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Resting energy expenditure in Gaucher's disease type 1: Effect of Gaucher's cell burden on energy requirements
Resting Energy Expenditure in Gaucher’s Disease Type 1: Effect of Gaucher’s Cell Burden on Energy Requirements Donald J. Barton,
Mark D. Ludman,
Keith Benkov, Gregory A. Grabowski,
and Neal S. LeLeiko
The resting energy expenditure (REE; kcal/d) of 25 patients with Gaucher’s disease type 1 was determined by indirect calorimetry. The average observed REE for the group was approximately 44% greater (P < .Ol) than that predicted (predicted REEI for these patient’s age, sex, height, and weight. The increased caloric requirements of these patients was manifested by a height-for-age less than or equal to the fifth percentile in seven of nine growing children and a muscle mass of less than the fifth percentile in 1 S of 1 g patients studied. The excess REE (observed REE - predicted REE) for individual Gaucher’s disease type 1 patients wes directly related to their liver volume as estimated from radionuolide scans and to the mass of the spleen as measured at splenectomy. The relationship between spleen mass and excess REE was demonstrated by an average 22.0% decrease in REE following splenectomy in five patients. Based on these data, the metabolic rate of the splenic tissue removed from the patients was calculated to be 96.8 kcal/d/kg, about twofold to threefold less than that of normal splenic tissue. These findings indicate that the elevated REE observed in these patients resulted from the large mass of Gaucher’s cells, which although individually hypometabolic, were cumulatively an excessive metabolic burden. Furthermore, they suggest that indirect calorimetry may be a quantitative tool for measuring disease progression and the effect of therapeutic intervention in Gaucher’s disease type 1. Q 1989 by W.S. Saunders Company.
G
AUCHER’S DISEASE TYPE 1 (nonneuronopathic) is the most prevalent lysosomal storage disease’ and the most prevalent genetic disease in the Ashkenazi Jewish population.2 This autosomal recessive disorder of glycosphingolipid metabolism results from the defective activity of the lysosomal hydrolase, acid j3-glucosidase (EC 3.2.1.45).‘S3The accumulation of this enzyme’s major substrate, glucosyl ceramide, within monocyte/macrophage derived cells (Gaucher’s cells) leads to the clinical manifestations including hepatosplenomegaly, hypersplenism, and skeletal disease.’ The metabolic consequences of the accumulation of these Gaucher’s cells in the viscera remain unknown. Until recently, it has been difficult to routinely determine the metabolic rate of a patient in the typical hospital setting. Estimates of daily resting energy expenditure (REE) of adults are generally made using the Harris-Benedict equation, a formula derived from the multiple regression analysis (age/sex/height/weight) of indirect calorimetric measurements of basal metabolic rates in healthy adults.4 Estimates of the daily energy expenditure of children can be made using
the tables developed by Benedict and Talbot5 who determined the sex and weight dependence of REE of children using indirect calorimetry. The introduction of automated devices to perform indirect calorimetry6*’ has made actual determinations of REE both rapid and accurate.8.9 After standardization against known volumes and gas concentrations, these devices determine oxygen consumption and carbon dioxide production by continuously measuring the flow rate and concentration of these gases in inspired and expired gas samples. Application of the Weir equation” permits the calculation of the REE and respiratory quotient (RQ) from these measurements. When performed preprandially, in the morning, the measured REE correlates well with the basal metabolic rate.” In this report, indirect calorimetry was used to determine the REE of 25 patients with Gaucher’s disease type 1. The increased REE in these patients was correlated with the degree of hepatosplenomegaly. In five paitents who underwent splenectomy, the change in the observed REE was correlated with the mass of Gaucher’s cells removed. MATERIALS AND METHODS
From the Department of Pediatrics, Division of Gastroenterology and Clinical Nutrition, and Division of Medical and Molecular Genetics, Mount Sinai School of Medicine, New York, NY. Supported by grants from the Heckscher Foundation for Children, a General Clinical Research Center grant from the National Institutes of Health (NIH) Division of Research Resources (RR71). the NIH (ROI-DK26729). the March of Dimes Birth Defects Foundation (l-857). the UJAjFederation of Jewish Philanthropies, the National Gaucher Foundation (NGF no. 19). and a grant from Florence and Theodore Baumritter to the Mount Sinai Center for Jewish Genetic Diseases. Gregory A. Grabowski is the recipient of an NIH Research Career Development Award (KOQ-DKOI351) and an Irma T. Hirsch1 Career Scientist Award. Mark D. Ludman is the recipient of a General Clinical Research Center Clinical Associate Physician Award (RR00071-25Sl). Address reprint requests to Neal S. LeLeiko, MD, PhD, Division of Pediatric Gastroenterology, Mount Sinai Medical Center, One Gustave Levy Place, New York, NY 10029. o 1989 by W.B. Saunders Company. 0026-0495/89/3812-0016$3.00/O 1230
Patient Population
Twenty-five patients (ages 7 to 66 years) with enzymatically confirmed Gaucher’s disease”,” were admitted to the Mount Sinai Hospital General Clinical Research Center. Patients were selected only by their willingness to participate in these studies; no patients were excluded. Informed consent and assent of children were obtained in accordance with the Mount Sinai Institutional Review Board and National Institutes of Health guidelines. Histories and physical examinations as well as routine blood studies, including liver function tests, revealed no other chronic or acute diseases in these patients. None of these Gaucher’s disease type 1 patients had evidence of central nervous sytem involvement or recent infarction of liver, spleen, or bone. The cardiac outputs of all 25 patients were normal as estimated from measurements of the heart rate and the ejection fraction measured using echocardiography. Fourteen patients were female. Eighteen patients were of Ashkenazi Jewish descent. All patients were euthyroid and all children had normal growth hormone studies. Two patients with other lysosomal storage diseases were used as disease controls, a lo-year-old girl with Metabolism, Vol38,
No 12 (December), 1989: pp 1238-l
243
1239
massive hepatosplenomegaly as a result of cholesteryl ester storage diseaseI and a 17-year-old boy with massive hepatomegaly as a result of mucopolysaccharidosis type II, Hunter syndrome,15 who had undergone splenectomy 10 years before. In addition, calorimetry was performed on 92 control individuals, 64 children and 28 adults. These controls were either healthy outpatient volunteers or inpatients who had been admitted for elective procedures or had recovered from acute illness.
