Sequential Changes in the Metabolic Response to Orthotopic Liver Transplantation During the First Year After Surgery

Abstract

Objective

To quantify the sequential changes in the metabolic response occurring in patients with end-stage liver disease after orthotopic liver transplantation (OLT).

Summary Background Data

Detailed quantification of the changes in energy expenditure, body composition, and physiologic function that occur in patients after OLT has not been performed. Understanding these changes is essential for the optimal management of these patients.

Methods

Fourteen patients who underwent OLT for end-stage liver disease had measurements of resting energy expenditure, body composition, and physiologic function immediately before surgery and 5, 10, 15, 30, 90, 180, and 360 days later.

Results

Resting energy expenditure was significantly elevated after surgery (24% above predicted), peaking around day 10 after OLT, when it averaged 42% above predicted. A significant degree of hypermetabolism was still present at 6 months, but at 12 months measured resting energy expenditure was close to predicted values. Before surgery, measured total body protein was 82% of estimated preillness total body protein. During the first 10 days after OLT, a further 1.0 kg (10%) of total body protein was lost, mostly from skeletal muscle. Only 54% of this loss was restored by 12 months. Significant overhydration of the fat-free body was seen before OLT, and it was still present 12 months later. Although significant losses of body fat and bone mineral occurred during the early postoperative period, only body fat stores were restored at 12 months. Both subjective fatigue score and voluntary hand grip strength improved rapidly after OLT to exceed preoperative levels at 3 months. At 12 months grip strength was close to values predicted for these patients when well. Respiratory muscle strength improved less markedly and was significantly lower than predicted normal levels at 12 months.

Conclusions

Before surgery, these patients were significantly protein-depleted, overhydrated, and hypermetabolic. After surgery, the period of hypermetabolism was prolonged, restoration of body protein stores was gradual and incomplete, and respiratory muscle strength failed to reach expected normal values. Our measurements indicate that OLT does not normalize body composition and function and imply that a continuing metabolic stress persists for at least 12 months after surgery.

Orthotopic liver transplantation (OLT) is the accepted treatment for patients with end-stage liver disease. The surgical death rate for this procedure has decreased progressively during the past decade as a result of improvements in surgical technique, anesthesia, and postoperative care. Overall 1-year graft and patient survival rates of 80% to 90% can now be expected. For elective patients with nonrecurrent disease, the 1-year survival rate exceeds 90%. ¹ Nevertheless, OLT is a major procedure often undertaken in patients in poor nutritional state. Further, the need for immunosuppression to prevent graft rejection increases the patient’s vulnerability to infectious complications, particularly during the first month after transplantation.

Although it is known that preoperative nutritional state is predictive of postoperative complications, ^2–5 limited information is available regarding the long-term sequential changes in body composition and function that occur after surgery in these patients. The present study was designed to provide a detailed quantification of the changes in resting energy expenditure (REE), body composition, and physiologic function that occur during the first year after OLT.

METHODS

Patients

All adults (16 years of age or older) with end-stage liver disease who were accepted for OLT at Auckland Hospital between January 5, 1998, and March 15, 1999, were considered for inclusion in this study. Patients with acute liver failure were excluded. The study was approved by the Auckland Ethics Committee, and written informed consent was obtained from each patient.

Clinical Management

The clinical status of all patients was followed at monthly intervals by the clinicians in the outpatient clinic according to current clinical practice. Severity of liver disease was assessed according to the Child-Pugh score. ^6,7 Patients received dietary advice based on their medical condition and identification of energy, protein, and other nutrient deficits from a dietary recall. All patients were advised to eat small, frequent meals and snacks. Supplemental nutrition was prescribed for patients whose estimated energy needs were not being met.

