Lower Liver Stiffness Measurement Research Articles

The associations between fibrosis changes and liver-related events in patients with metabolic dysfunction-associated steatotic liver disease.

The prognosis of metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with liver fibrosis. We investigated the associations between changes in liver stiffness measurement (LSM) over 3-year period and the development of cirrhosis or hepatocellular carcinoma (HCC) in patients with MASLD. This study involved patients with MASLD who underwent transient elastography at baseline and 3 years after baseline from 2012 to 2020. Low (L), indeterminate (I) and high (H) LSM values were classified as <8 kPa, 8-12 kPa and >12 kPa respectively. Among 1738 patients, 150 (8.6%) were diagnosed with cirrhosis or HCC. The proportions of patients with L, I and H risk were 69.7%, 19.9% and 10.5% at baseline, and 78.8%, 12.8% and 8.4% at 3 years after baseline, respectively. The incidence rates of cirrhosis or HCC per 1000 person-years were 3.7 (95% confidence interval [CI], 2.4-5.5) in the L → L + I group, 23.9 (95% CI, 17.1-32.6) in the I → L + I group, 38.3 (95% CI, 22.3-61.3) in the H → L + I group, 62.5 (95% CI, 32.3-109.2) in the I → H group, 67.8 (95% CI, 18.5-173.6) in the L → H group and 93.9 (95% CI 70.1-123.1) in the H → H group. Two risk factors for the development of cirrhosis or HCC were LSM changes and low platelet counts. LSM changes could predict clinical outcomes in patients with MASLD. Thus, it is important to monitor changes in the fibrotic burden by regular assessment of LSM values.

Prediction of Sinusoidal Obstructive Syndrome after Allogeneic Stem Cell Transplantation Using Liver Stiffness Measurement By Fibroscan

Background: Sinusoidal Obstructive Syndrome/ Veno-Occlusive Disease (SOS/VOD) is a potentially life-threatening complication post allogeneic transplantation (HSCT) with an incidence of ~ 10% in adults. The sensitivity of SOS symptoms (hyperbilirubinemia ≥2 mg/dl, weight gain&amp;gt;5%, painful hepatomegaly and ascites) is good, but the specificity is relatively low because other conditions such as infections, GvHD, and exacerbation of previous liver disease may cause similar symptoms. Transient elastography (TE) using FibroScan has been implemented as a non-invasive assessment of post-sinusoidal portal hypertension (PHTN) one of the hallmarks of SOS. We aimed to assess TE's applicability in predicting and diagnosis of SOS. Methods: This single-center study was conducted between January 2021 and June 2023. Twenty-seven patients (pts) underwent TE, 11 before HSCT (group 1) due to high risk of developing SOS in order to guide subsequent treatment, and 17 after HSCT (group 2) (1 pt was in both groups) due to an elevation of bilirubin ≥2 mg/dl. SOS was defined using the EBMT criteria. Results: Eleven pts were included in the 1 st group (M 5, F 6). The median age was 43 (22-65) years. 7 pts had acute myelogenous leukemia (AML) -4/7 secondary AML (sAML), and 4 pts had myelofibrosis (MF). 5/7 AML pts received a median of 4 (2-5) lines of chemotherapy before HSCT; 2/4 sAML pts got azacytidine/ venetoclax and all 4 MF pts received Ruxolitinib before HSCT. Two pts had chemotherapy for antecedent malignancy. Donors were HLA-matched siblings (n=5), matched unrelated (n=2), or haploidentical (n=4). Risk factors for developing VOD included: active disease (n=9), multiple lines of chemotherapy (n=7), elevated serum ferritin (n=5), splenomegaly (n=5 including 1 pt with overt PHTN), severe liver toxicity during previous treatment (n=4), age ≥60 (n=3), second transplantation (n=3), pre-existing liver disease including fatty liver (n=3, including 1 pt with liver cirrhosis), severe obesity (n=2), prior treatment with GO (n=2), baseline liver enzymes elevation (n=2), and alcohol abuse(n=1). The conditioning regimen included total body irradiation (n=1), busulphan (BU) alone (n=5), or double alkylating agents (DAC, n=5), respectively. Four patients had myeloablative conditioning (MAC). Most pts had several risk factors for VOD median 5 (3-8). This group had a median liver stiffness measurement (LSM) of 10.1 kPa (range, 3.3-28.3). In 6/11 pts with LSM ≥7.2 kPa, the conditioning was modified; Treosulfan was given instead of BU (n=3), non-DAC instead of DAC protocol (n=3), reduced intensity instead of MAC (n=4), methotrexate was omitted (n=2). One pt received Defibrotide prophylaxis. With these modifications only 2 pts developed SOS (1 died). The second group included 17 pts (M 10, F 7), median age 49 (32-62) years with AML/myelodysplastic syndrome (n=7), acute lymphoblastic leukemia (n=5), MF (n=4), and lymphoma (n=1). Ten had MAC, and 5 had DAC. Five had active disease at HSCT. Three had prior liver disease. All pts had bilirubin elevation ≥2 mg/dl after HSCT but only 10 fulfilled additional criteria for the diagnosis of SOS based on the EBMT criteria. Pts who developed SOS had significantly higher LSM compared to those who did not; 10.7 kPa (IQR, 7.5-25.2) versus 5.9 kPa (IQR, 5.1-7.4), respectively (p=0.007) (Figure 1A). There was a positive correlation between the diagnosis of SOS and LSM levels, with a correlation coefficient of 0.6 (p= 0.04) as determined by the Spearman correlation test. LSM was able to diagnose SOS with an AUC of 0.89 (p=0.008) (Figure 1B). The cut-off value for SOS diagnosis was 7.5 kPa, with a sensitivity of 80% and specificity of 88%. Pts with severe VOD were treated with defibrotide and none of them died .of VOD. Conclusions: Pts with a high risk for VOD may have a high baseline LSM. In these pts, modifying the planned conditioning and GVHD prophylaxis regimens to less hepato-toxic ones may reduce the incidence of subsequent VOD. LSM elevation after HSCT should increase awareness of SOS, while pts with hyperbilirubinemia and low LSM usually suffered from other causes of liver toxicity. High LSM could support the diagnosis of VOD in borderline cases. Therefore, LSM may be an additional diagnostic tool in diagnosing SOS after HSCT, but more studies are needed to confirm these findings.

