2. The Definition and Diagnosis of Frailty in the Research and Clinical Settings

Hui-Wei Chen¹ and Andres Duarte-Rojo^{1, 2}

(1)

Division of Gastroenterology Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA

(2)

Center for Liver Diseases and Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Andres Duarte-Rojo

Email: duarterojoa@upmc.edu

Keywords

Physical functionActivities of daily livingDeconditioningLiver Frailty IndexGait speed testCardiopulmonary enduranceCirrhosisLiver transplantation

Frailty is defined as physiologic decline and reduced physiological reserve that leads to increased vulnerability to health stressors with subsequent physical dependency and multiple adverse outcomes including death [1]. Sarcopenia, an anatomical loss of skeletal muscle mass and function, is not synonymous with frailty, but it often accompanies frailty. The concept of frailty was initially described in the geriatric literature as it is prevalent in advanced age populations; however, it is also ubiquitous in patients with chronic medical conditions.

It is important to recognize that frailty is a disorder of physical function that occurs on a continuum, which ranges from mild deconditioning that affects leisure activity (also known as “pre-frail”) to end-stage disease with failure to thrive (Fig. 2.1). In the elderly, it has been shown that pre-frail patients have similar negative outcomes as frail patients but in lesser degree and that the former are more likely to be able to regain the “robust” state when compared to the latter [2, 3]. This fact makes early identification of pre-frail state valuable in order to timely intervene and prevent progression or to serve as a model for frailty reversibility efforts.

../images/467095_1_En_2_Chapter/467095_1_En_2_Fig1_HTML.jpg — Fig. 2.1

The continuum of physical function disorders, its drivers, and ultimate consequences. Frailty occurs on a spectrum ranging from mild deconditioning to failure to thrive. As patients with cirrhosis begin to have decreased ability to perform ADLs and/or IADLs along with declining physical performance, they gradually become frailer with declining quality of life, worsening disability, and disease progression. Ultimately, significant physical deterioration or frailty leads to various adverse outcomes, such as unplanned hospitalization and death

While frailty and sarcopenia are major healthcare concerns for older adults, they are also very prevalent in people with chronic medical diseases such as chronic liver disease, chronic kidney disease, and cancer, which accelerate the progression of physical dysfunction and muscle atrophy regardless of age. Due to these conditions’ robust association with adverse outcomes, frailty and sarcopenia have attracted growing interest in cirrhosis and liver transplantation. From available studies, it is known that development of frailty in patients with cirrhosis leads to increased incidence of hepatic decompensation, recurrent/prolonged hospitalizations, posttransplantation complications, and mortality [1, 4–6]. It has also been validated repeatedly that frailty alone is an independent risk factor for waitlist removal and death while on the transplant waitlist, regardless of the standard prognostic tools such as the Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) scores [7–9]. Despite it being a growing field, there is currently no clinical practice guideline to provide directions to the clinician in assessing and diagnosing frailty.

Measurement of Frailty

There are many frailty assessment tools that have been developed to identify at-risk patients. Some of these incorporate mostly subjective components. Activities of daily living (ADL) and instrumental activities of daily living (IADL) are questionnaire-based tools that allow clinicians to assess patient’s difficulty with performing daily self-care activities and activities that allow an individual to live independently, respectively [10, 11]. The Karnofsky Performance Scale (KPS) and Clinical Frailty Scale (CFS) incorporate both the ADL and IDAL in addition to limitations one may experience with chronic diseases as well as cognitive decline. These scales (KPS and CFS) attempt to better categorize patients into different frailty groups by assigning the degree of frailty with numerical scores [4, 12]. The Braden Scale, a traditional tool used to risk-stratify for pressure ulcers based on physical exam and assessment of six criteria, has also been used as a standardized measure of frailty [8]. While these questionnaires are easily attainable and have been associated with adverse outcomes, they rely heavily on the self-reported information and judgment from the personnel administering the test. Moreover, when self-reported physical activity was compared with objective data collected by a physical activity tracker, it was noticed that patients overrepresented their activities disclosing mildly limited to normal physical function when in fact their physical activity was very limited [13]. Thus, as in many other self-reported scenarios, there is a tendency for magnifying the actual physical accomplishments potentially resulting in a high rate of false negatives (overestimates functionality) and precluding the usefulness of these scales as accurate screening methods.

