CHAPTER 48

Nutritional, Metabolic and Endocrine Disorders

Contents often have cutaneous signs reflecting their inade-

quate nutrition. Such problems are, not surprising-
Nutritional Disorders 1349
Marasmus
ly, most common in the Third World, but they may
1349
Kwashiorkor . . . . 1350 also occur in the poor, elderly, alcoholics, drug
Essential Fatty Acid Deficiency 1351 abusers, individuals with chronic diseases and
Noma . . . . . 1351 those with psychosomatic eating disorders or more
Tropical Ulcer 1352 severe psychiatric illnesses. Initially a variety of
Eating Disorders 1352
Bulimia . . . .
nutritional deficiencies were seen in postoperative
1352
Anorexia Nervosa 1353 patients or chronic bowel disease patients who re-
Metabolic Disorders 1353 ceived long-term parenteral nutrition. Today, how-
Cystic Fibrosis .. 1353 ever, the parenteral diets are so carefully monitored
Endocrine Disorders 1354 that deficiencies are the exception. In an experi-
Pituitary Gland . . 1354
Hypopituitarism
ment at the University of Minnesota volunteers re-
1355
Hyperpituitarism 1355 ceived a 1570 calorie diet for 23 weeks. Their skin
Acromegaly . . . 1355 showed changes also associated with aging, as it be-
Prolactinoma . . 1355 came thinner, drier and less elastic. Lack of protein
Cushing Disease 1355 and inadequate caloric intake lead to a variety of ill-
Diabetes Insipidus 1356
Thyroid Gland . . . .
nesses; while the spectrum is broad, one usually
1356
Hypothryoidism . 1356 speaks of marasmus and kwashiorkor although the
Congenital Hypothyroidism 1356 two frequently overlap.
Hashimoto Thyroiditis .. 1356
Hyperthryoidism 1357
Graves Disease . 1357
Thyroid Tumors
Marasmus
1357
Parathyroid Glands 1358
Adrenal Glands . . 1358 Definition. State of general malnutrition in which
Hyperadrenalism 1358 both proteins and calories are insufficient.
Cushing Syndrome 1358
Hypoadrenalism . 1359
Addison Disease
Epidemiology. Starvation is a problem across much
1359
Excessive Androgen Production 1359 of the world. World Health Organization estimates
Pheochromocytoma 1360 vary but a staggering number of people around the
Testes .. . 1360 globe go hungry. In western countries, malnutri-
Ovaries . . . . . . . . 1360 tion is a more appropriate designation; seriously
Pancreas . . . . . . 1360
Diabetes Mellitus .
and terminally ill patients, the elderly, and the poor
1360
Polyendocrine Disorders . . . . . 1363 are all at risk.
Polyendocrine Deficiency Disorders 1363
Multiple Endocrine Neoplasia 1363 Etiology and Pathogenesis. While one can write a
Bibliography .. . . . . . . . . . . . . 1364 great deal, the cause is simple. Starvation leads to
marasmus.

Clinical Findings. Patients with marasmus general-

Nutritional Disorders
A well-balanced di,et with sufficient protein and
calories is essential for normal skin. Patients with
malnutrition, inappropriate diets or malabsorption
O. Braun-Falco et al., Dermatology
© Springer-Verlag Berlin Heidelberg 2000
ly weigh less than 60 % of their ideal body weight
and have no edema. In developing countries, mar-
asmus is frequently seen as food supplies are
simply inadequate, especially during periods of
drought, pestilence or war. In western countries,
1350 Chapter 48' Nutritional, Metabolic and Endocrine Disorders

marasmus is almost only seen in dying patients, Clinical Findings. Kwashiorkor usually develops in
generally those with widespread cancer. Intake children older than 6 months, generally when they
of proteins, calories and vitamins is inadequate. cease to nurse. Not all patients have cutaneous in-
Many patients, especially children, have sunken volvement, but it may be very characteristic.
cheeks through loss of the buccal fat. What is typi- Pigmentary abnormalities are quite common.
cally absent is the edema associated with protein There may be hypopigmentation about the mouth
loss alone - also known as "hunger edema:' In and on the legs, which are also generally swollen
addition, the patients are hungry and eager to eat, and scaly. Hyperpigmentation may also be seen, es-
not apathetic. pecially following inflammatory changes, such as
Cutaneous signs are numerous. Most typically impetigo. The skin also shows discrete erythema-
the skin is very dry and may show excessive tous, hyperkeratotic lesions, which typically spare
folds, as the subcutaneous fat is markedly reduced. sun-exposed areas, in contrast to pellagra. The le-
For the same reason, some muscles may appear sions have been compared to peeling paint; they are
more prominent, although in truth most are re- irregular, sharply bordered and can be diffuse.
duced in size, especially those of the neck and Deep fissures may develop around the joints and
gluteal region. Follicular hyperkeratoses may de- the mouth. Mucosal surfaces may be dry and
velop. The hairs tend to be an early marker, as irritated; the lips and genital mucosa are most often
they become thin, pale, fragile and grow slowly. involved.
Telogen effluvium is almost an invariable compo- The hair may also be characteristic. Typically it is
nent of malnutrition, especially if the nutritional dry, lusterless, and has a pale red-brown color. Very
problem is of sudden onset. Similarly, the nails characteristic is the flag sign, in which there are
become more brittle and may be split. bands of normally colored and hypopigmented
hair. In contrast, in the flag sign of chemotherapy,
Therapy. An adequate diet is all that is needed. the bands of abnormal hair are darker than the nor-
mal color. The hairs are fine and easily broken. A
trichogram may reveal reduced numbers of anagen
Kwashiorkor hairs which appear atrophic.
The clinical manifestations of kwashiorkor are
Definition. Kwashiorkor is a Ghanaian tribal word often made more obvious by concomitant infec-
meaning (roughly paraphrased) "the first child gets tions. Because of the protein deficiency, not only is
it, when the second is on the way:' Kwashiorkor typ- growth deficient but there may be mental retarda-
ically appears in small children after nursing is tion as well. Muscle atrophy, fatty inflltration of the
stopped, as they receive insufficient proteins and liver, and a moon-like facies are also seen. A sec-
too much of their caloric intake (which is usually ondary kwashiorkor may be associated with bowel
adequate or even excessive) is made up of starches surgery and resultant malabsorption or inadequate
or sugars. nutrition.
If the nutritional defects are corrected, the
Epidemiology. Kwashiorkor is probably more com- systemic findings as well as the skin and hair
mon than marasmus, but limited to societies in changes are reversible. If the protein malnutri-
which adequate amounts of starch are available. tion continues, the process may be lethal or at a
When only maize products are on hand, pellagra minimum destroy the child's prospects for normal
may develop simultaneously with kwashiorkor. development.

