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Clinical and metabolic studies of chemically defined diets in the management of obesity
Clinical and Metabolic Studies of Chemically Defined Diets in the Management of Obesity I. McLean Baird, R. L. Parsons, and A. N. Howard Five severely obese subjects were treated for up to 1 yr, under metabolic study, with chemically defined diets of 60-360 kcal containing appropriate L-amino acids (or protein), carbohydrates, vitamins, and minerals. Acceptance of the diets was excellent, and the patients rarely complained of hunger. The optimum daily formulation contained 15 g amino acids and 3 0 - 4 5 g carbohydrate which achieved nitrogen balance, only moderate ketosis, normal serum electrolytes and uric acid,
and a mean weight loss of 4.1 Ib ( 1.8 kg) / week. Clinical abnormalities observed were alopecia, symptomless normochromic anemia, postural hypotension, and hypercholesterolemia. All these findings reverted to normal subsequentto resuming a normal diet. Low-calorie, chemically defined diets of approximately 6 0 - 3 6 0 kcal offer an acceptable and safer form of weight reduction than complete starvation in the severe and refractory obese patient.
OTAL STARVATION was advocated in the management of "refractory" obesity when other methods failed, and early reports were enthusiastic. 6'"'~4 However, there are doubts concerning the safety of prolonged starvation as well as its long-term usefulness. ~9 Garnett ~3 reported the death of a 20-yr-old girl who underwent starvation for 30 wk, and autopsy showed histologic loss and fragmentation of the myofibrils of the myocardium. Spencer 23 and Kahan16 described cardiac deaths due to inappropriate fasting. Similar fatalities have occurred in a diabetic with lactic acidosis, 7 and fatal acute volvulus has been described?~ The loss of lean body massl-3 during starvation may be as great as the loss from the fat depots, and electrocardiographic changes suggestive of decreased heart size have been reported. 17 The loss of body protein can be corrected by the addition of 40 60 g of egg albumin daily.4 One object of the present work is to provide a long-term low-calorie regime containing either mixtures of L-amino acids, or whole protein to correct this loss of lean body mass and avoid changes caused by negative nitrogen balance in total starvation. After 24 hr of fasting, obese subjects usually no longer complain of hunger. 6 The suppression of appetite is thought to be due to ketosis from carbohydrate deprivation. However, Silverstone et al. 22 found that obese patients on complete fasting were equally hungry as when taking a low-calorie diet with sufficient carbohydrate to abolish ketonuria. The relationship between blood and urinary ketones and appetite was examined in the present study. The purpose of the present work was to determine the acceptability of chemically defined diets in long-term weight reduction of severely obese patients; the
T
From the West Middlesex Hospital, Isleworth, Middlesex, and Department of Investigative Medicine, University of Cambridge, Cambridge, England. Received for publication December 3, 1973. Reprint requests should be addressed to Dr. I. McLean Baird, West Middlesex Hospital, Isleworth, Middlesex, England. 9 1974 by Grune & Stratton, Inc. Metabolism, Vol. 23, No. 7 (July), 1974
645
646
BAIRD, PARSONS, AND HOWARD
Table 1. Weight Losses of Patients on Different Diets (Weight Loss Ib (kg)/wk)
Case No.
Age (yr)
1
39
Study period Sex (wk) F
Initial Discharge Weight Weight
Chemically Hospital Defined Diet Diet (800 kcal) (900kcal) Starvation
Chemically Defined Diet (Carbohydrate g/day) O* 30180~
51
322
168
2.0
5.5
9.5
3.5
4.0
1.5
(146) 266
(76) 152
(0.9) 3.0
(2.4) 5.0
(4.2) 7.0
(1.6) 5.0
(1.8) 5.0
(0.6) 4.0
(121)
(69)
(1.3)
(2.3)
(3.2)
(2.3)
( 2 . 3 ) (1.8)
220
149
2.0
4.5
6.5
3.5
3.5
2.5
(100)
(68)
(0.9)
(2.0}
(2.9)
(1.6)
0.6)
(1.0)
325 (147) 336
209 (95) 254
4.0 (1.8) 4.0
5.0 (2.3) 4.0
11.5 (5.1) 13.0
6.5 (2.9) 3.7
5.1 (2.3) 3.0
5.5 (2.4) 0.5
(152)
(115)
(1.8)
(1.8)
(5.9)
(1.6)
(1.3) (0.1)
294 (133)
186 (84)
3.0 (1.3)
4.8 (2.0)
9.5 (4.2)
4.4 (2.0)
4.1 (1.8)
2
24
F
30
3
36
F
26
4
21
M
21
5
57
F
30
Mean Ib (kg)
2.8 (1.1)
* + 3 0 g/day amino acids; 120 kcal. 1"+15 g/day amino acids; 180 kcal. 515 g/day amino acids; 380 kcal.
minimum intake of appropriate L-amino acids necessary to maintain positive nitrogen balance; and the minimum intake of carbohydrate to abolish ketosis. Chemically defined diets containing essential vitamins and minerals are compared with total starvation, and with conventional low-calorie hospital diets. EXPERIMENTAL
DESIGN
AND
METHODS
Patients Four female and one male obese subjects who were more than 30% above the mean desirable weight of the Metropolitan Life Tables s were studied as inpatients for 21 52 wk (Table 1). All five patients had a normal 50-g glucose tolerance test, the 2-hr blood sugar being less than 140 mg/ 100 ml. Pretreatment weights ranged from 220-336 lbs (Table 1). The patients were selected by long history of failure to respond to conventional outpatient methods of caloric restriction. Two patients (cases 1 and 2) had psychologic problems. One patient had a history of pulmonary infarction, venous thrombosis, and lymphoedema of both legs. All were strongly motivated to undergo inpatient treatment and participate in the metabolic study. They strictly adhered to the diets, with the exception of two meals only. The patients were ambulatory and were permitted normal exercise within the hospital, except during the starvation period. Occasional weekend visits home were allowed after the first 10 wk for patients 2, 3 and 4 who lived near the hospital. This was beneficial psychologically and there was no evidence of deviation from the dietary regimes as judged by the degree of ketonuria or weight loss.
Clinical Examinations There was an initial full clinical examination and a record kept twice daily of weights, blood pressure, and "hunger ratings ''22 at 10 a.m. and 4 p.m. There was a complete 24-hr urine collection, and the number of stools was recorded. Twelve-lead electrocardiograms were performed twice weekly. The urinary ketones were measured daily by the ketostix test.
Laboratory Measurements Urine. The aliquots from the 24-hr total urinary collection were kept and the weekly excretion of total nitrogen was estimated by the Kjedahl method. Feces were very infrequent, and fecal nitrogen loss was considered insignificant. Nitrogen balance was calculated at levels of dietary
CHEMICALLY DEFINED DIETS IN OBESITY MANAGEMENT
647
Table 2. Sequence of Diets
Period
Diet
Kcal
Length of Studies (wk)
1 2
Hospital diet Standard chemically defined diet (Vivonex) Starvation Mixtures of L-amino acids and carbohydrate Mixtures of proteins and carbohydrate Hospital diet
800 900
2 2
0 60-360
2 12-42
180-200
4-10
3 4 5 6
800
2-4
amino acids of 15, 20, 30, 40, 45, 60, and 80 g/day. The estimated nitrogen balance was the urinary nitrogen excretion per day when the amino acid intake was just sufficient to give a positive nitrogen retention. Values were expressed as g/day amino acid mixture (N content, 14.1 g/100 g). Urinary urea, potassium, sodium, calcium, and creatinine was analyzed by conventional AutoAnalyzer (Technicon Instruments Corp., Tarrytown, N.Y.) methods. Blood. Samples were taken once weekly for blood and serum. The hematocrit, hemoglobin, and total and differential white cell count were measured once weekly. Bone marrow aspirate was examined in two patients. Serum. Albumin, globulin, and electrophoresis of proteins, potassium, sodium, calcium, iron, protein-bound iodine, inorganic phosphate, bilirubin, SGPT, SGOT, HBD, enzymes, creatinine, urea, uric acid, glucose, and cholesterol were estimated weekly and serum ketones every 2 wk by conventional laboratory methods.
