Studies of Tryptophan and Albumin Metabolism in a Patient with Carcinoid Syndrome, Pellagra, and Hypoproteinemia

Vol. 71 . No.3 Printed in U.S.A.

GuTllOllNTUOLOOY 71:484-489. 1976 Copyright «> 1976 by The Willi. IDa " Wilkin. Co.

STUDIES OF TRYPTOPHAN AND ALBUMIN METABOLISM IN A PATIENT WITH CARCINOID SYNDROME, PELLAGRA, AND HYPOPROTEINEMIA C. P.

SWAIN,

A.

S. TAVILL, AND

G.

NEALE

Clinical Re.earch Centre. Northwick Park Hospital. Harrow. Middlesex, and Department of Medicine. Royal Postgraduate Medical School. England

Detailed studies of protein metabolism were undertaken in a patient with pellagra and hypoproteinemia associated with the carcinoid syndrome both before and after treatment. The synthesis of albumin improved from 82 mg per kg per day to 135 mg per kg per day with little change in the daily excretion of 5-hydroxyindole acetic acid. After treatment with nicotinamide the patient made good progress with a complete resolution of the signs of pellagra and protein malnutrition. These results support the hypothesis that a reduced availability of the essential amino acid L-tryptophan may limit the synthesis of albumin and nicotinic acid in patients with the carcinoid syndrome who become anoretic. became unwell with fatigue and weight loss. Subsequently her periods stopped and when she complained of hot flushes all of her symptoms were ascribed to an early menopause. In 1968 she was referred to Hammersmith Hospital, London, for investigation of hepatomegaly. On examination there was evidence of recent weight loss but no signs of systemic disease apart from a much enlarged liver. Needle biopsy of the liver failed to give a diagnosis, but at laparotomy multiple nodules of carcinoid tumour were found in both lobes of the liver. The primary tumour could not be found. At that time the urinary excretion of 5-hydroxyindole acetic acid (5HIAA) was 124 mg per day (normal range 3 to 17 mg per day), but the symptoms of carcinoid disease were mild. Mrs. A. R. had occasional flushing attacks and intermittent slight diarrhea which was treated with codeine. She returned to Freetown and remained well for 12 months, after which more marked symptoms developed. In October 1969 she was seen again in London, at which time she was having at least one attack of flushing a day. diarrhea 8 to 10 times a day, and occasionally attacks of wheezing. On examination she was thin, with massive hepatomegaly. There was a pulmonary ejection systolic murmur but no evidence of right ventricular hypertrophy. The central venous pressure was normal and the cardiac output was well maintained. The diaphragms were elevated. but lung function tests were normal (forced expiratory volume in 1 sec, 2.4 liters, vital capacity 3.2 liters) . Biochemical studies showed serum bilirubin 0.5 mg per 100 ml, alkaline phosphatase 60 King-Armstrong (KA) U per 100 ml, albumin 3.0 g per 100 mi. prothrombin time 13 sec (control 12 sec). The excretion of 5HIAA was 89, 102. and 160 mg per day on 3 successive days. Treatment with cyproheptidine 6 mg three times a day controlled the diarrhea and the flushing attacks appeared to lessen on treatment with phenoxybenzamine 10 mg three times a day. Mrs. A. R. was able to return to her job in Freetown and remained reasonably well for the next 2 I! years. She was reviewed in London in April 1973. at which time her weight was 60 kg and although the liver appeared larger. reaching well into the right iliac fossa. there was little change in her general clinical condition. The 5HIAA excretion was 205 mg per day .

Recognition of the protean manifestations of the carcinoid syndrome during the 1950's led to many case reports of a pellagroid skin rash occurring in patients with long standing disease. \010 At that time it was suggested that high concentrations of serotonin might influence the nutrition of the skin in an adverse way, thereby causing a pellagroid rash which did not always respond well to specific anti pellagra treatment. 11 On the other hand, careful balance studies on patients with malignant carcinoid disease showed that in individual cases as much as 60% of the dietary L-tryptophan might be diverted into the serotonin biosynthetic pathway. As a result it was speculated that deficiency oC the essential amino acid L-tryptophan might lead to pellagra and hypoproteinemia .•' 7 In this report we describe studies of protein metabolism in a patient with carcinoid syndrome, pellagra, and hypoproteinemia before and after successful treatment with nicotinic acid which support this hypothesis.