Etiology and Pathogenesis. The primary cause is
protein deficiency. Thus kwashiorkor is most com-
mon in those primarily tropical lands where the di-
et is comprised mostly of beans, rice or corn. Vita-
min deficiency, infections and bowel diseases may
predispose or exacerbate kwashiorkor. Dark-skin-
ned races are more often involved, but this probably
reflects economic and social factors rather than ra-
cial predisposition.
Histopathology. The epidermis shows parakerato-
sis and necrotic basal cells. The changes are not
specific.
Diagnosis and Differential Diagnosis. The diagno-
sis is made when children achieve only 60 - 80 % of
their normal weight and at the same time have ede-
ma and/or hypo albuminuria. The skin and hair
changes aid in the diagnosis. As mentioned, there
are often associated vitamin deficiencies. Pellagra
 Noma
may lead to hyperpigmented, scaly skin changes,
but they are typically in sun-exposed areas.
Therapy. A diet with the appropriate amount of
protein is required. Vitamin and mineral supple-
ments should also be instituted.
Essential Fatty Acid Deficiency
Defmition. Shortage of essential fatty acids second-
ary to nutritional deficiencies.
Etiology and Pathogenesis. There is no natural es-
sential fatty acid deficiency. Patients fed a diet too
low in linoleic and linolenic acid can develop skin
findings, growth failure and impaired wound heal-
ing. A large study three decades ago evaluated over
400 infants who were maintained on diets low in
linoleic acid for many months. In addition, patients
on parenteral nutrition and following major gas-
trointestinal resections and otherwise healthy indi-
viduals on bizarre diets may develop essential fatty
acid deficiency. Premature infants also seem to be
at risk. The essential fatty acids are needed for pros-
taglandin synthesis but are also involved in many
membrane processes. They are a major constituent
of triglycerides and are also bound to sterol esters
in the epidermis.
Clinical Findings. The skin becomes dry, leathery
and flaky but with an underlying erythema. The
flexural areas are often eroded and weeping. In
the large study, the findings were more striking
in black children. While the severity of skin
changes correlates with low serum levels of lino-
leic acid, many deficient individuals have no skin
findings.
Course and Prognosis. The outlook is that of the
underlying disorder.
Differential Diagnosis. In patients on an inade-
quate diet who present with erythema and scaling,
often acrally or periorifically, one should consider
zinc deficiency, biotin disorders, cystic fibrosis and
free fatty acid deficiency, as well as the most likely
diagnosis of a mixed deficiency state.
Therapy. Systemic linoleic and linolenic acid sup-
plements rapidly reverse the problem. Sunflower
seed oil is a ready source. In some experimental
studies, topical sunflower seed oil helped the skin
1351
problems, but systemic administration is more rea-
sonable.
Noma
Synonyms. Cancrum oris, gangrenous stomatitis
Noma comes from the Greek and refers to an ulcer
or tumor that eats itself, as the root word is closest
to a meadow where animals graze.
Definition. Rare destructive disease involving the
orofacial tissues, most often of sick children.
Epidemiology. Noma is rarely seen in the United
States or western Europe but more often in coun-
tries where malnutrition is a problem. It is most
common in sub-Saharan Africa.
Etiology and Pathogenesis. Many factors combine
to produce noma. Most patients are children with
malnutrition, infections, immune disorders or
debilitating diseases. Actual tissue necrosis occurs
as a result of invasion by a variety of anaerobic
bacteria including Vincent spirochetes and fusi-
form bacilli. Noma shares many features in com-
mon with the less severe acute necrotizing ulcer-
ative gingivitis, including its occurrence in AIDS
patients.
Clinical Findings. The disorder usually begins with
a painful ulceration, either involving the gingiva or
the buccal mucosa. It may spread rapidly to pro-
duce massive destruction involving soft tissue,
teeth and bones. The entire mid-face may be de-
stroyed. Rarely, noma may start in other sites, such
as the nose or genitalia. The disease may be fatal if
not treated promptly.
Differential Diagnosis. Noma is primarily a clinical
diagnosis. The culture findings may guide therapy
but are not diagnostically specific. Sometimes oth-
er causes of severe oral ulceration, such as major
aphthae or myeloproliferative disease, can produce
a milder but similar picture.
Therapy
Systemic. Broad-spectrum antibiotics are necessary
but not sufficient treatment. Restoration of good
nutrition, intravenous fluids, and general support-
ive measures are equally important.
1352 Chapter 48 • Nutritional, Metabolic and Endocrine Disorders
Topical. Debridement may be helpful, as well as ex-
pert oral hygiene which usually must be supervised
by a health care provider. Topical antiseptics and
anesthetics may provide some relief but are clearly
adjunctive measures.
Surgery. Reconstructure facial surgery is of great
benefit for severely afflicted children.
Tropical Ulcer
Synonyms. Desert ulcer, tropical phagedena
Definition. Mixed bacterial infection, usually in-
volving traumatic wounds of the legs, often in pa-
tients with malnutrition.
Etiology and Pathogenesis. As the name suggests,
tropical ulcer is usually seen in warm, damp cli-
mates, primarily in adults. Epidemics may occur
in military troops or plantation workers, such as
those on rubber or banana plantations. But natives
suffering from malnutrition and chronic diseases
seem to be at greater risk. They are predisposed to
progressive, severe mixed cutaneous infections.
Staphylococci, streptococci and a variety of gram-
negative organisms can be cultured. The same
organisms found in noma may also be identified.
Clinical Findings. The most common site is the
lower aspects of the legs, just above the ankles, usu-
ally following minor injuries. Initially the lesion is
an ecthyma, often with blisters and bloody fluid.
Untreated the disease progresses to produce mas-
sive tissue necrosis, often involving subcutaneous
structures, fat, muscle or even periosteum. A seri-
ous complication is the destruction of larger blood
vessels leading to dangerous hemorrhage. Scarring
is expected and may produce such severe contrac-
tures that amputation is needed. Typically the
scarred tissue has a hyperpigmented periphery.
Minor injuries may lead to recrudescence in the
damaged skin.
Differential Diagnosis. The ulcers caused by Myco-
bacterium ulcerans (Chap. 4) are equally extensive
but not associated with malnutrition.
Therapy
Systemic. Broad-spectrum antibiotics, rationally
adjusted to culture results, have made the progno-
sis much better. While penicillin is most often used
because of its price and availability in poor regions,
cephalosporins, aminoglycosides and ciprofloxacin
have also been recommended. Once again, ade-
quate nutrition, vitamins and good supportive care
are essential.
Topical. Surgical debridement may be needed.
Moist wound care is helpful.
Eating Disorders
Eating disorders have become a fashionable disease
in the past decade and much public attention has
been focused on such patients, both because of the
number of celebrities suffering from an eating dis-
order and because of the difficulty in treating the
problems. Eating disorders are primarily a disease
of women.
Bulimia
Defmition. Eating disorder characterized by binge
eating and purging, either with self-induced vomit-
ing, laxatives and/or diuretics.
Epidemiology. Bulimia has a prevalence of 2 - 5 % in
young women in the USA, but a far higher number
have at least occasionally indulged in bingeing and
purging.
Etiology and Pathogenesis. The cause of bulimia is
unclear. The increasing emphasis on a thin body, as
typified by the Barbie doll, has exerted unusual
pressure on young women. Once one enters the
cycle of bingeing and purging, then a vicious cycle
results. Attempts at caloric restriction trigger more
binges and more purging.
Clinical Findings. Bulimic patients tend to be
healthier than those with anorexia nervosa. The
typical patient is a young, often depressed woman.
These individuals are underweight but have on
average less weight loss than anorexia nervosa
patients, are rarely amenorrheic and may have
normal sexual relations. Their skin is usually
normal, but they often have angular stomatitis or
perleche because they stretch and damage the
corners of their mouths as they induce vomiting.
They may also develop calluses on their knuckles
and the backs of their fingers because of contact
with the upper teeth during the same process
 Cystic Fibrosis
Fig.48.1. Knuckle calluses in a patient with bulimia. (Cour-
tesy of Johnannes Ring, M.D., Munich, Germany)
(Fig. 48.1). They tend to have marked caries and
periodontal disease, both from their inclination to
eat sweets and the repeated exposure of their oral
cavity to stomach acids.
Course and Prognosis. Bulimia patients may have
problems for many years that tend to wax and wane
and sometimes respond very well to therapy.
Differential Diagnosis. Other patients eat in binges
but do not purge. Not surprisingly they tend to be
obese. Men are affected about as often as women
and the onset of problems tends to be after 40 years
of age.
Therapy. Both antidepressant medications and
psychosocial or behavioral therapy can be bene-
ficial.
Anorexia Nervosa
Definition. Eating disorder characterized by mar-
ked dietary restrictions, extreme weight loss and
amenorrhea.
Epidemiology. Anorexia nervosa is much rarer
than bulimia. Its prevalence is around 0.2 % for
women and much less for men. Several studies sug-
gest that its incidence may be increasing.
Etiology and Pathogenesis. The same factors that
playa role in bulimia are important here. The pa-
tient has a weight phobia, with a desire for thinness
but an unrealistic assessment of her own status. De-
pression is also assbciated and there is a familial
tendency to the problem.
1353
Clinical Findings. Anorexia nervosa is character-
ized by extreme weight loss (more than 25 % of
body weight), a distorted body image and often
amenorrhea. The patients live in fear of becoming
fat and show signs as of starvation. Often there is a
history of obesity or excessive exercise. Their skin
is prematurely aged, thin and pale. It is usually dry
and scaly, mimicking a mild ichthyosis. Similarly
their hair tends to be sparse, brittle and often light
colored. The axillary and pubic hair is usually nor-
mal. The edema of kwashiorkor may occur but is un-
common as they tend to be starving themselves and
lack calories as well as proteins. They tend to suffer
from cold skin and especially acrocyanosis. The clin-
ical picture may be complicated by vitamin deficien-
cies. Some patients simply starve themselves, while
others starve, occasionally binge and purge.
Course and Prognosis. Anorexia nervosa patients
do poorly as their disease progresses relentlessly,
while they have little insight into their problem. It is
estimated that 5 % of anorexia nervosa patients die
of their disease or associated psychiatric problems,
including suicide. Often they express concern about
getting fat as they are literally wasting away.
Another 20 - 30 % remain abnormally thin de-
spite therapy, while the rest show some improve-
ment but are rarely normal.
Differential Diagnosis. Panhypopituitarism and
severe psychiatric disorders must be excluded, but
usually the diagnosis is obvious.
Therapy. Aggressive therapy, most often in special
clinics or with special support groups, offers the best
hope of interrupting the disease course and allowing
the patient to lead a normal life. A variety of tech-
niques are used to encourage eating and reward
weight gain. Antidepressants are less helpful than
in bulimia patients are they further suppress the ap-
petite. The skin requires only routine care.
Metabolic Disorders
Cystic Fibrosis
(ANDERSEN 1938)
Synonym. Mucoviscidosis
Definition. Inherited disorder with abnormal
transmembrane ion transport causing primarily
pulmonary and pancreatic problems.
1354 Chapter 48 • Nutritional, Metabolic and Endocrine Disorders

Epidemiology. Cystic fibrosis is one of the most Differential Diagnosis. The rare infant presenting
common genetic disorders. It has an incidence of with skin disease should be examined for acroder-
1/2000 in northern Europeans, but drops to matitis enteropathica, free fatty acid deficiency,
1/100,000 in Asians. The frequency of heterozygotes biotin disorders and inadequate nutrition. The rest
or carriers among Europeans is about 1 in 22. of the differential diagnosis is beyond our scope.

