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Liver resection for cancer: New developments in prediction, prevention and management of postresectional liver failure

  • Kim M.C. van Mierlo
    Affiliations
    Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
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  • Frank G. Schaap
    Affiliations
    Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
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  • Cornelis H.C. Dejong
    Affiliations
    Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands

    GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
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  • Steven W.M. Olde Damink
    Correspondence
    Corresponding author. Address: Universiteitssingel 50, H5.485, 6229 ER Maastricht, The Netherlands. Tel.: +31 43 3881497.
    Affiliations
    Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands

    Department of Surgery, Institute of Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom
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      Summary

      Hepatic failure is a feared complication that accounts for up to 75% of mortality after extensive liver resection. Despite improved perioperative care, the increasing complexity and extensiveness of surgical interventions, in combination with an expanding number of resections in patients with compromised liver function, still results in an incidence of postresectional liver failure (PLF) of 1–9%. Preventive measures aim to enhance future remnant liver size and function. Numerous non-invasive techniques to assess liver function and predict remnant liver volume are being developed, along with introduction of novel surgical strategies that augment growth of the future remnant liver. Detection of PLF is often too late and treatment is primarily symptomatic. Current therapeutic research focuses on ([bio]artificial) liver function support and regenerative medicine. In this review we discuss the current state and new developments in prediction, prevention and management of PLF, in light of novel insights into the aetiology of this complex syndrome.

      Lay summary

      Liver failure is the main cause of death after partial liver resection for cancer, and is presumably caused by an insufficient quantity and function of the liver remnant. Detection of liver failure is often too late, and current treatment focuses on relieve of symptoms. New research initiatives explore artificial support of liver function and stimulation of regrowth of the remnant liver.

      Abbreviations:

      PLF (postresectional liver failure), INR (international normalized ratio), RLV (remnant liver volume), CALI (chemotherapy-associated liver injury), CRLM (colorectal cancer liver metastasis), HCC (hepatocellular carcinoma), CCA (cholangiocarcinoma), SOS (sinusoidal obstruction syndrome), NRH (nodular regenerative hyperplasia), SD (sinusoidal dilatation), ALP (alkaline phosphatase), ICG-R15 (indocyanine green retention rate after 15min), APRI (AST-to-platelet-ratio index), NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis), MR (magnetic resonance), CT (computed tomography), TE (transient elastography), MRE (magnetic resonance elastography), ERCP (endoscopic retrograde cholangiopancreatography), PTBD (percutaneous transhepatic biliary drainage), PVE (portal vein embolization), ALPPS (associating liver partition and portal vein ligation for staged hepatectomy), FXR (Farnesoid X Receptor)

      Keywords

      Introduction

      Partial liver resection for hepatobiliary tumours is relatively safe and often the only curative treatment option. The unequalled capacity of the liver to regenerate and restore its functionalities permits the surgical removal of a substantial part of the liver mass. However, postresectional liver failure (PLF) occurs in up to 9% of patients and remains the main cause of postoperative mortality [
      • van den Broek M.A.
      • Olde Damink S.W.
      • Dejong C.H.
      • Lang H.
      • Malago M.
      • Jalan R.
      • et al.
      Liver failure after partial hepatic resection: definition, pathophysiology, risk factors and treatment.
      ,
      • Schindl M.J.
      • Redhead D.N.
      • Fearon K.C.
      • Garden O.J.
      • Wigmore S.J.
      • Edinburgh Liver S.
      • et al.
      The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection.
      ]. PLF has a subacute course, and an inadequate functional reserve of the remnant liver is central in its aetiology. Insufficient hepatic secretory capacity is reflected by hyperbilirubinemia, whereas decreased synthetic and detoxifying functions can manifest as coagulopathy and hepatic encephalopathy [
      • van den Broek M.A.
      • Olde Damink S.W.
      • Dejong C.H.
      • Lang H.
      • Malago M.
      • Jalan R.
      • et al.
      Liver failure after partial hepatic resection: definition, pathophysiology, risk factors and treatment.
      ].
      Postresectional liver failure (PLF) is the main cause of postoperative mortality after liver resection for hepatobiliary malignancy.
      Hyperbilirubinemia is included in all currently used definitions of PLF. The ‘50–50 criteria’ predict a 59% risk on early postoperative mortality if systemic bilirubin rises above 50 μmol/L and prothrombin time decreases to 50% on postoperative day 5 [
      • Balzan S.
      • Belghiti J.
      • Farges O.
      • Ogata S.
      • Sauvanet A.
      • Delefosse D.
      • et al.
      The “50-50 criteria” on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy.
      ]. The ‘peak bilirubin criterion’ defines PLF as a bilirubin level above 120 μmol/L within 90 days after major hepatectomy, and has a positive predictive value of 33% for liver-related death in non-cirrhotic patients [
      • Mullen J.T.
      • Ribero D.
      • Reddy S.K.
      • Donadon M.
      • Zorzi D.
      • Gautam S.
      • et al.
      Hepatic insufficiency and mortality in 1,059 noncirrhotic patients undergoing major hepatectomy.
      ]. The definition of PLF developed by the International Study Group of Liver Surgery encompasses bilirubin elevation (according to local criteria) on or after postoperative day 5, and grades PLF based on international normalized ratio (INR) derangement [
      • Rahbari N.N.
      • Garden O.J.
      • Padbury R.
      • Brooke-Smith M.
      • Crawford M.
      • Adam R.
      • et al.
      Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS).
      ]. Postoperative mortality in PLF grade A (INR <1.5), B (INR ⩾1.5 and <2.0) and C (INR ⩾2.0) was 0%, 12%, and 54%, respectively [
      • Rahbari N.N.
      • Garden O.J.
      • Padbury R.
      • Brooke-Smith M.
      • Crawford M.
      • Adam R.
      • et al.
      Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS).
      ]. In order to provide a comprehensive overview of this syndrome, no specific definition was selected for this review.

      Liver regeneration after partial liver resection

      Liver regeneration following partial hepatectomy is a tightly orchestrated process involving the spatiotemporal interplay between parenchymal and non-parenchymal cells and is driven by multiple signals (see for detailed reviews references [
      • Fausto N.
      • Campbell J.S.
      • Riehle K.J.
      Liver regeneration.
      ,
      • Michalopoulos G.K.
      Principles of liver regeneration and growth homeostasis.
      ]). First, immediately after partial liver resection, the total hepatic inflow passes through the vascular bed of the smaller remnant liver. Resultant shear stress, a relative increase in supply of signalling molecules from the (portal) circulation, and growth factors released after remodelling of the extracellular matrix, provide the triggers for initiation of liver regeneration. Interleukin 6 and tumour necrosis factor alpha released by activated Kupffer cells are important for cell cycle re-entry of normally quiescent hepatocytes, with further cell cycle progression driven by mitogens such as hepatocyte growth factor. Proliferation of the various non-parenchymal cell types enables re-establishment of the hepatic architecture. Through poorly understood molecular events, liver regeneration terminates when the original liver mass and functional capacity have been restored.

      Aetiology of postresectional liver failure

      Insufficient remnant liver volume and function are central in the aetiology of PLF, and detailed assessment of preoperative liver function is pivotal in surgical management of hepatobiliary tumours.
      During liver regeneration, a minimum amount of remnant liver is required to maintain vital liver functions and support regrowth. In a seminal study almost half of the patients with a remnant liver volume (RLV) smaller than 26.6% of the pre-resection value, developed severe hepatic dysfunction compared with 1.2% of patients with a larger RLV [
      • Schindl M.J.
      • Redhead D.N.
      • Fearon K.C.
      • Garden O.J.
      • Wigmore S.J.
      • Edinburgh Liver S.
      • et al.
      The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection.
      ]. Consequently, a RLV of 25–30% is currently used as lower limit in patients with normal liver function, whereas a minimum RLV of about 40% is mandatory in patients with impaired liver function [
      • Vauthey J.N.
      • Abbott D.E.
      Commentary on “Feasibility study of two-stage hepatectomy for bilobar liver metastases”.
      ]. Five main factors have been recognized in the aetiology of PLF (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Aetiology of postresectional liver failure. The altered blood-to-liver volume ratio causes elevated portal pressure and resultant shear stress and sinusoidal endothelial injury. Although Kupffer cells are activated, activity in the liver remnant is inadequate to initiate and/or maintain the innate immune response that drives postresectional liver regeneration. Combined with increased enteric bacterial translocation, the infectious risk is increased. Impaired canalicular secretion of bile salts results in intrahepatic accumulation and subsequent hepatocellular injury. In case of venous reconstruction, impaired hepatic outflow can result in hepatic venous congestion. Lastly, livers with compromised function due to chronic liver diseases are more vulnerable to perioperative ischemic reperfusion injury, as reflected in impaired recovery of postoperative liver function.

      Hepatic haemodynamic imbalance

      PLF shares features of the small-for-size syndrome that occurs in the setting of (partial) liver transplantation. Portal hyperperfusion of the remnant liver results in adaptive reduction of arterial blood flow through activation of the hepatic arterial buffer response (see reference [
      • Eipel C.
      • Abshagen K.
      • Vollmar B.
      Regulation of hepatic blood flow: the hepatic arterial buffer response revisited.
      ] for a detailed review). While increased perfusion and resultant shear stress are instrumental in initiating the regenerative cascade, portal hyperperfusion and arterial hypoperfusion may have deleterious effects on postoperative recovery of liver function [
      • Eipel C.
      • Abshagen K.
      • Vollmar B.
      Regulation of hepatic blood flow: the hepatic arterial buffer response revisited.
      ]. Increased portal flow and pressure after major hepatectomy increased the risk for PLF in non-cirrhotic patients [
      • Allard M.A.
      • Adam R.
      • Bucur P.O.
      • Termos S.
      • Cunha A.S.
      • Bismuth H.
      • et al.
      Posthepatectomy portal vein pressure predicts liver failure and mortality after major liver resection on noncirrhotic liver.
      ]. In patients undergoing partial liver transplantation, post-reperfusion portal hypertension resulted in sinusoidal damage and reduced levels of nitric oxide, a signal molecule engaged in the initiation of liver regeneration [
      • Golriz M.
      • Majlesara A.
      • El Sakka S.
      • Ashrafi M.
      • Arwin J.
      • Fard N.
      • et al.
      Small for Size and Flow (SFSF) syndrome: an alternative description for posthepatectomy liver failure.
      ].

      Unmet hepatic metabolic demand: disturbed bile salt homeostasis

      Impaired activity of the canalicular pump(s) involved in bilirubin secretion results in intrahepatic accumulation and systemic release of conjugated bilirubin [
      • Erlinger S.
      • Arias I.M.
      • Dhumeaux D.
      Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences.
      ]. While bilirubin is generally not regarded as detrimental to the liver, a more generalized dysfunction of canalicular transporters may result in hepatic accumulation of bile salts. Circulating levels of bile salts rise as early as one minute after partial hepatectomy in rats [
      • Doignon I.
      • Julien B.
      • Serriere-Lanneau V.
      • Garcin I.
      • Alonso G.
      • Nicou A.
      • et al.
      Immediate neuroendocrine signaling after partial hepatectomy through acute portal hyperpressure and cholestasis.
      ], and this is shortly followed by transient accumulation of bile salts in the liver [
      • Pean N.
      • Doignon I.
      • Garcin I.
      • Besnard A.
      • Julien B.
      • Liu B.
      • et al.
      The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice.
      ]. An important stimulatory role for bile salts and their membrane-bound and nuclear receptors in liver regeneration is emerging [
      • Huang W.
      • Ma K.
      • Zhang J.
      • Qatanani M.
      • Cuvillier J.
      • Liu J.
      • et al.
      Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration.
      ]. Being biological detergents, excessive intracellular accumulation of bile salts, however, causes damage to internal membranes (particularly in mitochondria) of the hepatocyte and results in apoptosis [
      • Perez M.J.
      • Briz O.
      Bile-acid-induced cell injury and protection.
      ]. In mice with deranged bile salt homeostasis, otherwise well-tolerated 70% partial hepatectomy results in massive hepatocyte necrosis and early mortality [
      • Uriarte I.
      • Fernandez-Barrena M.G.
      • Monte M.J.
      • Latasa M.U.
      • Chang H.C.
      • Carotti S.
      • et al.
      Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice.
      ]. Animal studies underscore that tight control of (hepatic) bile salt homeostasis is a prerequisite for unimpeded liver regeneration [
      • Uriarte I.
      • Fernandez-Barrena M.G.
      • Monte M.J.
      • Latasa M.U.
      • Chang H.C.
      • Carotti S.
      • et al.
      Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice.
      ,
      • Fan M.
      • Wang X.
      • Xu G.
      • Yan Q.
      • Huang W.
      Bile acid signaling and liver regeneration.
      ].