All patients received perioperative antimicrobial prophylaxis with flucloxacillin and gentamicin or aztreonam (if renal function was impaired). After surgery, nasojejunal feeding (Osmolite; Ross Laboratories, Columbus, OH) was commenced as soon as tolerated, usually within the first 24 hours, and withdrawn when more than 50% of calorie requirements were met by oral intake. Tacrolimus and methylprednisolone were used as primary immunosuppression, with steroids being tapered and withdrawn by 6 months if possible. The diagnosis of acute and chronic allograft rejection was based on abnormal liver function test results and typical histologic features on liver biopsy (using Banff criteria). Acute allograft rejection was treated with 1 g methylprednisolone for 3 days. Steroid-resistant rejection was treated with a 10-day course of OKT-3 or ATG. All significant clinical events such as reoperations, rejection, or infection episodes were recorded prospectively. Performance status at 12 months was estimated using the five-point Eastern Cooperative Oncology Group scale. ⁸

Study Design

Patients underwent measurements of energy expenditure, body composition, physiologic function, and fatigue score immediately before OLT. These measurements were repeated 5, 10, 15, 30, 90, 180 and 360, days after the transplant (Fig. 1). The body composition measurements were performed in the Department of Surgery in a facility especially designed for studying inpatients. ⁹

Figure 1. Study design. OLT, orthotopic liver transplantation.

Energy Measurements

Resting energy expenditure (REE) was measured by open-circuit indirect calorimetry (Deltatrac Metabolic Monitor; Datex Instruments, Helsinki) at least 4 hours after food intake and after a rest period of at least 30 minutes.

For each patient a predicted REE was calculated using the following equation, developed from measurements on 80 healthy volunteers in our department: predicted REE (kcal/day) = 16.85 × FFMc + 725, where FFMc is the fat-free mass (FFM, in kg) of the patient corrected for abnormal hydration, as derived below. Standard error of the estimate is 174 kcal/day (r² = 0.52).

Body Composition

Body weight, total body nitrogen, total body fat, bone mineral content, total body water (TBW), extracellular water, and total body potassium were measured on each study day. Body weight was recorded to the nearest 0.1 kg using a hoist weighing system used to transfer the patient from the bed to the body composition scanners or, in ambulant patients, a beam balance. Adjustment was made for estimated weight of clothing.

Total Body Nitrogen

Total body nitrogen was determined using a prompt gamma in vivo neutron activation (IVNAA) technique whereby total body nitrogen is calculated independently of total body hydrogen using a method previously described. ¹⁰ The body was scanned twice with a resultant precision of 2.5% and an accuracy compared with chemical analysis of within 4% (based on anthropomorphic phantoms). ¹¹ Total body protein (TBP) was calculated as 6.25 times total body nitrogen. For each patient, a preillness TBP (in kg) was estimated based on the following multiple regression equations developed in our laboratory from measurements on 223 female and 163 male healthy volunteers: for females, preillness TBP = 0.0527 preillness body weight (in kg) + 0.0727 height (in cm) - 0.0247 age (in years) - 5.979 (standard error of the estimate = 0.8 kg, r² = 0.59) and for males, preillness TBP = 0.0916 preillness body weight (in kg) + 0.0718 height (in cm) - 0.0296 age (in years) - 6.211 (standard error of the estimate = 1.1 kg, r² = 0.61). Preillness body weight is that recalled by the patient.

Total Body Fat and Bone Mineral Content

Total body fat and bone mineral content were measured by DEXA (model DPX+, software version 3.6y, extended research analysis mode; Lunar Radiation Corp., Madison, WI). Using anthropomorphic phantoms of known fat content and with different levels of overhydration, the precision of the technique for total body fat was 1.3% and the accuracy was better than 5%. ¹⁰ Precision for bone mineral content based on repeated measurements of healthy individuals has been reported as 0.8% using the current software version. ¹²

Total Body Water

Total body water was calculated from the IVNAA and DEXA results by a difference method that assumes a six-compartment model for the body:¹³ TBW equals body weight minus TBP minus total body fat minus bone mineral content minus glycogen minus nonbone mineral. The small nonbone mineral and glycogen compartments are estimated from total protein and total minerals, respectively, based on the sizes of these compartments in the Reference Man. ¹⁴ Nonbone mineral is calculated as 5.7% of TBP, and glycogen is estimated as 15% of total minerals (bone mineral content plus nonbone mineral). Error propagation calculations suggest that precision close to 1% may be achieved for TBW derived by this method with accuracy better than 3%.

