Diagnostic and prognostic performances of GALAD score in staging and 1-year mortality of hepatocellular carcinoma: A prospective study

BACKGROUND The GALAD score has improved early hepatocellular carcinoma(HCC)detection rate.The role of the GALAD score in staging and predicting tumor characteristics or clinical outcome of HCC remains of particular interest.AIM To determine the diagnostic/prognostic performances of the GALAD score at various phases of initial diagnosis,tumor features,and 1-year mortality of HCC and compare the performance of the GALAD score with those of other serum biomarkers.METHODS This prospective,diagnostic/prognostic study was conducted among patients with newly diagnosed HCC at the liver center of Vajira Hospital.Eligible patients had HCC staging allocation using the Barcelona Clinic Liver Cancer(BCLC)categorization.Demographics,HCC etiology,and HCC features were recorded.Biomarkers and the GALAD score were obtained at baseline.The performance of the GALAD score and biomarkers were prospectively assessed.RESULTS Exactly 115 individuals were diagnosed with HCC.The GALAD score increased with disease severity.Between BCLC-0/A and BCLC-B/C/D,the GALAD score predicted HCC staging with an area under the curve(AUC)of 0.868(95%CI:0.80–0.93).For identifying the curative HCC,the AUC of GALAD score was significantly higher than that of Alpha-fetoprotein(AFP)(0.753)and Lens culinaris agglutinin-reactive fraction of AFP-L3(0.706),and as good as that of Protein induced by vitamin K absence-II(PIVKA-II)(0.897).For detecting aggressive features,the GALAD score gave an AUC of 0.839(95%CI:0.75–0.92)and significantly outperformed compared to that of AFP(0.761)and AFP-L3(0.697),with a trend of superiority to that of PIVKA-II(0.772).The performance to predict 1-year mortality of GALAD score(AUC:0.711,95%CI:0.60–0.82)was better than that of AFP(0.541)and as good as that of PIVKA-II(0.736).The optimal cutoff value of GALAD score was≥6.83,with a specificity of 72.63%for exhibiting substantial reduction in the 1-year mortality.CONCLUSION The GALAD model can diagnose HCC at the curative stage,including the characteristic of advanced disease,more than that by AFP and AFP-L3,but not PIVKA-II.The GALAD score can be used to predict the 1-year mortality of HCC.

Associations of PNPLA3 and LEP genetic polymorphisms with metabolic-associated fatty liver disease in Thai people living with human immunodeficiency virus

BACKGROUND The prevalence of metabolic-associated fatty liver disease(MAFLD)is a growing public health issue in people living with human immunodeficiency virus(PLWH).However,the pathophysiology of MAFLD is still unknown,and the role of genetic variables is only now becoming evident.AIM To evaluate the associations of gene-polymorphism-related MAFLD in PLWH.METHODS The study employed transient elastography with a controlled attenuation parameter≥248 dB/m to identify MAFLD in patients from a Super Tertiary Hospital in central Thailand.Candidate single-nucleotide polymorphisms(SNPs)were genotyped using TaqMan®MGB probe 5'nuclease assays for seven MAFLD-related genes.Statistical analyses included SNP frequency analysis,Fisher's Exact and Chi-square tests,odds ratio calculations,and multivariable logistic regression.RESULTS The G-allele carriers of PNPLA3(rs738409)exhibited a two-fold rise in MAFLD,increasing by 2.5 times in MAFLD with human immunodeficiency virus infection.The clinical features and genetic patterns imply that LEP rs7799039 A-allele carriers had a nine times(P=0.001)more significant chance of developing aberrant triglyceride among PLWH.CONCLUSION The current study shows an association between PNPLA3 rs738409 and LEP rs7799039 with MAFLD in PLWH.

Thyroid hormones and thyroid hormone receptors: Effects of thyromimetics on reverse cholesterol transport

Reverse cholesterol transport (RCT) is a complex process which transfers cholesterol from peripheral cells to the liver for subsequent elimination from the body via feces. Thyroid hormones (THs) affect growth, develop- ment, and metabolism in almost all tissues. THs exert their actions by binding to thyroid hormone receptors (TRs). There are two major subtypes of TRs, TRα and TRβ, and several isoforms (e.g. TRα1, TRα2, TRβ1, and TRβ2). Activation of TRα1 affects heart rate, whereas activation of TRβ1 has positive effects on lipid and lipoprotein metabolism. Consequently, particular interest has been focused on the development of thyromimetic compounds targeting TRβ1, not only because of their ability to lower plasma cholesterol but also due their ability to stimulate RCT, at least in pre-clinical models. In this review we focus on THs, TRs, and on the effects of TRβ1-modulating thyromimetics on RCT in various animal models and in humans.

