Hepatic Morbidity Research Articles

Clinical characteristics and HLA associations of azithromycin-induced liver injury.

Azithromycin (AZ) is a widely used antibiotic. The aim of this study was to characterise the clinical features, outcomes, and HLA association in patients with drug-induced liver injury (DILI) due to AZ. The clinical characteristics of individuals with definite, highly likely, or probable AZ-DILI enrolled in the US Drug-Induced Liver Injury Network (DILIN) were reviewed. HLA typing was performed using an Illumina MiSeq platform. The allele frequency (AF) of AZ-DILI cases was compared to population controls, other DILI cases, and other antibiotic-associated DILI cases. Thirty cases (4 definite, 14 highly likely, 12 probable) of AZ-DILI were enrolled between 2004 and 2022 with a median age of 46 years, 83% white, and 60% female. Median duration of AZ treatment was 5 days. Latency was 18.5 days. 73% were jaundiced at presentation. The injury pattern was hepatocellular in 60%, cholestatic in 27%, and mixed in 3%. Ten cases (33%) were severe or fatal; 90% of these were hepatocellular. Two patients required liver transplantation. One patient with chronic liver disease died of hepatic failure. Chronic liver injury developed in 17%, of which 80% had hepatocellular injury at onset. HLA-DQA1*03:01 was significantly more common in AZ-DILI versus population controls and amoxicillin-clavulanate DILI cases (AF: 0.29 vs. 0.11, p = 0.001 and 0.002, respectively). Azithromycin therapy can lead to rapid onset of severe hepatic morbidity and mortality in adult and paediatric populations. Hepatocellular injury and younger age were associated with worse outcomes. HLA-DQA1*03:01 was significantly more common in AZ cases compared to controls.

Long-term outcomes of patients with toxic shock syndrome: A matched cohort study

We examined long-term outcomes of toxic shock syndrome. We conducted a matched cohort study of 630 patients with toxic shock syndrome and 5009 healthy controls between 2006 and 2021 in Quebec, Canada. Outcomes included hospitalization for renal, cardiovascular, hepatic, and other morbidity during 15 years of follow-up. We estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the risk of these outcomes over time, comparing patients with toxic shock syndrome relative to matched controls. Compared with healthy controls, rehospitalization rates at 15 years were higher for men with toxic shock syndrome (52.0 vs 30.0 per 100)but not for women (38.7 vs 45.6 per 100). In men, toxic shock syndrome was associated with an elevated risk of renal (HR 17.43, 95% CI 6.35-47.82), cardiovascular (HR 2.57; 95% CI 1.52-4.34), and hepatic hospitalization (HR 19.83, 95% CI 4.72-83.34). In women, toxic shock syndrome was associated with renal hospitalization (HR 4.71, 95% CI 1.94-11.45). Streptococcal toxic shock was associated with a greater risk of rehospitalization than staphylococcal toxic shock. Toxic shock syndrome is associated with rehospitalization up to 15 years later, especially in men. These patients may benefit from continued follow-up to prevent long-term morbidity.

Protocolo de valoración de la fibrosis hepática. Pruebas no invasivas para el diagnóstico de la enfermedad hepática crónica compensada

Liver fibrosis should be assessed in all cases of chronic liver disease to adjust follow-up to each individual's risk of hepatic morbidity and mortality. Non-invasive tests can identify both patients with no risk of advanced fibrosis and those with a high probability of having compensated advanced chronic liver disease (cACLD). Simple serum-based tests are accessible and their use is recommended in non-specialized care, where the prevalence of cACLD is low. They should be used to rule out cACLD and only when there are risk factors for liver disease. Elastography techniques are more specific and are used to confirm cACLD in a second stage. Vibration-controlled transient elastography is the most validated and follows the rule of 5 (10-15-20-25kPa), indicating progressively higher risks of decompensation and death. Acoustic radiation force impulse techniques are becoming more widespread as they can be performed as abdominal the same time as ultrasound.

