Publications by authors named "Alexandra Feldman"

19 Publications

  • Page 1 of 1

Liver-related Mortality is Increased in Lean Subjects with Non- alcoholic Fatty Liver Disease Compared to Overweight and Obese Subjects.

J Gastrointestin Liver Dis 2021 Aug 10. Epub 2021 Aug 10.

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

Background And Aims: Although non-alcoholic fatty liver disease (NAFLD) is linked to obesity, a proportion of lean subjects also have NAFLD with potentially distinct clinical features. We studied the outcome of lean NAFLD subjects.

Methods: 299 consecutive patients (215 male, 84 female, 49.5 ± 13.5years) with biopsy-proven NAFLD and a follow-up of 8.4 years (±4.1; range: 0.9-18.0) were stratified by body mass index (BMI) at the time of liver biopsy: lean (BMI ≤25.0 kg/m, n=38), overweight (BMI 25.0-29.9 kg/m2, n=165), obese (BMI ≥30.0 kg/m2, n=93). A control group of 1,013 subjects (547 male, 52.4 ± 5.8) was used for comparison. The time to the event was recorded. Multivariable Cox regression analyses were performed to assess associations with 10-year-mortality. Hazard ratios (HR) and adjusted hazard ratios (aHR) with 95% confidence intervals (CI) were calculated.

Results: Age and gender were similar, while components of the metabolic syndrome were less frequent in lean subjects. The proportion of subjects with significant fibrosis and the number of subjects with cirrhosis was increased in lean subjects while the proportion of non-alcoholic steatohepatitis was not different. Mortality in the NAFLD groups was significantly higher than in the control group. Multivariable analysis adjusting for age, gender, and glucose confirmed lower mortality in overweight (aHR 0.21; 95% CI 0.07-0.62, p=0.005) and in obese (aHR 0.22; 95% CI 0.06-0.76, p=0.02) compared to lean subjects. Further adjustment for fibrosis weakened the difference between lean and obese (p=0.12) while the difference to overweight subjects remained intact (p=0.01).

Conclusion: Lean subjects with NAFLD have a high risk of liver-related death. Our data support that lean NAFLD subjects deserve particular attention with regard to clinical follow-up.
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http://dx.doi.org/10.15403/jgld-3622DOI Listing
August 2021

PNPLA3 is the dominant SNP linked to liver disease severity at time of first referral to a tertiary center.

Dig Liver Dis 2021 Jul 11. Epub 2021 Jul 11.

First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria. Electronic address:

Background: Single nucleotide polymorphisms (SNPs) in genes including PNPLA3, TM6SF2, HSD17B13 and SERPINA1 have been identified as risk modifiers of progression in chronic liver disease (CLD). However, it is unclear whether genotyping for these risk variants is useful in clinical routine.

Methods: Liver disease severity was assessed by liver stiffness measurement (LSM) and by presence of clinical manifestations of advanced-chronic liver disease (ACLD) in 779 consecutive CLD patients at the time of referral to a tertiary center. The associations of risk variants with CLD severity were calculated individually and in a combined model using a polygenic risk-score.

Results: Non-alcoholic fatty liver disease (NAFLD) was the most common etiology (n = 511, 65.6%), and ACLD was present in 217 (27.9%) patients. The PNPLA3-G-allele remained independently associated with higher LSM (adjusted-B: 2.508 [95%CI: 0.887-4.130], P = 0.002) or the presence of ACLD (aOR: 1.562 [95%CI: 1.097-2.226], P = 0.013). SERPINA1-Z-allele was also independently associated with LSM (adjusted-B: 4.558 [95%CI: 1.182-7.934], P = 0.008), while the other risk alleles did not attain statistical significance. Combining these risk alleles into a polygenic risk-score was significantly associated with LSM (adjusted-B: 0.948 [95%CI: 0.153-1.743], P = 0.020).

Conclusion: PNPLA3 risk-variants are linked to liver disease severity at the time of first referral to an outpatient hepatology clinic.
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http://dx.doi.org/10.1016/j.dld.2021.06.015DOI Listing
July 2021

PNPLA3 and SERPINA1 Variants Are Associated with Severity of Fatty Liver Disease at First Referral to a Tertiary Center.

J Pers Med 2021 Mar 1;11(3). Epub 2021 Mar 1.

