[CANCER RESEARCH 37, 2373-2376, July 1977]
Effects of Cancers of the Endocrine and Central Nervous
Systems on Nutritional Status1
Mortimer B. Lipsett
Clinical Center, National Institutes of Health, Bethesda, Maryland 20014
Summary
Tumors of the endocrine system and cancers exhibiting
paraendocrine behavior can secrete peptides that stimulate
secretions of the gastrointestinal tract. This may lead to
malabsorption diarrhea and consequent weight loss. Tu
mors may also utilize excessive amounts of specific nutri
ents thereby creating deficiencies. Within the central nerv
ous system, strategically placed tumors can cause major
deviations from normal in appetite. Some of these perturba
tions, in lesser degree, may contribute to the weight
changes frequently observed in patients with cancer.
The converse of hypothalamic obesity, a specific central
nervous system lesion producing aphagia, has been re
ported rarely (17, 27). The presumption is that the tumor has
destroyed or denervated the ventrolateral hypothalamus. Of
course, many intracranial cancers, primary or metastatic,
will produce inanition, but this may be considered a rela
tively nonspecific event and can be associated with any
widespread central nervous system disease.
Of some relevance to central nervous system tumors and
nutrition is the development of diabetes insipidus due to
tumors. In 1 large series (7), almost half of the cases of
diabetes insipidus were due to tumors in and around the
pituitary gland and median eminence. Somewhat less than
5%of the casesof diabetesinsipidusweredueto metastatic
Introduction
Cancer or benign tumors of the endocrine glands or of
the central nervous system can alter nutritional status by
any of several mechanisms. Although the specific nutritional
disturbances are rare, they may serve as paradigms for the
many, apparently routine, clinical states of weight loss ac
companying cancer. AS primary events, the mechanisms
vary among marked deviations of food intake, loss of spe
cific nutrients, and effects of substances produced by the
cancers on the gastrointestinal tract. These possibilities are
detailed in Table 1. Since almost each topic listed in this
table has been the subject of a monograph, the “Refer
ences―will cite only recent or seminal papers.
Food Intake
It is clear that the centers concerned with regulation of
food intake lie in the hypothalamus. Experimentally, de
struction of the ventromedial hypothalamus by either an
electric current or gold thioglucose produces hyperphagia
and obesity (2), and destruction of the ventrolateral hypo
thalamus causes aphagia (2). Thus, tumors impinging on
these areas might well be expected to produce similar re
suIts.
There are several reports of bulimia and rapid weight gain
in children with acute leukemia due to infiltration of Ieu
kemic cells in the hypothalamus (8). In adults, similar docu
mentation has been more difficult to obtain, and even in the
5 patients reported by Bray and Gallagher (8) the rate of
weight gain was modest.
1 Presented
at
the
Conference
on
Nutrition
and
ber 29 to December 1, 1976, Key Biscayne, Fla.
Cancer
Therapy,
Novem
involvement of the pituitary stalk. Breast cancer and bron
chus cancer can have as their 1st manifestation diabetes
insipidus, when the metastasis interrupts the fibers between
the supraoptic nuclei and the posterior pituitary gland.
Although such lesions affect only water exchange, there
may be secondary results on nutrition. Severe diabetes
insipidus will lead to decreased food intake because of the
large volumes of fluid necessary to maintain water balance;
this is particularly relevant for children. Another reason for
nutritional effects is the use of calories to bring the large
volumes of cold water to body temperature. In small chil
dren, this may be a significant fraction of the calories de
rived from the diet.
Deviations in Metabolic Pathways
Tumors can affect nutrition by causing deviation of spe
cific essential food substances. This is different from the
tumor “nitrogen
trap―discussed in the past (25). In several
instances endocrine tumors have been responsible for
these effects.
One outstanding example of this is the pellagra produced
by metastatic carcinoid tumors (33). Niacin, the vitamin
necessary to prevent pellagra, is nonessential since it is
normally synthesized in vivo from dietary tryptophan, an
essential amino acid. The use of tryptophan for serotonin
synthesis preempts the amino acid so that the rate of niacin
synthesis is greatly reduced. The clinical signs of pellagra
that have appeared in patients with the carcinoid syndrome
have responded well to supplementary niacin. Hypoalbumi
nemia may also occur in the carcinoid syndrome caused, in
part, by the lack of tryptophan for protein synthesis.