Diets Dietary periods lasted 14 days and were chosen according to a predetermined sequence (Table 2). A conventional 800-kcal hospital diet prepared by the dietician was given for 2-4 wk to establish a steady state. This contained 60 g protein, 100 g carbohydrate, and 20 g fat. A standard liquid, chemically defined diet* containing 900 kcal comprised of 40 g appropriate amino acids, 180 g carbohydrate, and 1 g fat was given three times dailyat meal times for 2 wk. Subsequently, patients had total starvation with mineral and vitamin supplements three times daily for 2 wk. Water intake was unlimited. Different combinations of an amino acid mixture and carbohydrate were then given at two weekly intervals for the rest of the study to determine (1) the amino acid requirements for nitrogen balance and (2) the carbohydrate necessary for abolition of ketosis. The amino acid mixture contained essential and nonessential amino acids in the optimum proportions (Table 3), as suggested by Winitz et al. 24 In addition to water, black coffee or tea and dietetic soft drinks containing 1 kcal per drink up to a maximum of 10 kcal daily were allowed. The chemically defined diet was in powder form with sufficient water added to prevent osmotic diarrhea due to a hypertonic solution. The first two patients were given in sequence the amino acid mixture in stepwise levels of 20, 30, 40 g/day without carbohydrate. The amino acid mixture was then kept at 30 g/day and the carbohydrate increased stepwise from 20 to 80 g/day. Toward the end of the experiment, four patients were also given an equivalent amount of modified milk protein (M.M.P. 1, Scottish Milk Marketing Board) with a supplement of 400 mg L-methionine or egg albumin daily. Before discharge, a low-residue 900-kcal conventional hospital diet was given for at least 2 wk. RESULTS
Acceptability of Diet All the patients studied adhered to the chemically defined diets well and were observed to cheat on only two occasions. Except when given larger quantities
*Based on ingredients contained in Vivonex, Eaton Laboratories, Norwich, N.Y.
648
BAIRD, PARSONS, AND HOWARD
Table 3. Composition of a Typical Chemically Defined Diet* Amino acid mix (15 g) Stated to contain the following g/100 g: L-tsoleucine 0.344 L-Leucine 0.544 L-Lyslne 0.408 L-Methionine 0.352 L-Phenylalanine 0.392 L-Threonine 0.344 L-Tryptophan 0.106 L-Valine 0.379 L-Alanine 0.367
L-Arginine L-Aspartic acid L-Glutamine Glycine L-Histidine L-Praline L-Serine L-Tyrosine
0.671 0.781 1.290 0.598 0.167 0.490 0.252 0.429
Zinc Chloride Phosphate Acetate Sulfate Iodide Gluconate
0.083 mg 1.037 g 0.167 g 3.06 mg 2.37 mg 0.031 mg 1.44 g
Glucose polymers (oligosaccharides) (30 g) Containing about six glucose units/polymer Salt mix (20 g) Stated to contain the following g/100 g: Sodium 0.481 g Potassium 0.440 g Calcium 0.167 g Magnesium 32.5 mg Manganese 0.585 mg Iron 2.50 mg Copper 0.404 mg
Trace elements (0.5 g) Potassium iodide 0.05 g, copper acetate monohydrate 1.40 g, zinc acetate dihydrate 0.30 g, manganous acetate 2.86, standard salt mix as above 100 g Vitamin tablet Vitamins were supplied as one capsule daily (Plurivite, Boots, containing vitamin A, 5000 units; vitamin 81 , 2 rag; vitamin 82, 2 mg; vitamin fi6, 1 rag; vitamin B12, 2 #g; nicotinomide, 20 mg; vitamin C, 50 rag; vitamin D, 400 units. Essential fatty acids One capsule containing 1 ml safflower oil was given daily to supply essential fatty acids *Provides 15 g/day amino acid, 30 g/day carbohydrate, minerals, and vitamins.
of carbohydrate, the patients were continually ketotic, indicating their strict adherence to the regime. One patient had some initial diarrhea due to using insufficient water and drinking a hypertonic solution. Otherwise, the diets were well tolerated and gave rise to no immediate side effects. Patients found the chemically defined diets preferable to starvation, when all subjects felt unwell because of postural faintness or other symptoms. One patient (case 5) complained of severe general muscular aching during starvation, which may have been caused by potassium depletion due to an increased excretion of 57 meq/24 hr. The symptoms were severe enough to terminate the period of starvation after 10 days. Symptoms remitted on a chemically defined diet containing 15 g carbohydrate and 15 g amino acids. Behavior of the Patients Two patients (cases 1 and 2) had psychologic and social problems; one patient required psychiatric consultations. However, these problems preceded
CHEMICALLY DEFINED DIETS IN OBESITY MANAGEMENT
Casein
649
30
g/day, 0 Amino Acid Intake g/day.
40
Carboh~lrate Intake g/day.
100
0
0 K Calories
1, Q(IO
p r day.
Weight
0 310
~
mS. 290
Z70
Z50 230
Zl0
190 Fig. 1. Case 1. An obese female on a chemically defined diet for 1 yr, showing the composition of the diets and the weight loss.
170
150
III11111111111111111111111
0
4
8
I
12 16 20 24 28 32 36 40 44 48 52 Weeks
hospital admission. During starvation, all patients felt weak and spent more time in bed, and had some psychologic changes, usually marked by depression, aggressiveness, or lack of concentration. On other dietary regimes patients were normal and ambulatory.
Weight Loss A summary of weight losses is shown in Table 1, and a typical result for all cases is shown in Fig. 1. The mean weight loss during starvation was 9.5 lb (4.2 kg) and was as high as 13 lb (5.9 kg) a week in one patient. Much of this could be attributed to a loss of body water, since there was a large accompanying diuresis (Fig. 2). With the chemically defined 900-kcal diet, a high mean weight loss of 5 lb (2.27 kg) was achieved. Very-low-calorie diets (120 kcal/day) gave a mean weight loss of 4.4 lb (2.0 kg) a week. Diets with relatively high carbohydrate gave evidence of fluid retention in three patients, particularly with
BAIRD, PARSONS, AND HOWARD
650
Urinary Urea
30
g./day.
20 10 0
Urine Volume mls./day
1, 5000 1,O00 5O0 0
Uric Acid mg. / }ooml. 0 Mean degree of Ketosis per day.
+3 +2 +I 0
?otassium Iodide 25On~.
Protein Bound 16 Iodine o
l~J./lOOml. 8
0 Serum
400
Cholesterol rag./100ml. 100 Casein g./day.
30 0
Amino Acids g,/day
40 0
E
h
[_
Carbohydrates 100 g,/clay
K Calories
0 1, O00 5O0 0
IIl|llllllllllllJlllllillillllllllillillllllllllil|ll
0
4
8
12 16 ~
24 28 32 36 40 44 48 52
Weeks
Fig. 2. Changes in urinary urea, urine volume, serum uric acid, and cholesterol in case 1 during 1 yr of chemically defined diets.
80 g / d a y and in some instances led to weight increases (Fig. 1). On return to a carbohydrate-free diet a diuresis and a weight loss of 7 lb (3.18 kg) a week occurred.
Hunger Patients usually lost the sensation o f hunger during the first 2 wk of the chemically defined diet with the exception of case 1, who consistently recorded high
CHEMICALLY DEFINED DIETS IN OBESITY MANAGEMENT
651
hunger ratings, associated with recurring mental images of food at irregular intervals. Hunger sensations did not reappear when the urine ketones were absent, and there was no relationship between hunger and ketosis; for example, patient 5 was extremely hungry during the period of starvation when severe ketosis was present. Most patients lost interest in food after several days on the chemically defined diet. At the end of the period of study, there was no difficulty in gradually restarting normal diet, although initially patients were only able to take small quantities of food due to easily induced satiety sensations.