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

Single nucleotide polymorphisms (SNPs), including and have been identified as risk modifiers in the progression fatty liver disease (alcoholic (ALD) or non-alcoholic (NAFLD)). While has been studied in various settings, the value of both SNPs has so far not been addressed in a real-world cohort of subjects referred for a diagnostic work-up of liver disease. Thus, liver disease severity was assessed in 1257 consecutive patients with suspected ALD or NAFLD at the time of referral to a tertiary center. Advanced chronic liver disease (ACLD) was present in 309 (24.6%) patients and clinically significant portal hypertension (CSPH) was present in 185 (14.7%) patients. The G-allele was independently associated with a higher liver stiffness measurement (LSM; adjusted B: 2.707 (1.435-3.979), < 0.001), and higher odds of ACLD (adjusted odds ratio (aOR): 1.971 (1.448-2.681), < 0.001) and CSPH (aOR: 1.685 (1.180-2.406), = 0.004). While the Z-allele was not associated with a higher LSM or the presence of ACLD, it was independently associated with higher odds of CSPH (aOR: 2.122 (1.067-4.218), = 0.032). Associations of the G-allele and the Z-allele with CSPH were maintained independently of each other. The presence of both risk variants further increased the likelihood of ACLD and CSPH.
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http://dx.doi.org/10.3390/jpm11030165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999282PMC
March 2021

Similar clinical outcome of AMA immunoblot-M2-negative compared to immunoblot-positive subjects over six years of follow-up.

Postgrad Med 2021 Apr 25;133(3):291-298. Epub 2021 Feb 25.

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

: The detection of anti-mitochondrial antibodies (AMA) is considered a hallmark in diagnosing primary biliary cholangitis (PBC). The most important AMA-subtype is AMA-M2 directed against the E2-subunit of pyruvate dehydrogenase. It is common clinical interpretation that lack of M2 due to immunoblotting (IB) indicates absence of specific auto-reactivity. We aimed to define whether M2-IB confirmation is linked to clinical outcomes.: Our cohort comprised 302 patients who tested positive for AMA with indirect immunofluorescence between 2006 and 2015. One hundred and eighty-four subjects (60.9%; male n = 29 [15.8%]) were tested M2-positive by confirmatory IB, whereas 118 subjects were IB-M2-negative (39.1%; male n = 25 [21.2%]). The natural history of 236 patients (78.1%) was evaluated by clinical follow-up (FU) assessing causes of death, leading health condition and response to PBC standard therapy if applicable.: Mean time to FU was 6.8 years. Twenty-eight M2-positive patients (15.2% of 184) and 28 M2-negative patients (23.7% of 118) had died (p = 0.0958). Thirty-four M2-positives (18.5%) and 32 M2-negatives (27.1%) were not available for FU. According to the clinical course by the time of FU, subjects were allocated to one of four groups: a) 34 patients had known PBC with n = 16 having an adequate and 18 an inadequate treatment response, b) 1 de novo PBC was detected, c) 13 were AMA-positive without biochemical evidence of PBC and d) 9 subjects were tested AMA-negative at FU. These numbers were comparable to M2-positive subjects with similar long-term clinical outcome.: Our data suggest that the clinical value of confirmatory M2 immunoblotting in the diagnostic routine of PBC is overestimated as the clinical course appears not to be related to the test result.
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http://dx.doi.org/10.1080/00325481.2021.1885945DOI Listing
April 2021

Mesenchymal iron deposition is associated with adverse long-term outcome in non-alcoholic fatty liver disease.

Liver Int 2020 08 28;40(8):1872-1882. Epub 2020 May 28.

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

Background & Aims: Approximately one-third of patients with non-alcoholic fatty liver disease (NAFLD) show signs of mild-to-moderate iron overload. The impact of histological iron deposition on the clinical course of patients with NAFLD has not been established.

Methods & Results: For this retrospective study, 299 consecutive patients with biopsy-proven NAFLD and a mean follow-up of 8.4 (±4.1; range: 0.3-18.0) years were allocated to one of four groups according to presence of hepatic iron in the reticuloendothelial system (RES) and/or hepatocytes (HC): 156 subjects (52%) showed no stainable iron (NONE), 58 (19%) exclusively reticuloendothelial (xRES), 19 (6%) exclusively hepatocellular (xHC) and 66 (22%) showed a mixed (HC/RES) pattern of iron deposition. A long-term analysis for overall survival, hepatic, cardiovascular or extrahepatic-malignant events was conducted. Based on multivariate Cox proportional hazards models any reticuloendothelial iron was associated with fatal and non-fatal hepatic events. Specifically, xRES showed a cause-specific hazard ratio (csHR) of 2.4 (95%-CI, 1.0-5.8; P = .048) for hepatic as well as cardiovascular fatal and non-fatal events combined (csHR 3.2; 95%-CI, 1.2-8.2; P = .015). Furthermore, the mixed HC/RES iron pattern showed a higher rate of combined hepatic fatal and non-fatal events (csHR 3.6; 95%-CI, 1.4-9.5; P = .010), while xHC iron deposition was not associated with any defined events.

