Publications by authors named "Carolin Lackner"

83 Publications

Senescence markers in focal nodular hyperplasia of the liver: pathogenic considerations on the basis of immunohistochemical results.

Mod Pathol 2021 Oct 13. Epub 2021 Oct 13.

Diagnostic & Research Centre of Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria.

Focal nodular hyperplasia (FNH) is a polyclonal tumour-like hepatic lesion characterised by parenchymal nodules, connective tissue septa without interlobular bile ducts, pronounced ductular reaction and inflammation. It may represent a response to local arterial hyperperfusion and hyperoxygenation resulting in oxidative stress. We aimed at obtaining closer insight into the pathogenesis of FNH with its characteristic morphologic features. Immunohistochemistry and immunofluorescence microscopy was performed on FNH specimens using antibodies against keratins (K) 7 and 19, neural cell adhesion molecule (NCAM), lamin B1, senescence markers (CDK inhibitor 1/p21, CDK inhibitor /p16, senescence-associated (SA) β- galactosidase activity), proliferation markers (Ki-67, proliferating-cell nuclear antigen (PCNA)), and the abnormally phosphorylated histone γ-H2AX, indicating DNA double strand breaks; moreover SA β- galactosidase activity was determined histochemically. Ductular metaplasia of hepatocytes indicated by K7 expression in the absence of K19 plays a major role in the development of ductular reaction in FNH. Moreover, the expression of senescence markers (p21, p16, γ-H2AX, SA β-galactosidase activity) in hepatocytes and cholangiocytes suggests that stress-induced cellular senescence contributes to fibrosis and inflammation via production of components of the senescence-associated secretory phenotype. Expression of proliferation markers (Ki-67, PCNA) was not enhanced in hepatocytes and biliary cells. Senescence and ductular metaplasia of hepatocytes may thus be involved in inflammation, fibrosis and apoptosis resistance. Hence, fibrosis, inflammation and reduced apoptotic cell death, rather than proliferation (hyperplasia) may be responsible for increased tissue mass and tumour-like appearance of FNH.
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http://dx.doi.org/10.1038/s41379-021-00940-5DOI Listing
October 2021

Reply to: "Prognostic value of histologic parameters in alcoholic hepatitis: A word of caution".

J Hepatol 2021 Sep 16. Epub 2021 Sep 16.

Transitional and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Department of Pathology, Aretaieio Hospital, Medical School, National & Kapodistrian University of Athens, Athens 11528, Greece.

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http://dx.doi.org/10.1016/j.jhep.2021.09.005DOI Listing
September 2021

Development and prognostic relevance of a histologic grading and staging system for alcohol-related liver disease.

J Hepatol 2021 Oct 11;75(4):810-819. Epub 2021 Jun 11.

Transitional and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Department of Pathology, Aretaieio Hospital, Medical School, National & Kapodistrian University of Athens, Athens 11528, Greece.

Background & Aims: The SALVE Histopathology Group (SHG) developed and validated a grading and staging system for the clinical and full histological spectrum of alcohol-related liver disease (ALD) and evaluated its prognostic utility in a multinational cohort of 445 patients.

Methods: SALVE grade was described by semiquantitative scores for steatosis, activity (hepatocellular injury and lobular neutrophils) and cholestasis. The histological diagnosis of steatohepatitis due to ALD (histological ASH, hASH) was based on the presence of hepatocellular ballooning and lobular neutrophils. Fibrosis staging was adapted from the Clinical Research Network staging system for non-alcoholic fatty liver disease and the Laennec staging system and reflects the pattern and extent of ALD fibrosis. There are 7 SALVE fibrosis stages (SFS) ranging from no fibrosis to severe cirrhosis.

Results: Interobserver κ-value for each grading and staging parameter was >0.6. In the whole study cohort, long-term outcome was associated with activity grade and cholestasis, as well as cirrhosis with very broad septa (severe cirrhosis) (p <0.001 for all parameters). In decompensated ALD, adverse short-term outcome was associated with activity grade, hASH and cholestasis (p = 0.038, 0.012 and 0.001, respectively), whereas in compensated ALD, hASH and severe fibrosis/cirrhosis were associated with decompensation-free survival (p = 0.011 and 0.001, respectively). On multivariable analysis, severe cirrhosis emerged as an independent histological predictor of long-term survival in the whole study cohort. Severe cirrhosis and hASH were identified as independent predictors of short-term survival in decompensated ALD, and also as independent predictors of decompensation-free survival in compensated ALD.

Conclusion: The SALVE grading and staging system is a reproducible and prognostically relevant method for the histological assessment of disease activity and fibrosis in ALD.

Lay Summary: Patients with alcohol-related liver disease (ALD) may undergo liver biopsy to assess disease severity. We developed a system to classify ALD under the microscope by grading ALD activity and staging the extent of liver scarring. We validated the prognostic performance of this system in 445 patients from 4 European centers.
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http://dx.doi.org/10.1016/j.jhep.2021.05.029DOI Listing
October 2021

"Dual aetiology fatty liver disease": A recently proposed term associated with potential pitfalls.

J Hepatol 2021 04 16;74(4):979-982. Epub 2020 Dec 16.

CHRU de Lille, Service des maladies de l'appareil digestif, Université Lille 2 and Inserm U995, France.