Etiology and Pathogenesis. The cystic fibrosis gene
is on chromosome 7q31.3. It is a very large gene in
which many different mutations have been identi-
fied, but a single mutation o-F508 accounts for
about 70 % of all cases. The gene product, cystic fi-
brosis transmembrane regulator (CFTR) protein,
controls the chloride channel in the cell membrane.
Its absence leads to a high sodium content in the
sweat and a reduced water content in the respirato-
ry and intestinal mucus.
Clinical Findings. Onset of problems is usually ear-
ly in life. Patients present with repeated respiratory
infections, malabsorption, steatorrhea and, in
about 10 % of patients, meconium ileus. As the dis-
ease progresses, bronchiectasis, pancreatic insuffi-
ciency with diabetes mellitus, gallstones, mucoid
intestinal obstruction and infertility are problems.
The vas deferens fails to develop in over 95 % of
men. Heterozygous males (1/22 in Europe) may be
infertile for the same reason (Chap. 67). Women
may be fertile, but their limited life expectancy
threatens their chances to rear a family. Hetero-
zygous individuals may also be at increased risk for
chronic pancreatitis.
Striking skin findings occasionally can be seen,
primarily in the small subset of cystic fibrosis pa-
tients presenting with malnutrition. Erythematous
scaly papules and patches can be found on the dis-
tal aspects of the often edematous extremities,
perineum and periorificial areas. Erythroderma
and alopecia can develop. The skin findings stem
from the secondary deficiencies in zinc, proteins
and essential fatty acids.
Laboratory Findings. The diagnosis is based upon
measuring sweat chloride levels. The normal value
is usually less than 60 mmol/l. False-positive results
have occasionally been reported in atopic dermati-
tis patients, who may have similar skin changes.
Course and Prognosis. The outlook has improved
for cystic fibrosis patients. Fifty years ago 80 % died
in the first year. Today the average age at death is
around 30 years. The main cause of death is pulmo-
nary failure. Some patients have been treated with
lung transplants.
Therapy. The essence of therapy is pancreatic re-
placement and attentive pulmonary care with ap-
propriate and early treatment of infections. Recom-
bin ant human DNAse is used as an aerosol to thin
the respiratory mucus. Inhaled gene therapy has al-
so been tried, but with less success. The skin prob-
lems resolve if dietary measures are undertaken,
supporting their secondary nature.
Prophylaxis. Prenatal diagnosis is possible, but
carrier screening tests are still in developmental
stages.
Endocrine Disorders
In the German edition of this book, there is no spe-
cific section dealing with the cutaneous manifesta-
tions of endocrine diseases. Instead, the various
skin disorders are mentioned throughout the book;
for example, myxedema is discussed under the mu-
cinoses. In this section, we will review the various
endocrine disorders briefly, discuss their cutane-
ous findings and make extensive cross-references
to the relevant chapters. The basic science aspects
of the endocrine disorders will be discussed in
barest detail, while the laboratory diagnosis and
treatment will not be covered.
Pituitary Gland
The pituitary gland was formerly described as the
"master gland" but this is incorrect. It secretes a
number of hormones which direct the function of
other organs, but is regulated to a great extent by
the hypothalamus, which serves as a control center
for processing the many neural stimuli and then
redirecting the body's hormonal response. The
hypothalamic releasing hormones reach the ante-
rior pituitary by a vascular route; they stimulate
the release of growth hormone, thyroid stim-
ulating hormone (TSH), luteinizing hormone
(LH), follicle stimulating hormone (FSH), growth
hormone, prolactin and adrenocorticotropic hor-
mone (ACTH). The ACTH story is more complex,
as a prohormone, pro-opiomelanocortin (POMC)
 Pituitary Gland
is broken down into both ACTH, which is then split
to a-melanocyte stimulating hormone (a-MSH)
and corticotrophin-like peptide (CLIP), and fJ-lipo-
tropin which yields fJ-MSH endorphins and ence-
phalins. These hormones have few direct actions
on the skin, but can be identified by abnormal
function of their target glands. The hypothalamus
also manufactures antidiuretic hormone (ADH,
vasopressin) and oxytocin, which pass directly
down the neural stalk to the posterior lobe of the
pituitary.
Hypopituitarism
The main causes of reduced pltUltary function
include tumors, postpartum ischemia (Sheehan
syndrome), injury (radiation, trauma), granuloma-
tous disease (sarcoidosis, tuberculosis, Langerhans
cell histiocytosis) and in children developmental
defects. The tumors and granulomas may also
cause space-occupying defects, such as visual field
disturbances and headache. Usually the clinical
findings are the result of reduced production and
release of several hormones. Thus there may be
varying signs of hypogonadism, hypothyroidism
and adrenal insufficiency. Prolactin is rarely affect-
ed and growth hormone (GH) deficiency is not
clinically detectable in adults, although it causes
dwarfism in children. The overall cutaneous pic-
ture includes loss of body hair, usually first in-
volving the axillae, pallor, and dry perhaps slightly
puffy skin. The relative loss of pigmentation is
blamed on the lack of melanocyte-stimulating
hormone (MSH), but exactly what role MSH
plays in melanocyte stimulation is controversial.
The various hormones which are lacking can be
replaced.
Hyperpituitarism
While most pituitary tumors are not functional,
some produce increased levels of the various hor-
mones, causing a variety of cutaneous findings. Al-
most all pituitary tumors are benign. Different
morphologic types of tumors have different secre-
tion patterns.
Acromegaly
Acromegaly is the result of oversecretion of GH in
an adult. In a child, the same tumor causes gigan-
tism, but if the problem is not corrected, the indi-
vidual also develops features of acromegaly. Coarse
1355
facial features and enlarged hands and feet are the
most common findings. In adults the changes are
so gradual that diagnosis is often long delayed;
studying older photographs often demonstrates
how long the facial features have been changing.
The skin becomes thickened and furrowed; the un-
fortunate expression of a "basset hound look" is de-
scriptive. Some patients may develop cutis verticis
gyrata. About 10% of patients have acanthosis ni-
gricans or increased skin tags. Other skin findings
such as hypertrichosis, onychodystrophy and in-
creased oiliness may reflect overlaps with other
hormonal disturbances. Treatment is generally sur-
gical; if it is unsuccessful, bromocriptine, a dopa-
mine antagonist, is usually tried.
Prolactinoma
In women, prolactinomas are detected fairly early
because they lead to amenorrhea, infertility and
often galactorrhea. The main later problem is os-
teoporosis. In men, the changes are more subtle, but
include impotence, infertility and perhaps gyneco-
mastia and galactorrhea. The eruption of cherry
angiomas has been described with prolactinomas.
In addition, elevated prolactin levels can cause hy-
perandrogenism, producing androgenetic alopecia
and hirsutism. It appears that prolactin enhances
the end-organ response to normal androgen levels.
Phenothiazines and estrogens may also stimulate
increased prolactin levels. The usual treatment is
bromocriptine, with surgery reserved for medical
failures.
Cushing Disease
Isolated excess secretion of ACTH is true Cushing
disease. Cushing was a neurosurgeon who de-
scribed an ACTH-secreting pituitary tumor. Cu-
shing syndrome refers to any patient with the clin-
ical features produced by excessive corticosteroids,
as discussed below. Interestingly, one of Cushing's
first patients, Minnie G., appears to have had Car-
ney syndrome (Chap. 65), with an autoimmune
type of Cushing syndrome, not a tumor. In Nelson
syndrome, a secreting pituitary tumor develops
after bilateral adrenalectomy for adrenal hyper-
plasia. These patients have very high ACTH levels
because of reduced feedback inhibition, are invari-
ably hyperpigmented and often have evidence for
other hormonal problems.
 Chapter 48 • Nutritional, Metabolic and Endocrine Disorders