Conclusions: The presence of reticuloendothelial-accentuated hepatic iron distribution patterns is associated with detrimental long-term outcomes reflected in a higher rate of both liver-related and cardiovascular fatal and non-fatal events.
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http://dx.doi.org/10.1111/liv.14503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496452PMC
August 2020

Lysosomal acid lipase deficiency - early diagnosis is the key.

Hepat Med 2019 23;11:79-88. Epub 2019 May 23.

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

Lysosomal acid lipase deficiency (LAL-D) is an ultra-rare lysosomal storage disease that may present from infancy to late adulthood depending on residual enzyme activity. While the severe form manifests as a rapidly progressive disease with near universal mortality within the first 6 months of life, milder forms frequently go undiagnosed for prolonged periods and typically present with progressive fatty liver disease, enlarged spleen, atherogenic dyslipidemia and premature atherosclerosis. The adult variant of LAL-D is typically diagnosed late or even overlooked due to the unspecific nature of the presenting symptoms, which are similar to common changes observed in the context of the metabolic syndrome. This review is aimed at delineating clinically useful scenarios in which pediatric or adult medicine clinicians should be aware of LAL-D as a differential diagnosis for selected patients. This is particularly relevant as a potentially life-saving enzyme replacement therapy has become available and the diagnosis can easily be ruled out or confirmed using a dried blood spot test.
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http://dx.doi.org/10.2147/HMER.S201630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536894PMC
May 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

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

Gut 2019 06 1;68(6):1099-1107. Epub 2018 Aug 1.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Objective: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.

Design: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed.

Results: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)).

Conclusion: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.
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http://dx.doi.org/10.1136/gutjnl-2018-316228DOI Listing
June 2019

Response to Dr Braillon.

Am J Gastroenterol 2017 03;112(3):512

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

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http://dx.doi.org/10.1038/ajg.2016.581DOI Listing
March 2017

Metabolomic profiling identifies potential pathways involved in the interaction of iron homeostasis with glucose metabolism.

Mol Metab 2017 01 31;6(1):38-47. Epub 2016 Oct 31.

First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria. Electronic address:

Objective: Elevated serum ferritin has been linked to type 2 diabetes (T2D) and adverse health outcomes in subjects with the Metabolic Syndrome (MetS). As the mechanisms underlying the negative impact of excess iron have so far remained elusive, we aimed to identify potential links between iron homeostasis and metabolic pathways.

Methods: In a cross-sectional study, data were obtained from 163 patients, allocated to one of three groups: (1) lean, healthy controls (n = 53), (2) MetS without hyperferritinemia (n = 54) and (3) MetS with hyperferritinemia (n = 56). An additional phlebotomy study included 29 patients with biopsy-proven iron overload before and after iron removal. A detailed clinical and biochemical characterization was obtained and metabolomic profiling was performed via a targeted metabolomics approach.

Results: Subjects with MetS and elevated ferritin had higher fasting glucose (p < 0.001), HbA1c (p = 0.035) and 1 h glucose in oral glucose tolerance test (p = 0.002) compared to MetS subjects without iron overload, whereas other clinical and biochemical features of the MetS were not different. The metabolomic study revealed significant differences between MetS with high and low ferritin in the serum concentrations of sarcosine, citrulline and particularly long-chain phosphatidylcholines. Methionine, glutamate, and long-chain phosphatidylcholines were significantly different before and after phlebotomy (p < 0.05 for all metabolites).

Conclusions: Our data suggest that high serum ferritin concentrations are linked to impaired glucose homeostasis in subjects with the MetS. Iron excess is associated to distinct changes in the serum concentrations of phosphatidylcholine subsets. A pathway involving sarcosine and citrulline also may be involved in iron-induced impairment of glucose metabolism.
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http://dx.doi.org/10.1016/j.molmet.2016.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220278PMC
January 2017

The VEGF rise in blood of bevacizumab patients is not based on tumor escape but a host-blockade of VEGF clearance.