Hypoalbuminemia may result from involvement of the
gastrointestinal tract lymphatics with cancer (35) and the
JULY 1977
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1977 American Association for Cancer Research.
2373
M. B. Lipsett
Table 1
Mechanismsof tumor-induced weight change
Effects on the hypothalamus
Central nervoussystemtumors
Metastaticdisease
Bulimia
Inanition
Diabetesinsipidus
Deviations in metabolic pathways
Malignant carcinoid: niacin, albumin
Adrenal cancer: cholesterol
Carcinoid, lymphoma:albumin, protein-losing enteropathy
Substancesproduced by tumors associatedwith weight loss
Parathormone:
parathyroid tumors
Osteolytic substances: cancers
Vasoactiveintestinal peptide: pancreatic islet-cell tumors, severalcancers
Gastrin: pancreatic islet-cell tumors, gastric cancer
Enteroglucagon:cancer, probable islet-cell origin
Glucagon:
islet-cell
tumor
Calcitonin: medullary carcinoma of the thyroid
Histamine:
systemic
mastocytosis
resultant protein-losing enteropathy. This has often been
described in association with the carcinoid syndrome. The
reasons are multiple. First, the tricuspid insufficiency and
the right heart failure that complicate the carcinoid syn
drome can cause the protein-losing enteropathy. However,
some patients with metastatic carcinoid but without tricus
pid disease have also demonstrated albumin loss into the
gut, so that additional mechanisms must be postulated. The
diarrhea produced by metastatic carcinoid should also be
noted since it may contribute to the malnutrition. In contrast
to some of the other manifestations of the carcinoid syn
drome, it is likely that the serotonin increases small bowel
mobility, thereby producing the diarrhea.
A rare manifestation of a tumor causing loss of a specific
nutritional substance is the hypocholesterolemia produced
by an adrenal tumor. Leichter and Daughaday (18) reported
studies of a patient with a large adrenal adenoma whose
serum cholesterol concentration was 70 mg/100 ml. It has
been shown that plasma cholesterol is the preferred precur
sor for adrenal cortical steroid synthesis (4) so that the
active synthesis of steroid by the tumor may be assumed to
have used plasma cholesterol at a rate faster than it could
be synthesized. This may be related to the finding observed
by me more than 10 years ago that some patients with
adrenal cancer who responded to Ortho Para prime DDD
ethane mitotane had a rise in serum cholesterol (19).
An interesting alteration of metabolism that should be
recognized in analyzing the metabolic events accompany
ing cancer cachexia is the effect of malnutrition on thyroid
hormone metabolism. It seems probable that triiodothyro
nine is the active intracellular thyroid hormone, and plasma
triiodothyronine is derived almost exclusively from plasma
thyroxine. In protein-calorie malnutrition, plasma triiodo
thyronine falls in spite of a normal or slightly increased
plasma thyroxine. (10). On refeeding, triiodothyronine in
creases. Evidence for physiological hypothyroidism as mea
sured by plasma thyroid-stimulating hormone or speed of
the Achilles tendon reflex is lacking. It is, therefore, not
clear how changes in plasma triiodothyronine during pe
nods of starvation and refeeding will alter metabolic param
2374
eters, but thyroid function will certainly need to be consid
ered in sophisticated studies of intermediary metabolism in
cancer cachexia.
SubstancesProducedby EndocrineGlands and Paraen
docrineTumors
Hypercalcemia. Whether hypercalcemia results from par
athormone excess or is a product of tumor-induced osteoly
sis, it exerts a marked anorexigenic effect. In 1 series of
patients with hypercalcemia due to hyperparathyroidism,
30% of the patients had weight loss ranging between 10 and
65 pounds (20). When the hypercalcemia is caused by a
nonendocrine gland cancer, it is difficult to dissociate the
factors causing weight loss, but hypercalcemid needs al
ways to be considered.
