Current NAFLD guidelines for risk stratification in diabetic patients have poor diagnostic discrimination.

Patients with type 2 diabetes (T2D) are at risk for non-alcoholic fatty liver disease (NAFLD) and associated complications. This study evaluated the performance of international (EASL-EASD-EASO) and national (DGVS) guidelines for NAFLD risk stratification. Patients with T2D prospectively underwent ultrasound, liver stiffness measurement (LSM) and serum-based fibrosis markers. Guideline-based risk classification and referral rates for different screening approaches were compared and the diagnostic properties of simplified algorithms, genetic markers and a new NASH surrogate (FAST score) were evaluated. NAFLD risk was present in 184 of 204 screened patients (age 64.2 ± 10.7 years; BMI 32.6 ± 7.6 kg/m2). EASL-EASD-EASO recommended specialist referral for 60-77% depending on the fibrosis score used, only 6% were classified as low risk. The DGVS algorithm required LSM for 76%; 25% were referred for specialised care. The sensitivities of the diagnostic pathways were 47-96%. A simplified referral strategy revealed a sensitivity/specificity of 46/88% for fibrosis risk. Application of the FAST score reduced the referral rate to 35%. This study (a) underlines the high prevalence of fibrosis risk in T2D, (b) demonstrates very high referral rates for in-depth hepatological work-up, and (c) indicates that simpler referral algorithms may produce comparably good results and could facilitate NAFLD screening.

Evaluation of a novel tomographic ultrasound device for abdominal examinations.

Conventional ultrasound (US) is the first-line imaging method for abdominal pathologies, but its diagnostic accuracy is operator-dependent, and data storage is usually limited to two-dimensional images. A novel tomographic US system (Curefab CS, Munich, Germany) processes imaging data combined with three-dimensional spatial information using a magnetic field tracking. This enables standardized image presentation in axial planes and a review of the entire examination. The applicability and diagnostic performance of this tomographic US approach was analyzed in an abdominal setting using conventional US as reference. Tomographic US data were successfully compiled in all subjects of a training cohort (20 healthy volunteers) and in 50 patients with abdominal lesions. Image quality (35% and 79% for training and patient cohort respectively) and completeness of organ visualization (45% and 44%) were frequently impaired in tomographic US compared to conventional US. Conventional and tomographic US showed good agreement for measurement of organ sizes in the training cohort (right liver lobe and both kidneys with a median deviation of 5%). In the patient cohort, tomographic US identified 57 of 74 hepatic or renal lesions detected by conventional ultrasound (sensitivity 77%). In conclusion, this study illustrates the diagnostic potential of abdominal tomographic US, but current significant limitations of the tomographic ultrasound device demand further technical improvements before this and comparable approaches can be implemented in clinical practice.

Author Correction: Predicting hepatic complications of allogeneic hematopoietic stem cell transplantation using liver stiffness measurement.

In the original article, the affiliations were presented incorrectly. David Petroff is in fact the only author at affiliation 2. All other authors listed as being at affiliation 2 (Tina Weiße, Sebastian Beer, Franziska Gnatzy, Joachim Mössner, Michael Tröltzsch, Johannes Wiegand and Volker Keim) are in fact just at affiliation 1. These have now been corrected in the original article.

Predicting hepatic complications of allogeneic hematopoietic stem cell transplantation using liver stiffness measurement.

Allogeneic hematopoietic stem cell transplantation is the only curative option for a variety of diseases. Despite advances, it is associated with considerable morbidity and mortality, often involving liver complications. Liver disease can be characterized using ultrasound-based liver stiffness measurement. To assess its prognostic value, consecutive patients undergoing allogeneic hematopoietic stem cell transplantation were prospectively evaluated in a single-center study. Endpoints included liver event-free survival and all-cause mortality at 1 year. Competing risk and Cox-regression were used for analysis. We evaluated 106 patients (42 female, age 57) and observed 33 life-threatening events (14 died) including 16 liver complications at 100 days. At 1 year, 36 patients had died, 20 with disease relapse. The hazard ratios for liver-related complications at 100 days were 3.2 (95% CI: 1.8-14.6, p = 0.0022) and 4.4 (95% CI: 1.6-11.9, p = 0.0042) for elevated transient elastography (n = 11) and shear-wave velocity (n = 31), respectively. Results were analogous for all-cause mortality at 1 year. Prior stem cell therapy and elevated gamma glutamyltransferase were also associated with outcome. This demonstrates that elastography is a promising and viable tool for risk prediction and should be included in upcoming multi-center trials to establish new means of guiding treatment and prophylaxis.