Oncotarget 2016 Aug;7(35):57197-57212

Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria.

Vascular endothelial growth factor (VEGF) has become a major target in cancer treatment as it promotes tumor angiogenesis. Therapy with anti-VEGF antibody bevacizumab reportedly induces high levels of circulating VEGF which may potentially contribute to resistance. Based on animal or computational models, mechanisms of VEGF induction by bevacizumab have been proposed but not verified in the clinical setting. Hence, we evaluated sixty patients with colorectal cancer metastases for changes in plasma VEGF during neoadjuvant/conversion and adjuvant chemotherapy with or without bevacizumab. VEGF expression was assessed in tissue sections of liver metastases. The VEGF source was investigated with in vitro cultures of tumor, endothelial cells, fibroblasts and platelets, and potential protein stabilization due to anti-VEGF therapy was addressed. A VEGF rise was observed in blood of bevacizumab patients but not in chemotherapy controls, and VEGF was found to be largely complexed by the antibody. A comparable VEGF increase occurred in the presence (neoadjuvant) and absence of the tumor (adjuvant). Accordingly, VEGF expression in tumor tissue was not determined by bevacizumab treatment. Investigations with isolated cell types did not reveal VEGF production in response to bevacizumab. However, antibody addition to endothelial cultures led to a dose-dependent blockade of VEGF internalization and hence stabilized VEGF in the supernatant. In conclusion, the VEGF rise in cancer patients treated with bevacizumab is not originating from the tumor. The accumulation of primarily host-derived VEGF in circulation can be explained by antibody interference with receptor-mediated endocytosis and protein degradation. Thus, the VEGF increase in response to bevacizumab therapy should not be regarded as a tumor escape mechanism.
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http://dx.doi.org/10.18632/oncotarget.11084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302983PMC
August 2016

Clinical and Metabolic Characterization of Lean Caucasian Subjects With Non-alcoholic Fatty Liver.

Am J Gastroenterol 2017 01 16;112(1):102-110. Epub 2016 Aug 16.

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

Objectives: Non-alcoholic fatty liver disease (NAFLD) is closely linked to obesity; however, 5-8% of lean subjects also have evidence of NAFLD. We aimed to investigate clinical, genetic, metabolic and lifestyle characteristics in lean Caucasian subjects with NAFLD.

Methods: Data from 187 subjects allocated to one of the three groups according to body mass index (BMI) and hepatic steatosis on ultrasound were obtained: lean healthy (BMI≤25 kg/m, no steatosis, N=71), lean NAFLD (BMI≤25 kg/m, steatosis, N=55), obese NAFLD (BMI≥30 kg/m, steatosis; N=61). All subjects received a detailed clinical and laboratory examination including oral glucose tolerance test. The serum metabolome was assessed using the Metabolomics AbsoluteIDQ p180 kit (BIOCRATES Life Sciences). Genotyping for single-nucleotide polymorphisms (SNPs) associated with NAFLD was performed.

Results: Lean NAFLD subjects had fasting insulin concentrations similar to lean healthy subjects but had markedly impaired glucose tolerance. Lean NAFLD subjects had a higher rate of the mutant PNPLA3 CG/GG variant compared to lean controls (P=0.007). Serum adiponectin concentrations were decreased in both NAFLD groups compared to controls (P<0.001 for both groups) The metabolomics study revealed a potential role for various lysophosphatidylcholines (lyso-PC C18:0, lyso-PC C17:0) and phosphatidylcholines (PCaa C36:3; false discovery rate (FDR)-corrected P-value<0.001) as well as lysine, tyrosine, and valine (FDR<0.001).

Conclusions: Lean subjects with evidence of NAFLD have clinically relevant impaired glucose tolerance, low adiponectin concentrations and a distinct metabolite profile with an increased rate of PNPLA3 risk allele carriage.
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http://dx.doi.org/10.1038/ajg.2016.318DOI Listing
January 2017

Chemotherapy of colorectal liver metastases induces a rapid rise in intermediate blood monocytes which predicts treatment response.

Oncoimmunology 2016 Jun 22;5(6):e1160185. Epub 2016 Mar 22.

Department of Surgery, Medical University of Vienna, General Hospital, Waehringer Guertel, Vienna, Austria; Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel, Vienna, Austria.

