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Backgruound: Poor lifestyle habits may worsen nonalcoholic fatty liver disease (NAFLD), with progression to nonalcoholic steatohepatitis (NASH) and cirrhosis. This study investigated the association between glycemic control status and hepatic histological findings to elucidate the effect of glycemic control on NAFLD., Methods: This observational study included 331 patients diagnosed with NAFLD by liver biopsy. Effects of the glycemic control status on histological findings of NAFLD were evaluated by comparing the following four glycemic status groups defined by the glycosylated hemoglobin (HbA1c) level at the time of NAFLD diagnosis: ≤5.4%, 5.5%-6.4%, 6.5%-7.4%, and ≥7.5%., Results: Compared with the lowest HbA1c group (≤5.4%), the higher HbA1c groups (5.5%-6.4%, 6.5%-7.4%, and ≥7.5%) were associated with advanced liver fibrosis and high NAFLD activity score (NAS). On multivariate analysis, an HbA1c level of 6.5%- 7.4% group was significantly associated with advanced fibrosis compared with the lowest HbA1c group after adjusting for age, sex, hemoglobin, alanine aminotransferase, and creatinine levels. When further controlling for body mass index and uric acid, total cholesterol, and triglyceride levels, the higher HbA1c groups were significantly associated with advanced fibrosis compared with the lowest HbA1c group. On the other hand, compared with the lowest HbA1c group, the higher HbA1c groups were also associated with a high NAS in both multivariate analyses., Conclusion: Glycemic control is associated with NAFLD exacerbation, with even a mild deterioration in glycemic control, especially a HbA1c level of 6.5%-7.4%, contributing to NAFLD progression.

Purpose: Patients with a Fontan circulation tend to develop liver fibrosis, liver cirrhosis and even hepatocellular carcinoma. A noninvasive ultrasound technique for liver fibrosis and cardiac function assessment in Fontan-associated liver disease (FALD) is needed to evaluate disease progression in real time. This study aimed to evaluate whether hepatic vein (HV) waveform analysis and elastography could be alternative markers to cardiac index (CI) in patients with FALD and assess factors influencing elastography measurements in FALD cases., Methods: All patients underwent cardiac catheterization, B-mode ultrasound and ultrasound elastography measurement. Moreover, we measured serum markers related to fibrosis and examined HV blood flow using duplex Doppler ultrasonography., Results: Forty-three patients (median age, 17 years; interquartile range, 12-25 years; 29 men, 6 with liver biopsy) were enrolled. The real-time tissue elastography (RTE) value was significantly higher in patients who underwent surgery > 7 years prior, suggesting that this value probably reflects the liver fibrosis due to FALD from the early fibrosis stage. The ultrasound elastography did not significantly correlate with hemodynamic parameters. The area under the receiver operating curve for the diagnosis of CI < 2.2 L/min/m 2 using HV waveform was superior to the results from elastography and calculated fibrosis indices., Conclusion: HV waveform can be used as a noninvasive measurable surrogate marker for CI. The RTE value increased overtime after the operation and would reflect liver fibrosis. The combination of RTE and HV waveform type could be useful noninvasive tools to evaluate clinical conditions in FALD patients in real time.

