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Reversal of sarcopenia predicts survival after a transjugular intrahepatic portosystemic stent

Tsien, Cynthiaa; Shah, Shetal N.b; McCullough, Arthur J.a; Dasarathy, Srinivasana

European Journal of Gastroenterology & Hepatology: January 2013 - Volume 25 - Issue 1 - p 85–93
doi: 10.1097/MEG.0b013e328359a759
Original Articles: Cirrhosis

Background Sarcopenia is the most frequent complication of cirrhosis. A transjugular intrahepatic portosystemic stent (TIPS) lowers portal pressure in cirrhosis and alters the body composition. Changes in the skeletal muscle area and adipose tissue volume were quantified by computed tomography (CT) before and after TIPS.

Materials and methods Fifty-seven consecutive cirrhotics who had a CT scan before and after TIPS were studied. Simultaneous age-matched, sex-matched, Child’s score-matched, and Model for End-Stage Liver Disease score-matched cirrhotics (n=32) who did not undergo TIPS comprised the disease control and 57 healthy individuals who had undergone CT abdomen comprised the healthy control population. Muscle area and fat volume were obtained at the mid-L4 vertebra level on the CT scans.

Results Patients (mean age 55.5±8.1 years) were followed up for a mean of 13.5±11.9 months following TIPS. Total psoas and paraspinal muscle area increased significantly (P<0.0001) after TIPS (from 22.8±0.9 to 25.1±0.9 cm2 and 54.5±1.3 to 57.9±1.5 cm2, respectively). After TIPS, muscle area increased in 41 patients but remained unchanged or decreased in 16 patients. Post-TIPS visceral fat volume decreased significantly (47.7±4.1 to 40.5±3.4 cm3; P<0.001). Failure to reverse sarcopenia after TIPS was accompanied by higher (P=0.007) mortality (43.5%) compared with patients in whom the total muscle area increased (9.8%). On multivariate analysis, predictors of reversal of sarcopenia after TIPS included male sex and lower pre-TIPS muscle area. Cirrhotic patients who did not undergo TIPS showed no change in the mean muscle area over 13.1±1.3 months.

Conclusion TIPS reverses sarcopenia in cirrhotic patients. Failure to improve muscle area after TIPS was accompanied by a higher mortality.

aDepartments of Gastroenterology, Hepatology and Pathobiology

bImaging Institute, Cleveland Clinic, Cleveland, Ohio, USA

Correspondence to Srinivasan Dasarathy, MD, NE4-208 Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA Tel: +1 216 444 2980; fax: +1 216 445 3889; e-mail: dasaras@ccf.org

Received June 22, 2012

Accepted August 23, 2012

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Introduction

Malnutrition is the most common complication of cirrhosis, and adversely affects morbidity, mortality, development of other complications of cirrhosis, and quality of life 1–5. It is defined as either a loss of skeletal muscle mass (sarcopenia), an alteration in energy metabolism, or a combination of these 6. Sarcopenia is known to be an independent predictor of survival in patients with cirrhosis and liver disease both before and after liver transplantation 2,3,7. Sarcopenia of cirrhosis is also associated with a loss of fat mass, which is another predictor of poor outcome in cirrhotic patients 8,9. Animal studies suggest that reduced whole-body energy stores also contribute toward impaired skeletal muscle protein synthesis and consequent loss of skeletal muscle mass 10. Although sarcopenia worsens outcomes in patients with cirrhosis 2,7, its reversal has only been reported in animal studies 11. Human studies have shown that interventions can partially reverse malnutrition in cirrhosis, but increased muscle mass has not been reported 12,13. One reason is a lack of precise methods to quantify whole body and regional skeletal muscle mass in humans 14,15. Computed tomography (CT) is routinely used to evaluate patients with cirrhosis. CT has been established as a precise and reproducible method to quantify skeletal muscle and adipose tissue mass and can therefore be used to assess serial changes in muscle and fat mass in response to interventions 15,16.