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http://dx.doi.org/10.1016/j.jhep.2020.11.004DOI Listing
April 2021

Histological demonstration of BSEP/ABCB11 inhibition in transient neonatal cholestasis: a case report.

BMC Pediatr 2020 07 9;20(1):340. Epub 2020 Jul 9.

Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Auenbruggerplatz 34/2, 8036, Graz, Austria.

Background: Idiopathic or transient neonatal cholestasis (TNC) represents a group of cholestatic disorders with unidentified origin and remains a diagnosis of exclusion. Dysfunction of hepatobiliary transporters mediating excretion of biliary constituents from hepatocytes may play a central role in the pathogenesis of cholestasis. Despite variants of bile salt (BS) export pump (BSEP/ABCB11) have already been described in TNC, the pathogenic role of BSEP dysfunction in TNC remained so far elusive.

Case Presentation: We report on a newly-identified heterozygous ABCB11 missense variant (c.1345G > A, p.Glu449Lys) which was associated with prolonged cholestasis in a term infant after a complicated neonatal period. Moreover, we show for the first time almost completely abolished BSEP expression on the hepatocellular membrane in TNC.

Conclusion: This report demonstrates for the first time a close association between the prolonged cholestasis in infancy and impaired BSEP expression on the hepatocyte canalicular membrane in a heterozygous carrier of newly-identified ABCB11 variant.
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http://dx.doi.org/10.1186/s12887-020-02201-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346433PMC
July 2020

Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice.

Nat Commun 2020 05 14;11(1):2397. Epub 2020 May 14.

School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.

Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.
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http://dx.doi.org/10.1038/s41467-020-16298-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224297PMC
May 2020

Reply to: "Alcohol-related liver disease results in significant long-term mortality irrespective of the presence of steatohepatitis".

J Hepatol 2020 08 20;73(2):460. Epub 2020 Apr 20.

Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; EASL Consortium for the Study of alcohol-related liver disease (SALVE). Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.03.037DOI Listing
August 2020

Long-term outcomes in patients with decompensated alcohol-related liver disease, steatohepatitis and Maddrey's discriminant function <32.

J Hepatol 2020 04 15;72(4):636-642. Epub 2020 Jan 15.

Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; EASL Consortium for the Study of alcohol-related liver disease (SALVE). Electronic address:

Background & Aims: Patients with alcoholic hepatitis and a modified Maddrey's discriminant function (mDF) <32 have a low risk of short-term mortality. However, few data exist concerning long-term outcomes. The aims of this study were to evaluate 5-year survival rates and to identify predictive factors for long-term prognosis in this patient population.

Methods: We studied patients from 2 centers who were admitted for hepatic decompensation (ascites, hepatic encephalopathy, or jaundice) and who had histological findings of steatohepatitis and an mDF <32. Clinical and biological parameters were recorded at the time of liver biopsy and alcohol consumption was recorded during follow-up. We performed Cox proportional hazard survival analysis to identify factors associated with 5-year survival.

Results: One hundred and twenty-one patients were included (male: 64%, mean age: 51.5 ± 10.3 years, presence of cirrhosis: 84%). The median model for end-stage liver disease and mDF scores were 14 (IQR 11.7-16.1) and 19 (IQR 11.1-24), respectively. During follow-up, 30% of the patients remained abstinent. Survival rates at 1, 6, 12, 24, and 60 months were 96.7 ± 1.6%, 90.1 ± 2.7%, 80.8 ± 3.6%, 69.9 ± 4.3%, and 50.7 ± 4.9%, respectively. The majority of deaths (80%) were liver related. In multivariable analysis, encephalopathy at baseline and alcohol abstinence were predictive of 5-year survival. The 5-year survival rates of patients without and with encephalopathy at baseline were 60.5 ± 5.8% and 29.7 ± 8.0%, respectively, and the 5-year survival rates of abstinent and non-abstinent patients were 74.0 ± 8.0% and 40.9 ± 5.8%, respectively.

Conclusions: The mortality rate of patients with alcoholic hepatitis and an mDF <32 is around 50% at 5 years. Hepatic encephalopathy at baseline and lack of alcohol abstinence impair long-term prognosis. New treatment strategies, including measures to ensure abstinence, are required.

Lay Summary: Patients with alcoholic hepatitis that is of intermediate severity have a low risk of short-term mortality but not much is known regarding long-term outcomes for these patients. This study clearly indicates that patients with intermediate disease characteristics have poor long-term outcomes. The presence of hepatic encephalopathy at the time of diagnosis and the absence of alcohol abstinence during follow-up are factors that predict poor long-term mortality.
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http://dx.doi.org/10.1016/j.jhep.2019.12.023DOI Listing
April 2020

Evaluation and comparison of six noninvasive tests for prediction of significant or advanced fibrosis in nonalcoholic fatty liver disease.

United European Gastroenterol J 2019 10 12;7(8):1113-1123. Epub 2019 Jul 12.

Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Background: In nonalcoholic fatty liver disease (NAFLD), advanced fibrosis has been identified as an important prognostic factor with increased liver-related mortality and treatment need. Due to the high prevalence of NAFLD, noninvasive risk stratification is needed to select patients for liver biopsy and treatment.

Objective: To compare the diagnostic accuracy of several widely available noninvasive tests for assessment of fibrosis among patients with NAFLD with or without nonalcoholic steatohepatitis (NASH).