Electrocardiography Two patients (cases 1 and 2) developed bradycardias of less than 60/rain. These were attributed to iodine deficiency or a hypometabolic state. However, one patient continued to have a bradycardia despite iodine supplementation, and did not return to normal until shortly before discharge. One patient with minor ischemic changes initially and the two others with normal ECG patterns were unchanged during treatment.
Side Effects General. Insomnia was not a prominent feature, but all patients ingested a hypnotic intermittently, usually nitrazepam 5-10 mg at night or butobarbitone 100-200 mg. Diazepam 5-10 mg three times daily was periodically given in three patients during episodes of anxiety, but usually for a week or two at a time. Antidepressives were not required. During the period of starvation patients were frequently unable to concentrate and sometimes appeared euphoric. This corresponded with the severe ketosis. However, while adhering to the chemically defined diets, especially those containing at least 15 g / d a y carbohydrate, all patients were able to carry out normal physical activities within the ward and appeared able to read and write and concentrate normally. One patient (case 2) carried out part-time secretarial work while under study. Hair. Changes in the hair were noted in all patients. The head hair became thin and sparse with a faint red tinge, and tended to fall out more rapidly than normally. In two patients (cases 1 and 5) considerable alopecia developed toward the end of the period of study. The hair gradually returned to normal when diet was restored to normal conventional low-calorie intake, but it took 3 mo in case 1 and 6 mo in case 5 to return to its previous appearance. Gastrointestinal. One patient (case 1) had frequent diarrhea initially. This was controlled with lomotil and codeine. Because the chemically defined diet was low in residue, bowel motions were rare and occurred at intervals as long as 4 wk in some patients. In two patients, colicky abdominal pains occurred due to impacted feces in the rectum. Five months after discharge, while an outpatient on an 800-cal conventional diet, patient 2 developed, over several weeks, frequent attacks of diarrhea. He was reinvestigated for malabsorption, but a jejunal biopsy and d-xylose excretion were within normal limits, and the diarrhea subsided spontaneously within a few weeks and was considered unrelated to the previous regimes.
652
BAIRD, PARSONS, AND HOWARD
Table 4. Hematologic Changes on Chemically Defined Diets (Case 4)
Date
Diet/Day
9.6.71
800kcal hospital diet Amino acids 15 g carbohydrate 50 g (260 kcol) Amino acids 80 g carbohydrate 10 g (360 kcal) Amino acids 30 g carbohydrate 0 g (120 kcal)
18.8.71
15.9.71
6.10.71
RBC Hemoglobin (million PCV MCHC MCV WBC Neutrophils (g/100 ml) c/mm) (%) (%) (cu cm) (cu cm) (%) (No.) Platelets/cm 17
6.0
49
32
80
8,000
54
4320
240,000
14
5.2
44
32
82
3,800
45
1710
144,000
12
4.7
40
28
85
4,000
28
1120
99,000
12
4.5
37
34
80
3,300
41
1352
90,000
Hematologic Changes All patients developed a fall in hemoglobin during the study (Table 4). The mean initial hemoglobin was 14 g/100 ml in case 4 (range, 13-17 g/100 ml) and on completion of the dietary period this fell to 11 g/100 ml (range, 10-12 g/100 ml). The PCV also fell, but MCHC and MCV remained unchanged. A fall in the total white cells and neutrophils occurred, but in no case was the total white cell count lower than 2000/cu mm. The lowest neutrophil count was 1120/ cu mm. The platelet counts showed no consistent change. There were no symptoms attributed to the anemia, and in two patients bone marrow examinations were within normal limits; in particular, there was no evidence of iron deficiency, vitamin B~2 or folate deficiency. The serum folic acid and serum vitamin B~2 levels were within normal limits. 58Co-labeled vitamin B~2 absorption was normal (40~) in one patient. In all patients, the hemoglobin and white cell count returned to normal after 3 mo on a conventional diet. No symptoms of the anemia or neutropenia occurred and there was no tendency to develop infections during the study.
Biochemical Changes Nitrogen balance. Results are summarized in Fig. 3; with a carbohydratefree diet, the amino acid intake required for nitrogen balance was about 30 g/day. If carbohydrate was added to the diet, the minimum intake of amino acid required for nitrogen balance fell to about 15 g/day. The maximum "nitrogen sparing" effect was seen with 30 g/day carbohydrate in four patients and 45 g/day carbohydrate in one patient. Some nitrogen sparing effect was seen with intakes as low as 15 g/day carbohydrate. Patients given 30 g/day carbohydrate and 20 g/day modified milk protein supplemented with 400 mg/day L-methionine, or 15 g/day egg albumin, showed nitrogen balance. Serum and urinary ketones. Starvation and a carbohydrate-free diet induced high urine and serum ketone levels (Fig. 2). Gradually increasing carbohydrate intakes from 15-80 g/day progressively decreased the serum ketone levels such that ketosis was less than 5 mg/100 ml on 80 g/day and abolished at 160 g/day of carbohydrate (Fig. 4).
653
CHEMICALLY DEFINED DIETS IN OBESITY MANAGEMENT
Carbohydrate g.lday [ ] 0 15
[] [] []
30
45 80
~, 2o
E
PATIENT 1
Fig. 3. subjects.
L 2
4
3
5
Dietary amino-acid and carbohydrate requirements for nitrogen balance in five obese
Serum uric acid. No patient had clinical gout, but four of the patients (1, 2, 3, and 5) had a high serum uric acid (> 6.5 rag/100 ml) prior to therapy, and starvation greatly increased the serum uric acid further to even higher levels. With a carbohydrate-free diet, serum uric acid was still elevated in four patients, but all patients had levels in the normal range when 30 g / d a y carbohydrate and a minimum of 15 g amino acid was given. Serum cholesterol. Synthetic low-calorie diets cause an initial fall in serum cholesterol, followed by a slow rise to hypercholesteremic levels (Fig. 2). Initially, the mean serum cholesterol was 210 rag/100 ml (range, 175-252 rag/ I
:i:i:i:i:i:i:i:i:i:i:i:i:!;i:|
•••••••••••]]••]]••••••••••••••••••••••••••••••••••
3O
Dietary Carbohydrates (g.lday)
Case No. I 80 l
Fig. 4. Serum ketones in response to carbohydrate intake from 0 - 1 6 0 g daily in five obese subjects.
