Alpha-1 antitrypsin deficiency and Pi^(*)Z allele as important co-factors in the development of liver fibrosis

BACKGROUND Alpha-1 antitrypsin deficiency(AATD)is a codominant autosomal hereditary condition that predisposes patients to the development of lung and/or liver disease,and Pi*Z allele is the most clinically relevant mutation.AIM To evaluate the impact of clinical parameters and AATD phenotypes,particularly the Pi*Z allele,in liver fibrosis.METHODS Cross-sectional cohort study including consecutive patients with AATD followed in Pulmonology or Hepatology consultation.RESULTS Included 69 patients,49.3%had Pi*MZ phenotype and 10.1%Pi*ZZ.An age≥55 years,age at diagnosis≥41 years and AAT at diagnosis<77 mg/dL predicted a nonalcoholic fatty liver disease fibrosis score(NFS)not excluding advanced fibrosis[area under the curve(AUC)=0.840,P<0.001;AUC=0.836,P<0.001;AUC=0.681,P=0.025].An age≥50 years and age at diagnosis≥41 years predicted a fibrosis-4 index of moderate to advanced fibrosis(AUC=0.831,P<0.001;AUC=0.795,P<0.001).Patients with hypertension,type 2 diabetes mellitus(DM),dyslipidaemia,metabolic syndrome,and regular alcohol consumption were more likely to have a NFS not excluding advanced fibrosis(P<0.001,P=0.002,P=0.008,P<0.001,P=0.033).Patients with at least one Pi*Z allele and type 2 DM were 8 times more likely to have liver stiffness measurement≥7.1 kPa(P=0.040).CONCLUSION Risk factors for liver disease in AATD included an age≥50 years,age at diagnosis≥41 years,metabolic risk factors,regular alcohol consumption,at least one Pi*Z allele,and AAT value at diagnosis<77 mg/dL.We created an algorithm for liver disease screening in AATD patients to use in primary care,selecting those to be referred to Hepatology consultation.

Validation of conventional non-invasive fibrosis scoring systems in patients with metabolic associated fatty liver disease

BACKGROUND Non-invasive fibrosis scores are not yet validated in the newly defined metabolic associated fatty liver disease(MAFLD).AIM To evaluate the diagnostic performance of four non-invasive scores including aspartate aminotransferase to platelet ratio index(APRI),fibrosis-4 index(FIB-4),body mass index,aspartate aminotransferase/alanine aminotransferase ratio,diabetes score(BARD),and nonalcoholic fatty liver disease fibrosis score(NFS)in patients with MAFLD.METHODS Consecutive patients with histologically confirmed MAFLD were included.The discrimination ability of different non-invasive scores was compared.RESULTS A total of 417 patients were included;156(37.4%)of them had advanced fibrosis(Metavir≥F3).The area under receiver operating characteristic curve of FIB-4,NFS,APRI,and BARD for predicting advanced fibrosis was 0.736,0.724,0.671,and 0.609,respectively.The area under receiver operating characteristic curve of FIB-4 and NFS was similar(P=0.523),while the difference between FIB-4 and APRI(P=0.001)and FIB-4 and BARD(P<0.001)was statistically significant.The best thresholds of FIB-4,NFS,APRI,and BARD for diagnosis of advanced fibrosis in MAFLD were 1.05,-2.1,0.42,and 2.A subgroup analysis showed that FIB-4,APRI,and NFS performed worse in the pure MAFLD group than in the hepatitis B virus-MAFLD group.CONCLUSION APRI and BARD scores do not perform well in MAFLD.The FIB-4 and NFS could be more useful,but a new threshold is needed.Novel non-invasive scoring systems for fibrosis are required for MAFLD.

