Key words : Anthropometric measurement, Liver cirrhosis, Skeletal muscle index

Introduction

Sarcopenia, or severe muscle depletion, is increasingly recognized as a common consequence of advanced cirrhosis associated with adverse clinical outcomes.¹ A meta-analysis from Tantai and colleagues² revealed that, when sarcopenia was defined by the third lumbar-skeletal muscle index (L3-SMI), it may affect one-third of patients with cirrhosis and up to 50% of those with advanced cirrhosis (Child class C). Furthermore, the group reported that sarcopenia was independently associated with an ~2-fold increased risk of mortality in patients with cirrhosis.

Sarcopenia has been associated with increased wait list mortality and shown to be an independent predictor of wait list mortality. Hence, incorporating sarcopenia into prognostic algorithms can reduce mortality for patients on liver transplant (LT) wait lists. The currently used tool, the Model for End-Stage Liver Disease (MELD) score, purely assesses liver disease severity, without considering other systemic features.³ Therefore, early recognition of sarcopenia in cirrhosis is important, with subsequent optimal interventions aimed at improving muscle mass and consequently potentially improving survival.⁴

Data on the association between sarcopenia and outcomes after LT are more ambiguous, with conflicting findings on mortality. Some studies have reported that sarcopenia was associated with an increased risk of postoperative complications but not with a significant risk of mortality; however, other studies have reported sarcopenia to be associated with increased risk of posttransplant mortality.^5-8 Therefore, further clarification is needed on the influence of sarcopenia on post-LT outcomes. Such studies are deficient in our locality (Egypt) where hepatitis C virus (HCV)-related chronic liver disease is highly prevalent.⁹ The aim of our study was to assess the effects of sarcopenia on posttransplant recipients who had HCV-related cirrhosis within short-term follow-up (6 months).

Materials and Methods

Study design and study population
This cohort study was conducted at Assiut University Hospital, Assiut, Egypt, during the period between August 2018 and January 2022. During the study period, we included consecutive adult (≥18 years) patients with HCV-related cirrhosis who had undergone living donor LT (LDLT) at AL-Rajhi Liver University Hospital at Assiut University Hospital (Assiut, Egypt), a tertiary teaching hospital where LDLT was started in 2014. Diagnosis of HCV infection was based on the presence of anti-HCV antibodies and serum HCV RNA. The pretransplant diagnosis of liver cirrhosis was confirmed by clinical, laboratory, and imaging assessments.^10,11 The donors were related to the LT recipients.

Patients with evidence of non-HCV-related cirrhosis, coinfection with human immunodeficiency virus, hepatitis B virus, or malignancy, as well as those who were receiving anabolic steroids and those who refused to participate, were excluded.

Pretransplant evaluation
At study entry, patients underwent collection of medical history and clinical examinations, including age, gender, MELD score, comorbidities like diabetes, and presence of complications (eg, ascites, variceal hemorrhage, and hepatic encephalopathy). Blood samples were collected for laboratory investigations and included complete blood count, liver and kidney function tests, and serum sodium levels.

Before transplant, patients underwent measu-rements of height and weight for measurement of body mass index (BMI), anthropometric measu-rements for mid-arm circumference (MAC) using a non-stretchable tape measure, triceps skinfold thickness (TSF) using the Lange skinfold caliper, hand grip strength using the Hand Dynamometer Grip (AL169), and gait speed to assess physical performance. Patients also had abdominal computed tomography (CT) scans before LT.

In this study, sarcopenia was defined by direct quantification of skeletal muscle mass at cross-sectional imaging (CT scan), which is currently considered the gold standard in patients with cirrhosis due to its objective and reproducible measurements. In addition, among the different CT scores, we specifically choose L3-SMI to assess sarcopenia because of its good correlation with whole body skeletal muscle mass.^12,13

Assessment of abdominal muscle mass and definition of sarcopenia
All patients had a triphasic CT scan of the abdomen preoperatively, in which abdominal skeletal muscle mass was measured using analysis with NIH ImageJ software (DICOM). One expert radiologist calculated the total cross-sectional muscle area (cm²) at the L3 level, which was then divided by patient’s height squared (m2) to calculate SMI (cm²/m²). Measured muscles were the psoas, erector spinae, quadratus lumborum, transversus abdominus, external and internal abdominal obliques, and rectus abdominus on the corresponding axial images.¹⁴ Similar to previous studies in patients with cirrhosis waiting for LT,^5,15-17 sarcopenia was defined by SMI as <52.4 cm²/m² in men and <38.5 cm²/m² in women.¹⁸

Posttransplant evaluation
Patients were followed up at 6 months for posttransplant outcomes, including information on length of hospitalization, complications (eg, biliary complications, de novo malignancy, acute and chronic rejection, infections, bleeding ischemic changes), and patient survival. Moreover, at the end of month 6, patients again underwent clinical and laboratory assessments and a triphasic CT scan of the abdomen to evaluate sarcopenia.

