EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: We analyzed the nutritional condition of liver transplant recipients and the body mass index, the inner abdominal fat tissue, the outer abdominal fat tissue, the psoas muscle size, and the psoas muscle index of the recipients and evaluated the effects of these factors on patient outcomes after liver transplant.

Materials and Methods: We included recipients of liver transplants from January 2009 to December 2018 who had computed tomography at our center < 3 months before transplant. Preoperative, intraoperative, and postoperative data were evaluated. Outer abdominal fat tissue, inner abdominal fat tissue, and psoas muscle area were measured on the computed tomography abdominal images. We used univariate and multivariate regression analyses to evaluate the data.

Results: There were 265 patients; mean age was 54 years (SD, 13 years). The mean value for body mass index, calculated as weight in kilograms divided by height in meters squared, was 25 (SD, 5). The mean score for Model for End-Stage Liver Disease was 17 (SD, 6). All patients underwent orthotopic liver transplant by standard technique. After adjustment for multivariable analysis, the values for psoas muscle size and the psoas muscle index of the recipient were associated as independent factors for postoperative complications and duration of hospital stay. The survival rate at 1 year was 78.5%, and the rate of perioperative mortality was 16.6%. Independent factors associated with survival after liver transplant were inner abdominal fat tissue, etiology, and rate of major postoperative complications.

Conclusions: Inner abdominal fat tissue, psoas muscle size, and the psoas muscle index are significantly associated with postoperative complications and/or survival after liver transplant. Our results suggest that these prognostic factors may be useful to optimize the selection of appropriate candidates for liver transplant.

Key words : Body mass index, Curative treatment, Frailty, Survival, Visceral obesity

Liver transplant (LT) is a lifesaving treatment for patients with end-stage liver disease.^1,2 As a consequence of preexisting organ shortages, rigorous selection of appropriate patients is crucial.³ A widely established tool for organ allocation policy is the Model for End-Stage Liver Disease (MELD) score, which follows the so-called “sickest-first” principle.⁴ Such policies for organ allocation may not consider postoperative outcome, which we consider to be an essential factor for the selection of appropriate candidates for LT. The effect of obesity on surgical outcomes has been studied for many years.⁵ An excess in body fat is known to contribute to comorbidities in patients listed for LT and increases the risk for postoperative complications.^6,7 Also, data show that muscle mass reduction has a negative effect on outcomes after LT.⁸ The significance of inner abdominal fat tissue in patients with reduced muscle mass is not firmly established. However, all these factors are not included in routine preoperative evaluations of the recipient.⁹ We retrospectively reviewed data on body mass index (BMI, calculated as weight in kilograms divided by height in meters squared), outer abdominal fat tissue, inner abdominal fat tissue, psoas muscle size, and psoas muscle index and evaluated the influence of these factors on postoperative outcomes and survival rates after LT.

Materials and Methods

All patients who underwent deceased donor LT between January 2009 and December 2018 were reviewed retrospectively. Patients who had computed tomography (CT) images in the electronic system of our hospital less than 3 months before LT were identified and included in this study. Pediatric patients and patients with acute liver failure were excluded. Preoperative, intraoperative, and postoperative data were retrospectively reported from the electronic database of our hospital, and access to patients’ medical records and the electronic database were facilitated by the Eurotransplant International Foundation.

Values for BMI and the psoas muscle index were calculated. To determine the outer abdominal fat tissue (OAF), the inner abdominal fat tissue (IAF), and the psoas musculature of the patients, measurements were taken using CT images. Outer abdominal fat tissue was measured in millimeters at the thickest part of the anterior abdominal wall at the level of the navel (Figure 1). Inner abdominal fat tissue was measured in millimeters as the largest distance between kidney and the posterior abdominal wall at the level of the renal vein outlet from the left renal hilus (Figure 2). The technique of measurement of the OAF and IAF was described and established in a previous publication.10 Size of psoas muscle was identified by multiplying the measurement of the largest posterior-to-anterior size and the largest diagonal muscle diameter at the level of the navel.^11,12 The psoas muscle index was calculated by dividing the psoas muscle area (in mm2) by the square of the patient’s height in meters (Figure 3).

Orthotopic LT was performed with the standard technique with caval interposition in all patients. Intraoperative and postoperative data such as duration of surgery, blood transfusion, cold ischemic time, warm ischemic time, duration of intensive care unit (ICU) stay, postoperative complications, duration of hospital stay, and survival rates were reported. Perioperative mortality was defined as mortality within 30 days. The immunosuppressant therapy after LT was based on calcineurin inhibitors and prednisone, supplemented with mycophenolate mofetil. Modifications in dose or compounds were done individually, dependent on the clinical course. All patients were followed after LT according to the standard follow-up protocol. Morbidity was defined according to the Clavien-Dindo classification of surgical complications, with severe postoperative complications defined as grades IIIb and IV.¹³

This study was carried out in accordance with the principles of the World Medical Association, as defined in the Declaration of Helsinki and the national regulations for the conduct of clinical trials. Institutional review board approval was obtained.