Estimation of Liver Volume and Splenic Weight Twenty-one of the 25 Gaucher’s disease type 1 patients had technetium-99m-sulfur colloid liver/spleen scans. The linear dimensions of the livers were determined by measuring the organ images on both a PA and LAO projection, relative to a standard taped to the patient’s abdominal wall. Liver volumes were estimated to be one fourth that of a rectilinear prism, calculated as abc/4, where a is the liver height, b is the maximum liver width on PA projection, and c is the maximum liver width on LAO projection. Splenic weight (mass) was measured in five patients who underwent partial or total splenectomy.
Nutritional Status and REE determinations The midarm circumference and triceps skinfold thickness were determined on the nondominant arm using a flexible steei tape and a Lange Skinfold Caliper (Cambridge Scientific Industries, Cambridge, MD), respectively. These measurements were used to estimate each patient’s midarm fat and muscle mass relative to data published for age- and sex-matched normals.‘6 Ideal body weights for children” and adults’s were determined from published standards. Caloric intake for each patient was estimated from observed intake while on the General Clinical Research Center or from a 3-day diet diary. The predicted REE was calculated for adults from the Harris Benedict equation: whereas for children with weights less than 38 kg, it was estimated from the data of Benedict and Talbot.’ The observed REE was determined preprandially by indirect calorimetry (Horizon Metabolic Cart; Sensormedics, Anaheim, CA) using a flow-through head box. Before each study the calorimeter was calibrated against room temperature, a volume standard, and both calibration (20% 0,/0.75% CO,) and zero (100% NJ gases. To further compensate for sensor errors, the oxygen and carbon dioxide concentrations of the inspired room air were determined before each study. Prior to initiating data collection, the flow rate of room air circulating through the head box was adjusted to maintain a steady state carbon dioxide concentration of approximately 0.75%. During the study the steady state expired air was analyzed continuously for at least 20 minutes while the patient rested quietly in a darkened room maintained at 22OC.
Splenectomy The REE was determined in five patients (patients 3, 8, 13, 18, and 21) before and after splenectomy. The indication for surgery in each patient was severe persistent thrombocytopenia (<30,000/ mm’). The three adults (patients 13, 18, and 21) underwent total splenectomies and the two children (patients 3 and 8) had partial (-90%) splenectomies.‘9 All patients had uncomplicated operative and postoperative courses. The observed REE of each patient was determined on the day prior to surgery. Postsplenectomy REE determinations were made about 2 weeks after surgery, on the day of discharge from the hospital (patients 8, 13, and 21), or about 2 months after surgery (patients 3, 13, and 18). Patients 1, 10, 16, 17, and 20 had splenectomies from 6 months to 5 years before entering the study; no presplenectomy REE values were available for these patients.
Statistical Analyses Statistical analyses were performed on an IBM PC. Best-fit lines were determined using unweighted linear regression analyses evaluated by the method of least squares and 95% confidence limits calculated for each fitted line. Correlations were computed using Pearson’s product correlation coefficient (Statfast Statistical Package; Statsoft, Tulsa, OK). Significance (P values) for group comparisons was determined using the independent Student’s t test. RESULTS
Evaluation of Nutritional Status Table 1 summarizes the anthropometric characteristics of the 25 Gaucher’s disease type 1 patients. Weights were appropriate for height except for patient 25, who was overweight, and patients 14, 15, 16, 18, and 21, who were underweight. Seven of the nine children younger than 14 years were on or below the fifth percentile for height (patients 3 to 9). As estimated from triceps skinfold thicknesses and midarm circumferences, midarm muscle masses were below the fifth percentile in 15 of 19 patients and midarm fat masses were at or below the fifth percentile in six of 19 patients. In the presplenectomy patient population, the predicted REE ranged from 855 to 1,590 kcal/d (Table 1). By history, the weights of our adult patients were relatively constant, and the muscle and fat compartments were generally low. In the postsplenectomy patient population the predicted REE determined using postsplenectomy weights, ranged from 839 to 1,623 kcal/d.
Determination of Excess REE The observed REE (OREE) exceeded the predicted REE (PREE) in all presplenectomy patients (OREE - PREE). Because there is a wide variation in the predicted REE in this population, a method was sought to normalize the data for the purpose of comparison. By determining the ratio of the observed to the predicted REE for each patient, the relative increase of the observed REE over that predicted was determined. In a healthy population, the mean value of this ratio should be 1; the Harris-Benedict equation has been shown to accurately predict the REE in normals with a precision of 14% at the 95% confidence level.” To validate this method in our own control population, this ratio was determined and plotted as shown in Fig 1A. The mean ratio of 1.05 (SD = 0.17) does not significantly differ (P > .I) from that expected (1.0). In Fig 1B the OREE/PREE ratio for the presplenectomy Gaucher’s disease type 1 patients is shown. The average OREE/PREE of the presplenectomy patient group was 1.44 (SD = 0.19), which was significantly greater (P < .Ol) than that of our control population. The OREE/PREE ratios were unrelated to the age (P > .I) or sex (P > .5) of the patients. Correlation of Organ Involvement and REE Spleen and liver enlargement varied among the Gaucher’s disease type 1 patients, but organomegaly was present in all. To determine the effect of this organomegaly on metabolic rate, the excess REE (OREE - PREE) of each patient was correlated with the estimated volume of each patient’s liver
1240
BARTON ET AL
Table 1. Patient Characteristics Ideal
Patient NO.
