Liver failure after partial hepatic resection: definition, pathophysiology, risk factors and treatment

Authors

  • Maartje A. J. Van Den Broek,

    1. Department of Surgery, University Hospital Maastricht, Maastricht, the Netherlands
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  • Steven W. M. Olde Damink,

    1. Department of Surgery, University Hospital Maastricht, Maastricht, the Netherlands
    2. Department of Surgery, University College London Hospital, University College London, London, UK
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  • Cornelis H. C. Dejong,

    1. Department of Surgery, University Hospital Maastricht, Maastricht, the Netherlands
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  • Hauke Lang,

    1. Department of General, Visceral and Transplant Surgery, University Hospital Essen, Essen, Germany
    2. Department of General and Abdominal Surgery, Johannes Gutenberg University Mainz, Mainz, Germany
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  • Massimo Malagó,

    1. Department of Surgery, University College London Hospital, University College London, London, UK
    2. Department of General, Visceral and Transplant Surgery, University Hospital Essen, Essen, Germany
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  • Rajiv Jalan,

    1. Liver Failure Group, Institute of Hepatology, University College London, London, UK
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  • Fuat H. Saner

    1. Department of General, Visceral and Transplant Surgery, University Hospital Essen, Essen, Germany
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Correspondence
Steven W.M. Olde Damink, MD, MSc, PhD, Department of Surgery, University Hospital Maastricht, PO Box 5800, 6202 AZ, Maastricht, the Netherlands
Tel: +31 43 387 7489
Fax: +31 43 387 5473
e-mail: steven.oldedamink@ah.unimaas.nl

Abstract

Liver failure is a dreaded and often fatal complication that sometimes follows a partial hepatic resection. This article reviews the definition, incidence, pathogenesis, risk factors, risk assessment, prevention, clinical features and treatment of post-resectional liver failure (PLF). A systematic, computerized search was performed using key words related to ‘partial hepatic resection’ and ‘liver failure’ to review most relevant literature about PLF published in the last 20 years.

The reported incidence of PLF ranges between 0.7 and 9.1%. An inadequate quantity or quality of residual liver mass are key events in its pathogenesis. Major risk factors are the presence of comorbid conditions, pre-existent liver disease and small remnant liver volume (RLV). It is essential to identify these risk factors during the pre-operative assessment that includes evaluation of liver volume, anatomy and function. Preventive measures should be applied whenever possible as curative treatment options for PLF are limited. These preventive measures intend to increase RLV and protect remnant liver function. Management principles focus on support of end-organ and liver function. Further research is needed to elucidate the exact pathogenesis of PLF and to develop and validate adequate treatment options.

Abbreviations
CT,

computed tomography;

HCC,

hepatocellular carcinoma;

HE,

hepatic encephalopathy;

ICGR15,

indocyanine green retention in 15 min;

MEGX,

lidocaine-monoethylglycinexylidide test;

MELD,

model for end-stage liver disease;

PLF,

post-resectional liver failure;

PTD,

percutaneous transhepatic drainage;

RLV,

remnant liver volume.

Partial hepatic resection is a feasible and relatively safe procedure and is even used in living donor liver transplantation as an accepted alternative for cadaveric donor liver transplantation (1). However, hepatobiliary surgeons are still concerned about the risk of post-resectional liver failure (PLF). This review aims to discuss the definition, incidence, pathogenesis, risk factors and assessment, prevention, clinical features and treatment of PLF in a stepwise manner. The main focus of this article will be directed towards risk analysis for and prevention of PLF.

Methods

A systematic, computerized search of English literature (PubMed, Medline and Cochrane Database of Systematic Reviews) was performed using key words related to ‘partial hepatic resection’, ‘hepatectomy’, ‘liver failure’ and ‘liver dysfunction’ to review the most relevant literature of the last 20 years.

Definition

There is no uniformity concerning the definition of PLF. In general, PLF is characterized as failure of one or more of the hepatic synthetic and excretory functions that include hyperbilirubinaemia, hypoalbuminaemia, prolonged prothrombin time, elevated serum lactate and/or different grades of hepatic encephalopathy (HE) (2–6).