VasoactiveIntestinalPeptide.There are manypeptides
produced by endocrine and nonendocrine tumors that act
at the gastrointestinal tract. Only as immunoassays have
been developed has it been possible to relate these peptides
to specific illnesses.
The syndrome of watery diarrhea or pancreatic cholera
has been described in association with non-beta-cell tu
mors of the pancreas. The name, pancreatic cholera, is
descriptive of the usual origin of the peptide as well as the
clinical manifestations of the syndrome (34). The diarrhea is
due to stimulation of small bowel secretions by the peptide
hormone, vasoactive intestinal peptide. Vasoactive intes
tinal peptide has been shown to activate small bowel adenyl
cyclase as does choleragen with resultant secretion of
fluids (32).
This peptide can be bioassayed by its smooth muscle
relaxing property, but, more recently, an immunoassay has
been developed sensitive enough for plasma measurements
(6, 31). Using this assay, the vasoactive intestinal peptide
level was often too low to measure in normal individuals and
rarely exceeded 1 ng/mI. In a series of 30 patients with
watery diarrhea, the average plasma concentration of vaso
active intestinal peptide was 5 ng/mI (31). Since vasoactive
CANCER RESEARCHVOL. 37
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1977 American Association for Cancer Research.
Cancers of Endocrine and Central Nervous Systems
intestinal peptide occurs throughout the gastrointestinal
tract, it is not surprising that some tumors of the gastroin
testinal tract continue to secrete it.
Of particular
interest was the finding of high plasma vaso
active intestinal peptide levels in association with squa
mous carcinoma of the bronchus in patients with watery
diarrhea (31). This is another example of the paraendocrine
behavior of lung cancer and explains the poorly understood
diarrhea and weight loss occasionally noted in these pa
tients. How often vasoactive intestinal peptide is secreted in
lesser amounts by patients with lung cancer is unknown.
There is another and rarer type of diarrhea with weight
loss that is seen in children (38) and rarely in adults with
ganglioneuroblastoma (9). It seemed unlikely that the cate
cholamines could be the cause of the diarrhea because
patients with pheochromocytomas more often suffer from
constipation than diarrhea. The identification of vasoactive
intestinal peptide in plasma of patients with ganglioneuro
blastoma (26, 31) suggests the explanation for the diarrhea.
In general, the ganglioneuroblastomas
associated with
diarrhea have been functional as defined by the excretion of
large amounts of catecholamine metabolites.
Enteroglucagon.Althoughonly a single patient with a
tumorsecreting enteroglucagon has been reported (14), the
occurrence of malabsorption and weight loss makes the
case worthy of notice. Measurement of enteroglucagon has
not been performed routinely so that the extent of oc
currence of the syndrome is unknown.
The patient was a 47-year-old man with diarrhea and
intestinal malabsorption. He was subsequently shown to
have a renal tumor that appeared histologically to resemble
pancreatic alpha cells. Resection of the tumor caused re
mission of the symptoms. Subsequent analysis of the tumor
showed it to contain enterog@ucagon, as distinguished from
pancreatic glucagon, in high concentration (5). The mecha
nism of production of the sprue-like syndrome remains
unexplained but does suggest that this cause should be
sought in unexplained cases of malabsorption. It should be
noted in passing that 1 glucagonoma has been associated
with diarrhea and weight loss (21), although others are not
manifested in this way (22). The identification of enteroglu
cagon or glucagon does not prove that they are the etiologi
cal agents; tumors produce many peptides, and as yet uni
dentified peptides may be causative.
2 higher-molecular-weight
immunoreactive
gastrins
having
been described (16, 39).
It should be recognized
that a high percentage
of patients
with Zollinger-Ellison syndrome have 1 or more manifesta
tions of multiple endocrine adenomatosis Type I (12). This
hereditary syndrome is characterized by functional adeno
mas of the pituitary gland, parathyroids, and islet cells.