Based on a comprehensive review of frailty measurement tools in the geriatric literature, the Fried Frailty Phenotype (FFP) is the most commonly cited frailty diagnostic tool [14]. The FFP criteria were devised based on observation of physical declines and weakness in the geriatric population, whom are most vulnerable to adverse outcomes. This assessment tool encompasses five characteristics: weight loss, exhaustion, weakness, slow walking speed, and decreased physical activity. It divides patients into three different groups based on the number of characteristics that an individual has fulfilled: frail, when one fulfills three or more of the five criteria; pre-frail, when having one or two of these characteristics; and robust, when one does not have any characteristics [15]. While the FFP has been validated in multiple studies [14–17], its utility in assessing for frailty in patients with end-stage liver disease is more limited [4, 5, 7]. The reason being that the characteristics included in FFP are part of the symptoms and/or can be affected by the clinical manifestations commonly seen in patient with cirrhosis, which would lead to inaccurate assessment of frailty. As we know, fluid overload and ascites are very common manifestations of patients with cirrhosis, and its presence makes it difficult to accurately assess patient’s true weight. Moreover, exhaustion and weakness are subjective symptoms frequently reported in cirrhosis, and they are further aggravated in patients with hepatic encephalopathy. Because of the aforementioned confounding factors, FFP is unable to accurately assess frailty in patients with cirrhosis (underestimates functionality). As such, it is currently understood that assessment of frailty in the setting of cirrhosis or advanced liver disease must rely mainly on objective physical function characteristics.

In addition to the FFP criteria, there are other objective frailty measurement tools which have been employed to capture frailty in patients with cirrhosis. Grip strength and gait speed test (GST) are popular simple physical function tests to screen for frailty, and decline in either has been shown to be an independent risk factor for hospitalizations in patients with different chronic diseases [6, 18–20]. More comprehensive testing that is performance-based such as the Short Physical Performance Battery (SPPB) including repeated chair stands, balance testing, and 4-meter walk is also commonly used and has been predictive of disability, hospitalization, and mortality [7, 21]. A novel frailty assessment for patients with cirrhosis, termed the Liver Frailty Index (LFI), was devised after using available assessment frailty tools with subsequent modeling of different combinations. It was found that the combination of three simple tests – grip strength, chair stands, and balance – was able to best predict frailty in patients with cirrhosis [22]. Moreover, the predictive usefulness of LFI was independent of the degree of liver dysfunction, and it presumably outperformed both FFP and SPPB. LFI is also reproducible and practical, and although it has shown responsiveness to change over time, no data on improvement following an intervention has been published to date.

With so many assessment tools that are at a clinician’s disposal to use in clinic, it remains uncertain which test(s) should be incorporated into our clinical practice. Clinical accuracy, reproducibility, and practicality are essential values that the clinical frailty testing should have. These tools should also have an independent predictive value for outcomes from known disease-related prognostic variables including MELD score and CPT score [23]. Current data does not support the use of a screening test followed by a confirmatory test, and rather using any of the tests showed in Table 2.1 to diagnose frailty is encouraged. Although there are no head-to-head comparisons on the accuracy of these tests, LFI is the one most rigorously validated as a result of large multidisciplinary and multicenter research efforts.

Table 2.1

Operational characteristics of tests used to evaluate frailty in patients with cirrhosis

	FFP	SPPB	LFI	GST	6MWT	CPET
Includes subjective data	Yes	No	No	No	No	No
Clinical accessibility	Moderate	Easy	Moderate	Easy	Moderate	Poor
Changes over time	N/A	Yes	Yes	Yes	Yes	Yes
Changes post-intervention	N/A	N/A	N/A	N/A	Yes	Yes
Changes pre- to posttransplant	N/A	N/A	Yes	N/A	Yes	Yes

FFP Fried Frailty Phenotype, SPPB Short Physical Performance Battery, LFI Liver Frailty Index, GST gait speed test, 6MWT 6-minute walk test, CPET cardiopulmonary exercise testing

Clinical Relevance of Frailty

As mentioned previously, it is now recognized that frailty is a poor prognostic factor associated with increased morbidity and mortality in patients with chronic liver diseases (Table 2.2). It is found that cirrhotic patients with increasing frailty are associated with increased unplanned hospitalizations or death from cirrhosis-related complications regardless of the severity of the liver disease based on MELD scores [4–7].

Table 2.2

Prospective studies evaluating frailty assessed with performance-based tools and its relationship with clinical outcomes

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