PLF is quantitatively reasonably well defined by the so-called 50–50 criteria, which describe PLF as prothrombin index <50% (equal to an international standardized ratio >1.7) and serum bilirubin >50 μmol/L (2.9 mg/dL) on post-operative day 5 (4). When these 50–50 criteria were fulfilled, patients had a 59% risk of mortality compared with 1.2% when they were not met (sensitivity 69.6% and specificity 98.5%). These 50–50 criteria have been validated recently in a large retrospective study (7), which showed a sensitivity of 50% and a specificity of 96.6% for the prediction of PLF-related death in a cohort of patients without underlying liver disease who had undergone major hepatic resection. In this study, a peak bilirubin of 7.0 mg/dL (120 μmol/L) was identified as a sensitive and specific cut-off value for prediction of PLF-related death (7). However, both definitions of PLF are open to discussion and need prospective validation. Their shortcoming could be overcome by the development of a new definition comprising functional biomarkers. At the moment, definitions comprising functional biomarkers like indocyanine green elimination rate (8) or asymmetric dimethylarginine (9) do not exist.

Incidence

The incidence of PLF ranges anywhere between 0 and 32% (see Table 1) (2–5, 10–26), with the highest incidences being reported in subgroups of patients (27, 28). Owing to the lack of a uniform definition of PLF, a considerable number of clinical conditions may unintentionally be described as PLF, making it difficult compare and extrapolate results from clinical trials. Leaving the extremes out of consideration [e.g. (3, 5, 17, 26)], the incidence of PLF varies between 0.7 and 9.1%.

Table 1.   List of articles concerning the incidence of post-operative morbidity, post-resectional liver failure and mortality for all patient groups after partial hepatic resection (overview of descriptive case series with large patient numbers published between 1996 and 2007)
Author (reference)YearStart–stopNo. HxPost-operative
morbidity
PLFThirty-day
mortality
Operative
mortality
In-hospital
mortality
n%n%n%n%n%
  • PLF defined as a>100% increase in serum bilirubin; b50–50 criteria on post-operative day 5; cserum bilirubin ≥170 μmol/L; dbilirubin >5 mg/dL and/or prothrombin index < 50% during three consecutive days; eprolonged hyperbilirubinaemia, clinically apparent ascites, prolonged coagulopathy and/or HE; fHE, coagulopathy and cholestasis; gbilirubin >5 mg/dL; hHE, ascites, prothrombin index <40% and serum bilirubin >10 mg/dL; khepatorenal failure; and lhepatic coma.

  • *

    Data only available from a subset of 452 patients.

  • Significant decrease in group II vs group I (P<0.05).

  • Data only reported in the ‘healthy group’.

  • HE, hepatic encephalopathy; Hx, partial hepatic resection; NA not available; PLF, post-resectional liver failure.

Virani (10)20072001–200478317723NANA202.6NANANANA
Benzoni (12)20061989–200528713748269.1NANANANA134.5
Schroeder (3)20061991–NA58718832145*32.1a508.5NANANANA
Balzan (4)20051998–2002775NANA273.5bNANA263.4NANA
Sun (24)20052001–2004146372510.7cNANA11.4NANA
Poon (13)20041989–199640215037205.0174.2NANA307.5
 1996–200382024630273.3222.7NANA303.7
Dimick (14)20041988–200016 582NANANANANANANANA12277.4
Coelho (15)20041994–200383374567.278.4NANA89.6
Imamura (5)20031994–200210564003810.1d000000
Jarnagin (2)20021991–2001180381745995.5eNANA553.1NANA
McCall (11)20011998–2001123685597.3f32.4NANANANA
Alfieri (16)20011984–1999254652662.4g83.1103.9NANA
Das (19)20011994–1998100141444.0h11.0NANA33.0
Buell (25)20001990–1999160432721.3NANA31.8NANA
Akashi (17)20001985–19889637391111.5NANA55.21010
 1995–1998109171643.7NANA10.943.7
Belghiti (18)19991990–19977471642261.2334.4NANANANA
Midorikawa (26)19991994–19982771796500NANANANA00
Brancatisano (20)19981989–19952007437147.052.5NANA105.0
Finch (21)19981988–1996133584575.3kNANA64.5NANA
Taniguchi (22)19971988–19952101145441.9l52.4NANA94.3
Rees (23)19961986–1995150352310.710.7NANANANA

In the past decade, mortality after partial hepatic resection ranged from 0 to 5% and although the cause of death after partial hepatic resection is multifactorial, PLF seems to be the main cause (18–75%) (29–31).

Pathogenesis

After the resection of various amounts of functional liver mass, both death and regeneration of the remaining hepatocytes occur. Physiologically, regeneration outweighs hepatocyte death and both liver mass and function are restored rapidly (32, 33). For example, during the first 10 days after right hepatectomy for living donor liver transplantation, restoration of liver mass up to 74% of the initial volume has been reported (32). This regeneration is triggered by an increased metabolic demand placed upon remnant hepatocytes [see (34) for a review].