A recent literature review showed an increase in fat-free mass (FFM), BMI, and ascites-free weight 3 months after transjugular intrahepatic portosystemic stent (TIPS) 17. Several limitations of the published data were identified including the fact that bioelectrical impedance analysis (BIA) is an imprecise method to measure FFM 17–21 and failure to assess skeletal muscle mass separately from FFM as skeletal muscle constitutes only 40–60% of FFM 22. BIA has also been suggested to have reduced accuracy in the presence of ascites 17,23. There are no data on the relative contributions of subcutaneous adipose tissue (SAT) and the metabolically active visceral adipose tissue (VAT) in cirrhosis. Whole-body fat mass derived from BIA will not be able to distinguish between subcutaneous and visceral fat mass. Finally, previous reports have not included matched control populations to study the effect of TIPS on changes in body composition 17.

The responses of skeletal muscle area and adipose tissue volume (both subcutaneous and visceral) on CT-image analysis before and after TIPS insertion in cirrhotic patients were evaluated. These data were also compared with that from healthy controls as well as matched cirrhotics who did not undergo the TIPS procedure. The mean CT attenuation of the skeletal muscle that correlates with muscle fat content and strength 24,25 was also examined in the present study as a measure of muscle quality.

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Materials and methods

Participants

Between January 2008 and December 2011, 57 consecutive cirrhotic patients with TIPS placement who had also undergone a CT abdomen and pelvis both before and after the procedure comprised the study population. Cirrhosis was diagnosed by liver biopsy and/or clinical, biochemical, and imaging criteria. Patients with other chronic diseases (renal failure, heart failure, end-stage chronic obstructive lung disease, uncontrolled diabetes mellitus, and active malignancy) or those who used medications that affect skeletal muscle turnover were excluded. In the cirrhotic patients, CT scans were performed for screening or surveillance of hepatocellular carcinoma or abdominal pain. An equal number of simultaneous age-matched, sex-matched, and BMI-matched cohort of healthy individuals who had undergone abdominal CT either for work-up of acute abdominal pain or living donors for liver transplantation comprised the healthy control group. The disease control population included 32 cirrhotic patients who had undergone serial CT scans but did not undergo TIPS or liver transplantation followed for a mean of 13.1±1.3 months. Height and weight were measured after paracentesis in cirrhotics. The study was approved by the Institutional Review Board of the Cleveland Clinic and conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Written consent was waived because of the retrospective nature of the study population.

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Transjugular intrahepatic portosystemic stent procedure

All procedures were performed at a single institution using covered stents. After the placement of the TIPS, all patients were subjected to a Doppler ultrasound evaluation within 2 weeks and then at 3 and 6 months after TIPS to confirm stent patency.

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Biochemical and nutritional analysis

Biochemical assays carried out within 2 weeks of the CT scan were used and included blood glucose, bilirubin, urea nitrogen, aminotransferases, prothrombin time, albumin, and serum creatinine. All assays were carried out in the clinical core laboratory of the Cleveland Clinic using standard colorimetric assays. During the follow-up period, a dietary recall was used to determine whether the caloric and food intake was altered in the 6 months after TIPS compared with the same period before the procedure.

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Computed tomography scan body composition determination: method and analysis

Muscle areas were measured prospectively on a Leonardo Workstation using Oncocare (Seimens Healthcare, Erlangen, Germany) software by two investigators (C.T., S.N.S.) in consensus, both of whom were masked to the status or the outcome of the patients during the evaluation. CT scan dates, vascular phases, slice thicknesses, and all muscle and fat measurements were confirmed and recorded in consensus.