Prediction of outcomes in patients with metabolic dysfunction-associated steatotic liver disease based on initial measurements and subsequent changes in magnetic resonance elastography.

The prognosis of metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with liver fibrosis. We aimed to investigate whether liver stiffness measurement (LSM) and changes in LSM (ΔLSM) on magnetic resonance elastography (MRE) can predict clinical events in patients with MASLD. We included 405 patients with MASLD who underwent at least two MREs. The patients were divided into five groups corresponding to fibrosis stages (0-4) based on initial LSM and classified as progressors (ΔLSM ≥ 19%) or non-progressors (ΔLSM < 19%) based on the difference between the first and last LSM. The mean follow-up period was 72.6months, and the mean interval between MREs was 23.5months. There were 52 (12.8%) progressors and 353 (87.2%) non-progressors. The initial LSM was significantly associated with the cumulative probabilities of decompensated cirrhosis, hepatocellular carcinoma (HCC), liver-related events, extrahepatic malignancies, and overall mortality but not with cardiovascular disease. Progressors had significantly higher hazard ratios (HRs) for decompensated cirrhosis, HCC, and liver-related events but not for extrahepatic malignancies, cardiovascular disease, or overall mortality. Among patients without cirrhosis, the HR for developing cirrhosis among progressors was 60.15. Progressors had a significantly higher risk of liver-related events, even in the low initial LSM (fibrosis stage 0-2) subgroups. Both initial LSM and ΔLSM can predict liver-related events in patients with MASLD, even for low initial LSM. This integrated assessment can allow more detailed risk stratification compared with single LSM assessments and identify high-risk patients with MASLD among those previously considered as low risk.

A Healthy Diet is Associated with a Lower Risk of Hepatic Fibrosis

BackgroundHigher diet quality is associated with a lower risk of NAFLD. ObjectivesWe examined the relationship between diet quality and hepatic fibrosis. MethodsWe analyzed cross-sectional associations between 3 a priori diet quality scores—the Dietary Approaches to Stop Hypertension (DASH) score, the Alternative Healthy Eating Index (AHEI), and a modified Mediterranean-style Diet Score (MDS)—and hepatic fat [controlled attenuation parameter (CAP)] and fibrosis [liver stiffness measurement (LSM)] measured by vibration-controlled transient elastography (VCTE) in 2532 Framingham Heart Study (FHS) participants and 3295 participants of the National Health and Nutrition Examination Survey (NHANES). ResultsHigher diet quality scores were associated with lower LSM in both FHS and NHANES after adjustment for demographic and lifestyle factors. Additional adjustment for CAP or BMI attenuated the observed associations. Association strength was similar across all 3 diet quality scores. Fixed-effect meta-analysis demonstrated that, under CAP-adjusted models, the LSM decreases associated with 1-SD increase of the DASH, AHEI, and MDS scores were 2% (95% CI: 0.7%, 3.3%; P = 0.002), 2% (95% CI: 0.7%, 3.3%; P = 0.003), and 1.7% (95% CI: 0.7%, 2.6%; P = 0.001), respectively, whereas in the meta-analysis of BMI-adjusted models, LSM reductions associated with 1-SD increase of the DASH, AHEI, and MDS scores were 2.2% (95% CI: −0.1%, 2.2%; P = 0.07), 1.5% (95% CI: 0.3%, 2.7%; P = 0.02), and 0.9 (95% CI: −0.1%, 1.9%; P = 0.07), respectively. ConclusionsWe demonstrated associations of higher diet quality with favorable hepatic fat and fibrosis measures. Our data suggest that a healthy diet may reduce the likelihood of obesity and hepatic steatosis as well as the progression of steatosis to fibrosis.