Background and Aims: Lipoprotein(a) [Lp(a)] is an important independent cardiovascular risk factor. However, Lp(a) levels are lower in patients with chronic liver disease than in healthy subjects. Furthermore, Lp(a) levels decrease as residual liver function declines. Although non-alcoholic fatty liver disease (NAFLD), especially advanced non-alcoholic steatohepatitis (NASH), increases the risk of cardiovascular diseases, the relationship between serum Lp(a) level and NASH is unknown. Thus, we examined the relationship between serum Lp(a) levels and biopsy-proved NAFLD and clarified the significance of Lp(a) measurements for cardiovascular disease screening in patients with NAFLD., Methods: A total of 176 patients with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. The relationship between serum Lp(a) levels and NAFLD was analyzed., Results: Serum Lp(a) levels in advanced fibrosis (stage 3-4) were lower than those in non-advanced fibrosis (stage 0-2) (p < 0.05). After adjustment for age, sex, body mass index, alanine aminotransferase (ALT), creatinine (Cre), HbA 1c level, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and the use of lipid-lowering agents, the significant inverse association between advanced fibrosis and serum Lp(a) levels remained (p < 0.01). Although the Lp(a) level was inversely associated with an NAFLD Activity Score (NAS) of 5-8, there was no significant association between Lp(a) levels and NAS adjusted for age, sex, body mass index, ALT, Cre, HbA 1c level, HDL-C, LDL-C, TG, and the use of lipid-lowering agents., Conclusions: Advanced NASH is associated with low serum Lp(a) levels; therefore, Lp(a) levels may not be useful in evaluating cardiovascular risk., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to elucidate the efficacy of the combination of L-carnitine and exercise, reported to prevent muscle wasting, for muscle complications (function, volume, and cramping) in patients with liver cirrhosis (LC) who received branched-chain amino acid supplementation., Materials and Methods: From December 2017 to April 2018, 18 patients with LC who had been given branched-chain amino acid granule supplementation (12.45 g/day) were enrolled (mean age 68.4±10.8 years; 10 males and eight females; Child-Pugh A : B=9 : 9). After evaluating the average number of daily steps, oral L-carnitine supplementation (1000 mg/day) and additional exercise (plus 2000 steps/day) were added for 6 months. Every 4 weeks, a pedometer, a hand dynamometer, ergometer, and bioelectrical impedance analysis were used to evaluate daily steps, muscle function and muscle volume, and muscle cramps were recorded using a numerical rating scale., Results: Average steps and serum levels of total and free carnitine were increased from before treatment to the final measurement (1883.5±1211.6 vs. 3165.1±1800.0/day, 62.6±16.5 vs. 110.9±28.6 μmol/l, and 47.7±15.2 vs. 83.2±21.5 μmol/l, respectively; P<0.01), whereas there were no significant changes in the ratios of handgrip strength, leg strength, and muscle volume after 6 months [1.00±0.13 (P=0.991), 1.07±0.13 (P=0.073), and 0.992±0.036 (P=0.390), respectively]. However, the frequency of complaints of muscle cramping was reduced as compared with the start of therapy (baseline, 3 months, and 6 months: 6.3±4.8, 3.1±3.3, and 2.1±2.0, respectively) (P=0.025, Holm's method), whereas numerical rating scale did not show any significant improvement., Conclusion: L-Carnitine may have an important role for prevention of muscle wasting and reducing the frequency of muscle cramping.

Background/aim: Sarcopenia is recognized as a condition related to quality of life and prognosis in patients with chronic liver disease, although no useful strategy for improving muscle volume and strength has been established. Here, we evaluated the efficacy of supplementation with branched-chain amino acid (BCAA) administration and walking exercise., Patients and Methods: From December 2015 to July 2016, 33 Japanese outpatients with liver cirrhosis were enrolled (median: 67 years, HCV : HBV : alcohol : others=26 : 2 : 2 : 3, male : female=13 : 20, Child-Pugh A : B=30 : 3). None had a history of BCAA supplementation. After calculating the average number of daily steps using a pedometer for a 2-3-week period, BCAA supplementation (protein 13.5 g, 210 kcal/day) as a late evening snack and walking exercise (additional 2000 steps/day prescribed) were started. Body composition including muscle volume was analyzed using a bioelectrical impedance analysis method, and serological data and muscle strength (leg, handgrip) were evaluated at enrollment, and then 1, 2, and 3 months after starting the protocol., Results: The median average number of daily steps was 3791 (interquartile range: 2238-5484). The average period of BCAA supplementation was 2.7±0.7 months. During the period from enrollment to 3 months after starting the protocol, HbA1c and NH3 were not significantly changed, whereas the BCAA/tyrosine ratio improved (4.3±1.35 to 5.24±2.04, P=0.001). In addition, the ratios for average daily steps (1.595, P=0.02) as well as muscle volume, leg strength, and handgrip strength (1.013, 1.110, and 1.056, respectively; all P<0.01) were increased at 3 months., Conclusion: BCAA supplementation and walking exercise were found to be effective and easily implemented for improving muscle volume and strength in liver cirrhosis patients.