Unenhanced axial CT datasets from pre-TIPS and post-TIPS multiphase abdominal CT scans obtained as part of a routine clinical evaluation were evaluated. The mid fourth lumbar (L4) vertebral level was identified on each scan on the basis of midline sagittal images that were reformatted from the unenhanced axial CT dataset. On the corresponding axial image, we determined the total cross-sectional area and the mean attenuation of each of the following muscle groups: left and right major and minor psoas muscles; total paraspinal (left and right quadratus lumborum) muscles; and total abdominal wall muscles (left and right rectus abdominis, internal and external oblique, and transverse abdominis) (Fig. 1a). Core abdominal muscle area was defined as the combined psoas and paraspinal muscle areas and the total muscle area included the sum of the core muscle and the abdominal wall muscle area. Skeletal muscle and adipose tissue areas were distinguished by a bimodal image histogram resulting from the distribution of CT numbers in adipose tissue and muscle 26. A Hounsfield unit (HU) range of −190 to −30 was used to determine VAT and SAT. SAT was defined as adipose tissue below the skin and above the parietal peritoneal lining, and VAT was defined as intraperitoneal adipose tissue. Adipose tissue volume was determined in a predefined 3 mm section. Intermuscular adipose tissue was distinguished from the SAT by manually drawing lines along the deep fascial plane surrounding the various muscle groups. Care was taken to exclude excess scarring or fascia, bones, and fluid when determining adipose tissue mass (Fig. 1b).

Fig. 1

Fig. 1

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Statistical analysis

Descriptive statistics were computed for all variables. The Kolmogorov–Smirnov test showed that the individual and group muscle areas and the adipose tissue mass in the controls were distributed normally. Qualitative variables were compared using the χ 2-test. Analysis of variance with Bonferroni’s correction was used to compare multiple groups. In addition, a paired t-test was used to compare the data before and after TIPS. The Kaplan–Meier survival analysis was used to examine the impact of change in muscle area on survival and the data were compared using the log-rank test. Death was used as a censoring event. Changes in individual muscle as well as core and total abdominal muscle areas were analyzed separately. Baseline factors associated with improvement in muscle area (P<0.1) were also evaluated. Multivariable linear regression analysis was carried out to assess whether baseline muscle area, time from TIPS to CT, or other clinical characteristics were associated with changes in the total psoas or paraspinal muscle area. Improvement in muscle area was defined as an increase in muscle area over 5% of the baseline and was assessed for different muscle groups. A P value less than 0.05 was considered statistically significant. Muscle area and adipose tissue volumes were analyzed as determined and also after normalization for height (area/height in m2 or fat volume/height in m2). Analyses were carried out using SPSS (version 20.0; IBM, Armonk, New York, USA).

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Results

The baseline clinical and demographic characteristics of the cirrhotic patients who underwent TIPS (study participants) and those who did not (non-TIPS cirrhotic control individuals) are shown in Table 1. The matched healthy control individuals (n=57; age 54.7±8.1; 36 men and 21 women, BMI: 29.2±4.7 kg/m2) and cirrhotic non-TIPS controls were similar to the cirrhotic patients who underwent the TIPS procedure. The most common indication for TIPS was refractory ascites in 41 (71.9%) patients, followed by prevention of gastrointestinal bleeding in 14 (24.6%), and both in two (3.5%). TIPS placement was successful in all 57 patients as confirmed by a reduction in the portosystemic pressure gradient (10.4±4.4 mm; 59.5±17.1%) and patency on Doppler flow. After TIPS placement, patients were followed for a mean of 13.5±11.9 months, with no recurrent episodes of variceal bleeding. Ascites improved or were easily controlled in 46 patients (80.7%). The Child–Pugh score and Model for End-Stage Liver Disease (MELD), calculated at the time of the follow-up CT scan, did not change significantly after TIPS (Table 2). An increase in BMI occurred in 31 (54.4%) patients and the mean increase after TIPS was 1.1±5.7 kg/m2 (range −19.2 to 24.6 kg/m2). Most biochemical values did not change after TIPS, except for a significant increase in serum bilirubin (Table 2).

Table 1

Table 1

Table 2

Table 2

Before TIPS core, total and individual abdominal muscle areas and the mean muscle attenuation were significantly lower in cirrhotics as compared with the healthy controls (Table 3). The volume of VAT was similar (P>0.1) between cirrhotics before TIPS and controls, but the SAT volume was lower (P<0.05) in the limited number of patients (33 cirrhotics, 28 controls) in whom the entire SAT was included in the scans (Table 3). Despite similar Child–Pugh and MELD scores, pre-TIPS cirrhotics had lower muscle area compared with those who did not undergo TIPS (Table 3). However, a greater proportion of cirrhotics undergoing TIPS had severe ascites (58%) compared with those in the non-TIPS group (15%). All patients who underwent TIPS for refractory ascites had repeated paracentesis whereas the non-TIPS cirrhotics did not.