"
4
"
5
160
I
0
20 Serum Kelones (mq.llOOml.) 10
I 30
654
BAIRD, PARSONS, AND HOWARD
100 ml) that fell after 10 wk to 174 mg/100 ml (range, 142-236 rag/100 ml). At 20 wk, the mean serum cholesterol had again risen to 230 mg/100 ml (range, 185-250 mg/100 ml). After 30 wk in cases 1 and 2, the serum cholesterol had risen to 290 and 260 rag/100 ml, respectively, and subsequently the serum cholesterol was 350 mg/100 ml in case 1 after 50 wk. Serum cholesterol returned to normal upon resumption of a hospital diet. Electrolytes. There was no consistent change in the serum electrolytes in the study. The serum calcium and potassium levels did not show any change during the study with one exception in one patient who had a serum potassium of 2.9 meq/liter 5 wk after the starvation period and who was given potassium supplements (two capsules of Slow K containing 16 meq of potassium three times daily). The urinary sodium and potassium excretions were usually low, but wide fluctuations were often seen. The urinary calcium output had the same pattern, usually low, but sometimes fluctuating into the low normal range. Miscellaneous estimations. The blood urea consistently fell during the period on the chemically defined diet, the lowest level recorded being 8 mg/ 100 ml in case 2. The serum bilirubin did not change except in case 4 where an initially high serum bilirubin of 1.4 rag/100 ml rose to 2.2 mg after starvation and subsequently fell to less than 1 mg/100 ml and was considered to be a Gilbert's syndrome unrelated to the study. The other liver function tests were normal in this patient. Blood glucose, serum proteins, alkaline phosphatase, iron and protein-bound iodine (PBI) showed no Consistent change except in cases 1 and 2 where a fall in PBI was due to an initial formulation omission. Case 1 developed a PBI of 1.9 ug/100 ml after 17 wk and case 2 a PBI of 2.1 #g/100 ml after 18 wk, but both these patients returned to normal PBI levels after supplemental potassium iodide (250 rag/day). There was no evidence of clinical thyroid enlargement in these two patients. DISCUSSION
Chemically defined diets were an acceptable and safe form of low-calorie regime for periods up to 1 yr under conditions of metabolic study in all five severely obese subjects. The patients felt well and able to carry out normal physical and mental activities within the limits of the hospital environment. All preferred this form of dietary restriction to starvation, which was associated with postural hypotension, muscular aches, depression, euphoria, tiredness, and other symptoms. Although the initial weight loss during starvation was high, and in the present series there was a mean weekly weight loss of 9.5 lb (4.2 kg) over 2 wk, much of this weight loss was due to an initial loss of body water and subsequent diuresis. The overall weekly weight loss over long periods of months on diets containing 60-300 kcal daily was about 4 lb/wk (1.8 kg) and is similar to that described from total starvation for a similar period. ~s High-carbohydrate diets reduced the rate of weight loss because of water retention. Positive nitrogen balance was maintained by a daily intake of 15-30 g of amino acids. There was considerable individual variation and further work is
CHEMICALLY DEFINED DIETS IN OBESITY MANAGEMENT
655
necessary to determine whether these findings are relevant to other obese individuals under conditions of more strenuous activity. Nitrogen requirements were much lower than anticipated, and it is possible that after starvation adaptation to a lower nitrogen requirement occurs. Carbohydrate (30 45 g/ day) reduced the approximate amount of amino acid intake required for positive nitrogen balance from 30 g/day to 15 g/day. Ketosis did not correlate with appetite suppression and, this supports the work of Silverstone et a l . 22 Thus, there is no need to achieve high levels of ketones to obtain anorexia, and starvation offers no advantages in this respect. The severe ketosis seen in total starvation was associated with depression and other psychologic changes but the addition of as little as 15 g/day carbohydrate greatly reduced urinary and serum ketones and also led to a remarkable change in the mood of the patient, who became less aggressive and less depressed. Increasing carbohydrate up to 80 g / d a y abolished ketosis in four of the five patients, a finding that is consistent with other authors. 8 The hyperuricemia of starvation can lead to clinical gout ~~ and represents a hazard of prolonged starvation. Patients treated with the chemically defined diet containing at least 30 g / d a y carbohydrate had normal serum uric acid levels. It is noteworthy that the pretreatmerlt hyperuricemia was reduced to normal in all four cases on prolonged chemically defined diets (Table 5). The optimum composition for a chemically defined reducing diet consistent with good weight loss and well being is 15 g / d a y amino acids in the required proportions, and 30-45 g / d a y carbohydrate. This represents 180-240 kcal/ day. While good results were obtained with 30 g / d a y amino acids alone, the inclusion of a small amount of carbohydrate reduced ketosis to a more moderate level, returned the serum uric acid to normal and reduced the amino acid requirement by one half. Ketosis could be abolished by using 80 g / d a y carbohydrate, but this led to fluid retention in some cases. A high degree of ketosis produces some psychologic disturbances, but there is no evidence from the present study that moderate levels of serum ketones are harmful. In most of the present experimental work a mixture of L-amino was used. Proteins of high biologic value have been substituted with similar results. Two of the patients were given a chemically defined diet containing 15 g egg albumin and 30 g carbohydrate for up to 10 wk with identical results. Such less expensive compositions could be used for the routine treatment of refractory obese patients. The present study confirms the work of Bollinger et al. 4 that Table 5. Effect of Carbohydrate Intake on Serum Uric Acid Levels ( m g / l O 0 ml)
Patient
Hospital Diet (800 kcal)
Chemically Defined Diet (900 kcal)
Chemically Defined Diet Carbohydrate g/day 0 15 30 80
Starvation
1 2 3 4 5
9.4 8.2 6.5 4.6 6.7
5.9 5.2 5.6 4.6 5.8
13.7 14.0 7.4 8.5 10.3
9.1 7.9 6.1 7.4 150
8.0 6.3 5.9 7.1 8.5
3.6 6.0 4.0 6.3 6.3
4.7 7.0 4.0 6.2 5.0
Mean
7.1
5.4
10.8
8.1
7.2
5.2
5.4
656
BAIRD, PARSONS, AND HOWARD
the loss of body protein can be corrected by albumin, but our findings suggest that much lower amounts are needed in the presence of carbohydrates for nitrogen balance. Other hazards o f starvation such as h y p o n a t r e m i a and hypokalemia were not a feature of prolonged treatment with chemically defined diets. Urinary potassium was initially high during starvation and then settled at lower levels, confirming previous reports. 2~ Such potassium loss is thought to be due to increased gluconeogenesis utilizing lean body mass, ~2 followed by a period of conservation. Urinary excretion of sodium, potassium and calcium were consistently low with the chemically defined diets and serum electrolyte levels usually normal. The long-term use of chemically defined diets had some disadvantages. Changes in the hair may have been due to insufficient essential fatty acids, since similar changes have been observed with normal subjects on 1800-kcal chemically defined diets, and these can be corrected by increasing the safflower oil content to 3.5 g / d a y . 9 The n o r m o c h r o m i c anemia has been previously described, ~8 and there was also an unexplained neutropenia. N o s y m p t o m s occurred due to the hematologic changes. A gradual rise in the serum cholesterol after 20 wk synthetic diet may be due to diminished excretion of bile acids, consequent on a residue-free diet. The electrocardiographic changes in two patients, particularly the bradycardia, m a y be due to a hypometabolic state, but further study is necessary to determine the significance of such changes in a m b u l a t o r y outpatients. In view of these changes, long-term chemically defined diets should not be used for obese subjects undergoing strenuous physical activities, until further work on cardiovascular response to such diets is available. Short-term starvation is usually disappointing, and long-term starvation is hazardous. The use of chemically defined diets in the long-term m a n a g e m e n t of severely obese outpatients deserves further study. Periods of such dieting may prove acceptable to the severely obese individuals who cannot reduce food intake. However, to be entirely successful, such treatment of obesity must lead to a p e r m a n e n t alteration in eating habits after weight reduction. Equally important as diet is the m a n a g e m e n t of the psychologic and social problems that were manifest in two patients in the present series. REFERENCES