Objective: Performing shear wave imaging is simple, but can be difficult when inflammation, jaundice, and congestion are present. Therefore, the correct diagnosis of liver fibrosis using shear wave imaging alone might be difficult in mild-to-moderate fibrosis cases. Strain imaging can diagnose liver fibrosis without the influence of inflammation. Therefore, the combined use of strain and shear wave imaging (combinational elastography) for cases without jaundice and congestion might be useful for evaluating fibrosis and inflammation., Methods: We enrolled consecutive patients with liver disease, without jaundice or liver congestion. Strain and shear wave imaging, blood tests, and liver biopsy were performed on the same day. The liver fibrosis index (LF index) was calculated by strain imaging; real-time tissue elastography, and the shear wave velocity (Vs) was calculated by shear wave imaging. Fibrosis index (F index) and activity index (A index) were calculated as a multiple regression equation for determining hepatic fibrosis and inflammation using histopathological diagnosis as the gold standard. The diagnostic ability of F index for fibrosis and A index for inflammation were compared using LF index and Vs., Results: The total number of enrolled cases was 388. The area under the receiver operating characteristic (AUROC) was 0.87, 0.80, 0.83, and 0.80, at diagnosis of fibrosis stage with an F index of F1 or higher, F2 or higher, F3 or higher, and F4, respectively. The AUROC was 0.94, 0.74, and 0.76 at diagnosis of activity grade with an A index of A1 or higher, A2 or higher, and A3, respectively. The diagnostic ability of F index for liver fibrosis and A index for inflammation was higher than for other conventional diagnostic values., Conclusions: The combined use of strain and shear wave imaging (combinational elastography) might increase the positive diagnosis of liver fibrosis and inflammation., (© 2017 S. Karger AG, Basel.)

Background/aim: The frequency of sarcopenia, defined as loss of both muscle volume and strength, was analyzed in chronic liver disease (CLD)., Methods and Materials: From April to September 2015, 807 Japanese CLD patients treated as outpatients were enrolled (67.1±10.0 years, men : women=466 : 341, hepatitis C virus : hepatitis B virus : hepatitis B and C virus : alcohol : other=511 : 134 : 3 : 45 : 114). Sarcopenia was diagnosed when the patient showed muscle volume loss and reduced handgrip strength, whereas those with only muscle volume loss were classified as 'v-presarcopenia' and those with only reduced handgrip strength were classified as 's-presarcopenia'. Muscle volume loss was determined using computed tomography findings and a previously reported index (psoas index), and cut-off values for reduced handgrip strength presented by the Asia Working Group for Sarcopenia (AWGS) (AWGS/grip criteria) and European Working Group on Sarcopenia in Older People (EWGSOP) (EWGSOP/grip criteria) (men; 26 and 30 kg, women; 18 and 20 kg, respectively) were used. Clinical features were analyzed for diagnoses of chronic hepatitis (CH, n=381), liver cirrhosis Child-Pugh A (n=330), and liver cirrhosis Child-Pugh B/C (n=96)., Results: When the AWGS/grip criteria were used, the frequencies of sarcopenia, v-presarcopenia, and s-presarcopenia in CH were 3.9, 7.9, and 19.4%, whereas those in Child-Pugh A were 4.8, 17.6, and 21.8% and those in Child-Pugh B/C were 16.7, 11.5, and 39.6%, respectively. When the EWGSOP/grip criteria were used, these frequencies were 7.1, 4.7, and 33.1%, in CH, 11.8, 10.6, and 32.7%, in Child-Pugh A, and 21.9, 6.3, and 49.0%, in Child-Pugh B/C, respectively. The incidence rates of sarcopenia and both types of presarcopenia increased with progression of CLD., Conclusion: Evaluation of handgrip strength and psoas index is an easy and effective method for the detection of sarcopenia and presarcopenia.