Cystic fibrosis associated liver disease in children

Cystic fibrosis(CF)is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator gene.CF liver disease develops in 5%-10%of patients with CF and is the third leading cause of death among patients with CF after pulmonary disease or lung transplant complications.We review the pathogenesis,clinical presentations,complications,diagnostic evaluation,effect of medical therapies especially CF transmembrane conductance regulator modulators and liver transplantation in CF associated liver disease.

Clinical significance of connective tissue growth factor in hepatitis B virus-induced hepatic fibrosis

AIM:To determine the utility of connective tissue growth factor(CCN2/CTGF) for assessing hepatic fibrosis in hepatitis B virus(HBV)-induced chronic liver diseases(CLD-B).METHODS:Enzyme-linked immunosorbent assay was used to measure CCN2 in sera from 107 patients with chronic hepatitis B(CHB) and 39 patients with HBVinduced active liver cirrhosis and 30 healthy individuals.Liver samples from 31 patients with CHB,8 patients with HBV-induced liver cirrhosis and 8 HBV carriers with normal liver histology were examined for transforming growth factor β-1(TGF-β1) or CCN2 mRNA levels by in situ hybridization,and computer image analysis was performed to measure integrated optimal density(IOD) of CCN2 mRNA-positive cells in liver tissues.Histological inflammation grading and fibrosis staging were evaluated by H and E staining and Van Gieson's method.RESULTS:Serum CCN2 concentrations were,respectively,4.0-or 4.9-fold higher in patients with CHB or active liver cirrhosis as compared to healthy individuals(P < 0.01).There was good consistency between the levels of CCN2 in sera and CCN2 mRNA expression in liver tissues(r = 0.87,P < 0.01).The levels of CCN2 in sera were increased with the enhancement of histological fibrosis staging in patients with CLD-B(r = 0.85,P < 0.01).Serum CCN2 was a reliable marker for the assessment of liver fibrosis,with areas under the receiver operating characteristic(ROC) curves(AUC) of 0.94 or 0.85 for,respectively,distinguishing normal liver controls from patients with F1 stage liver fibrosis or discriminating between mild and significant fibrosis.CONCLUSION:Detection of serum CCN2 in patients with CLD-B may have clinical significance for assessment of severity of hepatic fibrosis.

Hyaluronic acid algorithm-based models for assessment of liver fibrosis： translation from basic science to clinical application

BACKGROUND： The estimation of liver fibrosis is usually dependent on liver biopsy evaluation. Because of its disadvantages and side effects, researchers try to find non-invasive methods for the assessment of liver injuries. Hyaluronic acid has been proposed as an index for scoring the severity of fibrosis, alone or in algorithm models. The algorithm model in which hyaluronic acid was used as a major constituent was more reliable and accurate in diagnosis than hyaluronic acid alone. This review described various hyaluronic acid algorithm-based models for assessing liver fibrosis.DATA SOURCE： A Pub Med database search was performed to identify the articles relevant to hyaluronic acid algorithmbased models for estimating liver fibrosis.RESULT： The use of hyaluronic acid in an algorithm model is an extra and valuable tool for assessing liver fibrosis.CONCLUSIONS： Although hyaluronic acid algorithm-based models have good diagnostic power in liver fibrosis assessment, they cannot render the need for liver biopsy obsolete and it is better to use them in parallel with liver biopsy. They can be used when frequent liver biopsy is not possible in situations such as highlighting the efficacy of treatment protocol for liver fibrosis.

Validation model of fibrosis-8 index score to predict significant fibrosis among patients with nonalcoholic fatty liver disease