sex
Ethnicity
Age (Yr)
Height kd
Weight* (kg)
Presplenectomy Weight (kg)
P REE (kcal/dl
-
Postsplenectomy Weight (kg)
P REE (kcal/d)
19.3
839
CEllOfic Intaket (kcal/d)
1
M
7
119
21.8
-
2
F
7
122
22.5
22.3
862
3
M
AJ
8
112
19.1
21.4
895
4
F
AJ
8
117
20.5
22.0
855
1,310 1,680
MUSCle$ 1%)
2,750
19.5
5
F
Ir/lt
11
132
28.1
27.3
982
6
M
AJ
11
132
27.5
29.3
1,098
7
M
AJ
11
120
21.8
26.7
1,038
8
F
AJ
12
119
21.1
24.3
909
9
M
AJ
14
141
33.6
33.6
10
F
AJ
17
151
40.9
-
1,192 -
11
F
AJ
17
162
60.0
60.7
1,455
12
F
Hisp
20
163
59.5
54.8
1,386
13
F
It
23
173
65.0
68.4
1,499
14
M
Ir/Ge
30
180
71.8
60.5
1,590
15
F
Gr
31
139
60.9
52.5
1,274
16
F
157
53.2
-
46
156
55.9
-
-
42.3
F
Aj It
33
17
52.7
18
M
AJ
48
170
87.3
68.2
1,535
57.3
19
F
AJ
49
160
57.7
53.2
1,228
20
M
AJ
51
178
71.4
-
-
73.8
21
M
AJ
52
168
85.0
52.3
1,272
45.0
22
F
AJ
54
159
61.4
83.8
1,305
23
M
AJ
57
174
68.6
89.1
24
M
AJ
63
178
69.5
70.9
25
F
AJ
66
165
60.9
84.1
847
2,510
21.0
830
1,520 -
Fat$ (%I
<5 -
t5 -
t5 -
t5 -
-
-
<5
lo-25
<5
-5
<5
1O-25
-
<5
5-10
2,250 3,400
<5 -
75-90 -
2,080
5-10
t5
3,000
<5
<5
<5
25-50
1,196
2,030 -
<5
lo-25
1,225
-
<5
lo-25
1,380
3,720
<5
-5
1,510
<5
5-10
1,623
2,050
-25
25-50
1,172
2,200
<5 25-50
25-50
1,501
1,950 -
<5
50-75
1,489
2,210
1,456
-
90-95 -
lo-25 -
37.3
60.5
1,211
1,441
5-10
Abbreviations: AJ, Ashkenazi Jewish; Hisp, Hispanic; Ir, Irish; It, Italian; Ge, German, Gr, Greek. l
Ideal weight expressed for patients less than 20 years old as the 50% weight for height15 and for adults as the average weight for height and frame.”
tCaloric intakes were determioned either from J-day diet diaries or observed intakes while hospitalized during initial evaluation. SMidarm muscle mess percentile (muscle) and midarm fat mess percentile (fat) determined from age/sex matched controls14 for presplenectomy observations. Postsplenectomy observations were determined only when available.
and, in those patients who had a splenectomy, the weight of the spleen. This relationship is shown in Fig 2A for splenic weight and in Fig 2B for liver volume, respectively. Excess REE was related directly to spleen weight (Table 2) (r = .9 1, P < .05) and liver volume (Table 3) (r = .78, P < .005). The patient with cholesteryl ester storage disease was found to have an excess REE of only 90 kcal/d [PREE = 1047, (OREE)/(PREE) = 1.091 despite marked hepatosple-
14 -
nomegaly. The patient with Hunter syndrome had an excess REE of only 58 kcal/d [PREE = 958, OREE/PREE = 1.061 despite marked hepatomegaly. Effect of Splenectomy on REE
The observed REE decreased in all patients following splenectomy (Table 2). The decrease in REE corresponded to an average of 445 + 197 kcal/d, or about 22.0%. The
‘: 12z ; IOd
7P E6 % 5i=
b
8- -
“04
= 6% I4z 2-
23 g21
A,+
0 0.5
0.7
0.9
I.1
(Ohs REE)/(Pred
1.3 REE)
1.5 RATIO
1.7
1.9
BL
0 (Ohs REE)/(Prad
REE)
RATIO
Fig 1. Frequency distributionof the ratios of OREE/PREE. The distributions for a control population (A) (mean rt SD, 1.06 f 0.17) and for the Gaucher’s disease type 1 population (1.44 f 0.19) before aplenectomy (8). The bell-ehaped curve in each figure represents the distribution obtained from the control population shown in (AI.
1241
METABOLIC RATE IN GAUCHER DISEASE
600 400 E
200 An
z
“0
4
2
6
0
2c10 8 10 0
‘0
AC
I
I
600
WEIGHT OF REMOVED SPLEEN (kg)
I
I
I
1200 LIVER
I
I
I
1800
I
I 2400
I
I
VOLUME ICC)
Fig 2. Correlation of excess ME and spkmic mass (A) and liver volume (B). The correlation between excess REE and the splenic mass (A) (mesrured as wrdght of spleen surgkxlly removed) and the correlation between excess REE and liver volwno (B) (measured by radionuclide scan) from Gauchw’s disease type 1 patients were significant (r = .Sl. P < .06 and r = .78, P c .Ol; reapectivdy). The solid lines represent linear regression of the data by the method of least squares. and the broken lines represent the 96% confidence limits.
average weights of the splenic tissue removed from these patients was 4.46 + 1.84 kg, which represented 10.3% k 2.7% of their respective preoperative body weight (Table 2). As shown in Table 2, the metabolic rate of the removed spleens (96.8 + 36.6 kcal/d/kg) was estimated from the weight of the excised splenic tissue and the changes in OREE following splenectomy. DISCUSSION
In this study indirect calorimetry was used to demonstrate that patients with Gaucher’s disease type 1 have an elevated REE. The degree of increase in REE was directly related to the extent of hepatosplenomegaly in the affected patients and apparently was specific for Gaucher’s disease type 1 because the patients with cholesteryl ester storage disease and Hunter syndrome did not have significantly increased REE despite massive organomegaly. Because the excess REE decreased in relation to the mass of spleen removed at surgery, this study suggests that the increased REE in Gaucher’s disease patients may be the result of the accumulation of Gaucher’s cells and, thereby, provide an indirect assessment of the accumulation of Gaucher’s cells in individual patients. Previous studies have shown that the metabolic rates of animal organs perfused in vitro” and human organs perfused in viva” were a function of their specific tissue type and their total mass. Thus, it is not unexpected that the total body
energy expenditure in Gaucher’s disease type 1 patients would be elevated due to the increased size (and mass) of their livers and spleens. However, the finding that the metabolic rate of the removed spleens was only 96.8 + 36.6 kcal/d/kg of splenic tissue (Table 2) was unexpected. The metabolic rate of normal human splanchnic tissue (ie, liver and spleen) is approximately 350 kcal/d/kg and that of lung, another part of the reticuloendothelial system, about 200 kcal/d/kg.2’ In comparison, the metabolic rate of the splenic tissue removed from the Gaucher’s disease type 1 patients was about twofold to threefold decreased compared with these normal splanchnic tissues. Because pathologic examination of the removed spleens from these patients revealed massive accumulation of Gaucher’s cells in the presence of normal stroma and few significant areas of infarction, the decreased calculated metabolic rate of the splenic tissue from these patients cannot be ascribed to large amounts of nonviable tissue. Because exogenously supplied glucosyl ceramide had no effect on cultured fibroblasts or cells other than macrophages,22 it is reasonable to assume that the splenic stromal cells may have normal metabolic requirements. Consequently, the decreased metabolic rate of the splenic tissue removed from the Gaucher’s disease patients was likely due to the large mass of Gaucher’s cells that individually were hypometabolic, ie, the caloric consumption of each Gaucher’s cell was decreased. However, because of
Table 2. Effect of Splenectomy on REE
pstlmt NO.