Predictive value of liver and spleen stiffness in advanced alcoholic cirrhosis with refractory ascites.

BACKGROUND: Recurrent ascitic decompensation is a frequent complication of advanced alcoholic liver disease. Ascites can be controlled by transjugular intrahepatic portosystemic shunt (TIPS) implantation, but specific pre-procedural outcome predictors are not well established. Liver and spleen stiffness measurement (LSM, SSM) correlate with outcome of compensated liver disease, but data for decompensated cirrhosis disease are scarce. Therefore, the predictive value of LSM and SSM was evaluated in patients with refractory ascites treated with TIPS insertion or receiving conservative therapy. MATERIAL AND METHODS: Patients with alcoholic liver cirrhosis and recurrent or refractory ascites were stratified according to TIPS eligibility. LSM was prospectively assessed by transient elastography (TE, XL probe) and point shear wave elastography (pSWE). pSWE was also used for SSM. The primary study endpoint was transplant-free survival after 12 months. In addition, correlation of LSM and SSM with TIPS complications was analyzed. RESULTS: 43 patients (16 % female, age 55.5 [28.6 - 79.6] years) were recruited, n = 20 underwent TIPS and n = 23 were treated with repeated paracenteses only. 15 patients died and five underwent liver transplantation during follow-up. LSM and SSM at baseline did not predict the patients' outcome in the TIPS cohort and in patients with conservative therapy. SSM was increased in two cases with spontaneous TIPS occlusion and declined after revision. CONCLUSION: LSM and SSM cannot be recommended for risk stratification in cirrhotic patients with refractory ascites. SSM may be useful in monitoring TIPS function during follow-up.

Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis.

OBJECTIVE: Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus. DESIGN: 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used. RESULTS: We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk. CONCLUSION: An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.

Association of fetuin B with markers of liver fibrosis in nonalcoholic fatty liver disease.

OBJECTIVE: The liver-derived plasma protein fetuin B is associated with nonalcoholic fatty liver disease (NAFLD) and impaired glucose homeostasis in mice. However, its association with non-invasive ultrasound- and magnetic resonance (MR)-based markers of liver fibrosis and steatosis, the enhanced liver fibrosis (ELF) score, liver biopsy, as well as rs738409 in PNPLA3, has not been elucidated in NAFLD, so far. DESIGN AND METHODS: The association of circulating fetuin B and transient elastography (TE), controlled attenuation parameter (CAP), 1H-MR-spectroscopy, the ELF score, liver biopsy, as well as risk alleles in rs738409 in PNPLA3, was studied in 101 NAFLD patients as compared to 15 healthy controls. RESULTS: Serum fetuin B levels did not differ between NAFLD patients and controls (p = 0.863). Fetuin B was independently and negatively associated with transient elastography liver stiffness measurement (LSM) (p = 0.002), but not with the steatosis markers CAP or 1H-MR-spectroscopy. Fetuin B serum concentrations were significantly lower in individuals with LSM > 7.0 kPa as compared to patients with LSM < 7.0 kPa (p = 0.024). Furthermore, the ELF score and histologically proven fibrosis were independent and negative predictors of circulating fetuin B. Moreover, serum fetuin B significantly depended on number of rs738409 risk alleles (p = 0.026). CONCLUSIONS: Fetuin B is independently and negatively associated with non-invasive markers of liver fibrosis and PNPLA3 status in NAFLD patients but does not show a correlation with the hepatic lipid content. Future studies need to elucidate the pathophysiological significance of fetuin B in NAFLD and its potential value as predictor for disease severity.

Correlation of cell-free DNA plasma concentration with severity of non-alcoholic fatty liver disease.