      Impaired liver innate immune defence

      Liver regeneration after partial hepatectomy involves activation of the livers’ innate immune system [
      • Fausto N.
      • Campbell J.S.
      • Riehle K.J.
      Liver regeneration.
      ]. Innate immune receptors of the Toll-like receptor family that recognize bacterial products, and downstream (adaptor) proteins that relay the signal intracellularly, are engaged in this activation step [
      • Chen Y.
      • Sun R.
      Toll-like receptors in acute liver injury and regeneration.
      ]. Liver-resident macrophages not only play an important role in the regenerative response after liver resection by producing priming factors, they also clear portal endotoxins and eliminate translocated bacteria [
      • Takeishi T.
      • Hirano K.
      • Kobayashi T.
      • Hasegawa G.
      • Hatakeyama K.
      • Naito M.
      The role of Kupffer cells in liver regeneration.
      ], thus limiting exposure of hepatocytes to (pro-apoptotic) lipopolysaccharide (LPS) and preventing systemic infection [
      • Prins H.A.
      • Meijer C.
      • Boelens P.G.
      • Diks J.
      • Holtz R.
      • Masson S.
      • et al.
      Kupffer cell-depleted rats have a diminished acute-phase response following major liver resection.
      ]. Following resection, adequate numbers of Kupffer cells should remain to preserve these essential functions. The risk of infection increases with the extent of resection, and a majority of patients with hepatic dysfunction also develops infectious complications [
      • Schindl M.J.
      • Redhead D.N.
      • Fearon K.C.
      • Garden O.J.
      • Wigmore S.J.
      • Edinburgh Liver S.
      • et al.
      The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection.
      ]. Cytokine release by activated Kupffer cells is hampered after major liver resection [
      • Prins H.A.
      • Meijer C.
      • Boelens P.G.
      • Diks J.
      • Holtz R.
      • Masson S.
      • et al.
      Kupffer cell-depleted rats have a diminished acute-phase response following major liver resection.
      ]. Likewise, impaired phagocytic activity of the reticuloendothelial system is observed after major resection [
      • Schindl M.J.
      • Millar A.M.
      • Redhead D.N.
      • Fearon K.C.
      • Ross J.A.
      • Dejong C.H.
      • et al.
      The adaptive response of the reticuloendothelial system to major liver resection in humans.
      ], and this likely contributes to increased infectious risk [
      • Schindl M.J.
      • Redhead D.N.
      • Fearon K.C.
      • Garden O.J.
      • Wigmore S.J.
      • Edinburgh Liver S.
      • et al.
      The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection.
      ].

      Gut microbiome-gut-liver axis

      An emerging concept is that the gut microbiota modulates the regenerative ability of the liver (reviewed in reference [
      • Liu H.X.
      • Keane R.
      • Sheng L.
      • Wan Y.J.
      Implications of microbiota and bile acid in liver injury and regeneration.
      ]). This is likely to involve interactions between the gut microbiome and host metabolism, effects of the gut microbiota on bile salt physiology, as well as effects of bacterial endotoxins [
      • Liu H.X.
      • Keane R.
      • Sheng L.
      • Wan Y.J.
      Implications of microbiota and bile acid in liver injury and regeneration.
      ,
      • Liu H.X.
      • Rocha C.S.
      • Dandekar S.
      • Yvonne Wan Y.J.
      Functional analysis of the relationship between intestinal microbiota and the expression of hepatic genes and pathways during the course of liver regeneration.
      ]. Bile salts exert direct anti-microbial activity and shape the composition of the gut flora. Conversely, certain microbial strains can convert the host’s primary bile salts into secondary species, thus affecting the signalling properties of bile salts. This again can impact host metabolism, bile salt homeostasis, and liver regeneration [
      • Joyce S.A.
      • MacSharry J.
      • Casey P.G.
      • Kinsella M.
      • Murphy E.F.
      • Shanahan F.
      • et al.
      Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut.
      ,
      • Sayin S.I.
      • Wahlstrom A.
      • Felin J.
      • Jantti S.
      • Marschall H.U.
      • Bamberg K.
      • et al.
      Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.
      ,
      • Liu H.X.
      • Hu Y.
      • Wan Y.Y.
      Microbiota and bile acid profiles in retinoic acid-primed mice that exhibit accelerated liver regeneration.
      ]. As discussed above, activation of the innate immune response in the liver is important for liver regeneration after partial hepatectomy, and microbial products including LPS are implicated in Kupffer cell activation [
      • Cornell R.P.
      Gut-derived endotoxin elicits hepatotrophic factor secretion for liver regeneration.
      ]. Failure of gut-derived endotoxins to reach the liver resulted in impaired DNA synthesis in replicating hepatocytes, likely through reduced production of priming factors [
      • Cornell R.P.
      Restriction of gut-derived endotoxin impairs DNA synthesis for liver regeneration.
      ]. On the other hand, excessive levels of endotoxin can impair liver regeneration and cause mortality after extended hepatectomy.

      Impaired background liver function

      Impaired liver quality plays a pivotal role in PLF and is frequently present in patients that undergo partial hepatectomy for the three most common indications: colorectal cancer liver metastasis (CRLM), hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Four types of liver pathology are related to these hepatobiliary tumours, viz. chemotherapy-associated liver injury, fatty degeneration, fibrotic progression, and cholestasis.

      Chemotherapy-associated liver injury (CALI)

      Four types of parenchymal dysfunction (chemotherapy-associated liver injury, fatty degeneration, fibrosis and cholestasis) are increasingly observed.
      Neoadjuvant chemotherapy is widely used for downstaging of CRLM. Oxaliplatin is central in most currently used regimens and is considered the main causative agent for development of sinusoidal obstruction syndrome (SOS) and nodular regenerative hyperplasia (NRH), whereas irinotecan has been associated with the development of chemotherapy-associated steatohepatitis.

      Sinusoidal obstruction syndrome

      SOS is seen in up to 80% of patients undergoing oxaliplatin-based chemotherapy [
      • Rubbia-Brandt L.
      • Audard V.
      • Sartoretti P.
      • Roth A.D.
      • Brezault C.
      • Le Charpentier M.
      • et al.
      Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer.
      ], and is characterized by injury of endothelial cells, parenchymal damage, and (fibrotic) venular lesions. Sinusoidal dilatation (SD) is the most common manifestation of SOS in the grading system of Rubbia-Brandt et al. [
      • Rubbia-Brandt L.
      • Audard V.
      • Sartoretti P.
      • Roth A.D.
      • Brezault C.
      • Le Charpentier M.
      • et al.
      Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer.
      ].
      Although exact mechanisms are unclear, a diminished preoperative functional reserve and longer hospital stay after major hepatectomy was reported in patients with SD [
      • Nakano H.
      • Oussoultzoglou E.
      • Rosso E.
      • Casnedi S.
      • Chenard-Neu M.P.
      • Dufour P.
      • et al.
      Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy.
      ]. The effect of SD on development of PLF is uncertain. Studies indicate no effect, or an incidence of PLF in up to 21% of patients with moderate to severe SD after major hepatectomy (0–4.2% in patients with absent or mild SD) [
      • Soubrane O.
      • Brouquet A.
      • Zalinski S.
      • Terris B.
      • Brezault C.
      • Mallet V.
      • et al.
      Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin-based chemotherapy for colorectal liver metastases: correlation with post-hepatectomy outcome.
      ,
      • Vigano L.
      • Ravarino N.
      • Ferrero A.
      • Motta M.
      • Torchio B.
      • Capussotti L.
      Prospective evaluation of accuracy of liver biopsy findings in the identification of chemotherapy-associated liver injuries.
      ]. Rodent models using monocrotalin or oxaliplatin to induce SOS revealed impairment of liver regeneration and induction of liver injury following partial hepatectomy [
      • Schiffer E.
      • Frossard J.L.
      • Rubbia-Brandt L.
      • Mentha G.
      • Pastor C.M.
      Hepatic regeneration is decreased in a rat model of sinusoidal obstruction syndrome.
      ]. This was accompanied by less pronounced induction of hepatic mitogens, reduced liver volume recovery, enhanced hepatocellular necrosis and higher serum alanine aminotransferase (ALT) and bilirubin levels [
      • Schiffer E.
      • Frossard J.L.
      • Rubbia-Brandt L.
      • Mentha G.
      • Pastor C.M.
      Hepatic regeneration is decreased in a rat model of sinusoidal obstruction syndrome.
      ,
      • Hubert C.
      • Dahrenmoller C.
      • Marique L.
      • Jabbour N.
      • Gianello P.
      • Leclercq I.
      Hepatic regeneration in a rat model is impaired by chemotherapy agents used in metastatic colorectal cancer.
      ].
      Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor A, decreased the incidence of SD in patients that received oxaliplatin-based chemotherapy [
      • Ribero D.
      • Wang H.
      • Donadon M.
      • Zorzi D.
      • Thomas M.B.
      • Eng C.
      • et al.
      Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases.
      ]. Downregulation of matrix metallopeptidase-9, a fibrotic remodelling factor involved in perisinusoidal extracellular matrix breakdown, may be accountable [
      • Rubbia-Brandt L.
      • Lauwers G.Y.
      • Wang H.
      • Majno P.E.
      • Tanabe K.
      • Zhu A.X.
      • et al.
      Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis.
      ].
      SD is a histological diagnosis and can be detected by biopsy, however the false-negative classification is high due to the spatial heterogeneity of its manifestation [
      • Vigano L.
      • Ravarino N.
      • Ferrero A.
      • Motta M.
      • Torchio B.
      • Capussotti L.
      Prospective evaluation of accuracy of liver biopsy findings in the identification of chemotherapy-associated liver injuries.
      ]. Surrogate measures are biochemical assessment, functional tests, imaging and spleen size measurement. Increased aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels can point to SD, but are non-specific. An indocyanine green retention rate after 15 min (ICG-R15) >10% and the preoperative AST-to-platelet-ratio index (APRI) are both independently associated with the presence of SD [
      • Nakano H.
      • Oussoultzoglou E.
      • Rosso E.
      • Casnedi S.
      • Chenard-Neu M.P.
      • Dufour P.
      • et al.
      Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy.
      ,
      • Soubrane O.
      • Brouquet A.
      • Zalinski S.
      • Terris B.
      • Brezault C.
      • Mallet V.
      • et al.
      Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin-based chemotherapy for colorectal liver metastases: correlation with post-hepatectomy outcome.
      ]. Patients with SD often have an increased spleen volume [
      • Imai K.
      • Emi Y.
      • Iyama K.I.
      • Beppu T.
      • Ogata Y.
      • Kakeji Y.
      • et al.
      Splenic volume may be a useful indicator of the protective effect of bevacizumab against oxaliplatin-induced hepatic sinusoidal obstruction syndrome.
      ], with an increase of ⩾30% reported to be predictive of SD [
      • Overman M.J.
      • Maru D.M.
      • Charnsangavej C.
      • Loyer E.M.
      • Wang H.
      • Pathak P.
      • et al.
      Oxaliplatin-mediated increase in spleen size as a biomarker for the development of hepatic sinusoidal injury.
      ]. Another typical SD-related abnormality seen in imaging is reticular hypointensity that presumably reflects locally impaired Kupffer cell function [
      • Ward J.
      • Guthrie J.A.
      • Sheridan M.B.
      • Boyes S.
      • Smith J.T.
      • Wilson D.
      • et al.
      Sinusoidal obstructive syndrome diagnosed with superparamagnetic iron oxide-enhanced magnetic resonance imaging in patients with chemotherapy-treated colorectal liver metastases.
      ]. Superparamagnetic iron oxide-enhanced MRI can detect moderate to severe SD [
      • Ward J.
      • Guthrie J.A.
      • Sheridan M.B.
      • Boyes S.
      • Smith J.T.
      • Wilson D.
      • et al.
      Sinusoidal obstructive syndrome diagnosed with superparamagnetic iron oxide-enhanced magnetic resonance imaging in patients with chemotherapy-treated colorectal liver metastases.
      ], but gadoxetic acid-enhanced MRI seems superior with a specificity of 96–100% on hepatobiliary phase images [
      • Shin N.Y.
      • Kim M.J.
      • Lim J.S.
      • Park M.S.
      • Chung Y.E.
      • Choi J.Y.
      • et al.
      Accuracy of gadoxetic acid-enhanced magnetic resonance imaging for the diagnosis of sinusoidal obstruction syndrome in patients with chemotherapy-treated colorectal liver metastases.
      ].