Diabetes Insipidus vium may result. Another suggestive fmding is loss

of lateral third of the eyebrows (Hertoghe sign).
Secretion of ADH creates no cutaneous changes. The nails grow slowly and may also be brittle. The
Diabetes insipidus is primarily of interest to der- tongue is thickened and enlarged, often interfering
matologists because of its association with Langer- with articulate speech. A puzzling feature is the
hans cell histiocytosis (in which infIltrates in the yellowish tint that the skin frequently acquires;
pituitary saddle damage the posterior lobe) and there is carotenemia but secondary apparently to
xanthoma disseminatum (in which the foam cells hepatic alterations, not increased ingestion of
damage the connection between the hypothalamus carrots.
and pituitary). Many of the skin findings, and systemic findings,
are relatively nonspecific. This works to the pa-
tient's disadvantage in two ways. The diagnosis of
Thyroid Gland hypothyroidism may be delayed, as fatigue or hair
loss maybe interpreted as physiologic. Conversely,
The thyroid gland takes up iodides out of the diet, hypothyroidism may diagnosed incorrectly, or
converts them to iodine and combines them with even worse, thyroid replacement may be used in
tyrosine to make iodotyrosines, which are compl- women with normal thyroid function who have
exed into thyroxine (T 4 ) or triiodothyronine (T3). hair loss, brittle hair, fatigue or obesity. The index of
These hormones are combined with thyroglobulin suspicion for hypothyroidism should be high, but
in the proteinaceous colloid of the thyroid gland. the diagnosis should only be made with absolute
The complexes are released into the circulation, laboratory confirmation. Replacement therapy re-
primarily bound to thyroid-binding globulin, but verses all the signs and symptoms.
only the free form (- 1 %) is active. The thyroid
hormones influence many aspects of carbohydrate, Congenital Hypothyroidism
protein and fat metabolism. Their classic role is
increasing the basal metabolic rate, but their func- Most patients with congenital hypothryoidism or
tion is much more finely tuned, as thyroid hor- cretinism have embryonic thyroid gland defects or
mones alter membrane function and regulate inborn errors in thyroid hormone production. In
transcription of various receptor proteins and endemic cretinism, there is a dietary lack of iodine
enzymes. in the mothers. Rare causes are use of antithyroid
medications by the mother and the presence of
Hypothryoidism maternal antithyroid antibodies. The main effects
of congenital hypothryoidism are on the CNS, the
The main cause of hypothryoidism in western infants are docile or inactive. In addition, they may
countries is autoimmune disease, usually Hashi- have an enlarged tongue, a puffy face, dry cool skin,
moto thyroiditis with destruction of the gland. brittle hair and a long list of other problems Al-
About 90 % of patients are women. Previous treat- though they surely have myxedema, it is the least of
ment for hyperthyroidism, whether surgical or the problems and rarely plays a role in the diagno-
with radioactive 1311 is also a common factor. In en- sis. In many countries, neonatal screening is per-
demic regions, lack of iodine may also playa major formed, because thyroid replacement can correct
role. Rarely, lack of TSH or even lack of hypotha- all of the problems, while an untreated infant may
lamic factors may be responsible. experience irreversible CNS changes prior to diag-
The symptoms of hypothyroidism are protean nosis.
and include weight gain, cold intolerance, fatigue
and constipation. The skin findings are also numer- Hashimoto Thyroiditis
ous. Typically the skin is puffy, waxy, cool and dry.
The most striking effect of this is a lack of facial ex- Hashimoto thyroiditis features an intense lym-
pression. The diffuse puffiness is secondary to in- phocytic infIltrate. Initially the patients may be
creased deposits of mucin in the skin, known as hyperthyroid, but as the fiisease burns out and
myxedema. On rare occasion, there may be localized the gland is destroyed, they become hypothyroid.
myxedema. (Chap. 43). The hair is dry, brittle and The main symptom is pain. Hashimoto thyroiditis
grows slowly. There may be diffuse. or patchy hair is associated with a variety of other autoimmune
loss; if the hypothyroidism is sudden, telogen efflu- diseases.
 Thyroid Gland
Hyperthryoidism
The most common cause of hyperthyroidism is
Graves disease. Once again, 90 % of patients are
women. Other causes include toxic multinodular
goiter, toxic adenoma, surreptitious ingestion of
thyroid hormones, acute stages of thyroiditis and,
rarely, pituitary tumors producing TSH. Important
symptoms include anxiety, heat intolerance, palpi-
tations, weight loss, weakness and eye problems. On
physical exam, there is often tachycardia, thyroid
enlargement and a tremor.
The cutaneous findings are also dramatic. The
skin tends to be warm, moist and smooth. Patients
complain of sweaty palms, often with striking
erythema. Flushing and urticaria can occur. There
may be diffuse alopecia, while nails often show dis-
tal onycholysis in which the free edge curves up-
ward (Plummer nail). Hyperpigmentation can de-
velop in those rare patients with overproduction of
TSH via overlaps with ACTH/MSH.
Graves Disease
(GRAVES 1835; VON BASED ow 1840)
Synonyms. Basedow disease, diffuse toxic goiter
Definition. Autoimmune thyroid disease often in
association with exophthalmos, pretibial myxede-
ma and acropachy. EMO is an acronym proposed
by BRAUN-FALCO and PETZOLDT (1967) for exoph-
thalmos, myxedema and osteoarthopathy, as first
described by THOMAS (1933). Von Basedow, a phy-
sician in Merseburg, Germany described the
Merseburg triad - exophthalmos, diffuse goiter and
tachycardia.
Etiology and Pathogenesis. There are a variety of
immune phenomena present in Graves disease.Au-
toantibodies (TRab) react with the TSH receptor;
most stimulate it but some block it. Antibodies may
also be directed against thyroglobulin and mi-
crosomes. In addition, there can be a diffuse lym-
phocytic infIltrate which is mild in the thyroid
gland but can be more severe in the ocular muscles.
The relationship of the TRab to the periorbital and
cutaneous deposits is poorly established. Presum-
ably fibroblasts are stimulated to secrete mucin
which accumulates in the skin. The antibodies can
cross the placenta and cause transient neonatal hy-
perthyroidism.
1357
Clinical Findings. Patients with Graves disease have
all the metabolic findings associated with thyroid
disease, but also a series of additional problems.
Systemic Findings. The thyroid gland is diffuse,
enlarged and smooth. There is usually a fine
tremor, tachycardia and an increased pulse pres-
sure. Most disturbing to the patient is the oph-
thalmic involvement. Early on they may complain
of swollen lids, foreign body sensation, tearing
and erythema. Later the more classic changes of
exophthalmos occur. The combination of mucin
deposition and lymphocytic inflammation appear
responsible. The conjunctival vessels are promi-
nent and the lids may become red and thickened
(chemosis). Visual disturbances are common, both
from the impaired lid mobility and involvement of
the ocular muscles.
Cutaneous Findings. The cutaneous findings of
pretibial myxedema and acropachy, as well as
EMO syndrome, are discussed in Chapter 43. Both
vitiligo and alopecia areata are somewhat more
common in Graves disease, with an incidence of
about 5%.
Course and Prognosis. The thyroid disease, ocular
changes and cutaneous involvement generally run
hand in hand. In some patients the mucin deposi-
tion is relatively independent of the thyroid dis-
ease, so that they may have exophthalmos without
thyroid disease or their eye problems may persist
or worsen even as the thyroid disease is being treat-
ed. The same relationship exists for the other types
of deposition but is not as clinically -important.
Differential Diagnosis. In the clinical setting of
hyperthyroidism, any hint of lid swelling or ex-
ophthalmos usually means Graves disease. If the
changes are unilateral, one should make the diag-
nosis with great caution after excluding all the
other possible causes.
Thyroid Tumors
While functional adenomas can cause hyperthy-
roidism, most thyroid carcinomas are not function-
al and are identified as masses in the neck. Patients
with multiple endocrine neoplasia (MEN) 2B have
multiple mucosal neuromas and medullary thyroid
carcinoma (Chap. 65).
1358 Chapter 48 • Nutritional, Metabolic and Endocrine Disorders
Parathyroid Gland
The parathyroid glands secrete parathormone
(PTH), which is mainly involved in calcium metab-
olism. The normal role of PTH and the problems
associated with hyperparathyroidism are discussed
in Chapter 45. Hyperparathyroidism is usually dis-
covered through routine blood chemistries reveal-
ing an elevated calcium. It is caused by functioning
adenomas in most cases. Jellinek sign refers to
darkening of the eyelids in hyperparathyroidism;
the so-called raccoon eyes can also be seen with
neuroblastoma and lupus erythematosus.
The usual cause of hypoparathyroidism is surgi-
cal removal of the parathyroid glands during thy-
roidectomy. They may also be involved in several
rare polyendocrinopathies. There are no skin
changes. Pseudo hypoparathyroidism is associated
with osteoma cutis (Chap. 59).
Adrenal Glands
Most of the diseases of the adrenal gland relate to
excessive, inappropriate or deficient secretion by
the adrenal cortex. The adrenal medulla is the sour-
ce of pheochromocytomas. Lack of the adrenal me-
dulla does not produce any significant clinical
problems.
Hyperadrenalism
Dermatologists are intimately familiar with the
effects of excess amount of glucocorticosteroids
because of the frequent occurrence of iatrogenic
Cushing syndrome in patients with pemphigus
vulgaris and other corticosteroid-dependent dis-
orders. The problems associated with adreno-
cortical hyperplasia are many, depending on
what types of hormones are produced in excess.
There are frequently overlaps. Excessive mineralo-
corticoid production has no specific skin findings.
Cushing Syndrome
(CUSHING 1912)
Definition. Disorder caused by excessive levels of Laboratory Findings. The diagnostic steps are
glucocorticosteroids.
Epidemiology. Cushing syndrome is extremely
rare, except as an iatrogenic disorder. The incidence Therapy. Treatment depends on the underlying
of the noniatrogenid forms is estimated at one per cause but is usually surgical. In some instances,
million.
Etiology and Pathogenesis. There are many causes,
including:
• Cushing disease, in which a pituitary adenoma
secretes ACTH. This accounts for 75 % of cases.
In rare instances there may be hypothalamic
overproduction of corticotrophin releasing fac-
tor (CRF) rather than a pituitary tumor.
• Autoimmune Cushing disease, in which autoan-
tibodies stimulate the adrenal ACTH receptors.
This is extremely rare but occurs in Carney syn-
drome (Chap. 65).
• Functional adrenal adenomas or carcinomas can
also produce excess levels of hormones. While
they are the most common cause of Cushing syn-
drome in children, these tumors account for only
a small group in adults.
• Ectopic secretion of either ACTH or even CRF by
a carcinoma, most often small cell tumors of the
lung.
• Long-term administration of corticosteroids is
the most common cause. While the usual route
is systemic, overuse of potent topical cortico-
steroids, especially in children, can also cause
Cushing syndrome.
Clinical Findings
Systemic Findings. The most common systemic
findings include diabetes mellitus, hypertension,
osteoporosis, and hypogonadism. They are present
in over 75 % of patients. Almost as common are
hemorrhagic problems secondary to vessel wall
weakness, muscle weakness and emotional distur-
bances.
Cutaneous Findings. The full plethoric facies is
known as moon facies. It appears early in the
disease and continues to worsen. The fat is redis-
tributed, leading to truncal obesity and the forma-
tion of an intrascapular clump of fat, known as a
buffalo hump. Other changes include acne (often
worse on the trunk; Chap. 28), hirsutism (Chap. 31),
purpura (especially on the forearms and asso-
ciated with trauma; Chap. 23) hyperpigmentation
(Chap. 26) and marked striae distensae (Chap. 18).
Wound healing is also often impaired.
complex and should be sought in an internal medi-
cine text.
even with a pituitary tumor, adrenal surgery and
 Adrenal Glands 1359