Spleen weight* (kg)
(% BWI
OREE Preoperative (kcsl/d)
Postoperative (kcal/d)
A REE (kcal/d)
(%I
A REE/ kQ!Wean (kceVd/ka)
3
3.14
(14.7%)
1,528
1,105
-423
(-27.7%)
134.9
8
2.61
(10.6%)
1,481
1,182
-299
(-20.2%)
114.6
13
5.80
18.7%)
2,358
1.826
-532
(-22.6%)
91.7
18
7.40
(10.9%)
2,754
1,983
-771
(-28.0%)
104.2
1,765
1,563
-202
(-11.4%)
37.6
-445
(-22.0%)
21
3.35
(6.4%)
Mean
4.46
(10.3%)
SD
1.84
*Spleen weights were determined from pathology specimens.
197
96.8 36.6
1242
BARTON
Table3. ExcessREEandLiverlnvolvement Liver Volume* ImL)
OREE (kcal/d)
OREE-PREE (kcal/d)
OREE/PREE
1
2,511
1,524
685
1.82
2
329
1,438
576
1.67 1.71
1,126 -
1,528
632
1,395
540
1.63
1,207
224
1.23
6
724 -
1,255
157
1.14
7
-
1,620
582
1.56
6
819
1,481
572
1.83
3 4 5
9
934
1,657
465
1.39
10
3,172
1,654
443
1.36
11
1,027
2,142
687
1.47
12
795
1,901
515
1.37
13
1,639
2,358
859
1.57
14
1,882
2,117
527
1.33
15
1,414
1,788
514
1.40
16
3,960
1,690
494
1.41
17
1,077
1,825
600
1.49
18
2,422
2,754
1,220
1.79
19
1,382
1,646
418
1.34
20
2,233
1,836
213
1.13
21
800
1.765
493
1.39
22
1,361
1,621
316
1.24
23
569
1,634
133
1.09
24
803
2,018
529
1.36
25
1,640
2,135
679
1.47
*Livervolume calculated from technetium-99m-sulfur colloid images.
the greatly increased numbers of these cells, the total caloric consumption (kcal/d) of the spleens from these patients was increased. Other explanations for the observed increase in REE may be considered but are less likely given the available data. Because the liver is a metabolically active organ, these patients could have had underlying hepatic dysfunction as a result of infiltration of the liver by Gaucher’s cells. However, as noted, none of the patients had clinical or enzymatic evidence of liver dysfunction. Also, blood sequestered in the enlarged livers and spleens might increase a patient’s blood volume and therefore increase the metabolic demands by increasing cardiac output. However, examination of all patients by echocardiography revealed normal cardiac outputs. Finally, the Harris-Benedict equation may underestimate the REE in cachectic paients with depleted fat stores”
ETAL
by as much as 18% to 20%. This is the result of the disproportionate loss of metabolically less active adipose tissue relative to lean body mass. The metabolic rates of our patients far exceeded this, having been increased by 44%. Moreover, although our patients tended to decrease lean body mass and fat stores, they were not depleted to the extent necessary to account for even the discrepancy postulated for cachectic patients. Regardless of the actual cause, it is evident from the anthropometric data that the increased REE of the Gaucher’s disease type I patients had a significant impact on their nutritional status. The effect of the increased REE in Gaucher’s disease type 1 patients is manifested by decreased muscle mass and linear growth. Muscle mass was determined to be below the fifth percentile in all but four patients in this study (patients 13, 20, 22, and 24). In addition, seven of nine children in this study had linear growth retardation. Two of these children (patients 3 and 8) required splenectomy and have been followed for 6 and 14 months, respectively. During this time they have experienced catch-up growth of 1.5 and 4 inches, respectively, coincident with their decreased REE. These results are consistent with the increased REE being the cause of their growth retardation. The potential for acceleration of destructive Gaucher’s bony disease23 as well as concern regarding increased susceptibility to infection following splenectomy suggests that in the absence of hematologic or other indications, growth retardation in affected children should not be treated by splenectomy. In specific Gaucher’s disease type 1 patients, nutritional supplementation might be used to treat or prevent linear growth regardation prior to splenectomy. The present study indicates the potential use of indirect calorimetry as an investigative tool for studying inborn errors of metabolism. In those enzymopathies that are associated with increased REE, sequential monitoring may provide a sensitive indicator of disease progression and/or response to therapeutic interventions. This would be particularly valuable in those disorders that are slowly progressive and/or difficult to follow in a quantitative manner with currently available testing procedures. ACKNOWLEDGMENT
The authors thank the members of the Divisions of Adult and Pediatric Cardiology for assessing cardiac output.