Non-Alcoholic Steato Hepatitis (NASH): A Case Report of Early Onset and Progression to Liver Damage

Non-alcoholic steato hepatitis (NASH) is a silent liver disease often resembling cirrhosis of liver but occurring among people who drink little or no alcohol. Its major feature is fat accumulation in liver with inflammation and damage. The presentation may vary from asymptomatic to cirrhosis to development of complications. Present case report explains NASH for a 53-yearold male with overt obesity admitted in Liver intensive care unit (ICU) with typical presentation of deteriorating sensorium, fever and breathlessness. The progression of the disease and the complicated unmanageable state in which the patient presented to the ICU of a super specialised centre for management is noteworthy. He rapidly progressed to fibrosis of liver over few months in spite of his young age. The estimated global prevalence and burden of non‐alcoholic fatty liver disease and its advanced stage that is development of steatohepatitis has been considerably increasing adding to hepatic morbidity and mortality. It also poses risk for increased cardiovascular complications, warranting a multidisciplinary approach. The knowledge of healthcare workers including nurses is however limited, especially with specialists outside the field of hepatology and gastroenterology. This paper aims to sensitise the nurses about the disease, symptomatology and management of such a case.

Appendicular Skeletal Muscle Mass to Visceral Fat Area Ratio Predicts Hepatic Morbidities.

: Reports on the association between sarcopenic visceral obesity and non-alcoholic fatty liver disease (NAFLD)-associated morbidities remain scarce. We investigated the association between sarcopenia and visceral obesity, and the influence of this association on hepatic and coronary comorbidities. : The appendicular skeletal muscle mass to visceral fat area ratio (SV ratio) was evaluated using bioelectric impedance analysis. NAFLD and significant liver fibrosis were assessed using transient elastography, and high atherosclerotic cardiovascular disease (ASCVD) risk was defined as a 10-year ASCVD risk score >10%. Sarcopenia was defined as appendicular skeletal muscle mass adjusted by body mass index (<0.789 for men and <0.512 for women). : In total, 82.0% (n=1,205) of the entire study population had NAFLD, and 14.6% of these individuals (n=176) exhibited significant liver fibrosis. Individuals with the lowest SV ratio had a significantly increased risk of NAFLD, significant liver fibrosis, and high ASCVD risk (all p<0.05). Individuals with both the lowest SV ratio and sarcopenia had the highest risk of developing NAFLD (odds ratio [OR]=3.11), significant liver fibrosis (OR=2.03), and high ASCVD risk (OR=4.15), compared with those with a higher SV ratio and without sarcopenia (all p<0.05). : Low SV ratio combined with sarcopenia was significantly associated with an increased risk of NAFLD, significant liver fibrosis, and high ASCVD risk among individuals with a high risk of NAFLD.

Glucocorticoid Replacement for Adrenal Insufficiency and the Development of Non-Alcoholic Fatty Liver Disease.

Glucocorticoid excess is a known risk factor for non-alcoholic fatty liver disease (NAFLD). Our objective was to analyse the impact of glucocorticoid replacement therapy on the development of NAFLD and NAFLD-related fibrosis and, therefore, on cardiovascular as well as hepatic morbidity in patients with adrenal insufficiency. Two hundred and fifteen individuals with primary (n = 111) or secondary (n = 104) adrenal insufficiency were investigated for hepatic steatosis and fibrosis using the fatty liver index (FLI), NAFLD fibrosis score (NAFLD-FS), Fibrosis-4 Index (FiB-4) plus sonographic transient elastography. Results were correlated with glucocorticoid doses and cardiometabolic risk parameters. The median dose of hydrocortisone equivalent was 20 mg daily, with a median therapy duration of 15 years. The presence and grade of hepatic steatosis and fibrosis were significantly correlated with cardiometabolic risk factors. We could not find any significant correlations between single, daily or cumulative doses of glucocorticoids and the grade of liver steatosis, nor with fibrosis measured via validated sonographic techniques. In patients with adrenal insufficiency, glucocorticoid replacement within a physiological range of 15-25 mg hydrocortisone equivalent per day does not appear to pose an additional risk for the development of NAFLD, subsequent liver fibrosis, or the cardiovascular morbidity associated with these conditions.