Extracellular and Intracellular Water

Extracellular water was measured using a Xitron 4000B multifrequency bioimpedance analyser (Xitron Technologies, San Diego, CA) while patients were supine on a nonconducting surface. A tetrapolar arrangement of electrodes was used. Pregelled current injection electrodes (IS 4000, Xitron Technologies) were placed on the dorsal surfaces of the right hand and foot at the distal metacarpals and metatarsals, respectively. Similar detection electrodes were applied to the dorsal surface of the right hand between the distal prominences of the radius and ulna and the dorsal surface of the right foot between the medial and lateral malleoli at the ankle. Electrode sites were precleaned with alcohol. Bioimpedance spectra were obtained at 48 logarithmically spaced frequencies between 5 and 500 kHz. The impedance and phase spectral data were fitted to an electrical circuit model of the body and extracellular water was determined from a theoretical volume equation using the Xitron software package. ¹⁵ We have shown ¹⁶ that application of this method to patients with serious illness reproduces closely the extracellular water results from bromide dilution, provided that significant localized fluid sequestration is not present.

Intracellular water was calculated as the difference between TBW and extracellular water.

Total Body Potassium

Total body potassium was measured by analyzing the gamma spectrum emitted from naturally occurring K⁴⁰ using a shadow shield counter. ¹⁷ The overall precision for a single measurement of total body potassium is 3% as determined from replicate measurements of anthropomorphic phantoms with different levels of overhydration (unpublished observations).

A value for intracellular potassium concentration, [K]_i, for each study day was calculated as: [K]d/c_i(mmol/L) = (total body potassium [mmol] - serum potassium concentration [mmol/L]) × extracellular water [L])/intracellular water (L). Measurements on 76 healthy volunteers in our laboratory using the body composition techniques described above yield a mean ± SEM for [K]_i equal to 153.7 ± 3.1 mmol/L.

Skeletal Muscle Mass

Appendicular skeletal muscle mass was derived from regional analysis of the data obtained by DEXA scanning using the method of Heymsfield et al. ¹⁸ Briefly, the FFM of the limbs less the mass of wet bone of the limbs was assumed to approximate limb skeletal muscle mass. Application of the method to patients with liver disease requires a correction to the measured FFM as described below to account for the deviation from normal hydration of lean tissue commonly seen in these patients. The hydration-corrected appendicular FFM was converted to appendicular muscle mass by subtraction of wet bone mass (1.82 × appendicular bone mineral content as determined by DEXA). Total skeletal muscle mass was calculated from appendicular muscle mass by multiplying by 1.26, a factor established from computed tomography scanning of normal subjects. ¹⁹ Protein content of total skeletal muscle was assumed to be 17%. ¹⁴ Remaining protein in the body was referred to as nonmuscle protein.

Derivation of Hydration-Corrected Fat-Free Mass

Measured FFM (total body weight minus total body fat) may be represented by the following equation: FFM = FFMc + TBW - TBWc, where (TBW - TBWc) represents the deviation of measured TBW from the water that accompanies FFMc. Rearranging this equation: FFMc = FFM (1 - TBW/FFM/(1 - TBWc/FFMc), where TBWc/FFMc is the ratio of TBW to FFM in healthy subjects, found to equal 0.73 in 176 healthy volunteers measured in our laboratory using the techniques described above. An analogous equation applies for hydration adjustment of the FFM of the limbs, provided the measured whole-body hydration (TBW/FFM) applies also to the appendicular FFM.

