Bjørn Stæhr Madsen

Transient and 2-Dimensional Shear-Wave Elastography Provide Comparable Assessment of Alcoholic Liver Fibrosis and Cirrhosis

BACKGROUND & AIMS Alcohol abuse causes half of all deaths from cirrhosis in the West, but few tools are available for noninvasive diagnosis of alcoholic liver disease. We evaluated 2 elastography techniques for diagnosis of alcoholic fibrosis and cirrhosis; liver biopsy with Ishak score and collagen-proportionate area were used as reference. METHODS We performed a prospective study of 199 consecutive patients with ongoing or prior alcohol abuse, but without known liver disease. One group of patients had a high pretest probability of cirrhosis because they were identified at hospital liver clinics (in Southern Denmark). The second, lower-risk group, was recruited from municipal alcohol rehabilitation centers and the Danish national public health portal. All subjects underwent same-day transient elastography (FibroScan), 2-dimensional shear wave elastography (Supersonic Aixplorer), and liver biopsy after an overnight fast. RESULTS Transient elastography and 2-dimensional shear wave elastography identified subjects in each group with significant fibrosis (Ishak score ≥3) and cirrhosis (Ishak score ≥5) with high accuracy (area under the curve ≥0.92). There was no difference in diagnostic accuracy between techniques. The cutoff values for optimal identification of significant fibrosis by transient elastography and 2-dimensional shear wave elastography were 9.6 kPa and 10.2 kPa, and for cirrhosis 19.7 kPa and 16.4 kPa. Negative predictive values were high for both groups, but the positive predictive value for cirrhosis was >66% in the high-risk group vs approximately 50% in the low-risk group. Evidence of alcohol-induced damage to cholangiocytes, but not ongoing alcohol abuse, affected liver stiffness. The collagen-proportionate area correlated with Ishak grades and accurately identified individuals with significant fibrosis and cirrhosis. CONCLUSIONS In a prospective study of individuals at risk for liver fibrosis due to alcohol consumption, we found elastography to be an excellent tool for diagnosing liver fibrosis and for excluding (ruling out rather than ruling in) cirrhosis.

Targeting the Gut–Liver Axis in Cirrhosis: Antibiotics and Non-Selective β-Blockers

The gut–liver axis in cirrhosis and portal hypertension is gaining increasing attention as a key pathophysiological mechanism responsible for progression of liver failure and development of complications such as spontaneous infections and hepatocellular carcinoma. Antibiotics and non-selective β-blockers (NSBB) intercept this axis and each drug has proven efficacy in clinical trials. A synergistic effect is a hitherto unproven possibility. There is an increasing body of evidence supporting improved outcome with expanded use of NSBB and antibiotic therapy beyond current indications. This review addresses the issue of pharmacological treatment of cirrhosis and portal hypertension with antibiotics and NSBB. We discuss their mechanism of action and suggest that combining the two treatment modalities could potentially reduce the risk of complications.

Association of markers of bacterial translocation with immune activation in decompensated cirrhosis.

Background Bacterial translocation (BT) may cause infections, in particular, spontaneous bacterial peritonitis (SBP). In the absence of overt infection, BT may further stimulate the immune system and contribute to haemodynamic alterations and complications. Bacterial DNA (bDNA) is claimed to be a promising surrogate marker for BT, although its clinical relevance has been questioned. Materials and methods In 38 cirrhotic patients with and without SBP, bDNA in blood and ascites were assessed by 16S rDNA quantitative PCR. Levels of lipopolysaccharide-binding protein in plasma and highly sensitive C-reactive protein, tumour necrosis factor-&agr;, soluble urokinase plasminogen activating receptor, interleukin-6, interleukin 8, interferon-&ggr; inducible protein-10 and vascular endothelial growth factor in plasma and ascites were measured by multiplex cytokine and ELISA assays. Results In patients without signs of SBP or positive cultures, we found a high frequency of bDNA but low concordance of bDNA between blood and ascites. Markers of inflammation were not significantly different between blood bDNA-positive (22%), ascites bDNA-positive (52%), and bDNA-negative patients. The 16S rDNA PCR failed to show bDNA in two out of six samples with SBP. Sequencing of positive samples did not determine the source of bDNA. Conclusion bDNA as assessed by this PCR method was largely unrelated to markers of inflammation and does not seem to be of clinical value in the diagnosis of SBP. According to our results, bDNA is not a reliable marker of BT.

