Application of Different Scores in Predicting Outcomes of Cirrhotic Patients Awaiting Liver Transplantation

c. Sample Size Calculation: Sample size was calculated using Epi Info 7. According to the results of a previous study (put ref.), frailty was detected in 17% of patients undergoing liver transplantation. Based on this percentage, with a confidence limit of 5%, a confidence level of 90%, and a design effect of 1, the estimated sample size required is approximately 153 patients.

All patients recruited in the current study will be subjected to the following:

• Detailed history taking such as age, sex, duration of disease, etiology of liver cirrhosis, endoscopic history, complications, previous hospitalization and indication for liver transplantation.
• Laboratory investigations: CBC (Complete Blood Count), Liver Function Test, Kidney Function test, Serum Electrolytes levels (Sodium, Potassium and Calcium).
• Calculation of - Child Pugh score . Figure (I) Child Pugh score

• MELD score = 10 x (0.957 x Ln (serum creatinine mg/dl) + 0.378 x Ln (serum bilirubin mg/dl) + 1.120 x Ln (INR) + 0.643).
• MELD-Na score = MELD + 1.59 x (135 - Na) with maximum and minimum Na of 135 and 120 mmol/l, respectively.
• MELD 3.0 = 1.33 if female+4.56 * loge(bilirubin) + 0.82*137 - Na- 0.24* 137 - Na *loge(bilirubin) + 9.09*loge (INR) + 11.14*loge(creatinine) + 1.85*3.5 - albumin- 1.83*3.5 -albumin *loge(creatinine) +6

• Anthropometric measurement:
• Weight in Kilograms (Kg).
• Height in Meters (m).
• Body Mass Index in (kg/m2): BMI was calculated as weight (kilograms) divided by height squared (meters) in kg/ m2 with normal range in adult between 18.5 - 24.9 kg/m2 .
• Waist Circumference in Centimeters (cm).
• Mid-arm circumference in Centimeters (cm).

• Fatigue Severity Assessment (via FSS and BFI):
• Fatigue Severity Scale (FSS) (1 = strongly disagree, 7 = strongly agree).
• Brief Fatigue Inventory (BFI) (Rating from 0-10).

I) Fatigue Severity Scale (FSS):

The FSS is a 9-item scale designed to assess the severity of fatigue and its impact on daily activities. Here are the items:

• I am easily fatigued.
• Fatigue interferes with my physical functioning.
• Fatigue causes frequent problems for me.
• Fatigue interferes with my ability to work, study, or engage in social activities.
• Fatigue interferes with my family life.
• Fatigue interferes with my leisure activities.
• When I am fatigued, I have difficulty concentrating.
• Fatigue is a problem for me.
• Fatigue interferes with my ability to maintain a regular exercise program. Scale will be from 9-63. Scale up to 35: no fatigue. Scales >35: severe fatigue.

II) Brief Fatigue Inventory (BFI):

The BFI includes 3 questions on fatigue severity and 6 on how fatigue interferes with daily activities. Here are the items:

Fatigue Severity:

• How would you rate your fatigue right now?
• How would you rate your usual fatigue over the past 24 hours?
• How would you rate your worst fatigue over the past 24 hours?

Interference with Daily Activities:

• Fatigue interferes with general activity.
• Fatigue interferes with mood.
• Fatigue interferes with walking ability.
• Fatigue interferes with normal work (including housework).
• Fatigue interferes with relations with other people.
• Fatigue interferes with enjoyment of life.

• Liver Transplant Comorbidity Index: This index includes the following components and their respective points Factor Points Coronary artery disease 6 Frailty (LFI more than 4.5) 5 HCC 5 Cr more than 1.0mg/dl or on dialysis 3 Diabetes 1

Total score = sum of points.

• Low risk: Few or no factors → ~93% 3 year survival.

• Moderate risk: Intermediate score → ~87% 3 year survival.

• High risk: Multiple factors → ~80% 3 year survival.

• Liver frailty index (LFI): The Liver Frailty Index (LFI) is the most widely validated frailty assessment tool in LT. It integrates three performance-based measures: handgrip strength, the Five-Times Sit-to-Stand Test (5xSST), and balance testing, to generate a continuous score that categorizes patients as robust, prefrail, or frail. The LFI has been shown to independently predict waitlist mortality, hospitalization, and delisting, even after adjustment for MELD score

A) Handgrip strength:

Handgrip strength is measured using a calibrated handheld dynamometer. Three measurements are obtained from the dominant hand, and the maximum value (in kilograms) is used for scoring. Grip strength reflects global muscle strength and correlates closely with sarcopenia and adverse clinical outcomes in patients with Cirrhosis.

B) Five-times sit-to-stand test (5xSST):

The Five-Times Sit-to-Stand Test, also referred to as chair-stand time, is a standardized, performance-based measure of lower extremity muscle strength, power, and functional mobility. The test is simple, rapid, and requires no specialized equipment, making it particularly well suited for use in patients with chronic liver disease and LT candidates. The 5xSST is performed as follows: the patient is seated upright in a chair; on command, the patient stands up fully and then sits down completely; this cycle is repeated five times as quickly as possible. The total time is recorded in seconds.