Physiologic Function

Grip Strength

Voluntary hand grip strength was measured in the dominant hand using a spring-loaded dynamometer (Smith & Nephew Rolyan, Inc., Menomonee Falls, WI). The best of three consistent readings, allowing approximately 1 minute of recovery between each attempt, was recorded as the maximum grip strength. A predicted normal grip strength (in kg) was calculated for each patient using the following multiple regression equations developed in our laboratory from measurements on 158 female (age range 19–74 years) and 89 male (age range 18–80 years) healthy volunteers: for females, predicted grip strength = 1.296 preillness TBP (in kg) + 0.205 height (in cm) - 0.0998 age (in years) - 12.323 (standard error of the estimate = 4.0 kg, r² = 0.39) and for males, predicted grip strength = 0.960 preillness TBP + 0.232 height (in cm) - 0.218 age (in years) + 1.808 (standard error of the estimate = 5.3 kg, r² = 0.43).

Respiratory Muscle Strength

Respiratory muscle strength was calculated as the average of maximal inspiratory pressure measured at functional residual lung capacity after maximal expiration and maximal expiratory pressure at total lung capacity after maximal inspiration. Maximal inspiratory pressure and maximal expiratory pressure were measured as the best of at least two consistent readings with a bidifferential pressure transducer (Validyne Engineering Corp., Northridge, CA). Pressures had to be maintained for at least 1 second, and a small leak was introduced in the circuit to prevent falsely high readings due to activity of the cheek muscles. A predicted preillness respiratory muscle strength was estimated for each patient based on his or her preillness body weight, age, height, and sex.²⁰

Fatigue Score

Subjective fatigue from 1 (fit) to 10 (fatigued) was scored by the patients using the Christensen-Kehlet ordinal fatigue scale. ²¹

Radiation Dosimetry

IVNAA and DEXA scans involve a radiation dose to the patient of approximately 0.3 mSv on each day of measurement.

Statistical Analysis

Repeated measures analysis of variance with asphericity correction was used to detect significant changes over time (SAS Institute, Cary, NC). The Student t tests for paired data were used when significant differences were detected on analysis of variance. In all cases, the 5% level was chosen for statistical significance. Results are expressed as mean ± SEM unless otherwise stated.

RESULTS

Patients

A total of 17 patients were listed for elective OLT, all of whom were eligible to enter the study and consented to participate. None of the patients was listed for regraft or multiple organ graft. Fourteen patients completed the protocol. One patient died before transplantation, one patient withdrew because of intractable claustrophobia, and one patient requested withdrawal from the study after the transplant operation. Clinical details of the 14 patients are listed in Table 1. All patients had histologic evidence of cirrhosis before OLT. Pathogenesis of liver disease was hepatitis B infection (six patients), hepatitis C infection (two patients), combined hepatitis B and C infection (one patient), primary sclerosing cholangitis (three patients), and hemochromatosis (two patients). Hepatocellular carcinoma was present in 4 of the 14 patients. Median time on the waiting list for the 14 patients was 51.5 days (range 5–110). Eight patients consumed a nutritional supplement (710 kcal/d, Ensure Plus; Abbott Laboratories, Columbus, OH) while on the waiting list. Three patients were grade A, three grade B, and eight grade C, according to Child-Pugh scores, at the time of transplantation. Ascites was present in two patients at laparotomy; ascitic volumes were 600 (patient 6) and 150 mL (patient 11). The median hospital stay after the transplant was 14 days. Five of the patients required reoperation for surgical complications of the transplant operation. Steroids were withdrawn a median 9.4 months after OLT, with three patients continuing on steroids at 12 months. Rejection episodes (confirmed by liver biopsy) occurred in 10 patients, 3 of whom required OKT-3 for steroid-resistant rejection. One patient developed late steroid-resistant rejection and was treated with ATG but went on to develop chronic rejection, which was eventually controlled with a combination of tacrolimus and sirolimus. Nine patients were treated for postoperative infections. At 12 months, graft function was normal in all but three patients, and Eastern Cooperative Oncology Group performance status was either 0 or 1 for all patients.

Table 1. CLINICAL DATA

DCCM, Department of Critical Care Medicine; ECOG, Eastern Cooperative Oncology Group performance status; FS, fatigue score; HCC, hepatocellular carcinoma; M, methylprednisolone.