The ability of the liver remnant to surmount the effect of surgical resection depends on its capacity to limit hepatocyte death, to resist metabolic stress, to preserve or recover an adequate synthetic function and to enhance its regenerative power (34–36). These factors rely on both the quality and the quantity of remaining liver parenchyma (37). A variety of intra-operative as well as post-operative hits can be identified that may attribute to the development of PLF. These include hepatic parenchymal congestion, ischaemia–reperfusion injury and reduced phagocytosis capacity (38–40).

Hepatic parenchymal congestion

Partial hepatic resection leads to a relatively augmented sinusoidal perfusion (39), leading to shear–stress and congestion of hepatic parenchyma and resulting in vascular and parenchymal damage similar to the small-for-size syndrome after liver transplantation, although less severe (41). Moreover, inadequate venous drainage of the liver remnant induces hepatic venous congestion and functional hepatic volume loss (42). Hepatic parencymal congestion may be less severe in patients with cirrhosis of the liver with pre-existing portacaval collaterals.

Hepatic ischaemia–reperfusion injury

Hepatic ischaemia–reperfusion injury follows massive bleeding or hepatic in- or outflow occlusion during liver surgery. Although the resistance of the liver to warm ischaemia is relatively high, hepatic ischaemia and reperfusion activate a complex cascade [see (38) for a review] that triggers the innate immune response by recruitment and activation of Kupffer cells, endothelial cells and the complement system. These express pro-inflammatory proteins [nuclear factor-κB, tumour necrosis factor-α, interleukin-6], reactive oxygen species, chemokines, complement factors and vascular cell adhesion molecules. Subsequently, polymorphonuclear neutrophils are activated, which aggravate hepatic injury. Although these processes are primarily intended to maintain homoeostasis, unrestrained activation may become destructive.

Reduced phagocytosis capacity

Infection complicates the course of PLF either as a precipitant or during later stages (6). Partial hepatectomy reduced the phagocytosis capacity of the hepatic reticuloendothelial system with an S-shaped correlation to the extent of the hepatic resection (40). Nevertheless, the liver remnant has to clear bacteria and their products following bacterial translocation or intra-abdominal infection (43). Diminished hepatic clearance of bacteria might enhance the susceptibility for the development of infections and PLF.

Risk factors

Independent predictors for the development of PLF (see Table 2) are small remnant liver volume (RLV), excessive intra-operative blood loss and need for blood transfusion, pre-operative hypoalbuminaemia, prolonged operating time, male gender and advanced age (2, 5, 6, 13, 44). At present, it is unclear whether extra-hepatic procedures, like concomitant biliary or vascular reconstructions, influence the incidence of PLF individually or by increasing operating time and/or blood loss.

Table 2.   Risk factors for post-resectional liver failure
Surgery related
 Small remnant liver volume
 Excessive intra-operative blood loss
 Prolonged operating time
Patient related
 Pre-existent liver disease
  Cirrhosis
  Steatosis
  Cholestasis
  Chemotherapy-associated hepatotoxicity
 Male gender
 Advanced age (≥65 years)
 Comorbid conditions
 Malnutrition
Miscellaneous
 Hepatic parenchymal congestion
 Ischaemia–reperfusion injury
 Infection

Comorbid conditions like diabetes mellitus as well as pre-existent liver diseases like steatosis, cirrhosis, cholestasis or chemotherapy-associated hepatotoxicity predispose for the development of PLF (28, 45–48).

Small remnant liver volume

The number of hepatic segments resected significantly correlated with the post-operative complication rate [odds ratio (OR) 1.2; 95% confidence interval (CI) 1.12–1.29] (2). RLV, defined as percentage remaining functional liver volume compared with pre-operative functional liver volume, is regarded as a reliable parameter to predict PLF and death, even more than the anatomic extent of the resection (6, 27, 49). However, the exact amount of residual liver mass required to preserve sufficient liver function is unknown. In general, an RLV≥25–30% in otherwise healthy livers is consistent with a good post-resectional outcome (6, 44). RLV below 25% in normal livers predicted PLF with a positive predictive value of 90% (95% CI 68–99%) and a specificity of 98% (95% CI 92–100%) (44). When liver function is restricted, RLV should be as high as 40% to guarantee adequate remnant liver function (5, 50).