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METABOLIC RATE IN GAUCHER DISEASE
indirect calorimetry system for the assessment of resting energy expenditure. JPEN 845-481984 9. Swaminathan R, King RFGJ, Holmfield J, et al: Thermic effect of feeding carbohydrate, fat, protein and mixed meal in lean and obese subjects. Am J Clin Nutr 42:177-181, 1985 10. de Weir JB: New Methods for calculating metabolic rate with special reference to protein metabolism. J Physiol 109:1-9,1949 Il. Roza AM, Shizgal HM: The Harris Benedict equation reevaluated: Resting energy requirements and body cell mass. Am J Clin Nutr 40:168-182, 1984 12. Grabowski GA, Dinur T, Gatt S, et al: Gaucher type 1 (Askenzai) disease: A new method for heterozygote detection using a novel fluorescent natural substrate. Clin Chim Acta 124:123-135, 1982 13. Grabowski GA, Goldblatt J, Dinur T, et al: Genetic heterogeneity in Gaucher disease: Physicokinetic and immunologic studies of the residual enzyme in cultured fibroblasts from non-neuronopathic and neuronopathic patients. Am J Med Genet 21:529-549, 1985 14. Assman G, Fredrickson DS: Acid lipase deficiency: Wolman’s disease and cholesteryl ester storage disease, in Stanbury JB, Wyngarrden JB, Fredrickson DS, et al (eds): The Metabolic Basis of Inherited Disease (ed 5). New York, NY, McGraw-Hill, 1983, pp 803-819 15. McKusick VA, Neufeld EF: The mucopolysaccharide storage
1243
diseases, in Stanbury JB, Wyngarrden JB, Fredrickson DS, et al (eds): The Metabolic Basis of Inherited Disease (ed 5). New York, NY, McGraw-Hill, 1983, pp 751-777 16. Frisancho AR: New norms of upper limb fat and muscle areas for assessment of nutritional status. Am J Clin Nutr 34:2540-2545, 1981 17. Hamill PVV, Drizd TA, Johnson CL, et al: Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr 32:607-629,1979 18. Metropolitan Life: 1983 Metropolitan height and weight tables. New York, NY, Metropolitan Life Insurance Co, 1983 19. Bar-Maor JA, Gorvin-Yehudain J: Partial splenectomy in children with Gaucher’s disease. Pediatrics 76:398-401, 1985 20. Field J, Belding HS, Martin AW: An analysis of the relation between basal metabolism and summated tissue respiration in the rat. J Cell Comp Physiol 14:143-157, 1939 21. Holliday MA, Potter D, Bearg S: The relation of metabolic rate to body weight and organ size. Pediatr Res 1:185-195.1967 22. Gery I, Zigler JS Jr, Brady RO, et al: Selective effects of glucocerebroside (Gaucher’s storage material) on macrophage cultures. J Clin Invest 68:1182-l 189,198l 23. Rose JS, Grabowski GA, Barnett S, et al: Accelerated skeletal deterioration after splenectomy in Gaucher type 1 disease. AJR 139:1202-1204,1982
Mark D. Ludman,
Keith Benkov, Gregory A. Grabowski,
and Neal S. LeLeiko
The resting energy expenditure (REE; kcal/d) of 25 patients with Gaucher’s disease type 1 was determined by indirect calorimetry. The average observed REE for the group was approximately 44% greater (P < .Ol) than that predicted (predicted REEI for these patient’s age, sex, height, and weight. The increased caloric requirements of these patients was manifested by a height-for-age less than or equal to the fifth percentile in seven of nine growing children and a muscle mass of less than the fifth percentile in 1 S of 1 g patients studied. The excess REE (observed REE - predicted REE) for individual Gaucher’s disease type 1 patients wes directly related to their liver volume as estimated from radionuolide scans and to the mass of the spleen as measured at splenectomy. The relationship between spleen mass and excess REE was demonstrated by an average 22.0% decrease in REE following splenectomy in five patients. Based on these data, the metabolic rate of the splenic tissue removed from the patients was calculated to be 96.8 kcal/d/kg, about twofold to threefold less than that of normal splenic tissue. These findings indicate that the elevated REE observed in these patients resulted from the large mass of Gaucher’s cells, which although individually hypometabolic, were cumulatively an excessive metabolic burden. Furthermore, they suggest that indirect calorimetry may be a quantitative tool for measuring disease progression and the effect of therapeutic intervention in Gaucher’s disease type 1. Q 1989 by W.S. Saunders Company.
G
AUCHER’S DISEASE TYPE 1 (nonneuronopathic) is the most prevalent lysosomal storage disease’ and the most prevalent genetic disease in the Ashkenazi Jewish population.2 This autosomal recessive disorder of glycosphingolipid metabolism results from the defective activity of the lysosomal hydrolase, acid j3-glucosidase (EC 3.2.1.45).‘S3The accumulation of this enzyme’s major substrate, glucosyl ceramide, within monocyte/macrophage derived cells (Gaucher’s cells) leads to the clinical manifestations including hepatosplenomegaly, hypersplenism, and skeletal disease.’ The metabolic consequences of the accumulation of these Gaucher’s cells in the viscera remain unknown. Until recently, it has been difficult to routinely determine the metabolic rate of a patient in the typical hospital setting. Estimates of daily resting energy expenditure (REE) of adults are generally made using the Harris-Benedict equation, a formula derived from the multiple regression analysis (age/sex/height/weight) of indirect calorimetric measurements of basal metabolic rates in healthy adults.4 Estimates of the daily energy expenditure of children can be made using
the tables developed by Benedict and Talbot5 who determined the sex and weight dependence of REE of children using indirect calorimetry. The introduction of automated devices to perform indirect calorimetry6*’ has made actual determinations of REE both rapid and accurate.8.9 After standardization against known volumes and gas concentrations, these devices determine oxygen consumption and carbon dioxide production by continuously measuring the flow rate and concentration of these gases in inspired and expired gas samples. Application of the Weir equation” permits the calculation of the REE and respiratory quotient (RQ) from these measurements. When performed preprandially, in the morning, the measured REE correlates well with the basal metabolic rate.” In this report, indirect calorimetry was used to determine the REE of 25 patients with Gaucher’s disease type 1. The increased REE in these patients was correlated with the degree of hepatosplenomegaly. In five paitents who underwent splenectomy, the change in the observed REE was correlated with the mass of Gaucher’s cells removed. MATERIALS AND METHODS
From the Department of Pediatrics, Division of Gastroenterology and Clinical Nutrition, and Division of Medical and Molecular Genetics, Mount Sinai School of Medicine, New York, NY. Supported by grants from the Heckscher Foundation for Children, a General Clinical Research Center grant from the National Institutes of Health (NIH) Division of Research Resources (RR71). the NIH (ROI-DK26729). the March of Dimes Birth Defects Foundation (l-857). the UJAjFederation of Jewish Philanthropies, the National Gaucher Foundation (NGF no. 19). and a grant from Florence and Theodore Baumritter to the Mount Sinai Center for Jewish Genetic Diseases. Gregory A. Grabowski is the recipient of an NIH Research Career Development Award (KOQ-DKOI351) and an Irma T. Hirsch1 Career Scientist Award. Mark D. Ludman is the recipient of a General Clinical Research Center Clinical Associate Physician Award (RR00071-25Sl). Address reprint requests to Neal S. LeLeiko, MD, PhD, Division of Pediatric Gastroenterology, Mount Sinai Medical Center, One Gustave Levy Place, New York, NY 10029. o 1989 by W.B. Saunders Company. 0026-0495/89/3812-0016$3.00/O 1230
Patient Population
Twenty-five patients (ages 7 to 66 years) with enzymatically confirmed Gaucher’s disease”,” were admitted to the Mount Sinai Hospital General Clinical Research Center. Patients were selected only by their willingness to participate in these studies; no patients were excluded. Informed consent and assent of children were obtained in accordance with the Mount Sinai Institutional Review Board and National Institutes of Health guidelines. Histories and physical examinations as well as routine blood studies, including liver function tests, revealed no other chronic or acute diseases in these patients. None of these Gaucher’s disease type 1 patients had evidence of central nervous sytem involvement or recent infarction of liver, spleen, or bone. The cardiac outputs of all 25 patients were normal as estimated from measurements of the heart rate and the ejection fraction measured using echocardiography. Fourteen patients were female. Eighteen patients were of Ashkenazi Jewish descent. All patients were euthyroid and all children had normal growth hormone studies. Two patients with other lysosomal storage diseases were used as disease controls, a lo-year-old girl with Metabolism, Vol38,
No 12 (December), 1989: pp 1238-l
243
1239
massive hepatosplenomegaly as a result of cholesteryl ester storage diseaseI and a 17-year-old boy with massive hepatomegaly as a result of mucopolysaccharidosis type II, Hunter syndrome,15 who had undergone splenectomy 10 years before. In addition, calorimetry was performed on 92 control individuals, 64 children and 28 adults. These controls were either healthy outpatient volunteers or inpatients who had been admitted for elective procedures or had recovered from acute illness.
