Key words : Ascites, Body mass index, Cirrhosis, Density, Hydrothorax, Skeletal muscle index

Introduction

Testosterone is an anabolic steroid that builds muscle mass, muscle strength, and bone density. Testosterone also promotes hematopoiesis and improves insulin resistance, mood, libido, and cognitive function. Testosterone deficiency in male patients with chronic liver disease is associated with greater morbidity and mortality.^1,2 Testosterone replacement therapy in patients with chronic liver disease does not improve hepatic function, hepatic histological changes, or survival outcomes; however, it improves gynecomastia, muscle strength, and hemoglobin and also reduces body fat and lowers hemoglobin A_1c. After liver transplant (LTx), testosterone deficiency with functional sarcopenia could persist. However, after LTx, the prevalence and severity of testosterone deficiency and the utility of short-term testosterone replacement therapy have so far, to our knowledge, not been studied. The aims of the present study were to (1) define post-LTx functional sarcopenia and examine testos-terone level with clinical functional sarcopenia and utility of post-LTx short-term testosterone replace-ment therapy, (2) review testosterone replacement therapy in chronic liver disease and sarcopenia, and (3) show the correlation of functional sarcopenia with ascites and pleural effusion subtracted (APES) body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) with radiological computed tomography (CT), skeletal muscle index (SMI, calculated as skeletal muscle area in centimeters squared divided by height in meters squared), and skeletal muscle density (SMD).

Materials and Methods

Institutional review board permission was obtained before the retrospective data collection and analysis were initiated. After institutional review board approval, the retrospective electronic database from June 2014 to June 2017 was searched at our academic LTx center. Sixteen male post-LTx recipients who received testosterone replacement therapy for defined functional sarcopenia were identified. Basic demographics of the study patients, clinical history, postoperative progress, and radiological and labora-tory results were obtained from a secure electronic database. From the last available CT scan before LTx, total skeletal muscle area (SMA) was calculated at the L3 midvertebral level, including the circumferential abdominal wall, psoas, and paraspinal muscle groups. The SMI was calculated from SMA and normalized to patient height in meters squared. The SMD is obtained using threshold values of -29 to +150 Hounsfield units (HU) for muscle tissue on the Aquarius iNtuition software (version 4.4.11, TeraRecon) by experienced radiologists. Cut-off values for SMD to BMI and methodology have been described by Hayashi and colleagues and Fearon and colleagues.^3,4 Detail is given in the results section. The patient in case 3 had all CT scans performed at an outside facility; hence, SMI/SMD was not evaluated.

Criteria used for clinical functional sarcopenia after liver transplant

Although there are several different ways to assess functional sarcopenia, most such methods are not applicable or reliable in the immediate post-LTx period.^5-8 Post-LTx functional sarcopenia was considered in 2 different scenarios: (1) inability to get out of bed with the support of 2 physiotherapists within 24 hours after extubation and able to stand and (2) ventilator support for more than 2 days after LTx with functional hepatic allograft and without major complications. This was based on an alternative definition of sarcopenia by Delmonico and colleagues, who emphasized the importance of performance of lower extremities.⁹ This is also in line with the revised definition and diagnosis by the European Working Group on Sarcopenia in Older People (EWGSOP) in 2019, for which greater importance was emphasized with the functional aspect of the muscle, and sarcopenia was recognized as muscle disease or muscle failure.⁶ Total serum testosterone levels were tested with post-LTx functional sarcopenia. Patients with low serum testosterone concentration, <20% of expected for that age group,¹⁰ received intramuscular testosterone replacement therapy (testosterone cypionate, 200 mg). The testosterone dose was repeated after 2 weeks (2 half-lives of testosterone cypionate) if the patient was still hospitalized and the functional sarcopenia had not resolved.

Management of functional sarcopenia with frequent in-bed active exercise

We engaged our providers, in rotation, to visit patients every 2 hours during the daytime, while the patient was awake, to encourage in-bed frequent active participation with flexion and extension exercises of all the joints of upper and lower extremities along with standard incentive spirometry for about 5 to 10 minutes per session.