hormone replacement are chosen. Pharmacologic
blockers of corticosteroids are available but quite
toxic.
Hypoadrenalism
may also be hyperpigmentation of the oral mucosa
and lips.
Histopathology. There is increased melanin but not
an increased number of melanocytes.

The failure of the adrenal gland to produce normal Laboratory Findings. The diagnosis is usually
amounts of gluco- and mineralocorticosteroids made on the 9 A.M. plasma cortisol level and its re-
may be either primary, known as Addison disease, sponse to an injection of ACTH. More complicated
or secondary, due to lack of appropriate ACTH se- endocrinologic and imaging tests can be employed
cretion. The latter may be the result of pituitary or depending on the clinical setting.
hypothalamic disease.
Therapy. Lifelong hormonal treatment is required
Addison Disease with a glucocorticosteroid, e. g., hydrocortisone
(ADDISON 1855) 20 mg in the morning and 10 mg in the afternoon
and a mineralocorticosteroid, e. g., fludrocortisone
Epidemiology. Addison disease has a prevalence of 0.1- 0.2 mg daily. In the event of surgery, trauma
around 50 per million; thus it is more common than or other metabolic stress, the dosages must be in-
non-iatrogenic Cushing syndrome. It occurs more creased. An Addisonian crisis is a medical emer-
often in women. gency requiring intravenous hydrocortisone and
generous fluid replacement.
Etiology and Pathogenesis. Autoimmune damage
to the adrenal cortex is responsible for 75 % of. Excessive Androgen Production
Most of these patients have circulating antibodies
against adrenal cortical structures. Tuberculosis The adrenal gland can produce excessive amounts
accounts for about 20 % while a variety of rare of androgens. The main adrenal processes involved
destructive processes accounts for the balance. are secretory tumors in adults and congenital
Systemic fungal infections and malignant lym- adrenal hyperplasia in children. In adults, the
phomas are included in this group. Waterhouse- tumors, both adenomas and carcinomas, have ab-
Friderichsen syndrome is caused by fulminant normal production pathways so that androgens
meningococcal infection (Chap.4) with exten- may be overproduced. In infants, there may en-
sive purpura (Chap. 22); hemorrhage into the zymatic defects, usually 21-hydroxylase deficiency,
adrenal gland may cause an acute Addisonian so that glucocorticosteroids are not produced,
crisis. Occasionally there is a family history of ACTH levels increase and the androgen precursors
Addison disease or other autoimmune endocrine that occur along the synthetic pathway before the
disorders. step involving the enzymatic defect are overpro-
duced. Depending on the defect, the problem
Clinical Findings may appear in infancy or later on, even in adult
Systemic Findings. The early systemic findings are life. Functional adrenal tumors can also be seen in
vague, so that the diagnosis is often overlooked. children.
The patients may complain of fatigue, dizziness The main clinical findings in women include
or lethargy. Later there may be weight loss and acne (Chap. 28), hirsutism (Chap. 31), cliteromegaly,
abdominal complaints. Often the disorder is first frontal baldness, deepened voice and amenorrhea.
identified when an Addisonian crisis is triggered by In men, there may be decreased testicular volume.
a second problem such as a severe infection, trauma In infants and children, girls experience mascu-
or even elective surgery. linization (pseudohermaphroditism), while boys
show signs of precocious puberty. The diagnosis
Cutaneous Findings. The main skin finding is hy- is usually based on finding elevated levels of both
perpigmentation (Chap. 26). The high ACTH level testosterone and dihydroepiandrosterone sulfate
produced as a response to the lack of corticosteroid (DHEA-S) in the serum. Treatment is either surgi-
production is primarily responsible for the hyper- calor, if this is not possible, then with adrenal
pigmentation, which is greatest in sun-exposed blockers such as mitotane. In the 21-hydroxylase
areas, in scars and over pressure points. There deficiency, glucocorticosteroids can be adminis-
1360 Chapter 48 • Nutritional, Metabolic and Endocrine Disorders

tered and the integrity of the feedback loop thereby Ovaries

restored.
A discussion of the many endocrine actions of the
Pheochromocytoma ovaries is beyond the scope of this text. Several cu-
taneous diseases have been identified as hormonal-
Epidemiology. Pheochromcytomas are rare tu- ly sensitive because of their tendency to flare with
mors. They are present on autopsies in perhaps menses. In many cases, this is probably not a firm
1: 5000 -10,000 cases but when one looks at series association but still a worthwhile clue. Chap. 36
of hypertensive patients, they account for several considers the wide range of changes associated
per thousand. with pregnancy. The ovaries are the other main
source of androgens, so they playa role in both hir-
Etiology and Pathogenesis. The adrenal medulla is sutism (Chap. 31) and acne (Chap. 28).
one of the sites responsible for the production of
epinephrine, which it manufactures from dopa-
mine. Epinephrine has numerous effects on inter- Pancreas
mediate metabolism and cardiac function; surpris-
ingly, it does not need to be replaced in patients The main problems associated with pancreatic dis-
following surgical adrenalectomy. The medulla ease are diabetes mellitus and necrolytic migratory
may be destroyed in Addison disease, but once erythema, usually associated with a glucagon-se-
again no problems result. creting tumor (Chap. 14).
Most pheochromocytomas are adrenal, but
10 - 20 % are extraadrenal, found throughout the Diabetes Mellitus
abdomen and even the thorax. The most com-
mon sites are along the vertebrae or in the organ Definition. Clinical syndrome representing an in-
of Zuckerkandl (paraaortic bodies). Bilateral pheo- teraction between genetic and environmental fac-
chromocytomas are seen in neurofibromatosis, tors that is characterized by elevated blood sugar
MEN -2 and several other syndromes. About 10- values and a variety of end organ changes. Two ba-
15 % of pheochromocytomas are malignant, al- sic types have been identified: insulin dependent
though it is hard to distinguish sometimes between diabetes mellitus (IDDM or type I) and noninsulin-
a metastasis and multifocal primary tu-mors. dependent diabetes mellitus (NIDDM or type 11).

