Alexander Dechêne

Non‐alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis

Non‐alcoholic fatty liver disease (NAFLD) is the most common liver disease in developed countries, and accumulating evidence suggests it as the hepatic manifestation of the metabolic syndrome (MS). Although the published prevalence of hepatocellular carcinoma (HCC) is low in NAFLD/NASH patients, most of these data have been derived from areas endemic for viral hepatitis. We recruited 162 adults with HCC between February 2007 and March 2008, investigated the underlying etiologies and determined the prevalence of the MS and related features within each group. Patients with NAFLD/NASH‐associated HCC exhibited a higher prevalence of metabolic features (Type 2 diabetes mellitus, hypertension, dyslipidemia, coronary artery disease) compared to non‐NAFLD/NASH‐HCC. Intriguingly, a significant number (41.7%; p < 0.005) of individuals with NAFLD/NASH‐HCC had no evidence of cirrhosis. Patients with alcohol‐induced liver disease also displayed many features (14/19, 73.7%) of the MS, although, in contrast to NAFLD/NASH‐HCC, alcohol‐associated HCC was highly associated with cirrhosis (95.0%; p = 0.064). NAFLD/NASH as the hepatic entity of the MS may itself pose a risk factor for HCC, even in the absence of cirrhosis. The MS may also promote development of HCC among those with alcoholic liver disease. Increased awareness of liver manifestations in the MS may instigate early interventions against developing HCC.

Acute liver failure is associated with elevated liver stiffness and hepatic stellate cell activation

Acute liver failure (ALF) is associated with massive short‐term cell death, whereas chronic liver injury is accompanied by continuous cell death. Hepatic stellate cells (HSCs) contribute to tissue repair and liver fibrosis in chronic liver injury, although their role in ALF remains unexplained. Twenty‐nine patients (median age = 43 years, 17 females and 12 males) with ALF according to the Acute Liver Failure Study Group criteria were included. Upon the diagnosis of ALF and after 7 days, we determined liver stiffness (LS) with FibroScan, standard laboratory parameters, and serum levels of matrix metalloproteinase 1 (MMP‐1), MMP‐2, MMP‐9, tissue inhibitor of metalloproteinases 1 (TIMP‐1), TIMP‐2, hyaluronic acid, and markers of overall cell death (M65) and apoptosis (M30). Stellate cell activation and progenitor response were analyzed immunohistochemically in biopsy samples of 12 patients with α‐smooth muscle actin (α‐SMA), keratin‐17, and keratin‐19 staining, respectively. Cell death markers (M30 level = 2243 ± 559.6 U/L, M65 level = 3732 ± 839.9 U/L) and fibrosis markers (TIMP‐1 level = 629.9 ± 69.4 U/mL, MMP‐2 level = 264 ± 32.5 U/mL, hyaluronic acid level = 438.5 ± 69.3 μg/mL) were significantly increased in patients versus healthy controls. This was paralleled by collagen deposition, elevated α‐SMA expression, and higher LS (25.6 ± 3.0 kPa). ALF was associated with ductular progenitor proliferation. Conclusion: Our results demonstrate HSC activation and a progenitor response in ALF. Positive correlations between LS, the degree of liver cell damage, and the intensity of HSC activation suggest that fibrosis is a response to ALF in an attempt to repair damaged tissue. (Hepatology 2010)

Aortoesophageal fistula after thoracic aortic stent-graft placement: a rare but catastrophic complication of a novel emerging technique.

OBJECTIVES Our goal was to report characteristics and outcomes of 6 patients with aortoesophageal fistula (AEF) after thoracic endovascular aortic repair (TEVAR). BACKGROUND Neurologic events are severe complications of TEVAR. With growing experience of TEVAR, other yet unexpected devastating complications have emerged. METHODS Between July 1999 and August 2008, 268 patients underwent TEVAR for various thoracic aortic diseases at our institution. RESULTS Six of 268 patients (age 49 to 77 years, 50% female patients) developed AEF (incidence 1.9%) within 1 to 16 months after the procedure. Indications for TEVAR were acute aortic dissection (n = 3), chronic aortic dissection (n = 1), and thoracic aortic aneurysm (n = 2). Four patients presented with sudden massive hematemesis whereas 2 patients were readmitted for new-onset fever and elevated markers of inflammation that preceded hematemesis. Esophago-gastro-duodenoscopy identified deep esophageal ulcerations at the level of the implanted aortic stent-graft in 4 patients, but only mild erosive lesions within the proximal esophagus without signs of active bleeding in the remaining 2 patients. Surgical repair was performed in only 1 patient and declined in the remaining because of comorbidities and multiorgan system failure. Despite this, all patients died due to fatal rebleeding (n = 4) or mediastinitis (n = 2). CONCLUSIONS AEF is a rare and unusual complication of TEVAR that occurs relatively early after the procedure and is almost invariably fatal. New-onset fever with elevated inflammatory markers or hematemesis should heighten clinical suspicion of AEF in TEVAR patients and prompt computed tomography or esophago-gastro-duodenoscopy in the hope of detecting, triaging, and treating this early to improve the otherwise dismal outcomes of these patients.