BACKGROUND: The assessment of fibrosis and inflammatory activity is essential to identify patients with non-alcoholic fatty liver disease (NAFLD) at risk for progressive disease. Serum markers and ultrasound-based methods can replace liver biopsy for fibrosis staging, whereas non-invasive characterization of inflammatory activity remains a clinical challenge. Cell-free DNA (cfDNA) is a novel non-invasive biomarker for assessing cellular inflammation and cell death, which has not been evaluated in NAFLD. METHODS: Patients and healthy controls from two previous studies were included. NAFLD disease activity and severity were non-invasively characterized by liver stiffness measurement (transient elastography, TE) including steatosis assessment with controlled attenuation parameter (CAP), single-proton magnetic resonance spectroscopy (1H-MRS) for determination of hepatic fat fraction, aminotransferases and serum ferritin. cfDNA levels (90 and 222 bp fragments) were analyzed using quantitative real-time PCR. RESULTS: Fifty-eight NAFLD patients (age 62 ± 11 years, BMI 28.2 ± 3.5 kg/m2) and 13 healthy controls (age 38 ± 12 years, BMI 22.4 ± 2.1 kg/m2) were included. 90 bp cfDNA levels were significantly higher in NAFLD patients compared to healthy controls: 3.7 (1.3-23.1) vs. 2.9 (1.4-4.1) ng/mL (p = 0.014). In the NAFLD cohort, circulating cfDNA correlated significantly with disease activity and severity, especially in patients with elevated liver stiffness (n = 13, 22%) compared to cases with TE values ≤7 kPa: cf90 bp 6.05 (2.41-23.13) vs. 3.16 (1.29-7.31) ng/mL (p < 0.001), and cf222 bp 14.41 (9.27-22.90) vs. 11.32 (6.05-18.28) ng/mL (p = 0.0041). CONCLUSIONS: Cell-free DNA plasma concentration correlates with established non-invasive markers of NAFLD activity and severity. Therefore, cfDNA should be further evaluated as biomarker for identifying patients at risk for progressive NAFLD.

An unusual hypoechoic solid mass in the pancreatic head.

Solid pancreatic lesions found on imaging procedures are suspicious for malignancy and, therefore, demand immediate diagnostic evaluation and therapy. In the case of indeterminate histology, a primary resection should be considered in order to preserve the possibility of curative surgery, although rare entities may be initially disregarded. We present here the case of a 48-year-old female patient with a hypoechoic lesion of the pancreatic head, which was clearly delineated from the surrounding pancreatic tissue. The challenging diagnosis of metastatic leiomyosarcoma could only be established by considering the long-term clinical history and former histology specimens.

Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis.

BACKGROUND & AIMS: The prevalence of fatty liver underscores the need for non-invasive characterization of steatosis, such as the ultrasound based controlled attenuation parameter (CAP). Despite good diagnostic accuracy, clinical use of CAP is limited due to uncertainty regarding optimal cut-offs and the influence of covariates. We therefore conducted an individual patient data meta-analysis. METHODS: A review of the literature identified studies containing histology verified CAP data (M probe, vibration controlled transient elastography with FibroScan®) for grading of steatosis (S0-S3). Receiver operating characteristic analysis after correcting for center effects was used as well as mixed models to test the impact of covariates on CAP. The primary outcome was establishing CAP cut-offs for distinguishing steatosis grades. RESULTS: Data from 19/21 eligible papers were provided, comprising 3830/3968 (97%) of patients. Considering data overlap and exclusion criteria, 2735 patients were included in the final analysis (37% hepatitis B, 36% hepatitis C, 20% NAFLD/NASH, 7% other). Steatosis distribution was 51%/27%/16%/6% for S0/S1/S2/S3. CAP values in dB/m (95% CI) were influenced by several covariates with an estimated shift of 10 (4.5-17) for NAFLD/NASH patients, 10 (3.5-16) for diabetics and 4.4 (3.8-5.0) per BMI unit. Areas under the curves were 0.823 (0.809-0.837) and 0.865 (0.850-0.880) respectively. Optimal cut-offs were 248 (237-261) and 268 (257-284) for those above S0 and S1 respectively. CONCLUSIONS: CAP provides a standardized non-invasive measure of hepatic steatosis. Prevalence, etiology, diabetes, and BMI deserve consideration when interpreting CAP. Longitudinal data are needed to demonstrate how CAP relates to clinical outcomes. LAY SUMMARY: There is an increase in fatty liver for patients with chronic liver disease, linked to the epidemic of the obesity. Invasive liver biopsies are considered the best means of diagnosing fatty liver. The ultrasound based controlled attenuation parameter (CAP) can be used instead, but factors such as the underlying disease, BMI and diabetes must be taken into account. Registration: Prospero CRD42015027238.

Evaluation of Transient Elastography, Acoustic Radiation Force Impulse Imaging (ARFI), and Enhanced Liver Function (ELF) Score for Detection of Fibrosis in Morbidly Obese Patients.