Controlled attenuation parameter and alcoholic hepatic steatosis: Diagnostic accuracy and role of alcohol detoxification

BACKGROUND & AIMS Controlled attenuation parameter (CAP) is a novel non-invasive measure of hepatic steatosis, but it has not been evaluated in alcoholic liver disease. Therefore, we aimed to validate CAP for the assessment of biopsy-verified alcoholic steatosis and to study the effect of alcohol detoxification on CAP. METHODS This was a cross-sectional biopsy-controlled diagnostic study in four European liver centres. Consecutive alcohol-overusing patients underwent concomitant CAP, regular ultrasound, and liver biopsy. In addition, we measured CAP before and after admission for detoxification in a separate single-centre cohort. RESULTS A total of 562 patients were included in the study: 269 patients in the diagnostic cohort with steatosis scores S0, S1, S2, and S3 = 77 (28%), 94 (35%), 64 (24%), and 34 (13%), respectively. CAP diagnosed any steatosis and moderate steatosis with fair accuracy (area under the receiver operating characteristic curve [AUC] ≥S1 = 0.77; 0.71-0.83 and AUC ≥S2 = 0.78; 0.72-0.83), and severe steatosis with good accuracy (AUC S3 = 0.82; 0.75-0.88). CAP was superior to bright liver echo pattern by regular ultrasound. CAP above 290 dB/m ruled in any steatosis with 88% specificity and 92% positive predictive value, while CAP below 220 dB/m ruled out steatosis with 90% sensitivity, but 62% negative predictive value. In the 293 patients who were admitted 6.3 days (interquartile range 4-6) for detoxification, CAP decreased by 32 ± 47 dB/m (p <0.001). Body mass index predicted higher CAP in both cohorts, irrespective of drinking pattern. Obese patients with body mass index ≥30 kg/m2 had a significantly higher CAP, which did not decrease significantly during detoxification. CONCLUSIONS CAP has a good diagnostic accuracy for diagnosing severe alcoholic liver steatosis and can be used to rule in any steatosis. In non-obese but not in obese, patients, CAP rapidly declines after alcohol withdrawal. LAY SUMMARY CAP is a new ultrasound-based technique for measuring fat content in the liver, but has never been tested for fatty liver caused by alcohol. Herein, we examined 562 patients in a multicentre setting. We show that CAP highly correlates with liver fat, and patients with a CAP value above 290 dB/m were highly likely to have more than 5% fat in their livers, determined by liver biopsy. CAP was also better than regular ultrasound for determining the severity of alcoholic fatty-liver disease. Finally, we show that three in four (non-obese) patients rapidly decrease in CAP after short-term alcohol withdrawal. In contrast, obese alcohol-overusing patients were more likely to have higher CAP values than lean patients, irrespective of drinking.

High risk of misinterpreting liver and spleen stiffness using 2D shear-wave and transient elastography after a moderate or high calorie meal

Food intake increases liver stiffness, but it is believed that liver stiffness returns to baseline two hours after a meal. The aim of this study was to investigate the impact of different sized meals on liver stiffness. Liver and spleen stiffness was measured with transient elastography (TE) and real-time 2-dimensional shear wave elastography (2D-SWE). Patients ingested a 625 kcal and a 1250 kcal liquid meal on two consecutive days. We measured liver and spleen elasticity, Controlled attenuation parameter (CAP) and portal flow at baseline and after 20, 40, 60, 120 and 180 minutes. Sixty patients participated, 83% with alcoholic liver disease. Twenty-eight patients had METAVIR fibrosis score F0-3 and 32 patients had cirrhosis. Liver stiffness, spleen stiffness and CAP increased after both meals for all stages of fibrosis. False positive 2D-SWE liver stiffness measurements caused 36% and 52% of patients with F0-3 fibrosis to be misclassified with higher stages of fibrosis after the moderate and high caloric meal. Likewise, 10% and 13% of compensated cirrhosis patients were misclassified with clinically significant portal hypertension after the two meals. We observed similar misclassification rates with TE. After three hours, liver stiffness remained elevated more than 20% from baseline in up to 50% of patients. In conclusion: Liver stiffness, spleen stiffness and CAP increase after a meal across all stages of fibrosis and across elastography techniques. Up to half of patients may be misclassified with higher stages of fibrosis, if they are assessed after less than three hours fasting period.