Case Report Mrs. A. R., a black woman born in Guyana in 1936. was 30 years old and working in Freetown, Sierra Leone when she first Received December 17. 1975. Accepted March 5, 1976. Address requesh for reprinta to: Professor G. Neale, Department of Clinical Medicine. Trinity College, St. James's Hospital, Dublin, Eire.

Dr. Swain waslupported by a Medical Research Council fellowship. Professor Tavill's present addreu is: Department of Medicine, Cleveland Metropolitan General Hospital, 3395 Scranton Road, Cleveland. Ohio 44106. The authors gratefully acknowledge of the assistance of Dr. A. R. Varcoe with the first turnover study, and Sister M. Pullen and staff of the Metabolic Ward of the Clinical Research Centre for expert supervision during the albumin turnover studies. They also wish to thank Dr. Michael Joseph and Mr. John Hopkins (or the measurement of metabolites of L·tryptophan and serotonin in the pluma and of nicotinamide in urine. 484

Sept,'mber 1976

485

CASE REPORTS

On returning to Freetown she became progressively more lethargic and anoretic. her weight fell dramatically to 4!) kg. and the diarrhea (up to 12 times a day) became uncontrollable. She developed soreness of her mouth and skin and marked edema of the lower limbs. In Octoher 1973 she returned to London. She had a swollen, smooth. beefy red tongue and distinctive skin changes. with erythema. scaling. and hypermelanosis affecting the dorsa of the hands. the elbows. the shins. and the exterior aspects of the feet (fig. I). The findings were considered to be diagnost ic of pellagra. There was marked edema but no evidence of heart failure. Biochemical studies showed showed serum billirubin (l.9 mg per 100 ml. alkaline phosphatase :WO KAU per 100 mI. albumin 2.1 g per \00 ml. prothrombin time 14 sec (control 12 set'), Studies of serotonin and its metabolites in plasma and urine are shown in table 1. Serum I.-tryptophan was 4.8 Ilg per ml (control values 8 to 14 Ilg per ml). Other serum amino acid concentrat ions are shown in tahle 2. The urinary excretion of N'-methvlnicotinamide on :1 successive days measured hv a method ~dapted from Carpenter and Kodicek" was 1.1. '1.4. and 1.8 mg per 24 hr (control values 2.6 to 13.0 mg per 24 hrl. On a diet containing 70 g of fat the patient excreted 19.0 g of fat per day (mean of results from two 3-day fecal collections). Mrs. A. R. was transferred to the Metabolic Ward of the Clinical Research Centre. Northwick Park. for studies of protein metaholism. the details of which are given below. Suhsequentl~·. she was given a well-balanced diet together with nimtinamide 2!)0 mg daily. Cyproheptidine was used to control

the diarrhea and to act as a stimulant to the appetite. Her general condition improved slowly and the signs of pellagra recorded. One year later Mrs. A. R. weighed 60 kg and felt well. She had stopped all treatment except for nicotinamide 20 mg a day and codeine phosphate :10 mg a day. She had no edema and the skin lesions had healed completely (fig. :21. She required no treatment for the occasional attacks of flushing. Investigations showed serum bilirubin 0.;; mg per \00 ml. alkaline phosphatase If) KAU per HXl m!. albumin :l.7 g per 100 m!. Serum L-tryptophan was 14.4 Ilg per ml and the urinary excretion of N' -methylnicotinamide was 4.2 mg per day 1 month after discontinuation of supplements of nicotinamide. A later estimation gave a value of 2.4 mg per day and the patient was again asked to take a vitamin tablet t'Cllltaining 20 mg of nicotinamide. Fecal fat ext'Tetion was 4.2 g per day; !)HIAA excretion was 149 mg per day (mean of two estimations).

Studies of Protein Metabolism Meth()d.~

Two studies of albumin metabolism using "'I albumin were carried out. The first was at a time when there was severe hypoalbuminemia and the second was l:l months later when clinically evident pellagra and hypoalbuminemia had completel~' remitted after a full course of oral nicotinamide. During both studies the patient was in a steady metabolic state as defined by a

486

CASE REPORTS T:ULE 1. Serotonin and its metabolites

Pla.ma Date (month/day/yearl

l1/2na 11I28na

2/12n4 2/lOns Normal range

Tryp· tophan· ("I/mll

4.8 6.8 14.4 13.6 8-14

sHT·

(ng/mll

360 350 0-30

Urine SHIAA'

(ng/mll

1270 970 Undetectable

5H1AA

(mg/24hr)

180 152 146 3-17

• Plasma "tryptophan was measured by the method of Denckla and Dewey'· as modified by Bloxham and Warren.'· • Plasma levels of 5HT (5-hydroxytryptamine) and 5HIAA were measured by a modification of the method of Curzon and Green" as described by Joseph and Baker (in prepCJ1'CJtion).