Coffee Consumption Is Associated With Lower Liver Stiffness: A Nationally Representative Study

Coffee is associated with a reduced risk of liver disease. This association is limited by important sources of confounding such as recall bias, healthy user bias, and indirect measures of liver outcomes or health. We aimed to examine the impact of coffee consumption with liver fibrosis and steatosis in a nationally representative sample. We evaluated 4510 subjects 20 years and older from the 2017 to 2018 National Health and Nutrition Examination Survey study who underwent both transient elastography and two 24-hour dietary recall examinations. We tested the associations between liver stiffness measurements (LSM) of 9.5 kpa or greater or controlled attenuation parameter (CAP) and coffee consumption. We used decaffeinated coffee and tea consumption as controls. As a sensitivity analysis, we included all drinks in 1 model, examined the impact of caffeine consumption, and adjusted for the Healthy Eating Index-2015 and sugar-sweetened beverage consumption as separate models. The study sample described was aged 48 ± 0.6 years, 73% were overweight or obese, 10.6% had diabetes, 47.5% reported participation in vigorous physical activity, and 23% drank 2 or more alcoholic drinks per day. After multivariate adjustment, there was no association between coffee and controls with CAP. Subjects who drank more than 3 cups of coffee, but not other drinks, had a 0.9 lower kPa (95% CI, -1.6 to -0.1; P= .03). More than 3 cups of coffee were protective for LSM of 9.5 kpa or higher (odds ratio, 0.4; 95% CI, 0.2-1.0; P= .05). Accounting for all beverages in the same model, only consuming more than 3 cups of coffee remained independently associated with LSM (odds ratio, 0.5; 95% CI, 0.2-0.9; P= .03). Caffeine was not associated significantly with LSM at any dose. Finally, adjusting for sugar-sweetened beverage consumption and Healthy Eating Index-2015, coffee consumption remained associated with a lower LSM. The protective nature of coffee consumption therefore is not attributable to caffeine and persists in participants regardless of their diet quality. Coffee is associated with lower liver stiffness, but not steatosis, as measured by CAP among US adults.

The impact of elastography with virtual touch quantification of future remnant liver before major hepatectomy.

Liver elastography with virtual touch quantification (VTQ) measures the velocity of the shear wave generated by a short-duration acoustic force impulse, with values expressed in units of velocity (m/s). VTQ can evaluate right or left hepatic lobes separately. VTQ might be appropriate for the evaluation of future remnant liver after hepatectomy. We analyzed 95 patients underwent liver elastography with VTQ and both future remnant liver and resected side before hepatectomy of more than two sections, except for central bisectionectomy. We divided the patients into a high VTQ group (≥1.52 m/s, n=37, 39%) and a low VTQ group (<1.52 m/s, n=58, 61%) according to the VTQ of future remnant liver. Transient elastography could not be performed in 22 cases due to tumor size. We defined the group with liver stiffness measurement (LSM) ≥7.9 kPa as the high LSM group (n=29, 40%) and those with LSM <7.9 kPa as the low LSM group (n=44, 60%). We investigated the outcome after hepatectomy and the correlations between the VTQ of future remnant liver and other indicators for hepatic fibrosis. The high VTQ group showed significantly higher postoperative ascites (19% vs. 3%; P=0.01), pathological fibrosis (19% vs. 5%; P=0.03), and rates of patients with postoperative T-bil ≥2.0 mg/dL (70% vs. 40%; P<0.01). The high LSM group showed no significant postoperative outcomes compared to the low LSM group. The high VTQ group showed a higher frequency of male gender (78% vs. 57%; P=0.03), higher indocyanine green retention rate at 15 min (ICGR15) (10.5% vs. 6.3%; P<0.01), hyaluronic acid (100 vs. 67 ng/mL; P=0.02), type IV collagen 7S (7.6 vs. 5.1 ng/mL; P<0.01), Mac-2 binding protein glycan isomer (M2BPGi) (1.19 vs. 1.00; P=0.01), Fibrosis-4 (FIB-4) index (2.25 vs. 1.76; P=0.01), and aspartate aminotransferase to platelet ratio index (APRI) score (0.64 vs. 0.41; P<0.01). We also observed an especially strong positive correlation between the high VTQ and hyaluronic acid or type IV collagen 7S. Elastography with VTQ for future remnant liver before major hepatectomy is an accurate and useful method as a preoperative evaluation.