BACKGROUND: Liver fibrosis induced by non-alcoholic fatty liver disease causes peri-interventional complications in morbidly obese patients. We determined the performance of transient elastography (TE), acoustic radiation force impulse (ARFI) imaging, and enhanced liver fibrosis (ELF) score for fibrosis detection in bariatric patients. PATIENTS AND METHODS: 41 patients (median BMI 47 kg/m2) underwent 14-day low-energy diets to improve conditions prior to bariatric surgery (day 0). TE (M and XL probe), ARFI, and ELF score were performed on days -15 and -1 and compared with intraoperative liver biopsies (NAS staging). RESULTS: Valid TE and ARFI results at day -15 and -1 were obtained in 49%/88% and 51%/90% of cases, respectively. High skin-to-liver-capsule distances correlated with invalid TE measurements. Fibrosis of liver biopsies was staged as F1 and F3 in n = 40 and n = 1 individuals. However, variations (median/range at d-15/-1) of TE (4.6/2.6-75 and 6.7/2.9-21.3 kPa) and ARFI (2.1/0.7-3.7 and 2.0/0.7-3.8 m/s) were high and associated with overestimation of fibrosis. The ELF score correctly classified 87.5% of patients. CONCLUSION: In bariatric patients, performance of TE and ARFI was poor and did not improve after weight loss. The ELF score correctly classified the majority of cases and should be further evaluated.

Estimating steatosis and fibrosis: Comparison of acoustic structure quantification with established techniques.

AIM: To compare ultrasound-based acoustic structure quantification (ASQ) with established non-invasive techniques for grading and staging fatty liver disease. METHODS: Type 2 diabetic patients at risk of non-alcoholic fatty liver disease (n = 50) and healthy volunteers (n = 20) were evaluated using laboratory analysis and anthropometric measurements, transient elastography (TE), controlled attenuation parameter (CAP), proton magnetic resonance spectroscopy ((1)H-MRS; only available for the diabetic cohort), and ASQ. ASQ parameters mode, average and focal disturbance (FD) ratio were compared with: (1) the extent of liver fibrosis estimated from TE and non-alcoholic fatty liver disease (NAFLD) fibrosis scores; and (2) the amount of steatosis, which was classified according to CAP values. RESULTS: Forty-seven diabetic patients (age 67.0 ± 8.6 years; body mass index 29.4 ± 4.5 kg/m²) with reliable CAP measurements and all controls (age 26.5 ± 3.2 years; body mass index 22.0 ± 2.7 kg/m²) were included in the analysis. All ASQ parameters showed differences between healthy controls and diabetic patients (P < 0.001, respectively). The ASQ FD ratio (logarithmic) correlated with the CAP (r = -0.81, P < 0.001) and (1)H-MRS (r = -0.43, P = 0.004) results. The FD ratio [CAP < 250 dB/m: 107 (102-109), CAP between 250 and 300 dB/m: 106 (102-114); CAP between 300 and 350 dB/m: 105 (100-112), CAP ≥ 350 dB/m: 102 (99-108)] as well as mode and average parameters, were reduced in cases with advanced steatosis (ANOVA P < 0.05). However, none of the ASQ parameters showed a significant difference in patients with advanced fibrosis, as determined by TE and the NAFLD fibrosis score (P > 0.08, respectively). CONCLUSION: ASQ parameters correlate with steatosis, but not with fibrosis in fatty liver disease. Steatosis estimation with ASQ should be further evaluated in biopsy-controlled studies.

Noninvasive characterization of graft steatosis after liver transplantation.

OBJECTIVE: Liver graft steatosis has not been noninvasively evaluated yet. We therefore characterized liver transplant recipients by transient elastography (TE) and controlled attenuation parameter (CAP) and correlated the results with clinical and genetic risk factors. METHODS: A total of 204 patients (pretransplant disease: n = 102 nonalcoholic etiology, nonalcoholic liver cirrhosis (non-ALC); n = 102 alcoholic liver disease, ALC; 42% female; median age 57.8 years; median time since transplantation 66 months) underwent ultrasound, TE, CAP, and nonalcoholic fatty liver disease (NAFLD) fibrosis score. Recipient DNA samples were genotyped for patatin-like phospholipase domain-containing protein 3 (PNPLA3) (rs738409) and IL28B (rs8099917, rs12979860) polymorphisms. RESULTS: Increased hepatic echogenicity at ultrasound was observed in 36% of patients, CAP values >252 and >300 dB/m indicated steatosis and advanced steatosis in 44% and 24% of individuals. Advanced fibrosis (TE >7.9 kPa) was associated with increased CAP results (266 vs. 229 dB/m, p = 0.012). PNPLA3 G-allele carriers had increased CAP values (257 vs. 222 dB/m, p = 0.032), higher liver stiffness (TE 6.4 vs. 5.5 kPa, p = 0.005), and prevalence of diabetes mellitus (40% vs. 22%, p = 0.016). No such association was observed for IL28B polymorphisms. ALC compared to non-ALC patients had higher body mass index (28.1 vs. 25.5 kg/m², p < 0.001), higher prevalence of diabetes mellitus (41% vs. 25%, p = 0.017), and PNPLA3 CG + GG genotype (73% vs. 47%, p = 0.006), and had elevated TE (6.3 vs. 5.4 kPa, p = 0.022), CAP (266 vs. 221 dB/m, p = 0.001), and NAFLD fibrosis score (score -0.5 vs. -1.3, p < 0.001). CONCLUSION: Modern noninvasive liver graft assessment frequently detects hepatic steatosis, which is associated with graft fibrosis, components of the metabolic syndrome and recipient PNPLA3 rs738409 genotype, especially in ALC patients.