Excessive intra-operative blood loss and need for blood transfusion

Intra-operative blood loss and need for blood transfusion predispose patients to PLF (OR 4.17; 95% CI 1.04–17.5) (2, 5, 51). The cut-off point for an adverse outcome is suggested to be above 1000–1250 mL blood loss. Excessive blood loss leads to massive fluid shifts, which might induce bacterial translocation and systemic inflammation (52). Massive bleeding also results in severe coagulopathy, which predisposes for intra-abdominal haematoma and infection (53). Furthermore, post-operative blood transfusions exert an immunosuppressive effect (54).

Male sex

Male sex doubles the propensity for developing PLF and post-resectional morbidity (OR 1.98; 95% CI not available) (7, 44), consistent with earlier observations that males are more susceptible to develop complications after surgery. Circulating sex hormones play a pivotal role whereby testosterone is thought to exert an immunodepressive effect while oestrogens exert an immunoprotective effect (55).

Advanced age

Although data in the literature are conflicting, advanced age (≥65 years) seems to predispose for PLF and post-resectional mortality (OR 1.8; 95% CI 0.78–4.19) (4), especially after extended hepatic resections (16, 56). Elderly patients suffer frequently from comorbid conditions and have reduced regenerative capacity of hepatocytes (57, 58).

Nutritional status

Approximately 65–90% of patients with advanced liver disease and 20–55% of patients with colorectal cancer suffer from protein–calorie malnutrition (59, 60). Malnutrition seems to predispose subjects to a higher post-resectional complication rate because of malnutrition-related immune deficiency, reduced hepatic protein synthesis and reduced regenerative capacity (61–63). However, a clear-cut relation between malnutrition and PLF has not yet been established.

Steatosis

Subjects suffering from different grades of steatosis experience more post-operative complications than controls (52 vs 35%, P<0.01) (64). Patients with biopsy-proven moderate hepatic steatosis had a higher incidence of PLF (14%) than patients with healthy livers (4%) (28). The presence of steatosis is hypothesized to be associated with impaired hepatic microcirculation (65), decreased resistance to ischaemia–reperfusion injury, increased intrahepatic oxidative stress and dysfunction in mitochondrial adenosine triphosphate synthesis (66). Animal studies report an impaired regeneration of steatotic livers, but this finding is not supported by sparse clinical data from living donors suffering from mild hepatic steatosis (67, 68).

Cholestasis

Patients with jaundice, because of either bile duct obstruction or parenchymal liver disease, have significantly increased morbidity rates after partial hepatic resection (19, 69). Cherqui et al. (69) demonstrated a morbidity rate of 50% in patients with obstructive jaundice vs 15% in patients with normal serum bilirubin (P<0.01), but the incidence of PLF and mortality did not differ from matched controls. Experimental animal models show that liver regeneration is impaired in bile duct-ligated rats as the upregulation of hepatic growth factors is reduced (70).

Cirrhosis

The incidence of PLF after partial hepatic resection in patients with cirrhosis ranges between 5 and 10% taking into account a higher number of restrictive surgical procedures in this subgroup (27, 45, 47). The high risk of developing PLF in patients with cirrhosis can be explained by the wide range of comorbid conditions like portal hypertension (71), diabetes mellitus, jaundice (72), malnutrition, hypersplenism and coagulopathy as well as frequent impaired pre-operative liver function and hepatic functional reserve (73). Furthermore, patients with cirrhosis have an impaired hepatic regenerative capacity (37).

Neoadjuvant chemotherapy treatment

Several clinical studies report that partial hepatic resection after systemic neoadjuvant chemotherapy treatment is accompanied by increased post-resectional morbidity and PLF-related death caused by chemotherapy-associated hepatotoxicity (74, 75). Hepatic parenchymal injury occurring in 78% of patients receiving oxaliplatin is addressed as the sinusoidal obstruction syndrome (76, 77). Systemic treatment with irinothecan is associated with an increased risk of steatohepatitis [chemotherapy-associated steatohepatitis (78)], which negatively affects 90-day mortality rate (74).

Risk assessment

Pre-operative risk assessment should ideally consist of four features including clinical, biochemical, volumetric and functional data [see (79, 80) for a review]. An assessment focusing on only one of these aspects is not considered to be useful. A thorough evaluation of risk factors is generally believed to enable the selection of candidates suitable for a safe partial hepatic resection with a low risk of PLF; however, its onset will remain unpredictable in a subset of patients.

Assessment of clinical condition

The identification of comorbid conditions like obesity, diabetes mellitus, cardiovascular, pulmonary, hepatic or renal disease is pivotal as they increase the susceptibility for major complications even if hepatic functional reserve is adequate (3, 48). Additionally, the existence of portal hypertension must be objectified, as this elevates the risk of extensive bleeding and PLF (71).