BACKGROUND Identifying hepatic fibrosis is crucial for nonalcoholic fatty liver disease(NAFLD)management.The fibrosis-8(FIB-8)score,recently developed by incorporating four additional variables into the fibrosis-4(FIB-4)score,showed better performance in predicting significant fibrosis in NAFLD.AIM To validate the FIB-8 score in a biopsy-proven NAFLD cohort and compare the diagnostic performance of the FIB-8 and FIB-4 scores and NAFLD fibrosis score(NFS)for predicting significant fibrosis.METHODS We collected the data of biopsy-proven NAFLD patients from three Asian centers in three countries.All the patients with available variables for the FIB-4 score(age,platelet count,and aspartate and alanine aminotransferase levels)and FIB-8 score(the FIB-4 variables plus 4 additional parameters:The body mass index(BMI),albumin to globulin ratio,gamma-glutamyl transferase level,and presence of diabetes mellitus)were included.The fibrosis stage was scored using nonalcoholic steatohepatitis CRN criteria,and significant fibrosis was defined as at least fibrosis stage 2.RESULTS A total of 511 patients with biopsy-proven NAFLD and complete data were included for validation.Of these 511 patients,271(53.0%)were female,with a median age of 51(interquartile range:41,58)years.The median BMI was 29(26.3,32.6)kg/m2,and 268(52.4%)had diabetes.Among the 511 NAFLD patients,157(30.7%)had significant fibrosis(≥F2).The areas under the receiver operating characteristic curves of the FIB-8 and FIB-4 scores and NFS for predicting significant fibrosis were 0.774,0.743,and 0.680,respectively.The FIB-8 score demonstrated significantly better performance for predicting significant fibrosis than the NFS(P=0.001)and was also clinically superior to FIB-4,although statistical significance was not reached(P=0.073).The low cutoff point of the FIB-8 score for predicting significant fibrosis of 0.88 showed 92.36%sensitivity,and the high cutoff point of the FIB-8 score for predicting significant fibrosis of 1.77 showed 67.51%specificity.CONCLUSION We demonstrated that the FIB-8 score had significantly better performance for predicting significant fibrosis in NAFLD patients than the NFS,as well as clinically superior performance vs the FIB-4 score in an Asian population.A novel simple fibrosis score comprising commonly accessible basic laboratories may be beneficial to use for an initial assessment in primary care units,excluding patients with significant liver fibrosis and aiding in patient selection for further hepatologist referral.

Cystic fibrosis patients on cystic fibrosis transmembrane conductance regulator modulators have a reduced incidence of cirrhosis

BACKGROUND Cystic fibrosis transmembrane conductance regulator(CFTR)modulators significantly improve pulmonary function in patients with cystic fibrosis(CF)but the effect on hepatobiliary outcomes remains unknown.We hypothesized that CF patients on CFTR modulators would have a decreased incidence of cirrhosis compared to patients not on CFTR modulators or on ursodiol.AIM To investigate the effect of CFTR modulators on the development of cirrhosis in patients with CF.METHODS A retrospective analysis was performed using Truven MarketScan from January 2012 through December 2017 including all patients with a diagnosis of CF.Patients were excluded if they underwent a liver transplantation or if they had other etiologies of liver disease including viral hepatitis or alcohol use.Subjects were grouped by use of CFTR modulators,ursodiol,dual therapy,or no therapy.The primary outcome was development of cirrhosis.Kaplan-Meier curves estimated the incidence of cirrhosis and log-rank tests compared incidence curves between treatment groups.RESULTS A total of 7201 patients were included,of which 955(12.6%)used a CFTR modulator,529(7.0%)used ursodiol,105(1.4%)used combination therapy,and 5612(74.3%)used neither therapy.The incidence of cirrhosis was 0.1%at 1 year and 0.7%at 4 years in untreated patients,5.9%and 10.1%in the Ursodiol group,and 1.0%and 1.0%in patients who received both therapies.No patient treated with CFTR modulators alone developed cirrhosis.Patients on CFTR modulators alone had lower cirrhosis incidence than untreated patients(P=0.05),patients on Ursodiol(P<0.001),and patients on dual therapy(P=0.003).The highest incidence of cirrhosis was found among patients treated with Ursodiol alone,compared to untreated patients(P<0.001)or patients on Ursodiol and CFTR modulators(P=0.01).CONCLUSION CFTR modulators are associated with a reduction in the incidence of cirrhosis compared to other therapies in patients with CF.