Relationship between coffee consumption, sleep duration and smoking status with elastographic parameters of liver steatosis and fibrosis; controlled attenuation parameter and liver stiffness measurements.

our aim was to explore the association between life habits and the controlled attenuation parameter (CAP) and liver stiffness measurements (LSM) as the surrogate markers of liver steatosis and fibrosis in a large cohort of non-alcoholic fatty liver disease (NAFLD) patients. In this prospective, cross-sectional study we had analysed 1998 patients with diagnosed NAFLD. Sleeping duration was categorised in three groups: short (S) (<6hours), moderate (M) (6-8hours) and long (L) (>8hours) sleep duration. Coffee drinking was categorized into no (0), moderate (1-2) and frequent (≥3) consumption (in cups/day). Smoking was categorised as yes versus no. Frequent coffee consumers had the lowest prevalence of obesity, hypertension, dyslipidaemia and diabetes. Furthermore, coffee non-consumers had highest values of hepatic enzymes, CAP and LSM. Moderate sleep duration was associated with lower values of CAP and LSM. Coffee consumption was associated with lower CAP in all the multivariate models (CAP unadjusted and model 1, 2 and 3), with largest effect in most frequent coffee consumers (≥3, model 3). Also, most frequent coffee consumers were associated with lower LSM in unadjusted model, model 1 and 2, while this was not the case for model 3 and those who consumed 1-2 cups of coffee per day. Reduced sleeping was confirmed as risk factor for elevated CAP in most of the models (unadjusted and model 1 and 2). Also, negative association of LSM was also confirmed in unadjusted model and model 2. Patients which slept 6-8hours per day were mostly associated with lower CAP and LSM. Smoking status was not associated with CAP or LSM values. Coffee consumption has beneficial effect on CAP and LSM and this effect is dose dependent since and independent of a variety of relevant confounders. We have shown that moderate sleep duration has also beneficial effect on CAP and LSM.

Hepatic steatosis is highly prevalent but is not correlated with stiffness in autoimmune hepatitis.

The prevalence and impact of hepatic steatosis among patients with autoimmune hepatitis (AIH) is not well described.We conducted a cross-sectional study to determine the prevalence of hepatic steatosis in AIH patients and examined its relationship with hepatic fibrosis using vibration controlled transient elastography. Liver stiffness measurement (LSM), controlled attenuation parameter (CAP), gender, current age, and body mass index (BMI) were collected from 277 AIH patients. Hepatic steatosis was defined as CAP >263 db/m.The study participants were mostly female (82%) with an average age of 49 years and BMI 29.7 kg/m2. Mean LSM was 12.5 (standard deviation 13.5) kPa and CAP was 244 (standard deviation 63) db/m. The prevalence of coexisting steatosis was 33.2%, and steatosis did not correlate with LSM (r = 0.05, P = .46). In this study, only gender (females with 31% lower LSM on average compared to males, P = .001) and BMI (each unit increase of BMI resulted in a 1.48% increase on average LSM, P = .01) correlated with LSM. Male gender had significant association with increased LSM, after controlling for age, BMI, and CAP (P = .001).This exploratory study using noninvasive vibration controlled transient elastography revealed hepatic steatosis is highly prevalent in patients with AIH but not associated with liver fibrosis.

Different Performance of Liver Stiffness Measurement According to Etiology and Outcome for the Prediction of Liver-Related Events

Liver stiffness measurement (LSM) by transient elastography (TE) has shown promising results for prediction of hepatocellular carcinoma (HCC) and hepatic decompensation in patients with chronic liver disease (CLD). However, whether prognostic performance of TE differs according to etiology or type of outcome remains further clarification. Performance of LSM for the prediction of HCC and hepatic decompensation was analyzed in a cohort of 4026 patients with asymptomatic CLD. During median 4.5years of follow-up (range 3.0-6.2years), liver-related events (LRE) were observed in 196 patients (166 with HCC, 45 with hepatic decompensation, and 15 with both). In the multivariate analysis, LSM was independent factor associated with LRE and showed high AUROC (0.78). When stratified by type of outcome and etiology of liver disease, LSM showed high AUROC for the prediction of HCC for patients with non-viral hepatitis (0.89), while it showed relatively low AUROC for the prediction of HCC for patients with viral hepatitis (0.75). For the prediction of hepatic decompensation, LSM showed high AUROC for patients with both viral- and non-viral hepatitis (0.90, 0.90, respectively). LSM showed powerful prognostic role for the prediction of LRE in patients with CLD. Notably, HCC risk was not negligible in patients with viral hepatitis who showed LSM value < 10kPa, indicating watchful attention for HCC is still needed for viral hepatitis patients with low LSM.

Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers

Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease. We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank. In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals. Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling.

Non-obese patients with nonalcoholic fatty liver disease may use a lower liver stiffness cut-off to assess fibrosis stages.