Estimation of Liver Volume and Splenic Weight Twenty-one of the 25 Gaucher’s disease type 1 patients had technetium-99m-sulfur colloid liver/spleen scans. The linear dimensions of the livers were determined by measuring the organ images on both a PA and LAO projection, relative to a standard taped to the patient’s abdominal wall. Liver volumes were estimated to be one fourth that of a rectilinear prism, calculated as abc/4, where a is the liver height, b is the maximum liver width on PA projection, and c is the maximum liver width on LAO projection. Splenic weight (mass) was measured in five patients who underwent partial or total splenectomy.
Nutritional Status and REE determinations The midarm circumference and triceps skinfold thickness were determined on the nondominant arm using a flexible steei tape and a Lange Skinfold Caliper (Cambridge Scientific Industries, Cambridge, MD), respectively. These measurements were used to estimate each patient’s midarm fat and muscle mass relative to data published for age- and sex-matched normals.‘6 Ideal body weights for children” and adults’s were determined from published standards. Caloric intake for each patient was estimated from observed intake while on the General Clinical Research Center or from a 3-day diet diary. The predicted REE was calculated for adults from the Harris Benedict equation: whereas for children with weights less than 38 kg, it was estimated from the data of Benedict and Talbot.’ The observed REE was determined preprandially by indirect calorimetry (Horizon Metabolic Cart; Sensormedics, Anaheim, CA) using a flow-through head box. Before each study the calorimeter was calibrated against room temperature, a volume standard, and both calibration (20% 0,/0.75% CO,) and zero (100% NJ gases. To further compensate for sensor errors, the oxygen and carbon dioxide concentrations of the inspired room air were determined before each study. Prior to initiating data collection, the flow rate of room air circulating through the head box was adjusted to maintain a steady state carbon dioxide concentration of approximately 0.75%. During the study the steady state expired air was analyzed continuously for at least 20 minutes while the patient rested quietly in a darkened room maintained at 22OC.
Splenectomy The REE was determined in five patients (patients 3, 8, 13, 18, and 21) before and after splenectomy. The indication for surgery in each patient was severe persistent thrombocytopenia (<30,000/ mm’). The three adults (patients 13, 18, and 21) underwent total splenectomies and the two children (patients 3 and 8) had partial (-90%) splenectomies.‘9 All patients had uncomplicated operative and postoperative courses. The observed REE of each patient was determined on the day prior to surgery. Postsplenectomy REE determinations were made about 2 weeks after surgery, on the day of discharge from the hospital (patients 8, 13, and 21), or about 2 months after surgery (patients 3, 13, and 18). Patients 1, 10, 16, 17, and 20 had splenectomies from 6 months to 5 years before entering the study; no presplenectomy REE values were available for these patients.
Statistical Analyses Statistical analyses were performed on an IBM PC. Best-fit lines were determined using unweighted linear regression analyses evaluated by the method of least squares and 95% confidence limits calculated for each fitted line. Correlations were computed using Pearson’s product correlation coefficient (Statfast Statistical Package; Statsoft, Tulsa, OK). Significance (P values) for group comparisons was determined using the independent Student’s t test. RESULTS
Evaluation of Nutritional Status Table 1 summarizes the anthropometric characteristics of the 25 Gaucher’s disease type 1 patients. Weights were appropriate for height except for patient 25, who was overweight, and patients 14, 15, 16, 18, and 21, who were underweight. Seven of the nine children younger than 14 years were on or below the fifth percentile for height (patients 3 to 9). As estimated from triceps skinfold thicknesses and midarm circumferences, midarm muscle masses were below the fifth percentile in 15 of 19 patients and midarm fat masses were at or below the fifth percentile in six of 19 patients. In the presplenectomy patient population, the predicted REE ranged from 855 to 1,590 kcal/d (Table 1). By history, the weights of our adult patients were relatively constant, and the muscle and fat compartments were generally low. In the postsplenectomy patient population the predicted REE determined using postsplenectomy weights, ranged from 839 to 1,623 kcal/d.
Determination of Excess REE The observed REE (OREE) exceeded the predicted REE (PREE) in all presplenectomy patients (OREE - PREE). Because there is a wide variation in the predicted REE in this population, a method was sought to normalize the data for the purpose of comparison. By determining the ratio of the observed to the predicted REE for each patient, the relative increase of the observed REE over that predicted was determined. In a healthy population, the mean value of this ratio should be 1; the Harris-Benedict equation has been shown to accurately predict the REE in normals with a precision of 14% at the 95% confidence level.” To validate this method in our own control population, this ratio was determined and plotted as shown in Fig 1A. The mean ratio of 1.05 (SD = 0.17) does not significantly differ (P > .I) from that expected (1.0). In Fig 1B the OREE/PREE ratio for the presplenectomy Gaucher’s disease type 1 patients is shown. The average OREE/PREE of the presplenectomy patient group was 1.44 (SD = 0.19), which was significantly greater (P < .Ol) than that of our control population. The OREE/PREE ratios were unrelated to the age (P > .I) or sex (P > .5) of the patients. Correlation of Organ Involvement and REE Spleen and liver enlargement varied among the Gaucher’s disease type 1 patients, but organomegaly was present in all. To determine the effect of this organomegaly on metabolic rate, the excess REE (OREE - PREE) of each patient was correlated with the estimated volume of each patient’s liver
1240
BARTON ET AL
Table 1. Patient Characteristics Ideal
Patient NO.