C) Balance testing:

Balance testing evaluates postural stability and neuromuscular coordination, which are frequently impaired in patients with cirrhosis due to sarcopenia, peripheral neuropathy, and hepatic encephalopathy. Within the LFI, balance is assessed using three hierarchical standing positions that are performed sequentially and held for up to 10 s each.

The three components of the LFI are combined using a validated formula: LFI = (0.330 ×sex-adjusted grip strength in kg) + (0.529 × 5xSST in seconds) + (0.040 × balance time in seconds) + 6.

(calculator available at http://liverfrailtyindex.ucsf.edu).

7.Sarcopenia assessment will be done for those prepared for transplantation: Definition of sarcopenia is based on: -

• Computed tomography-skeletal muscle index (CT-SMI) with cut-offs of < 41 cm2/m2 for men and < 32 cm2/m2 for women
• Hand grip strength with cut-offs of < 27 kg in men and < 16 kg in women
• Bioimpedance analysis-skeletal muscle index (BIA-SMI) with cut-offs of < 8.87 kg/m2 for men and < 6.42 kg/m2 for women . According to guideline for European working group on sarcopenia in older people (EWGSOP, the Sarcopenia Working Group) sarcopenia identification was based on both low muscle mass and strength using CT-SMI and hand grip strength

• Imaging for assessment of Sarcopenia using:

• Computed tomography (CT scan):

The CT scanner differentiated body tissues; organs, adipose, skeletal muscle and bone, water and air based on tissue-specific attenuation values such as SM (-29, +150) and adipose tissue (-190, -30). These attenuation values were reported in Hounsfield Units (HU) named after Sir Godfrey Newbold Hounsfield, the scientist and electrical engineer who invented the CT scanner .The L3 region contains the spinal vertebrae, intestine, kidney and liver, in addition to visceral adipose, subcutaneous adipose and seven muscle groups; the psoas, erector spinae, quadratus lumborum, transversus abdominus, external and internal obliques and rectus abdominus

Step-by-step Guidelines for analyzing a single cross-sectional image:

A) Extraction of CT images: The electronic medical record was assessed to determine if the patient of interest had a CT study that included the L3 region during the desired time interval. Once the CT study had been verified, the patient medical record number, CT study type, scan date and storage device (if transporting images) was provided to the radiologist .

B) Technique for assessment of waist circumference (WC) and skeletal muscle (SM) area Once the L3 image was obtained and determined to be of good quality, the following CT imaging protocol was used for assessment of waist circumference (WC) and skeletal muscle (SM) area at the L3 region.

Computed tomography-based assessment at the level of the third lumbar vertebra (L3) is widely regarded as the reference standard for quantitative muscle assessment in patients with cirrhosis and LT candidates. CT uses tissue-specific X-ray attenuation values, expressed in Hounsfield units (HU), to distinguish skeletal muscle, adipose tissue, and bone .Commonly used CT-derived metrics include the psoas muscle area (PMA), psoas muscle index (PMI), and skeletal muscle index (SMI), the latter typically expressed as cross-sectional area divided by height squared (cm²/m²)

• Abdominal ultrasound (US):

Abdominal ultrasound examinations were performed with the subject in the supine position using a 3.75-MHz convex Ultrasound probe. After the routine screening for the abdomen, a transverse scan at the right groin area demonstrated a cross-sectional view of the right iliac artery and vein, which was used as the landmark to detect the iliopsoas muscle located outside the vessels . The iliopsoas muscle area was measured by manual tracing on the image. The iliopsoas muscle index (IP index) was determined by the muscle area divided by the square of height (m2) .

• Bioimpedance analysis (BIA):

Bioimpedance analysis (BIA) involved passage of a small AC electrical current through the body. As current was conducted by body water, impedance was inversely related to total body water, thus allowing calculation of total muscle mass, which was the largest water-rich tissue in the body .Body composition was assessed with bioimpedance analysis (BIA) using Body Composition Analyzer Fat free mass was measured by BIA and skeletal muscle mass (SMM) was calculated by the following equation: SMM (kg) = 0.566 x FFM (fat free mass) Skeletal muscle mass index (SMMI) was calculated as skeletal muscle mass (kg) /height (m)2.

Inclusion criteria

• • All patients with liver cirrhosis (whatever the etiology) eligible for liver transplantation above the age of 18.

• Written informed consent provided.

Exclusion criteria

• Old age (above 60 years old)
• Acute liver cell failure without underlying cirrhosis
• Absolute contraindications (e.g., uncontrolled sepsis, severe cardiopulmonary dysfunction, active malignancy).
• Extra-MELD indications (e.g., hepatopulmonary syndrome, refractory ascites, cholestatic pruritus, hepatoblastoma). We restricted our cohort to patients listed for liver transplantation based on MELD-driven indications. This decision was made to reduce heterogeneity and ensure that eligibility determinations were primarily driven by MELD scores, thereby allowing us to isolate the relative contribution of frailty in the context of MELD-based allocation