Hormones that may be produced in excess are growth hor
mone, parathormone, and insulin. Of the patients with mul
tiple endocrine and adenomatosis Type I, about 50% have
ulcers that can probably be related to gastrin secretion (3).
The aggregation of these adenomas and the interactions of
the secreted hormones may make it difficult to identify with
surety the reasons for weight loss.
The question of gastrin secretion by gastric cancers has
been considered. In general, patients with gastric cancer
involving the pylorus have lowered gastrin secretion,
whereas carcinoma of the body of the stomach has been
associated with high plasma gastrin levels, due presumably
to destruction of the acid-producing cells (23). In 1 case of
gastric cancer, however, convincing evidence of gastrin
secretion has been obtained (30).
The similarity of structure among many of the gut peptide
hormones has only recently become apparent (36, 37). Thus
tumors may be expected to synthesize 1 or more of these
peptides at times, and a systematic study should be made of
all islet-cell pancreatic tumors, whether or not they are
symptomatic. The existence of other gut peptides (28, 29)
that have seldom been analyzed in humans may provide
explanations for some of the alterations of appetite and the
weight loss seen in patients with cancer.
Histamine,Thereareseveralreportsof malabsorption
and
diarrhea occurring in patients with systemic mastocytosis
(1, 11), a disease associated with increased secretion of
histamine from the mast cells. The etiology of the malab
sorption is not clear since it is not always a result of gastric
acid hypersecretion. When malabsorption and diarrhea oc
cur together in patients with systemic mastocytosis, there
may be profound weight loss. Blood histamine has been
normal and tissue histamine high in some patients (1). The
marked improvement in 1 patient treated with Metiamide, a
histamine blocker (13), suggested that the histamine was
exerting its effects on other than gastric histamine recep
tors since the effects of Metiamide were much more pro
Gastrin.The Zollinger-Ellisonsyndromeis characterized nounced than in patients with peptic ulcer and high acid
by secretion of large volumes of gastric acid, refractory
secretion.
peptic ulcer, diarrhea, malabsorption, and weight loss (24).
Calcitonin. Medullarycancerof the thyroid is generally
Definition of the role of gastrin as the etiological agent recognized as part of multiple endocrine adenomatosis
required the isolation of gastrin and the development of a Type II. Diarrhea and weight loss may be associated with
radioimmunoassay (24). The malabsorption and weight loss this cancer and have been variously attributed to secretion
may be attributed to damage to the duodenal mucosa by the of prostaglandins and serotonin. Calcitonin, the important
large volumes of acid as well as precipitation of bile salts secretory product of this tumor, has been shown to cause
and denaturation of pancreatic lipase.
secretion of water and electrolytes by the jejunal mucosa,
Eighty % of patients with the Zollinger-Ellison syndrome
thereby explaining the diarrhea (15). This adds to the list of
have a pancreatic tumor of which 60% are cancerous. Gas
peptides involved in stimulation of the gut with resulting
trin is most abundant in the pyloric and proximal duodenal
diarrheogenic syndromes.
mucosa, but it is present in small amounts in pancreatic
delta cells. It should, therefore, not be unexpected that
References
tumors of these pancreatic islet cells retain the capacity to
1. Ammann, A. W., Vetter, D., and Deyhie, P. Gastrointestinal Involvement
synthesize gastrin. As with other peptide-secreting cancers,
in Systemic Mastocytosis. Gut, 17: 107—112,
1976.
there is heterogeneity of the secreted products with at least
2. Assimacopoulos-Jeannet, F., and Jeamenaud, B. The Hormonal and
JULY 1977
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1977 American Association for Cancer Research.
2375
M. B. Lipsett
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Metabolic Basis of Experimental Obesity. Clin. Endocrinol., 5: 337-365,
1976.
Ballard, H. S., Frame, B., and Hartsock, A.J. Familial Multiple Endocrine
Adenoma-Peptic Ulcer Complex. Medicine, 43: 481-516, 1964.
Barkowski, A. J., Levin, 5., Delcroix, C., Mahier, A., and Verhas, V.