Suppression of bile acid synthesis by thyroid hormone in primary human hepatocytes

AIM： It is known that thyroid hormones alter the bile acid metabolism in humans, however the effect on individual enzymes has been difficult to elucidate. This is mainly due to the lack of human liver cell lines producing bile acids. We used cultures of primary human hepatocytes to study the effects of triiodothyronine （T3） on bile acid synthesis.METHODS： Primary hepatocytes were isolated from liver tissue obtained from three different patients undergoing liver resection due to underlying malignancy. The hepatocytes were cultured under serum-free conditions and treated from d 1 to d 5 with culture containing 0.1 - 1000 nmol/L of T3. Bile acid formation and mRNA levels of key enzymes were analysed. RESULTS： The lowest concentration of T3 decreased cholic acid （CA） formation to 43%-53% of controls and chenodeoxycholic acid （CDCA） to 52%-75% of controls on d 5. The highest dose further decreased CA formation to 16%-48% of controls while CDCA formation remained at 50%-117% of controls. Expression of mRNA levels of cholesterol 7α-hydroxylase （CYP7A1） and sterol 12α-hydroxylase （CYPSB1） dose-dependently decreased. Sterol 27-hydroxylase （CYP27A1） levels also decreased, but not to the same extent. CONCLUSION： T3 dose-dependently decreased total bile acid formation in parallel with decreased expression of CYP7A1 and CYP8B1. CA formation is inhibited to a higher degree than CDCA, resulting in a marked decrease in the CA/CDCA ratio.

Analysis of ileal sodium/bile acid cotransporter and related nuclear receptor genes in a family with multiple cases of idiopathic bile acid malabsorption

The etiology of most cases of idiopathic bile acid malabsorption （IBAH） is unknown. In this study, a Swedish family with bile acid malabsorption in three consecutive generations was screened for mutations in the ileal apical sodium-bile acid cotransporter gene （ASBT; gene symbol, SLC10A2） and in the genes for several of the nuclear receptors known to be important for ASBT expression： the farnesoid X receptor （FXR） and peroxisome proliferator activated receptor alpha （PPARα）. The patients presented with a clinical history of idiopathic chronic watery diarrhea, which was responsive to cholestyramine treatment and consistent with IBAH. Bile acid absorption was determined using ^75Se-homocholic acid taurine （SeHCAT）; bile acid synthesis was estimated by measuring the plasma levels of 7α-hydroxy-4-cholesten-3-one （C4）. The ASBT, FXR, and PPARα genes in the affected and unaffected family members were analyzed using single stranded conformation polymorphism （SSCP）, denaturing HPLC, and direct sequencing. No ASBT mutations were identified and the ASBT gene did not segregate with the bile acid malabsorption phenotype. Similarly, no mutations or polymorphisms were identified in the FXR or PPARα genes associated with the bile acid malabsorption phenotype. These studies indicate that the intestinal bile acid malabsorption in these patients cannot be attributed to defects in ASBT. In the absence of apparent ileal disease, alternative explanations such as accelerated transit through the small intestine may be responsible for the IBAM.

尼曼匹克C1样1蛋白与胆固醇结石病

胆囊结石占胆石病的绝大部分,主要成分是胆固醇,因而称为胆固醇结石病（简称胆石病）,其主要发病机制是体内胆固醇代谢紊乱,表现为胆汁胆固醇过饱和,进一步在胆囊内成核形成胆固醇结晶,最终导致胆固醇结石形成。机体胆固醇代谢包括若干过程：胆固醇的重新合成、肠道吸收食物与胆汁来源的胆固醇以及肝脏向胆汁分泌胆固醇等。

Zinc deficiency in patients with chronic pancreatitis

BACKGROUND Zinc is a key element in numerous proteins and plays an important role in essential cell functions such as defense against free radicals and DNA damage repair. Chronic pancreatitis(CP) is a chronic inflammation with progressive fibrosis of pancreas ultimately resulting in pancreatic exocrine insufficiency(PEI),which is associated with malnutrition. Studies analyzing zinc levels in patients with CP are sparse and lead to conflicting results.AIM To investigate serum zinc levels in patients with CP of various etiologies.METHODS Between October 2015 and March 2018, patients with a diagnosis of CP were identified and recruited from the Pancreatic Outpatient Clinic at the Karolinska University Hospital in Stockholm, Sweden. Demographic, clinical and laboratory data were analyzed. Etiology of CP was determined according to the MANNHEIM classification system into the following etiological subcategories:alcohol consumption, nicotine consumption, hereditary factors, efferent pancreatic duct factors and immunological factors. Pancreatic exocrine function was defined as normal(fecal elastase 1 > 200 μg/g), mildly reduced(100-200μg/g) and severely reduced(fecal elastase 1 < 100 μg/g).RESULTS A total of 150 patients were included in the analysis. Zinc deficiency(< 11μmol/L) was present in 39(26.0%) of patients: 22 females and 17 males. In the group of patients with zinc deficiency, 76.7% of patients had an exocrine pancreatic insufficiency(FE-1 < 200 μg/g). Older age was significantly associated with low zinc levels. Following a univariate analysis, patients aged 60-69 and patients ≥ 70 years of age had a significantly higher prevalence of zinc deficiencies compared to patients < 40 years of age [OR: 3.8, 95%CI(1.08-13.4); P= 0.04]; [OR 6.26, 95%CI(1.94-20.2), P > 0.002]. Smoking and number of packyears were additionally associated with low zinc levels. The risk of zinc deficiency in current smokers and smokers with ≥ 20 pack-years was approximately three times higher compared to those who had never smoked.Gender, body mass index, etiology of CP, presence of diabetes mellitus, levels of glycated hemoglobin(HbA1 c), bone mineral density, alcohol intake and presence of PEI were not associated with low zinc levels.CONCLUSION Zinc deficiency is common in patients with CP and is significantly associated with age ≥ 60, smoking and the number of pack-years, but not with PEI.