Macrophage metabolism in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) and its inflammatory and often progressive subtype nonalcoholic steatohepatitis (NASH), have emerged as significant contributors to hepatic morbidity worldwide. The pathophysiology of NAFLD/NASH is multifaceted, variable, and remains incompletely understood. The pivotal role of liver-resident and recruited macrophages in the pathogenesis of NAFLD and NASH is widely acknowledged as a crucial factor in innate immunity. The remarkable plasticity of macrophages enables them to assume diverse activation and polarization states, dictated by their immunometabolism microenvironment and functional requirements. Recent studies in the field of immunometabolism have elucidated that alterations in the metabolic profile of macrophages can profoundly influence their activation state and functionality, thereby influencing various pathological processes. This review primarily focuses on elucidating the polarization and activation states of macrophages, highlighting the correlation between their metabolic characteristics and the transition from pro-inflammatory to anti-inflammatory phenotypes. Additionally, we explore the potential of targeting macrophage metabolism as a promising therapeutic approach for the management of NAFLD/NASH.

Morbidity, mortality, and prognostic factors in gestational trophoblastic neoplasia with liver metastasis.

Liver metastases of gestational trophoblastic neoplasia (GTN) are rare, but associated with poor prognosis. The additional concomitant presence of brain or intra-abdominal metastases, with liver metastases has been described as worsening factors, but the literature on this topic is reduced. To estimate the overall mortality, specific hepatic morbidity, and mortality, and to identify prognostic factors for patients with GTN and liver metastases. The medical records of 26 GTN patients with liver metastases registered in the French Center for Trophoblastic Diseases and treated between November 1999 and December 2019 were reviewed. Overall survival was described using Kaplan-Meier estimates. Prognostic factors were identified using univariate and multivariate Cox analyses. The 5-year overall survival rate was 60.7% for all patients with liver metastasis. The survival rate was higher in patients who achieved complete remission after first-line chemotherapy than in those who did not (100% vs 20%, p=0.001). The only factor independently associated with prognosis was the presence of 6 or more liver metastases (5-year survival, 16.7% vs. 82.4% otherwise; HR =11.1, 95%CI, 2.3-53.1; p=0.003). None of the five patients with a single liver metastasis died. GTN with liver metastasis is very rare (1.6%). The prognosis of patients seems to be improving. The results of this study are also reassuring for patients with complete remission after first-line combination chemotherapy, as well as for those with a single liver metastasis.

Non-alcoholic fatty liver disease and cardiovascular risks: A review

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. NAFLD may be associated with concomitant metabolic disorders (obesity, type 2 diabetes mellitus, dyslipidemia) and is often considered a hepatic manifestation of metabolic syndrome. In addition to hepatic morbidity and mortality, NAFLD is closely associated with asymptomatic and overt cardiovascular disease (CVD), leading to increased cardiovascular morbidity and mortality, and the more severe the hepatic disorder, the higher the risk. This review describes the main pathophysiological mechanisms linking NAFLD and CVD, discusses the role of NAFLD as a CVD risk factor, and addresses non-drug and drug therapies for NAFLD in the context of cardiovascular risk reduction. NAFLD makes patients candidates for more intensive therapeutic intervention to reduce hepatic and cardiovascular risks. Lifestyle modifications, including weight loss, increased physical activity, and nutritional adjustment, form the basis of NAFLD treatment. Correction of cardiovascular risk factors includes statins, antihypertensive agents, preferably renin-angiotensin system blockers. Ursodeoxycholic acid has therapeutic potential for beneficial effects on hepatic disorders and reducing cardiovascular risk.

A global survey of health care workers' awareness of non-alcoholic fatty liver disease: The AwareNASH survey.

The estimated global prevalence and burden of non-alcoholic fatty liver disease (NAFLD) and its advanced stage, non-alcoholic steatohepatitis (NASH), is increasing. Yet, NAFLD remains largely underdiagnosed. In addition to hepatic morbidity and mortality, NAFLD is associated with increased cardiovascular complications, warranting a multidisciplinary approach. Despite its rapidly increasing prevalence, knowledge of NAFLD among healthcare workers is limited, especially with specialists outside the field of hepatology and gastroenterology. To investigate knowledge, practice and opinions/attitudes of healthcare workers towards diagnosis and management of NAFLD/NASH. The survey was designed in collaboration with a multidisciplinary scientific committee established especially for this study. The survey was disseminated to healthcare workers from seven different disciplines through four collaborating societies, social media and at a cardiology-themed conference from February to June 2022. Median and interquartile range were mentioned for numeric responses and proportions for categorical responses or responses on a Likert scale. Likert scale responses were treated as ordinal data and analysed with the appropriate tests. The full dataset included 613 respondents from 88 different countries (including 488 physicians). 64% of the surveyed physicians underestimated the prevalence of NAFLD. General practitioners and cardiologists underestimated the prevalence most often (74% and 77%, respectively). Compared to the other disciplines, cardiologists were least familiar with the symptoms and diagnostic criteria and felt least confident in diagnosing and managing NAFLD. Overall, 65% of physicians reported regularly using evidence-based guidelines for managing NAFLD, yet 72% reported challenges in providing lifestyle recommendations. A lack of awareness was the most common reported reason for the lack of screening for NAFLD (68% respectively). Despite the growing burden of NAFLD, there is a significant gap in awareness, knowledge, and management among physicians treating patients with cardiometabolic comorbidities, particularly cardiologists. Hepatologists and gastroenterologists could play a role in educating their fellow physicians.