Methods: We enrolled consecutive patients with NAFLD admitted to two Austrian referral centers who underwent liver biopsy. Liver stiffness measurement (LSM) was obtained by vibration-controlled transient elastography (VCTE, FibroScan) and blood samples were collected for determination of enhanced liver fibrosis (ELF) test, FibroMeter, FibroMeter, NAFLD fibrosis score (NFS), and fibrosis-4 index (FIB-4).

Results: Our study cohort contained 186 patients with histologically confirmed NAFLD. On liver histology, NASH was present in 92 patients (50%), significant fibrosis (F ≥ 2) in 71 patients (38%), advanced fibrosis (F ≥ 3) in 49 patients (26%), and F ≥ 3 plus NASH in 35 patients (19%). For diagnosis of F ≥ 2, F ≥ 3, and F ≥ 3 plus NASH, respectively, receiver operating characteristic (ROC) analysis revealed superior diagnostic accuracy of ELF score (area under ROC curve (AUROC) 0.85, 0.90, 0.90), FibroMeter (AUROC 0.86, 0.88, 0.89), FibroMeter (AUROC 0.84, 0.88, 0.88), and LSM per protocol (AUROC 0.87, 0.95, 0.91) versus FIB-4 (AUROC 0.80, 0.82, 0.81) or NFS (AUROC 0.78, 0.80, 0.79).

Conclusion: Proprietary fibrosis panels and VCTE show superior diagnostic accuracy for noninvasive diagnosis of fibrosis stage in NAFLD as compared to FIB-4 and NFS.
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http://dx.doi.org/10.1177/2050640619865133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794685PMC
October 2019

Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers.

Hepatology 2020 07 20;72(1):88-102. Epub 2020 May 20.

Departments of Gastroenterology and Hepatology, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland.

Background And Aims: Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC.

Approach And Results: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 × 10 ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 × 10 ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 × 10 ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 × 10 ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (OR , 0.75; 95% CI, 0.64-0.87; P = 1.72 × 10 ).

Conclusions: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.
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http://dx.doi.org/10.1002/hep.30996DOI Listing
July 2020

Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis.

Nat Commun 2019 07 16;10(1):3126. Epub 2019 Jul 16.

UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, WC1E 6BT, UK.

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH.
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http://dx.doi.org/10.1038/s41467-019-11004-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635373PMC
July 2019

Diethylnitrosamine (DENA) recapitulates formation of hepatic angiosarcoma in pigs.

PLoS One 2019 16;14(5):e0214756. Epub 2019 May 16.

Diagnostic & Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz, Graz, Austria.

Background & Aim: Primary hepatic angiosarcoma is a rare tumor with poor prognosis. The aim of this study was to generate a new angiosarcoma model to improve research on hepatic angiosarcoma.

Methods: Pigs sus scrofa were treated with different regimens of diethylnitrosamine (DENA). Tissues were analyzed by histology and immunohistochemistry. Serum parameters were determined. Angiosarcoma tissue was investigated for chromosomal aberrations by aCGH analysis.

Results: Animals of almost all different treatment regimens developed a multitude of variable liver lesions. Different tumor types such as granulation tissue type, cellular-like, hyalinization necrosis-like, angiosarcoma-like, dysplastic nodule-like, hepatocellular-like, glandular structure-like, and leiomyoma-like lesions were observed. Weekly treatment with 15 mg/kg for up to 52 weeks or a single shot of 200 mg/kg DENA led to the development of hepatic angiosarcomas. aCGH analysis of angiosarcoma tissue revealed increased alterations in tumors compared to non-tumorous tissue. Most of the chromosomal alterations were found on chromosomes 6, 7, 12, and 14.

Conclusion: In this preliminary study treatment of sus scrofa with weekly injections of 15 mg/kg DENA results in a new model for primary hepatic angiosarcoma. This model may help to shed light on the pathomechanisms of primary hepatic angiosarcoma and might therefore open new treatment options.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214756PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522042PMC
January 2020

Convergent Evolution of Copy Number Alterations in Multi-Centric Hepatocellular Carcinoma.

Sci Rep 2019 03 14;9(1):4611. Epub 2019 Mar 14.

Institute of Pathology, University Hospital Basel and University of Basel, Schoenbeinstrasse 40, 4056, Basel, Switzerland.

In the recent years, new molecular methods have been proposed to discriminate multicentric hepatocellular carcinomas (HCC) from intrahepatic metastases. Some of these methods utilize sequencing data to assess similarities between cancer genomes, whilst other achieved the same results with transcriptome and methylome data. Here, we attempt to classify two HCC patients with multi-centric disease using the recall-rates of somatic mutations but find that difficult because their tumors share some chromosome-scale copy-number alterations (CNAs) but little-to-no single-nucleotide variants. To resolve the apparent conundrum, we apply a phasing strategy to test if those shared CNAs are identical by descent. Our findings suggest that the conflicting alterations occur on different homologous chromosomes, which argues for multi-centric origin of respective HCCs.
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http://dx.doi.org/10.1038/s41598-019-40843-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418287PMC
March 2019

Fibrosis and alcohol-related liver disease.

J Hepatol 2019 02;70(2):294-304

Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; Dept of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Vas. Sofias Avenue 76, Athens 11528, Greece.