Nutritional status should be assessed using anthropometry, subjective global assessment, measurement of hand-grip strength or estimation of body cell mass (81). Weight and (pre)albumin levels are unreliable parameters for nutritional status as they are influenced by ascites and diminished liver function or inflammation rather than malnutrition per se (82).

Assessment of biochemical parameters

Tests analyzing hepatic synthetic (serum albumin and clotting factors) or excretory function (serum bilirubin) are non-specific for the assessment of hepatic function and do not correlate to post-resectional outcome; however, they may indicate hepatic dysfunction (73, 79, 83). Furthermore, serum activity of transaminases as well as alkaline phosphatase and γ-glutamyl-transferase is non-specific for the evaluation of hepatic function but can signal hepatocyte necrosis, increased hepatitic activity or the presence of cholestasis.

Assessment of liver anatomy and volumetry

Standard liver resection planning is based on two-dimensional (2D) computed tomography (CT) or magnetic resonance imaging, supplemented with intra-operative ultrasonography. These imaging techniques provide good-quality data about total, functional (i.e. total liver volume minus tumour volume) and remnant liver volume. Furthermore, information about the condition of hepatic parenchyma and the anatomy of liver segments, biliary structures, hepatic vasculature and tumour localization can be extracted. However, 2D CT supplies marginal information about the distribution pattern of hepatic venous in- and outflow related to hepatic segments and precise tumour localization (84). In this context, 3D reconstructions have proven to deliver useful additional information in selected cases like extended hepatic resections (85, 86).

Appropriate formulas combining body surface area and weight are available for different populations for the calculation of total liver volume (87) and these formulas are hypothesized to reflect the metabolic demands more exactly than CT volumetry alone.

Assessment of liver function

Assessment of liver function is critical to determine hepatic functional reserve and to predict the risk of PLF. Several dynamic tests can quantitatively evaluate liver function, among which indocyanine green retention in 15 min (ICGR15), the galactose elimination test, the lidocaine–monoethylglycinexylidide test (MEGX) and the 14C aminopyrine breath test are most frequently used and assess hepatic clearance or conversion of xenobiotics (79).

Indocyanine green retention in 15 min depends on hepatic perfusion rate, and subjects with an ICGR15 above 15–20% are generally believed to have an impaired hepatic functional reserve. In this particular group, adequate remnant liver function needs to be preserved (19, 45, 88). The hepatic cytosolic capacity is reflected by the galactose elimination test and the critical value is considered to be elimination of <6 mg/min/kg in patients without and <4 mg/min/kg in patients with hepatocellular carcinoma (HCC) (89).

The MEGX test and the 14C aminopyrine breath test are based on the rate of metabolite formation of drugs. MEGX test reflects the conversion rate of lidocaine by hepatic cytochrome P450, and a value ≤25 μg/L is related to PLF in patients with cirrhosis (90). Finally, the aminopyrine breath test evaluates the hepatic oxidative function by measurement of 14CO2 exhalation. The normal value is an exhalation of 7%14CO2 and the critical value seems to be below 2.3% (91, 92). There is no consensus regarding the validity of a sole test for assessment of liver function and hepatic functional reserve in operative planning.

Scoring systems reflecting liver function in patients with cirrhosis

Scoring systems used to assess the feasibility of a partial hepatic resection in patients with cirrhosis are the Child–Pugh score and the model for end-stage liver disease (MELD) score (3, 93, 94). As they are both designed for other purposes, their validity to predict post-resectional liver function has only recently been established and results are inconsistent. In general, Child–Pugh class C is considered to be an absolute contra-indication for surgery and class B permits only minor liver resections (95).

Schroeder et al. (3) reported the superiority of the Child–Pugh score to the MELD score in predicting short-term morbidity and mortality after partial hepatic resection. However, other authors state that the pre-operative MELD score is a highly reliable predictor in certain subgroups. A MELD score above 11 in patients with cirrhosis could predict PLF accurately [area under receiver operating characteristic curve 0.92 (95% CI 0.87–0.96)] (96).

Prevention

For patients with limited hepatic functional reserve or small RLV, preventive measures are obligatory.

Small remnant liver volume

Small RLV can be prevented by pre-operative portal vein embolization, two-stage hepatectomy, local tumour destruction and/or tumour downsizing by neoadjuvant chemotherapy.