Clinical Findings. While many pheochromocyto-
mas are asymptomatic, those that cause clinical
problems almost always cause hypertension. While
classically one reads of pheochromocytomas caus-
ing paroxysmal hypertension, they are about as
likely to cause sustained hypertension. Other prob-
lems may include headache, palpitations, hyper-
hidrosis, anxiety and a tremor. Skin findings are
minimal. In contrast to carcinoid syndrome, flush-
ing does not occur; instead there may be facial pal-
lor. The features of Raynaud phenomenon are occa-
sionally triggered or worsened. Treatment is surgi-
cal removal under careful medical control to avoid
hypertensive crisis.
Testes
The diseases of the testes relevant to dermatologic
practice are discussed in Chap. 67.
Epidemiology. The prevalence in the USA is around
2 - 3 %. Certain small populations such as the Pima
Indians have much higher rates, supporting a
genetic component. Type I disease frequently ap-
pears before the age of 30 years, while the more
common type II disease usually starts later.
Etiology and Pathogenesis. Diabetes mellitus does
not have a single cause, but many causes. IDDM
preferentially involves patients with selected HLA
types. In these individuals viral infections may trig-
ger an autoimmune response against the pancreat-
ic islet cells with resultant failure to manufacture
insulin. This usually occurs in children; without in-
sulin, such patients die.
In type II disease the peripheral cells appear to
lose their sensitivity to insulin. In this group, most
patients are adults and over 90 % are obese. While
they may require insulin for proper management,
they can live without it. There are also genetic dis-
orders with abnormalities of the insulin receptors;
such patients may also have other endocrine abnor-
 Pancreas

malities and often have acanthosis nigricans. Preg- brown macules found on the shins of many nor-
nancy may trigger a temporary or gestational dia- mal patients but of almost all diabetics. A per-
betes mellitus, while a variety of medications may haps extreme variant of the diabetic shin spot is
also derange the glucose control mechanisms. the acral erythema of diabetics, which presents
Many end organs are involved. One unifying fea- as a sharply circumscribed erythematous patch
ture is small vessel disease, or diabetic microangi- on the shin or foot. It mimics erysipelas but
opathy, which may lead to retinal and renal glomer- the skin is not warm and the patient is not ill.
ular disease as well as skin changes. While small In addition, it is a permanent change. Rubeosis
vessel disease is most common in IDDM, large ves- diabeticorum is a dusky facial erythema that is
sel disease or accelerated arteriosclerosis is a com- similar to acral erythema. In addition, necro-
mon finding in NIDDM. Peripheral neuropathy is biosis lipoidica diabeticorum (Chap. 50) is an
also frequently found and may contribute to skin uncommon but highly suggestive sign of dia-
changes. betes mellitus. Patients typically have a sharply
bordered, yellow atrophic patch usually on the
Clinical Findings. Diabetes mellitus has a number shin. Histologically small vessel disease and the
of cutaneous manifestations, which are discussed characteristic necrobiosis of collagen are found.
below. Unfortunately, they do not allow themselves Disseminated granuloma annulare is another
to fall into any easy grouping. It is uncommon to necrobiotic disorder that may be a marker for
diagnose diabetes mellitus because of skin find- diabetes mellitus. Patients with severe arterio-
ings, although occasionally the skin may be the first sclerotic disease may develop diabetic gangrene
site of involvement. with necrotic regions on their extremities secon-
• Infections: Diabetics are more susceptible than dary to arterial obstruction.
normal individuals to a variety of bacterial and • Neuropathy. The lack of sensation in the feet
fungal disorders. The disease-specific neuropa- predisposes to many minor injuries which can
thy and vascular disease may predispose the skin evolve into diabetic neurotrophic ulcers (Chap.
to minor injuries and to inadequate healing. The 25). Bacterial infections complicate neuropathic
latter is more common in NIDDM where obesity injuries. It is essential for diabetic patients to
is so common. In the preantibiotic era, severe be carefully instructed in foot care; they should
staphylococcal infections such as furuncles or inspect their feet daily for injuries and report
carbuncles could produce massive gangrenous promptly to their physician with any suspicious
necrosis and even death. Similarly, streptococcal lesions. Comfortable, often specially fitted shoes
erysipelas was often severe and recurrent, pro- are helpful, as is routine podiatric care. It is often
ducing marked lymphedema. Even today, recur- better for the podiatrist to cut the patient's toe
rent folliculitis or erysipelas should prompt a nails, to minimize the risk of injury.
search for diabetes mellitus.
Of the fungal diseases, Candida albicans is the There are a number of disorders which do not fit
most common infectious agent. In addition to its into the above categories but which are commonly
typical sites of the mouth and genitalia, candi- seen in diabetics.
diasis may also involve normal skin in diabetic • Bullous disease of diabetes: This poorly under-
patients, presenting as folliculitis or intertrigo. stood disorder, also known as bullosis
The latter is more common in obese patients diabeticorum, typically involves elderly diabet-
with NIDDM. While diabetics may not have ics. Large, relatively stable bullae develop on the
more tinea pedis, they have more trouble with extremities, last for several weeks and then re-
the disease, as the minor crevices between the solve. Histologic examination shows a subepi-
toes can easily become infected by a variety of dermal blister with little inflammation. Immun-
bacteria. In addition, erythrasma is more com- ofluorescent evaluation has not identified any
mon in diabetics. Some far more serious fungal immunoglobulin deposition, in contrast to
disorders, such as rhino cerebral phycomycosis bullous pemphigoid which is the main differen-
(mucormycosis, zygomycosis), also show a pre- tial diagnostic consideration. Topical antibiotics,
dilection for diabetes mellitus patients. such as silver sulfadiazine, are usually sufficient
• Vascular Disease.,. A variety of skin findings are therapy.
associated with diabetic micro angiopathy. They • Diabetic thick skin: Some diabetics develop
include Binkley spots or diabetic shin spots, tiny thickened waxy skin, especially of the hands, as-
1362 Chapter 48 • Nutritional, Metabolic and Endocrine Disorders

sociated with limited joint motility. They typi- making effective binding impossible. Type B
cally cannot press their palms together, as the disease is associated with circulating antibodies
hands remain slightly flexed (Fig. 48.2). Some- against parts of the insulin receptor; they
times numerous small papules are seen. Most block the attachment of insulin and may be
patients have antibodies to glutamic acid di- a paraneoplastic sign. Type C disease is less
carboxylase in their serum. Very similar anti- well defined, but seems to involve signal trans-
bodies are found in the stiff man syndrome, a duction problems after insulin has successfully
neurologic disorder often associated with poly- bound. In patients with unexplained acanthosis
endocrine disorders. There appears to be in- nigricans, one must think of diabetes mellitus as
creased glycosylation and cross-linking of col- well as the possibility of an underlying malig-
lagen. The main differential diagnostic consider- nancy.
ation is scleroderma, but the patient has diabetes • Skin tags (soft fibromas): Skin tags are histolog-
mellitus and lacks other stigmata. Treatment ically quite similar to acanthosis nigricans, so it
with aldose reductase inhibitors appears prom- seems theoretically possible that they too could
ising. be a marker for diabetes mellitus. However, they
• Scleredema adultorum: A thick brawny in- are so common in obese people that it is hard to
duration of the nape and back is a rare but document any special association.
almost pathognomonic sign (Chap. 43). The • Yellow skin: Some patients have increased levels
dermis is thickened because of increased glyco- of carotene, as well as of glycosylated collagen,
sylation of collagen, just as in diabetic stiff skin but no evidence of increased ingestion of caro-
syndrome. tene, liver disease or other risk factors for caro-
• Acanthosis nigricans: In diabetics, acanthosis tenemia. Their skin is identical to that of patients
nigricans is generally associated with one of who eat too many carrots (Chap. 49).
the syndromes of insulin resistance and hyper-
insulinemia. Type A insulin resistance usually In addition the disease has been associated with a
reflects a mutation of the insulin receptor, long list of dermatologic disorders (Table 48.1).

Table 48.1. Skin diseases possibly associated with

diabetes mellitus

Disseminated granuloma annulare

Pruritus
Lichen simplex chronicus
Prurigo nodularis
Vitiligo
Lichen planus, especiaJly oral lichen planus
Perforating disease of renal failure/diaJysis
Fibromatoses
Lipodystrophy