Feasibility of transient elastography versus real-time two-dimensional shear wave elastography in difficult-to-scan patients

Abstract Background and aims: Transient elastography (TE) is hampered in some patients by failures and unreliable results. We hypothesized that real time two-dimensional shear wave elastography (2D-SWE), the FibroScan XL probe, and repeated TE exams, could be used to obtain reliable liver stiffness measurements in patients with an invalid TE examination. Methods: We reviewed 1975 patients with 5764 TE exams performed between 2007 and 2014, to identify failures and unreliable exams. Fifty-four patients with an invalid TE at their latest appointment entered a comparative feasibility study of TE vs. 2D-SWE. Results: The initial TE exam was successful in 93% (1835/1975) of patients. Success rate increased from 89% to 96% when the XL probe became available (OR: 1.07, 95% CI 1.06–1.09). Likewise, re-examining those with a failed or unreliable TE led to a reliable TE in 96% of patients. Combining availability of the XL probe with TE re-examination resulted in a 99.5% success rate on a per-patient level. When comparing the feasibility of TE vs. 2D-SWE, 96% (52/54) of patients obtained a reliable TE, while 2D-SWE was reliable in 63% (34/54, p < 0.001). The odds of a successful 2D-SWE exam decreased with higher skin-capsule distance (OR = 0.77, 95% CI 0.67–0.98). Conclusions: Transient elastography can be accomplished in nearly all patients by use of the FibroScan XL probe and repeated examinations. In difficult-to-scan patients, the feasibility of TE is superior to 2D-SWE.

Antifibrotic and molecular aspects of rifaximin in alcoholic liver disease: Study protocol for a randomized controlled trial

BackgroundAlcoholic liver disease is the leading cause of cirrhosis worldwide. Due to an increase in alcohol overuse, alcoholic liver disease has become an increased burden on health care systems. Abstinence from alcohol remains the cornerstone of alcoholic liver disease treatment; however, this approach is hampered by frequent relapse and lack of specific therapy for treating advanced cases of liver disease. In the present study, we hypothesized that gut microbiota drive the development of liver fibrosis and that modulation of gut microbiota with the gut-selective, nonabsorbable antibiotic rifaximin attenuates alcoholic liver fibrosis.Methods/designOur double-blind, placebo-controlled trial will include 136 participants with biopsy-verified alcoholic fibrosis (Ishak liver fibrosis score of 1–4). Participants are randomized 1:1 to receive placebo or 550 mg of rifaximin twice daily for 18 months. A liver biopsy will be performed at the end of the treatment period to evaluate the effect of drug treatment on liver fibrosis. Stool, urine, and saliva specimens will be collected before treatment begins, at 1 month, and at the end of the treatment period. Fecal samples are used for microbiome deep sequencing. Changes in microbiome composition are compared before and after the trial medication period and linked to changes in liver fibrosis.DiscussionThis is the first clinical trial to evaluate the effect of gut microbiota on liver fibrosis in humans. If gut microbiota are an important promoter of alcoholic liver disease, current results may open new therapeutic avenues and revolutionize the current understanding of chronic liver diseases.Trial registrationEudraCT, 2014–001856-51. Registered on 16 August 2014.

Non-invasive diagnosis of liver fibrosis in patients with alcohol-related liver disease by transient elastography: an individual patient data meta-analysis