Statistical analyses
We conducted statistical analysis using SPSS version 16 for Windows (IBM Corp). The Shapiro test was used to test the normality of data. Continuous data were expressed as means ± standard deviation (SD) or median (minimum-maximum) and were compared using t test or Mann-Whitney U test and paired t test. Categorical variables were expressed as a percentage and compared using chi-square or the Fisher exact probability test. We constructed Kaplan-Meier curves to estimate the overall survival rates. We plotted receiver operating characteristic curves (ROC) to measure the performance of the investigated parameters (pre-LT SMI on CT) in predicting the post-LT mortality and to select its optimal cut-off value in which the sensitivity, specificity, and likelihood ratios were calculated. For all analyses, P < .05 was statistically significant.

Ethical considerations
The local ethics committee of Assiut University Hospital approved the study (study No. 17200236). The study was conducted in accordance with the previsions of the Declaration of Helsinki. All
patients were informed about the study, and written consent was obtained from each patient before enrollment.

Results

Pretransplant characteristics of patients with cirrhosis
During the study period, of 331 patients on the LT wait list who were screened for eligibility, 61 patients with HCV-related cirrhosis had undergone LDLT and were included in our study. The donors were first- and second-degree relatives of the LT recipients. The mean age of study patients was 48.7 ± 12.5 years, with 75.4% male patients. The mean MELD score at the time of transplant was 22.03 ± 4.3. The mean BMI of the study cohort was 23.9 ± 3.9. The mean L3-SMI was 45.3 ± 6.7 cm²/m². Using the cutoff values from the normal controls, we found that sarcopenia was present in 27/61 (44.3%) patients with cirrhosis before transplant.

We found that ascites and advanced liver cirrhosis based on Child-Pugh score were significantly more prominent in those with pre-LT sarcopenia. In addition, those with pre-LT sarcopenia had signifi-cantly lower serum albumin levels, TSF, MAC, BMI, hand grip, and gait speed and higher alanine transa-minase (ALT) and international normalized ratio (INR) levels compared with those without pre-LT sarcopenia. Further pretransplant clinical and laboratory data of the study patients and their subgroups at and during admission were sum-marized in Table 1.

Posttransplant patient characteristics
Of 61 patients who underwent LT, 15 patients (24.6%) died during the 6-month follow-up period posttransplant; 13 of the patients who died had pre-LT sarcopenia. Causes of mortality were massive pulmonary embolism (n = 2), hepatic artery throm-bosis (n = 2), sepsis, renal failure and disseminating intravascular coagulopathy (n = 6), portal vein thrombosis, multiple cholangitic abscesses (n = 2), acute liver failure and bleeding (n = 3).

When we compared pre-LT and post-LT anthro-pometric and SMI values in the 46 patients who survived, we observed significant improvements in TSF, MAC, BMI, hand grip, gait speed, and SMI CT values at 6 months post-LT (Table 2). The number of patients who had a reversal of sarcopenia was too small (4 patients) to perform more detailed characterizations.

Characteristics of posttransplant survivors
There were 46 patients (75.4%) who were alive at the 6-month post-LT follow-up (9 women, 37 men; age 48.5 ± 12.6 years). Of these patients, 14 (30.4%) had sarcopenia, with 12 having pre-LT sarcopenia and 2 developing sarcopenia post-LT. All patients with sarcopenia were men, and we were able to compare their pre-LT and post-LT characteristics. Post-LT complications were found in 13 patients (with patients possibly having more than 1 complication), including, infections (eg, pneumonia, wound infection, cellulitis) in 9 patients; 6 of 13 (46.2%) patients with sarcopenia had infections during the early post-LT period. Other complications included biliary leakage or stricture in 8 patients, bleeding in 3 patients, and lower limb ischemia and portal vein thrombosis in 2 patients. None of these patients had de novo malignancy.