• Cutaneous complications of therapy: Either in-

Fig. 48.2. Diabetic stiff skin syndrome
sulin or oral hypoglycemic agents can be em-
ployed. Insulin is likely to cause a variety of
allergic reactions. When insulin from an animal
source is used, many patients have a local, imme-
diate, usually IgG-mediated reaction. Delayed re-
actions are more likely to be cell-mediated, while
generalized reactions are often caused by IgE.
Some patients have both IgG and IgE antiinsulin
antibodies with a biphasic reaction. In all such
cases, the easiest solution is to switch to human
recombinant insulin. With this agent, reactions
 Polyendocrine Disorders
are rare and probably reflect changes in the
tertiary structure of the new protein, making it
antigenic.
Injections of insulin may also cause lipoatrophy
or lipodystrophy (Chap. 21), producing either a
depressed or bumpy area at the injection site.
Insulin may be lipolytic, but changes in the fat
probably reflect a wide variety of immunologic
reactions, just as in the skin.
The oral hypoglycemic agents cause several
problems, including phototoxic and photo-
allergic reactions, as well as a macular exanthem.
It is often possible to simply treat the latter reac-
tion. Chlorpropamide may produce flushing by
release of endogenous opioids; over 10 % of indi-
viduals cannot tolerate the medication for this
reason. The predisposition appears to be inherit-
ed in an autosomal dominant pattern.
The further aspects of diabetes mellitus, such as
pathology, laboratory evaluation, diagnostic criteria
and therapy, are beyond the scope of this book.
Polyendocrine Disorders
There are a group of disorders that frequently oc-
cur together, involving several endocrine glands
and many other organs. There are two basic groups:
polyendocrine deficiency syndromes and multiple
endocrine neoplasia.
Polyendocrine Deficiency Disorders
This group of autoimmune disorders is character-
ized by lymphocytic infiltrates and autoantibodies.
One major group is hypoadrenalism, hypoparathy-
roidism and mucocutaneous candidiasis, usually
Table 48.2. Features Endocrine diseases
of polyendocrine defi- Graves disease
ciency syndromes Hashimoto thyroiditis
Idiopathic hypothyroidism
Idiopathic Addison disease
Idiopathic hypoparathyroidism
Diabetes mellitus
Primary gonadal insufficiency
Pituitary insufficiency (hypophysitis)
occurring in childhood. Another is Schmidt syn-
drome with hypoadrenalism, Hashimoto thyroidi-
tis and often diabetes mellitus with onset in young
adult life. Patients may present with vitiligo or
alopecia totalis. Many combinations are possible, as
seen in Table 48.2: one can combine one or more of
the diseases from each column. The presence of any
one disease should prompt the physician to search
for or at least be alert to the other problems. In this
way, early diagnosis and more effective treatment
will be possible.
Multiple Endocrine Neoplasia
There are two separate syndromes with totally sep-
arate defects in which multiple endocrine tumors
can be found. Both are inherited in an autosomal
dominant pattern. In each case both adenomas and
carcinomas can develop; many are functional but
some are silent.
MEN 1 (Wermer syndrome) is caused by a defect
on chromosome llql3. Typical tumors include pa-
rathyroid, pancreatic islet cell and pituitary ade-
nomas. The most common finding is hypercalce-
mia; gastrointestinal problems and diabetes melli-
tus may also occur. Cushing syndrome (from
ACTH-secreting tumors), acromegaly and prolac-
tinomas are also found. Both mutiple facial angiofi-
bromas and connective tissue nevi have been de-
scribed, even though the gene is not related to ei-
ther of the tuberous sclerosis genes.
MEN 2 involves mutations in the ret oncogene
on chromosome lOqll. Two syndromes whose re-
lationship has been argued for years have been
shown to have slightly different mutations in the
same gene. (1) MEN 2A (Sipple syndrome) features
medullary thyroid carcinoma, parathyroid adeno-
mas and pheochromocytomas. (2) MEN 2B (mul-
Associated diseases
Vitiligo
Alopecia areata
Dermatitis herpetiformis
Gluten sensitive enteropathy
Chronic mucocutaneous candidiasis
Myasthenia gravis
jogren syndrome
Chronic atrophic gastritis
Pernicious anemia
Autoimmune hepatitis
Primary biliary cirrhosis
 Chapter 48 • Nutritional, Metabolic and Endocrine Disorders
tiple mucosal neuroma syndrome) is discussed in
Chapter 65. The patients have distinctive mucosal
neuromas, a marfanoid facies, medullary thyroid
carcinomas and pheochromcytomas.
Bibliography
Nutritional Disorders
Miller SJ (1989) Nutritional deficiency and the skin. J Am
Acad Dermatol 21: 1- 30
Prendeville JS, Manfredi LN (1992) Skin signs of nutritional
disorders. Semin Dermatol11 : 88 - 97
Telfer NR, Moy RL (1993) Drug and nutrient aspects of
wound healing. Dermatol Clin 11: 729 -737
Marasmus
Barbul A, Purtill WA (1994) Nutrition in wound healing. Clin
Dermatol12 : 133 -140
Briend A, Lacsala R, Prudhon C et al. (1999) Ready-to-use
therapeutic food for treatment of marasmus. Lancet
353: 1767 -1768
Souba WW (1997) Nutritional support. N Engl J Med 336:
41-48
Kwashiorkor
Albers SE, Brozena SJ, Fenske NA (1993) A case of kwash-
iorkor. Cutis 51:445-446
Eastlack JP, Grande KK, Levy ML et al. (1999) Dermatosis in
a child with kwashiorkor secondary to food aversion.
Pediatr Dermatol16: 95 -102
Jelliffe DB, Jelliffe EF (1992) Causation of kwashiorkor: to-
ward a multifactorial consensus. Pediatrics 90: 110 -113
Lathham MC (1991) The dermatosis of Kwashiorkor in
young children. Semin DermatollO: 270 - 272
Lipschitz DA (1991) Malnutrition in the elderly. Semin Der-
matollO: 273 - 281
McLaren DS (1985) Aetiology of kwashiorkor. Lancet (i): 55
McLaren DS (1987) Skin in protein energy malnutrition.
Arch Dermatol123: 1674 -1676
Essential Fatty Acid Deficiency
Burton JL (1989) Dietary fatty acids and inflammatory skin
diseases. Lancet 7: 27 - 30
Cederholm TE, Berg AB, Johansson EK et al. (1994) Low
levels of essential fatty acids are related to impaired de-
layed skin hypersensitivity in malnourished chronically
ill elderly people. Eur J Clin Invest 24:615-620
IsseroffRR (1988) Fish again for dinner! The role of fish and
other dietary oils in the therapy of skin disease. J Am
Acad Dermatol19: 1073 -1080
Ozsoylu S (1998) Clinical importance of essential fatty acid
deficiency. Eur J Pediatr 157:779
Ziboh VA (1989) Implications of dietary oils and polyunsat-
urated fatty acids in the management of cutaneous disor-
ders. Arch Dermatol125: 241- 245
Noma
Adolph HP, Yugueros P, Woods JE (1996) Noma: a review.
Ann Plast Surg 37:657-668
Enwonwu CO, Falkler WA Jr, Idigbe EO et al. (1999) Patho-
genesis of cancrum oris (noma): confounding inter-
actions of malnutrition with infection. Am J Trop Med
Hyg 60: 223 - 232
Enwonwu CO (1995) Noma: a neglected scourge of children in
sub-Saharan Africa. Bull World Health Organ 73: 541- 545
Lin JY, Wang DW, Peng CT et al. (1992) Noma neonatorum:
an unusual case of noma involving a full-term neonate.
Acta Paediatr 81: 720 -722
Valadas G, Leal MJ (1998) Cancrum oris (noma) in children.
Eur J Pediatr Surg 8: 47 - 51
Tropical Ulcer
Adriaans B, Hay R, Drasar B et al. (1987) The infectious
aetiology of tropical ulcer - a study of the role of an-
aerobic bacteria. Br J Dermatol116: 31- 37
Robinson DC, Adriaans B, Hay RJ et al. (1988) The clinical
and epidemiologic features of tropical ulcer (tropical
phagedenic ulcer). Int J DermatoI27:49- 53
Webb J, Murdoch DA (1992) Tropical ulcers after sports in-
juries. Lancet 339: 129 -130
Eating Disorders
Becker AE, Grinspoon SK, Klibanski A et al. (1999) Eating
disorders. N Engl J Med 340: 1092 -1098
Halmi KA (1996) Eating disorder research in the past de-
cade. Ann N Y Acad Sci 789: 67-77
Kaye WH (1997) Persistent alterations in behavior and sero-
tonin activity after recovery from anorexia and bulimia
nervosa. Ann N Y Acad Sci 817: 162 -178
Marcos A (1997) The immune system in eating disorders:an
overview. Nutrition 13: 853 - 862
Walsh BT, Devlin MJ (1998) Eating disorders: progress and
problems. Science 280: 1387 -1390
