Progression to cirrhosis is similar among all ages in nonalcoholic fatty liver disease, but liver-related events increase with age.

BACKGROUND: NAFLD is increasingly common among young people. Whether NAFLD carries a more benign course in younger adults is not known. We aimed to characterize genetic and metabolic risk factors for NAFLD and their effects on disease progression across age groups. METHODS: We conducted a retrospective study of adults with NAFLD seen within Michigan Medicine, a tertiary care center, between 2010 and 2021. NAFLD was defined by hepatic steatosis on imaging, biopsy, or transient elastography in the absence of other chronic liver diseases. Cirrhosis was determined by validated International Classification of Diseases-9/10 codes or imaging. Fine-Gray competing risk models were generated, with incident cirrhosis and liver-related events (LREs) as the primary outcomes and death without cirrhosis or LREs as a competing risk. The primary predictor was the age category. RESULTS: We included 31,505 patients with NAFLD, with 8,252 aged 18 to younger than 40, 15,035 aged 40 to younger than 60, and 8,218 aged 60 years or older years at diagnosis. Compared with older patients, young adults more often had obesity, higher ALT, and high-risk PNPLA3 alleles, and fewer had prevalent cirrhosis, hypertension, hyperlipidemia, and diabetes. The 10-year risk of incident cirrhosis was similar between ages (3.4% in age 18 to <40 vs 3.7% in age 40 to <60 vs 4.7% in age ≥60; p = 0.058). Predictors of LREs were advancing age and diabetes, with a significantly higher 10-year risk of LREs in the oldest age group (0.2% in age 18 to <40 vs 0.7% in age 40 to <60 vs 1.1% in age ≥60; p = 0.008). CONCLUSIONS: While the baseline prevalence of cirrhosis was higher among older adults, the rate of NAFLD progression to cirrhosis was similar in young and older adults. Older patients were more likely to have LREs.

A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects.

Notch signaling is a conserved pathway that converts extracellular receptor-ligand interactions into changes in gene expression via a single transcription factor (CBF1/RBPJ in mammals; Su(H) in Drosophila). In humans, RBPJ variants have been linked to Adams-Oliver syndrome (AOS), a rare autosomal dominant disorder characterized by scalp, cranium, and limb defects. Here, we found that a previously described Drosophila Su(H) allele encodes a missense mutation that alters an analogous residue found in an AOS-associated RBPJ variant. Importantly, genetic studies support a model that heterozygous Drosophila with the AOS-like Su(H) allele behave in an opposing manner to heterozygous flies with a Su(H) null allele, due to a dominant activity of sequestering either the Notch co-activator or the antagonistic Hairless co-repressor. Consistent with this model, AOS-like Su(H) and Rbpj variants have decreased DNA binding activity compared to wild type proteins, but these variants do not significantly alter protein binding to the Notch co-activator or the fly and mammalian co-repressors, respectively. Taken together, these data suggest a cofactor sequestration mechanism underlies AOS phenotypes associated with RBPJ variants, whereby the AOS-associated RBPJ allele encodes a protein with compromised DNA binding activity that retains cofactor binding, resulting in Notch target gene dysregulation.

Systematic review: radiomics for the diagnosis and prognosis of hepatocellular carcinoma.

BACKGROUND: Advances in imaging technology have the potential to transform the early diagnosis and treatment of hepatocellular carcinoma (HCC) through quantitative image analysis. Computational "radiomic" techniques extract biomarker information from images which can be used to improve diagnosis and predict tumour biology. AIMS: To perform a systematic review on radiomic features in HCC diagnosis and prognosis, with a focus on reporting metrics and methodologic standardisation. METHODS: We performed a systematic review of all full-text articles published from inception through December 1, 2019. Standardised data extraction and quality assessment metrics were applied to all studies. RESULTS: A total of 54 studies were included for analysis. Radiomic features demonstrated good discriminatory performance to differentiate HCC from other solid lesions (c-statistics 0.66-0.95), and to predict microvascular invasion (c-statistic 0.76-0.92), early recurrence after hepatectomy (c-statistics 0.71-0.86), and prognosis after locoregional or systemic therapies (c-statistics 0.74-0.81). Common stratifying features for diagnostic and prognostic radiomic tools included analyses of imaging skewness, analysis of the peritumoural region, and feature extraction from the arterial imaging phase. The overall quality of the included studies was low, with common deficiencies in both internal and external validation, standardised imaging segmentation, and lack of comparison to a gold standard. CONCLUSIONS: Quantitative image analysis demonstrates promise as a non-invasive biomarker to improve HCC diagnosis and management. However, standardisation of protocols and outcome measurement, sharing of algorithms and analytic methods, and external validation are necessary prior to widespread application of radiomics to HCC diagnosis and prognosis in clinical practice.

