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Markers of Liver Regeneration—The Role of Growth Factors and Cytokines

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Markers of Liver Regeneration—The Role of Growth Factors and Cytokines Hoffmann et al. BMC Surgery (2020) 20:31 https://doi.org/10.1186/s12893-019-0664-8 RESEARCH ARTICLE Open Access Markers of liver regeneration—the role of growth factors and cytokines: a systematic review Katrin Hoffmann*†, Alexander Johannes Nagel†, Kazukata Tanabe, Juri Fuchs, Karolin Dehlke, Omid Ghamarnejad, Anastasia Lemekhova and Arianeb Mehrabi Abstract Background: Post-hepatectomy liver failure contributes significantly to postoperative mortality after liver resection. The prediction of the individual risk for liver failure is challenging. This review aimed to provide an overview of cytokine and growth factor triggered signaling pathways involved in liver regeneration after resection. Methods: MEDLINE and Cochrane databases were searched without language restrictions for articles from the time of inception of the databases till March 2019. All studies with comparative data on the effect of cytokines and growth factors on liver regeneration in animals and humans were included. Results: Overall 3.353 articles comprising 40 studies involving 1.498 patients and 101 animal studies were identified and met the inclusion criteria. All included trials on humans were retrospective cohort/observational studies. There was substantial heterogeneity across all included studies with respect to the analyzed cytokines and growth factors and the described endpoints. Conclusion: High-level evidence on serial measurements of growth factors and cytokines in blood samples used to predict liver regeneration after resection is still lacking. To address the heterogeneity of patients and potential markers, high throughput serial analyses may offer a method to predict an individual’s regenerative potential in the future. Keywords: Liver regeneration, Biochemical markers, Post-hepatectomy liver failure , Cytokines, Growth factors Introduction operative assessments and careful indications, PHLF is a Post-hepatectomy liver failure (PHLF) is a serious com- major contributor to mortality rates of up to 5% after plication after liver resection and the incidence varies liver resection [7, 8]. Various patient- (comorbidities, from 1.2 to 32% [1–4]. PHLF is defined as functional de- age, and previous chemotherapy), parenchyma- (cirrho- terioration of the liver associated with an increased sis, fibrosis, cholestasis, and steatosis), and surgery- international normalized ratio (INR) and hyperbilirubi- related factors (extent of resection, blood loss, and ische- nemia on, or after, the fifth postoperative day [1]. There mia reperfusion injury) affect the regenerative capacity are recommendations that PHLF could be prevented if of the FLR [9, 10]. However, to predict the adequate size the future liver remnant (FLR) is not smaller than 20% and individual regenerative capacity of the FLR remains of the original liver size in patients with normal liver a significant challenge for clinicians, surgeons, and scien- function and 30–40% in patients with steatohepatitis or tists. The current PHLF therapy focuses on symptomatic cirrhosis [5, 6]. Nevertheless, even with adequate pre- and supportive treatment of the progredient dysregula- tion in the hepato-organic axis. However, the ultima ra- tio for PHLF is liver transplantation if patients fulfill * Correspondence: [email protected] † listing regulations. This poses a marked morbidity and Katrin Hoffmann and Alexander Johannes Nagel contributed equally to this work. mortality risk for patients, and surgeons and clinicians Department of General, Visceral and Transplant Surgery, Ruprecht Karls should aim to ensure that postoperative liver failure does University, Im Neuenheimer Feld, 110 69120 Heidelberg, Germany © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hoffmann et al. BMC Surgery (2020) 20:31 Page 2 of 15 not occur. In clinical practice, there is a high variety of additional studies. Non-peer reviewed studies were morphological and biochemical assessment methods for excluded. qualitative (indocyanine green retention rates; LiMAx- Information sources: The MEDLINE and Cochrane Li- tests, MELD or CHILD-PUGH scores) and quantitative brary databases were searched for relevant studies; last (computed tomography liver volumetry, analysis of biliru- search was conducted in April 2019. bin, transaminases, albumin) predictions for liver function Search: Search strategies included the following Medical in the context of