Frailty has emerged as a powerful predictor of outcomes in patients with cirrhosis and has inevitably made its way into decision making within liver transplantation. In an effort to harmonize ...integration of the concept of frailty among transplant centers, the AST and ASTS supported the efforts of our working group to develop this statement from experts in the field. Frailty is a multidimensional construct that represents the end‐manifestation of derangements of multiple physiologic systems leading to decreased physiologic reserve and increased vulnerability to health stressors. In hepatology/liver transplantation, investigation of frailty has largely focused on physical frailty, which subsumes the concepts of functional performance, functional capacity, and disability. There was consensus that every liver transplant candidate should be assessed at baseline and longitudinally using a standardized frailty tool, which should guide the intensity and type of nutritional and physical therapy in individual liver transplant candidates. The working group agreed that frailty should not be used as the sole criterion for delisting a patient for liver transplantation, but rather should be considered one of many criteria when evaluating transplant candidacy and suitability. A road map to advance frailty in the clinical and research settings of liver transplantation is presented here.
This summary statement about frailty in liver transplantation addresses how to define and measure frailty, and how to incorporate frailty into the care of patients with end‐stage liver disease, including those awaiting liver transplantation.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Robust physical activity after liver transplantation is an important determinant of longterm health, similar in its importance to the value of pretransplant activity for withstanding the immediate ...stress of transplantation. Although transplantation normally enables rapid recovery of liver synthetic and metabolic functions, the recovery of physical capacity and performance to normal levels is delayed and often incomplete. Anatomic measurements of sarcopenia and the physical performance indicators of frailty both tend to improve slowly, and they may, in fact, decrease further in the posttransplant period, especially when the common extrahepatic drivers of muscle loss, such as the elements of the metabolic syndrome, persist or intensify after transplantation. Posttransplant exercise improves fitness, which is a conclusion based on 2 observational studies and 3 randomized trials that assessed endpoints of strength testing, energy expenditure in metabolic equivalents, and peak or maximal oxygen uptake. Importantly, 1 controlled trial found that exercise also improved quality of life (QOL) measured by the Short Form 36 survey, consistent with multiple reports of the value of social support and engagement in sports activity for improving posttransplant QOL. Developing evidence‐based standards for post–liver transplant physical activity baseline testing and sustainment of intensity and quality is a key unmet need in transplant hepatology. At present, it is reasonable for transplant teams to assess fitness and design a tailored exercise program when a recipient is first discharged, to record and reinforce progress at all posttransplant visits, and to set realistic longterm performance goals that will often achieve recommended standards for the healthy general population.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Loss of muscle mass and function, or sarcopenia, is a common feature of cirrhosis and contributes significantly to morbidity and mortality in this population. Sarcopenia is a main indicator of ...adverse outcomes in this population, including poor quality of life, hepatic decompensation, mortality in patients with cirrhosis evaluated for liver transplantation (LT), longer hospital and intensive care unit stay, higher incidence of infection following LT, and higher overall health care cost. Although it is clear that muscle mass is an important predictor of LT outcomes, many questions remain, including the best modality for assessing muscle mass, the optimal cut‐off values for sarcopenia, the ideal timing and frequency of muscle mass assessment, and how to best incorporate the concept of sarcopenia into clinical decision making. For these reasons, we assembled a group of experts to form the North American Working Group on Sarcopenia in Liver Transplantation to use evidence from the medical literature to address these outstanding questions regarding sarcopenia in LT. We believe sarcopenia assessment should be considered in all patients with cirrhosis evaluated for liver transplantation. Skeletal muscle index (SMI) assessed by computed tomography constitutes the best‐studied technique for assessing sarcopenia in patients with cirrhosis. Cut‐off values for sarcopenia, defined as SMI < 50 cm2/m2 in male and < 39 cm2/m2 in female patients, constitute the validated definition for sarcopenia in patients with cirrhosis. Conclusion: The management of sarcopenia requires a multipronged approach including nutrition, exercise, and