      Nodular regenerative hyperplasia

      A second histological characteristic of SOS is NRH, which is observed in over 24% of patients after oxaliplatin-based chemotherapy [
      • Rubbia-Brandt L.
      • Lauwers G.Y.
      • Wang H.
      • Majno P.E.
      • Tanabe K.
      • Zhu A.X.
      • et al.
      Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis.
      ]. NRH is characterized by diffuse transformation of liver parenchyma into regenerative nodules that compress the surrounding parenchyma, and is graded according to Wanless et al. [
      • Wanless I.R.
      Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules.
      ]. NRH probably arises due to changes in intrahepatic sinusoidal or portal blood flow [
      • Wanless I.R.
      Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules.
      ].
      The incidence of PLF is increased in patients with NRH, even rising to 25% after major hepatectomy in patients with moderate to severe NRH [
      • Vigano L.
      • Rubbia-Brandt L.
      • De Rosa G.
      • Majno P.
      • Langella S.
      • Toso C.
      • et al.
      Nodular regenerative hyperplasia in patients undergoing liver resection for colorectal metastases after chemotherapy: risk factors, preoperative assessment and clinical impact.
      ]. Furthermore, coexistence of NRH with moderate to severe SD has been noted [
      • Vigano L.
      • Rubbia-Brandt L.
      • De Rosa G.
      • Majno P.
      • Langella S.
      • Toso C.
      • et al.
      Nodular regenerative hyperplasia in patients undergoing liver resection for colorectal metastases after chemotherapy: risk factors, preoperative assessment and clinical impact.
      ]. Since SD, in contrast to NRH, was no indisputable risk indicator for postoperative outcome, it was suggested that NRH is the true determinant of poor short-term outcome after liver resection. Although the mechanism is not elucidated, hepatic injury, portal hypertension and a lower platelet count may predispose to PLF [
      • van den Broek M.A.
      • Olde Damink S.W.
      • Driessen A.
      • Dejong C.H.
      • Bemelmans M.H.
      Nodular regenerative hyperplasia secondary to neoadjuvant chemotherapy for colorectal liver metastases.
      ].
      A decreased platelet count combined with elevated ALP, gamma-glutamyltransferase (GGT), and total bilirubin levels can be found in NRH [
      • Wicherts D.A.
      • de Haas R.J.
      • Sebagh M.
      • Ciacio O.
      • Levi F.
      • Paule B.
      • et al.
      Regenerative nodular hyperplasia of the liver related to chemotherapy: impact on outcome of liver surgery for colorectal metastases.
      ]. APRI can predict NRH [
      • Vigano L.
      • Rubbia-Brandt L.
      • De Rosa G.
      • Majno P.
      • Langella S.
      • Toso C.
      • et al.
      Nodular regenerative hyperplasia in patients undergoing liver resection for colorectal metastases after chemotherapy: risk factors, preoperative assessment and clinical impact.
      ]. Percutaneous or transjugular liver biopsy with hepatic venous pressure gradient measurement may be used as a diagnostic tool, but should solely be applied in selected high-risk patients [
      • Vigano L.
      • Rubbia-Brandt L.
      • De Rosa G.
      • Majno P.
      • Langella S.
      • Toso C.
      • et al.
      Nodular regenerative hyperplasia in patients undergoing liver resection for colorectal metastases after chemotherapy: risk factors, preoperative assessment and clinical impact.
      ]. Reversibility of histological features is uncertain and bevacizumab seems to protect against development of NRH [
      • Rubbia-Brandt L.
      • Lauwers G.Y.
      • Wang H.
      • Majno P.E.
      • Tanabe K.
      • Zhu A.X.
      • et al.
      Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis.
      ].

      Chemotherapy-associated steatohepatitis

      Irinotecan is associated with chemotherapy-induced steatohepatitis with widely ranging incidence reported in literature [
      • Robinson S.M.
      • Wilson C.H.
      • Burt A.D.
      • Manas D.M.
      • White S.A.
      Chemotherapy-associated liver injury in patients with colorectal liver metastases: a systematic review and meta-analysis.
      ], and steatohepatitis after irinotecan proved to increase the risk of death from PLF [
      • Vauthey J.N.
      • Pawlik T.M.
      • Ribero D.
      • Wu T.T.
      • Zorzi D.
      • Hoff P.M.
      • et al.
      Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases.
      ]. Histopathological findings, prediction and prevention will be discussed below in conjunction with steatosis/steatohepatitis.

      Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

      The prevalence of non-alcoholic fatty liver disease (NAFLD) in the adult Western population is approximately 20–30% and around 3–5% of adults are estimated to have non-alcoholic steatohepatitis (NASH) [
      • Vernon G.
      • Baranova A.
      • Younossi Z.M.
      Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.
      ]. Despite lack of absolute consensus [
      • Little S.A.
      • Jarnagin W.R.
      • DeMatteo R.P.
      • Blumgart L.H.
      • Fong Y.
      Diabetes is associated with increased perioperative mortality but equivalent long-term outcome after hepatic resection for colorectal cancer.
      ,
      • Newberry E.P.
      • Kennedy S.M.
      • Xie Y.
      • Luo J.
      • Stanley S.E.
      • Semenkovich C.F.
      • et al.
      Altered hepatic triglyceride content after partial hepatectomy without impaired liver regeneration in multiple murine genetic models.
      ], steatosis and NAFLD seem to be risk factors for PLF and higher overall postoperative morbidity and mortality [
      • Schindl M.J.
      • Redhead D.N.
      • Fearon K.C.
      • Garden O.J.
      • Wigmore S.J.
      • Edinburgh Liver S.
      • et al.
      The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection.
      ,
      • de Meijer V.E.
      • Kalish B.T.
      • Puder M.
      • Ijzermans J.N.
      Systematic review and meta-analysis of steatosis as a risk factor in major hepatic resection.
      ,
      • Reddy S.K.
      • Marsh J.W.
      • Varley P.R.
      • Mock B.K.
      • Chopra K.B.
      • Geller D.A.
      • et al.
      Underlying steatohepatitis, but not simple hepatic steatosis, increases morbidity after liver resection: a case-control study.
      ].
      Rodent models show that vulnerability of the steatotic liver may be due to reduced tolerance against ischemic injury caused by decreased perfusion of the liver [
      • Tashiro H.
      • Kuroda S.
      • Mikuriya Y.
      • Ohdan H.
      Ischemia-reperfusion injury in patients with fatty liver and the clinical impact of steatotic liver on hepatic surgery.
      ]. In addition, mitochondrial dysfunction in NAFLD results in impaired ATP synthesis, while Kupffer cell dysfunction increases reactive oxygen production which causes hepatocellular injury [
      • Tashiro H.
      • Kuroda S.
      • Mikuriya Y.
      • Ohdan H.
      Ischemia-reperfusion injury in patients with fatty liver and the clinical impact of steatotic liver on hepatic surgery.
      ,
      • Vetelainen R.
      • van Vliet A.
      • Gouma D.J.
      • van Gulik T.M.
      Steatosis as a risk factor in liver surgery.
      ]. In the steatotic liver the ability of hepatocytes to regenerate after major tissue loss is impaired [
      • Selzner M.
      • Clavien P.A.
      Failure of regeneration of the steatotic rat liver: disruption at two different levels in the regeneration pathway.
      ]. Multiple pathways contribute to unresponsiveness of fatty hepatocytes to regenerative stimuli, and subsequent cell cycle arrest [
      • Yang S.Q.
      • Lin H.Z.
      • Mandal A.K.
      • Huang J.
      • Diehl A.M.
      Disrupted signaling and inhibited regeneration in obese mice with fatty livers: implications for nonalcoholic fatty liver disease pathophysiology.
      ]. Furthermore, cell cycle transition may be negatively affected by disturbed energy homeostasis in the fatty liver [
      • Vetelainen R.
      • van Vliet A.
      • Gouma D.J.
      • van Gulik T.M.
      Steatosis as a risk factor in liver surgery.
      ].
      Biopsy remains the most reliable method for assessment of NAFLD but is increasingly replaced by non-invasive alternatives due to a small risk for complications and sampling errors [
      • Myers R.P.
      • Fong A.
      • Shaheen A.A.
      Utilization rates, complications and costs of percutaneous liver biopsy: a population-based study including 4275 biopsies.
      ,
      • Regev A.
      • Berho M.
      • Jeffers L.J.
      • Milikowski C.
      • Molina E.G.
      • Pyrsopoulos N.T.
      • et al.
      Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection.
      ]. Non-invasive methods consist of functional liver tests, breath tests, imaging, and biomarkers that assess steatosis and fibrosis. The majority of patients with NAFLD have normal liver function tests, however some have elevated ALT, AST, GGT, and/or serum ferritin. Ultrasonography is still the imaging modality of choice in patients with >33% parenchymal steatosis, but its accuracy decreases in obese patients [
      • de Moura Almeida A.
      • Cotrim H.P.
      • Barbosa D.B.
      • de Athayde L.G.
      • Santos A.S.
      • Bitencourt A.G.
      • et al.
      Fatty liver disease in severe obese patients: diagnostic value of abdominal ultrasound.
      ]. Magnetic resonance (MR) imaging (MRI) and MR spectroscopy directly quantify fat and outperform computed tomography (CT) and ultrasonography for prediction of steatosis when the fat content is >5.5% [
      • Lee S.S.
      • Park S.H.
      • Kim H.J.
      • Kim S.Y.
      • Kim M.Y.
      • Kim D.Y.
      • et al.
      Non-invasive assessment of hepatic steatosis: prospective comparison of the accuracy of imaging examinations.
      ].
      Transient elastography (TE) and MR elastography (MRE) indicate fibrosis by measuring liver stiffness. TE predominantly detects cirrhosis [
      • Tsochatzis E.A.
      • Gurusamy K.S.
      • Ntaoula S.
      • Cholongitas E.
      • Davidson B.R.
      • Burroughs A.K.
      Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy.
      ], and MRE can distinguish advanced from mild fibrosis [
      • Loomba R.
      • Wolfson T.
      • Ang B.
      • Hooker J.
      • Behling C.
      • Peterson M.
      • et al.
      Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study.
      ]. Especially TE is easily applied in clinic but its use is limited by obesity, although utilization of an XL-probe improves accuracy in obese patients [
      • de Ledinghen V.
      • Vergniol J.
      • Foucher J.
      • El-Hajbi F.
      • Merrouche W.
      • Rigalleau V.
      Feasibility of liver transient elastography with FibroScan using a new probe for obese patients.
      ].
      Simultaneous measurement of steatosis and fibrosis can be accomplished by integration of the controlled attenuation parameter in TE or acoustic radiation force impulse in a conventional ultrasonography machine [
      • Shi K.Q.
      • Tang J.Z.
      • Zhu X.L.
      • Ying L.
      • Li D.W.
      • Gao J.
      • et al.
      Controlled attenuation parameter for the detection of steatosis severity in chronic liver disease: a meta-analysis of diagnostic accuracy.
      ,
      • Palmeri M.L.
      • Wang M.H.
      • Rouze N.C.
      • Abdelmalek M.F.
      • Guy C.D.
      • Moser B.
      • et al.
      Noninvasive evaluation of hepatic fibrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease.
      ]. Serum fibroblast growth factor 21 (Fgf21) and cytokeratin 18 are biomarkers that can discriminate between NASH and NAFLD [
      • Shen J.
      • Chan H.L.
      • Wong G.L.
      • Choi P.C.
      • Chan A.W.
      • Chan H.Y.
      • et al.
      Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers.
      ,
      • Cusi K.
      • Chang Z.
      • Harrison S.
      • Lomonaco R.
      • Bril F.
      • Orsak B.
      • et al.
      Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease.
      ], and NAFLD, NASH and fibrosis [
      • Shen J.
      • Chan H.L.
      • Wong G.L.
      • Choi P.C.
      • Chan A.W.
      • Chan H.Y.
      • et al.
      Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers.
      ,
      • Cusi K.
      • Chang Z.
      • Harrison S.
      • Lomonaco R.
      • Bril F.
      • Orsak B.
      • et al.
      Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease.
      ]. The fibrosis-4 score showed a negative predictive value of 98% for detecting patients without advanced fibrosis [
      • Sumida Y.
      • Yoneda M.
      • Hyogo H.
      • Itoh Y.
      • Ono M.
      • Fujii H.
      • et al.
      Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population.
      ]. Other combined parameters that assess hepatic fibrosis are the APRI, FibroMeter NAFLD, NAFLD fibrosis score, and BARD score [
      • Harrison S.A.
      • Oliver D.
      • Arnold H.L.
      • Gogia S.
      • Neuschwander-Tetri B.A.
      Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease.
      ,
      • Angulo P.
      • Hui J.M.
      • Marchesini G.
      • Bugianesi E.
      • George J.
      • Farrell G.C.
      • et al.
      The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD.
      ,
      • Cales P.
      • Oberti F.
      • Michalak S.
      • Hubert-Fouchard I.
      • Rousselet M.C.
      • Konate A.
      • et al.
      A novel panel of blood markers to assess the degree of liver fibrosis.
      ,
      • Wai C.T.
      • Greenson J.K.
      • Fontana R.J.
      • Kalbfleisch J.D.
      • Marrero J.A.
      • Conjeevaram H.S.
      • et al.
      A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C.
      ].