Table 3

Table 3

Clinical variables that were correlated negatively with the total muscle area and the individual component muscle groups in cirrhotic patients before TIPS included higher Child’s score and serum bilirubin, but not elevated MELD scores (Table 4). Muscle area was significantly lower (P<0.05) in patients with severe ascites (psoas 21.2±6.7 cm2 and paraspinal 52.3±8.9 cm2) compared with those with mild or moderate ascites (psoas 24.9±7.1 cm2 and paraspinal 57.7±9.5 cm2).

Table 4

Table 4

The total and core muscle area increased significantly (P<0.01) after TIPS and the differences in the total skeletal muscle area between cirrhotics and healthy controls were no longer significant (P>0.05). When the individual components of the total abdominal muscle area were analyzed, the mean psoas muscle area increased but was still lower (P<0.01) than that in the healthy controls, whereas the mean abdominal wall muscle area did not increase significantly (P>0.05). Post-TIPS mean muscle CT attenuation did not change significantly and remained lower than that of the controls (P<0.01) in all the muscle groups (psoas, paraspinal, and abdominal wall, core and total muscle area). In contrast to these observations in the cirrhotics who underwent TIPS, the non-TIPS cirrhotic controls did not show any significant change in the muscle area or attenuation over a similar time period of follow-up. Of the 30 (52.6%) patients in whom we obtained a dietary history by recall, only 13 (43.3%) recalled a notable increase in their appetite and the total dietary intake after TIPS. The rest of the patients either showed no change or experienced a decrease in their appetite and total dietary intake after TIPS. Patients with an increase in psoas muscle area did not have an increase in food intake compared with those with a decrease in muscle area.

VAT volume was measured in all patients before and after TIPS. VAT decreased after TIPS in 38 (66.7%) patients and was significantly (P<0.001) lower than that in healthy controls. The change in VAT correlated inversely with the increase in psoas muscle area (P<0.05) and paraspinal muscle area (P<0.05). In the 17 cirrhotic patients undergoing TIPS, in whom we were able to measure SAT before and after TIPS (46.0±27.9 vs. 55.7±20.8 cm3/3 mm; P<0.05), an increase was found in 12 (70.6%) patients. Serial SATs were not measured in an adequate number of patients to determine its relationship with either the muscle area or the VAT volume. Even with the increase, the SAT was significantly lower than that in healthy controls (72.7±31.9; P<0.01). Before TIPS, 19 cirrhotics were obese (BMI>30 kg/m2), with a significantly (P<0.0.001) higher VAT (68.6±28.9 mm3) and SAT (112.6±29.5 mm3) than the nonobese patients (VAT 37.1±25.6 mm3; SAT 45.6±25.2 mm3). VAT showed a trend (P=0.06) toward a decrease after TIPS, but when percentage changes were calculated, there was no difference between obese and nonobese cirrhotics. In contrast, psoas muscle area increased significantly (P<0.01) in the nonobese (20.2±18.7%) but not the obese (2.9±17.3%) cirrhotics after TIPS. Diabetes mellitus (n=18 in cirrhotics who underwent TIPS and n=12 in cirrhotics who did not undergo TIPS) did not have an impact on the changes in muscle area or adipose tissue volume over time. When the muscle area and fat volume were normalized to height, these results did not change.