Portal vein embolization is advised in patients with normal liver function if RLV is estimated to be below 25–30% or in patients with impaired liver function (reflected by an IGCR15 between 15 and 20%) and estimated RLV below 40–45% (97–99). Its effectiveness depends on the severity of pre-existent liver disease and comorbid conditions, ranging from a 28 to 46% volume increase after 2–4 weeks (98, 99). Portal vein embolization increased the feasibility of hepatectomy by 19% (98), but had a complication rate between 9 and 13% [see (97) for a review]. Portal vein embolization is hypothesized to facilitate intrahepatic tumour growth, but this does not seem to affect long-term outcome after partial hepatic resection for colorectal liver metastases (100).

Two-stage hepatectomy utilizes the regenerative capacity of the liver, aiming to perform a safe, curative hepatic resection for initially irresectable tumours. Studies focusing on the feasibility of two-stage hepatectomy, combined with other techniques like chemotherapy and/or portal vein embolization, reported a success rate of 70–81%, together with an increase in median survival time when compared with palliative chemotherapy alone in case of colorectal metastases (101, 102) [see (103) for a review]. Tanaka et al. (104) reported that two-stage hepatectomy combined with portal vein embolization induced a significantly greater hypertrophy ratio when compared with portal vein embolization alone.

Excessive intra-operative blood loss

Lowering central venous pressure during dissection to ≤5 mmHg limits intra-operative blood loss without deterioration of renal function (105, 106). A combination of the former with continuous as well as intermittent portal triad clamping or application of total vascular exclusion is most advantageous for the prevention of excessive intra-operative blood loss (107). The latter procedures are equally effective but total vascular exclusion induces more important haemodynamic changes and higher complication rates (108).

Ischaemic preconditioning

An improvement of post-operative liver function is reported after ischaemic preconditioning by temporarily clamping the portal triad before a prolonged episode of hepatic ischaemia when compared with no preconditioning. This procedure reduced hepatocyte damage in a murine (109, 110) as well as a human model (66, 111, 112). Recently, Petrowsky et al. (113) reported that ischaemic preconditioning combined with continuous portal triad clamping is as effective as intermittent clamping in non-cirrhotic livers, although intermittent clamping was accompanied by significantly increased intra-operative blood loss, transfusion requirement and operating time.

Advanced age

The protective effect of ischaemic preconditioning seems to diminish in patients aged above 65–70 years (112, 113). Consequently, intermittent clamping is suggested to be superior to continuous clamping in elderly (113).

Nutritional status

It has been hypothesized that the nutritional status of depleted patients should be corrected via oral, enteral or parenteral methods before surgery. A meta-analysis on the effect of total parenteral nutrition compared with enteral nutrition on morbidity and mortality after liver resection revealed no superiority of either form of nutrition (114). However, a beneficial effect of additional parenteral nutrition has been demonstrated in a subgroup of patients who had cirrhosis and underwent major hepatectomy (63).

Steatosis

Data from living liver donors suffering from biopsy-proven moderate steatosis revealed that a body weight reduction of 5% or intervention with a low-fat, high-protein diet and exercise significantly improved hepatic steatosis (115, 116). The effect of voluntary weight loss before hepatectomy for malignancy has never been studied. However, weight reduction before surgery may not be feasible because of time deficit and the often pre-existent malnutrition.

Cholestasis

Various studies failed to show an advantage of pre-operative percutaneous transhepatic drainage (PTD) in patients suffering from obstructive jaundice; moreover, PTD-associated complication rate was high and total hospital stay significantly increased (117, 118). A recent meta-analysis confirmed these results and concluded that pre-operative PTD should not be routinely used in patients with jaundice (119). Selective PTD significantly reduced morbidity rate only when intrahepatic segmental cholangitis accompanied biliary carcinoma (120).

Cirrhosis

Patients with cirrhosis of the liver are more susceptible to the development of PLF in case of resection of comparable tumour volumes. However, cirrhosis of the liver cannot be prevented and, therefore, prevention of PLF in these patients can only be achieved by careful patient selection, adequate nutritional support and the use of an appropriate surgical technique [see (45) for a detailed discussion]. In general, patients with cirrhosis and Child–Pugh C are considered not eligible for surgery and patients with class B should undergo only minor liver resections (95).

Manifestation

Post-resectional liver failure reflects a deregulation of the synthetic, excretory and detoxifying capacity of the liver remnant. In addition, the majority of patients suffering from PLF will also meet the criteria of the systemic inflammatory response syndrome and experience multiple organ failure (121). Unfortunately, a substantial number of patients suffering from PLF deteriorate, leading to a fatal outcome in approximately 80% (44). However, PLF is a potentially reversible disorder because of the regenerative capacity of the liver remnant.