De Novo Cost-Effectiveness Model Framework for Nonalcoholic Steatohepatitis-Modeling Approach and Validation.

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with hepatic morbidity and mortality and extra-hepatic comorbidities. Published NASH cost-effectiveness models (CEMs) are heterogeneous and consistently omit comorbid conditions that frequently co-exist alongside NASH. We aimed to develop a de novo CEM framework that incorporates extra-hepatic disease states and outcomes alongside hepatic components to enable future estimation of the cost-effectiveness of NASH interventions. Patient-level simulation and cohort-level Markov models were implemented in the same framework. Model inputs included fibrosis progression; late-stage liver disease outcomes; comorbidity outcomes for cardiovascular disease, type 2 diabetes, and obesity; mortality; health-related quality of life; and direct medical costs. The prototype analysis assessed the cost-effectiveness of obeticholic acid versus standard of care from a US payer perspective over a lifetime horizon with costs and effects discounted at 3% per annum. However, the CEM was designed for easy adaptation to other countries, time horizons, and other considerations. Efficacy and adverse event parameters were obtained from the 18-month interim analysis of the REGENERATE trial. Outputs include total and incremental costs, total life years, and quality-adjusted life years. In this model, total costs, total life years, and quality-adjusted life years were all higher with obeticholic acid compared with standard of care. Cross-validation of this model with the 2016 and 2020 Institute for Clinical and Economic Review models revealed marked differences, mainly driven by mortality inputs, transition probability estimates, and incorporation of the effect of treatment and comorbidities. This is the first CEM in NASH to incorporate the clinical consequences of several comorbidities. The flexible yet standardized framework permits estimation of the cost-effectiveness of NASH interventions in a variety of settings. The model currently includes several assumptions and will be further developed as more relevant data become available.

Liver stiffness, hepatorenal index, and microRNA-130b as predictors for chronic kidney disease in patients with non-alcoholic fatty liver disease

Background and aimCurrently, nonalcoholic liver disease (NAFLD) is the most predominant chronic liver disorder. NAFLD has been linked to hepatic and extrahepatic morbidities. We aimed to investigate the role of acoustic radiation force impulse (ARFI), hepatorenal index (HRI), and serum microRNA-130b as non-invasive predictors for chronic kidney disease (CKD) in NAFLD patients.Material and methodsIn a case–control design, we included 40 NAFLD patients (20 NAFLD with CKD and 20 NAFLD without CKD) and 20 healthy controls. After clinical evaluation, laboratory assessments including liver test profile, renal function test, and quantification of microRNA-130b were done. Liver steatosis and stiffness were evaluated using HRI and ARFI.ResultsHRI and ARFI readings were significantly higher among NAFLD with CKD patients compared to other groups (P < 0.001). The median values of microRNA-130b were 32.1, 27.01, and 25.36 copies/µl in NAFLD with CKD, NAFLD without CKD, and healthy controls, respectively, with significant differences between groups (P < 0.05). ARFI values and HRI were positively correlated with microRNA-130b (P < 0.05). At a cutoff value > 28.13 copies/µl, microRNA-130b could differentiate between “NAFLD with CKD” and “NAFLD without CKD” patients with a sensitivity and specificity of 75% and 70%, respectively (AUC = 71.9%, P = 0.018).ConclusionsSerum microRNA-130b, HRI, and ARFI are valuable noninvasive markers for the assessment of NAFLD. MicroRNA-130b is suggested as a sensitive biomarker for the prediction of CKD among NAFLD patients with good sensitivity and specificity.