1. Ball MF, Canary J J, Kyle LH: Comparative effects of caloric restriction and total starvation on body composition and obesity. Ann Intern Med 67:60, 1967 2. Ball MF, Kyle LH, Canary JJ: Comparative effects of caloric restriction and metabolic acceleration on body composition in obesity. J Clin Endocrinol Metab 27:273, 1967 3. Benoir FL, Martin RL, Watten RH: Changes in body composition during weight reduction in obesity. Ann Intern Med 63:604, 1965 4. Bollinger RE, Lukert BP, Brown RW,
Gueuara L, Steinberg R: Metabolic balance of obese subjects during fasting. Arch Intern Med 118:3, 1966 5. Chicago Society of Actuaries: Build and Blood Pressure Study, 1959 6. Bloom WL: Fasting as an introduction to the treatment of obesity. Metabolism 8:214, 1959 7. Cubberley PJ, Polster SA, Schulman CL: Lactic acidosis and death after the treatment of obesity by fasting. N Engl J Med 272: 628, 1965 8. Davidson S, Passmore R, Brock JF (eds):
CHEMICALLY DEFINED DIETS IN OBESITY MANAGEMENT
Human Nutrition and Dietetics. Edinburgh, Churchill Livingstone, 1972, p 75 9. Davis CS: Personal communication, 1973 10. Drenick EJ, Swendseid ME, Tuttle SG, Brand WH: Prolonged starvation. JAMA 187: 100, 1964 11. Duncan GC, Jenson WF, Cristofori FC, Schlers GL: Intermittent fasts in the treatment and control of intractable Obesity. AM J Med Sci 245:515, 1963 12. Felig P, Owen OE, Wahren J, Cahill G F Jr: Amino acid metabolism during prolonged starvation. J Clin Invest 48:584, 1969 13. Garnett ES, Barnard DL, Ford J, Goodbody RA, Wodehouse MA: Gross fragmentation of cardiac myofibrils after therapeutic starvation for obesity. Lancet 1:914, 1969 14. Harrison MT, Harden RM: The longterm value of fasting in the treatment of obesity. Lancet 2:1340, 1966 15. Howard AN: Dietary treatment of obesity, in Baird IM, Howard AN (eds): Obesity: Medical and Scientific Aspects. Edinburgh, Livingstone, 1969, p 96 16. Kahan A: Death during therapeutic starvation. Lancet 1:1378, 1968
657
17. Keys A, Brozek J, Henschel A, Michelsen O, Taylor HL (eds): The Biology of Human Starvation. Minneapolis, Univ Minnesota Pr, 1950 18. Lawlor T, Wells DG: Fasting as a treatment of obesity. Postgrad Med J 47:452, 1971 19. MacCuish AC, Munro JF, Duncan LJP: Follow-up study of refractory obesity. Br Med J 1:91, 1968 20. Runcie J, Thomson TJ: Prolonged starvation--a dangerous procedure. Br Med J 3:432, 1970 21. Runcie J: Urinary sodium and potassium excretion in fasting obese subjects. Br Med J 2:22, 1971 22. Silverstone JT, Stark JE, Buckle RM: Hunger during total starvation. Lancet 1:1343, 1966 23. Spencer lOB: Death during therapeutic starvation for obesity. Lancet 1:1288, 1968 24. Winitz M, Adams RF, Seedman DA, Davis PH, Jayko LG, Hamilton JA: Studies in metabolic nutrition employing chemically defined diets, lI. Effects on gut microflora populations. Am J Clin Nutr 23:546, 1970
and a mean weight loss of 4.1 Ib ( 1.8 kg) / week. Clinical abnormalities observed were alopecia, symptomless normochromic anemia, postural hypotension, and hypercholesterolemia. All these findings reverted to normal subsequentto resuming a normal diet. Low-calorie, chemically defined diets of approximately 6 0 - 3 6 0 kcal offer an acceptable and safer form of weight reduction than complete starvation in the severe and refractory obese patient.
OTAL STARVATION was advocated in the management of "refractory" obesity when other methods failed, and early reports were enthusiastic. 6'"'~4 However, there are doubts concerning the safety of prolonged starvation as well as its long-term usefulness. ~9 Garnett ~3 reported the death of a 20-yr-old girl who underwent starvation for 30 wk, and autopsy showed histologic loss and fragmentation of the myofibrils of the myocardium. Spencer 23 and Kahan16 described cardiac deaths due to inappropriate fasting. Similar fatalities have occurred in a diabetic with lactic acidosis, 7 and fatal acute volvulus has been described?~ The loss of lean body massl-3 during starvation may be as great as the loss from the fat depots, and electrocardiographic changes suggestive of decreased heart size have been reported. 17 The loss of body protein can be corrected by the addition of 40 60 g of egg albumin daily.4 One object of the present work is to provide a long-term low-calorie regime containing either mixtures of L-amino acids, or whole protein to correct this loss of lean body mass and avoid changes caused by negative nitrogen balance in total starvation. After 24 hr of fasting, obese subjects usually no longer complain of hunger. 6 The suppression of appetite is thought to be due to ketosis from carbohydrate deprivation. However, Silverstone et al. 22 found that obese patients on complete fasting were equally hungry as when taking a low-calorie diet with sufficient carbohydrate to abolish ketonuria. The relationship between blood and urinary ketones and appetite was examined in the present study. The purpose of the present work was to determine the acceptability of chemically defined diets in long-term weight reduction of severely obese patients; the
T
From the West Middlesex Hospital, Isleworth, Middlesex, and Department of Investigative Medicine, University of Cambridge, Cambridge, England. Received for publication December 3, 1973. Reprint requests should be addressed to Dr. I. McLean Baird, West Middlesex Hospital, Isleworth, Middlesex, England. 9 1974 by Grune & Stratton, Inc. Metabolism, Vol. 23, No. 7 (July), 1974
645
646
BAIRD, PARSONS, AND HOWARD
Table 1. Weight Losses of Patients on Different Diets (Weight Loss Ib (kg)/wk)
Case No.
Age (yr)
1
39
Study period Sex (wk) F
Initial Discharge Weight Weight
Chemically Hospital Defined Diet Diet (800 kcal) (900kcal) Starvation
Chemically Defined Diet (Carbohydrate g/day) O* 30180~
51
322
168
2.0
5.5
9.5
3.5
4.0
1.5
(146) 266
(76) 152
(0.9) 3.0
(2.4) 5.0
(4.2) 7.0
(1.6) 5.0
(1.8) 5.0
(0.6) 4.0
(121)
(69)
(1.3)
(2.3)
(3.2)
(2.3)
( 2 . 3 ) (1.8)
220
149
2.0
4.5
6.5
3.5
3.5
2.5
(100)
(68)
(0.9)
(2.0}
(2.9)
(1.6)
0.6)
(1.0)
325 (147) 336
209 (95) 254
4.0 (1.8) 4.0
5.0 (2.3) 4.0
11.5 (5.1) 13.0
6.5 (2.9) 3.7
5.1 (2.3) 3.0
5.5 (2.4) 0.5
(152)
(115)
(1.8)
(1.8)
(5.9)
(1.6)
(1.3) (0.1)
294 (133)
186 (84)
3.0 (1.3)
4.8 (2.0)
9.5 (4.2)
4.4 (2.0)
4.1 (1.8)
2
24
F
30
3
36
F
26
4
21
M
21
5
57
F
30
Mean Ib (kg)
2.8 (1.1)
* + 3 0 g/day amino acids; 120 kcal. 1"+15 g/day amino acids; 180 kcal. 515 g/day amino acids; 380 kcal.
minimum intake of appropriate L-amino acids necessary to maintain positive nitrogen balance; and the minimum intake of carbohydrate to abolish ketosis. Chemically defined diets containing essential vitamins and minerals are compared with total starvation, and with conventional low-calorie hospital diets. EXPERIMENTAL
DESIGN
AND
METHODS
Patients Four female and one male obese subjects who were more than 30% above the mean desirable weight of the Metropolitan Life Tables s were studied as inpatients for 21 52 wk (Table 1). All five patients had a normal 50-g glucose tolerance test, the 2-hr blood sugar being less than 140 mg/ 100 ml. Pretreatment weights ranged from 220-336 lbs (Table 1). The patients were selected by long history of failure to respond to conventional outpatient methods of caloric restriction. Two patients (cases 1 and 2) had psychologic problems. One patient had a history of pulmonary infarction, venous thrombosis, and lymphoedema of both legs. All were strongly motivated to undergo inpatient treatment and participate in the metabolic study. They strictly adhered to the diets, with the exception of two meals only. The patients were ambulatory and were permitted normal exercise within the hospital, except during the starvation period. Occasional weekend visits home were allowed after the first 10 wk for patients 2, 3 and 4 who lived near the hospital. This was beneficial psychologically and there was no evidence of deviation from the dietary regimes as judged by the degree of ketonuria or weight loss.
Clinical Examinations There was an initial full clinical examination and a record kept twice daily of weights, blood pressure, and "hunger ratings ''22 at 10 a.m. and 4 p.m. There was a complete 24-hr urine collection, and the number of stools was recorded. Twelve-lead electrocardiograms were performed twice weekly. The urinary ketones were measured daily by the ketostix test.