The major causes of death in patients undergoing TIPS included progressive hepatic failure (n=2), uncontrolled sepsis (n=6), and multiple factors (n=2). Among the non-TIPS cirrhotics, the causes of death included uncontrolled sepsis (n=4), hepatocellular carcinoma and hepatic failure (n=1), motor vehicle accident (n=1), and multiple factors (n=2). Predictors of survival after TIPS (Table 5) included changes in the MELD score, Child’s score, total, and core muscle area. After TIPS, MELD increased in 31 patients, of whom 10 died (32.3%). The MELD score decreased or remained unchanged in 26 patients, of whom only one (3.8%) died (P<0.01). Similarly, the Child–Pugh score increased in 28 patients after TIPS, of whom nine (32.1%) died (P<0.01), whereas Child’s score decreased in 29 patients, of whom only two (6.9%) died. Failure to increase the total, core, and psoas muscle area predicted reduced survival after TIPS. Kaplan–Meier survival analysis showed that failure to increase the core muscle area (but not the abdominal wall muscles) was accompanied by significantly (P<0.01) increased post-TIPS mortality (Fig. 2). Univariate analysis of the differences between patients who showed an increase in psoas muscle area and those who did not is shown in Table 6. A multivariable analysis showed that independent predictors of an increase in muscle area after TIPS included younger age, male sex, and lower pre-TIPS muscle area (Table 7). An increase in psoas muscle area after TIPS was also an independent predictor of survival (Table 8).

Table 5

Table 5

Fig. 2

Fig. 2

Table 6

Table 6

Table 7

Table 7

Table 8

Table 8

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Discussion

Our study found a lower total and core abdominal muscle area as well as a lower CT attenuation in cirrhotics before TIPS compared with an age-matched and sex-matched healthy control population. Lower VAT and SAT were observed in cirrhotics compared with controls. TIPS resulted in a significant reduction in the portosystemic pressure gradient, an increase in the total and core abdominal muscle area, and a decrease in VAT. Increased core abdominal muscle area was associated with better survival after TIPS, independent of the MELD or Child’s score. In contrast, in cirrhotic patients who did not undergo TIPS, the muscle area and VAT were unaltered over a similar period of follow-up.

TIPS increases lean body mass and improves outcome in cirrhosis 17. Our observation of a significant increase in total and core abdominal skeletal muscle area in cirrhotics is the first report of reversal of sarcopenia of cirrhosis as defined by objective imaging criteria. Although there was no significant difference in the total muscle area between controls and cirrhotic patients after TIPS, the psoas muscle area improved after TIPS, but did not normalize, indicating that persistent underlying liver disease prevents complete reversal of sarcopenia 6. Failure of only certain muscle groups to recover completely may be either because of the persistent hepatocellular dysfunction of cirrhosis or the differential response of the muscles as muscle fiber type has been shown to affect the response to atrophic and hypertrophic stimuli 27. Our observations are of interest as, in a simultaneous cohort of cirrhotic patients who did not undergo TIPS, neither fat volume nor muscle area increased. It must also be emphasized that as the CT measurement of muscle area is a more precise measure of skeletal muscle mass and correlates well with whole-body muscle mass, small but significant changes in muscle area translate into much larger alterations in whole-body muscle mass 15. Despite similar MELD and Child–Pugh scores, muscle area was lower in cirrhotics undergoing TIPS than that in the non-TIPS group. This may be related to clinical differences, the effect of repeated paracentesis with loss of proteins, or the duration of disease, which has been shown to affect muscle mass in animal studies 28.

Skeletal muscle CT attenuation was lower in cirrhotics before TIPS compared with healthy controls but did not change after TIPS. Lower CT attenuation of the skeletal muscle has been reported to be because of an increased lipid content of the muscle in aging and diabetes 24,25. This is the first report of reduced CT attenuation of skeletal muscle in cirrhosis and may be related to insulin resistance 21. Lower muscle CT attenuation has also been reported to be associated with reduced muscle strength in the thigh muscles 25. In accordance with our observation of reduced muscle attenuation values in cirrhotic patients, muscle strength has been reported to be lower in patients with cirrhosis 29. This is especially relevant, as one of the potential mechanisms whereby TIPS reverses sarcopenia may be a reduction in muscle myostatin. Myostatin is a TGFβ superfamily member that is responsible for reduced skeletal muscle mass 11. Myostatin knockout mice have larger muscles, but are not stronger 30. As muscle strength rather than size alone has been shown to be associated strongly with survival 31, it is critical to examine the strength of the larger muscles after TIPS. Finally, changes in hydration result in changes in CT attenuation of organs 32 and resolution of ascites after TIPS may have resulted in lower muscle CT attenuation. We did not, however, observe any association between the severity of ascites or ascites resolution (a measure of whole-body water content) and CT attenuation of skeletal muscle. These data indicate that the reduced attenuation of the skeletal muscle in cirrhosis is likely because of an increased lipid content and lower strength.