Associations between Liver Enzymes, Lifestyle Risk Factors and Pre-Existing Medical Conditions in a Population-Based Cross-Sectional Sample.

While alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) enzymes are commonly used indicators of liver dysfunction recent studies have suggested that these may also serve as predictive biomarkers in the assessment of extrahepatic morbidity. In order to shed further light on the interactions between serum liver enzyme abnormalities, factors of lifestyle and health status we examined ALT and GGT activities in a population-based sample of 8743 adult individuals (4048 men, 4695 women from the National FINRISK 2002 Study, mean age 48.1 ± 13.1 years) with different levels of alcohol drinking, smoking, physical activity, body weight and the presence or absence of various pre-existing medical conditions. The assessments also included laboratory tests for inflammation, lipid status and fatty liver index (FLI), a proxy for fatty liver. The prevalence of ALT and GGT abnormalities were significantly influenced by alcohol use (ALT: p < 0.0005 for men; GGT: p <0.0005 for both genders), smoking (GGT: p <0.0005 for men, p =0.002 for women), adiposity (p < 0.0005 for all comparisons), physical inactivity (GGT: p <0.0005; ALT: p <0.0005 for men, p <0.05 for women) and coffee consumption (p <0.0005 for GGT in both genders; p <0.001 for ALT in men). The total sum of lifestyle risk factor scores (LRFS) influenced the occurrence of liver enzyme abnormalities in a rather linear manner. Significantly higher LRFS were observed in the subgroups of individuals with pre-existing medical conditions when compared with those having no morbidities (p <0.0005). In logistic regression analyses adjusted for the lifestyle factors, both ALT and GGT associated significantly with fatty liver, diabetes and hypertension. GGT levels also associated with coronary heart disease, angina pectoris, cardiac insufficiency, cerebrovascular disease, asthma and depression. Combinations of abnormal ALT and GGT activities significantly increased the odds for hypertension coinciding with abnormalities in biomarkers of inflammation, lipid status and FLI. The data indicates that ALT and GGT activities readily respond to unfavorable factors of lifestyle associating also with a wide array of pre-existing medical conditions. The data supports close links between both hepatic and extrahepatic morbidities and lifestyle risk factors and may open new insights on a more comprehensive use of liver enzymes in predictive algorithms for assessing mechanistically anchored disease conditions.

Hyperglycemia Alters O-GlcNAcylation Patterns of Hepatocytes in Mice Treated With Hepatoxic Carcinogen.

Diabetes mellitus (DM) is an established risk for hepatocellular carcinoma (HCC), with unclarified mechanisms. This study investigated the effects of hyperglycemia on O-GlcNacylation in hepatocytes and its associations with hepatocarcinogenesis. Mouse and human HCC cell lines were used in an in vitro model of hyperglycemia. Western blotting was used to determine the effects of high glucose on O-GlcNacylation in HCC cells. Twenty 4-week-old C3H/HeNJcl mice were randomized into four groups: non-DM control, non-DM plus diethylnitrosamine (DEN), DM, and DM plus DEN. DM was induced using intraperitoneal injection of a single high dose of streptozotocin. DEN was used to induce HCC. All mice were euthanized at week 16 after DM induction, and the liver tissues were histologically examined using hematoxylin and eosin, and immunohistochemistry. High glucose increased O-GlcNacylated proteins in mouse and human HCC cell lines compared with those cultured at normal glucose concentration. Mice with hyperglycemia or DEN treatment had increased O-GlcNacylated proteins in hepatocytes. No gross tumors were evident at the end of the experiment but hepatic morbidity was observed. Mice with hyperglycemia and DEN treatment showed greater histological morbidity in their livers, i.e. increased nuclear size, hepatocellular swelling and sinusoidal dilatation, compared with mice in the DM group or treated with DEN alone. Hyperglycemia increased O-GlcNAcylation in both in vitro and animal models. Increased O-GlcNAcylated proteins may be associated with hepatic histological morbidities which then promote HCC development in carcinogen-induced tumorigenesis.

Predictive risk markers in alcoholism.