Correction of ascites and pleural effusion subtracted body mass index with skeletal muscle index and skeletal muscle density

Measured pre-LTx weight was corrected by APES if present. For the ascitic fluid volume measurement, we used an objective 3-dimensional measurement on CT scans including fluid pockets in all 4 quadrants. In addition, when present, pleural effusion was measured and added to the ascitic fluid volume. The total volume of the ascitic fluid and pleural effusion was subtracted from the weight of the patient (1 mL fluid = 1 g of body weight), and the corrected weight and BMI were adjusted. The APES BMI was categorized as underweight (BMI <18.5), normal weight (BMI from ≥18.5 and <25), overweight (BMI from 25 to <30), or obese (BMI ≥30). The APES BMI was correlated with radiological measurements of SMI and SMD for sarcopenia.^3,4

Follow-up

All patients were followed until November 2020 by the same team of providers. Values for mean, median, and SD were calculated in Microsoft Excel. Kaplan-Meier survival estimations were calculated in IBM SPSS software (version 26). All recipients were commenced on tacrolimus, mycophenolate mofetil, and steroid-based immunosuppression.¹¹

Results

Between June 2014 and June 2017, 55 male patients received a deceased donor LTx, of which 16 (30.8%) recipients were tested for serum total testosterone levels based on clinical functional sarcopenia. Patient 12 received a combined liver and kidney transplant, and patient 2 had post-LTx pontine myelinolysis (Table 1). For the remaining 39 concurrent male recipients, functional sarcopenia and testosterone levels were not determined. The mean testosterone concentration was 28 ± 19 ng/dL (median, 22; range 10-83 ng/dL) (Table 1), which was 4.8% (median, 3.7 ± 3.8%) of the expected concentrations for age-matched healthy men.^10,12

Pretransplant characteristics of the study patients

Pretransplant demographic details of each patient are shown in (Table 1). The mean age at the time of transplant was 56.0 ± 9.3 years. The mean weight was 94.3 ± 18.9 kg; the mean BMI was 32.0 ± 7.4; the Model for End-Stage Liver Disease (MELD) score¹³ was 33.5 ± 8 (median, 36); and the Child-Pugh score distribution was C15 to C10 for 11 patients, B9 for 2 patients, B8 for 2 patients, and A5 for 1 patient.¹⁴ Pre-LTx signs of hepatic decompensation included ascites in 15 patients (94%); of those, 12 (75%) required multiple paracenteses, and 10 (63%) had spontaneous bacterial peritonitis. Five (31%) patients had hepatic hydrothorax, of whom 3 required thoracentesis. Fourteen patients (88%) had hyponatremia, 15 (94%) had encephalopathy, and 11 (69%) had hepatorenal syndrome, 8 of whom required renal replacement therapy. All patients were followed until November 2020; mean post-LTx follow-up was 53.8 ± 13.4 months (median, 51.5; range, 33.2-76.8 months).

Testosterone replacement after liver transplant

All 16 recipients tested received intramuscular testosterone (testosterone cypionate, 200 mg) replacement therapy. Twelve patients (75%) received a single dose of testosterone. Three patients (patients 8, 12, and 13) received a second dose of testosterone injection, 2 weeks apart. Patient 2, who was hospitalized after LTx for 80 days with pontine myelinolysis, received 4 doses of testosterone when the testosterone level fell below <20% of the expected level. Of 4 patients who received >1 dose of testosterone, 3 required tracheostomies for prolonged ventilator dependency (Table 2).

Hospital stays

The overall mean initial post-LTx hospital stay was 26 ± 17 days (median, 22 days). Seven (44%) patients were discharged home, 6 (38%) were sent to a rehabilitation facility, 2 (13%) went to acute rehabilitation, and 1 (6%) was discharged to a skilled nursing home. Patient 2 had pontine myelinolysis, patient 5 had renal failure, and patient 7 had recurrent hepatocellular carcinoma (HCC), all of whom required readmission. None of the patients required readmission for functional sarcopenia alone.

Patient and graft survival

All study patients retained their primary hepatic allograft and did not require retransplant. Hence, patient and graft survival results were the same at all time points. Two patients died during the study; patient 5 died 2 months after LTx at home after discharge from rehabilitation, presumably from a cardiovascular event, and patient 7 died from recurrent metastatic hepatocellular carcinoma 20.5 months after LTx. This provided actuarial 1-year patient and graft survival of 93.8% and 5-year actuarial survival of 87.5% (Figure 1).