Laboratory Measurements Urine. The aliquots from the 24-hr total urinary collection were kept and the weekly excretion of total nitrogen was estimated by the Kjedahl method. Feces were very infrequent, and fecal nitrogen loss was considered insignificant. Nitrogen balance was calculated at levels of dietary
CHEMICALLY DEFINED DIETS IN OBESITY MANAGEMENT
647
Table 2. Sequence of Diets
Period
Diet
Kcal
Length of Studies (wk)
1 2
Hospital diet Standard chemically defined diet (Vivonex) Starvation Mixtures of L-amino acids and carbohydrate Mixtures of proteins and carbohydrate Hospital diet
800 900
2 2
0 60-360
2 12-42
180-200
4-10
3 4 5 6
800
2-4
amino acids of 15, 20, 30, 40, 45, 60, and 80 g/day. The estimated nitrogen balance was the urinary nitrogen excretion per day when the amino acid intake was just sufficient to give a positive nitrogen retention. Values were expressed as g/day amino acid mixture (N content, 14.1 g/100 g). Urinary urea, potassium, sodium, calcium, and creatinine was analyzed by conventional AutoAnalyzer (Technicon Instruments Corp., Tarrytown, N.Y.) methods. Blood. Samples were taken once weekly for blood and serum. The hematocrit, hemoglobin, and total and differential white cell count were measured once weekly. Bone marrow aspirate was examined in two patients. Serum. Albumin, globulin, and electrophoresis of proteins, potassium, sodium, calcium, iron, protein-bound iodine, inorganic phosphate, bilirubin, SGPT, SGOT, HBD, enzymes, creatinine, urea, uric acid, glucose, and cholesterol were estimated weekly and serum ketones every 2 wk by conventional laboratory methods.
Diets Dietary periods lasted 14 days and were chosen according to a predetermined sequence (Table 2). A conventional 800-kcal hospital diet prepared by the dietician was given for 2-4 wk to establish a steady state. This contained 60 g protein, 100 g carbohydrate, and 20 g fat. A standard liquid, chemically defined diet* containing 900 kcal comprised of 40 g appropriate amino acids, 180 g carbohydrate, and 1 g fat was given three times dailyat meal times for 2 wk. Subsequently, patients had total starvation with mineral and vitamin supplements three times daily for 2 wk. Water intake was unlimited. Different combinations of an amino acid mixture and carbohydrate were then given at two weekly intervals for the rest of the study to determine (1) the amino acid requirements for nitrogen balance and (2) the carbohydrate necessary for abolition of ketosis. The amino acid mixture contained essential and nonessential amino acids in the optimum proportions (Table 3), as suggested by Winitz et al. 24 In addition to water, black coffee or tea and dietetic soft drinks containing 1 kcal per drink up to a maximum of 10 kcal daily were allowed. The chemically defined diet was in powder form with sufficient water added to prevent osmotic diarrhea due to a hypertonic solution. The first two patients were given in sequence the amino acid mixture in stepwise levels of 20, 30, 40 g/day without carbohydrate. The amino acid mixture was then kept at 30 g/day and the carbohydrate increased stepwise from 20 to 80 g/day. Toward the end of the experiment, four patients were also given an equivalent amount of modified milk protein (M.M.P. 1, Scottish Milk Marketing Board) with a supplement of 400 mg L-methionine or egg albumin daily. Before discharge, a low-residue 900-kcal conventional hospital diet was given for at least 2 wk. RESULTS
Acceptability of Diet All the patients studied adhered to the chemically defined diets well and were observed to cheat on only two occasions. Except when given larger quantities
*Based on ingredients contained in Vivonex, Eaton Laboratories, Norwich, N.Y.
648
BAIRD, PARSONS, AND HOWARD
Table 3. Composition of a Typical Chemically Defined Diet* Amino acid mix (15 g) Stated to contain the following g/100 g: L-tsoleucine 0.344 L-Leucine 0.544 L-Lyslne 0.408 L-Methionine 0.352 L-Phenylalanine 0.392 L-Threonine 0.344 L-Tryptophan 0.106 L-Valine 0.379 L-Alanine 0.367
L-Arginine L-Aspartic acid L-Glutamine Glycine L-Histidine L-Praline L-Serine L-Tyrosine
0.671 0.781 1.290 0.598 0.167 0.490 0.252 0.429
Zinc Chloride Phosphate Acetate Sulfate Iodide Gluconate
0.083 mg 1.037 g 0.167 g 3.06 mg 2.37 mg 0.031 mg 1.44 g
Glucose polymers (oligosaccharides) (30 g) Containing about six glucose units/polymer Salt mix (20 g) Stated to contain the following g/100 g: Sodium 0.481 g Potassium 0.440 g Calcium 0.167 g Magnesium 32.5 mg Manganese 0.585 mg Iron 2.50 mg Copper 0.404 mg
Trace elements (0.5 g) Potassium iodide 0.05 g, copper acetate monohydrate 1.40 g, zinc acetate dihydrate 0.30 g, manganous acetate 2.86, standard salt mix as above 100 g Vitamin tablet Vitamins were supplied as one capsule daily (Plurivite, Boots, containing vitamin A, 5000 units; vitamin 81 , 2 rag; vitamin 82, 2 mg; vitamin fi6, 1 rag; vitamin B12, 2 #g; nicotinomide, 20 mg; vitamin C, 50 rag; vitamin D, 400 units. Essential fatty acids One capsule containing 1 ml safflower oil was given daily to supply essential fatty acids *Provides 15 g/day amino acid, 30 g/day carbohydrate, minerals, and vitamins.
of carbohydrate, the patients were continually ketotic, indicating their strict adherence to the regime. One patient had some initial diarrhea due to using insufficient water and drinking a hypertonic solution. Otherwise, the diets were well tolerated and gave rise to no immediate side effects. Patients found the chemically defined diets preferable to starvation, when all subjects felt unwell because of postural faintness or other symptoms. One patient (case 5) complained of severe general muscular aching during starvation, which may have been caused by potassium depletion due to an increased excretion of 57 meq/24 hr. The symptoms were severe enough to terminate the period of starvation after 10 days. Symptoms remitted on a chemically defined diet containing 15 g carbohydrate and 15 g amino acids. Behavior of the Patients Two patients (cases 1 and 2) had psychologic and social problems; one patient required psychiatric consultations. However, these problems preceded
CHEMICALLY DEFINED DIETS IN OBESITY MANAGEMENT
Casein
649
30
g/day, 0 Amino Acid Intake g/day.
40
Carboh~lrate Intake g/day.
100
0
0 K Calories
1, Q(IO
p r day.
Weight
0 310
~
mS. 290
Z70
Z50 230
Zl0
190 Fig. 1. Case 1. An obese female on a chemically defined diet for 1 yr, showing the composition of the diets and the weight loss.
170
150
III11111111111111111111111
0
4
8
I
12 16 20 24 28 32 36 40 44 48 52 Weeks
hospital admission. During starvation, all patients felt weak and spent more time in bed, and had some psychologic changes, usually marked by depression, aggressiveness, or lack of concentration. On other dietary regimes patients were normal and ambulatory.
Weight Loss A summary of weight losses is shown in Table 1, and a typical result for all cases is shown in Fig. 1. The mean weight loss during starvation was 9.5 lb (4.2 kg) and was as high as 13 lb (5.9 kg) a week in one patient. Much of this could be attributed to a loss of body water, since there was a large accompanying diuresis (Fig. 2). With the chemically defined 900-kcal diet, a high mean weight loss of 5 lb (2.27 kg) was achieved. Very-low-calorie diets (120 kcal/day) gave a mean weight loss of 4.4 lb (2.0 kg) a week. Diets with relatively high carbohydrate gave evidence of fluid retention in three patients, particularly with
BAIRD, PARSONS, AND HOWARD
650
Urinary Urea
30
g./day.
20 10 0
Urine Volume mls./day
1, 5000 1,O00 5O0 0
Uric Acid mg. / }ooml. 0 Mean degree of Ketosis per day.
+3 +2 +I 0
?otassium Iodide 25On~.