Histological fibrosis stage is one of the most important prognostic factors in compensated and decompensated alcohol-related liver disease (ALD). Morphological assessment of fibrosis is useful for patient stratification, enabling individualised management, and for evaluation of treatment effects in clinical studies. In contrast to most chronic liver diseases where fibrosis is portal-based, fatty liver disease (FLD) of alcoholic or non-alcoholic aetiology (NAFLD) is associated with a centrilobular pattern of injury which leads to perivenular fibrosis and/or pericellular fibrosis. Progression of FLD drives expansive pericellular fibrosis, linking vascular structures and paving the way for the development of cirrhosis. At the cirrhotic stage, ongoing tissue damage leads to increasing fibrosis severity due to parenchymal loss and proliferation of fibrous scars. Histologic fibrosis staging systems have been devised, based on topography and the extent of fibrosis, for most chronic liver diseases. The utility of histological staging is reflected in different risks associated with individual fibrosis stages which cannot be reliably distinguished by non-invasive fibrosis assessment. In contrast to NAFLD, ALD-specific staging systems that enable the standardised prognostication required for clinical management and trials are lacking. Although morphological similarities between NAFLD and ALD exist, differences in clinical and histological features may substantially limit the utility of established NAFLD-specific staging systems for prognostication in ALD. This review summarises morphological features of fibrosis in ALD and compares them to other chronic liver diseases, particularly NAFLD. ALD-related fibrosis is examined in the context of pathogenetic mechanisms of fibrosis progression, regression and clinical settings that need to be considered in future prognostically relevant ALD staging approaches.
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http://dx.doi.org/10.1016/j.jhep.2018.12.003DOI Listing
February 2019

Pseudoachalasia as First Manifestation of a Malignancy.

Dig Dis 2019 2;37(5):347-354. Epub 2019 Jan 2.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria,

Pseudoachalasia is a condition in which symptoms, radiologic, endoscopic, and manometric findings mimick idiopathic achalasia. About 4% of patients with a typical constellation for idiopathic achalasia will turn out to have pseudoachalasia, posing a major diagnostic challenge. A large spectrum of underlying causes of pseudoachalasia has been described. However, in about 70% of affected patients, this condition is caused by a malignancy (mostly adenocarcinoma of the esophagogastric junction or cardia). We describe a 16-year-old high school student referred for management of achalasia who turned out to have pseudoachalasia due to adenocarcinoma of the cardia. He was cured with preoperative chemotherapy followed by radical surgery. Therapy of pseudoachalasia secondary to neoplasia is directed against the tumor or may be palliative to keep the lumen open. Other causes of pseudoachalasia include esophageal motility disturbances as a paraneoplastic phenomenon (e.g., with small cell lung cancer), post fundoplication or post bariatric surgery, in association with a thoracic aortic aneurysm, or with sarcoidosis or amyloidosis. Therapy is directed accordingly to eliminate or correct the underlying cause.
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http://dx.doi.org/10.1159/000495758DOI Listing
July 2019

Lean Patients with Non-Alcoholic Fatty Liver Disease Have a Severe Histological Phenotype Similar to Obese Patients.

J Clin Med 2018 Dec 17;7(12). Epub 2018 Dec 17.

First Department of Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.

A small proportion of lean patients develop non-alcoholic fatty liver disease (NAFLD). We aimed to report the histological picture of lean NAFLD in comparison to overweight and obese NAFLD patients. Biopsy and clinical data from 466 patients diagnosed with NAFLD were stratified to groups according to body mass index (BMI): lean (BMI ≤ 25.0 kg/m², confirmed to be appropriate = 74), overweight (BMI > 25.0 ≤ 30.0 kg/m², = 242) and obese (BMI > 30.0 kg/m², = 150). Lean NAFLD patients had a higher rate of lobular inflammation compared to overweight patients (12/74; 16.2% vs. 19/242; 7.9%; = 0.011) but were similar to obese patients (25/150; 16.7%). Ballooning was observed in fewer overweight patients (38/242; 15.7%) compared to lean (19/74; 25.7%; = 0.014) and obese patients (38/150; 25.3%; = 0.006). Overweight patients had a lower rate of portal and periportal fibrosis (32/242; 13.2%) than lean (19/74; 25.7%; = 0.019) and obese patients (37/150; 24.7%; = 0.016). The rate of cirrhosis was higher in lean patients (6/74; 8.1%) compared to overweight (4/242; 1.7%; = 0.010) and obese patients (3/150; 2.0% = 0.027). In total, 60/466; 12.9% patients were diagnosed with non-alcoholic steatohepatitis (NASH). The rate of NASH was higher in lean (14/74; 18.9% = 0.01) and obese (26/150; 17.3%; = 0.007) compared to overweight patients (20/242; 8.3%)). Among lean patients, fasting glucose, INR and use of thyroid hormone replacement therapy were independent predictors of NASH in a multivariate model. Lean NAFLD patients were characterized by a severe histological picture similar to obese patients but are more progressed compared to overweight patients. Fasting glucose, international normalized ratio (INR) and the use of thyroid hormone replacement may serve as indicators for NASH in lean patients.
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http://dx.doi.org/10.3390/jcm7120562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306845PMC
December 2018

Publisher Correction: Alcoholic liver disease.

