Professional Documents
Culture Documents
keratinocytes are
virtually invisible. An
adjacent hair shaft
passes through the
specimen. Melanocytes
contain long dendritic
processes that deliver
protective melanosomes
to nearby keratinocytes.
Fig. 1.1 Normal skin: trunk. Note epidermal layers from the surface: stratum
corneum, stratum granulosum, stratum spinosum and stratum basale. Tightly
packed dermal collagen is seen near the epidermaldermal junction, and more
loosely arranged collagen is found deeper in the dermis. A cluster of small
blood vessels and nerves is seen in the dermis.
Fig. 1.2 Normal skin: palm. Note that the epidermis is thicker than that seen
in Figure 1.1. The compact and thick stratum corneum is typical of skin on the
palms and soles. Courtesy, Lorenzo Cerroni, MD.
possible and even likely that two or more disease processes and/or
susceptibilities underlie an illness and that such simultaneous occur-
rences may alter the clinical presentation. In fact, practicing dermatolo-
gists are quite aware of the unusual morphologic features of pityriasis
Knowledge of the Function and Structure of Skin rosea when it occurs in a patient with underlying psoriasis or when a
Begins with Skin Disease patient with atopic dermatitis improves substantially following treat-
We have chosen to present in the remainder of this chapter a conceptual ment with an antibiotic, even in the absence of obvious infection. A
framework into which the other chapters of this textbook may be growing array of genetic factors and infectious agents are known to
placed. This framework is derived from the assertion that knowledge modulate the course of otherwise conventional skin diseases. Witness
of cutaneous function begins with disease. One corollary of this asser- the presence of numerous viral warts or tumors of molluscum conta-
tion is that there may be unrecognized functions of skin, either because giosum in patients with immunodeficiency from occult HIV infection
there is no corresponding disease or because the disease is fatal. For or from iatrogenic immunosuppression. Thus, dermatologists have an
example, no one would have guessed that incontinentia pigmenti was extra assignment: to find otherwise hidden genetic, infectious and
lethal in males had it not been for the survival of heterozygous females environmental factors that modify the appearance and severity of cuta-
with this X chromosome-linked disease6,7. Overwhelming apoptosis is neous disease.
thought to explain the death of male fetuses in utero. All plants and animals possess limiting membranes that define an
Two other prejudices color the picture we choose to paint. First, we internal space and at the same time protect against external insults. In
44 deviate from the concept that physicians should invariably attempt to mammals, these membranes, which may be described functionally as
develop a single diagnosis for an illness. Rather, we believe that it is barriers, occur primarily in three organs: the lung, gastrointestinal
tract and skin (Ch. 124). Although similar in concept, the barrier prop-
erties of these organs are fundamentally different. Pulmonary and gas- SELECTED REQUIREMENTS AND FAILINGS OF SKIN
trointestinal barriers, by virtue of their internal location, are protected
from many environmental influences, and at the same time they Requirement Selected failings
CHAPTER
promote rather than retard the transfer of gases, nutrients and wastes. Prevent infection via innate and Fungal, bacterial and viral infections;
By contrast, and with the possible exception of UV radiation-facilitated
vitamin D3 production8, there is no obvious benefit to skin penetration,
adaptive immunity
Maintain a barrier
autoimmunity, cancer
Infection, dehydration
1
or, at least, there are as yet no recognized diseases attributed to the
several individuals are chronically infected, whereas other family onstrate the relevance of effective cellular immunity to protection
members, in the face of obvious exposure, are seemingly never against infections with a wide variety of agents, including Mycobacte-
infected. On the other hand, experience from tropical climates indi- rium tuberculosis, Pneumocystis jiroveci, varicella zoster (Figs 1.8 &
cates that individuals who are relatively resistant in a dry environ- 1.9) and herpes simplex viruses. What more evidence would one want
ment may lose that resistance as the ambient humidity increases or to demonstrate the relevance of cellular immune protection of skin
when occlusive military shoes are worn17. Obviously, dermatophyte than the diseases that are described in Chapter 78?
infection and resistance include a complicated interplay among
genetic susceptibilities, immune responsiveness and environmental Hansens disease (leprosy)
circumstances. Hansens disease is instructive in that the majority of humans exposed
to its causative organism, Mycobacterium leprae, develop an effective
immune response that is seemingly curative (Ch. 75). On the
other hand, a small percentage of exposed individuals develop chronic
infection that may take any one of several forms, based on immuno-
logic resistance. In fact, observations made in patients with Hansens
disease have been important in formulating the Th1/Th2 paradigm
(Ch. 4), with each patients clinical response falling along a spectrum
from tuberculoid to lepromatous18. Importantly, Hansens disease also
illustrates the relevance of cutaneous sensation to protection against
traumatic injury, as will be presented later.