At present, there is no validated organ failure score for the prediction of PLF and PLF-related death. Recently, the sequential organ failure assessment score has been shown to be superior to acute physiology and chronic health evaluation, MELD and Child–Pugh for the prediction of mortality in patients with acute-on-chronic liver failure (122). Future research should explore the value of these organ failure scores in patients who have undergone partial hepatic resection.

Liver

The clinical consequences of PLF are jaundice, coagulopathy, ascites, oedema and/or HE (123). Data from Suc et al. (33) and Balzan et al. (4) concerning liver function on different days after uncomplicated hepatic resection showed an initial increase of serum bilirubin and a decrease of prothrombin time before normalization of these values on the seventh post-operative day. However, when the prothrombin index dropped below 50% and serum bilirubin exceeded 50 μmol/L on post-operative day 5, the risk of early mortality increased significantly (4).

Circulation

Circulatory failure occurring during PLF resembles the circulatory failure of patients with sepsis (121). The pathophysiological changes usually observed are enhanced vascular permeability, diffuse intravascular coagulation and peripheral vasodilatation that are clinically represented by reduced peripheral resistance and haemodynamic instability (124).

Kidneys

Post-resectional renal dysfunction can either result from perioperative disturbances in renal circulation inducing acute tubular necrosis (105) or accompany PLF. It is characterized by azotaemia or oliguria and may cause ascites formation, pleural effusion and fluid overload requiring diuretics or haemofiltration (125). There is a distinct chance of reversibility of renal failure when there is recovery of PLF. Furthermore, it can be hypothesized that the pivotal role of the kidney in ammonia excretion is impaired, leading to hyperammonaemia and HE in patients suffering from PLF (126).

Lung

Although moderate pulmonary oedema seems to be a normal finding after partial hepatic resection owing to general haemodynamic alterations, this usually does not impair oxygen exchange (127). Severe remote lung injury, pulmonary oedema and acute respiratory distress syndrome can develop as part of the multiple organ dysfunction syndrome that accompanies PLF.

Hepatic encephalopathy

Hepatic encephalopathy is a potentially reversible neuropsychiatric disorder, characterized by varying degrees of confusion and disorientation (128). Hyperammonaemia plays a central role in its development (129) and has a direct toxic effect on neurotransmission and astrocyte function. It has become clear that inflammation makes the brain more vulnerable to ammonia (130) and may play an additional role in the development of HE during PLF. However, data concerning HE after partial hepatic resection are sparse.

Treatment

Large, randomized trials concerning the treatment of PLF are lacking, and therefore, recommendations for treatment modalities are difficult to make. Management principles resemble those applied to patients with acute liver failure, acute-on-chronic liver failure or sepsis and focus on support of liver and end-organ function (124, 131).

Goal-directed therapy should be provided for circulatory disturbances, renal and ventilatory dysfunction, coagulopathy, malnutrition and HE (see Table 3). As there seems to be a strong link between infection and PLF, frequent cultures for bacteria and fungi are essential. The use of prophylactic antibiotics after hepatectomy for the prevention of infectious complications is not supported by evidence from the literature (132). However, the administration of antibiotics in patients suffering from acute liver failure is associated with a significant decrease in infectious complications and this may also be advantageous in patients suffering from PLF (133).

Table 3.   Goal-directed therapy in patients suffering from post-resectional liver failure
  1. CVP, central venous pressure; MAP, mean arterial pressure.

Circulatory disturbancesCVP 8–12 mmHg
MAP 65–90 mmHg
Haematocrit ≥30%
Pulmonary capillary wedge pressure ≤12–15 mmHg
Renal dysfunctionUrine output ≥0.5 mL/kg/h
Ventilatory dysfunctionArterial oxygen saturation ≥93%
Central venous oxygen saturation ≥70%
Hepatic encephalopathyImprovement to grade ≤2
CoagulopathyIn case of bleeding
 Platelet count ≥50 × 109/L
 International standardized ratio ≤1.5
MalnutritionEnteral energy supply of 2000 kcal/day

Support of liver function

Plasma exchange

Plasma exchange is an extracorporeal supportive procedure in which plasma is separated from blood cells and treated or substituted with fresh-frozen plasma. This technique supplies defective plasma components (e.g. albumin and clotting factors) and removes water-soluble toxins related to hepatic coma (e.g. ammonium), thereby improving the clinical condition of patients suffering from PLF but not survival (134, 135).