Our patients with cirrhosis had lower SAT before TIPS and lower VAT compared with controls. These are consistent with previous reports on lower body fat mass in cirrhosis 9. After TIPS, VAT decreased whereas the SAT increased. Our data on adipose tissue changes after TIPS are consistent with an earlier report on an increase in SAT (triceps skinfold thickness) after TIPS 18, because the abdominal wall subcutaneous fat measured on CT increased after TIPS. However, as adipose tissue consists of both SAT and the metabolically active VAT, there appears to be a differential response to interventions. Conventional measures of whole-body fat using bioelectrical impedance or only subcutaneous fat (measured by anthropometry) are not precise measures of specific adipose tissue compartments and our data show that studies on specific tissues need to be examined in response to interventions to reverse malnutrition in cirrhosis. Cirrhosis is a state of accelerated starvation 12 that is believed to be responsible for the reduced skeletal and adipose tissue mass. Reduction in VAT after TIPS may be related to additional energy demands placed by the increase in muscle mass that requires protein synthesis.

We also observed that the increase in the total and core skeletal muscle area was independently associated with a reduction in mortality. Thus, the temporal response of the skeletal muscle area to interventions is a better predictor of outcome rather than a single static pre-TIPS measure, such as Child-Pugh score and MELD score. As an increase in muscle area is associated with improved survival, predictors of an increase in the total psoas muscle area are of clinical relevance and included a lower pre-TIPS total psoas muscle area. With multivariable linear regression analysis lower pre-TIPS psoas area, lower age, and male sex were also significantly associated with an increase in the total psoas muscle area.

Our study is the first to report reversal of sarcopenia after TIPS, but the exact mechanism or mechanisms responsible for this observation are unclear. Improvement in body composition observed after TIPS has been suggested to be secondary to the reduction of ascites and decrease of portal pressure (portosystemic pressure gradient) 17. Another mechanism could be an improved caloric and protein intake, although only 25% of our study patients reported an increase in the total dietary intake and there was no significant impact of change in caloric intake on a change in muscle area. This must, however, be tempered by the limitations of dietary recall 33. An improvement in insulin resistance, increase in circulating insulin-like growth factor 1 (IGF1), or a decrease in skeletal muscle myostatin after TIPS may be additional potential causes of improved muscle mass 17. Although these were not specifically examined in the present study, others have reported that neither plasma IGF1 concentration nor insulin resistance was altered after TIPS 19,21. Despite the retrospective nature of the study, which precluded protocol CT scans, the inclusion of a large number of patients to evaluate changes in body composition in patients before and after TIPS, and the use of contemporary and not historical controls, significantly mitigates this limitation. Finally, even though our studies suggest that sarcopenia improves after TIPS and is associated with improved survival, we do not recommend TIPS as an intervention to reverse sarcopenia. Rather, our observations suggest that sarcopenia of cirrhosis is reversible and is associated with improved survival.

The present study shows that alterations in body composition after TIPS are because of a combination of an increase in muscle area and a reduction in fat mass. These data are of clinical significance because the increase in muscle mass contributes to the improved long-term outcome of these patients and can explain the reports of higher survival after TIPS in cirrhosis. Future prospective studies are required to specifically quantify skeletal muscle mass and strength in patients undergoing TIPS and nutritional measures should be standard outcome measures for therapeutic interventions in cirrhosis.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

cirrhosis; sarcopenia; skeletal muscle area; transjugular intrahepatic portosystemic stent

© 2013 Lippincott Williams & Wilkins, Inc.