      Fibrosis and cirrhosis

      Hepatic fibrosis is mainly present in patients undergoing partial liver resection for HCC, and is mostly caused by progression of steatosis or related to chronic viral hepatitis [
      • de Lope C.R.
      • Tremosini S.
      • Forner A.
      • Reig M.
      • Bruix J.
      Management of HCC.
      ]. In the past, the decreased regenerative capacity of the fibrotic liver increased the risk of PLF and caused postoperative mortality rates of around 15% [
      • Makuuchi M.
      • Sano K.
      The surgical approach to HCC: our progress and results in Japan.
      ]. Present mortality rates have declined to 0–5% due to advances in preoperative liver function assessment and strict patient selection [
      • de Lope C.R.
      • Tremosini S.
      • Forner A.
      • Reig M.
      • Bruix J.
      Management of HCC.
      ] (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Flow chart for decision-making in liver surgery. 5′,5′-nucleotidase; AFRI, acoustic radiation force impulse imaging; ALP, alkaline phosphatase; ALPPS, associating liver partition and portal vein ligation for staged hepatectomy; ALT, alanine transaminase; AOS, arterial oxygen saturation; AST, aspartate transaminase; BAL, bio-artificial liver; bili, total bilirubin; BD, bile duct; BMI, body mass index; BS, bile salts; C18, cytokeratin 18; CALI, chemotherapy-associated liver injury; CASH, chemotherapy-associated steatohepatitis; CP, Child-Pugh; CPV, central venous pressure; CRLM, colorectal liver metastases; CT, computed tomography; Ctx, chemotherapy; CVOS, central venous oxygen saturation; EOB, gadoxetic acid-enhanced; ERCP, endoscopic retrograde cholangiopancreatography; Fgf21, fibroblast growth factor 21; GGT, gamma-glutamyl transferase; HCC, hepatocellular carcinoma; HCT, hematocrit; HE, hepatic encephalopathy; I/R, ischemia-reperfusion injury; ICG, indocyanine green clearance; IM, imaging; INR, international normalized ratio; ISGLS, International Study Group of Liver Surgery; Lab, laboratory findings; Ltx, liver transplantation; MAP, mean arterial pressure; MARS, molecular absorbent recirculation system; MBS, metabolic syndrome; MR, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreatography; MRE, magnetic resonance elastography; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NRH, nodular regenerative hyperplasia; PA, pathology; PCWP, pulmonary capillary wedge pressure; plat, platelets; PLI, postoperative liver insufficiency; POD, postoperative day; PT, prothrombin time; PTBD, percutaneous transhepatic biliary drainage; PVE, portal vein embolization; Re-PVE, recurrent portal vein embolization; RFA, radiofrequency ablation; SPIO, superparamagnetic iron oxide-enhanced; SV, splenic volume; TE, transient elastography; US, ultrasonography. ^Barcelona clinic criteria ∗Resection criteria are expanded and presumably differ between centres; †in case of bleeding; ‡only tested pre-clinically or in acute liver failure/acute-on-chronic liver failure.
      Little is known about the influence of fibrosis on PLF. Regeneration of the fibrotic liver is suggested to be a progenitor cell-mediated process, in contrast to replication of existing mature hepatocytes in the non-compromised liver [
      • Kuramitsu K.
      • Sverdlov D.Y.
      • Liu S.B.
      • Csizmadia E.
      • Burkly L.
      • Schuppan D.
      • et al.
      Failure of fibrotic liver regeneration in mice is linked to a severe fibrogenic response driven by hepatic progenitor cell activation.
      ]. Animal studies indicate that impaired regeneration and subsequent hepatic dysfunction following partial liver resection are due to inefficient induction of cell cycle transition mediators, hepatocyte necrosis, and a pronounced fibrogenic response [
      • Kuramitsu K.
      • Sverdlov D.Y.
      • Liu S.B.
      • Csizmadia E.
      • Burkly L.
      • Schuppan D.
      • et al.
      Failure of fibrotic liver regeneration in mice is linked to a severe fibrogenic response driven by hepatic progenitor cell activation.
      ,
      • Kato A.
      • Bamba H.
      • Shinohara M.
      • Yamauchi A.
      • Ota S.
      • Kawamoto C.
      • et al.
      Relationship between expression of cyclin D1 and impaired liver regeneration observed in fibrotic or cirrhotic rats.
      ]. Enhanced bacterial translocation and decreased innate and adaptive immune system activity add to vulnerability of the fibrotic liver as shown in animal and human studies [
      • Jalan R.
      • Fernandez J.
      • Wiest R.
      • Schnabl B.
      • Moreau R.
      • Angeli P.
      • et al.
      Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013.
      ].
      For diagnostic purposes, percutaneous biopsy is increasingly replaced by four-pass transjugular biopsy [
      • Vibhakorn S.
      • Cholongitas E.
      • Kalambokis G.
      • Manousou P.
      • Quaglia A.
      • Marelli L.
      • et al.
      A comparison of four- vs. three-pass transjugular biopsy using a 19-G Tru-Cut needle and a randomized study using a cassette to prevent biopsy fragmentation.
      ], which provides the advantage of concurrent measurement of the hepatic venous pressure gradient (HVPG). Class I biomarkers (e.g., AST) reflect activity of fibrogenesis, whereas class II biomarkers (e.g. APRI) correlate with fibrosis [
      • Wong G.L.
      • Espinosa W.Z.
      • Wong V.W.
      Personalized management of cirrhosis by non-invasive tests of liver fibrosis.
      ]. TE is the most applied technique, but shows low accuracy in patients with obesity or ascites [
      • Bota S.
      • Herkner H.
      • Sporea I.
      • Salzl P.
      • Sirli R.
      • Neghina A.M.
      • et al.
      Meta-analysis: ARFI elastography vs. transient elastography for the evaluation of liver fibrosis.
      ]. Both TE and acoustic radiation force impulse have high accuracy for assessment of cirrhosis [
      • Bota S.
      • Herkner H.
      • Sporea I.
      • Salzl P.
      • Sirli R.
      • Neghina A.M.
      • et al.
      Meta-analysis: ARFI elastography vs. transient elastography for the evaluation of liver fibrosis.
      ]. Additionally, multiple combination serum tests, such as the FibroTest, Hepascore, and FibroMeter, are used with or without TE [
      • Tsochatzis E.A.
      • Bosch J.
      • Burroughs A.K.
      Liver cirrhosis.
      ]. Gadolinium-enhanced MRI is promising as it showed significant signal intensity differences between patients with and without fibrosis [
      • Verloh N.
      • Utpatel K.
      • Haimerl M.
      • Zeman F.
      • Fellner C.
      • Fichtner-Feigl S.
      • et al.
      Liver fibrosis and Gd-EOB-DTPA-enhanced MRI: a histopathologic correlation.
      ].
      Two preoperative parameters that directly predict development of PLF in patients with cirrhosis are an RLV-to-body weight ratio <1.4% [
      • Lin X.J.
      • Yang J.
      • Chen X.B.
      • Zhang M.
      • Xu M.Q.
      The critical value of remnant liver volume-to-body weight ratio to estimate posthepatectomy liver failure in cirrhotic patients.
      ] and the change in portal venous pressure [
      • Chen X.
      • Zhai J.
      • Cai X.
      • Zhang Y.
      • Wei L.
      • Shi L.
      • et al.
      Severity of portal hypertension and prediction of postoperative liver failure after liver resection in patients with Child-Pugh grade A cirrhosis.
      ]. Furthermore, whereas portal hypertension ought to be a contraindication for hepatic resection in patients with HCC, a recent study on the relationship between the HVPG and the development of PLF found that even in patients with a pressure gradient ⩾10 mmHg, one-quarter of the patients experienced an uneventful postoperative course [
      • Cucchetti A.
      • Cescon M.
      • Golfieri R.
      • Piscaglia F.
      • Renzulli M.
      • Neri F.
      • et al.
      Hepatic venous pressure gradient in the preoperative assessment of patients with resectable hepatocellular carcinoma.
      ].