sex
Ethnicity
Age (Yr)
Height kd
Weight* (kg)
Presplenectomy Weight (kg)
P REE (kcal/dl
-
Postsplenectomy Weight (kg)
P REE (kcal/d)
19.3
839
CEllOfic Intaket (kcal/d)
1
M
7
119
21.8
-
2
F
7
122
22.5
22.3
862
3
M
AJ
8
112
19.1
21.4
895
4
F
AJ
8
117
20.5
22.0
855
1,310 1,680
MUSCle$ 1%)
2,750
19.5
5
F
Ir/lt
11
132
28.1
27.3
982
6
M
AJ
11
132
27.5
29.3
1,098
7
M
AJ
11
120
21.8
26.7
1,038
8
F
AJ
12
119
21.1
24.3
909
9
M
AJ
14
141
33.6
33.6
10
F
AJ
17
151
40.9
-
1,192 -
11
F
AJ
17
162
60.0
60.7
1,455
12
F
Hisp
20
163
59.5
54.8
1,386
13
F
It
23
173
65.0
68.4
1,499
14
M
Ir/Ge
30
180
71.8
60.5
1,590
15
F
Gr
31
139
60.9
52.5
1,274
16
F
157
53.2
-
46
156
55.9
-
-
42.3
F
Aj It
33
17
52.7
18
M
AJ
48
170
87.3
68.2
1,535
57.3
19
F
AJ
49
160
57.7
53.2
1,228
20
M
AJ
51
178
71.4
-
-
73.8
21
M
AJ
52
168
85.0
52.3
1,272
45.0
22
F
AJ
54
159
61.4
83.8
1,305
23
M
AJ
57
174
68.6
89.1
24
M
AJ
63
178
69.5
70.9
25
F
AJ
66
165
60.9
84.1
847
2,510
21.0
830
1,520 -
Fat$ (%I
<5 -
t5 -
t5 -
t5 -
-
-
<5
lo-25
<5
-5
<5
1O-25
-
<5
5-10
2,250 3,400
<5 -
75-90 -
2,080
5-10
t5
3,000
<5
<5
<5
25-50
1,196
2,030 -
<5
lo-25
1,225
-
<5
lo-25
1,380
3,720
<5
-5
1,510
<5
5-10
1,623
2,050
-25
25-50
1,172
2,200
<5 25-50
25-50
1,501
1,950 -
<5
50-75
1,489
2,210
1,456
-
90-95 -
lo-25 -
37.3
60.5
1,211
1,441
5-10
Abbreviations: AJ, Ashkenazi Jewish; Hisp, Hispanic; Ir, Irish; It, Italian; Ge, German, Gr, Greek. l
Ideal weight expressed for patients less than 20 years old as the 50% weight for height15 and for adults as the average weight for height and frame.”
tCaloric intakes were determioned either from J-day diet diaries or observed intakes while hospitalized during initial evaluation. SMidarm muscle mess percentile (muscle) and midarm fat mess percentile (fat) determined from age/sex matched controls14 for presplenectomy observations. Postsplenectomy observations were determined only when available.
and, in those patients who had a splenectomy, the weight of the spleen. This relationship is shown in Fig 2A for splenic weight and in Fig 2B for liver volume, respectively. Excess REE was related directly to spleen weight (Table 2) (r = .9 1, P < .05) and liver volume (Table 3) (r = .78, P < .005). The patient with cholesteryl ester storage disease was found to have an excess REE of only 90 kcal/d [PREE = 1047, (OREE)/(PREE) = 1.091 despite marked hepatosple-
14 -
nomegaly. The patient with Hunter syndrome had an excess REE of only 58 kcal/d [PREE = 958, OREE/PREE = 1.061 despite marked hepatomegaly. Effect of Splenectomy on REE
The observed REE decreased in all patients following splenectomy (Table 2). The decrease in REE corresponded to an average of 445 + 197 kcal/d, or about 22.0%. The
‘: 12z ; IOd
7P E6 % 5i=
b
8- -
“04
= 6% I4z 2-
23 g21
A,+
0 0.5
0.7
0.9
I.1
(Ohs REE)/(Pred
1.3 REE)
1.5 RATIO
1.7
1.9
BL
0 (Ohs REE)/(Prad
REE)
RATIO
Fig 1. Frequency distributionof the ratios of OREE/PREE. The distributions for a control population (A) (mean rt SD, 1.06 f 0.17) and for the Gaucher’s disease type 1 population (1.44 f 0.19) before aplenectomy (8). The bell-ehaped curve in each figure represents the distribution obtained from the control population shown in (AI.
1241
METABOLIC RATE IN GAUCHER DISEASE
600 400 E
200 An
z
“0
4
2
6
0
2c10 8 10 0
‘0
AC
I
I
600
WEIGHT OF REMOVED SPLEEN (kg)
I
I
I
1200 LIVER
I
I
I
1800
I
I 2400
I
I
VOLUME ICC)
Fig 2. Correlation of excess ME and spkmic mass (A) and liver volume (B). The correlation between excess REE and the splenic mass (A) (mesrured as wrdght of spleen surgkxlly removed) and the correlation between excess REE and liver volwno (B) (measured by radionuclide scan) from Gauchw’s disease type 1 patients were significant (r = .Sl. P < .06 and r = .78, P c .Ol; reapectivdy). The solid lines represent linear regression of the data by the method of least squares. and the broken lines represent the 96% confidence limits.