Yager J (1994) Psychosocial treatments for eating disorders.
Psychiatry 57: 153- 164
Cystic Fibrosis
Andersen DH (1938) Cystic fibrosis of the pancreas and its
relation to celiac disease. A clinical and pathological
study. Am J Dis Child 56:344-399
Darmstadt GL, Schmidt CP, Wechsler DS et al. (1992) Derma-
titis as a presenting sign of cystic fibrosis. Arch Dermatol
128: 1358 -1364
Hansen RC, Lemen R, Revsin B (1983) Cystic fibrosis mani-
festing with acrodermatitis enteropathica-like eruption.
Association with essential fatty acid and zinc deficien-
cies. Arch Dermatolu9: 51- 55
Laufer P, Laufer R (1985) Contact dermatitis in cystic fibro-
sis. Cutis 35: 557
Phillips RJ, Crock CM, Dillon MJ et al. (1993) Cystic fibrosis
presenting as kwashiorkor with florid skin rash. Arch Dis
Child 69:446-448
Rosenstein BJ, Zeitlin PL (1998) Cystic fibrosis. Lancet
351:277-282
Schmidt CP, Tunnessen W (1991) Cystic fibrosis presenting
with periorificial dermatitis. J Am Acad Dermatol 25:
896-897
Stern RC (1997) The diagnosis of cystic fibrosis. N Engl J
Med 336: 487 - 491
Endocrine Disorders
Thiboutot DM (1995) Clinical review 74: Dermatological
manifestations of endocrine disorders. J Clin Endocrinol
Metab 80: 3082 - 3087
 Bibliography
Pituitary Gland
Shimon I, Melmed S (1998) Management of pituitary tu-
mors.Ann Intern Med 129:472-483
Veznedaroglu E,Armonda RA,Andrews DW (1999) Diagno-
sis and therapy for pituitary tumors. Curr Opin Oncol
11:27-31
Acromegaly
Colao A, Lombardi G {1998) Growth-hormone and prolactin
excess. Lancet 352: 1455 -1461
Melmed S (1990) Acromegaly. N Engl J Med 322: 966 - 977
Melmed S, Jackson I, Kleinberg D, Klibanski A (1998) Cur-
rent treatment guidelines for acromegaly. J Clin Endoc-
rinol Metab 83: 2646 - 2652
Prolactinoma
Colao A, Lombardi G (1998) Growth-hormone and prolactin
excess. Lancet 352: 1455 -1461
Molitch ME (1999) Diagnosis and treatment of prolactin-
omas. Adv Intern Med 44: 117 -153
Diabetes Insipidus
Baylis PH, Cheetham T (1998) Diabetes insipidus. Arch Dis
Child 79: 84 - 89
Robinson AG, Verbalis JG (1997) Diabetes insipidus. Curr
Ther Endocrinol Metab 6: 1-7
Shimizu H, Obi T, Miyajima H (1997) Anhidrosis:an unusual
presentation of diabetes insipidus. Neurology 49:1708-
1710
Singer I, Oster JR, Fishman LM (1997) The management of
diabetes insipidus in adults. Arch Intern Med 23
157: 1293 -1301
Thyroid Gland
Baker JR Jr (1997) Autoimmune endocrine disease. JAMA
278: 1931- 1937
Braun-Falco 0, Petzoldt D (1967) E.M.O.-Syndrom. Exoph-
thalmus, Myxoedema circumscriptum praetibiale und
Osteoarthropathia hypertrophicans (E.M.O.-Syndrom).
Mtinchn Med Wochenschr 79:1523-1529
Hamlet KR, Stevens SR, Gushurst C et al. (1995) Juvenile
pemphigus vulgaris associated with Graves' disease. J
Am Acad Dermatol 33: 132 -134
Missner SC, Ramsay EW, Houck HE et al. (1998) Graves'
disease presenting as localized myxedema in a thigh
donor graft site. J Am Acad Dermatol39: 846 - 849
Nagai Y, Ishikawa 0, Miyachi Y (1996) Multiple eccrine hi-
drocystomas associated with Graves' disease. J Dermatol
23:652-654
Omohundro C, Dijkstra JW, Camisa C et al. (1996) Early
onset pretibial myxedema in the absence of ophthalmo-
pathy: a morphologic evolution. Cutis 58: 211- 214
Peacey SR, Flemming L, Messenger A et al. (1996) Is Graves'
dermopathy a generalized disorder? Thyroid 6: 41- 45
Priestley GC (1994) Skin fibroblast activity in pretibial myx-
oedema and the effect of octreotide (Sandostatin) in
vitro. Br J Dermatol131: 52 - 56
Somach SC, Helm TN, Lawlor KB et al. (1993) Pretibial
mucin. Histologic patterns and clinical correlation. Arch
Dermatol129:1152-1156
Thomas HM Jr (1933) Acropachy. Secondary subperiosteal
new bone formation. Arch Int Med 51: 571- 588
Wortsman J (1996) Graves' dermopathy. Thyroid 6: 655 - 657
Cushing Disease
Bornstein SR, Stratakis CA, Chrousos GP (1999) Adrenocor-
tical tumors: recent advances in basic concepts and clin-
ical management. Ann Intern Med 130: 759 -771
Cushing H (1912) The pituitary body and its disorders.
Lippincott, Philadelphia
Freda PU, Wardlaw SL, Bruce IN et al. (1995) Differential
diagnosis in cushing syndrome. Use of corticotropin-
releasing hormone. Medicine 74: 74 - 82
Stratakis CA, Mastorakos G, Mitsiades NS et al. (1998) Skin
manifestations of Cushing disease in children and adole-
scents before and after the resolution of hypercorti-
solemia. Pediatr Dermatol15: 253 - 258
Addison Disease
Addison T (1855) On the constitutional and local effects of
the suprarenal capsula. Samuel Highley, London
Babich DJ (1996) Clinical problem-solving: identifying Ad-
dison's disease. N Engl J Med 334: 1403 -1404
Kong MF, Jeffcoate W (1994) Eighty-six cases of Addison's
disease. Clin Endocrinol (Oxf) 41:757-761
Schloot N, Eisenbarth GS (1995) Isohormonal therapy of
endocrine autoimmunity. Immunol Today 16: 289 - 294
Pheochromocytoma
Bravo EL (1991) Diagnosis of pheochromocytoma. Reflec-
tions on a controversy. Hypertension 17:742-744
Bravo EL (1997) Pheochromocytoma. Curr Ther Endocrinol
Metab 6:195-197
McGrath PC, Sloan DA, Schwartz RW et al. (1998) Advances
in the diagnosis and therapy of adrenal tumors. Curr
Opin Oncol1O : 52 - 57
Walther MM, Keiser HR, Linehan WM (1999) Pheochro-
mocytoma: evaluation, diagnosis, and treatment. World J
Urol17:35-9
Diabetes Mellitus
Eaglstein WH (1998) Dermagraft treatment of diabetic ul-
cers. J Dermatol 25: 803 - 804
Jelinek JE (1994) Cutaneous manifestations of diabetes mel-
litus. Int J Dermatol33: 605 - 617
Joshi N, Caputo GM, Weitekamp R (1999) Infections in pa-
tients with diabetes mellitus. NEJ Med 1912:341
Goodfield MJ, Millard L (1988) The skin in diabetes mellitus.
Diabetologia 31: 567 - 575
Jelinek JE (1995) Cutaneous manifestations of diabetes mel-
litus. J Am Acad Dermatol32: 143 -144
Mathur SK, Bhargava P (1997) Insulin resistance and skin
tags. Dermatology 195: 184
O'Toole EA, Kennedy U, Nolan JJ et al. (1999) Necrobiosis
lipoidica: only a minority of patients have diabetes
mellitus. Br J Dermatol140: 283 - 286
Perez MI, Kohn SR (1994) Cutaneous manifestations of dia-
betes mellitus. J Am Acad Dermatol30: 519 - 531
Requena L, Sarasa JL, Pique E et al. (1997) Clear-cell
porocarcinoma: another cutaneous marker of diabetes
mellitus. Am J Dermatopathol19: 540 - 544
Rosenbloom AL (1989) Diabetic thick skin and stiff joints.
Diabetologia 32:74-76
Shemer A, Bergman R, Linn S et al. (1998) Diabetic dermo-
pathy and internal complications in diabetes mellitus.
Int J Dermatol37: 113 -115
1366 Chapter 48 • Nutritional, Metabolic and Endocrine Disorders
Polyendocrine Disorders
Betterle C, Volpato M, Greggio AN et al. (1996) Type 2
polyglandular autoimmune disease (Schmidt's syndro-
me). J Pediatr Endocrinol Metab 1: 113 -123
Betterle C, Greggio NA, Volpato M (1998) Autoimmune
polyglandular syndrome type 1. J Clin Endocrinol Metab
83: 1049 -1055 (Clinical review, vol 93)
Chung AD, English JC III (1997) Cutaneous hyperpigmenta-
tion and polyglandular autoimmune syndrome type II.
Cutis 59:77-80
Garty B (1998) Erythema annulare centrifugum in a patient
with polyglandular autoimmune disease type 1. Cutis
62:231-232
Torrelo A, Espana A, Balsa J, Ledo A (1992) Vitiligo and
polyglandular autoimmune syndrome with selective IgA
deficiency. Int J Dermato131: 343 - 344
Multiple Endocrine Neoplasia
Darling TN, Skarulis MC, Steinberg SM et al. (1997) Multiple
facial angiofibromas and collagenomas in patients with
multiple endocrine neoplasia type 1. Arch Dermatol1333:
853-857
Kousseff BG (1995) Multiple endocrine neoplasia 2 (MEN
2)/MEN 2A (Sipple syndrome). Dermatol Clin 13:91-
97
Marx S, Spiegel AM, Skarulis MC et al. (1998) Multiple endo-
crine neoplasia type 1: clinical and genetic topics. Ann
Intern Med 129 : 484 - 494
Pacini F, Fugazzola L, Bevilacqua G et al. (1993) Multiple
endocrine neoplasia type 2A and cutaneous lichen
amyloidosis: description of a new family. J Endocrinol
Invest 16: 295 - 306
Pujol RM, Matias-Guiu X, Miralles J et al. (1997) Multiple
idiopathic mucosal neuromas: a minor form of multiple
endocrine neoplasia type 2B or a new entity? JAm Acad
Dermatol37: 349 - 352