Nat Rev Dis Primers 2018 08 28;4(1):18. Epub 2018 Aug 28.

University of Southern California Keck School of Medicine and Greater Los Angeles VA Healthcare System, Los Angeles, CA, USA.

The originally published article contained an error in figure 8 part a, in which cut off values for F3 fibrosis, cirrhosis, and screening for oesophageal varices and HCC were incorrectly presented as <8 kPa, <12.5 kPa and <20 kPa, respectively. These cut off values have been corrected in the HTML and PDF versions of the manuscript to >8 kPa for F3 fibrosis, >12.5 kPa for cirrhosis and >20 kPa for screening for oesophageal varices and HCC.
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http://dx.doi.org/10.1038/s41572-018-0021-8DOI Listing
August 2018

Alcoholic liver disease.

Nat Rev Dis Primers 2018 08 16;4(1):16. Epub 2018 Aug 16.

University of Southern California Keck School of Medicine and Greater Los Angeles VA Healthcare System, Los Angeles, CA, USA.

Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease worldwide. ALD can progress from alcoholic fatty liver (AFL) to alcoholic steatohepatitis (ASH), which is characterized by hepatic inflammation. Chronic ASH can eventually lead to fibrosis and cirrhosis and in some cases hepatocellular cancer (HCC). In addition, severe ASH (with or without cirrhosis) can lead to alcoholic hepatitis, which is an acute clinical presentation of ALD that is associated with liver failure and high mortality. Most individuals consuming >40 g of alcohol per day develop AFL; however, only a subset of individuals will develop more advanced disease. Genetic, epigenetic and non-genetic factors might explain the considerable interindividual variation in ALD phenotype. The pathogenesis of ALD includes hepatic steatosis, oxidative stress, acetaldehyde-mediated toxicity and cytokine and chemokine-induced inflammation. Diagnosis of ALD involves assessing patients for alcohol use disorder and signs of advanced liver disease. The degree of AFL and liver fibrosis can be determined by ultrasonography, transient elastography, MRI, measurement of serum biomarkers and liver biopsy histology. Alcohol abstinence achieved by psychosomatic intervention is the best treatment for all stages of ALD. In the case of advanced disease such as cirrhosis or HCC, liver transplantation may be required. Thus, new therapies are urgently needed.
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http://dx.doi.org/10.1038/s41572-018-0014-7DOI Listing
August 2018

Lysyl oxidase-like protein 2 (LOXL2) modulates barrier function in cholangiocytes in cholestasis.

J Hepatol 2018 08 28;69(2):368-377. Epub 2018 Apr 28.

Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria; Department of Internal Medicine, Medical University of Graz, Austria. Electronic address:

Background & Aims: The lysyl oxidase-like protein 2 (LOXL2) promotes stabilization of the extracellular matrix, chemotaxis, cell growth and cell mobility. We aimed to (i) identify stimuli of LOXL2 in cholangiopathies, (ii) characterize the effects of LOXL2 on biliary epithelial cells' (BECs) barrier function, (iii) compare LOXL2 expression in primary sclerosing cholangitis (PSC), primary biliary cholangitis, and disease controls, and (iv) to determine LOXL2 expression and its cellular sources in four mouse models of cholangiopathies.

Methods: Cultured murine BECs were challenged with well-known triggers of cellular senescence, hypoxia, phospholipid-deficient Abcb4 mouse bile and chenodeoxycholic acid and investigated for LOXL2, SNAIL1 and E-cadherin expression and transepithelial electrical resistance with and without LOX-inhibition. In vivo, LOXL2 expression was studied in PSC livers, and controls and mouse models. We compared LOXL2 serum levels in patients with PSC, secondary SC, primary biliary cholangitis, and controls.

Results: Cellular senescence, hypoxia, Abcb4 bile and chenodeoxycholic acid induced LOXL2 and SNAIL1 expression, repressed E-cadherin expression, and significantly reduced transepithelial electrical resistance in BECs. Notably, all of the pathological changes could be recovered via pharmacological LOX-inhibition. Mouse models showed induced LOXL2 expression in the portal region and in association with ductular reaction. LOXL2 serum levels were significantly elevated in patients with cholangiopathies. In PSC, LOXL2 expression was located to characteristic periductal onion skin-type fibrosis, ductular reaction, Kupffer cells, and fibrotic septa. Importantly, in PSC, LOXL2 overexpression was paralleled by E-cadherin loss in BECs from medium-sized bile ducts.

Conclusions: Reactive BECs produce LOXL2, resulting in increased tight junction permeability, which can be ameliorated by pharmacological LOX-inhibition in vitro. Reactive BECs, portal myofibroblasts, and Kupffer cells are the main sources of LOXL2 in cholangiopathies.

Lay Summary: In this study, we investigate the role of lysyl oxidase-like protein 2 (LOXL2), an enzyme pivotal in the development of organ fibrosis, in the pathogenesis of cholangiopathies (diseases of bile ducts), such as primary sclerosing cholangitis. We found LOXL2 to be expressed in association with bile duct epithelial injury and uncovered mechanisms for its upregulation and the subsequent effects in vitro and in vivo. Our findings support testing of anti-LOXL2 treatment strategies for patients with primary sclerosing cholangitis.
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http://dx.doi.org/10.1016/j.jhep.2018.04.009DOI Listing
August 2018

Fibrolamellar carcinoma in the Carney complex: PRKAR1A loss instead of the classic DNAJB1-PRKACA fusion.