Compared with that shown before LT, those with post-LT sarcopenia had significantly prolonged disease duration (P = .012), higher Child-Pugh score (P = .018), lower serum albumin (P = .003), and elevated ALT (P = .001) compared with those without post-LT sarcopenia. Moreover, pre-LT values of anthropometric parameters, including TSF, BMI, and gait speed (P < .001), MAC (P = .015), and handgrip strength (P = .001) were significantly lower in patients with post-LT sarcopenia than in those without (Table 3).

Regarding post-LT characteristics, patients with post-LT sarcopenia had significantly prolonged intensive care unit (ICU) stay duration (P = .04), more post-LT complications (P = .003), elevated ALT, and lower serum albumin, TSF, MAC, BMI, handgrip strength, and speed gait values than those without post-LT sarcopenia. Furthermore, ascites was significantly prominent in patients with post-LT sarcopenia (Table 4).

Pretransplant risk factors for posttransplant morbidity and mortality
On univariate analysis, Child-Pugh score (P = .036; odds ratio [OR] 1.654; 95% CI, 1.033-2.647), TSF (P = .025; OR 0.761; 95% CI, 0.6-0.967), BMI (P = .003; OR 0.754; 95% CI, 0.628-0.906), serum albumin (P = .037; OR 0.3; 95% CI, 0.097-0.929), massive ascites (P = .019; OR 3.059; 95% CI, 1.204-7.775), recent pre-LT infections (P = .018; OR 6.214; 95% CI, 1.372-28.147), and pre-LT sarcopenia (P = .007; OR 7.2; 95% CI, 1.731-29.94) were associated with post-LT morbidity; however, on multivariate analysis, none of these measurements showed statistical significance.

On univariate analysis, we found that patients who died were significantly older (P = .004) and had higher frequency of pre-LT sarcopenia (P = .001) than those who survived. In addition, pretransplant serum albumin (P = .008), BMI (P = .033), TSF (P = .014), gait speed (P = .005), and SMI on CT (P =.002) were significantly associated with posttransplant mortality. On multivariate analysis, age (P = .011) and pre-LT sarcopenia (P = .008) were found to be independent predictors of post-LT mortality (Table 5).

Survival analysis after liver transplant
Kaplan-Meier survival curves were generated for post-LT patients with and without pre-LT sarcopenia. The curves showed that patients with pre-LT sarcopenia had significantly reduced (short-term) survival after transplant (P < .001) (Figure 1).

Diagnostic accuracy of pretransplant skeletal muscle index to predict mortality after liver transplant
We generated ROC curves that plotted sensitivity versus specificity to evaluate the overall performance of pretransplant SMI on CT. Among male patients, using the pretransplant SMI CT result at a cutoff of <45 cm²/m², we determined that the area under the curve (AUC) was 0.842 (95% CI, 0.705-0.933) with 100% sensitivity, 67.7% specificity, 49.8% positive predictive value, 100% negative predictive value, and positive likelihood ratio of 3.08 (P = .002) to predict post-LT mortality (Figure 2A). Among female patients, the AUC of pretransplant SMI CT at a cut-off <36 cm²/m² was 0.917 (95% CI, 0.658-0.989) with 83.3% sensitivity, 100% specificity, 100% positive predictive value, 74.9% negative predictive value, and negative likelihood ratio of 0.17 (P < .001) to predict post-LT mortality (Figure 2B).

Discussion

Sarcopenia is common in patients with cirrhosis on LT wait lists.^5-8,19,20 However, the effect of pretrans-plant sarcopenia on the risk of complications and survival after transplant remains controversial.^5,6,19,20 In this study, we highlighted the effects of sarcopenia on LT recipients.

In our study patients, pre-LT sarcopenia was shown in 44.3% of patients with HCV-related cirrhosis on the LT wait list, which was within the range (22.2% to 70%) mentioned in previous studies.^21-25 Our rate was higher than that reported by Montano-Loza and colleagues¹⁶ (40%) and Erkan and colleauges²⁶ (39.7%) and lower than that reported by Hanai and colleagues¹⁷ (68%). These differences in frequency of sarcopenia in different studies may be attributed to different sample sizes, study design, participants, genetic variations, muscle mass, lifestyle, and dietary intake. Moreover, the sarcopenia definition cut-off point lacks a consensus. In agreement with our study, most studies defined sarcopenia using the L3-SMI CT cut-off values as suggested by Prado and colleagues¹⁸ (L3-SMI CT of <38.5 cm²/m² for women and <52.4 cm²/m² for men).^5,15-17

