions

Targeting patients with risk factors for chronic liver disease and stratifying them using TE can detect significant chronic liver disease above and beyond the approach based on liver enzyme elevation.

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<![CDATA[Three Cases of Alcohol-Induced Acute-On-Chronic Liver Failure With Successful Support by Adipose-Derived Stem Cells]]> https://www.researchpad.co/article/N99167091-5168-43da-94d8-6923d467711a

OBJECTIVES:

Acute liver failure (ALF) and acute-on-chronic liver failure (AOCLF) are critical medical conditions with urgent therapy requirements. When ALF or AOCLF are due to alcohol intoxication or based on chronic alcohol abuse, virtually, no therapeutic options are available as liver transplantation is prohibited. In this case series, treatment of alcohol-induced ALF/AOCLF with adipose--derived stem cells (ASC) was tested under compassionate use.

METHODS:

ASC from 2 donors were isolated, cultured, and expanded by established protocols. ASC were administered to 3 individuals with either ALF or AOCLF due to alcohol abuse under compassionate use. Clinical presentation, serum measurements, and other diagnostic methods were compiled before ASC treatment and during the disease course after ASC administration.

RESULTS:

Three patients were admitted to the Department of Gastroenterology, Hepatology, and Infectious Diseases (University Hospital Magdeburg) with acute or AOCLF due to alcohol abuse. All 3 patients presented in impaired general condition and with elevated, in 1 case drastically elevated, serum liver enzyme concentrations. Treatment with ASC led to improvements in general condition and reduction of serum transaminases. In 2 cases, reduction of liver stiffness and increase of liver function by the C13 methacetin breath test were observed after ASC treatment. Recovery to a normal condition was achieved between 1 and 2 months after ASC treatment. No adverse effects associated to ASC treatment were observed.

DISCUSSION:

ASC treatment may be a feasible option to enhance recovery from alcohol-induced ALF or AOCLF. ASC treatment seems safe in the presented cases.

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<![CDATA[Sex Differences in the Association Between Frailty and Sarcopenia in Patients With Cirrhosis]]> https://www.researchpad.co/article/N2d2b666a-7a6d-413d-b825-79d475ed9875

OBJECTIVES:

Frailty is prevalent in patients with cirrhosis and is hypothesized to result in part from sarcopenia, but the precise contribution of sarcopenia to frailty in this population is poorly understood.

METHODS:

Included were patients with cirrhosis from 2011 to 2014 who had an ambulatory frailty assessment and abdominal computed tomography scan within 3 months. Logistic regression assessed the associations between frailty (=Liver Frailty Index ≥4.5), and sarcopenia (=skeletal muscle index of <39 cm2/m2 for women and <50 cm2/m2 for men).

RESULTS:

Two hundred ninety-one participants were included: 33% were female. The median (interquartile range) Liver Frailty Index was 3.7 (3.3–4.2); 19% were frail. The median (interquartile range) skeletal muscle index was 49 cm2/m2 (31–69); 36% had sarcopenia. Among the 54 frail participants, 48% had sarcopenia. In univariable logistic regression, sarcopenia was associated with a 1.86× increased odds of being frail (95% confidence interval [CI], 1.02–3.38). After adjusting for sex, etiology, hepatocellular carcinoma, MELDNa, ascites, encephalopathy, and hypertension, sarcopenia was associated with a 2.38× increased odds of being frail (95% CI, 1.17–4.85). After stratifying by sex and adjusting for MELDNa, sarcopenia among males was associated with a significantly increased odds of frailty (odds ratio 2.81, 95% CI, 1.19–6.67), whereas sarcopenia among females was not (odds ratio 1.38; 95% CI, 0.45–4.25).

DISCUSSION:

In patients with cirrhosis, sarcopenia was associated with a nearly 2-fold increased odds of being frail. Two-thirds of frail men displayed sarcopenia compared with only one-quarter of frail women. Contributors to the frail phenotype may differ by sex and support the need for sex-specific strategies to reduce frailty in this population.

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<![CDATA[Metabolic effects of the dietary monosaccharides fructose, fructose–glucose, or glucose in mice fed a starch‐containing moderate high–fat diet]]> https://www.researchpad.co/article/N4ba083a7-3fe2-4fc8-8fe4-f1a8b0418263

Abstract

Fructose consumption has been linked to obesity and increased hepatic de novo lipogenesis (DNL). Excessive caloric intake often confounds the results of fructose studies, and experimental diets are generally low‐fat diets, not representative for westernized diets. Here, we compared the effects of dietary fructose with those of dietary glucose, in adult male and female mice on a starch‐containing moderate high–fat (HF) diet. After 5 weeks fattening on a HF high‐glucose (HF‐G) diet, mice were stratified per sex and assigned to one of the three intervention diets for 6 weeks: HF high fructose (HF‐F), HF with equimolar glucose and fructose (HF‐GF), or HF‐G. Bodyweight (BW) and food intake were measured weekly. Indirect calorimetry was performed on week 5; animals were sacrificed in food‐deprived state on week 6. Data were analyzed within sex. BW gain was similar among animals on the HF‐G, HF‐GF, and HF‐F diets. Cumulative food intake was slightly lower in HF‐F animals (both sexes). However, energy expenditure was not affected, or were circulating insulin and glucose concentrations, and hepatic triglyceride levels at endpoint. Hepatic gene expression analysis showed only minor alterations in hexokinase and glycolysis‐related expression in males, and no alterations in sugar transporters, or DNL‐related enzymes. In females, no consistent alterations in hepatic or small intestine gene expression were seen. Concluding, partial or complete replacement of dietary glucose with fructose does not increase caloric intake, and does not affect BW, hepatic triglyceride levels, or insulin concentrations in male and female mice on a moderate high–fat diet.

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