Hepatology 2018 10 11;68(4):1441-1447. Epub 2018 May 11.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Fibrolamellar carcinomas are characterized by activation of protein kinase A, a kinase composed of catalytic and regulatory subunits. PRKACA encodes a catalytic subunit of protein kinase A, and almost all fibrolamellar carcinomas have a heterozygous 400-kb deletion that leads to the fusion of DNAJB1 and PRKACA. The resulting DNAJB1-PRKACA fusion transcript is believed to activate protein kinase A by dysregulation of the catalytic portion of the protein. In contrast, PRKAR1A encodes one of the regulatory subunits of protein kinase A. We hypothesized that loss of function of this regulatory unit could also lead to protein kinase A activation and thus to fibrolamellar carcinoma. Because PRKAR1A mutations underlie the Carney complex, we searched for liver tumors in individuals with the Carney complex. We identified 3 individuals with fibrolamellar carcinomas and a personal history of the Carney complex. All three tumors displayed the typical morphology of fibrolamellar carcinoma and were positive for arginase, cytokeratin 7, and cluster of differentiation 68. Fluorescence in situ hybridization was negative for PRKACA rearrangements. However, PRKAR1A sequencing identified pathogenic mutations in two of two cases with successful sequencing. In addition, all three cases were negative for PRKAR1A protein expression, consistent with inactivation of this key regulatory unit of protein kinase A. We also identified one additional fibrolamellar carcinoma in an individual without a documented history of the Carney complex who was negative for PRKACA rearrangements but had loss of PRKAR1A protein expression as well as PRKAR1A mutations.

Conclusion: Fibrolamellar carcinoma can be part of the Carney complex; in this setting, fibrolamellar carcinomas have inactivating PRKAR1A mutations instead of the DNAJB1-PRKACA fusion gene found in sporadic fibrolamellar carcinomas, providing an alternate means for activation of protein kinase A. (Hepatology 2017).
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http://dx.doi.org/10.1002/hep.29719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151295PMC
October 2018

SOX9 is a proliferation and stem cell factor in hepatocellular carcinoma and possess widespread prognostic significance in different cancer types.

PLoS One 2017 9;12(11):e0187814. Epub 2017 Nov 9.

Department of Internal Medicine, Division of Oncology, Medical University of Graz, Graz, Austria.

SOX9 has been previously shown to be involved in hepatocellular carcinoma (HCC) and other types of cancer. However, prognostic studies so far involved rather small cohorts or lack external validation and experimental data. In this study, we firstly determined the histological expression pattern of SOX9 in human HCC by immunohistochemistry (n = 84) and evaluated its prognostic value. External cohorts of publicly available datasets were used to validate its prognostic relevance in HCC (n = 359) and other types of cancer including breast (n = 3951), ovarian (n = 1306), lung (n = 1926) and gastric cancer (n = 876). Functional SOX9 knock-down studies using siRNA and cancer stem cell models were generated in a panel of liver and breast cancer cell lines. High level of SOX9 was associated with poor survival even after adjustment for other prognostic factors in multivariate analysis (HR = 2.103, 95%CI = 1.064 to 4.156, p = 0.021). SOX9 prevailed a poor prognostic factor in all cancer validation cohorts (p<0.05). Reduced SOX9 expression by siRNA decreased the growth of liver cancer cells (p<0.05). SOX9 expression was associated with stem cell features in all tested cell lines (p<0.05). In conclusion, this study demonstrated in a large number of patients from multiple cohorts that high levels of SOX9 are a consistent negative prognostic factor.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187814PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679634PMC
November 2017

The non-invasive serum biomarker soluble Axl accurately detects advanced liver fibrosis and cirrhosis.

Cell Death Dis 2017 10 26;8(10):e3135. Epub 2017 Oct 26.

Department of Internal Medicine I, Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.

Soluble Axl (sAxl) was recently shown to be strongly released into the blood during liver fibrogenesis and hepatocellular carcinoma suggesting sAxl as a biomarker of liver diseases. In this study we are the first to evaluate sAxl in human serum in comparison to Enhanced Liver Fibrosis (ELF) test and transient elastography (TE; Fibroscan) for its value to detect significant (F≥2), advanced fibrosis (F≥3), and cirrhosis (F4) in different liver disease etiologies and healthy controls. To properly determine the diagnostic accuracy of sAxl, a test cohort as well as a validation cohort was employed using liver biopsy as a reference method. Most notably, sAxl was confirmed to be an accurate biomarker of liver fibrosis and cirrhosis. Its accuracy was increased, if total serum albumin was added to build a sAxl/albumin ratio. Thereby an AUC of 0.763, 0.776, 0.826, and 0.832 was achieved corresponding to histological fibrosis stages F≥2, F≥3, F4 with liver biopsy as a reference method, and cirrhosis according to imaging techniques, respectively. With a cut-off of 1.29, a sensitivity, specificity, PPV, and NPV of 78.5%, 80.1%, 44%, 94.9% for the detection of cirrhosis was achieved. In comparison, ELF test and TE showed an AUC of 0.910, and 0.934, respectively, for the detection of cirrhosis. However, performance of TE was not possible in 14.4% of patients and both, ELF™ test and TE bear the disadvantage of high costs. In conclusion, the sAxl/albumin ratio is suggested as an accurate biomarker of liver fibrosis and cirrhosis. Due to its easy applicability and low costs it is suitable as screening parameter for significant to advanced liver fibrosis and cirrhosis, especially if TE is not available or not applicable.
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http://dx.doi.org/10.1038/cddis.2017.554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680921PMC
October 2017

Niacin-Associated Acute Hepatotoxicity Leading to Emergency Liver Transplantation.