Protein Bound 16 Iodine o
l~J./lOOml. 8
0 Serum
400
Cholesterol rag./100ml. 100 Casein g./day.
30 0
Amino Acids g,/day
40 0
E
h
[_
Carbohydrates 100 g,/clay
K Calories
0 1, O00 5O0 0
IIl|llllllllllllJlllllillillllllllillillllllllllil|ll
0
4
8
12 16 ~
24 28 32 36 40 44 48 52
Weeks
Fig. 2. Changes in urinary urea, urine volume, serum uric acid, and cholesterol in case 1 during 1 yr of chemically defined diets.
80 g / d a y and in some instances led to weight increases (Fig. 1). On return to a carbohydrate-free diet a diuresis and a weight loss of 7 lb (3.18 kg) a week occurred.
Hunger Patients usually lost the sensation o f hunger during the first 2 wk of the chemically defined diet with the exception of case 1, who consistently recorded high
CHEMICALLY DEFINED DIETS IN OBESITY MANAGEMENT
651
hunger ratings, associated with recurring mental images of food at irregular intervals. Hunger sensations did not reappear when the urine ketones were absent, and there was no relationship between hunger and ketosis; for example, patient 5 was extremely hungry during the period of starvation when severe ketosis was present. Most patients lost interest in food after several days on the chemically defined diet. At the end of the period of study, there was no difficulty in gradually restarting normal diet, although initially patients were only able to take small quantities of food due to easily induced satiety sensations.
Electrocardiography Two patients (cases 1 and 2) developed bradycardias of less than 60/rain. These were attributed to iodine deficiency or a hypometabolic state. However, one patient continued to have a bradycardia despite iodine supplementation, and did not return to normal until shortly before discharge. One patient with minor ischemic changes initially and the two others with normal ECG patterns were unchanged during treatment.
Side Effects General. Insomnia was not a prominent feature, but all patients ingested a hypnotic intermittently, usually nitrazepam 5-10 mg at night or butobarbitone 100-200 mg. Diazepam 5-10 mg three times daily was periodically given in three patients during episodes of anxiety, but usually for a week or two at a time. Antidepressives were not required. During the period of starvation patients were frequently unable to concentrate and sometimes appeared euphoric. This corresponded with the severe ketosis. However, while adhering to the chemically defined diets, especially those containing at least 15 g / d a y carbohydrate, all patients were able to carry out normal physical activities within the ward and appeared able to read and write and concentrate normally. One patient (case 2) carried out part-time secretarial work while under study. Hair. Changes in the hair were noted in all patients. The head hair became thin and sparse with a faint red tinge, and tended to fall out more rapidly than normally. In two patients (cases 1 and 5) considerable alopecia developed toward the end of the period of study. The hair gradually returned to normal when diet was restored to normal conventional low-calorie intake, but it took 3 mo in case 1 and 6 mo in case 5 to return to its previous appearance. Gastrointestinal. One patient (case 1) had frequent diarrhea initially. This was controlled with lomotil and codeine. Because the chemically defined diet was low in residue, bowel motions were rare and occurred at intervals as long as 4 wk in some patients. In two patients, colicky abdominal pains occurred due to impacted feces in the rectum. Five months after discharge, while an outpatient on an 800-cal conventional diet, patient 2 developed, over several weeks, frequent attacks of diarrhea. He was reinvestigated for malabsorption, but a jejunal biopsy and d-xylose excretion were within normal limits, and the diarrhea subsided spontaneously within a few weeks and was considered unrelated to the previous regimes.
652
BAIRD, PARSONS, AND HOWARD
Table 4. Hematologic Changes on Chemically Defined Diets (Case 4)
Date
Diet/Day
9.6.71
800kcal hospital diet Amino acids 15 g carbohydrate 50 g (260 kcol) Amino acids 80 g carbohydrate 10 g (360 kcal) Amino acids 30 g carbohydrate 0 g (120 kcal)
18.8.71
15.9.71
6.10.71
RBC Hemoglobin (million PCV MCHC MCV WBC Neutrophils (g/100 ml) c/mm) (%) (%) (cu cm) (cu cm) (%) (No.) Platelets/cm 17
6.0
49
32
80
8,000
54
4320
240,000
14
5.2
44
32
82
3,800
45
1710
144,000
12
4.7
40
28
85
4,000
28
1120
99,000
12
4.5
37
34
80
3,300
41
1352
90,000
Hematologic Changes All patients developed a fall in hemoglobin during the study (Table 4). The mean initial hemoglobin was 14 g/100 ml in case 4 (range, 13-17 g/100 ml) and on completion of the dietary period this fell to 11 g/100 ml (range, 10-12 g/100 ml). The PCV also fell, but MCHC and MCV remained unchanged. A fall in the total white cells and neutrophils occurred, but in no case was the total white cell count lower than 2000/cu mm. The lowest neutrophil count was 1120/ cu mm. The platelet counts showed no consistent change. There were no symptoms attributed to the anemia, and in two patients bone marrow examinations were within normal limits; in particular, there was no evidence of iron deficiency, vitamin B~2 or folate deficiency. The serum folic acid and serum vitamin B~2 levels were within normal limits. 58Co-labeled vitamin B~2 absorption was normal (40~) in one patient. In all patients, the hemoglobin and white cell count returned to normal after 3 mo on a conventional diet. No symptoms of the anemia or neutropenia occurred and there was no tendency to develop infections during the study.
Biochemical Changes Nitrogen balance. Results are summarized in Fig. 3; with a carbohydratefree diet, the amino acid intake required for nitrogen balance was about 30 g/day. If carbohydrate was added to the diet, the minimum intake of amino acid required for nitrogen balance fell to about 15 g/day. The maximum "nitrogen sparing" effect was seen with 30 g/day carbohydrate in four patients and 45 g/day carbohydrate in one patient. Some nitrogen sparing effect was seen with intakes as low as 15 g/day carbohydrate. Patients given 30 g/day carbohydrate and 20 g/day modified milk protein supplemented with 400 mg/day L-methionine, or 15 g/day egg albumin, showed nitrogen balance. Serum and urinary ketones. Starvation and a carbohydrate-free diet induced high urine and serum ketone levels (Fig. 2). Gradually increasing carbohydrate intakes from 15-80 g/day progressively decreased the serum ketone levels such that ketosis was less than 5 mg/100 ml on 80 g/day and abolished at 160 g/day of carbohydrate (Fig. 4).
653
CHEMICALLY DEFINED DIETS IN OBESITY MANAGEMENT
Carbohydrate g.lday [ ] 0 15
[] [] []
30
45 80
~, 2o
E
PATIENT 1
Fig. 3. subjects.
L 2
4
3
5
Dietary amino-acid and carbohydrate requirements for nitrogen balance in five obese
Serum uric acid. No patient had clinical gout, but four of the patients (1, 2, 3, and 5) had a high serum uric acid (> 6.5 rag/100 ml) prior to therapy, and starvation greatly increased the serum uric acid further to even higher levels. With a carbohydrate-free diet, serum uric acid was still elevated in four patients, but all patients had levels in the normal range when 30 g / d a y carbohydrate and a minimum of 15 g amino acid was given. Serum cholesterol. Synthetic low-calorie diets cause an initial fall in serum cholesterol, followed by a slow rise to hypercholesteremic levels (Fig. 2). Initially, the mean serum cholesterol was 210 rag/100 ml (range, 175-252 rag/ I
:i:i:i:i:i:i:i:i:i:i:i:i:!;i:|
•••••••••••]]••]]••••••••••••••••••••••••••••••••••
3O
Dietary Carbohydrates (g.lday)
Case No. I 80 l
Fig. 4. Serum ketones in response to carbohydrate intake from 0 - 1 6 0 g daily in five obese subjects.