In line with previous studies,^26,27 we found an association between sarcopenia and increasing severity of liver dysfunction based on Child-Pugh score but not MELD score and elevated ALT with lowering anthropometric parameters (TSF, MAC, BMI), particularly in male patients. In their preoperative analysis, Golse and colleagues¹⁹ reported that patients with sarcopenia had lower BMI (P = .003) and more frequency of ascites (P = .006); however, unlike our study, sarcopenic recipients presented with higher MELD score (22 vs 18; P = .01) compared with those without sarcopenia.Cirrhosis-related sarcopenia is likely multifac-torial and can include factors such as poor nutrient intake and synthesis, abnormal protein metabolism, relative physical inactivity, increased muscle breakdown induced by increased myostatin and ammonia, and decreased testosterone and insulin-like growth factor 1 levels.^28,29 In addition, deteriorating liver function and altered intestinal flora are additional causes of sarcopenia.³⁰

In our study, of 331 patients with cirrhosis awaiting LT, 61 patients underwent LT and were followed up for 6 months. Of these, 15 patients died during the post-LT observation period. Moreover, 16 of the remaining 46 patients had pre-LT sarcopenia; at the end of the post-LT 6-month follow-up, sarcopenia was found in 14 patients (30.4%) and all were men. Twelve of those patients had pre-LT sarcopenia and the remaining 2 (14.3%) had de novo post-LT sarcopenia. Despite significant improve-ments of anthropometric parameters after LT, pre-LT sarcopenia failed to improve, possibly due to our short follow-up post-LT period. Bhanji and colleagues³¹ reported that sarcopenia did not always improve after LT, but it may continue and progress posttransplant in many patients with possible effects on patient outcomes. Therefore, physicians need to recognize sarcopenia in these patients and treat it. Moreover, the investigators revealed de novo sarcopenia to be a common entity, possibly seen in up to 25% of post-LT recipients.³¹

Postoperative progressive worsening of sarco-penia and development of de novo post-LT sarcopenia may also be related to a persistent catabolic state, prolonged hospitalization, immuno-suppression, corticosteroid use, renal failure, and possibly recurrent liver disease. Any of those factors with transplant-related complications may influence muscle mass, strength, and function.^29,30,32

Among those with post-LT morbidity, our LDLT recipients with sarcopenia had lower postoperative anthropometric measures compared with those without sarcopenia. In addition, we found that sarcopenia was associated with a higher rate (64.3%) of complications after LDLT, with about 46.2% of recipients with sarcopenia having infections during the early posttransplant period, which led to longer ICU stays. In agreement with these results, previous studies reported that sarcopenia was associated with an increased rate of infections and increased posttransplant complications.^6,26,33 These results suggest that patients with sarcopenia are more susceptible to infections, and thus antibiotic prophylaxis may be considered during this post-LT period. Golse and colleagues reported that pulmonary complications, infections, bleeding, and acute graft rejection were the major complications observed during early hospitalization.¹⁹

In our study, preoperative liver dysfunction severity, including higher Child-Pugh score, massive ascites, and low serum albumin and TSF, recent pre-LT infections, and pre-LT sarcopenia were associated with these post-LT morbidities. On the other hand, on univariate analysis, post-LT mortality was associated with older age and pre-LT sarcopenia, lower serum albumin pre-LT, lower anthropometric measures pre-LT, and lower SMI CT values. On multivariate analysis, age and pre-LT sarcopenia were found to be independent predictors of post-LT mortality. We also found that LDLT recipients with pre-LT sarcopenia had significantly reduced short-term survival after transplant, as shown by ROC analysis. In line with our findings, some studies reported that sarcopenia was associated with poorer survival.^34,35 However, others reported no differences in survival between patients with and without sarcopenia after LT.^6,7,20 Negative effects of sarcopenia have included increased post-LT complications, poor functional status, prolonged hospitalization, increased drug toxicity, more medical costs, and lower survival rates.^5,34,35

Limitations
Our sample size was small and included patients at a single center; therefore, the results may not exactly represent patient populations from other regions. Large, prospective multicenter studies are needed to confirm these findings and to assess the impact of sarcopenia on post-LT long-term outcomes and survival.

Conclusions

Sarcopenia is a common entity in patients with cirrhosis awaiting LT and may continue after LT; de novo post-LT sarcopenia is also a common finding. Sarcopenia can affect patient outcomes, including prolonged ICU stay, frequent postoperative compli-cations, and poor short-term survival.

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