Background: Although impaired glucose tolerance is common in cirrhosis, this condition's pathogenesis remains undefined. This study aimed to clarify pathogenesis related to the pancreas in cirrhotic patients, and to evaluate associations between insulin secretion and pancreatic congestion due to portal hypertension., Methods: Pancreatic perfusion parameters were analyzed by dynamic contrast-enhanced ultrasound (CE-US) in 41 patients (20 cirrhotic, 21 non-cirrhotic; age, 67.9 ± 13.3; female, 19), and prospectively compared to delta C-peptide immunoreactivity (ΔCPR). In a separate study, a retrospective chart review with human autopsy specimens was conducted, and vessels and islets of the pancreas were analyzed in 43 patients (20 cirrhotic, 23 controls; age, 71.5 ± 11.6; female, 15)., Results: In the CE-US study, the clinical characteristics indicative of portal hypertension (e.g., ascites and varices) had significantly higher incidences in the cirrhotic group than in the control group. Pancreatic drainage times were greater in the cirrhotic group (p < 0.0001), and had a significant negative correlation with ΔCPR (R = 0.42, p = 0.0069). In the histopathological study, the islets were enlarged in the cirrhotic group (p < 0.0001). However, the percentage of insulin-positive area per islet was decreased in the cirrhotic group (p < 0.0001), and had a significant negative correlation with the wall thickness of the pancreatic vein (R = 0.63, p < 0.0001)., Conclusions: Pancreatic congestion was present in cirrhotic patients. Moreover, pancreatic congestion and insulin secretion were significantly correlated. This pathogenesis could be a key factor underlying the development of hepatogenous diabetes in cirrhotic patients.

Background/aims: We evaluated the diagnostic efficacy for advanced fibrosis of real-time tissue elastography (RTE), is a newly introduced non-invasive method, in hepatitis C virus (HCV) patients., Methodology: Sixty-six chronic liver diseases with HCV (CLD-HCV) were evaluated by RTE, FIB-4, and APRI, as well as biopsy or hepatectomy findings. Seventeen healthy volunteers, and 1 with elevation of transaminase and 5 with liver tumors within their normal liver were enrolled for normal controls. Severe fibrosis was defined as METAVIR score 3 or 4. The tissue elasticity value was expressed by LF-index created by the program incorporated in the ultrasound device. The percentage of fibrosis area in each specimen (%FA) was determined with a personal computer. A receiver operating characteristic curve (ROC) was calculated for each non-invasive method of estimation of fibrosis., Results: The values for the area under the ROC for LF-index, APRI, and FIB-4 were 0.88, 0.81, and 0.84, respectively. Accuracy, sensitivity, and specificity for prediction of LF-index (>2.8) for severe fibrosis were 86.5%, 78.6%, and 93.6%, respectively, which were better than those of FIB-4 and APRI. LF-index showed a good relationship to %FA (r=0.276, P=0.020)., Conclusion: RTE is an effective method for predicting severe fibrosis in CLD-HCV.

Unlabelled: The aim of this study was to prospectively measure liver stiffness with real-time tissue elastography in patients with nonalcoholic fatty liver diseases (NAFLD) and to compare the result with the clinical assessment of fibrosis using histological stage. One hundred and eighty-one prospectively enrolled patients underwent real-time tissue elastography, with the first 106 being analyzed as the training set and the remaining 75 being evaluated as the validation set. Hepatic and splenic elastic ratios were calculated and compared with stage of histological fibrosis. Portal hypertension (PH) was assessed. Real-time tissue elastography cut-off values by stage in the training set were 2.47 for F1, 2.67 for F2, 3.02 for F3, and 3.36 for F4. Using these cut-off values, the diagnostic accuracy of hepatic fibrosis in the validation set was 82.6%-96.0% in all stages. Only portal fibrosis correlated with the hepatic elastic ratio by multivariate analysis. The area under the receiver operating characteristic curve of elastic ratio better correlated than serum fibrosis markers in both early and advanced fibrosis stages. Patients with PH, defined by splenic elasticity, had early fibrosis. Patients with severe PH were found only in the group with cirrhosis., Conclusion: Real-time tissue elastography is useful in evaluating hepatic fibrosis and PH in patients with NAFLD., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Branched-chain amino acid (BCAA) supplements have mainly been administered as a nutritional intervention for decompensated liver cirrhosis. Several studies have shown that short-term BCAA supplementation improves insulin and glucose tolerance in patients with liver cirrhosis. However, the long-term effects of BCAA supplementation on glucose tolerance and in patients with nonalcoholic steatohepatitis (NASH)-related liver cirrhosis are unknown. Herein, we report 2 cases of NASH-related liver cirrhosis in which long-term BCAA supplementation improved glycemic control. We conclude that in the absence of an effective conventional therapy for NASH-related liver cirrhosis, BCAA supplementation should be considered as an alternative treatment.