additional pharmacological therapy as deemed necessary. Future studies should evaluate whether recovery of sarcopenia with nutritional management in combination with an exercise program is sustainable as well as how improvement in muscle mass might be associated with improvement in clinical outcomes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Sarcopenia and physical deconditioning are frequent complications in patients with cirrhosis and end‐stage liver disease (ESLD). They are the end result of impaired dietary intake, chronic ...inflammation, altered macronutrient and micronutrient metabolism, and low physical activity. Frailty is the end result of prolonged sarcopenia and physical deconditioning. It severely affects a patient's functional status and presents in approximately 1 in 5 patients on the liver transplantation waiting list. Sarcopenia, poor physical fitness/cardiopulmonary endurance (CPE), and frailty are all associated with increased mortality in ESLD. Clinical trials addressing the usefulness of exercise in patients with cirrhosis have shown that it improves the metabolic syndrome, sarcopenia, CPE, health‐related quality of life, and hepatic venous pressure gradient. Although evidence on the benefits of exercise on clinical outcomes derived from large clinical trials is still missing, based on existing literature from multiple medical subspecialties, we believe that an exercise program coupled to a tailored nutritional intervention benefits both cardiopulmonary and musculoskeletal functions, ultimately translating into improved functional status, sense of well‐being, and possibly less complications from portal hypertension. In conclusion, although supervised exercise training is the prevailing approach to manage ESLD patients, such intervention is not sustainable or feasible for most patients. Innovative home‐based physical activity interventions may be able to effectively reach a larger number of patients. Liver Transplantation 24 122–139 2018 AASLD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Failure of liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) and unreliable results occur in ≈5% and 15% of patients, respectively, mainly due to obesity. In this ...multicenter study, we evaluated the feasibility and performance of the novel FibroScan XL probe in 276 patients with chronic liver disease (42% viral hepatitis, 46% nonalcoholic fatty liver disease NAFLD) and a body mass index (BMI) ≥28 kg/m2. Patients underwent liver biopsy and TE with the standard M and XL probes. TE failure was defined as no valid LSMs and unreliable examinations as <10 valid LSMs or an interquartile range (IQR)/LSM >30% or success rate <60%. Probe performance for diagnosing ≥F2 fibrosis and cirrhosis (F4) versus biopsy were examined using areas under receiver operating characteristic curves (AUROC). FibroScan failure was less frequent with the XL probe than the M probe (1.1% versus 16%) and the XL probe was more often reliable (73% versus 50%; both P < 0.00005). Reliable results with the XL probe were obtained in 61% of patients in whom the M probe was unreliable. Among 178 patients with ≥10 valid LSMs using both probes, liver stiffness was highly correlated between probes (ρ = 0.86; P < 0.0005); however, median liver stiffness was lower using the XL probe (6.8 versus 7.8 kPa; P < 0.00005). The AUROC of the XL and M probes were similar for ≥F2 fibrosis (0.83 versus 0.86; P = 0.19) and cirrhosis (0.94 versus 0.91; P = 0.28). Conclusion: Compared with the M probe, the FibroScan XL probe reduces TE failure and facilitates reliable LSM in obese patients. Although the probes have comparable accuracy, lower liver stiffness cutoffs will be necessary when the XL probe is used to noninvasively assess liver fibrosis. (HEPATOLOGY 2012)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A consensus conference on frailty in kidney, liver, heart, and lung transplantation sponsored by the American Society of Transplantation (AST) and endorsed by the American Society of Nephrology ...(ASN), the American Society of Transplant Surgeons (ASTS), and the Canadian Society of Transplantation (CST) took place on February 11, 2018 in Phoenix, Arizona. Input from the transplant community through scheduled conference calls enabled wide discussion of current concepts in frailty, exploration of best practices for frailty risk assessment of transplant candidates and for management after transplant, and development of ideas for future research. A current understanding of frailty was compiled by each of the solid organ groups and is presented in this paper. Frailty is a common entity in patients with end‐stage organ disease who are awaiting organ transplantation, and affects mortality on the waitlist and in the posttransplant period. The optimal methods by which frailty should be measured in each organ group are yet to be determined, but studies are underway. Interventions to reverse frailty vary among organ groups and appear promising. This conference achieved its intent to highlight the importance of frailty in organ transplantation and to plant the seeds for further discussion and research in this field.