Diagnostic and therapeutic implications of the association between ferritin level and severity of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD),defined by excessive liver fat deposition related to the metabolic syndrome,is a leading cause of progressive liver disease,for which accurate non-invasive staging systems and effective treatments are still lacking.Evidence has shown that increased ferritin levels are associated with the metabolic insulin resistance syndrome,and higher hepatic iron and fat content.Hyperferritinemia and iron stores have been associated with the severity of liver damage in NAFLD,and iron depletion reduced insulin resistance and liver enzymes.Recently,Kowdley et al demonstrated in a multicenter study in 628 adult patients with NAFLD from the NAFLD-clinical research network database with central re-evaluation of liver histology and iron staining that the increased serum ferritin level is an independent predictor of liver damage in patients with NAFLD,and is useful to identify NAFLD patients at risk of non-alcoholic steatohepatitis and advanced fibrosis.These data indicate that incorporation of serum ferritin level may improve the performance of noninvasive scoring of liver damage in patients with NAFLD,and that iron depletion still represents an attractive therapeutic target to prevent the progression of liver damage in these patients.

Overview and developments in noninvasive diagnosis of nonalcoholic fatty liver disease

High prevalence of non-alcoholic fatty liver disease (NAFLD) and very diverse outcomes that are related to disease form and severity at presentation have made the search for noninvasive diagnostic tools in NAFLD one of the areas with most intense development in hepatology today.Various methods have been investigated in the recent years,including imaging methods like ultrasound and magnetic resonance imaging,different forms of liver stiffness measurement,various biomarkers of necroinflammatory processes (acute phase reactants,cytokines,markers of apoptosis),hyaluronic acid and other biomarkers of liver fibrosis.Multicomponent tests,scoring systems and diagnostic panels were also developed with the purposes of differentiating non-alcoholic steatohepatitis from simple steatosis or discriminating between various fibrosis stages.In all of the cases,performance of noninvasive methods was compared with liver biopsy,which is still considered to be a gold standard in diagnosis,but is by itself far from a perfect comparative measure.We present here the overview of the published data on various noninvasive diagnostic tools,some of which appear to be very promising,and we address as well some of still unresolved issues in this interesting field.

The Level of Serum Intact Terminal Peptide of Procollagen and Its Clinical Significance in Patients with Chronic Keshan Disease

Objectives To evaluate the changes of serum intact terminal peptide of procollagen in patients with chronic Keshan disease (KD) and investigate their clinical significance. Methods The concentrations of serum intact N-terminal peptide of type procollagen (P NP) and intact N-terminal peptide of type procollagen were measured by radioimmunoassay in 35 patients with chronic KD and 31 normal control. Doppler ultrasounds was used to determine several parameters of left ventricular systole and diastole functions. Results The concentration of serum P NP (74.07±16.74)μg/L and the ratio of P NP/ P NP (18.02 ±4.60) in chronic KD were significantly increased as compared to the control (39.63±12.07 μg/L, 12.12±4.24; P< 0.001). Serum P NP (4.19±0.64)μg/L in chronic KD was higher than that in the control (3.36±0.65 μg/L,P < 0.001) too. The higher of serum concentration of P NP and the ratio of P NP/ P NP, the worse of cardiac function in patients with chronic KD. A negative correlation was found between serum P NP/ P NP, P NP and VE/VA, LVEF (γ=-0.4502, -0.4608, P< 0.01 and γ=-0.3936, -0.3904, respectively; P<0.05). Conclusions These findings suggested that tissue synthesis of collagen type and type was abnormally increased in chronic KD. On the other hand, our results indicated that P NP and P NP were related to several functional alterations of the left ventricle. Serum procollagen peptide measurements might therefore provide indirectly diagnostic information on myocardial fibrosis associated with chronic KD.