The medical disorders of alcoholism rank among the leading public health problems worldwide and the need for predictive and prognostic risk markers for assessing alcohol use disorders (AUD) has been widely acknowledged. Early-phase detection of problem drinking and associated tissue toxicity are important prerequisites for timely initiations of appropriate treatments and improving patient's committing to the objective of reducing drinking. Recent advances in clinical chemistry have provided novel approaches for a specific detection of heavy drinking through assays of unique ethanol metabolites, phosphatidylethanol (PEth) or ethyl glucuronide (EtG). Carbohydrate-deficient transferrin (CDT) measurements can be used to indicate severe alcohol problems. Hazardous drinking frequently manifests as heavy episodic drinking or in combinations with other unfavorable lifestyle factors, such as smoking, physical inactivity, poor diet or adiposity, which aggravate the metabolic consequences of alcohol intake in a supra-additive manner. Such interactions are also reflected in multiple disease outcomes and distinct abnormalities in biomarkers of liver function, inflammation and oxidative stress. Use of predictive biomarkers either alone or as part of specifically designed biological algorithms helps to predict both hepatic and extrahepatic morbidity in individuals with such risk factors. Novel approaches for assessing progression of fibrosis, a major determinant of prognosis in AUD, have also been made available. Predictive algorithms based on the combined use of biomarkers and clinical observations may prove to have a major impact on clinical decisions to detect AUD in early pre-symptomatic stages, stratify patients according to their substantially different disease risks and predict individual responses to treatment.

Nonalcoholic Fatty Liver Disease and MicroRNAs: A Weighty Consideration

MicroRNAs (miRNAs) are small endogenous, noncoding RNA molecules that regulate the expression of their target genes. The biological functions of miRNAs have been explored considerably. Numerous studies have demonstrated that extracellular miRNA could be implemented as a biomarker for several diseases. Nonalcoholic fatty liver disease (NAFLD) has become one of the leading causes of chronic liver disease worldwide. NAFLD embodies an array of defects extending from elementary steatosis to nonalcoholic steatohepatitis, which might advance to fibrosis, cirrhosis, and even hepatocellular carcinoma, which are closely linked to increased activity hepatic morbidity and mortality. Liver biopsy is acknowledged as the most precise practice for diagnosis and staging of NAFLD. Invasive drawbacks have prompted the likelihood of introducing an alternative noninvasive approach for consideration. Several lines of evidence have revealed that miRNAs are emerging as a potentially useful noninvasive marker for the development and progression of NAFLD. In addition, recent studies have identified that miRNAs take part in lipid metabolism linked to NAFLD and its advancement to severity. This article reviews the contemporary corroboration associating miRNAs and NAFLD and emphasizes the potential role of miRNA as a circulatory biomarker that could alert the growing prevalence of NAFLD. Furthermore, it acknowledges the valuable compendium of information regarding biogenesis and the role of circulating miRNA in lipid metabolism, which is intimately linked to NAFLD.

Pregnane X receptor gene variant rs7643645 and total mortality in subjects with nonalcoholic fatty liver disease.

Pregnane X receptor (PXR) gene variants rs7643645 and rs2461823 are reported to associate with clinically and histologically more severe liver injury in nonalcoholic fatty liver disease (NAFLD). It is known that the more progressive the NAFLD, the higher the hepatic and extra-hepatic mortality and morbidity. Thus, we investigated the total mortality in Finnish middle-aged ultrasonographically verified NAFLD patients with PXR rs7643645 AA/AG ( n = 217) or GG ( n = 27) variants and rs2461823 CC/CT ( n = 215) or TT ( n = 27) variants. In up to 30 years of follow-up, PXR rs7643645 GG subjects were at an increased risk of total mortality compared with AA/AG subjects, 1.676 (1.014-2.772), P = 0.044. The statistically significant difference prevailed after multiple adjustments for potentially confounding factors, RR, 2.024 (1.191-3.440), P = 0.009. In the subjects without NAFLD ( n = 731), the mortality risk was not associated with rs7643645 variants, 1.051 (0.708-1.560; P = 0.804). There was no difference in the total mortality between the PXR rs2461823 variant subgroups, 1.141 (0.663-1.962; P = 0.634). As the rs7643645 G variant disrupts a putative hepatocyte nuclear factor 4α binding site located in the PXR gene promoter and is associated with lower hepatic expression of PXR and its target genes, our result suggests that genetic disruption of xenobiotic metabolism increases mortality in subjects with NAFLD. Further studies are needed to confirm the results of the present study.