Neutrophil-to-Lymphocyte Ratio Predicts High-Risk Explant Features and Waitlist Survival But Is Not Independently Associated With Recurrence or Survival Following Liver Transplantation for Hepatocellular Carcinoma.

We assessed the prognostic significance and the clinical stability of the neutrophil-to-lymphocyte ratio (NLR) before liver transplantation (LT) in a large cohort of patients with hepatocellular carcinoma (HCC) from a region with a long waitlist time. A high preoperative NLR ≥5 has been reported to predict poor outcomes following LT for HCC, and the NLR has been incorporated into several prognostic models. We evaluated 758 patients with HCC with Model for End-Stage Liver Disease exceptions and listed for LT from 2002 to 2015 at a single LT center, of which 505 underwent LT and 253 dropped out before LT. The NLR was collected in all patients at LT and, if available, between 15 and 90 days before LT (NLR2) or at dropout. An NLR ≥5 was associated with microvascular invasion (MVI), poorer tumor differentiation, and more advanced pathology on explant. Patients with an NLR ≥5 exhibited no differences in alpha-fetoprotein, tumor burden at listing, or number of locoregional therapies compared with patients with an NLR <5. After a median post-LT follow-up of 4.7 years, overall survival and recurrence rates were similar for patients with an NLR ≥5 versus patients with an NLR <5. The NLR changed frequently, and 47% of patients whose NLR2 was ≥5 had an NLR <5 by LT. The NLR was ≥5 in 47.6% of patients at dropout compared with 14.9% of patients undergoing LT. Although the NLR at LT correlated with MVI and tumor stage at explant, the NLR did not predict post-LT survival or HCC recurrence. The NLR appeared to be a relatively unstable inflammatory marker during the immediate 3 months before LT for HCC.

Social Support Does Not Modify the Risk of Readmission for Patients with Decompensated Cirrhosis.

BACKGROUND: Patients with decompensated cirrhosis are at high risk of frequent hospitalizations. Whether the level of perceived social support impacts this risk is unknown. We sought to determine the relationship between social support and burden of hospitalization in patients with decompensated cirrhosis. METHODS: A total of 73 patients, all with decompensated cirrhosis and an index cirrhosis-related admission between 7/1/2017 and 7/1/2019, completed the modified medical outcomes study social support (mMOS-SS) survey. We retrospectively assessed the relationship between mMOS-SS scores and probability of readmission 90-days after the index admission. Additionally, we prospectively analyzed the association between mMOS-SS scores at enrollment and risk of 90-day hospitalization. RESULTS: At enrollment, 50.7% were female, median age 61 years, and median mMOS-SS score was 87.5. Median model for end-stage liver disease sodium (MELD-Na) at the time of the index admission was 15 and was 13 at the time of enrollment. The mMOS-SS score did not modify the rate of readmission 90 days after the index admission date (adjusted HR 1.01, 95%CI 0.98-1.03) nor was it associated with the rate of admission 90 days after enrollment prospectively (adjusted HR 0.99, 95%CI 0.96-1.02). The MELD-Na score at enrollment was the only significant predictor of hospitalization during prospective follow-up (adjusted HR 1.18, 95%CI 1.09-1.27). CONCLUSIONS: Social support, as measured by the mMOS-SS survey, in patients with decompensated cirrhosis was high. However, this did not modify the risk of cirrhosis-related hospitalizations. Future investigation to define the specific components of social support that could modify readmission risk is needed.

Accuracy of medical billing data against the electronic health record in the measurement of colorectal cancer screening rates.