Statistical analyses
Values are reported either as median values and interquartile range (IQR, in parentheses) or as mean values and standard deviation. We used the Mann-Whitney test to compare continuous variables and the Fisher exact test or the chi-square test for comparisons of proportions. Univariate and multivariate regression analyses and linear multivariate analyses were performed to identify independent prognostic factors for overall survival, postoperative complications, duration of surgery, blood transfusion during surgery, and hepatocellular carcinoma (HCC) recurrence. Because BMI, OAF, IAF, psoas muscle area, and psoas muscle index are integrative variables, these were tested in different models. Statistical significance was defined as P < .05. A professional biostatistician used the SPSS 23.0 statistical package for Windows to perform all statistical analyses.

There were 265 adult patients with a mean age of 54 years (SD, 13 years) included in the study. There were 152 male patients (57.4%) and 113 female patients (42.6%). The etiology of liver cirrhosis was hepatitis C virus infection in 54 patients (20.4%), alcoholic liver disease in 46 patients (17.4%), cryptogenic cirrhosis in 45 patients (16.9%), hepatitis B infection in 29 patients (10.9%), primary sclerosing cholangitis in 23 patients (8.7%), autoimmune liver disease in 22 patients (8.3%), and other etiologies in 46 patients (17.4%). A total of 63 of these patients (23.7%) were diagnosed with HCC in addition to their liver cirrhosis. Relevant comorbidities such as diabetes, cardiovascular disease, chronic kidney disease, or pulmonary disease were seen in 155 patients (58.5%). The mean laboratory MELD score was 17 (SD, 6). The mean values for BMI, OAF, IAF, psoas muscle area, and psoas muscle index are shown in Table 1.

The mean duration of surgery was 322 minutes (SD, 98 minutes). Blood transfusion was given in 107 patients (40.3%). There were no intraoperative complications. The mean duration of stay in ICU was 9 days (SD, 14 days). The mean duration of hospital stay was 24 days (SD, 21 days). Major postoperative complications were seen in 64 patients (24.2%). Perioperative death within 30 days after LT was seen in 44 patients (16.6%). Of 63 patients with HCC, 8 patients developed recurrence after LT (12.7%). A total of 24 patients required liver retransplant (9.1%) for primary nonfunction, arterial thrombosis, recurrent disease, or chronic liver failure. The 1-year and 5-year survival rates were 78.5% and 70.2%, respectively.

The multivariate hazard regression analyses identified etiology of the cirrhosis, major postoperative complications, and the thickness of the IAF as statistically significant prognostic factors for overall survival after LT. Interestingly, factors such as BMI, psoas muscle area, psoas muscle index, or OAF were not significant for overall survival (Table 2). Statistically significant factors for major postoperative complication were identified to be etiology of the cirrhosis, psoas muscle area, and psoas muscle index (Table 3). According to the univariate analyses, the duration of hospital stay was significantly influenced by the thickness of IAB, the psoas muscle area, psoas muscle index, and the number of blood transfusions during the LT. The same factors could be also identified as significant by the linear multivariate analyses, except for the thickness of the IAF, which did not reach a level of statistical significance on the multivariate analyses (Table 4). Interestingly, the duration of surgery and the duration of ICU stay were not affected significantly by any of the factors.

Additional subgroup analyses of patients with HCC were performed to evaluate whether IAF, OAF, psoas muscle area, and psoas muscle index correlate with recurrence rate. Significant correlation was not found for any of these factors.

At present, there remains a shortage of available organs for transplant; therefore, the indications for LT and the best possible prognostic assessment of potential transplant candidates are becoming increasingly important.¹⁴ Presently, the MELD score alone is widely used for allocation of LT recipients. This shows many advantages, such as objectivity, because it is based on blood values only. However, it does not correlate with outcomes of patients after LT. Previous studies have reported that the nutritional and functional status of the patients has an effect on the outcome after LT.^15,16 These factors are not covered by the MELD score. The prediction of the outcome after LT is as important as the prediction of wait list mortality for organ allocation. Consequently, it may be useful to identify factors associated with outcome after LT in order to apply these factors to improve the rigor of the candidate selection process.¹⁷