* Day refers to days after liver transplantation.

Body Composition Measurements

Table 2 lists the mean (±SEM) data for the measurements of body weight, total body fat, TBW, extracellular water, total body nitrogen, bone mineral content, skeletal muscle mass, and total body potassium on days −1, 5, 10, 15, 30, 90, 180, and 360.

Table 2. RESULTS OF BODY COMPOSITION, RESTING ENERGY EXPENDITURE (REE), AND PHYSIOLOGIC FUNCTION MEASUREMENTS

Values are mean ± standard error of the mean.

* Repeated measures analysis of variance.

†p < .05,

‡p < .01,

§p < .001 for paired t test vs. preceding measurement.

Resting Energy Expenditure

Figure 2 shows the mean (±SEM) measured REE and the mean (±SEM) predicted REE during the study period. Measured REE changed significantly during the study period, peaking at around day 10 after OLT, when it averaged 42% above predicted. Before surgery, REE was significantly elevated (24% above predicted), and a significant degree of hypermetabolism was still present at 6 months (P = .015). At 12 months, measured REE was close to predicted values.

Figure 2. Resting energy expenditure (REE) in 14 patients measured before and during 12 months after liver transplantation performed on day 0 (closed circles), with REE predicted from fat-free mass after correction to normal hydration (open circles) (mean ± SEM). *P < .05 vs. preceding measurement.

Protein Metabolism

Figure 3 shows the estimated preillness TBP and the changes in TBP that occurred during the study period. Maximum loss of protein occurred during the first 10 days after OLT, amounting to 0.99 ± 0.12 kg or 1.0% of TBP/d. After this time, TBP increased gradually so that by 12 months a significant but small gain in protein was recorded (0.53 ± 0.24 kg, P = .048), amounting to 54% of that lost. Before surgery, measured TBP was 81.5 ± 1.6% of preillness TBP.

Figure 3. Total body protein (TBP) in 14 patients measured before and during 12 months after liver transplantation performed on day 0, with estimated preillness TBP shown by dotted line (mean ± SEM). *P < .05 vs. preceding measurement.

Figure 4 shows that during the first 10 days of the study, there was an appreciable loss of protein from skeletal muscle, amounting to 62% of the total protein lost. During the first 90 postoperative days, the changes in skeletal muscle protein closely paralleled those of TBP. Beyond this time, no further gains in skeletal muscle protein (or skeletal muscle mass) could be detected. In contrast, the initial loss of protein from nonmuscle sources did not begin to recover until after 90 days.

Figure 4. Skeletal muscle protein (closed circles) and nonmuscle protein (open circles) in 14 patients measured before and during 12 months after liver transplantation performed on day 0 (mean ± SEM). *P < .05 vs. preceding measurement.

Fat Metabolism

Figure 5 shows that during the early postoperative period there was a significant loss of total body fat, which was fully regained by 3 months. During the subsequent 9 months, the changes in total body fat were not statistically significant.

Figure 5. Total body fat in 14 patients measured before and during 12 months after liver transplantation performed on day 0 (mean ± SEM). *P < .05 vs. preceding measurement.

Bone Metabolism

A significant reduction in absolute bone mineral content occurred in the first 2 weeks after OLT (0.07 ± 0.02 kg, P = .003). This loss was not regained at 12 months.

Water Metabolism

The changes in total and extracellular water during the study period were not statistically significant. Before surgery, TBW was 76.5 ± 0.4% of FFM compared with an expected normal value of 73% (95% confidence limits: 69–76%) measured in healthy volunteers in our laboratory. At 12 months, relative overhydration of the FFM was still present (TBW/FFM = 0.767 ± 0.004).

Cell Composition

Figure 6 shows the changes in total body potassium and [K]_i that occurred during the study period in 5 of the 14 patients. Total body potassium decreased significantly during the first 10 postoperative days (P = .013). The pattern of changes followed that observed for TBP and reflected the early postoperative loss of lean tissue and the subsequent repletion of this compartment. Before surgery, [K]_i was 132.0 ± 9.8 mmol/L, compared with the normal value for our laboratory of 153.7 ± 3.1 mmol/L (P = .08) A significant reduction in [K]_i occurred during the first 10 to 15 postoperative days, but during the subsequent 12 months this parameter returned to preoperative levels.