Correlation of body mass index with skeletal muscle index and skeletal muscle density

Patients were divided into 4 groups based on APES BMI: underweight (BMI <18.5, n = 2), normal weight (BMI ≥18.5 and <25, n = 2), overweight (BMI ≥25 and <30, n = 6), and obese (BMI ≥30, n = 5). We compared these patient groups with skeletal muscle parameters of SMI and SMD as surrogate markers for skeletal muscle mass and quality to assess sarcopenia (Table 3 and Figure 2).³ For underweight and normal weight conditions, SMI <43 was considered as sarcopenic and SMD <41 was considered poor muscle quality. Sarcopenic values and poor muscle quality values are indicated in (Table 3). For overweight and obese patients, SMI <53 was considered to be a sarcopenic value and SMD <33 HU was considered abnormal muscle quality.³ Both underweight patients had low SMD but were not sarcopenic by SMI. Of 2 normal-weight patients, 1 patient was in the sarcopenic range and 1 patient had low SMD <41 HU. Of the 6 overweight patients, 2 had low SMD <33 HU in poor muscle quality range, whereas all had SMI >53 (nonsarcopenic range). Among the 5 obese patients, 1 patient was sarcopenic (SMI <53) and had low muscle quality (SMD <33 HU). Three other patients were sarcopenic by SMI <53 alone, and 1 patient (case 8) had skeletal muscle parameters within the reference range. Overall, 4 patients were sarcopenic by SMI, 5 patients had poor muscle quality by SMD, and 1 patient was sarcopenic with poor muscle quality and muscle density.

Discussion

Review of sarcopenia, diagnostic challenges, and implication in cirrhotic patients

Diagnosis of sarcopenia has become more difficult as more components have been added to the definition, including muscle mass, muscle fat, muscle strength, and physical performance. The term sarcopenia was first suggested in 1988 by Rosenberg to define an age-related decline in body muscle mass index that affects functional capacity in older patients.¹⁵ With a better understanding of sarcopenia, the definition of sarcopenia has changed in the past 2 decades. In 2010, the EWGSOP⁵ added fat content and functional capacity aspects to sarcopenia (recognized as sarcopenic obesity). This description was further revised in 2018 (EWGSOP2) to recognize sarcopenia as a muscle disease (muscle failure) and the advised early detection of low muscle quantity and quality.⁶ Noticeably, the functional aspect of the muscle was given more emphasis in the diagnosis of sarcopenia. Additionally, in 2017, Golse and colleagues retrospectively studied 256 post-LTx recipients to develop an L3 lumbar vertebral SMI for sarcopenia by using the third lumbar vertebral index (L3MSA) measurement of the psoas muscle area at L3 normalized by height and body surface area.⁷Diagnostic tools and methods, such as the 6-minute walk test and the stair climb power test, could not be utilized for most recipients after LTx. Mid-arm circumference, skinfold thickness, and calf circumference are affected with edema and may be unreliable in obese patients. Often, the term frailty has been used when there is a functional decline in global health without sarcopenia. However, most of these are subjective observations and often difficult to differentiate objectively. Sarcopenia secondary to malnutrition, incurable malignancy, or chronic illness is easily recognized.^16-18 Atkins and colleagues alluded to sarcopenic obesity resulting in higher morbidity and mortality from cardiovascular and coronary disease in elderly people.¹⁹ The effect of sarcopenia with chronic liver disease has a poor outcome, as it is often associated with frailty and muscle wasting.^18,20,21 Sarcopenia with liver disease affects the prognosis and increases morbidity and mortality.^8,18 We have incorporated functional sarcopenia impairment for older people by Delmonico and colleagues⁹ for a postoperative LTx recipient. Recipients who were unable to get out of bed and stand on their feet with the help of 2 physiotherapists within 24 hours of extubation or who were ventilator dependent for more than 2 days post-LTx with a functioning hepatic allograft without any major complications were considered to have functional sarcopenia impairment.