Objective: Transient elastography is a rapid, noninvasive, and reproducible approach to assessment of liver fibrosis by measurement of liver elasticity. However, transient elastographic measurements are of limited utility in patients with ascites or severe obesity. The aim of this study was to determine whether measurements of liver stiffness with real-time tissue elastography can be altered for patients with ascites., Subjects and Methods: The subjects were 54 patients being treated at a university hospital between January and December 2009. In 42 patients, real-time tissue elastography to evaluate liver stiffness was performed before and after injection to produce artificial ascites for radiofrequency ablation. The other 12 patients had ascites due to cirrhosis, and liver stiffness was measured with real-time tissue elastography before and after control of ascites., Results: Elastic ratios evaluated with real-time tissue elastography did not differ significantly before and after injection for artificial ascites or before and after control of ascites. This ratio was the same for patients with and those without cirrhosis and was unaffected by distance between the body surface and the targeted liver area. Stable values thus were measured with real-time tissue elastography., Conclusion: Liver stiffness can be measured reproducibly with real-time tissue elastography even in patients with ascites. This method has the potential of being superior to transient elastography for assessment of liver stiffness, particularly in patients with decompensated cirrhosis.

Purpose: To prospectively measure liver stiffness with real-time tissue elastography in patients with chronic hepatitis C and to compare the results with those of clinical assessment of fibrosis by using histologic stage as the reference standard., Materials and Methods: All subjects gave informed consent, and the study was approved by the institutional ethics committee. Seventy hospitalized patients (46 men, 24 women; mean age, 65.5 years ± 11.7 [standard deviation]; age range, 33-87 years) with chronic hepatitis C underwent real-time elastography between January 2009 and September 2009. Elastography was performed at four liver locations by two independent observers. The elastic ratio (ratio of the value in the intrahepatic venous small vessels divided by the value in the hepatic parenchyma) was calculated and was compared with histologic fibrosis stage at liver biopsy. The elastic ratio and clinical fibrosis markers were assessed by using receiver operating characteristic (ROC) analysis. The differences between body site and observers were assessed with κ statistics and intraclass correlation coefficients (ICCs)., Results: Real-time tissue elastography cutoff values were 2.73 for F of 2 or greater, 3.25 for F of 3 or greater, and 3.93 for F of 4. No site differences were observed (κ = 0.835, ICC = 0.966), and the elastic ratio measurement was correlated between the two examiners (r(2) = 0.869, P < .0001). The areas under the ROC curves for elastic ratio, hyaluronic acid, type IV collagen, aspartate aminotransferase-to-platelet ratio index, FibroIndex, Forns score, and Hepascore were 0.95, 0.32, 0.73, 0.76, 0.76, 0.87, and 0.70, respectively; the elastic ratio performed better than the serum fibrosis markers and other scores., Conclusion: Real-time tissue elastography is not invasive and could be used to evaluate liver fibrosis in patients with chronic hepatitis C., Supplemental Material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100319/-/DC1., (© RSNA, 2011)

The present report represents the case of a 36-year-old woman with congenital hepatic fibrosis (CHF). She was admitted to our hospital because of gastric varices. She was asymptomatic and her liver function tests were within normal limits. Computed tomography showed hepatomegaly, splenomegaly and collateral circulation, but no evidence of liver cirrhosis. Real-time tissue elastography suggested severe fibrosis of the liver. Laparoscopy showed wide and discrete white markings on the surface of the liver and she was diagnosed with CHF based on the histological examination. The findings obtained from elastography and laparoscopy were useful for making the diagnosis of CHF., (© 2010 The Authors. Digestive Endoscopy © 2010 Japan Gastroenterological Endoscopy Society.)