We have previously reported that intermediate monocytes (CD14(++)/CD16(+)) were increased in colorectal cancer (CRC) patients, while the subset of pro-angiogenic TIE2-expressing monocytes (TEMs) was not significantly elevated. This study was designed to evaluate changes in frequency and function of intermediate monocytes and TEMs during chemotherapy and anti-angiogenic cancer treatment and their relation to treatment response. Monocyte populations were determined by flow cytometry in 60 metastasized CRC (mCRC) patients who received neoadjuvant chemotherapy with or without bevacizumab. Blood samples were taken before treatment, after two therapy cycles, at the end of neoadjuvant therapy and immediately before surgical resection of liver metastases. Neoadjuvant treatment resulted in a significant increase in circulating intermediate monocytes which was most pronounced after two cycles and positively predicted tumor response (AUC = 0.875, p = 0.005). With a cut-off value set to 1% intermediate monocytes of leukocytes, this parameter showed a predictive sensitivity and specificity of 75% and 88%. Anti-angiogenic therapy with bevacizumab had no impact on monocyte populations including TEMs. In 15 patients and six healthy controls, the gene expression profile and the migratory behavior of monocyte subsets was evaluated. The profile of intermediate monocytes suggested functions in antigen presentation, inflammatory cytokine production, chemotaxis and was remarkably stable during chemotherapy. Intermediate monocytes showed a preferential migratory response to tumor-derived signals in vitro and correlated with the level of CD14(+)/CD16(+) monocytic infiltrates in the resected tumor tissue. In conclusion, the rapid rise of intermediate monocytes during chemotherapy may offer a simple marker for response prediction and a timely change in regimen.
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http://dx.doi.org/10.1080/2162402X.2016.1160185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938316PMC
June 2016

The Potential Role of Iron and Copper in Pediatric Obesity and Nonalcoholic Fatty Liver Disease.

Biomed Res Int 2015 26;2015:287401. Epub 2015 Jul 26.

Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria ; Department of Pediatrics, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.

Obesity is a rapidly growing health problem and is paralleled by a multitude of comorbidities, including nonalcoholic fatty liver disease (NAFLD). NAFLD has become the most common chronic liver disease in both adults and children. The current understanding of NAFLD is still fragmentary. While simple steatosis is characterized by the interplay between excessive free fatty acid accumulation and hepatic insulin resistance, the progression to NASH has been related to oxidative stress and a proinflammatory state with dysbalanced adipokine, cytokine levels, and endotoxin-mediated immune response. In addition, oxidative stress has been suggested to play a central role for the sequelae leading to NASH. Trace elements are critical in regulatory, immunologic, and antioxidant functions resulting in protection against inflammation and peroxidation and consequently against the known comorbidities of obesity. Disruptions of the metal detoxification processes located in the liver are plausibly related to NAFLD development via oxidative stress. Perturbations of iron and copper (Cu) homeostasis have been shown to contribute to the pathogenesis of NAFLD. This review presents current data from pediatric studies. In addition, data from adult studies are summarized where clinical relevance may be extrapolated to pediatric obesity and NAFLD.
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http://dx.doi.org/10.1155/2015/287401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529901PMC
May 2016

Natural course of subjects with elevated liver tests and normal liver histology.

Liver Int 2016 Jan 6;36(1):119-25. Epub 2015 Sep 6.

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

Background & Aims: Liver biopsy (LB) is performed if non-invasive work-up of liver disease is inconclusive. The examination of liver tissue occasionally reveals normal histology. Long-term follow-up of such patients has not been performed.

Methods: We identified a total 70 subjects from our LB database with elevated liver tests and normal liver histology after a mean of 90.5 ± 52.3 (range 15-216) months and conducted reassessment of medical history, physical examination, laboratory testing, ultrasound, transient elastography and LB if indicated.

Results: At follow-up examination, 15 (7 females (f)/8 males (m); 21.4%) subjects had normal liver tests and no further evidence of liver disease. A subset of 37 (29 f/8 m; 52.9%) subjects had persistently elevated liver tests without evidence indicating progressive liver disease but the cause thereof remained unexplained also at the follow-up visit. Three (0 f/3 m; 4.3%) subjects had consumed excessive alcohol with indicators of alcoholic liver disease. Eleven subjects (4 f/7 m; 15.7%) had developed steatosis on ultrasound examination along with weight gain and/or biochemical features of the metabolic syndrome. In addition, three (2 f/1 m) patients developed autoimmune hepatitis, one female presented with primary biliary cirrhosis. One male was diagnosed with cholangiocellular carcinoma 3 months after the initial evaluation.