Non-invasive assessment of hepatic steatosis in patients with NAFLD using controlled attenuation parameter and 1H-MR spectroscopy.

INTRODUCTION: Non-invasive assessment of steatosis and fibrosis is of growing relevance in non-alcoholic fatty liver disease (NAFLD). 1H-Magnetic resonance spectroscopy (1H-MRS) and the ultrasound-based controlled attenuation parameter (CAP) correlate with biopsy proven steatosis, but have not been correlated with each other so far. We therefore performed a head-to-head comparison between both methods. METHODS: Fifty patients with biopsy-proven NAFLD and 15 healthy volunteers were evaluated with 1H-MRS and transient elastography (TE) including CAP. Steatosis was defined according to the percentage of affected hepatocytes: S1 5-33%, S2 34-66%, S3 ≥67%. RESULTS: Steatosis grade in patients with NAFLD was S1 36%, S2 40% and S3 24%. CAP and 1H-MRS significantly correlated with histopathology and showed comparable accuracy for the detection of hepatic steatosis: areas under the receiver-operating characteristics curves were 0.93 vs. 0.88 for steatosis ≥S1 and 0.94 vs. 0.88 for ≥S2, respectively. Boot-strapping analysis revealed a CAP cut-off of 300 dB/m for detection of S2-3 steatosis, while retaining the lower cut-off of 215 dB/m for the definition of healthy individuals. Direct comparison between CAP and 1H-MRS revealed only modest correlation (total cohort: r = 0.63 [0.44, 0.76]; NAFLD cases: r = 0.56 [0.32, 0.74]). For detection of F2-4 fibrosis TE had sensitivity and specificity of 100% and 98.1% at a cut-off value of 8.85 kPa. CONCLUSION: Our data suggest a comparable diagnostic value of CAP and 1H-MRS for hepatic steatosis quantification. Combined with the simultaneous TE fibrosis assessment, CAP represents an efficient method for non-invasive characterization of NAFLD. Limited correlation between CAP and 1H-MRS may be explained by different technical aspects, anthropometry, and presence of advanced liver fibrosis.

Rapid progression of a splenic aneurysm due to segmental arterial mediolysis: a rare cause of acute pancreatitis.

BACKGROUND: The etiology of acute pancreatitis can be manifold, beside the usual causes. We are reporting an unusual cause that triggered acute pancreatitis. PATIENT & RESULTS: A 50 year-old male experienced attacks of acute pancreatitis (abdominal pain and elevated amylase and lipase) during sexual arousal. Serial imaging showed a rapidly-progressing, partly-thrombosed splenic artery aneurysm, with local compression of the pancreas. After angiographic coiling, the attacks subsided. Further angiography revealed additional aneurysms consistent with segmental arterial mediolysis at other sites of the body. Molecular analysis regarding Ehlers-Danlos-syndrome and genetic factors for pancreatitis, autoantibodies and Syphilis serology was negative. CONCLUSIONS: Acute pancreatitis was triggered by a transient rise in blood pressure during sexual stimulation, which caused rapid progression of a splenic artery aneurysm as part of systemic segmental arterial mediolysis.

Heap of stones: an unusual cause for biliary colic and elevated liver function tests.

A 40-year old woman presented with symptomatic intrahepatic gallstones in one liver segment only four years after cholecystectomy for cholelithiasis. Multiple small, yellow and round calculi were completely removed from the intrahepatic bile ducts via ERCP. The young age of the patient, recurrence of gallstones after cholecystectomy and intrahepatic gallstones suggested a subtype of the low-phospholipid associated cholelithiasis syndrome, a monogenic form of cholesterol cholelithiasis due to variations of the ABCB4 gene that encodes the canalicular phospholipid transporter MDR3.