Warts, dermatophytosis, opportunistic infections in the setting of
HIV infection, and Hansens disease all illustrate important aspects of
Fig. 1.7
Dermatophytosis. This
annular presentation of
tinea corporis typifies
cutaneous dermatophyte
infections.
46 Fig. 1.9 Tzanck smear from a patient with herpes zoster. Note the
multinucleated giant cell.
cutaneous function, ranging from a structural barrier provided by the from within the body and, at the same time, prevents penetration by
stratum corneum to immunologic recognition and protective microorganisms, toxic materials and UV radiation22,23 (Ch. 86). For all
immunity. but UV radiation, the stratum corneum is the central element in that
function. By contrast, protection against UV radiation occurs through
Faulty immunity: autoimmunity several independent phenomena, including photon scattering in the CHAPTER
We have made a case for the concept that the primary task of immunity
is to recognize and destroy infectious organisms. Having stated this,
stratum corneum and photon absorption by underlying melanin. 1
Failure of protection against toxic chemicals
47
patients with keratosis follicularis, even though no mechanism could preparations that include UV-absorbing or UV-blocking molecules,
be imagined that would link keratin function with CNS function. In several characteristics of the skin itself limit UV radiation-induced
retrospect, however, hexachlorophene had been recommended as a damage. Due to its optical characteristics, the stratum corneum tends
useful antibacterial agent soon after its introduction in 1944. Several to reflect and scatter photons, and those that penetrate the stratum
SECTION
decades later, it was recognized that it was potentially neurotoxic, with corneum are usually absorbed by molecules such as melanin. Addi-
1 use eventually curtailed in the 1970s28. Since that time, there have been
fewer reports of neuropsychiatric findings in keratosis follicularis. Our
tional mechanisms are the scavenging of reactive oxygen species by
antioxidants and repair of damage with DNA repair enzymes.
conclusion is that hexachlorophene penetrates a defective barrier in The importance of cutaneous pigment in protecting the skin against
Overview of Basic Science
toxic amounts. However, an alternative explanation proposed by others UV damage is demonstrated in patients with oculocutaneous albinism
is that dysfunction of SERCA2 within the brain may potentially lead (OCA)31. The impact of melanin in limiting UV penetration may be
to neuropsychiatric findings29. In contrast, there is no debate about the seen unequivocally in patients who have type 1 OCA due to an absence
more recently reported enhanced absorption of topical tacrolimus in or reduction in tyrosinase activity and, as a result, melanin production
patients with Netherton syndrome. (Fig. 1.15)31. Striking amongst the evidence is the experience of the
In sum, the barrier for chemical penetration is invested in the stratum Cuna Indians, residents of islands near Panama, in whom there is an
corneum (Ch. 124), and this barrier is defective in diseases of extraordinarily high frequency of type 1 OCA and little relief from year-
keratinization. long intense exposure to sunlight. In the context of this high back-
ground genetic frequency (approximately 1%), there is a parallel high
Failure to protect against dehydration and infection: frequency of skin cancer. Likewise, acute toxicity, photosensitivity dis-
toxic epidermal necrolysis eases and premature photoaging (Ch. 87) are known complications for
The most dramatic form of epidermal failure occurs in patients with these patients.