The widely accepted factor to assess the nutritional and functional status of the patients is BMI. The correlation of BMI with survival or major complications after LT is controversial, as previously reported. Some studies describe an increased risk for postoperative complications and longer durations of ICU stay and hospital stay after LT for patients with BMI-defined obesity.^18,19 Some studies²⁰ describe an increased mortality rate after LT for patients with BMI > 30. Thuluvath and colleagues^21,22 have shown the same effect of BMI on survival for patients with BMI > 35. However, several studies report the opposite result, ie, an improved survival rate for patients with higher BMI.²³ For various patient groups, including patients after LT, this phenomenon is known as the “obesity paradox.” In another interesting study, Tanaka and colleagues²⁴ demonstrated more negative outcomes after LT for patients with extreme BMI values (ie, BMI > 40 or BMI < 18.5). The results of our study clearly show no influence of BMI on overall survival or occurrence of postoperative complications after LT. Many studies in the literature have reported similar results.^25-28 The heterogeneous results in the literature reflect the heterogeneity of the BMI itself. The major problem is this: BMI does not differentiate between fat tissue or muscle tissue or even ascites; ie, the BMI is simply a value based on weight and height, irrespective of other factors. However, the differentiation of fat tissue versus muscle tissue is generally accepted to be a factor for outcomes after major surgeries.^9,29

Sarcopenia, defined as loss of psoas muscle area, has been described in several studies as a significant factor for postoperative complications, especially severe infections or sepsis.^23,30 Sarcopenia has also been shown to have a negative influence on the durations of ICU stay and hospital stay after LT.^17,31 Some studies have shown sarcopenia to be a factor for increased mortality rate after LT.^32-35 The overall survival rate does not correlate significantly with psoas muscle area or the psoas index in our study; however, it correlates significantly with major postoperative complications and duration of hospital stay. Patients with small psoas muscle area have significantly higher rate of major postoperative complications and longer duration of hospital stay after LT. Because muscle mass is related to protein synthesis and metabolism, the question arises, Does muscle mass also correlate with the MELD score? The results of previous studies showed no correlation between sarcopenia and MELD score.^31,36 Our results confirm these data.

A possible explanation for the correlation between the muscle mass and the postoperative outcome is the fact that muscle tissue is the source for protein synthesis and gluconeogenesis after oxidative stress. Liver transplant causes extreme stress, and patients with low muscle mass may not have sufficient reserves for an adequate protein synthesis and gluconeogenesis.^23,37

With regard to the effect of fat tissue on the outcome after major surgeries, the existing data suggest the necessity to differentiate between IAF and OAF to answer this question. Several studies have shown that OAF does not have any significant effect on the outcome after major surgeries.^10,29 Our results confirm that OAF does not have any effect on the duration of surgery, rate of morbidity, or rate of mortality, nor on duration of hospital stay or overall survival rate, whereas IAF is a significant, independent negative factor for overall survival. Patients with greater IAF had significantly lower rates of overall survival after LT. In 2017, Hamaguchi and colleagues showed that a high ratio of IAF to OAF had a significant negative effect on survival after living donor LT.³⁸ Another study analyzed the influence of IAF on the outcome after major liver resection and demonstrated a negative effect on duration of surgery, postoperative complications, 30-day mortality rate, and duration of hospital stay.¹⁰ However, several studies report no influence of IAF and OAF on the outcome after major surgery.^25,39 The results of our study demonstrate clearly that, in addition to psoas muscle area, IAF is also an independent negative predictive factor for overall survival after LT.

A major limitation of the present study is its retrospective aspect. The inclusion criteria of the study allow the possibility of selection bias, because only patients with a CT scan 3 months prior to LT were included in the study. Patients with an indication of CT scan are likely to have some distinctive clinical problems and may be more likely to have negative clinical aspects compared with those patients without the indication for CT scan. Another point of interest is the measurement method of IAF, OAF, and psoas muscle area. There are various methods by which to measure fat tissue and muscle tissue, as described in the literature. We have chosen a simple method of distance measurement in millimeters and area measurement in square millimeters on 1 cut image layer, which has been previously described as an established method.^10,39 There are various accepted methods of measurement, and so direct comparison to published data may be difficult if there are different methods among the compared studies. Some studies have used software programs to calculate the fat tissue volume from CT scan data from 3 to 4 different cut image layers based on Hounsfield units.^30,31 However, there are many published studies that compare different measurement techniques, and a common conclusion is that simple techniques may provide results with high consistency similar to complex techniques.⁴⁰ Also, for the measurement of the psoas muscle, studies have shown that the simple method of measurement of psoas muscle area produces results similar to those obtained with specialized software programs. Furthermore, it is widely accepted that the psoas muscle correlates with whole lumbar muscle and is representative for the body muscle volume.¹²

We showed that IAF, psoas muscle area, and psoas muscle index are significant prognostic factors for the outcome after LT. Body mass index is unspecific and does not have any predictive value for any of the outcome parameters. Furthermore, MELD score does not correlate with these factors and does not reflect the nutritional and functional status of the patients, which are essential for outcome prediction. Our results show that consideration of these factors together with the MELD score would be beneficial for facilitating rigorous selection of appropriate candidates for LT.

Volume: 19 Issue: 2 February 2021

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