Molecular absorbent recirculating system

The molecular absorbent recirculating system (MARS®,Gambro, Lund, Sweden) removes water-soluble along with albumin-bound toxins from the plasma by means of dialysing blood against an albumin-containing dialysate across an albumin-impregnated membrane (136, 137). Promising results have been shown when applied during acute liver failure or acute-on-chronic liver failure (138), but the use of MARS® for treatment of PLF has only been validated in small, uncontrolled and non-randomized trials. Unfortunately, MARS® treatment for PLF and progressive septic multi-organ failure did not positively affect patient survival (139–141).

Prometheus®

Prometheus® (Fresenius Medical Care, St. Wendel, Germany) uses the principle of fractionated plasma separation and adsorption for removal of water-soluble along with albumin-bound toxins. Albumin-bound toxins pass an albumin-permeable membrane and native albumin is subsequently detoxified by adsorption, after which the cleansed albumin is returned to the patient (136, 137). The detoxifying capacity of Prometheus® appears to be superior to that of MARS® when applied during acute-on-chronic liver failure, but no clinical survival benefit has been proven yet (142). Studies on the application of Prometheus® for PLF are lacking.

Bioartificial liver and the extracorporeal liver assist device

Bioartificial liver-supporting systems using cryopreserved xenogenic or human hepatocytes have been validated in one large, prospective controlled trial for acute liver failure and primary non-function after liver transplantation. Results are promising as the application is safe, but survival only significantly improved for acute liver failure patients (143). Again, data on the application of these bioartificial liver-supporting systems for the treatment of PLF are lacking. Moreover, bioartificial liver-supporting systems are not routinely available in a substantial number of hospitals.

Rescue hepatectomy and liver transplantation

The use of a rescue hepatectomy and subsequent liver transplantation in patients suffering from PLF may be of value in desperate situations where conventional measures fail. It is based on the concept that the ‘necrotic liver’ is the source of unknown humoral substances that contribute to the systemic inflammatory response syndrome (144). The efficacy of orthotopic liver transplantation for PLF has only recently been reported (145). Although orthotopic liver transplantation for patients suffering from PLF was associated with considerable morbidity, the mean survival time was prolonged from 1.4 to 42.2 months. All patients (n=4) who suffered from PLF but were not appropriate candidates for liver transplantation died, while those undergoing orthotopic liver transplantation all survived (n=7). However, no criteria are available for the selection of patients who will benefit from emergency liver transplantation for PLF and these need to be defined by the appropriate committees. We propose to consider patients eligible for emergency transplantation who have favourable tumour characteristics (i.e. R0 resection, low T and negative N status, HCC within Milan criteria and absence of extra-hepatic disease), without comorbid conditions and without a limited life expectancy because of other medical conditions. King's College Criteria may be applied when those patient criteria are met.

Conclusion

The incidence of PLF after partial hepatic resection ranges between 0.7 and 9.1%. An inadequate quantity or quality of residual liver mass are key events in the pathogenesis of PLF. Additional hits include hepatic parenchymal congestion, intra-operative ischaemia–reperfusion injury and post-operative infection.

Risk factors for the development of PLF are small RLV, excessive intra-operative blood loss, need for blood transfusion, malnutrition, advanced age, male gender and pre-existent liver disease. A prerequisite for the avoidance of PLF is a thorough pre-operative assessment that includes evaluation of liver volume, anatomy and function. Preventive measures should be applied whenever possible as curative treatment options are limited. When an RLV below 25–30% in livers without and below 40% in livers with pre-existing liver disease is expected, portal vein embolization and/or two-stage hepatectomy are recommended. Additional liver damage can be prevented by ischaemic preconditioning. Management principles focus on support of liver and end-organ function and resemble those applied during acute liver failure and sepsis.

Till the establishment of a uniform definition of PLF, the extrapolation of study results will remain difficult. Further research is needed to elucidate the exact pathogenesis of PLF and to develop a highly reliable model to predict the development of PLF. Treatment modalities for PLF have barely been studied in randomized-controlled trials, leaving the treatment of a patient suffering from PLF to the expert opinion.

Acknowledgements

Grants and financial support: Steven W. M. Olde Damink was supported by the Hendrik Casimir Karl Ziegler Fellowship of the Nordrheinwestfälische Akademie für Wissenschaften and the Royal Dutch Academy of Science (KNAW) and a Clinical Fellowship from the Netherlands Organization for Health Research and Development (Grant 907-06-177). Cees H. C. Dejong was supported by a Clinical Fellowship from the Netherlands Organization for Health Research and Development (Grant 907-00-033).

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