OBJECTIVE: Medical billing data are an attractive source of secondary analysis because of their ease of use and potential to answer population-health questions with statistical power. Although these datasets have known susceptibilities to biases, the degree to which they can distort the assessment of quality measures such as colorectal cancer screening rates are not widely appreciated, nor are their causes and possible solutions. METHODS: Using a billing code database derived from our institution's electronic health records, we estimated the colorectal cancer screening rate of average-risk patients aged 50-74 years seen in primary care or gastroenterology clinic in 2016-2017. 200 records (150 unscreened, 50 screened) were sampled to quantify the accuracy against manual review. RESULTS: Out of 4611 patients, an analysis of billing data suggested a 61% screening rate, an estimate that matches the estimate by the Centers for Disease Control. Manual review revealed a positive predictive value of 96% (86%-100%), negative predictive value of 21% (15%-29%) and a corrected screening rate of 85% (81%-90%). Most false negatives occurred due to examinations performed outside the scope of the database-both within and outside of our institution-but 21% of false negatives fell within the database's scope. False positives occurred due to incomplete examinations and inadequate bowel preparation. Reasons for screening failure include ordered but incomplete examinations (48%), lack of or incorrect documentation by primary care (29%) including incorrect screening intervals (13%) and patients declining screening (13%). CONCLUSIONS: Billing databases are prone to substantial bias that may go undetected even in the presence of confirmatory external estimates. Caution is recommended when performing population-level inference from these data. We propose several solutions to improve the use of these data for the assessment of healthcare quality.

Gut microbiome-targeted therapies in nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression.

BACKGROUND: Preclinical evidence suggests that modulation of the gut microbiome could represent a new therapeutic target in nonalcoholic fatty liver disease (NAFLD). OBJECTIVES: The aim of this study was to evaluate the most current evidence for liver-specific and metabolic effects of microbiome-targeted therapies (MTTs) in persons with NAFLD. METHODS: We searched multiple electronic databases for randomized controlled trials (RCTs) published from January 1, 2005 to December 1, 2018 that enrolled persons with NAFLD who received MTT rather than placebo or usual care. MTT was defined as antibiotics, probiotics, synbiotics, or fecal microbiota transplantation (FMT). Clinical outcomes were pooled with the use of random-effects models and heterogeneity was assessed with the I2 statistic. A random-effects meta-regression was performed to determine sources of heterogeneity in prevalence estimates between studies. RESULTS: Twenty-one RCTs (1252 participants) were included; 9 evaluated probiotics and 12 evaluated synbiotics, with treatment duration ranging from 8 to 28 wk. No RCTs examined the efficacy of antibiotics or FMT. Probiotics/synbiotics were associated with a significant reduction in alanine aminotransferase activity [ALT, weighted mean difference (WMD): -11.23 IU/L; 95% CI: -15.02, -7.44 IU/L] and liver stiffness measurement (LSM) by elastography (reflecting inflammation and fibrosis) (WMD: -0.70 kPa; 95% CI: -1.00, -0.40 kPa), although analyses showed heterogeneity (I2 = 90.6% and I2 = 93.4%, respectively). Probiotics/synbiotics were also associated with increased odds of improvement in hepatic steatosis, as graded by ultrasound (OR: 2.40; 95% CI: 1.50, 3.84; I2 = 22.4%). No RCTs examined sequential liver biopsy findings. Probiotics (WMD: -1.84; 95% CI: -3.30, -0.38; I2 = 23.6%), but not synbiotics (WMD: -0.85; 95% CI: -2.17, 0.47; I2 = 96.6%), were associated with a significant reduction in body mass index. CONCLUSIONS: The use of probiotics/synbiotics was associated with improvement in liver-specific markers of hepatic inflammation, LSM, and steatosis in persons with NAFLD. Although promising, given the heterogeneity in pooled analyses, additional well-designed RCTs are needed to define the efficacy of probiotics/synbiotics for treatment of NAFLD. This study was registered with PROSPERO as CRD42018091455.

Correction to: Vascular Ehlers-Danlos Syndrome Presenting as a Pulsatile Neck Mass: a Case Report and Review of Literature.

This paper was inadvertently published with open access; the authors have requested the copyright revert to the society. It has been re-published with appropriate licensing.

Spontaneous Bacterial Peritonitis due to Lactobacillus paracasei in Cirrhosis.

Lactobacillus species colonize the human gastrointestinal tract and are rarely pathogenic. We present a case involving a cirrhotic patient who presented with sepsis and was found to have peritoneal cultures demonstrating Lactobacillus as the sole pathogen concerning for spontaneous bacterial peritonitis. Treatment was achieved with high-dose penicillin and clindamycin but the patient developed hepatorenal syndrome and died from acute renal failure. Intra-abdominal Lactobacillus infections are typically seen in patients undergoing peritoneal dialysis or who have recently had bowel perforation. There are few case reports of spontaneous Lactobacillus peritonitis in patients with cirrhosis. Our case report addresses the challenges of Lactobacillus treatment and suggests antibiotic coverage of commensal organisms in patients who do not improve with standard management.