      Cholestasis

      Obstructive cholestasis is characterized by retention of biliary constituents and a ductular reaction, and upon longer duration by hepatocyte degeneration, bile salt stasis, and progression of the ductular reaction to biliary fibrosis [
      • Desmet V.J.
      Histopathology of cholestasis.
      ]. Patients with perihilar CCA often present with jaundice, weight loss, and cholangitis, whereas intrahepatic CCA is frequently associated with a silent clinical course and general symptoms such as malaise and loss of appetite resulting in late detection [
      • Razumilava N.
      • Gores G.J.
      Classification, diagnosis, and management of cholangiocarcinoma.
      ].
      After extensive resection for perihilar CCA, PLF is seen in up to 30% of patients and mortality occurs in around 8–12% of patients [
      • Neuhaus P.
      • Thelen A.
      • Jonas S.
      • Puhl G.
      • Denecke T.
      • Veltzke-Schlieker W.
      • et al.
      Oncological superiority of hilar en bloc resection for the treatment of hilar cholangiocarcinoma.
      ,
      • Nuzzo G.
      • Giuliante F.
      • Ardito F.
      • Giovannini I.
      • Aldrighetti L.
      • Belli G.
      • et al.
      Improvement in perioperative and long-term outcome after surgical treatment of hilar cholangiocarcinoma: results of an Italian multicenter analysis of 440 patients.
      ], possibly due to a combination of cholangitis and a small RLV [
      • Wiggers J.K.
      • Koerkamp B.G.
      • Cieslak K.P.
      • Doussot A.
      • van Klaveren D.
      • Allen P.J.
      • et al.
      Postoperative mortality after liver resection for perihilar cholangiocarcinoma: development of a risk score and importance of biliary drainage of the future liver remnant.
      ]. A complication rate of up to 38% is reported after surgical removal of intrahepatic CCA, with few patients developing PLF and a mortality rate of approximately 1% [
      • Endo I.
      • Gonen M.
      • Yopp A.C.
      • Dalal K.M.
      • Zhou Q.
      • Klimstra D.
      • et al.
      Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection.
      ].
      Animal studies suggest that biliary dilatation caused by distal obstruction compresses the portal triad resulting in a decreased portal flow with subsequent compensatory increased arterial flow in combination with portosystemic shunting (reviewed in reference [
      • Yokoyama Y.
      • Nagino M.
      • Nimura Y.
      Mechanism of impaired hepatic regeneration in cholestatic liver.
      ]). Additionally, the interrupted enterohepatic circulation, lower expression of proliferative mediators in the priming and early phase of regeneration, and toxic bile-associated hepatocyte apoptosis, add to defective regeneration after partial resection of the obstructed liver in rodents [
      • Yokoyama Y.
      • Nagino M.
      • Nimura Y.
      Mechanism of impaired hepatic regeneration in cholestatic liver.
      ]. A significant suppression of mitotic indices and lower hepatic weight gain after partial hepatectomy is observed in cholestatic rats [
      • Tracy Jr., T.F.
      • Bailey P.V.
      • Goerke M.E.
      • Sotelo-Avila C.
      • Weber T.R.
      Cholestasis without cirrhosis alters regulatory liver gene expression and inhibits hepatic regeneration.
      ]. Furthermore, animal studies provided evidence for enhanced susceptibility to post-ischemic reperfusion injury in cholestatic rats [
      • Yoshidome H.
      • Miyazaki M.
      • Shimizu H.
      • Ito H.
      • Nakagawa K.
      • Ambiru S.
      • et al.
      Obstructive jaundice impairs hepatic sinusoidal endothelial cell function and renders liver susceptible to hepatic ischemia/reperfusion.
      ]. The detrimental role of Kupffer cells in cholestatic injury is demonstrated by amelioration of injury in bile duct-ligated mice with prior depletion of Kupffer cells [
      • Gehring S.
      • Dickson E.M.
      • San Martin M.E.
      • van Rooijen N.
      • Papa E.F.
      • Harty M.W.
      • et al.
      Kupffer cells abrogate cholestatic liver injury in mice.
      ]. Moreover, an excessive inflammatory response through pro-inflammatory cytokine production led to deterioration of hepatic function after bile duct ligation, resulting in enhanced susceptibility to infection [
      • Morita Y.
      • Yoshidome H.
      • Kimura F.
      • Shimizu H.
      • Ohtsuka M.
      • Takeuchi D.
      • et al.
      Excessive inflammation but decreased immunological response renders liver susceptible to infection in bile duct ligated mice.
      ]. Jaundiced patients undergoing laparotomy additionally showed significantly more bacterial translocation [
      • Kuzu M.A.
      • Kale I.T.
      • Col C.
      • Tekeli A.
      • Tanik A.
      • Koksoy C.
      Obstructive jaundice promotes bacterial translocation in humans.
      ]. This is in line with the high clinical incidence of postoperative infectious complications in cholestatic patients undergoing partial hepatectomy [
      • Nuzzo G.
      • Giuliante F.
      • Ardito F.
      • Giovannini I.
      • Aldrighetti L.
      • Belli G.
      • et al.
      Improvement in perioperative and long-term outcome after surgical treatment of hilar cholangiocarcinoma: results of an Italian multicenter analysis of 440 patients.
      ].
      Obstructive cholestasis is biochemically characterized by elevated serum bilirubin, ALP and GGT levels [
      Liver EAftSot. EASL Clinical Practice Guidelines: management of cholestatic liver diseases.
      ]. Inflammatory parameters are elevated in case of acute cholangitis [
      • Mosler P.
      Diagnosis and management of acute cholangitis.
      ]. Imaging of cholestatic parenchyma using ultrasonography, CT or MR cholangiopancreatography is not focused on assessing quality but on detection of dilated intrahepatic bile ducts.

      Assessment of liver volume and function

      Both assessment of liver volume and function is mandatory to predict postoperative functional reserve. Methods for measurement of future RLV range from 2D volumetry on computed tomography, to perioperative 3D modelling. Computational software allows manual or automatic delineation of the liver on all CT or MRI sections, thereby allowing calculation of liver volume [
      • van der Vorst J.R.
      • van Dam R.M.
      • van Stiphout R.S.
      • van den Broek M.A.
      • Hollander I.H.
      • Kessels A.G.
      • et al.
      Virtual liver resection and volumetric analysis of the future liver remnant using open source image processing software.
      ,
      • Dello S.A.
      • van Dam R.M.
      • Slangen J.J.
      • van de Poll M.C.
      • Bemelmans M.H.
      • Greve J.W.
      • et al.
      Liver volumetry plug and play: do it yourself with ImageJ.
      ].
      Liver function can be estimated by preoperative biochemistry, breath tests and imaging. Hepatic secretory (bilirubin), synthetic (INR) and detoxifying (ammonia) functions and liver damage (ALT, AST) are evaluated by clinical chemistry. Metabolic liver function testing can be performed with the LiMAx test and the indocyanine green clearance rate (ICGR-15) [
      • Golriz M.
      • Majlesara A.
      • El Sakka S.
      • Ashrafi M.
      • Arwin J.
      • Fard N.
      • et al.
      Small for Size and Flow (SFSF) syndrome: an alternative description for posthepatectomy liver failure.
      ,
      • Erlinger S.
      • Arias I.M.
      • Dhumeaux D.
      Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences.
      ]. The LiMAx test measures metabolism of intravenously injected 13C-labeled methacetin in exhaled breath. Imaging techniques used in the clinic include 99mTc-labeled galactosyl serum albumin (GSA) liver scintigraphy, 99mTc-mebrofenin hepatobiliary scintigraphy with single-photon emission computed tomography (SPECT), and gadolinium-enhanced MRI using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) [
      • Mao Y.
      • Du S.
      • Ba J.
      • Li F.
      • Yang H.
      • Lu X.
      • et al.
      Using Dynamic 99mT c-GSA SPECT/CT fusion images for hepatectomy planning and postoperative liver failure prediction.
      ,
      • Verloh N.
      • Haimerl M.
      • Zeman F.
      • Schlabeck M.
      • Barreiros A.
      • Loss M.
      • et al.
      Assessing liver function by liver enhancement during the hepatobiliary phase with Gd-EOB-DTPA-enhanced MRI at 3 Tesla.
      ,
      • de Graaf W.
      • van Lienden K.P.
      • van Gulik T.M.
      • Bennink R.J.
      (99m)Tc-mebrofenin hepatobiliary scintigraphy with SPECT for the assessment of hepatic function and liver functional volume before partial hepatectomy.
      ]. Impaired enhancement of labeled contrast indicates decreased hepatic uptake and reflects compromised liver quality. Liver enhancement in gadolinium-enhanced MRI shows good correlation with regional liver function, and offers the advantage of simultaneous diagnostic evaluation and functional assessment [
      • Verloh N.
      • Haimerl M.
      • Zeman F.
      • Schlabeck M.
      • Barreiros A.
      • Loss M.
      • et al.
      Assessing liver function by liver enhancement during the hepatobiliary phase with Gd-EOB-DTPA-enhanced MRI at 3 Tesla.
      ].

      Prevention of postresectional liver failure

      Prevention of PLF consists of four principles: optimizing preoperative liver function, enlarging RLV, limiting hepatic haemodynamic disbalance and providing optimal perioperative care.

      (Pre-)clinical methods of preoperative liver optimization

      The liver of patients with SOS is in a prothrombotic state as reflected by upregulation of plasminogen activator inhibitor-1, Von Willebrand factor and factor X [
      • Robinson S.M.
      • Mann J.
      • Vasilaki A.
      • Mathers J.
      • Burt A.D.
      • Oakley F.
      • et al.
      Pathogenesis of FOLFOX induced sinusoidal obstruction syndrome in a murine chemotherapy model.
      ]. The fibrinolytic agent defibrotide is administered in bone marrow transplant recipients for treatment of SOS [
      • Benimetskaya L.
      • Wu S.
      • Voskresenskiy A.M.
      • Echart C.
      • Zhou J.F.
      • Shin J.
      • et al.
      Angiogenesis alteration by defibrotide: implications for its mechanism of action in severe hepatic veno-occlusive disease.
      ], and might be beneficial in chemotherapy-related SOS as well. Anti-platelet therapy such as aspirin seems to protect against oxaliplatin-induced SOS in patients [
      • Brouquet A.
      • Benoist S.
      • Julie C.
      • Penna C.
      • Beauchet A.
      • Rougier P.
      • et al.
      Risk factors for chemotherapy-associated liver injuries: a multivariate analysis of a group of 146 patients with colorectal metastases.
      ]. Oxaliplatin is conjugated to glutathione and subsequently excreted from the cell, which is the probable cause of reduced hepatic glutathione levels seen in SOS [
      • Robinson S.M.
      • Mann J.
      • Vasilaki A.
      • Mathers J.
      • Burt A.D.
      • Oakley F.
      • et al.
      Pathogenesis of FOLFOX induced sinusoidal obstruction syndrome in a murine chemotherapy model.
      ]. Supplementation of antioxidant therapy (hydroxyanisole) or flavonoids reduced the severity of sinusoidal injury in rodents [
      • Robinson S.M.
      • Mann J.
      • Vasilaki A.
      • Mathers J.
      • Burt A.D.
      • Oakley F.
      • et al.
      Pathogenesis of FOLFOX induced sinusoidal obstruction syndrome in a murine chemotherapy model.
      ,
      • Ezzat T.
      • van den Broek M.A.
      • Davies N.
      • Dejong C.H.
      • Bast A.
      • Malago M.
      • et al.
      The flavonoid monoHER prevents monocrotaline-induced hepatic sinusoidal injury in rats.
      ]. This effect has not yet been confirmed in humans. Chemotherapy-free interval prior to liver resection may reverse SOS, as suggested by a longer period since the last cycle of chemotherapy in patients without histological evidence of SD at the time of liver resection [
      • Nakano H.
      • Oussoultzoglou E.
      • Rosso E.
      • Casnedi S.
      • Chenard-Neu M.P.
      • Dufour P.
      • et al.
      Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy.
      ]. On the other hand, hepatic sinusoidal lesions and even progression of fibrosis are reported up to several months after cessation of chemotherapy [
      • Rubbia-Brandt L.
      • Audard V.
      • Sartoretti P.
      • Roth A.D.
      • Brezault C.
      • Le Charpentier M.
      • et al.
      Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer.
      ]. Portal hypertension can be diminished by perioperative splenic artery ligation in patients with severe NRH and portal hypertension, and might decrease postoperative morbidity [
      • Schwarz L.
      • Faitot F.
      • Soubrane O.
      • Scatton O.
      Splenic artery ligation for severe oxaliplatin induced portal hypertension: a way to improve postoperative course and allow adjuvant chemotherapy for colorectal liver metastases: Letter to editor: comment about “Nodular regenerative hyperplasia (NRH) complicating oxaliplatin chemotherapy in patients undergoing resection of colorectal liver metastases”.
      ].
      Liver steatosis can be reduced by a preoperative very-low calorie diet, as has been shown in potential liver transplant donors [

      Doyle A, Dillon J, MacArthur M, Marquez M, Smith R, Grant D, et al. Treatment with optifast reduces hepatic steatosis and safely increases candidacy rates for live donor liver transplantation. The AASLD Liver Meeting, 2015.