Am J Gastroenterol 2017 Aug;112(8):1345-1346

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

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http://dx.doi.org/10.1038/ajg.2017.171DOI Listing
August 2017

Soluble Axl is an accurate biomarker of cirrhosis and hepatocellular carcinoma development: results from a large scale multicenter analysis.

Oncotarget 2017 Jul;8(28):46234-46248

Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.

Patients with chronic liver disease (CLD) and cirrhosis are at high risk for hepatocellular carcinoma (HCC). Current diagnostic tools for HCC detection include imaging techniques and serum biomarkers such as α-fetoprotein (AFP). Yet, these methods are limited in sensitivity and specificity to accurately detect early HCC. Here we focused on the potential of soluble Axl (sAxl) as a biomarker in CLD patients by analyzing serum samples of 1067 patients and healthy controls from centers in Europe and Asia. We show that serum concentrations of sAxl were significantly increased at early (82.57 ng/mL) and later stages of HCC (114.50 ng/mL) as compared to healthy controls (40.15 ng/mL). Notably, no elevated sAxl levels were detected in patients with CLD including chronic viral hepatitis, autoimmune hepatitis, cholestatic liver disease, or non-alcoholic fatty liver disease versus healthy controls. Furthermore, sAxl did not rise in liver adenomas or cholangiocarcinoma (CCA). Yet, patients with advanced fibrosis (F3) or cirrhosis (F4) showed enhanced sAxl concentrations (F3: 54.67 ng/mL; F4: 94.74 ng/mL). Hepatic myofibroblasts exhibited an increased release of sAxl, suggesting that elevated sAxl levels arise from these cells during fibrosis. Receiver operating characteristic curve analysis of sAxl displayed a strongly increased sensitivity and specificity to detect both cirrhosis (80.8%/92.0%) and HCC (83.3%/86.7%) with an area under the curve of 0.935/0.903 as compared to AFP. In conclusion, sAxl shows high diagnostic accuracy at early stage HCC as well as cirrhosis, thereby outperforming AFP. Importantly, sAxl remains normal in most common CLDs, liver adenomas and CCA.
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http://dx.doi.org/10.18632/oncotarget.17598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542263PMC
July 2017

Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival.

Nat Commun 2017 03 14;8:14689. Epub 2017 Mar 14.

Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.

The metabolic pathway of de novo lipogenesis is frequently upregulated in human liver tumours, and its upregulation is associated with poor prognosis. Blocking lipogenesis in cultured liver cancer cells is sufficient to decrease cell viability; however, it is not known whether blocking lipogenesis in vivo can prevent liver tumorigenesis. Herein, we inhibit hepatic lipogenesis in mice by liver-specific knockout of acetyl-CoA carboxylase (ACC) genes and treat the mice with the hepatocellular carcinogen diethylnitrosamine (DEN). Unexpectedly, mice lacking hepatic lipogenesis have a twofold increase in tumour incidence and multiplicity compared to controls. Metabolomics analysis of ACC-deficient liver identifies a marked increase in antioxidants including NADPH and reduced glutathione. Importantly, supplementing primary wild-type hepatocytes with glutathione precursors improves cell survival following DEN treatment to a level indistinguishable from ACC-deficient primary hepatocytes. This study shows that lipogenesis is dispensable for liver tumorigenesis in mice treated with DEN, and identifies an important role for ACC enzymes in redox regulation and cell survival.
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http://dx.doi.org/10.1038/ncomms14689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424065PMC
March 2017

Reply to: "Effect of abstinence on the prognosis of patients with alcoholic liver disease: A word of caution".

J Hepatol 2017 06 2;66(6):1330-1331. Epub 2017 Mar 2.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

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http://dx.doi.org/10.1016/j.jhep.2017.02.028DOI Listing
June 2017

Perspectives on NASH Histology: Cellular Ballooning.

Ann Hepatol 2017 March-April;16(2):182-184

The University of Virginia, Division of GI/Hepatology, Charlottesville, Virginia, USA.

Interpretation of liver biopsy in NAFLD can be challenging to distinguish histological NASH from non-NASH fatty liver - a broad dichotomy which carries significant prognostic and therapeutic implications and underlies the utility of many non-invasive tests. There is usually a reasonable degree of inter-observer agreement for some key parameters like steatosis, inflammation and fibrosis staging. However, the assessment of cellular ballooning can be a stumbling block even for experienced observers. Below, we recount some aspects of the history of histological definitions in NASH and propose specific methods to more objectively identify cellular ballooning in routine biopsy assessments.
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http://dx.doi.org/10.5604/16652681.1231550DOI Listing
April 2017

Caspase-cleaved keratin-18 fragments increase during alcohol withdrawal and predict liver-related death in patients with alcoholic liver disease.