We aimed to estimate the optimal cut-off values of liver stiffness measurement (LSM) for diagnosing and staging fibrosis in non-obese and obese patients with nonalcoholic fatty liver disease (NAFLD). NAFLD patients diagnosed by liver biopsy according to the Nonalcoholic Steatohepatitis Clinical Research Network scoring system were enrolled in this study. Non-obesity was defined as a body mass index (BMI) less than 25 kg/m2 . LSM was performed by experienced physicians within 2 weeks before or after liver biopsy. A total of 158 patients were included. Average BMI of the non-obese (n = 68) and obese (n = 90) groups was 23.2 ± 1.6 and 27.9 ± 2.5 kg/m2 , respectively. After adjusted for age, fibrosis stage, steatosis grade and type 2 diabetes mellitus, the obese group had a LSM of 3.522 kPa higher than the non-obese patients (P = 0.003). LSM values of the non-obese patients had a lower trend when stratified by fibrosis stage, especially in cirrhosis (F4; P = 0.021). Applying separate cut-off values for patients with NAFLD in individual fibrosis stage, 5.8 vs 7.5 kPa (≥ F1), 7.6 vs 8.5 kPa (≥ F2), 9.1 vs 11.2 kPa (≥ F3), and 12.5 vs 14.3 kPa (F4), improved their diagnostic odds ratios compared with overall cut-off values. In the non-obese NAFLD group, using a separate cut-off avoided underestimating 9.1% of patients with cirrhosis. Non-obese NAFLD group had lower LSM than the obese group. Different cut-off values should be used to measure liver fibrosis stage in non-obese and obese NAFLD patients.

Predictors for the progression of hepatic cirrhosis to hepatocellular carcinoma under long-term antiviral therapy.

Patients diagnosed with hepatitis B virus (HBV)-related hepatic cirrhosis have the potential for progression to hepatocellular carcinoma (HCC) even while undergoing long-term nucleos(t)ide analog (NA) therapy. This study investigated the predictors for the progression of hepatic cirrhosis to HCC under long-term NA therapy. This retrospective study enrolled 898 patients diagnosed with HBV-related hepatic cirrhosis. They received NA therapy between January 2012 and January 2015. The values for the liver stiffness measurement (LSM), laboratory tests, and disease history were collected. The diagnostic specificity of the serum, was assessed with a receiver operating characteristic curve. The overall 2- and 3-year cumulative incidence of HCC was 6.8% and 15.15%, respectively. The LSM values were higher in the patients who had progressed to HCC. The serum PIVKA-II levels were more efficient than the serum AFP levels for the diagnosis of early HCC as the larger area under curve (0.866 vs. 0.687). The multivariate logistic regression analysis showed that HCC occurrence was significantly associated with the baseline LSM value (odds ratio = 1.035). At the end of the study, the death rate for the patients with larger LSM values was higher than that for those with lower LSM values (67.88% vs. 39.90%). Patients with HBV-related cirrhosis have the potential for progression to HCC even under long-term NA therapy. The LSM value and the serum PIVKA-II level are significant predictors of HCC occurrence.

Multiple Cycles of Granulocyte Colony-Stimulating Factor Increase Survival Times of Patients With Decompensated Cirrhosis in a Randomized Trial

There is controversy regarding the inclusion of granulocyte colony stimulating factor (G-CSF) in the treatment of decompensated cirrhosis. Previous studies tested only a single cycle of G-CSF administration or were underpowered to detect changes in survival time. We performed an adequately powered study to determine whether multiple cycles of G-CSF increased the survival of patients 1 year after the start of therapy. We conducted an open-label trial of 100 patients with decompensated cirrhosis without acute-on-chronic liver failure at a tertiary center from July 2016 through June 2018. The patients were assigned randomly to a group given 5 days of G-CSF every 3 months, with standard medical therapy, in 4 cycles (group A, n=50), or standard medical therapy alone (group B, n=50). The primary outcome was survival for 12 months after treatment began. Secondary outcomes were an increase in the number of CD34+ cells at day 6 compared with day 0, along with reductions in Child-Turcotte-Pugh and model for end-stage liver disease scores, increased control of ascites, reduced decompensation and episodes of infection, fewer hospitalizations, lower liver stiffness measurements, increased quality of life and nutrition, fulfilment of liver transplant criteria, and fewer adverse events at 12 months after the start of treatment. Groups A and B were comparable at baseline. Survival at 12 months after initiation of treatment was significantly higher in group A (74%) than in group B (42%) (P<.001). Blood samples from patients in group A had significantly more CD34+ cells on day 6 than on day0 (P<.001); there was no significant change in group B. Compared with patients in group B, patients in group A had significant reductions in Child-Turcotte-Pugh and model for end-stage liver disease scores, increased ascites control, fewer infections and hospitalizations, lower liver stiffness measurements, an increased quality of life, and a lower number fulfilled the liver transplant criteria (P<.05). There was no improvement in nutrition in either group compared with baseline. G-CSF was safe and well tolerated. Administration of multiple cycles of G-CSF increases the numbers of hematopoietic stem cells and survival of patients with decompensated cirrhosis receiving standard medical treatment. The addition of G-CSF to medical treatment might provide a bridge to liver transplantation for these patients. ClincialTrials.gov no: NCT03415698.

Liver stiffness measurement in non-alcoholic fatty liver disease: Two is better than one.