      ]. Less steatosis and steatohepatitis was observed in patients with one week of calorie restriction prior to resection for benign or malignant liver disease, compared to ad lib fed patients [
      • Reeves J.G.
      • Suriawinata A.A.
      • Ng D.P.
      • Holubar S.D.
      • Mills J.B.
      • Barth Jr., R.J.
      Short-term preoperative diet modification reduces steatosis and blood loss in patients undergoing liver resection.
      ]. However, despite less intraoperative blood loss in the diet group, no effect was seen on postoperative complications in this patient group.
      Optimization of liver function in patients with cirrhosis has not yet been attempted, however, platelet infusion may be an option. Thrombocytopenia in cirrhosis may be caused by a decrease in (hepatic) thrombopoetin production and systemic removal of platelets in the spleen [
      • Giannini E.
      • Borro P.
      • Botta F.
      • Fumagalli A.
      • Malfatti F.
      • Podesta E.
      • et al.
      Serum thrombopoietin levels are linked to liver function in untreated patients with hepatitis C virus-related chronic hepatitis.
      ]. Platelets have a stimulatory effect on liver regeneration [
      • Matsuo R.
      • Nakano Y.
      • Ohkohchi N.
      Platelet administration via the portal vein promotes liver regeneration in rats after 70% hepatectomy.
      ], and platelet infusion might provide an option for preoperative optimization.
      The preventive role of preoperative biliary drainage in obstructive cholestasis is uncertain. Internal (stenting via endoscopic retrograde cholangiopancreatography, ERCP) or external (percutaneous transhepatic biliary drainage, PTBD) drainage in pancreatic head cancer patients has been shown to have no benefits on surgical outcome and induced drainage-related complications [
      • van der Gaag N.A.
      • Rauws E.A.
      • van Eijck C.H.
      • Bruno M.J.
      • van der Harst E.
      • Kubben F.J.
      • et al.
      Preoperative biliary drainage for cancer of the head of the pancreas.
      ], whereas its role in proximal malignant bile duct obstruction is inconclusive. Preoperative improved secretory liver function, improved postoperative liver regeneration, and a reduction of mortality after right hemihepatectomy were reported [
      • Farges O.
      • Regimbeau J.M.
      • Fuks D.
      • Le Treut Y.P.
      • Cherqui D.
      • Bachellier P.
      • et al.
      Multicentre European study of preoperative biliary drainage for hilar cholangiocarcinoma.
      ], but this could not be reproduced by others [
      • Ferrero A.
      • Lo Tesoriere R.
      • Vigano L.
      • Caggiano L.
      • Sgotto E.
      • Capussotti L.
      Preoperative biliary drainage increases infectious complications after hepatectomy for proximal bile duct tumor obstruction.
      ,
      • Hochwald S.N.
      • Burke E.C.
      • Jarnagin W.R.
      • Fong Y.
      • Blumgart L.H.
      Association of preoperative biliary stenting with increased postoperative infectious complications in proximal cholangiocarcinoma.
      ]. Drainage-related complications such as cholangitis and haemorrhage are seen in up to 33% of patients [
      • Farges O.
      • Regimbeau J.M.
      • Fuks D.
      • Le Treut Y.P.
      • Cherqui D.
      • Bachellier P.
      • et al.
      Multicentre European study of preoperative biliary drainage for hilar cholangiocarcinoma.
      ]. Especially infectious complications are more frequent after ERCP stenting [
      • Kloek J.J.
      • van der Gaag N.A.
      • Aziz Y.
      • Rauws E.A.
      • van Delden O.M.
      • Lameris J.S.
      • et al.
      Endoscopic and percutaneous preoperative biliary drainage in patients with suspected hilar cholangiocarcinoma.
      ], whereas PTBD causes interruption of the enterohepatic cycle and impairment of liver regeneration [
      • Huang W.
      • Ma K.
      • Zhang J.
      • Qatanani M.
      • Cuvillier J.
      • Liu J.
      • et al.
      Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration.
      ]. Bile salt reinfusion during PTBD had beneficial effects on postoperative liver function [
      • Ishizawa T.
      • Hasegawa K.
      • Sano K.
      • Imamura H.
      • Kokudo N.
      • Makuuchi M.
      Selective vs. total biliary drainage for obstructive jaundice caused by a hepatobiliary malignancy.
      ].

      Enlarging of future remnant liver volume

      Hypertrophy-inducing procedures and surgical adaptations should be performed if the RLV is expected to be <25% in patients without liver disease and <35–40% in patients with impaired liver function [
      • Vauthey J.N.
      • Abbott D.E.
      Commentary on “Feasibility study of two-stage hepatectomy for bilobar liver metastases”.
      ]. In general, portal vein embolization (PVE, Fig. 3) enlarges the RLV with approximately 35–40% and improves eligibility for hepatectomy by 20% [
      • van den Broek M.A.
      • Olde Damink S.W.
      • Dejong C.H.
      • Lang H.
      • Malago M.
      • Jalan R.
      • et al.
      Liver failure after partial hepatic resection: definition, pathophysiology, risk factors and treatment.
      ]. In less than 5% of patients the hypertrophic response following PVE is inadequate [
      • van Lienden K.P.
      • van den Esschert J.W.
      • de Graaf W.
      • Bipat S.
      • Lameris J.S.
      • van Gulik T.M.
      • et al.
      Portal vein embolization before liver resection: a systematic review.
      ]. Major PVE-related complications occur in approximately 2.5% of patients and include intra-abdominal abscess, liver hematoma, and backflow of embolization material [
      • van Lienden K.P.
      • van den Esschert J.W.
      • de Graaf W.
      • Bipat S.
      • Lameris J.S.
      • van Gulik T.M.
      • et al.
      Portal vein embolization before liver resection: a systematic review.
      ]. A recent meta-analysis comparing PVE with ligation of the portal vein (PVL) showed comparable preoperative hypertrophic responses and postoperative morbidity [
      • Pandanaboyana S.
      • Bell R.
      • Hidalgo E.
      • Toogood G.
      • Prasad K.R.
      • Bartlett A.
      • et al.
      A systematic review and meta-analysis of portal vein ligation vs. portal vein embolization for elective liver resection.
      ]. New developments exist of polyvinyl alcohol particles with plugs or coils as embolizing materials, and have resulted in lower recanalization rates, enhanced hypertrophy, and a decreased occurrence of PLF [
      • Malinowski M.
      • Geisel D.
      • Stary V.
      • Denecke T.
      • Seehofer D.
      • Jara M.
      • et al.
      Portal vein embolization with plug/coils improves hepatectomy outcome.
      ].
      Figure thumbnail gr3
      Fig. 3Visualization of pre- or perioperative interventions and their effect on liver remnant volume. (A) Malignant liver disease (B) Embolization/ligation of the right portal branch (1) results in atrophy of the right hemi-liver and compensatory growth of the left hemi-liver, which can be removed when appropriate hypertrophy has been achieved (2). (C) Removal of tumours from the left hemi-liver and occlusion of the right portal branch (1). After 4–6 weeks, the volume of the left hemi-liver is increased and the right hemi-liver can be removed (2). (D) Removal of tumours from the left hemi-liver, in situ splitting of the hemi-livers, and simultaneous ligation of the right portal vein branch (1). After one week, augmented hypertrophy of the left hemi-liver permits removal of the right hemi-liver (2).
      Disease progression after PVE occurs in up to 66% of patients, and is likely due to increased arterial flow to the embolized lobe and/or waiting period to surgery [
      • Hoekstra L.T.
      • van Lienden K.P.
      • Doets A.
      • Busch O.R.
      • Gouma D.J.
      • van Gulik T.M.
      Tumor progression after preoperative portal vein embolization.
      ]. The interval between PVE and surgery should therefore be as short as possible but not less than 2–3 weeks [
      • Hoekstra L.T.
      • van Lienden K.P.
      • Doets A.
      • Busch O.R.
      • Gouma D.J.
      • van Gulik T.M.
      Tumor progression after preoperative portal vein embolization.
      ]. Post-PVE chemotherapy before resection may halt disease progression without affecting subsequent liver regeneration [
      • Vetelainen R.
      • van Vliet A.K.
      • van Gulik T.M.
      Severe steatosis increases hepatocellular injury and impairs liver regeneration in a rat model of partial hepatectomy.
      ].
      PVE is commonly performed after the administration of chemotherapy [
      • Brouquet A.
      • Benoist S.
      • Julie C.
      • Penna C.
      • Beauchet A.
      • Rougier P.
      • et al.
      Risk factors for chemotherapy-associated liver injuries: a multivariate analysis of a group of 146 patients with colorectal metastases.
      ]. Evidence for the influence of CALI on post-PVE hypertrophy is conflicting. Whereas SD seems to have a clear inhibitory effect on hypertrophy [
      • Narita M.
      • Oussoultzoglou E.
      • Chenard M.P.
      • Rosso E.
      • Casnedi S.
      • Pessaux P.
      • et al.
      Sinusoidal obstruction syndrome compromises liver regeneration in patients undergoing two-stage hepatectomy with portal vein embolization.
      ], chemotherapy has no effect on liver regrowth [
      • van Lienden K.P.
      • van den Esschert J.W.
      • de Graaf W.
      • Bipat S.
      • Lameris J.S.
      • van Gulik T.M.
      • et al.
      Portal vein embolization before liver resection: a systematic review.
      ,
      • de Baere T.
      • Teriitehau C.
      • Deschamps F.
      • Catherine L.
      • Rao P.
      • Hakime A.
      • et al.
      Predictive factors for hypertrophy of the future remnant liver after selective portal vein embolization.
      ]. Moreover, patients with NASH show a trend towards less post-PVE liver volume gain compared to patients with normal liver function [
      • Narita M.
      • Oussoultzoglou E.
      • Chenard M.P.
      • Rosso E.
      • Casnedi S.
      • Pessaux P.
      • et al.
      Sinusoidal obstruction syndrome compromises liver regeneration in patients undergoing two-stage hepatectomy with portal vein embolization.
      ]. Although robust evidence is lacking [
      • van Lienden K.P.
      • van den Esschert J.W.
      • de Graaf W.
      • Bipat S.
      • Lameris J.S.
      • van Gulik T.M.
      • et al.
      Portal vein embolization before liver resection: a systematic review.
      ], cholestasis appears to have no negative impact on hypertrophy after PVE. After right hepatectomy in patients with chronic liver disease, PLF developed in 50% of patients without PVE vs. 7.1% in patients with PVE [
      • Farges O.
      • Belghiti J.
      • Kianmanesh R.
      • Regimbeau J.M.
      • Santoro R.
      • Vilgrain V.
      • et al.
      Portal vein embolization before right hepatectomy: prospective clinical trial.
      ]. Impaired hypertrophy after technically successful PVE in patients with chronic liver disease is a contraindication for major resection [
      • Farges O.
      • Belghiti J.
      • Kianmanesh R.
      • Regimbeau J.M.
      • Santoro R.
      • Vilgrain V.
      • et al.
      Portal vein embolization before right hepatectomy: prospective clinical trial.
      ].
      The two-staged hepatectomy is an excellent method to increase RLV and consequently achieve curation in patients with bilobar tumours, who are not deemed resectable in one attempt. PVL concurrent with two-stage hepatectomy resulted in an RLV gain of about 50–60% after four weeks. This strategy is advised in case of an RLV after the first stage of <25–30% and <40% in patients without and with chronic liver disease, respectively. Liver cirrhosis is a contraindication for the two-staged procedure.
      The recently developed associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure is based on the same principle as two-stage hepatectomy, albeit that during the first stage in ALPPS the liver is split in situ combined with portal vein ligation, and the second stage consists of removal of the ligated lobe 7–14 days later [
      • Schnitzbauer A.A.
      • Lang S.A.
      • Goessmann H.
      • Nadalin S.
      • Baumgart J.
      • Farkas S.A.
      • et al.
      Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings.
      ]. An astonishing average hypertrophy rate of 80% can be achieved with this procedure, creating a curative opportunity for initially non-resectable patients who have insufficient hypertrophy on PVE [
      • Schadde E.
      • Ardiles V.
      • Robles-Campos R.
      • Malago M.
      • Machado M.
      • Hernandez-Alejandro R.
      • et al.
      Early survival and safety of ALPPS: first report of the International ALPPS Registry.
      ]. However, the high morbidity and mortality rates up to 28% and 9% respectively restrict the use of ALPPS to fit patients under the age of 60 years [
      • Schadde E.
      • Ardiles V.
      • Robles-Campos R.
      • Malago M.
      • Machado M.
      • Hernandez-Alejandro R.
      • et al.
      Early survival and safety of ALPPS: first report of the International ALPPS Registry.
      ]. The second stage of ALPPS should probably be (temporarily) abolished in patients who develop major complications after the first stage [
      • Truant S.
      • Scatton O.
      • Dokmak S.
      • Regimbeau J.M.
      • Lucidi V.
      • Laurent A.
      • et al.
      Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): impact of the inter-stages course on morbi-mortality and implications for management.
      ].
      Treatments to enhance liver regeneration may enlarge the number of patients eligible for curative intent surgery.
      Although ALPPS is currently performed in all liver backgrounds, histological changes comprising fibrosis, steatosis, and chemotherapy-related alterations resulted in lower hypertrophy rates [
      • Schadde E.
      • Ardiles V.
      • Robles-Campos R.
      • Malago M.
      • Machado M.
      • Hernandez-Alejandro R.
      • et al.
      Early survival and safety of ALPPS: first report of the International ALPPS Registry.
      ]. The ALPPS procedure resulted in a quadrupled mortality rate, doubled median hospital stay, and doubled risk for PLF in patients with intermediate-stage HCC [
      • D’Haese J.G.
      • Neumann J.
      • Weniger M.
      • Pratschke S.
      • Bjornsson B.
      • Ardiles V.
      • et al.
      Should ALPPS be used for liver resection in intermediate-stage HCC?.
      ] and should therefore only be applied in HCC patients with low-grade fibrosis. ALPPS should not, or with great caution, be applied in patients with perihilar and intrahepatic CCA due to the (already) high postoperative mortality rate in this patient category [
      • Schadde E.
      • Ardiles V.
      • Robles-Campos R.
      • Malago M.
      • Machado M.
      • Hernandez-Alejandro R.
      • et al.
      Early survival and safety of ALPPS: first report of the International ALPPS Registry.
      ,
      • Serenari M.
      • Zanello M.
      • Schadde E.
      • Toschi E.
      • Ratti F.
      • Gringeri E.
      • et al.
      Importance of primary indication and liver function between stages: results of a multicenter Italian audit of ALPPS 2012–2014.
      ]. Modifications such as monosegment ALPPS, in which only one instead of two or more Couinaud segments remain, showed promising results in a small cohort of 12 patients, with a PLF rate of 33% but without mortality [
      • Schadde E.
      • Malago M.
      • Hernandez-Alejandro R.
      • Li J.
      • Abdalla E.
      • Ardiles V.
      • et al.
      Monosegment ALPPS hepatectomy: extending resectability by rapid hypertrophy.
      ].