Vascular Ehlers-Danlos Syndrome Presenting as a Pulsatile Neck Mass: a Case Report and Review of Literature.

Ehlers-Danlos syndrome refers to a spectrum of connective tissue disorders typically caused by mutations in genes responsible for the synthesis of collagen. Patients with Ehlers-Danlos syndrome often exhibit hyperflexibility of joints, increased skin elasticity, and tissue fragility. Vascular Ehlers-Danlos (vEDS) is a subtype of Ehlers-Danlos syndrome with a predilection to involve blood vessels. As such, it often manifests as vascular aneurysms and vessel rupture leading to hemorrhage. There are few reports describing primary prevention of aneurysms in the setting of undiagnosed, suspected vEDS. We present a case of a 30-year-old woman who presents with a pulsatile neck mass found to have multiple arterial aneurysms on imaging, hyperflexibility, and characteristic facial features consistent with vEDS. As described in this case, management of a suspected connective tissue disorder is a multidisciplinary approach including vascular surgery, medical therapy, and genetic testing to confirm the diagnosis. We review literature regarding the care of patients with vascular Ehlers-Danlos as it might pertain to hospitalized patients.

Defective K-Ras oncoproteins overcome impaired effector activation to initiate leukemia in vivo.

Reversing the aberrant biochemical output of oncogenic Ras proteins is one of the great challenges in cancer therapeutics; however, it is uncertain which Ras effectors are required for tumor initiation and maintenance. To address this question, we expressed oncogenic K-Ras(D12) proteins with "second site" amino acid substitutions that impair PI3 kinase/Akt or Raf/MEK/ERK activation in bone marrow cells and transplanted them into recipient mice. In spite of attenuated signaling properties, defective K-Ras oncoproteins initiated aggressive clonal T-lineage acute lymphoblastic leukemia (T-ALL). Murine T-ALLs expressing second site mutant proteins restored full oncogenic Ras activity through diverse mechanisms, which included acquiring novel somatic third site Kras(D12) mutations and silencing PTEN. T-ALL cell lines lacking PTEN had elevated levels of phosphorylated Akt, a gene expression pattern similar to human early T-cell precursor ALL, and were resistant to the potent and selective MEK inhibitor PD0325901. Our data, which demonstrate strong selective pressure to overcome the defective activation of PI3 kinase/Akt and Raf/MEK/ERK, implicate both Ras effector pathways as drivers of aberrant growth in T-ALL and further suggest that leukemia cells will deploy multiple mechanisms to develop resistance to targeted inhibitors in vivo.

Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus.

NRAS is frequently mutated in hematologic malignancies. We generated Mx1-Cre, Lox-STOP-Lox (LSL)-Nras(G12D) mice to comprehensively analyze the phenotypic, cellular, and biochemical consequences of endogenous oncogenic Nras expression in hematopoietic cells. Here we show that Mx1-Cre, LSL-Nras(G12D) mice develop an indolent myeloproliferative disorder but ultimately die of a diverse spectrum of hematologic cancers. Expressing mutant Nras in hematopoietic tissues alters the distribution of hematopoietic stem and progenitor cell populations, and Nras mutant progenitors show distinct responses to cytokine growth factors. Injecting Mx1-Cre, LSL-Nras(G12D) mice with the MOL4070LTR retrovirus causes acute myeloid leukemia that faithfully recapitulates many aspects of human NRAS-associated leukemias, including cooperation with deregulated Evi1 expression. The disease phenotype in Mx1-Cre, LSL-Nras(G12D) mice is attenuated compared with Mx1-Cre, LSL-Kras(G12D) mice, which die of aggressive myeloproliferative disorder by 4 months of age. We found that endogenous Kras(G12D) expression results in markedly elevated Ras protein expression and Ras-GTP levels in Mac1(+) cells, whereas Mx1-Cre, LSL-Nras(G12D) mice show much lower Ras protein and Ras-GTP levels. Together, these studies establish a robust and tractable system for interrogating the differential properties of oncogenic Ras proteins in primary cells, for identifying candidate cooperating genes, and for testing novel therapeutic strategies.