Review of testosterone deficiency and replacement therapy with chronic liver disease

Testosterone deficiency was first studied for patients with Laennec cirrhosis in 1948 by Lloyd and Williams.²² They observed a 71% decrease in libido and potency, 84% of the patients had a decrease in axillary hair 87% and noted testicular atrophy in 70% of patients and gynecomastia in 42% of patients from testosterone deficiency with cirrhosis. Wells reported survival advantages with testosterone therapy for chronic liver disease with prednisolone in 1960.²³ Puliyel and colleagues reported that administering testosterone 100 mg intramuscularly on alternate days for 4 weeks resulted in a reduction in ascites and pedal edema with an increase in albumin.²⁴ A double-blind, placebo-controlled, multicenter Copenhagen trial (1986) reported that oral testosterone treatment (200 mg, 3 times per day) improved hemoglobin and decreased gynecomastia without changing hepatic biochemistry.²⁵ Gluud and colleagues conducted a placebo-controlled prospective randomized trial using oral testosterone 300 mg, 3 times per day, without any benefit on liver biopsy after a median follow-up of 30 months.²⁶ Yurci and colleagues found that transdermal testosterone replacement improved muscle strength, ameliorated gynecomastia, and altered body fat distribution in hypogonadal men with cirrhosis.²⁷ Sinclair and colleagues concluded that low-dose testosterone replacement therapy with cirrhosis is safe and increases muscle mass with a reduction in fat mass and improves bone mass, hemoglobin, and hemoglobin A1c without any survival benefits.²⁸ Sinclair and colleagues claimed testosterone deficiency in chronic liver disease has more of an impact on survival outcomes than MELD.²⁹

Testosterone deficiency and replacement therapy

Testosterone replacement therapy for hypogonadism in male patients is a well-established treatment.^30-33 Sarcopenia and testosterone deficiency can exist concurrently with chronic liver disease with or without muscle wasting. Testosterone replacement therapy with advanced chronic liver disease was not successful with incurable underlying pathology. However, hepatic replacement resolves the underlying hepatic pathology, and a short-term testosterone replacement therapy with functional sarcopenia has not been studied.³⁴In the present report, we have utilized functional sarcopenia for post-LTx recipients based on impairment of lower extremity for older people by Delmonico and colleagues.⁹ We have defined it as an inability to get out of bed and stand with the help of 2 physiotherapists within 24 hours of extubation or requirement for prolonged in-bed ventilator depen-dency for more than 2 days post-LTx with a functional hepatic allograft, without major complication. We have described 16 consecutive male post-LTx recipients who received short-term testosterone replacement therapy soon after LTx for functional sarcopenia and extremely low total testosterone serum concentrations (mean <5% of expected).¹⁰ Most often a single dose of testosterone cypionate at 200 mg intramuscularly (75% of patients) was adequate. A small proportion of patients (18.75%) received a second dose after 2 weeks, and 1 patient (6.25%) with a prolonged hospital stay received 4 doses during a period of 80 days. In addition, providers in rotation visited the patients every 2 hours during the daytime, to encourage patients’ participation in-bed exercises with flexion and extension of all joints of both upper and lower extremities for 5 to 10 minutes per session. Within a day or so, we observed a progressive improvement in mobility. This has been very useful for the confidence-building of patients and their visiting family members and friends. Recently, Falqueto and colleagues in their meta-analysis have alluded to the benefit of combined exercise with short-term anabolic-androgenic steroids for sarcopenia and cachexia atrophy due to inactivity.³⁵

Potential side effects of testosterone administration

Testosterone is an anabolic steroid with several functions in the body besides improving muscle strength in the body. Excessive use is not without negative side effects on the body. Androgen and androgen receptor signaling can initiate carcinogen-related and hepatitis B-related HCC.^36-38 Androgen and androgen receptors play a role in HCC and cholangiocarcinoma. Furthermore, testosterone could affect the vascular responsiveness and the vascular reactivity hemostatic system, which is associated with cardiovascular risk.^39-41 However, in our present report, we used testosterone as a replacement when the serum testosterone levels were 2% to 16% (mean, 5%) of expected levels. Seventy-five percent of the patients received a single dose. Others received an additional testosterone dose when serum testosterone levels were <20% of expected and while in the hospital under supervision. One patient who died from recurrent HCC at 20 months after transplant had received a single dose of testosterone. His testosterone level was <4% of expected. We do not believe testosterone replacement therapy had any influence on this outcome.