      Limiting hepatic haemodynamic imbalance

      Splenectomy and splenic artery ligation can be effective strategies that limit the postresectional increase in portal blood flow and pressure, by activating the hepatic arterial buffer response. These procedures resulted in increased arterial inflow, and enhanced liver regeneration and liver function after (extended) partial hepatectomy in rodent models [
      • Ren Y.S.
      • Qian N.S.
      • Tang Y.
      • Liao Y.H.
      • Liu W.H.
      • Raut V.
      • et al.
      Beneficial effects of splenectomy on liver regeneration in a rat model of massive hepatectomy.
      ]. Furthermore, in animal models of partial hepatectomy and small-for-size liver grafts, the administration of terlipressin and somatostatin seemed to reduce postresectional portal hyperperfusion and increase regenerative parameters [
      • Ren Z.
      • Xu Y.
      • Zhu S.
      The effect of terlipressin on hepatic hemodynamics in small-for-size livers.
      ,
      • Fahrner R.
      • Patsenker E.
      • de Gottardi A.
      • Stickel F.
      • Montani M.
      • Stroka D.
      • et al.
      Elevated liver regeneration in response to pharmacological reduction of elevated portal venous pressure by terlipressin after partial hepatectomy.
      ,
      • Xu X.
      • Man K.
      • Zheng S.S.
      • Liang T.B.
      • Lee T.K.
      • Ng K.T.
      • et al.
      Attenuation of acute phase shear stress by somatostatin improves small-for-size liver graft survival.
      ].

      Providing optimal perioperative care

      Excessive perioperative blood loss, blood transfusion, ischemia-reperfusion injury, and hepatic manipulation predispose to PLF. Blood transfusion enhances postoperative morbidity and tumour recurrence presumably via a transfusion-related inflammatory response [
      • Miki C.
      • Hiro J.
      • Ojima E.
      • Inoue Y.
      • Mohri Y.
      • Kusunoki M.
      Perioperative allogeneic blood transfusion, the related cytokine response and long-term survival after potentially curative resection of colorectal cancer.
      ]. A recent meta-analysis confirmed that hepatic preconditioning (i.e., intermittent vascular inflow occlusion) results in less intraoperative blood loss and a shorter operating time in comparison to hepatectomy alone, but without improved postoperative outcome [
      • Simillis C.
      • Robertson F.P.
      • Afxentiou T.
      • Davidson B.R.
      • Gurusamy K.S.
      A network metaanalysis comparing perioperative outcomes of interventions aiming to decrease ischemia reperfusion injury during elective liver resection.
      ]. Prolonged clamping should nonetheless be avoided since ischemia-reperfusion injury has been shown to induce severe hepatic damage [
      • Datta G.
      • Fuller B.J.
      • Davidson B.R.
      Molecular mechanisms of liver ischemia reperfusion injury: insights from transgenic knockout models.
      ]. Hepatic manipulation per se elicits an inflammatory response [
      • van den Broek M.A.
      • Shiri-Sverdlov R.
      • Schreurs J.J.
      • Bloemen J.G.
      • Bieghs V.
      • Rensen S.S.
      • et al.
      Liver manipulation during liver surgery in humans is associated with hepatocellular damage and hepatic inflammation.
      ]. Methods to minimize mobilisation of the liver include laparoscopic surgery and the hanging method [
      • Belghiti J.
      • Guevara O.A.
      • Noun R.
      • Saldinger P.F.
      • Kianmanesh R.
      Liver hanging maneuver: a safe approach to right hepatectomy without liver mobilization.
      ]. Laparoscopic resection of HCCs reduced the incidence of PLF compared to open surgery [
      • Morise Z.
      • Ciria R.
      • Cherqui D.
      • Chen K.H.
      • Belli G.
      • Wakabayashi G.
      Can we expand the indications for laparoscopic liver resection? A systematic review and meta-analysis of laparoscopic liver resection for patients with hepatocellular carcinoma and chronic liver disease.
      ].
      Since infectious complications such as bile leakage or abdominal collections may contribute to the development of PLF and negatively affect the postresectional course, several preventive measures have been explored. Postresectional primary placement of abdominal drains proved not to be beneficial after major liver resection and is even associated with increased rates of complications such as bile leakage and PLF [
      • Squires 3rd, M.H.
      • Lad N.L.
      • Fisher S.B.
      • Kooby D.A.
      • Weber S.M.
      • Brinkman A.
      • et al.
      Value of primary operative drain placement after major hepatectomy: a multi-institutional analysis of 1,041 patients.
      ,
      • Olthof P.B.
      • Coelen R.J.
      • Wiggers J.K.
      • Besselink M.G.
      • Busch O.R.
      • van Gulik T.M.
      External biliary drainage following major liver resection for perihilar cholangiocarcinoma: impact on development of liver failure and biliary leakage.
      ]. Multiple human studies focused on either pre- or postresectional antibiotic prophylaxis, without evidence for a significant effect on the rate of infectious complications [
      • Hirokawa F.
      • Hayashi M.
      • Miyamoto Y.
      • Asakuma M.
      • Shimizu T.
      • Komeda K.
      • et al.
      Evaluation of postoperative antibiotic prophylaxis after liver resection: a randomized controlled trial.
      ,
      • Zhou Y.M.
      • Chen Z.Y.
      • Li X.D.
      • Xu D.H.
      • Su X.
      • Li B.
      Preoperative antibiotic prophylaxis does not reduce the risk of postoperative infectious complications in patients undergoing elective hepatectomy.
      ]. Preoperative selective bowel contamination has been explored in rodent models, showing amelioration of parenchymal injury and increased liver regeneration after partial liver resection [
      • Ren W.
      • Wang X.
      • Zhang A.
      • Li C.
      • Chen G.
      • Ge X.
      • et al.
      Selective bowel decontamination improves the survival of 90% hepatectomy in rats.
      ]. A meta-analysis of human transplant studies however showed no benefits on infectious complications [
      • Gurusamy K.S.
      • Nagendran M.
      • Davidson B.R.
      Methods of preventing bacterial sepsis and wound complications after liver transplantation.
      ].