Characterization of Hepatic Dysfunction in Subjects Diagnosed With Chronic GVHD by NIH Consensus Criteria

Hepatic chronic graft-versus-host disease (cGVHD) causes morbidity and current diagnostic criteria are nonspecific. An accurate diagnosis is imperative because overdiagnosis can lead to unnecessary treatment with immunosuppressive agents and raising the risk of opportunistic infections. We aim to characterize different patterns of liver injury and cytokine profiles associated with hepatic dysfunction in cGVHD, to evaluate the accuracy of the NIH Consensus Criteria (NCC) for hepatic cGVHD and to explore predictors for hepatic cGHVD. Patients were evaluated in this prospective cross-sectional study of patients with cGVHD recruited under a natural history protocol. Laboratory tests and cytokines were measured. The cGVHD were diagnosed and scored based on NCC. Clinically indicated liver biopsy specimens or autopsies were reviewed by an expert hepatopathologist (D.E.K.). Comparisons were made between groups, and univariable and multivariable logistic regression were calculated. Of the 302 patients enrolled, 151 fulfilled hepatic cGVHD based on NCC; however, 69% had at least 1 abnormal liver test result. Abnormal alanine aminotransferase (ALT) and aspartate aminotransferase were associated with lower platelets, higher total bilirubin (TB), total cholesterol, serum amyloid A, and IL 15. Abnormal ALP and gamma-glutamyl transpeptidase were associated with higher cholesterol, and IL7. Lower platelet count was associated with higher ALT, TB, and triglycerides and lower albumin. Of the 27 with liver tissue, 16 had histologic features of GVHD, only eight met clinical criteria for hepatic GVHD. Sensitivity and specificity of NCC in identifying hepatic GVHD were 50% and 27% (Kappa=-0.23). Only 6 had only hepatic GVHD, whereas 10 had hepatic GVHD with either iron overload, nodular regenerative hyperplasia, or steatosis. Multivariable logistic regression showed that ALP and total cholesterol were associated with hepatic GVHD and total cholesterol >220 mg/dL increased the sensitivity for histologic hepatic GVHD. In conclusion, abnormal liver enzymes in cGVHD are nonspecific and have poor correlation with histologic evidence for hepatic GVHD, highlighting the importance of histology. Cytokines provide insight into the pathogenesis of hepatic cGVHD. Decreased platelet count was associated with factors associated with liver disease including portal vein diameter, which may suggest progression of liver disease. This highlights the need of incorporating these factors in natural history study and using liver biopsy to understand the development of liver dysfunction in hematopoietic stem cell transplantation and to develop better instruments to decreased hepatic cGVHD related morbidity and mortality. The study was registered with a ClinicalTrials.gov identifier NCT00092235.

Minimally invasive resection of congenital tracheobiliary fistula with thoracoscopic cholangiography

Minimally invasive resection of congenital tracheobiliary fistula with thoracoscopic cholangiography

Nonalcoholic Fatty Liver Disease and Cardiovascular Disease: a Review of Shared Cardiometabolic Risk Factors.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is rising. NAFLD/nonalcoholic steatohepatitis (NASH) is associated not only with hepatic morbidity and mortality but also with an increased cardiovascular risk. NAFLD and cardiovascular disease (CVD) share several risk factors, such as obesity, metabolic syndrome, hypertension, dyslipidemia, type 2 diabetes, and chronic kidney disease. This review summarizes the evidence linking cardiometabolic risk factors and NAFLD in the context of risk for CVD. The cause of NAFLD/NASH is complex, involving a range of factors from genetics to lifestyle and energy balance. Genetically driven high liver fat content does not appear to be causally associated with increased CVD risk. In contrast, metabolic dysfunction not only predisposes to liver pathology but also leads to a significantly higher CVD risk. Given that NAFLD pathophysiology is influenced by multiple factors, each patient is unique as to their risk of developing CVD and liver pathology. At the same time, the rising burden of NAFLD/NASH is closely linked with the global increase in metabolic disorders, including obesity and type 2 diabetes. Therefore, both personalized therapeutic approaches that recognize individual pathophysiology, as well as public health policies that address the root causes of cardiometabolic risk factors for NAFLD may be needed to effectively address the NAFLD/NASH epidemic.