Blood Cholesterol and Hydrocortisone Production in Man: Quantitative
Aspects of the Utilization of Circulating Cholesterol by the Adrenals at
Rest and Under Adrenocorticotropin Stimulation. J. Clin. invest. , 46:
797-811, 1967.
Bloom, S. A. An Enteroglucagon Tumour. Gut, 13: 520—523,
1972.
Bloom, S. A., and Polak, J. VIP Measurement in Distinguishing Verner
Morrison Syndrome and Pseudo Verner-Morrison Syndrome. Clin. En
docrinol. 5 (Suppl): 223-228, 1976.
Blotner, H. Primary or Idiopathic Diabetes insipidus: A System Disease.
Metabolism, 7: 191-200, 1958.
Bray, G. A., and Gallagher, T. F., Jr. Manifestations of Hypothalamic
Obesity in Man. Medicine, 54: 301-330, 1975.
Cameron, D. G., Warner, H. A., and Szabo, A. J. Chronic Diarrhea in an
Adult with Hypokalemic Nephropathy and Osteomalacia due to a Func
tioning Ganglioneurobiastoma. Am. J. Med. Sci., 253: 417-424, 1967.
Chopra, I. J., and Smith, S. A. Circulating Thyroid Hormones and Thyro
tropin in Adult Patients with Protein-Caloric Malnutrition. J. Clin. Endo
crinol. Metab., 40: 221-227, 1975.
Dantzig, P. L. Tetany, Malabsorption and Mastocytosis. Arch. internal
Med.,135:1514—1518,
1975.
Ellison, E. H., and Wilson, S. 0. The Zoilinger-Ellison Syndrome. Reap
praisal and Evaluation of 260 Registered Cases. Ann. Surg., 160: 512530, 1964.
Feldman, E. J., and lsenberg, J. I. Effects of Metiamide on Gastric and
Hypersecretion, Steatorrhea, and Bone-Marrow Function in a Patient
with Systemic Mastocytosis. New Engi. J. Med., 295: 1178-1 179, 1976.
Gleason, M. H., BloomS. A., Polak,J.M.Henry,K.,and
Dowling, A. H.
Endocrine Tumour in Kidney Affecting Small Bowel Structure, Motility,
and Absorptive Function. Gut, 12: 773-782, 1971.
Gray, T. K., Bieberdorf, J. A., and Fordtran, J. S. Thyrocalcitonin and the
Jejunal Absorption of Calcium, Water, and Electrolytes in Normal Sub
jects. J. CIin. Invest., 52: 3084-3088, 1973.
Gregory, A. A., and Tracey, H. J. isolation of Two “Big
Gastrins―from
Zollinger-Eliison Tumour Tissue. Lancet, 2: 797-799, 1972.
Kagan, H. Anorexia and Severe Inanition Associated with a Tumour
Involving the Hypothalamus. Arch. Diseases Children, 33: 257-260, 1958.
Leichter, S. B., and Daughaday, W. H. Massive Steroid Excretion and
Hypocholesterolemia with an Adrenal Adenoma. Ann. Internal Med., 81:
638-640, 1974.
Lipsett, M. B. Treatment of Adrenal Carcinoma. Modern Treat. 3: 13771388, 1966.
Mallette, L. E., Bilezikian, J. P., Heath, 0. A., and Aurbach, G. D. Primary
Hyperparathyroidism: Clinical and Biochemical Features. Medicine, 53:
127-146, 1974.
Mallison, C. N. A Glucagonoma Syndrome. Lancet, 2: 1-4, 1974.
2376
22.McGarran,
M. H.,Unger,A.H.,Recant,
L.,Polk,
H.C.,Kilo,
C.,and
Levin, M. E. A Glucagon-Secreting Alpha-Cell Carcinoma of the Pan
creas. New Engi. J. Med., 274: 1408-1413, 1966.
23. McGuigan, J. E. Disorders of Gastrin Secretion. Advan. Internal. Med.,
19: 175-193,1974.
24. McGuigan, J. E., and Trudeau, W. L. immunochemical Measurement of
Elevated Levels of Gastrin in Serum of Patients with Pancreatic Tumors
of the Zollinger-Ellison Variety. New Engl. J. Med., 278: 1308-1313, 1968.