Figure 6. Total body potassium (TBK) and intracellular potassium concentration ([K]_i) in five patients measured before and during 12 months after liver transplantation performed on day 0 (mean ± SEM). *P < .05 vs. preceding measurement.

Physiologic Function

Table 2 lists the mean (±SEM) data for the measurements of grip strength and respiratory muscle strength on days −1, 5, 10, 15, 30, 90, 180, and 360. Figure 7 shows the changes in grip strength and respiratory muscle strength, expressed as percentages of expected preillness values, during the study period. Before surgery, grip strength and respiratory muscle strength averaged 83% and 72%, respectively, of predicted normal values. After an initial decrease after surgery, grip strength improved rapidly to exceed preoperative values by 3 months. At 12 months, grip strength was significantly greater than that measured before surgery (P = .008) and was not significantly different from the predicted value (P = .26). Respiratory muscle strength could not be measured on study days 5, 10, and 15 because of abdominal discomfort. At 12 months, although significant improvement had occurred compared with preoperative values (P = .011), respiratory muscle strength was still significantly lower (P = .024) than that predicted for these patients when well.

Figure 7. Grip strength (open circles) and respiratory muscle strength (closed circles) as percentages of predicted normal values in 14 patients measured before and during 12 months after liver transplantation performed on day 0 (mean ± SEM). *P < .05 vs. preceding measurement.

Fatigue

The changes in fatigue score during the study period are shown in Figure 8. By 3 months after OLT, our patients felt subjectively less fatigued than they did before surgery (P = .0006). Further reduction in fatigue occurred out to 6 months. Fatigue scores at 12 months are shown in Table 1.

Figure 8. Fatigue score (arbitrary units) in 14 patients measured before and during 12 months after liver transplantation performed on day 0 (mean ± SEM). *P < .05 vs. preceding measurement.

DISCUSSION

These results provide, for the first time, a detailed picture of the sequential changes in REE, body composition, and physiologic function that occur in patients during the first 12 months after OLT. Before surgery, our patients were significantly protein-depleted, overhydrated, and hypermetabolic, a metabolic picture characteristic of catabolic stress. During the first 2 weeks after OLT, these patients lost a further 10% of their body protein stores and their REE increased by about 11%. After the immediate surgical stress period had passed, there was a rapid improvement in subjective fatigue level and grip strength. Total body fat returned to preoperative levels within 3 months. In contrast, restoration of protein stores occurred very slowly and incompletely, and only about half of the protein lost in the early postoperative phase was regained by 12 months. Similarly, the hypermetabolism resolved slowly so that at 6 months REE was still significantly higher than predicted. The overhydration of the FFM that was evident before surgery was still present 12 months later. Respiratory muscle strength, in contrast to grip strength, did not show marked improvement after surgery and was still 20% below expected normal levels at 12 months.

The lack of a marked anabolic response after OLT in these patients is in stark contrast to measurements carried out in our laboratory on the recovery of ulcerative colitis patients who have undergone panproctocolectomy and ileoanal J-pouch anastomosis. ²² By 12 months after surgery, these latter patients had returned to normal body composition—in other words, body protein and fat stores had returned to what they were before the colitis flared, and the hydration of the fat-free body had returned to normal (73%). ^23,24 Both the colitis patients and the end-stage liver disease patients were overhydrated and in similar protein deficit before surgery. For the post-OLT patients to emulate the sort of recovery seen in the colitis patients requires an expectation that the implanted liver achieves normal or near-normal metabolic function and that the episodes of infection and graft rejection that complicate the postoperative course of many of these patients do not compromise the recovery process, nor does the corticosteroid and immunosuppressive drug therapy necessary after transplantation. Some or all of these expectations may not hold true.