Vol. 71, No.3

of albumin were within the normal range, but as the intravascular albumin pool was much depleted the absolute catabolic rate and therefore the synthetic rate of albumin was very much reduced. Correction of the nutritional deficiencies was associated with a fall in the till of albumin and an increase in the fractional catabolic rate to the upper limit of normal. In absolute terms this represents an increase in synthetic rate of more than 100% and a value which, on a body weight basis, was also much increased. At the same time gut loss of protein was normal (equivalent to 0.74 g :I: 0.32 of albumin per day as estimated from the clearance of &ICr-labeled chromic chloride). If the only defect in albumin metabolism had been one of synthesis, however, a prolongation of till and a fall in fractional catabolic rate of albumin would have occurred. These effects were probably balanced by hypercatabolism of albumin as a result of diffuse tumor spread. Additionally, in normal circumstances, a till (albumin) of 18.2 days would be associated with a fractional catabolic rate (as calculated by Matthews' method 20) of 10 to 12% rather than the measured value of 8.5%. This anomaly may be explained in part by the abnormally high extravascular to intravascular ratio which persisted despite treatment. The distribution and metabolism of albumin within the tumor mass are important factors in the analysis of this data and it is of in· terest to note that the increased synthetic rate of albu· min after treatment was not sufficient to correct entirely for the extravascular sequestration of albumin.

constant plasma albumin concentration and body weight. Human serum albumin was prepared by Sepha· dex G150, DEAE·cellulose chromatography, and prepa· rative polyacrylamide electrophoresis, and labeled with 1211 at a ratio of less than 1 atom per mole by the iodine monochloride method of McFarlane. II. 1t Trichloroacetic acid.precipitable radioactivity exceeded 99%. Control studies on the same preparations confirmed that the albumin had retained its native properties as defined by a normal plasma half·life (till) of 17 to 21 days. A single measured dose of about 60 ",c of taSI-labeled albumin was administered intravenously after blocking the thyroid uptake of radioactive iodine with oral potassium iodide. Discussion Plasma samples were taken at 10 and 20 min and then daily thereafter. Radioactivity was measured on l.O-ml Patients with carcinoid syndrome usually become aliquots of plasma in a Wallac Decum gamma spectrom- . progressively cachetic during the terminal phase of their eter. Degradation was studied over a period of 12 to 14 illness. Anorexia, profound weakness, disabling diar· days and calculated by the method of Matthews. 20 In a rhea, and edema with or without heart failure are metabolic steady state the degradation rate so deter· mined can be equated with albumin synthesis. Plasma albumin was measured by the Bromcresol Green bind· TABLE 2. Serum amino acid concentrations be/ore and alter treatment" ing method21 on Ii Vic-Rers-MultichanneI300 AutoanalyNormal adult Amino acid Nov 1973 Feb 1975 rangeser.

Results and their Interpretation The metabolic data of the albumin turnover studies in the patient both when she was clinically pellagrinous and hypoalbuminemic and later when she had been fully treated and was normoalbuminemic are shown in table 3. In the first study the plasma volume expressed on the basis of body weight was normal. On the second occasion, when the edema had regressed, the plasma volume expressed this way was subnormal, although the absolute change was small. In interpreting these measurements it is important to note that the tumor mass made a significant contribution to body weight, especially as a percentage of lean body mass. True body weight and muscle bulk increased considerably between the two studies. Plasma albumin concentration increased to almost normal values and there was an expansion of both the intravascular and total exchangeable albumin pools. In the first study the till and fractional catabolic rates

"mole./liter

Asp Thr Ser GIn Gly Ala Val Met Ile Leu Tyr Phe Lys His Arg

57 270 308 278 520 368 118 5 50 112

29 160 173 265

325 395 225 34 84

130

99

85

78 250 175 203

216 105

56

lOS

0-24 79-193 73-167 415-695 120-554 210-662 141-317 6-40 37-98 75-176 22-88 37-88 83-238 23-77 21-137

"In spite of the patient's malnourished state the concentration of serum amino acids (excluding tryptophan) were well maintained except for the somewhat low levels of valine and methionine. This pattern is similar to that seen in pellagra." • Adapted from Niederweiser and Pataki. n