Hepatology 2017 07 9;66(1):96-107. Epub 2017 May 9.

Institute of Pathology, RWTH-University Hospital Aachen, Aachen, Germany.

Noninvasive assessment of disease activity in patients with nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) is still unsettled, but essential for the evaluation of disease progression. We here studied the association of total (M65) and caspase-cleaved (M30) serum keratin-18 fragments (n = 204) with histological parameters (n = 106) in heavy drinkers primarily admitted for alcohol withdrawal before and after alcohol detoxification. An age-, sex-, and fibrosis-stage matched NAFLD cohort (n = 30) was used for comparison. The prognostic value of M30 and M65 levels were assessed in an additional prospectively followed-up cohort of 230 patients with alcoholic cirrhosis (AC) using competing risk analyses. Among the histological parameters, both M30/65 correlated significantly and better than any other serum marker with apoptosis and liver damage, such as ballooning (r = 0.65; P < 0.001), followed by lobular inflammation (0.48; P < 0.001), steatosis (0.46; P < 0.001), but less with fibrosis (0.24; P < 0.001). Area under the receiver operating characteristics curves to detect ballooning, steatosis, or steatohepatitis (SH) were slightly better for M30 (P < 0.005). Optimal M30 cut-off values for mild and severe ballooning were 330 and 420 U/L, and 290 and 330 U/L for SH grades 1 and 2. No significant differences of M30/65 were found between the matched NAFLD and ALD cohort. In contrast to aspartate-amino-transferase and M65, M30 levels increased significantly from 391 to 518 U/L during alcohol detoxification. Moreover, levels of M30 and M65 predicted non-hepatocellular carcinoma liver-related mortality in patients with AC during a mean observation interval of 67.2 months.

Conclusion: Our data suggest M30 as highly specific marker of liver apoptosis both in ALD and NAFLD. In addition, hepatocellular apoptosis, as determined by M30 levels, occurs during alcohol withdrawal, and survival data point toward a novel underestimated role of apoptosis in patients with ALD. (Hepatology 2017;66:96-107).
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http://dx.doi.org/10.1002/hep.29099DOI Listing
July 2017

Fibrosis evaluation by transient elastography in alcoholic liver disease: Is the histological scoring system impacting cutoff values?

Hepatology 2017 05 3;65(5):1758-1761. Epub 2017 Apr 3.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1002/hep.29075DOI Listing
May 2017

Primary liver injury and delayed resolution of liver stiffness after alcohol detoxification in heavy drinkers with the variant I148M.

World J Hepatol 2016 Dec;8(35):1547-1556

Vanessa Rausch, Teresa Peccerella, Helmut-Karl Seitz, Sebastian Mueller, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany.

Aim: To investigate the influence of genotype in heavy drinkers on serum markers and liver stiffness (LS) during alcohol withdrawal and its association with histology.

Methods: Caucasian heavy drinkers ( = 521) with a mean alcohol consumption of 192.1 g/d (median alcohol consumption: 169.0 g/d; 95%CI: 179.0-203.3) were enrolled at the Salem Medical Center, University of Heidelberg. LS was measured by transient elastography (Fibroscan, Echosens SA, Paris, France). LS and serum markers were prospectively studied in these patients with all stages of alcoholic liver disease (steatosis, steatohepatitis, fibrosis) prior and after alcohol detoxification with a mean observation interval of 6.2 ± 3.2 d. A liver biopsy with histological analysis including the Kleiner score was obtained in 80 patients.

Results: The genotype distribution for CC, CG and GG was 39.2%, 52.6% and 8.2%. GG genotype primarily correlated with histological steatohepatitis ( = 0.404, < 0.005), ballooning ( = 0.319, < 0.005) and less with steatosis ( = 0.264, < 0.05). Mean LS was lowest in CC carriers (13.1 kPa) as compared to CG and GG carriers (17.6 and 17.2 kPa). Notably, LS primarily correlated with fibrosis stage ( = 0.828, < 0.005), ballooning ( = 0.516, < 0.005), steatohepatitis ( = 0.319, < 0.005) but not with steatosis. After alcohol withdrawal, LS did not change in CC carriers, significantly decreased in CG-carriers from 17.6 to 12.7 kPa but to a lesser extent in GG carriers from 17.6 to 14.5 kPa. This was due to prolonged resolution of inflammation with significantly elevated aspartate transaminase levels after alcohol withdrawal in GG carriers. Non-invasive fibrosis assessment by LS in all patients showed a significantly higher F0 rate as compared to the biopsy cohort (47% 6%) with 3.8% more CC carriers while 3.7% less were seen in the F4 cirrhosis group. Thus, about 20% of patients with alcoholic liver cirrhosis would be attributable to G variants. The OR to develop cirrhosis corrected for age, gender and body mass index was 1.295 (95%CI: 0.787-2.131) for CG + GG carriers.

Conclusion: In heavy drinkers, GG primarily correlates with ballooning/steatohepatitis but not steatosis resulting in a delayed inflammation-associated resolution of LS. Consequently, sustained ballooning-associated LS elevation seems to be a potential risk factor for fibrosis progression in GG carriers.
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http://dx.doi.org/10.4254/wjh.v8.i35.1547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5165268PMC
December 2016
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