Repeating liver stiffness measurement (LSM) was recently reported to improve accuracy to diagnose fibrosis stage in patients with non-alcoholic fatty liver disease (NAFLD). There are to date no other studies confirming this finding. This aims to evaluate the accuracy of repeating LSM for the diagnosis of fibrosis stage in NAFLD patients. Retrospective analysis of prospectively collected data on adult NAFLD patients who had two FibroScan examination within 6months prior to liver biopsy. F3-F4 fibrosis was excluded using LSM cut-off of 7.9kPa. A total of 136 patients were recruited. Eighty-five percent (115/136) of patients had high baseline LSM (≥7.9kPa). Among them, 25% (29/115) had low repeat LSM (<7.9kPa), with only two patients having F3 fibrosis. Forty-eight percent (41/86) of patients with high baseline and repeat LSMs had greater than or equal to F3-F4 fibrosis. All 21 patients with low baseline LSM had F0-F2 fibrosis, except one patient with high repeat LSM who had F3 fibrosis. A strategy of repeating LSM, where only patients with high LSM on both baseline and repeat scans are considered for liver biopsy, will be able to reduce the number of patients being considered for liver biopsy from 85% to 63%. The sensitivity, specificity, positive predictive value, and negative predictive value based on only the baseline scan was 98%, 22%, 37%, and 95%, respectively, while based on the strategy of repeating LSM was 93%, 51%, 48%, and 94%, respectively. False positive diagnosis of advanced fibrosis in NAFLD patients can be reduced, and unnecessary liver biopsy can be avoided by repeating LSM.

Low Sensitivity to Thrombomodulin Correlates with Liver Stiffness in Advanced Chronic Liver Disease

Advanced chronic liver disease (ACLD) is characterized by changes in the coagulation system that embrace not only hypo-, but also hyper-coagulability. Global hemostatic tests such as thrombin generation (TG) assays are used to evaluate the hemostatic balance, in order to better assess bleeding and thrombotic risks. In addition, procoagulant state in ACLD patients has been demonstrated using modified TG assays with thrombomodulin (TM), a cofactor for protein C activation. Evaluation of the liver stiffness by transient elastography (Fibroscan) is a reliable method for the diagnosis of cirrhosis and disease staging. Increased liver stiffness is associated with clinically significant portal hypertension (PVT) in patients with ACLD. Here, we aimed to investigate whether TG parameters in patients with ACLD could be associated to liver stiffness. Of 147 enrolled patients with ACLD, we excluded 69 patients (5 patients received anticoagulation, 3 were on chemotherapy, 48 with other liver diseases and 13 had a history of orthotopic liver transplantation), leaving a study sample of 78 patients. Liver stiffness measurement (LSM) was performed by transient elastography in each patient. Cut-offs of 13 and 21 kPa were used to subgroup the studied ACLD patients sample, as a LSM of ≥13 kPa has been associated with the diagnosis of cirrhosis and ≥21 kPa with the development of a clinically significant PVT (Deillon et al., 2019). TG was evaluated by ST Genesia® Thrombin Generation System (STG) using Thromboscreen with/without TM (TS-TM/+TM) assay and the Calibrated Automated Thrombography (CAT) using PPP reagent low (Stago) with/without TM. TG was measured by STG in 50 patients with ACLD. ETP inhibition by TM correlated with LSM (r =-0.339, p=0.0184). The discriminant analysis (ANOVA with multiple comparison) among the study groups showed that ETP inhibition by TM was higher in ACLD patients with LSM &lt;13 kPa than in those with LSM ≥13 but &lt;21 kPa (p=0.003), indicating a lower sensitivity to TM in patients with liver stiffness values ≥13 but &lt;21 kPa. However, there was no difference in ETP inhibition by TM between the group with LSM ≥13 but &lt;21 kPa and the group with LSM ≥21 kPa (p=0.995). TG was measured by CAT in 56 patients with ACLD and ETP inhibition by TM was evaluated using a normalized ETP ratio in presence and in absence of TM. Similarly to STG data, ETP inhibition by TM measured by CAT correlated with LSM (r=0.4108, p=0.0018). The discriminant analysis among the study groups revealed that ETP inhibition by TM was higher in ACLD patients with LSM &lt;13 kPa than in those with ≥13 but &lt;21 kPa (p=0.0098) as well as with the group with LSM ≥21kPa (p=0.0022), indicating a lower sensitivity to TM in patients with liver stiffness values ≥13 kPa. However, there was no difference in ETP inhibition by TM between the group with LSM ≥13 but &lt;21 and the group with LSM ≥21 kPa (p=0.721). In addition, TG was measured by both by STG and CAT in 35 patients with ACLD in order to compare the two methods. ETP inhibition by TM measured by STG correlated with the normalized ETP inhibition determined by CAT (r = -0.61, p&lt;0.0001). Low sensitivity to TM measured in ST Genesia® and CAT, correlated with liver stiffness in patients with ACLD. Sensitivity to TM discriminated between ACLD groups with low (≤13 kPa) and high (≥13 kPa) LSM, confirming a procoagulant state in patients with ALCD. However, it did not differ between patients with ACLD with high LSM (≥13 and &lt;21 kPa) and patients prone to the decompensation defined by higher (≥21 kPa) LSM. Sensitivity to TM measurements determined by ST Genesia® correlated with those obtained with CAT. Further studies are needed to determine whether sensitivity to TM and LSM in patients with ACLD could help to identify patients at higher risk of portal vein thrombosis Disclosures No relevant conflicts of interest to declare.