September 1976

CASE REPORTS

487

Flc. 2. Patient in February 1975 showing improved nutritional state and healing of skin lesions.

common symptoms. The patient described in this report appeared to have reached this stage of the disease 8 years after the onset of symptoms. Much consideration was given to the possibility of treatment by hepatic resection, "." by infusion of hepatic artery with cytotoxic drugs. 25-2' 'and by the systemic use of cytotoxic agents such as streptozotocin,2"3' but her general condition appeared too poor for heroic measures . For this reason efforts were concentrated on improving her nutritional state. Clinicallv and hiochemicallv this patient had evidence of both peilagra and protein malnutrition. The concentrat ion of circulating I.-tryptophan was much reduced, whereas the plasma concentrations of other amino acids were well maintained apart from small reductions in valine and methionine. In nutritional pellagra plasma levels of I.-tryptophan are also reduced, possihly as a result of the diversion of di€tary ~ryptophan into the synthetic pathway for niacin." In the patient forming the suhject of this case report it seems likely that most of the available L-tryptophan was diverted into the production of serotonin bv the tumor . A simplified scheme of the normal metabolic pathways for I.·tryptophan is shown in figure :3. Our investigation showed remarkably well maintained values for the concentrations of circu-

lating 5-hydroxytryptamine and 5HIAA and for the excretion of 5HIAA irrespective of the patient's nutritional state. On t he other hand t he metabolic st udies suggest that the supply of L.tryptophan was rate-limiting for the synthesis of both niacin and circulat ing albumin. Although hypoproteinemia is well documented in association with the carcinoid syndrome t here have been no previously reported studies of its pathogenesis. In these studies we have shown that the synthetic rate for albumin was reduced to less than one-half of that found in normal subjects at a time when the concentratiol] of circulating L-tryptophan was low (4.8 Ilg per ml). After treatment both the concentration of circulating tryptophan and the rate of albumin synthesis improved and it seems likely t hat these two findings are related. It has been show~. for example. that tryptophan ma~' playa rate-limiting role in protein synthesis by the livers (If both rats and rabbits .. •· 3', This may he because L·trypto· phan is the least abundant amino acid both in the free amino acid pool and in body proteins. Moreover albumin synthesis may be particularl~' sensit ive to a deficiency of L-tryptophan because of the position of the tr.vptophan residue close to the amino-terminal end of the molecule"·· 37

488

CASE REPORTS

TABLB 3. Albumin metabolic data from two .tudie. in Mrr. A. R. Parameter Body wt (kg) Plasma volume (m\) (ml/kg) Plasma albumin (g/l00 mil IV albumin pool (g) (mg/kg) EV/lVratio Total exchangeable albumin pool (g) (mg/kg) T .. (daya) Fractional cata· bolicrate (% iv pool/day) Absolute catabolic rate (g/day) (mg/kg/day)

Study 2"

Study 1· (Nov 1973)

(Feb 1975)

49.3

61.1 1830 30.1 3.5

2098

42.5 2.0

Normal value

41.1 % 5.6 3.82 % 0.11

42.0 0.85 1.86

64.0 1.05 1.71

1.73 % 0.02 1.44 % 0.06

120 2.43 18.2

173 2.83 15.0

4.23 % 0.16 17-21

8.5

12.9

7-13

3.6 82

8.3 135

188 % 14

• While pellagrinoUi. • After treatment oC pellagra with nicotinamide.

L-Tryptophan

/

Serotonin

/

\ Kynu,\, Nicotinamide

5HIAA Protein Synthesis

FIG. 3. Simplified diagram showing relationship of circulating v tryptophan to production of serotonin and its metabolites. to nicotina· mide. and to protein synthesis.

It is difficult, however, to disentangle the effects of nicotinic acid deficiency and protein malnutrition. We considered the possibility of supplementing the diet of the patient we describe with parenteral L·tryptophan. This was not done because of the fear that such treatment might have exacerbated the symptoms of carcinoid disease. The improved nutrition of the patient led to a remarkable change in her well· being together with healing of the skin lesions and diminution of the diarrhea and steatorrhea. It is suggested that nicotinic acid may be helpful in the treatment of many patients with carcinoid disease even when skin lesions are not clinically apparent. Addendum Mrs. A. W. remains well 21/2 years after having been treated for pellagra.

Vol. 71. No.3 REFERENCES

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