It would appear that throughout the study period, continuing metabolic stress limits the recovery process. In Figure 9 we compared the changes in TBP (expressed as a percentage of expected TBP when well) during the 12-month period for the colitis patients with those for the OLT patients. The colitis patients recovered significantly better (P < .0001) than the OLT patients. OLT failed to reverse the preoperative protein depletion and overhydration in patients who are generally functionally well at 12 months (see Table 1). This continuing protein deficit, combined with the persistent overhydration, suggests persisting metabolic stress. Given that the calcineurin phophatase inhibitor tacrolimus is an antagonist to the action of insulinlike growth factor 1, ²⁵ it could be postulated that ongoing tacrolimus therapy is the metabolic stressor in question. However, empirical data from human liver allograft recipients suggest that tacrolimus would diminish REE. ²⁶

Figure 9. Total body protein (TBP), expressed as a percentage of estimated preillness (PI) values, measured before and during 12 months after liver transplantation, with comparative data for patients who underwent restorative panproctocolectomy ²² (n = 16, open circles) (mean ± SEM). *P < .05 vs. transplant group.

Our study is the first to use neutron activation techniques to assess body protein changes after liver transplantation. Other groups have measured nitrogen balance in the early postoperative period after OLT ^27–29 and confirmed the profound protein catabolism that occurs after this operation. The cumulative 10-day catabolic loss of protein after OLT was estimated as 0.9 kg by O’Keefe et al ²⁷ based on daily urinary urea excretion measurements, not dissimilar from our result (1.0 kg). This degree of postoperative protein catabolism is as great as any we have observed in surgical patients and is similar to the loss observed in patients with serious sepsis or major trauma. ^30,31

Limited published data are available describing the body composition changes over the longer term after OLT. Hussaini et al ¹² used DEXA and whole-body counting (for total body potassium) to study 55 patients before OLT and for up to 24 months after OLT. Thirty-two of these patients had cholestatic liver disease and only one had cirrhosis from viral hepatitis. They found a significant decrease in lean tissue mass (4.8 ± 1.2 kg) during the first 2 to 5 months after OLT. During the 12- and 24-month periods of follow-up there were no significant changes in lean tissue mass from preoperative levels. The reduction in lean tissue mass was paralleled by a decrease in total body potassium, suggesting that the change measured by DEXA is not due to loss of water but represents a reduction in body cell mass, presumably muscle mass. Both body weight and fat mass were significantly greater than pretransplant values at the 12- and 24-month intervals. These results are in broad agreement with those of the present study, although overall fat gain in our patients at 12 months was not significant in contrast to the 12.9 ± 2.2 kg observed by Hussaini et al. DEXA measurements carried out by Keogh et al ³² before and around 19 months after OLT showed a significant loss of lean mass and a gain in fat mass. Measurements carried out longitudinally on renal transplant patients, although limited to 4 to 6 months of follow-up, also indicate a lack of recovery in TBP ³³ and lean tissue mass ³⁴ after the transplant.

Before surgery, TBW in our patients was significantly greater than normal relative to their FFM. None of our patients had appreciable ascites, which would have increased further the extent of overhydration. The persistence of an overhydrated FFM through 12 months after OLT in these patients may be due to the combined effects of a continuing metabolic stress and the toxicity of the drugs used for immunosuppression. We have shown elsewhere ^13,16 that measurements of TBW using the multicompartment method agree well with those of tritium dilution in severely ill patients. We have also shown that the multifrequency bioimpedance method for measuring extracellular water provides close agreement with bromide dilution in seriously ill patients who do not have demonstrable localized fluid retention. ¹⁶ The intracellular water values derived from these measurements, coupled with our measurements of total body potassium, suggest that the intracellular potassium concentration at 12 months may also be abnormal, although recovery from the initial decrease in intracellular potassium concentration over the immediate postoperative period had occurred.