Follow-Up Liver Stiffness Measurements after Liver Resection Influence Oncologic Outcomes of Hepatitis-B-Associated Hepatocellular Carcinoma with Liver Cirrhosis.

The severity of liver fibrosis can be noninvasively evaluated by measuring liver stiffness (LS) using transient elastography. This study aimed to evaluate the prognostic value of achieving low liver stiffness measurement (LSM) in patients with cirrhosis confirmed from the resected liver due to hepatocellular carcinoma (HCC). A total of 184 patients that received curative surgery for HCC related to the hepatitis B virus at Barcelona Clinic Liver Cancer stage 0–A, and had a METAVIR fibrosis score of 4 were investigated. LSM significantly decreased after antiviral therapy during follow-up (p = 0.001), and achieving LSM ≤8 kilopascal (kPa) suggested a reduced risk of late recurrence (>12 months) (hazard ratio (HR), 0.519; 95% confidence interval (CI), 0.307–0.877; p = 0.014). Older age at surgery (≥45 years) and multiple HCC nodules predicted an increased risk of late recurrence (HR, 3.270; 95% CI, 1.296–8.251; p = 0.012; and HR, 3.146; 95% CI, 1.396–7.089; p = 0.006). Decreased LSM also suggested decreased mortality (HR, 0.251; 95% CI, 0.086–0.756; p = 0.045) along with baseline low aspartate aminotransferase-to-platelet ratio index (APRI) score (<1.5) (HR, 0.251; 95% CI, 0.086–0.759; p = 0.041). Having early HCC recurrence (HR, 9.416; 95% CI, 3.566–24.861; p < 0.001) and microvascular tumor invasion (HR, 3.191; 95% CI, 1.188–8.568; p = 0.021) predicted increased mortality. Among HCC patients with liver cirrhosis under antiviral therapy, achieving low LSM (≤8 kPa) predicted reduced late HCC recurrence.

Direct acting antiviral agent for Chinese patients with chronic hepatitis C genotype 1b infection——a real world experience

Objective To evaluate the effectiveness and safety of direct-acting antiviral agents (DAA) treatment in Chinese chronic hepatitis C (CHC) patients with genotype (GT) 1b HCV infection in a real world setting. Methods The consecutive GT1b CHC Chinese patients treated with sofosbuvir (SOF) plus daclatasvir (DCV) (n=62) or SOF plus ledipasvir (LDV) (n=171) were enrolled from July 2014 to December 2016 at 302 Military Hospital of China. The treatment duration for all the patients was 12 weeks. All the clinical parameters were measured at baseline and then 4-weekly till 12 weeks after the end-of-treatment (EOT). Baseline clinical characteristics, treatment efficacy, safety and tolerance were compared. Serum HCV RNA concentration was detected by means of COBAS TaqMan assay with a lower detection limit of 15 IU/mL, and liver stiffness was measured using FibroScan®. Sustained virologic response (SVR) was defined as HCV RNA under the lower limit of quantification 12 weeks after EOT (SVR12). Students′ t-test, pearson χ2 test, Spearman rank correlation analysis and Fisher exact test were used for comparison between groups when appropriate. Results Among 233 patients, 173 cases had baseline HCV RNA level ≥6.0 lg IU/mL and 97 cases hade liver stiffness measurement (LSM)≥17.5 kPa. The baseline liver inflamation, liver fibrosis, and HCV RNA load of patients in the two groups were not significantly different (all P>0.05). The HCV RNA of all the 233 patients was undetectable at the end of 12-week treatment, while 2 patients relapsed after 12 weeks of EOT with the overall SVR12 of 99.1%. HCV RNA decline was significantly faster in patients with lower LSM than those with higher LSM (ρ=0.233, P=0.001), and SVR12 was higher in those with lower LSM. In terms of other clinical characteristics of SOF+ DCV and SOF+ LVD groups, alanine transaminase declined from (68.0±60.1) and (70.1±56.1) U/L to (21.1±10.9) U/L and (15.3±9.5) U/L, respectively, total bilirubin declined from (21.3±17.3) and (18.2±14.0) μmol/L to (13.2±6.7) and (10.2±4.6) μmol/L, respectively, AFP declined from 19.6 (10.6, 62.3) and 15.0 (12.0, 25.0) μg/L to 6.5(4.5, 18.7) and 7.8(5.3, 15.4) μg/L, respectively, LSM declined from 17.6 (8.9, 25.4) and 15.7 (7.8, 23.9) kPa to 13.9(6.5, 21.4) and 9.1(5.6, 19.9) kPa, respectively, serum album elevated form (37.5±5.8) and (38.7±5.5) g/L to (41.3±4.7) and (42.8±5.1) g/L, respectively, platelet elevated from (120.9±78.2) ×109/L and (136.6±65.8)×109/L to (139.5±71.8)×109/L and (149.7±71.4)×109/L, respectively. Reports of adverse events were low in both groups. Conclusions Both SOF+ DCV and SOF/LDV therapy are highly effective with >98% of SVR12 and reduce LSM value significantly with good safety for CHC GT1b Chinese patients. Key words: Hepatitis C, chronic; Treatment; Direct-acting antiviral agents

Repeating measurements by transient elastography in non-alcoholic fatty liver disease patients with high liver stiffness.