average weights of the splenic tissue removed from these patients was 4.46 + 1.84 kg, which represented 10.3% k 2.7% of their respective preoperative body weight (Table 2). As shown in Table 2, the metabolic rate of the removed spleens (96.8 + 36.6 kcal/d/kg) was estimated from the weight of the excised splenic tissue and the changes in OREE following splenectomy. DISCUSSION
In this study indirect calorimetry was used to demonstrate that patients with Gaucher’s disease type 1 have an elevated REE. The degree of increase in REE was directly related to the extent of hepatosplenomegaly in the affected patients and apparently was specific for Gaucher’s disease type 1 because the patients with cholesteryl ester storage disease and Hunter syndrome did not have significantly increased REE despite massive organomegaly. Because the excess REE decreased in relation to the mass of spleen removed at surgery, this study suggests that the increased REE in Gaucher’s disease patients may be the result of the accumulation of Gaucher’s cells and, thereby, provide an indirect assessment of the accumulation of Gaucher’s cells in individual patients. Previous studies have shown that the metabolic rates of animal organs perfused in vitro” and human organs perfused in viva” were a function of their specific tissue type and their total mass. Thus, it is not unexpected that the total body
energy expenditure in Gaucher’s disease type 1 patients would be elevated due to the increased size (and mass) of their livers and spleens. However, the finding that the metabolic rate of the removed spleens was only 96.8 + 36.6 kcal/d/kg of splenic tissue (Table 2) was unexpected. The metabolic rate of normal human splanchnic tissue (ie, liver and spleen) is approximately 350 kcal/d/kg and that of lung, another part of the reticuloendothelial system, about 200 kcal/d/kg.2’ In comparison, the metabolic rate of the splenic tissue removed from the Gaucher’s disease type 1 patients was about twofold to threefold decreased compared with these normal splanchnic tissues. Because pathologic examination of the removed spleens from these patients revealed massive accumulation of Gaucher’s cells in the presence of normal stroma and few significant areas of infarction, the decreased calculated metabolic rate of the splenic tissue from these patients cannot be ascribed to large amounts of nonviable tissue. Because exogenously supplied glucosyl ceramide had no effect on cultured fibroblasts or cells other than macrophages,22 it is reasonable to assume that the splenic stromal cells may have normal metabolic requirements. Consequently, the decreased metabolic rate of the splenic tissue removed from the Gaucher’s disease patients was likely due to the large mass of Gaucher’s cells that individually were hypometabolic, ie, the caloric consumption of each Gaucher’s cell was decreased. However, because of
Table 2. Effect of Splenectomy on REE
pstlmt NO.
Spleen weight* (kg)
(% BWI
OREE Preoperative (kcsl/d)
Postoperative (kcal/d)
A REE (kcal/d)
(%I
A REE/ kQ!Wean (kceVd/ka)
3
3.14
(14.7%)
1,528
1,105
-423
(-27.7%)
134.9
8
2.61
(10.6%)
1,481
1,182
-299
(-20.2%)
114.6
13
5.80
18.7%)
2,358
1.826
-532
(-22.6%)
91.7
18
7.40
(10.9%)
2,754
1,983
-771
(-28.0%)
104.2
1,765
1,563
-202
(-11.4%)
37.6
-445
(-22.0%)
21
3.35
(6.4%)
Mean
4.46
(10.3%)
SD
1.84
*Spleen weights were determined from pathology specimens.
197
96.8 36.6
1242
BARTON
Table3. ExcessREEandLiverlnvolvement Liver Volume* ImL)
OREE (kcal/d)
OREE-PREE (kcal/d)
OREE/PREE
1
2,511
1,524
685
1.82
2
329
1,438
576
1.67 1.71
1,126 -
1,528
632
1,395
540
1.63
1,207
224
1.23
6
724 -
1,255
157
1.14
7
-
1,620
582
1.56
6
819
1,481
572
1.83
3 4 5
9
934
1,657
465
1.39
10
3,172
1,654
443
1.36
11
1,027
2,142
687
1.47
12
795
1,901
515
1.37
13
1,639
2,358
859
1.57
14
1,882
2,117
527
1.33
15
1,414
1,788
514
1.40
16
3,960
1,690
494
1.41
17
1,077
1,825
600
1.49
18
2,422
2,754
1,220
1.79
19
1,382
1,646
418
1.34
20
2,233
1,836
213
1.13
21
800
1.765
493
1.39
22
1,361
1,621
316
1.24
23
569
1,634
133
1.09
24
803
2,018
529
1.36
25
1,640
2,135
679
1.47
*Livervolume calculated from technetium-99m-sulfur colloid images.
the greatly increased numbers of these cells, the total caloric consumption (kcal/d) of the spleens from these patients was increased. Other explanations for the observed increase in REE may be considered but are less likely given the available data. Because the liver is a metabolically active organ, these patients could have had underlying hepatic dysfunction as a result of infiltration of the liver by Gaucher’s cells. However, as noted, none of the patients had clinical or enzymatic evidence of liver dysfunction. Also, blood sequestered in the enlarged livers and spleens might increase a patient’s blood volume and therefore increase the metabolic demands by increasing cardiac output. However, examination of all patients by echocardiography revealed normal cardiac outputs. Finally, the Harris-Benedict equation may underestimate the REE in cachectic paients with depleted fat stores”
ETAL
by as much as 18% to 20%. This is the result of the disproportionate loss of metabolically less active adipose tissue relative to lean body mass. The metabolic rates of our patients far exceeded this, having been increased by 44%. Moreover, although our patients tended to decrease lean body mass and fat stores, they were not depleted to the extent necessary to account for even the discrepancy postulated for cachectic patients. Regardless of the actual cause, it is evident from the anthropometric data that the increased REE of the Gaucher’s disease type I patients had a significant impact on their nutritional status. The effect of the increased REE in Gaucher’s disease type 1 patients is manifested by decreased muscle mass and linear growth. Muscle mass was determined to be below the fifth percentile in all but four patients in this study (patients 13, 20, 22, and 24). In addition, seven of nine children in this study had linear growth retardation. Two of these children (patients 3 and 8) required splenectomy and have been followed for 6 and 14 months, respectively. During this time they have experienced catch-up growth of 1.5 and 4 inches, respectively, coincident with their decreased REE. These results are consistent with the increased REE being the cause of their growth retardation. The potential for acceleration of destructive Gaucher’s bony disease23 as well as concern regarding increased susceptibility to infection following splenectomy suggests that in the absence of hematologic or other indications, growth retardation in affected children should not be treated by splenectomy. In specific Gaucher’s disease type 1 patients, nutritional supplementation might be used to treat or prevent linear growth regardation prior to splenectomy. The present study indicates the potential use of indirect calorimetry as an investigative tool for studying inborn errors of metabolism. In those enzymopathies that are associated with increased REE, sequential monitoring may provide a sensitive indicator of disease progression and/or response to therapeutic interventions. This would be particularly valuable in those disorders that are slowly progressive and/or difficult to follow in a quantitative manner with currently available testing procedures. ACKNOWLEDGMENT
The authors thank the members of the Divisions of Adult and Pediatric Cardiology for assessing cardiac output.
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