Our results confirm the net decrease in bone mineral during the 12 months after OLT reported by others. ^12,35 Bone mineral density at the lumbar spine and femoral neck is also reported to be significantly reduced after transplantation. ³² Osteoporosis is a common complication of chronic liver disease ³⁶ and immunosuppression therapy after liver transplantation further contributes to bone loss. ³⁷

Other groups have measured REE before and after OLT. 28,29,38–40 That REE may be elevated for a prolonged period after transplantation is supported by the study of Muller et al, ⁴⁰ who measured REE before OLT and an average of 432 days after OLT. Measurements during the early postoperative period were carried out by Plevak et al ²⁸ and Hasse et al. ²⁹ The former group found no significant changes in REE during the 28 days of the study, but Hasse et al ²⁹ showed that REE increased significantly by some 30% between days 2 and 12 after OLT. The variability observed in the results from these studies and our own may to some extent be due to differences in primary disease etiology between the groups.

Our conclusion that before surgery our patients were hypermetabolic and that this hypermetabolism continued after surgery for a prolonged period is based on the use of a predicted normal REE that is a function of the FFM of each patient after correction to normal hydration. ⁴¹ Small adjustments to the assumed ratio of water to FFM that is considered normal do not alter these conclusions. The use of total body potassium as a measure of the metabolically active compartment of the body may also be appropriate. ^30,42 In the five patients who had total body potassium measurements, we found (data not shown) that REE predicted using either total body potassium or FFMc yielded similar conclusions. The question of how best to estimate the expected REE when well for an individual patient is problematic in liver disease. ^42,43 Most published studies, for which detailed body composition analysis is not available, have relied on the Harris-Benedict equations ⁴⁴ to predict REE. Using these equations, which use body weight as a predictor, may seriously underestimate the extent of hypermetabolism. ³⁸ For example, in our 14 patients, REE measured before surgery was 16% greater than that predicted by the Harris-Benedict equations.

There was a significant and rapid improvement in grip strength after OLT: preoperative levels were exceeded within 3 months. These changes more closely parallel the changes in fatigue reported by our patients rather than the changes in body protein. Clearly, psychological and other metabolic parameters may play important roles in these measurements, quite apart from the effects of reduced skeletal muscle and protein deposition. Other work from our laboratory on the physiologic and psychological correlates of postoperative fatigue in abdominal surgery patients suggests that the apparent muscular weakness registered by voluntary grip strength in the early postoperative phase is probably secondary to central fatigue rather than related to loss of skeletal muscle. ⁴⁵ Respiratory muscle strength, however, did not show the same marked improvement after OLT, suggesting a greater reliance on body protein stores for respiratory function.

In conclusion, we showed that despite the clear benefits of a successful graft, ^46,47 abnormalities in body composition persist for a prolonged period after OLT, suggesting ongoing metabolic stress in what appear to be clinically well patients. The continued significant deficit in body protein reserve and respiratory function may further compromise the host’s ability to resist infection, increasing the rate of death and complications during the first year after the transplant. Parameters of liver synthetic function, namely international normalized ratio (INR) and serum albumin, returned to normal within 3 months after the transplant in all patients with normal graft function. Whether the body protein depletion reflects increased peripheral utilization, rather than hepatic synthesis, is yet to be determined.

Will therapeutic interventions be able to prevent these detrimental effects? First, clinical trials need to be undertaken to evaluate the benefit of intensive nutritional therapy before and after liver transplantation. We are aware of only one randomized trial that addresses the issue of nutritional therapy of adult transplant candidates, ⁴⁸ although it is well known that pretransplant nutritional status affects the postoperative rate of death and complications. ^2–5 Second, further information on the specific metabolic effects of individual immunosuppressive agents is needed. The huge growth in primary and adjuvant immunosuppressive agents may allow the development of specific regimens that have minimal adverse effects on posttransplant metabolic status. In the future, the patient’s immunosuppressive regimen may be individualized according to nutritional and metabolic status along with other pretransplant predictors of posttransplant outcome, including age, sex, cardiovascular risk factors, and primary liver disease (and associated risk of recurrent liver disease and malignancy).