GuTllOllNTUOLOOY 71:484-489. 1976 Vol. 71 . No.

3
Copyright «> 1976 by The Willi. IDa " Wilkin. Co. Printed in U.S.A.

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 treat-
ment. 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.

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 syn-
drome, 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, Cleve-
land. 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
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 phenoxybenzam-
ine 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 .
Sept,'mber 1976 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
485
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 al-
bumin 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 Vol. 71, No.3

T:ULE 1. Serotonin and its metabolites of albumin were within the normal range, but as the
Pla.ma intravascular albumin pool was much depleted the
Date
Urine absolute catabolic rate and therefore the synthetic rate
(month/day/yearl Tryp· sHT· SHIAA' 5H1AA of albumin was very much reduced. Correction of the
tophan· (ng/mll (ng/mll (mg/24hr)
("I/mll nutritional deficiencies was associated with a fall in the
till of albumin and an increase in the fractional catabolic
l1/2na 4.8 180 rate to the upper limit of normal. In absolute terms this
11I28na 6.8 360 1270 represents an increase in synthetic rate of more than
2/12n4 14.4 152 100% and a value which, on a body weight basis, was also
2/lOns 13.6 350 970 146
Normal range 8-14 0-30 Undetectable 3-17
much increased. At the same time gut loss of protein was
normal (equivalent to 0.74 g :I: 0.32 of albumin per day
• Plasma "tryptophan was measured by the method of Denckla and as estimated from the clearance of &ICr-labeled chromic
Dewey'· as modified by Bloxham and Warren.'· chloride). If the only defect in albumin metabolism had
• Plasma levels of 5HT (5-hydroxytryptamine) and 5HIAA were been one of synthesis, however, a prolongation of till and
measured by a modification of the method of Curzon and Green" as a fall in fractional catabolic rate of albumin would have
described by Joseph and Baker (in prepCJ1'CJtion). occurred. These effects were probably balanced by
hypercatabolism of albumin as a result of diffuse tumor
constant plasma albumin concentration and body spread. Additionally, in normal circumstances, a till
weight. Human serum albumin was prepared by Sepha· (albumin) of 18.2 days would be associated with a
dex G150, DEAE·cellulose chromatography, and prepa· fractional catabolic rate (as calculated by Matthews'
rative polyacrylamide electrophoresis, and labeled with method 20) of 10 to 12% rather than the measured value of
1211 at a ratio of less than 1 atom per mole by the iodine 8.5%. This anomaly may be explained in part by the
monochloride method of McFarlane. II. 1t Trichloroacetic abnormally high extravascular to intravascular ratio
acid.precipitable radioactivity exceeded 99%. Control which persisted despite treatment. The distribution and
studies on the same preparations confirmed that the metabolism of albumin within the tumor mass are im-
albumin had retained its native properties as defined by portant factors in the analysis of this data and it is of in·
a normal plasma half·life (till) of 17 to 21 days. A single terest to note that the increased synthetic rate of albu·
measured dose of about 60 ",c of taSI-labeled albumin was min after treatment was not sufficient to correct entirely
administered intravenously after blocking the thyroid for the extravascular sequestration of albumin.
uptake of radioactive iodine with oral potassium iodide.
Plasma samples were taken at 10 and 20 min and then Discussion
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 Autoanaly- Amino acid Nov 1973 Feb 1975 Normal adult
range-
ser.
"mole./liter
Results and their Interpretation Asp 57 29 0-24
The metabolic data of the albumin turnover studies in Thr 270 160 79-193
the patient both when she was clinically pellagrinous Ser 308 173 73-167
and hypoalbuminemic and later when she had been fully GIn 278 265 415-695
Gly 520 325 120-554
treated and was normoalbuminemic are shown in table 3. Ala 368 395 210-662
In the first study the plasma volume expressed on the Val 118 225 141-317
basis of body weight was normal. On the second occa- Met 5 34 6-40
sion, when the edema had regressed, the plasma volume Ile 50 84 37-98
expressed this way was subnormal, although the abso- Leu 112 130 75-176
lute change was small. In interpreting these measure- Tyr 99 85 22-88
ments it is important to note that the tumor mass made Phe 78 56 37-88
a significant contribution to body weight, especially as a Lys 250 216 83-238
percentage of lean body mass. True body weight and His 175 105 23-77
muscle bulk increased considerably between the two Arg 203 lOS 21-137
studies. Plasma albumin concentration increased to "In spite of the patient's malnourished state the concentration of
almost normal values and there was an expansion of serum amino acids (excluding tryptophan) were well maintained
both the intravascular and total exchangeable albumin except for the somewhat low levels of valine and methionine. This
pools. pattern is similar to that seen in pellagra."
In the first study the till and fractional catabolic rates • Adapted from Niederweiser and Pataki. n
September 1976
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 resec-
tion, "." 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 concen-
trat 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 produc-
tion 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-
CASE REPORTS 487
lating 5-hydroxytryptamine and 5HIAA and for the
excretion of 5HIAA irrespective of the patient's nutri-
tional state. On t he other hand t he metabolic st udies
suggest that the supply of L.tryptophan was rate-limit-
ing 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 trypto-
phan 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 mole-
cule"·· 37
488 CASE REPORTS Vol. 71. No.3

TABLB 3. Albumin metabolic data from two .tudie. in Mrr. A. R. REFERENCES

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/
5HIAA Nicotinamide
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
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