25. Mider, G. B., Tesluk, H., and Morton, J. J. Effects of Walker Carcinoma
256 on Food Intake Body Weight and Nitrogen Metabolism of Growing
Rats. Acta Unio Intern. Contra Cancrum, 6: 409-420, 1948.
26. Mitchell, C. H., Sinatra, F. A., crast, F. W., Griffin, R., and Sunshine, P.
Intractable Watery Diarrhea, Ganglioneuroblastoma, and Vasoactive In
testinal Peptide. J. Pediatr., 89: 593-594, 1976.
27. Nicholson, M., Keitel, H., Williams, J., Miliican, F., Lowrie, A. S., Lo
Presti, J. M., Stevens, H., and Gum, G. H. Pinealoma with Associated
Hypematremia and Symptoms of Anorexia Nervosa. Clin. Proc. Chil
dren's Hosp. Washington, D. C., 13: 133—145,
1957.
28. Rayford, P. L., Miller, T. A., and Thompson, J. C. Secretin, Choiecysto
kinin and Newer G-I Hormones. New Engl. J. Med., 294: 1093-1100,
1976.
29. Rayford, P. L., Miller, T. A., and Thompson, J. C. Secretin, Cholecysto
kinin and Newer G-i Hormones. New EngI. J. Med., 294: 1157-1164,
1976.
30. Royston, C. M. S., Brew, D. St. J., and J. Garnham, J. R. The Zollig
ner-Ellison Syndrome Due to an infiltrating Tumour of the Stomach.
Gut.,
13:638-642,
1972.
31. Said, S. I., and Faloona, G. A. Vasoactive Intestinal Peptide and Watery
Diarrhea. New Engi. J. Med., 293: 155-160, 1975.
32. Schwartz, C. J., Kimberg, D. V., Sheerin, H. E., Field, M., and Said, S. I.
Vasoactive Intestinal Peptide Stimulation of Adenyiate Cyclase and Ac
tive Electrolyte Secretion in Intestinal Mucosa. J. Clin. Invest. , 54: 536—
544, 1974.
33. Sjoerdsma, A. Serotonin. New Engi. J. Med., 261: 181-188; 231-237,
1959.
34. Verner, J. V., and Morrison, A. B. Endocrine Pancreatic Islet-Cell Dis
ease with Diarrhea. Arch. Intemal Med., 133: 492-500, 1974.
35, Waldmann, T. A., Broder, 5., and Strober, W. Protein-Losing Enteropa
thies in Malignancy. Ann. N. Y. Acad. Sci., 230: 306-317, 1974.
36. Walsh, J. H., and Grossman, M. I. Gastrin. New Engl. J. Med., 292: 1324—
1334; 1377-1384, 1975.
37, Walsh, J. H., and Grossman, M. I. Gastrin. New Engi. J. Med., 292:
1377-1384, 1975.
38. Williams, T. H., House, A. F., Jr., Burgert, E. 0., Jr., and Lynn, H. B.
Unusual Manifestations of Neurobiastoma: Chronic Diarrhea, Polymy
oclonia-Opsoclonus and Erythrocyte Abnormalities. Cancer, 29: 475480, 1972.
39. Yaiow, A. S., and Berson, S. A. And Now “Big,
Big―Gastrin. Biochem.
Biophys. Aes. Commun., 48: 391-395, 1972.
CANCER RESEARCHVOL. 37
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1977 American Association for Cancer Research.
Effects of Cancers of the Endocrine and Central Nervous
Systems on Nutritional Status
Mortimer B. Lipsett
Cancer Res 1977;37:2373-2376.
Updated version
E-mail alerts
Reprints and
Subscriptions
Permissions
Access the most recent version of this article at:
http://cancerres.aacrjournals.org/content/37/7_Part_2/2373
Sign up to receive free email-alerts related to this article or journal.
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Department at [email protected].
To request permission to re-use all or part of this article, contact the AACR Publications
Department at [email protected].
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1977 American Association for Cancer Research.