The Baveno VI Consensus recommends repeating examination in patients with high liver stiffness measurement (LSM) by transient elastography to reduce false-positive diagnosis of advanced liver disease. We tested whether repeating transient elastography can increase the overall diagnostic accuracy. Ninety-seven patients with non-alcoholic fatty liver disease who underwent two FibroScan examinations within 6months prior to liver biopsy were evaluated. An LSM cut-off of 7.9kPa was used to exclude F3-4 fibrosis. Seventy-eight patients had high LSM at baseline, among whom 27 had low LSM on repeated testing; only four had F3 and none had cirrhosis. In contrast, 31 of 51 patients with high LSM at both examinations had F3-4. Nineteen patients had low LSM at baseline; none of them had F3-4 regardless of the second LSM results. If we took LSM <7.9kPa at either examination as sufficient to exclude F3-4, the negative predictive value remained high at 91%. The positive predictive value for F3-4 increased from 45% in patients with high LSM at baseline to 61% in those with high LSM at both examinations. Sensitivity analysis using different cut-offs yielded similar results, with 76% of patients with LSM >12kPa at both examinations having F3-4. Transient elastography is a highly sensitive screening test to exclude F3-4 fibrosis in non-alcoholic fatty liver disease patients. One-third of patients with high LSM may have normal results on repeated examination. By repeating examination in cases with high LSM, one may spare patients from unnecessary liver biopsy.

Th17/Treg imbalance is an indicator of liver cirrhosis process and a risk factor for HCC occurrence in HBV patients

To determine the impact of T helper 17 cell (Th17)/regulatory T cell (Treg) ratio imbalance on the process and prognosis of hepatitis B virus (HBV)-related liver cirrhosis. Patients with HBV who refused to accept any therapy from were recruited from 2009 to 2014 and followed-up to August 2016. Based on a liver stiffness measurement (LSM), the patients were divided into a low LSM group and a high LSM group. After propensity score matching, 150 patients were included. The peripheral blood of all subjects was tested using a flow cytometer to measure the Th17 and Treg cell frequencies and the Th17/Treg ratio. Spearman rank correlation, log-rank test, Cox regression model, and receiver operating characteristic (ROC) curves were applied to analyze the correlation between the Th17/Treg ratio and LSM level and the risk factors of HCC occurrence and to predict the Th17/Treg ratio for the LSM level. Th17 and Treg cell frequencies and the Th17/Treg ratio were significantly different between the low and high LSM groups. The Th17/Treg ratio showed a strong positive association with LSM level (r=0.631, P<0.01). Furthermore, the Th17/Treg ratio was an independent factor influencing the HCC occurrence, which was tested using a Cox regression model. The area under the ROC curve of the Th17/Treg ratio for predicting LSM level was 0.783 (95% CI 0.705-0.861). Th17/Treg ratio imbalance is an indicator of the liver cirrhosis process and a risk factor for HCC occurrence in patients infected with HBV.

Prediction for Improvement of Liver Function after Balloon-Occluded Retrograde Transvenous Obliteration for Gastric Varices to Manage Portosystemic Shunt Syndrome

PurposeTo investigate predictive factors and cutoff value of transient elastography (TE) measurements for assessing improvement in liver function after balloon-occluded retrograde transvenous obliteration (BRTO) for gastric varices (GV). Materials and MethodsRetrospective analysis was performed of 50 consecutive patients followed for > 3 months after BRTO, who had undergone TE before BRTO between January 2011 and February 2015. The correlation between change in liver function (total bilirubin, albumin, and prothrombin time) and baseline liver function values and liver stiffness measurement (LSM) by TE was evaluated by Pearson correlation test. Receiver operating characteristic curves were used to determine cutoff values for discriminating between patients who had improved liver function and patients who did not. The time interval from BRTO to aggravation of esophageal varices (EV) (worsening morphology, development of new varices, or variceal rupture) grouped by cutoff values was also analyzed. ResultsSerum albumin was significantly improved at 3 months after BRTO (3.57 g/dL vs 3.74 g/dL, P < .001). There was a significant negative correlation between change in albumin and baseline LSM (r = –0.50, P < .001). The best cutoff point for LSM was ≤ 22.9 kPa, with sensitivity and specificity of 78.4% and 69.2%, respectively, for predicting which patients would have improved albumin after BRTO. Among 33 patients, 29 (88%) patients had improved albumin. The 1-year progression rate of EV after BRTO was 13.6% in patients with LSM ≤ 22.9 kPa. ConclusionsThe predictive factor for improvement in albumin after BRTO was lower LSM (≤ 22.9 kPa) using TE.