Correlation of sarcopenia with body mass index and radiological findings for skeletal muscle index and skeletal muscle density

Two underweight patients were not sarcopenic by SMI, but both had poor muscle quality by SMD. Of 2 patients with normal body weight, 1 patient was sarcopenic by SMI, and another had low SMD. Of 6 overweight patients, none was sarcopenic by SMI, and 2 patients had poor muscle quality by low SMD. Of the 5 obese patients, 4 were sarcopenic by SMI, of whom 1 also had poor muscle quality by SMD. If we combine underweight, normal-weight, and over-weight patients, of 10 patients, 1 was sarcopenic by SMI (10%), and 5 had poor muscle quality by SMD (50%); in contrast, among 5 obese patients, 3 were sarcopenic by SMI (60%), and 1 was sarcopenic by SMA with poor muscle quality by low SMD (20%).^3,4 Sarcopenia was more prevalent in obese patients by SMI, and poor muscle quality was observed more often in underweight patients by low SMD.

Survival outcome

Patient and graft survival rates have improved since 1990 after the introduction of tacrolimus, with overall 5-year patient and graft survival being 71% and 59%, respectively.⁴² With better management and availability of antiviral and antifungal medications, the survival rates have improved further.^43,44 The Scientific Registry of Transplant Recipients (SRTR) showed patient and graft survival rates of 87% and 77% for patients <35 years of age and of 80% and 77% for patients >65 years of age, respectively.⁴⁵ In the present study population with functional sarcopenia and severe testosterone deficiency, we showed that short-term replacement therapy provided 87.5% patient and graft survival at 5 years. Our selection criteria for functional sarcopenia were more from clinical observations of (1) inability to get out of bed with the support of 2 physiotherapists within 24 hours postextubation and able to stand and (2) ventilator support for more than 2 days post-LTx with functional hepatic allograft and without major complications. This takes into account the description by Delmonico and colleagues of performance of lower extremity⁹ and recent modifications of EWGSOP 2019 that recognized sarcopenia as muscle disease or muscle failure,⁶ as described in our Materials and Methods section.Although there are several methods for testos-terone replacement therapy, we preferred the intramuscular route because we expect it to be highly effective (testosterone cypionate, 200 mg), as recommended by the Endocrine Society clinical practice guideline.⁴⁶We believe that testosterone deficiency after LTx could be more common than previously identified. We did not evaluate all 55 male patients for sarcopenia and testosterone concentration. However, patients with functional sarcopenia according to our current guidelines have more to gain from short-term replacement therapy. Although in the definition of functional sarcopenia we have included “without major complication,” these patients could be included as a separate category. Our patient 2 had severe functional sarcopenia from pontine myelinolysis and testosterone deficiency. At the last follow-up, he was alive with good hepatic function. Our proposed definition of post-LTx sarcopenia may be strict; however, it benefits the patients who need it the most. Certainly, more prospective studies with variable dosage and frequency of testosterone, including risks and benefits, would be useful. We have used the intramuscular formulation of testosterone; however, dermal patches of testosterone are available, which could be more suitable in less severe cases.²⁷

Conclusions

Male patients with chronic liver disease and high MELD scores often have functional sarcopenia with or without muscle wasting. Soon after a major surgical LTx procedure, testosterone deficiency persists and functional sarcopenia is difficult to diagnose by conventional criteria.^6-8 We have utilized functional sarcopenia based on the lower extremity performance suggested by Delmonico and colleagues⁹ for older people. Patients with the inability to get out of bed and stand on their feet with the help of 2 physiotherapists within 24 hours of extubation or who are ventilator dependent for more than 2 days post-LTx have benefited from testosterone replacement therapy. Sarcopenia by SMI was more common with obese patients (80%), whereas a rate of poor muscle quality by SMD decreases from underweight (100%) to obese patients (25%). In our experience, a single replacement dose of testosterone cypionate at 200 mg and frequent in-bed active exercises of all upper and lower joints are useful and provide 1-year and 5-year patient and graft survival of 93.8% and 87.5%, respectively. Our present report provided a descriptive, proof-of-concept study. Ideally, further work should include a large population-based prospective trial with well-defined clinical parameters to identify the prevalence. The dosing, frequency, route of administration, risk, and benefit of testosterone replacement therapy for LTx recipients with various degrees of functional sarcopenia could be evaluated. Although we did not include women in the present study, women could also be considered in future studies with the potential side effects of testosterone replacement therapy.

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