Conclusion: The clinical course of most patients was benign, but in approximately 20% of the subjects a liver disease developed. Particular attention should be given to autoimmune liver diseases in subjects with positive autoantibodies. In addition, lifestyle factors such as weight gain and alcohol consumption were associated with the manifestation of liver diseases.
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http://dx.doi.org/10.1111/liv.12935DOI Listing
January 2016

Obesity as an emerging risk factor for iron deficiency.

Nutrients 2014 Sep 11;6(9):3587-600. Epub 2014 Sep 11.

Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.

Iron homeostasis is affected by obesity and obesity-related insulin resistance in a many-facetted fashion. On one hand, iron deficiency and anemia are frequent findings in subjects with progressed stages of obesity. This phenomenon has been well studied in obese adolescents, women and subjects undergoing bariatric surgery. On the other hand, hyperferritinemia with normal or mildly elevated transferrin saturation is observed in approximately one-third of patients with metabolic syndrome (MetS) or nonalcoholic fatty liver disease (NAFLD). This constellation has been named the "dysmetabolic iron overload syndrome (DIOS)". Both elevated body iron stores and iron deficiency are detrimental to health and to the course of obesity-related conditions. Iron deficiency and anemia may impair mitochondrial and cellular energy homeostasis and further increase inactivity and fatigue of obese subjects. Obesity-associated inflammation is tightly linked to iron deficiency and involves impaired duodenal iron absorption associated with low expression of duodenal ferroportin (FPN) along with elevated hepcidin concentrations. This review summarizes the current understanding of the dysregulation of iron homeostasis in obesity.
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http://dx.doi.org/10.3390/nu6093587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4179177PMC
September 2014

Endogenous H2O2 produced by Streptococcus pneumoniae controls FabF activity.

Biochim Biophys Acta 2010 Sep 23;1801(9):1098-104. Epub 2010 Jun 23.

Pediatric Infectious Disease Unit, Soroka University Medical Center, Faculty of Health Sciences, Beer Sheva, Israel.

FabF elongation condensing enzyme is a critical factor in determining the spectrum of products produced by the FASII pathway. Its active site contains a critical cysteine-thiol residue, which is a plausible target for oxidation by H2O2. Streptococcus pneumoniae produces exceptionally high levels of H2O2, mainly through the conversion of pyruvate to acetyl-P via pyruvate oxidase (SpxB). We present evidence showing that endogenous H2O2 inhibits FabF activity by specifically oxidizing its active site cysteine-thiol residue. Thiol trapping methods revealed that one of the three FabF cysteines in the wild-type strain was oxidized, whereas in an spxB mutant, defective in H2O2 production, none of the cysteines was oxidized, indicating that the difference in FabF redox state originated from endogenous H2O2. In vitro exposure of the spxB mutant to various H2O2 concentrations further confirmed that only one cysteine residue was susceptible to oxidation. By blocking FabF active site cysteine with cerulenin we show that the oxidized cysteine was the catalytic one. Inhibition of FabF activity by either H2O2 or cerulenin resulted in altered membrane fatty acid composition. We conclude that FabF activity is inhibited by H2O2 produced by S. pneumoniae.
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http://dx.doi.org/10.1016/j.bbalip.2010.06.004DOI Listing
September 2010

Apoptosis of Hodgkin-Reed-Sternberg cells in classical Hodgkin lymphoma revisited.

APMIS 2010 May;118(5):339-45

Department of Pathology, Soroka University Medical Center, Beer-Sheva, Israel.

We scrutinized the role of apoptosis of the Hodgkin-Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) and critically reviewed its features in the light of conflicting evidence. In this study, we found that tumor cells in this neoplasm showed inhibition of apoptosis in 55% of the 217 cHL cases only. It is also suggested that the two factors considered responsible for apoptosis inhibition in HRS cells, nuclear factor-kappaB and the latent membrane protein-1 of the Epstein-Barr virus, do not correlate with apoptosis inhibition, in contrast with the findings in the consensual pathogenetic scheme. The most significant association of HRS cell apoptosis was with p53, the negative expression of which related with a high apoptotic index (p = 0.001). These findings support our contention that the role of apoptosis in the HRS cells of Hodgkin lymphoma has not been completely elucidated and is at variance with that in the consensus.
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http://dx.doi.org/10.1111/j.1600-0463.2010.02600.xDOI Listing
May 2010
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