Assessment of allograft fibrosis by transient elastography and noninvasive biomarker scoring systems in liver transplant patients.

Background. This prospective, monocentric study was designed to assess the efficacy of transient elastography (TE), biochemical tests, and more complex scores in determining fibrosis stage in 157 patients transplanted for hepatitis C virus (HCV) infection or non–HCV-related liver diseases. Methods and Results. The optimal TE cutoff values for HCV patients and non-HCV patients were 4.7 and 5.0 kPa for F≥1, 7.1 and 7.3 kPa for F≥2, 10.9 kPa and 9.9 kPa for F≥3, and 17.3 and 12.6 kPa for F=4, respectively. The corresponding area under the receiver operating characteristic (AUROC) curves for F≥1, F≥2, F≥3, and F=4 were 0.95 and 0.86, 0.89 and 0.85, 0.97 and 0.88, and 0.99 and 0.97 for HCV and non-HCV patients, respectively. On the basis of the logistic regression equation, we created a model (FibroTransplant score) to identify advanced fibrosis (F≥3). The accuracy of this model was tested in a validation group (n=74). AUROCs for diagnosis of F≥3 in HCV patients and non-HCV patients of the training group were 0.89 and 0.83 (FibroTransplant score), 0.86 and 0.66 (Benlloch score), 0.81 and 0.71 (aspartate aminotransferase-to-platelet ratio index), 0.80 and 0.77 (Hepascore), 0.79 and 0.70 (FibroTest), 0.78 and 0.71 (FIB-4), 0.75 and 0.60 (Forns index), 0.73 and 0.69 (FibroIndex), and 0.70 and 0.59 (Lok score). Among the validation group, AUROCs of the FibroTransplant score for F≥3 were 0.90 and 0.91, respectively. Conclusions. TE and the FibroTransplant score can be reliably used for diagnosing advanced fibrosis in transplanted patients.

Acute Management of Refractory Variceal Bleeding in Liver Cirrhosis by Self-Expanding Metal Stents

Background and Aims: Current treatment strategies of variceal bleeding (VB) include banding and sclerotherapy. However, up to 10% of bleeding events remain refractory to standard therapy with high mortality. With this study, we aimed to evaluate the implantation of self-expanding metal stents (SEMS) for the management of therapy-refractory variceal bleeding. Patients and Methods: Eight cirrhotic patients who presented to our unit with a total of 9 refractory bleeding events were treated by SEMS placement. Results: Stenting resulted in immediate hemostasis in all cases without recurrent bleeding with SEMS in situ. After stabilization, 1 patient was treated by transjugular intrahepatic portosystemic shunt (TIPS) and after the second bleeding episode by TIPS dilation. One patient underwent orthotopic liver transplantation (OLT). The remaining patients were treated with standard drug regimens to reduce portal pressure. The SEMS were removed after a median of 11 days. No acute hemorrhage was noted on stent retrieval. While no early rebleeding occurred in the patients after TIPS implant, TIPS dilation or OLT, 3 out of 5 patients on conservative treatment experienced recurrence of VB within 9 days after SEMS removal. Conclusions: SEMS placement sufficiently stops hemorrhage in refractory VB. Due to the high rebleeding rate after conservative treatment alone following SEMS removal, this procedure may be utilized as a mere bridging method. Additional interventional and/or surgical methods to effectively reduce portal pressure (i.e. TIPS, OLT) should be considered. Further studies to evaluate the optimum treatment algorithm of refractory esophageal VB are warranted.

In intermediate stage hepatocellular carcinoma: radioembolization with yttrium 90 or chemoembolization?

Transarterial chemoembolization (TACE) is one of the standard treatments recommended for intermediate stage hepatocellular carcinoma (HCC). At the same time, only little is known about the use of radioembolization with Yttrium‐90 microspheres (TARE Y‐90) for this subset of patients. To perform comparative analysis between both locoregional therapies in intermediate HCCs. Primary endpoint was overall survival (OS), while safety, response rate and time‐to‐progression (TTP) were considered as secondary endpoints.