liver resection [11]. However, non- Subject Headings (MeSH) in various combinations: liver invasive individualized identification of valid predictive regeneration, liver resection, partial hepatectomy, major and prognostic biomarkers of PHLF based on the cyto- liver resection, hemi-hepatectomy, post-hepatectomy liver kines and hepatic growth factors in the liquid-biopsy sam- failure, cytokine, growth factor, hepatocyte growth factor ples might be a novel approach in the peri-operative (HGF), tumor necrosis factor alpha (TNF-α), interleukin diagnosis and monitoring of regeneration on a molecular 6, epidermal growth factor (EGF), insulin-like growth fac- basis. The growing subgroup of high-risk patients with tor (IGF), vascular endothelial growth factor (VEGF), hepatic steatosis, steatohepatitis, or sinusoidal obstruction fibroblast growth factors (FGFs), angiopoietin, platelet- syndrome, after neo-adjuvant chemotherapy, in particular, derived growth factor (PDGF), proliferating cell nuclear would benefit from markers that indicate the livers’ indi- antigen (PCNA), Ki-67, and micro-RNA (miRNA). vidual abilities to cope with extended surgical resection Study selection: Two authors (AN and YT) independ- [12]. Since liver regeneration is a well-orchestrated process ently screened the titles and abstracts of all retrieved ref- controlled by various cytokines and growth factors, these erences and obtained full-text articles in cases of might also be promising targets for modulation. Despite potential eligibility. Full texts of all animal studies and the growing knowledge of regeneration-associated signal- studies including patients that provided data on cyto- ing pathways and regulatory mediators in rodents, conver- kine- and growth factor- mediated regeneration pro- sion of the process into humans and clinical practice has cesses were analyzed according to the eligibility criteria. just begun [13]. A third author (KH) was consulted in case of disagree- Therefore, the purpose of this review was to systemat- ment. Three thousand three hundred fifty- three articles ically summarize current evidence on the cytokine- and were identified. After excluding duplicates (n = 294) and growth factor- mediated signaling pathways in liver re- non-English studies (n = 43), 1172 animal studies and generation for the benefit of clinicians and surgeons, and 1844 human studies were analyzed. Ultimately, 40 stud- to discuss their suitability for individual mediator-based ies including 1498 patients were included in this review regeneration predictions in patients. (Fig. 1). Studies were included based on predefined se- lection criteria: relevant information regarding measure- Methods ments of available markers; clearly defined outcome Protocol and registration: there was no review protocol parameters (such as PHLF according to International and the study was not registered. Study Group of Liver Surgery definitions); regeneration Eligibility criteria: inclusion of the studies was based measured by clinically relevant methods such as com- on the Population, Intervention, Comparison, Outcome puterized tomography scans, magnetic resonance im- and Study design (PICOS) strategy with the following in- aging, or well-established laboratory methods such as clusion criteria [14]: cytology including any standard staining techniques (i.e. hematoxylin and eosin, Papanicolaou); molecular detec- Population: all patients undergoing liver resection tion methods (with or without immunocytochemistry); Intervention: reports of measurements of cytokines any form of reverse-transcriptase polymerase chain reac- and growth factors in the context of PHLF tion ([RT]-PCR) tests; and protein analyses which may Comparator: no measurements of cytokines and include Western Blots or Fluorescence-activated cell growth factors, sorting. Outcome: association with PHLF Studies were excluded if the language was not English, Study design: any study except study protocols, not published in peer-reviewed journals, and if the letters, and common overviews. above-mentioned definitions of cytology or molecular diagnostics were not met. However, human trials in- Report characteristics: There were no restrictions re- cluded no randomized controlled trials, no multi-center garding languages, years of publication, or publication trials, 37 prospective single-center trials, and 3 retro- status in the initial search. Original articles, case reports, spective analyses. Case numbers were < 50 in the major- clinical trials, reviews, meta-analyses, and systematic re- ity of trials. views were all included.
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