The authors summarize the proceedings of the American Society of Transplantation consensus conference on frailty in solid organ transplantation, an emerging concept with potential consequences for patient risk stratification and optimization that arises before and after transplant.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. ...Hepatoblastoma‐derived C3A cells express anti‐inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End‐Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3‐5 days of continuous ELAD treatment plus SOC. After a minimum follow‐up of 91 days, overall survival (OS) was assessed by using a Kaplan‐Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent‐to‐treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated. Liver Transplantation 24 380–393 2018 AASLD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background and Aims
Frailty is a well‐established risk factor for poor outcomes in patients with cirrhosis awaiting liver transplantation (LT), but whether it predicts outcomes among those who have ...undergone LT is unknown.
Approach and Results
Adult LT recipients from 8 US centers (2012–2019) were included. Pre‐LT frailty was assessed in the ambulatory setting using the Liver Frailty Index (LFI). “Frail” was defined by an optimal cut point of LFI ≥ 4.5. We used the 75th percentile to define “prolonged” post‐LT length of stay (LOS; ≥12 days), intensive care unit (ICU) days (≥4 days), and inpatient days within 90 post‐LT days (≥17 days). Of 1166 LT recipients, 21% were frail pre‐LT. Cumulative incidence of death at 1 and 5 years was 6% and 16% for frail and 4% and 10% for nonfrail patients (overall log‐rank p = 0.02). Pre‐LT frailty was associated with an unadjusted 62% increased risk of post‐LT mortality (95% CI, 1.08–2.44); after adjustment for body mass index, HCC, donor age, and donation after cardiac death status, the HR was 2.13 (95% CI, 1.39–3.26). Patients who were frail versus nonfrail experienced a higher adjusted odds of prolonged LT LOS (OR, 2.00; 95% CI, 1.47–2.73), ICU stay (OR, 1.56; 95% CI, 1.12–2.14), inpatient days within 90 post‐LT days (OR, 1.72; 95% CI, 1.25–2.37), and nonhome discharge (OR, 2.50; 95% CI, 1.58–3.97).
Conclusions
Compared with nonfrail patients, frail LT recipients had a higher risk of post‐LT death and greater post‐LT health care utilization, although overall post‐LT survival was acceptable. These data lay the foundation to investigate whether targeting pre‐LT frailty will improve post‐LT outcomes and reduce resource utilization.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Accurate tools for the noninvasive detection of hepatic steatosis are needed. The Controlled Attenuation Parameter (CAP) specifically targets liver steatosis using a process based on ...transient elastography.
Methods
Patients with chronic liver disease and body mass index (BMI) ≥28 kg/m2 underwent biopsy and liver stiffness measurement (LSM) with simultaneous CAP determination using the FibroScan® M probe. The performance of the CAP for diagnosing steatosis compared with biopsy was assessed using areas under receiver operating characteristic curves (AUROC).
Results
A total of 153 patients were included: 69% were male, median BMI was 32 kg/m2; 47% had nonalcoholic fatty liver disease (NAFLD); and 65% had significant (≥10%) steatosis. The CAP was significantly correlated with the percentage of steatosis (ρ = 0.47) and steatosis grade (ρ = 0.51; both P < 0.00005). The median CAP was higher among patients with significant steatosis (317 IQR 284–339 vs. 250 227–279 dB/m with <10% steatosis; P < 0.0005) and the AUROC for this outcome was 0.81 (95% CI 0.74–0.88). At a cut‐off of 283 dB/m, the CAP was 76% sensitive, 79% specific, and had positive and negative predictive values of 87% and 64%, respectively. CAP performance was not influenced by measurement variability, but was higher in patients with mild (F0‐F1) fibrosis (AUROC 0.89 vs. 0.72 with F2‐F4; P = 0.03). The AUROCs of the CAP for ≥5%, >33% and >66% steatosis were 0.79, 0.76 and 0.70, respectively.
Conclusions
The CAP is a promising tool for the noninvasive detection of hepatic steatosis. Advantages of CAP include its ease of measurement, operator‐independence and simultaneous availability with LSM for fibrosis assessment.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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