Biliary Strictures and Recurrence After Liver Transplantation for Primary Sclerosing Cholangitis: A Retrospective Multicenter Analysis

Liver transplantation (LT) is the only definitive treatment for patients with end‐stage liver disease due to primary sclerosing cholangitis (PSC), but a high rate of biliary strictures (BSs) and of recurrent primary sclerosing cholangitis (recPSC) has been reported. In this multicenter study, we analyzed a large patient cohort with a long follow‐up in order to evaluate the incidence of BS and recPSC, to assess the impact on survival after LT, and to identify risk factors. We collected clinical, surgical, and laboratory data and records on inflammatory bowel disease (IBD), immunosuppression, recipient and graft outcome, and biliary complications (based on cholangiography and histology) of all patients who underwent LT for PSC in 10 German transplant centers between January 1990 and December 2006; 335 patients (68.4% men; mean age, 38.9 years; 73.5% with IBD) underwent transplantation 8.8 years after PSC diagnosis with follow‐up for 98.8 months. The 1‐, 5‐, and 10‐year recipient and graft survival was 90.7%, 84.8%, 79.4% and 79.1%, 69.0%, 62.4%, respectively. BS was diagnosed in 36.1% after a mean time of 3.9 years, and recPSC was diagnosed in 20.3% after 4.6 years. Both entities had a significant impact on longterm graft and recipient survival. Independent risk factors for BS were donor age, ulcerative colitis, chronic ductopenic rejection, bilirubin, and international normalized ratio (INR) at LT. Independent risk factors for recPSC were donor age, IBD, and INR at LT. These variables were able to categorize patients into risk groups for BS and recPSC. In conclusion, BS and recPSC affect longterm graft and patient survival after LT for PSC. Donor age, IBD, and INR at LT are independent risk factors for BS and recPSC and allow for risk estimation depending on the recipient‐donor constellation. Liver Transpl 22:42‐52, 2016.

Steroid and Ursodesoxycholic Acid Combination Therapy in Severe Drug-Induced Liver Injury

Background: Drug-induced liver injury (DILI) is the leading cause of acute severe liver disease in Western countries. Treatment strategies for DILI are still not well defined. Aim: We studied the safety and outcomes of steroid/ursodesoxycholic acid (UDCA) combination therapy in DILI patients. Patients, Materials and Methods: 15 consecutive patients with severe DILI were analyzed for clinical, biochemical and histological data. Nine patients were treated with a steroid step-down therapy with reduction of the daily dose over several weeks; 6 patients received a steroid pulse therapy for 3 days. UDCA was administered for several weeks in both groups. Results: Patients without histological signs of preexistent liver damage (n = 10) showed the most favorable clinical course. Bilirubin and serum transaminases dropped to <50% of peak values within 2 weeks, and normalized within 4–8 weeks. In contrast, patients with positive autoimmune antibodies (anti-nuclear antibodies and/or soluble liver antigen) and/or histological features of chronic hepatitis (n = 3) exhibited a slower reduction in bilirubin and serum transaminase levels. These patients were given immunosuppressants (steroids, azathioprine) for a further 6 months. Conclusion: Treatment of severe DILI with corticosteroids (both pulse and step-down therapy) and UDCA appears to be safe, and leads to a more rapid reduction in bilirubin and transaminases after DILI.

Genetic, immunological and clinical risk factors for biliary strictures following liver transplantation

Biliary strictures after liver transplantation (LT) are a major cause of morbidity and reduced graft survival.

Comparison of different MRCP techniques for the depiction of biliary complications after liver transplantation

ObjectiveBiliary strictures after liver transplantation are common. We aimed to compare different magnetic resonance cholangiopancreatography (MRCP) sequences with regard to their diagnostic accuracy in depicting anastomotic stenoses (AST), ischaemic-type biliary lesions (ITBL) and cholelithiasis.MethodsIn patients with clinically suspected biliary obstruction after liver transplantation, MRCP was performed at 1.5 T using two-dimensional (2D) single-shot RARE, 2D T2-weighted (T2w) HASTE, 2D TrueFISP and 3D T2w TSE RESTORE sequences. The presence and localisation of lesions were assessed for each sequence independently and all sequences together. Endoscopic retrograde cholangiopancreatography (ERCP) served as the “gold standard”.ResultsBiliary strictures were detected with a sensitivity of 96% by MRCP and most accurately depicted when all sequences were analysed together. AST was visualised with highest sensitivity on TrueFISP and 3D T2w TSE sequences (79%). For ITBL highest sensitivity was found with the HASTE sequence (81%). Highest sensitivity for filling defects was revealed by the 3D T2w TSE sequence (54%). Receiver operating characteristic (ROC) curve/area under the curve (AUC) analysis revealed the best results for the 3D T2w TSE sequence.ConclusionOur results underline the value of different MRCP sequence types for the depiction of biliary lesions. A clinical protocol consisting of different sequences may be helpful depending on the clinical question and the likely underlying abnormality.