      Regenerative interventions

      Augmentation of the regenerative response after liver resection may be an option for prevention and treatment of PLF. The nuclear bile salt receptor FXR (farnesoid X receptor, Fig. 4) may be an attractive therapeutic candidate, through effects on hepatic haemodynamics, bile salt and lipid homeostasis, hepatic inflammation, and hepatocellular proliferation [
      • Fan M.
      • Wang X.
      • Xu G.
      • Yan Q.
      • Huang W.
      Bile acid signaling and liver regeneration.
      ,
      • Verbeke L.
      • Farre R.
      • Trebicka J.
      • Komuta M.
      • Roskams T.
      • Klein S.
      • et al.
      Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats.
      ,
      • Hollman D.A.
      • Milona A.
      • van Erpecum K.J.
      • van Mil S.W.
      Anti-inflammatory and metabolic actions of FXR: insights into molecular mechanisms.
      ,
      • Schaap F.G.
      • Trauner M.
      • Jansen P.L.
      Bile acid receptors as targets for drug development.
      ]. Being the key regulator of hepatic bile salt homeostasis, genetic disruption of Fxr in mice resulted in mortality and delayed liver regeneration after partial hepatectomy. Conversely, activation of Fxr by its endogenous ligands (i.e., bile salts) or synthetic agonists enhanced liver regeneration in hepatectomized mice. Furthermore, the FXR-regulated enterokine FGF19 reduced mortality in an acute liver failure mouse model [
      • Uriarte I.
      • Fernandez-Barrena M.G.
      • Monte M.J.
      • Latasa M.U.
      • Chang H.C.
      • Carotti S.
      • et al.
      Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice.
      ]. FXR agonists undergo current clinical evaluation, and already showed efficacy in halting fibrotic progression in NASH patients [
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Sanyal A.J.
      • Lavine J.E.
      • Van Natta M.L.
      • Abdelmalek M.F.
      • et al.
      Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
      ].
      Figure thumbnail gr4
      Fig. 4Targeting of bile salt receptors may improve liver regeneration after partial hepatectomy through direct trophic and bile salt homeostatic effects. Control of bile salt homeostasis ensures proper progression of postresectional liver regeneration. Bile salt receptor FXR in small intestine and liver exerts homeostatic control by regulating import, synthesis, conjugation (i.e., N-amidation) and export of bile salts. Moreover, bile salt signaling via FXR results in induction of genes engaged in cell cycle control (e.g., Foxm1b). On the other hand, hepatic bile salt overload gives rise to liver injury. Bile salt toxicity may be reduced by stimulation of phase I/II metabolism and phase III efflux via agonistic activation of nuclear receptors PXR and CAR. An excessive inflammatory response of Kupffer cells may be dampened by TGR5 agonism. OCA, obeticholic acid (FXR agonist); PB, phenobarbital (CAR activator); FGFR4, fibroblast growth factor receptor 4.
      Bearing in mind that tight control of bile salt homeostasis and hepatic inflammatory tone is warranted to allow normal progression of liver regeneration, targeting of the membrane bile salt receptor TGR5 may be considered in PLF. In the liver, TGR5 is expressed in liver endothelial cells, cholangiocytes, and Kupffer cells [
      • Keitel V.
      • Donner M.
      • Winandy S.
      • Kubitz R.
      • Haussinger D.
      Expression and function of the bile acid receptor TGR5 in Kupffer cells.
      ,
      • Keitel V.
      • Haussinger D.
      TGR5 in the biliary tree.
      ]. Tgr5 enhances bile salt elimination in urine, reduces bile salt hydrophobicity and prevents excessive cytokine production by Kupffer cells, in case of bile salt overload [
      • Pean N.
      • Doignon I.
      • Garcin I.
      • Besnard A.
      • Julien B.
      • Liu B.
      • et al.
      The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice.
      ]. Other nuclear receptors that play a direct role in liver regeneration, and have the potential to reduce intrahepatic bile salt toxicity by promoting phase I/II metabolism, are the pregnane X receptor and constitutive androstane receptor [
      • Wagner M.
      • Halilbasic E.
      • Marschall H.U.
      • Zollner G.
      • Fickert P.
      • Langner C.
      • et al.
      CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice.
      ,
      • Tschuor C.
      • Kachaylo E.
      • Limani P.
      • Raptis D.A.
      • Linecker M.
      • Tian Y.
      • et al.
      Constitutive androstane receptor (Car)-driven regeneration protects liver from failure following tissue loss.
      ]. A recent study showed that the pregnane X receptor agonist rifampicin improved hyperbilirubinemia and clinical status in patients with persistent hepatocellular failure, including one patient with PLF [
      • van Dijk R.
      • Kremer A.E.
      • Smit W.
      • van den Elzen B.
      • van Gulik T.
      • Gouma D.
      • et al.
      Characterization and treatment of persistent hepatocellular secretory failure.
      ]. Despite in-depth knowledge of the processes controlled by the above (nuclear) receptors, their roles in liver regeneration and implication in PLF have only been studied in animal models.
      A recently discovered negative regulator of liver regeneration after partial hepatectomy, viz. thrombospondin-1 [
      • Hayashi H.
      • Sakai K.
      • Baba H.
      • Sakai T.
      Thrombospondin-1 is a novel negative regulator of liver regeneration after partial hepatectomy through transforming growth factor-beta1 activation in mice.
      ], might be a target to accelerate regeneration by antagonizing its action through administration of leucine-serine-lysine-leucine (LSKL) peptide [
      • Kuroki H.
      • Hayashi H.
      • Nakagawa S.
      • Sakamoto K.
      • Higashi T.
      • Nitta H.
      • et al.
      Effect of LSKL peptide on thrombospondin 1-mediated transforming growth factor beta signal activation and liver regeneration after hepatectomy in an experimental model.
      ]. Likewise, usefulness of colony stimulating factor to accelerate postresectional restoration of phagocytic capacity in the human setting is worth exploring [
      • Stutchfield B.M.
      • Antoine D.J.
      • Mackinnon A.C.
      • Gow D.J.
      • Bain C.C.
      • Hawley C.A.
      • et al.
      CSF1 Restores Innate Immunity After Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure.
      ]. Given the multifactorial origin of PLF strategies that simultaneously target multiple aetiological pillars may prove most effective.
      Transplantation of hepatocytes and other cell types have been moderately successful in several liver diseases in terms of spontaneous recovery or bridging to orthotopic liver transplantation (see reference [
      • Forbes S.J.
      • Gupta S.
      • Dhawan A.
      Cell therapy for liver disease: from liver transplantation to cell factory.
      ] for a review), and might be of interest for preoperative optimization of liver parenchyma or management of PLF. Moreover, intrahepatic or extrahepatic (scaffold-bound) introduction of induced pluripotent stem cells (iPSC), iPSC-derived or Lgr5+ stem cell-derived organoids, cultured hepatocytes are extensively studied in a pre-clinical setting, and might offer advanced possibilities for pre- or postoperative liver repopulation [
      • Duncan A.W.
      • Dorrell C.
      • Grompe M.
      Stem cells and liver regeneration.
      ,
      • Huch M.
      • Dorrell C.
      • Boj S.F.
      • van Es J.H.
      • Li V.S.
      • van de Wetering M.
      • et al.
      In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration.
      ,
      • Huang P.
      • Zhang L.
      • Gao Y.
      • He Z.
      • Yao D.
      • Wu Z.
      • et al.
      Direct reprogramming of human fibroblasts to functional and expandable hepatocytes.
      ,
      • Takebe T.
      • Sekine K.
      • Enomura M.
      • Koike H.
      • Kimura M.
      • Ogaeri T.
      • et al.
      Vascularized and functional human liver from an iPSC-derived organ bud transplant.
      ,
      • Takahashi K.
      • Yamanaka S.
      Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
      ].

      Management of postoperative liver failure

      Management of PLF consists of goal-directed therapy and functional support.
      Due to the lack of randomized controlled trials with PLF as primary outcome measure, almost no treatments for acute and acute-on-chronic liver failure have been validated for PLF. When PLF is detected after resection in (non-)compromised liver, goal-directed therapy and functional support can be offered (Fig. 2).

      Goal-directed therapy

      PLF is frequently accompanied by multi-organ dysfunction, requiring a systemic treatment approach [
      • Kimura F.
      • Shimizu H.
      • Yoshidome H.
      • Ohtsuka M.
      • Kato A.
      • Yoshitomi H.
      • et al.
      Circulating cytokines, chemokines, and stress hormones are increased in patients with organ dysfunction following liver resection.
      ]. Goal-directed therapy focuses on support of circulatory, ventilatory, and renal function in combination with treatment of hepatic encephalopathy, coagulopathy and malnutrition as reviewed elsewhere [
      • van den Broek M.A.
      • Olde Damink S.W.
      • Dejong C.H.
      • Lang H.
      • Malago M.
      • Jalan R.
      • et al.
      Liver failure after partial hepatic resection: definition, pathophysiology, risk factors and treatment.
      ].

      Functional support

      Molecular absorbent recirculation system, an extracorporeal artificial liver support device that reduces liver failure-induced toxicity by facilitating exchange of albumin-bound and water-soluble toxins from plasma, is applicable as treatment for PLF [
      • van de Kerkhove M.P.
      • de Jong K.P.
      • Rijken A.M.
      • de Pont A.C.
      • van Gulik T.M.
      MARS treatment in posthepatectomy liver failure.
      ]. In addition, extracorporeal bio-artificial liver devices fulfil functions of the liver (including synthetic and immunological) by separation and passage of blood plasma through a reactor containing layers of animal or human hepatocytes [
      • van Wenum M.
      • Chamuleau R.A.
      • van Gulik T.M.
      • Siliakus A.
      • Seppen J.
      • Hoekstra R.
      Bioartificial livers in vitro and in vivo: tailoring biocomponents to the expanding variety of applications.
      ]. The recently developed University College London-Liver Dialysis Device extracts albumin by hemofiltration and removes certain endotoxins by haemoperfusion, in combination with human albumin infusion [
      • Lee K.C.
      • Baker L.A.
      • Stanzani G.
      • Alibhai H.
      • Chang Y.M.
      • Jimenez Palacios C.
      • et al.
      Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: results of a pivotal pre-clinical study.
      ]. Unfortunately, although the latter two devices show survival benefits, they have thus far been tested only in a pre-clinical setting. Furthermore, promising treatment modalities that focus on extracorporeal high-flux haemodialysis in combination with albumin dialysis (Prometheus®), and patient plasma replacement with fresh frozen plasma (high-volume plasmapheresis), have been tested almost exclusively as treatment for acute and acute-on-chronic liver failure with sparse (underpowered) data on its use in the context of liver failure after hepatic resection [
      • Larsen F.S.
      • Schmidt L.E.
      • Bernsmeier C.
      • Rasmussen A.
      • Isoniemi H.
      • Patel V.C.
      • et al.
      High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial.
      ,
      • Rifai K.
      • Ernst T.
      • Kretschmer U.
      • Bahr M.J.
      • Schneider A.
      • Hafer C.
      • et al.
      Prometheus–a new extracorporeal system for the treatment of liver failure.
      ].

      Rescue and elective liver transplantation

      The limited data on rescue liver transplantation in patients with PLF showed a 5-year overall survival of 40% [
      • Otsuka Y.
      • Duffy J.P.
      • Saab S.
      • Farmer D.G.
      • Ghobrial R.M.
      • Hiatt J.R.
      • et al.
      Postresection hepatic failure: successful treatment with liver transplantation.
      ], however appropriate criteria for patient selection are lacking. Hence, rescue liver transplantation is barely applied nowadays. Moreover, rescue liver transplantation should not be performed if the patient was not eligible for transplantation before partial hepatectomy.

      Conclusion

      The incidence of liver failure after surgical resection is relatively low. This is accomplished to a large extent by (I) better insight into the aetiology of PLF and liver regeneration, (II) new imaging techniques and biochemical tests for preoperative assessment of liver quality, (III) highly effective preventive measures, and (IV) improved perioperative care. Due to the low event rate, prospective studies with PLF as primary endpoint are nearly unachievable [
      • van den Broek M.A.
      • van Dam R.M.
      • Malago M.
      • Dejong C.H.
      • van Breukelen G.J.
      • Olde Damink S.W.
      Feasibility of randomized controlled trials in liver surgery using surgery-related mortality or morbidity as endpoint.
      ], and most evidence is based on retrospective cohort studies. Furthermore, a uniform definition and outcome set are lacking, but imperative to compare different cohorts [
      • van den Broek M.A.
      • van Dam R.M.
      • van Breukelen G.J.
      • Bemelmans M.H.
      • Oussoultzoglou E.
      • Pessaux P.
      • et al.
      Development of a composite endpoint for randomized controlled trials in liver surgery.
      ]. In view of the current increase of extensive resections in a compromised liver background, the development of universal prediction models, more advanced surgical techniques, and efficient preventive measures become particularly important to obtain curability in these challenging patients. Global collaborations and registrations such as seen in the EASL-CLIF consortium (acute-on-chronic liver failure) [
      • Schadde E.
      • Ardiles V.
      • Robles-Campos R.
      • Malago M.
      • Machado M.
      • Hernandez-Alejandro R.
      • et al.
      Early survival and safety of ALPPS: first report of the International ALPPS Registry.
      ] or the ALPPS-registry [
      • Arroyo V.
      • Moreau R.
      • Jalan R.
      • Gines P.
      Study E-CCC. Acute-on-chronic liver failure: a new syndrome that will re-classify cirrhosis.
      ] seem the only manner to obtain the required number of events for robust evidence on risk factors, prediction models and interventions.

      Conflict of interest

      The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

      Authors’ contributions

      Study concept and design: KvM, FS, CD, SOD; Drafting of the manuscript: KvM, Critical revision of the manuscript: FS, CD, SOD; Acquisition of data/Analysis and interpretation of data/Statistical analysis/administrative support/study supervision: n/a. All authors approve of and take responsibility for the final version of this manuscript.

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