The Liver X-Receptor (Lxr) Governs Lipid Homeostasis in Zebrafish during Development

The liver X-receptors (LXRs) act as cholesterol sensors and participate in the regulation of lipid and cholesterol metabolism. The objective of this study was to determine the role of LXR during development using the zebrafish model. By in situ hybridization we showed distinct expression of lxr in the brain and the retina in the developing and adult zebrafish. Lxr ligand activation affected the expression of genes involved in lipid metabolism in zebrafish adult brain and eye as well as in zebrafish embryos. Morpholino knock down of lxr resulted in an overall impaired lipid deposition as determined by oil red O staining particularly in the head and around the eyes, and to significantly elevated levels of both total and free cholesterol in the yolk of lxr morphant embryos. The expression of genes involved in lipid and cholesterol metabolism was also changed in the lxr morphants. Furthermore, alcian blue staining revealed malformation of the pharyngeal skeleton in the lxr morphant. Our data show that lxr is an important component of the regulatory network governing the lipid homeostasis during zebrafish development, which in turn may support a role of lxr for normal development of the central nervous sytem, including the retina.

Associations between C-Reactive Protein and Apolipoproteins, Lipoprotein (a) and Conventional Serum Lipids in Outpatients: Correlations and Time Trends

Background: Correlations between CRP and serum lipids are weak, and there are conflicting and incomplete results in the literature. The aim of the present study was to clarify the strength and independence of relationships between CRP and serum lipids in outpatients. Methods: Inclusion criteria were outpatients where all the following analyses were requested in clinical routine: high sensitivity CRP, total cholesterol, triglycerides, LDL-cholesterol, HDL-cholesterol, ApoB, ApoA-1 and Lp(a). Data for patients meeting the above criteria during a period of six years (2004-2010) were copied from Aleris Medilab’s Laboratory Information System to the software Statistica. Basic statistics and correlations were calculated for 2771 patients. In patients with two (n = 959) or more sampling times changes over time were calculated. The study was a quality assurance project without access to patient files. Results: Median age was 59 years and median serum CRP concentration was 1.5 mg/L. The strongest correlations (Spearman R) were seen between CRP and triglycerides (0.25), ApoB/ApoA-1 ratio (0.21) and HDL-cholesterol (&minus;0.18). Stepwise regression analysis showed that ApoB, total cholesterol, log triglycerides and log Lp(a) together explained 8% of the variation in log CRP. Unfavourable time trends for CRP and triglycerides counteracted a significant decrease in LDL-cholesterol and total cholesterol. Conclusion: In a large cohort of outpatients CRP showed stronger correlation with triglycerides and ApoB/ApoA-1 ratio than with LDL-cholesterol and Lp(a). LDL-cholesterol concentrations changed favorably over time whereas CRP and triglycerides did not.

Impact of small molecule-mediated inhibition of ammonia detoxification on lung malignancies and liver metabolism

Dear Editor,Metabolically induced cancer heterogeneity creates a large source of novel potential targets towards an enhanced therapeutic window alone and in combination with classic chemo-and radiotherapy[1,2].This is of particular interest for non-small cell lung cancer(NSCLC),which accounts for more than 80%of all lung tumor types characterized by limited responses to current treatment options[3–5].

四氢生物蝶呤缺乏型苯丙酮尿症的筛查诊断

对20例确诊为PKU的患儿进行了四氢生物蝶呤(BH_4)负荷试验、尿液蝶呤分析和红细胞二氢生物蝶呤还原酶(DHPR)活性检测。结果显示:所有患儿在口服BH4(20mg/kg)后血浆苯丙氨酸浓度与试验前比较无统计学差异;尿液新蝶呤和生物蝶呤分析数值均在典型PKU症范围内;除1例外,19例患儿DHPR酶活性在正常范围内。根据本组结果,BH_4缺乏型PKU占全部患儿的5%(1/20)。与国外报道近似。