"
4
"
5
160
I
0
20 Serum Kelones (mq.llOOml.) 10
I 30
654
BAIRD, PARSONS, AND HOWARD
100 ml) that fell after 10 wk to 174 mg/100 ml (range, 142-236 rag/100 ml). At 20 wk, the mean serum cholesterol had again risen to 230 mg/100 ml (range, 185-250 mg/100 ml). After 30 wk in cases 1 and 2, the serum cholesterol had risen to 290 and 260 rag/100 ml, respectively, and subsequently the serum cholesterol was 350 mg/100 ml in case 1 after 50 wk. Serum cholesterol returned to normal upon resumption of a hospital diet. Electrolytes. There was no consistent change in the serum electrolytes in the study. The serum calcium and potassium levels did not show any change during the study with one exception in one patient who had a serum potassium of 2.9 meq/liter 5 wk after the starvation period and who was given potassium supplements (two capsules of Slow K containing 16 meq of potassium three times daily). The urinary sodium and potassium excretions were usually low, but wide fluctuations were often seen. The urinary calcium output had the same pattern, usually low, but sometimes fluctuating into the low normal range. Miscellaneous estimations. The blood urea consistently fell during the period on the chemically defined diet, the lowest level recorded being 8 mg/ 100 ml in case 2. The serum bilirubin did not change except in case 4 where an initially high serum bilirubin of 1.4 rag/100 ml rose to 2.2 mg after starvation and subsequently fell to less than 1 mg/100 ml and was considered to be a Gilbert's syndrome unrelated to the study. The other liver function tests were normal in this patient. Blood glucose, serum proteins, alkaline phosphatase, iron and protein-bound iodine (PBI) showed no Consistent change except in cases 1 and 2 where a fall in PBI was due to an initial formulation omission. Case 1 developed a PBI of 1.9 ug/100 ml after 17 wk and case 2 a PBI of 2.1 #g/100 ml after 18 wk, but both these patients returned to normal PBI levels after supplemental potassium iodide (250 rag/day). There was no evidence of clinical thyroid enlargement in these two patients. DISCUSSION
Chemically defined diets were an acceptable and safe form of low-calorie regime for periods up to 1 yr under conditions of metabolic study in all five severely obese subjects. The patients felt well and able to carry out normal physical and mental activities within the limits of the hospital environment. All preferred this form of dietary restriction to starvation, which was associated with postural hypotension, muscular aches, depression, euphoria, tiredness, and other symptoms. Although the initial weight loss during starvation was high, and in the present series there was a mean weekly weight loss of 9.5 lb (4.2 kg) over 2 wk, much of this weight loss was due to an initial loss of body water and subsequent diuresis. The overall weekly weight loss over long periods of months on diets containing 60-300 kcal daily was about 4 lb/wk (1.8 kg) and is similar to that described from total starvation for a similar period. ~s High-carbohydrate diets reduced the rate of weight loss because of water retention. Positive nitrogen balance was maintained by a daily intake of 15-30 g of amino acids. There was considerable individual variation and further work is
CHEMICALLY DEFINED DIETS IN OBESITY MANAGEMENT
655
necessary to determine whether these findings are relevant to other obese individuals under conditions of more strenuous activity. Nitrogen requirements were much lower than anticipated, and it is possible that after starvation adaptation to a lower nitrogen requirement occurs. Carbohydrate (30 45 g/ day) reduced the approximate amount of amino acid intake required for positive nitrogen balance from 30 g/day to 15 g/day. Ketosis did not correlate with appetite suppression and, this supports the work of Silverstone et a l . 22 Thus, there is no need to achieve high levels of ketones to obtain anorexia, and starvation offers no advantages in this respect. The severe ketosis seen in total starvation was associated with depression and other psychologic changes but the addition of as little as 15 g/day carbohydrate greatly reduced urinary and serum ketones and also led to a remarkable change in the mood of the patient, who became less aggressive and less depressed. Increasing carbohydrate up to 80 g / d a y abolished ketosis in four of the five patients, a finding that is consistent with other authors. 8 The hyperuricemia of starvation can lead to clinical gout ~~ and represents a hazard of prolonged starvation. Patients treated with the chemically defined diet containing at least 30 g / d a y carbohydrate had normal serum uric acid levels. It is noteworthy that the pretreatmerlt hyperuricemia was reduced to normal in all four cases on prolonged chemically defined diets (Table 5). The optimum composition for a chemically defined reducing diet consistent with good weight loss and well being is 15 g / d a y amino acids in the required proportions, and 30-45 g / d a y carbohydrate. This represents 180-240 kcal/ day. While good results were obtained with 30 g / d a y amino acids alone, the inclusion of a small amount of carbohydrate reduced ketosis to a more moderate level, returned the serum uric acid to normal and reduced the amino acid requirement by one half. Ketosis could be abolished by using 80 g / d a y carbohydrate, but this led to fluid retention in some cases. A high degree of ketosis produces some psychologic disturbances, but there is no evidence from the present study that moderate levels of serum ketones are harmful. In most of the present experimental work a mixture of L-amino was used. Proteins of high biologic value have been substituted with similar results. Two of the patients were given a chemically defined diet containing 15 g egg albumin and 30 g carbohydrate for up to 10 wk with identical results. Such less expensive compositions could be used for the routine treatment of refractory obese patients. The present study confirms the work of Bollinger et al. 4 that Table 5. Effect of Carbohydrate Intake on Serum Uric Acid Levels ( m g / l O 0 ml)
Patient
Hospital Diet (800 kcal)
Chemically Defined Diet (900 kcal)
Chemically Defined Diet Carbohydrate g/day 0 15 30 80
Starvation
1 2 3 4 5
9.4 8.2 6.5 4.6 6.7
5.9 5.2 5.6 4.6 5.8
13.7 14.0 7.4 8.5 10.3
9.1 7.9 6.1 7.4 150
8.0 6.3 5.9 7.1 8.5
3.6 6.0 4.0 6.3 6.3
4.7 7.0 4.0 6.2 5.0
Mean
7.1
5.4
10.8
8.1
7.2
5.2
5.4
656
BAIRD, PARSONS, AND HOWARD
the loss of body protein can be corrected by albumin, but our findings suggest that much lower amounts are needed in the presence of carbohydrates for nitrogen balance. Other hazards o f starvation such as h y p o n a t r e m i a and hypokalemia were not a feature of prolonged treatment with chemically defined diets. Urinary potassium was initially high during starvation and then settled at lower levels, confirming previous reports. 2~ Such potassium loss is thought to be due to increased gluconeogenesis utilizing lean body mass, ~2 followed by a period of conservation. Urinary excretion of sodium, potassium and calcium were consistently low with the chemically defined diets and serum electrolyte levels usually normal. The long-term use of chemically defined diets had some disadvantages. Changes in the hair may have been due to insufficient essential fatty acids, since similar changes have been observed with normal subjects on 1800-kcal chemically defined diets, and these can be corrected by increasing the safflower oil content to 3.5 g / d a y . 9 The n o r m o c h r o m i c anemia has been previously described, ~8 and there was also an unexplained neutropenia. N o s y m p t o m s occurred due to the hematologic changes. A gradual rise in the serum cholesterol after 20 wk synthetic diet may be due to diminished excretion of bile acids, consequent on a residue-free diet. The electrocardiographic changes in two patients, particularly the bradycardia, m a y be due to a hypometabolic state, but further study is necessary to determine the significance of such changes in a m b u l a t o r y outpatients. In view of these changes, long-term chemically defined diets should not be used for obese subjects undergoing strenuous physical activities, until further work on cardiovascular response to such diets is available. Short-term starvation is usually disappointing, and long-term starvation is hazardous. The use of chemically defined diets in the long-term m a n a g e m e n t of severely obese outpatients deserves further study. Periods of such dieting may prove acceptable to the severely obese individuals who cannot reduce food intake. However, to be entirely successful, such treatment of obesity must lead to a p e r m a n e n t alteration in eating habits after weight reduction. Equally important as diet is the m a n a g e m e n t of the psychologic and social problems that were manifest in two patients in the present series. REFERENCES
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CHEMICALLY DEFINED DIETS IN OBESITY MANAGEMENT
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