BACKGROUND The value of transient elastography for the non-invasive diagnosis of alcohol-related liver fibrosis is subject to debate. We did an individual patient data (IPD) meta-analysis to determine specific diagnostic cutoff values for liver stiffness in alcohol-related fibrosis, and to assess the effect of aminotransferase concentrations, bilirubin concentrations, and presence of asymptomatic and non-severe alcoholic hepatitis on liver stiffness. METHODS We searched for studies that included patients with alcohol-related liver disease, liver biopsy, and transient elastography, and with a statistical method for determining the diagnostic cutoffs for alcohol-induced liver fibrosis on the basis of the FibroScan results, in PubMed between Jan 1, 2000, and Sept 30, 2017. Native data bases were obtained from corresponding authors in an Excel form. Pooled diagnostic cutoffs for the various fibrosis stages were determined in a two-stage, random-effects meta-analysis. The effects of aspartate aminotransferase (AST) concentrations, bilirubin concentrations, and histological features of asymptomatic and non-severe alcoholic hepatitis on liver stiffness cutoff were assessed in one-stage, random-effects meta-analysis. FINDINGS Of 188 studies assessed, ten studies comprising 1026 patients were included in the meta-analysis, yielded liver stiffness cutoffs of 7·0 kPa (area under the receiver operating characteristic curve 0·83 [SE 0·02; 95% CI 0·79-0·87]) for F≥1 fibrosis, 9·0 kPa (0·86 [0·02; 0·82-0·90]) for F≥2, 12·1 kPa (0·90 [0·02; 0·86-0·94]) for F≥3, and 18·6 kPa (0·91 [0·04; 0·83-0·99]) for F=4. AST and bilirubin concentrations had a significant effect on liver stiffness, with higher concentrations associated with higher liver stiffness values (p<0·0001), and with significantly higher cutoff values for diagnosis of all fibrosis stages but F≥1. The presence of histological features of asymptomatic and non-severe alcoholic hepatitis was associated with increased liver stiffness (p<0·0001). In a multivariate analysis, AST (p<0·0001) and bilirubin (p=0·0002) concentrations, and prothrombin activity (p=0·01), were independently associated with the presence of histological features of asymptomatic and non-severe alcoholic hepatitis. Lastly, specific liver stiffness cutoffs were determined on the basis of concentrations of AST and bilirubin. Liver stiffness cutoff values increased in patients with increased AST concentrations, bilirubin concentrations, or both. INTERPRETATION This IPD meta-analysis highlights the link between liver stiffness and the histological features of asymptomatic and non-severe alcoholic hepatitis, reflected by AST and bilirubin concentrations. In alcohol-related liver disease, FibroScan assessments of liver fibrosis should take into account AST and bilirubin concentrations through the use of specifically adjusted liver stiffness cutoffs. FUNDING None.

Is liver stiffness equal to liver fibrosis

We read with interest the article by Koehler and colleagues. The elaborate study provides important information on the prevalence of increased liver stiffness in a suburban population in the Netherlands. By systematically investigating 3,041 participants, the authors conclude that 5.6% of the general population over 45 years of age has increased liver stiffness above 8 kPa, suggestive of clinically relevant fibrosis. Diabetes and ultrasound-assessed steatosis in combination was a particularly strong predictor of increased liver stiffness. We commend the authors for their large-scale, thorough work, which is an important step toward early detection of chronic liver disease in the general population. With increasing availability of noninvasive markers of liver fibrosis, it is likely that more studies similar to the Rotterdam Study will be conducted. We therefore wish to use the opportunity to discuss the pitfalls of equating liver stiffness with liver fibrosis in a population with a low prevalence of chronic liver disease. The authors chose 8 kPa as a cutoff for clinically relevant fibrosis ( F3). The biopsy-controlled study used for reference assessed transient elastography in 246 nonalcoholic fatty liver disease patients referred for investigations at a hospital liver clinic, where 23% of patients had severe fibrosis. When this result is extrapolated to the general population, one should consider the problem of spectrum bias—that disease prevalence affects test performance. In an unsorted background population, the prevalence of severe fibrosis is most likely lower than the 5.6% with elevated liver stiffness reported in the Rotterdam Study. An “optimistic” estimate is 5%. Given this prevalence and assuming that transient elastography has the same accuracy as in the index study— a sensitivity of 91% and a specificity of 75% for detecting severe fibrosis—the positive predictive value is only 16%. As an example of spectrum bias, in a recent screening study of type 2 diabetics, 18% had elevated liver stiffness, whereas only half of those with elevated liver stiffness undergoing liver biopsy had severe fibrosis. Consequently, we need strategies to increase the positive predictive value when screening for chronic liver diseases in the general population or in groups with low prevalence such as those with diabetes or alcoholism. We suggest considering pretest probabilities or disease prevalence before interpreting the result of a diagnostic test. Only in high-prevalence populations can liver stiffness with certainty be equated with liver fibrosis.