toxic epidermal necrolysis (TEN; Ch. 20). In this drug-induced disease,
rapidly progressive keratinocyte death leads to detachment of the epi- Maintaining the Integrity of Skin: Repair
dermis over large areas of the body. There is a complete loss of barrier Mechanisms
function (Figs 1.13 & 1.14). TEN is most often associated with sul- Physical injury occurs commonly in the skin, including many small
fonamides, anticonvulsants and nonsteroidal anti-inflammatory drugs. breaks from blunt and sharp objects that are repaired almost without
It has a mortality rate that depends upon the area of skin involved, but notice. A special type of injury is caused by the penetration of UV
death is not uncommon. There is as yet no specific treatment for TEN. radiation. This includes a variety of effects that range from sunburn to
However, there is evidence that drug-induced triggering of massive immune suppression, accelerated aging and carcinogenesis. Thermal
keratinocyte apoptosis may underlie the disease30, and inhibition of the injury occurs upon exposure to a hot object or radiant energy, e.g. from
apoptosis signaling pathway (e.g. by administration of intravenous fire, that heats the skin excessively (see below, Thermoregulation).
immunoglobulin) may improve survival. However, the point of this Injury also occurs when there is interruption of the underlying vascular
discussion is that the complications that accompany loss of the epider- supply. Each episode of injury is followed by a sequence of repair proc-
mis reveal all of its functions. Despite intensive treatment with similar esses that eliminate foreign objects and cover defects. This wound
techniques as those employed for burns, complications are common
and can include enormous fluid and electrolyte losses leading to dehy-
dration as well as infections with bacteria and yeast.
Fig. 1.13 Toxic epidermal necrolysis. Full-thickness epidermal cell death, with
secondary bulla formation. Courtesy, Jean L Bolognia, MD.
these individuals
prompts one to examine
their features with
interest. Courtesy, Kimball Art
Museum, Fort Worth, Texas.
A Fig. 1.18 Vitiligo. This African-American man has vitiligo on the distal portions
of his fingers. Pigmentary disorders of this sort are much more obvious in
patients with substantial natural pigmentation.
concerns the types of changes that are considered to be defective. The Undesirable fat distribution
defects that are most disagreeable do vary from culture to culture, so With the possible exception of hemifacial atrophy and lipodystrophy
that one cannot assume that what is unattractive in one culture is syndromes, indications for the absolute removal and for the movement
necessarily unattractive elsewhere. of fat are based on psychologic needs rather than on abnormalities in
the structure of the skin and subcutaneous tissues. Nevertheless, the
Pigmentary turmoil movement of fat is becoming a fairly common procedure and, once
Pigmentary disorders tend to be more pronounced, and thus more again, dermatologists are playing increasingly important roles in this
important, in populations with greater amounts of natural pigmenta- arena65 (Ch. 156).
tion. For this reason, Western cultures, which until recently have been
derived primarily from European immigrants, may underestimate the The next steps
critical role of pigmentation throughout the world. Although derma- We could go on at length about dermabrasion for acne scars, rejuvena-
tologists care for patients who have many different disorders of pigmen- tion protocols, blepharoplasties, and other techniques to reverse the
tation, two diseases predominate: vitiligo (Fig. 1.18; Ch. 66)58 and effects of aging. However, the point has been made. What we propose
melasma (Ch. 67). is that anxiety about appearance is genetically programmed. The disci-
The preference for unblemished skin is exceedingly important in pline of cosmetic dermatology has arisen to address that anxiety, with
cultures in which altered pigmentation may be confused with Hansens the important goals of alleviating scars, hiding defects and preventing
disease (Ch. 75) or viewed as hereditary. In Indian culture, for example, photoaging.
it is not uncommon for the discovery of vitiligo to invalidate a marriage
contract59. The defect in vitiligo is the absence of epidermal melano- An Important Corollary, with an Eye to the Future
cytes after physical destruction guided by autoimmune influences. Not In this introductory chapter, we have asserted that the structure and
only is vitiligo an important disease in its own right, the associated function of skin is revealed through careful study of skin disease. An
autoimmune phenomena have profound implications for melanoma important corollary to this statement becomes apparent when we apply
therapy (Ch. 113). our knowledge of skin disease to patient care: the structure and func-
Likewise, melasma has a high frequency in Hispanic individuals in tion of skin is also revealed by observing the outcomes of our specific
the Americas, and it is often extraordinarily distressing60 (Ch. 67). It interventions. Whether the outcomes are anticipated or completely
52 is not uncommon to observe that money for necessities may be diverted unexpected, much can be learned by studying the way skin responds
to this seemingly inconsequential problem. to our attempts at manipulation through medicine and surgery. This
Fig. 1.19 Alopecia point has been recently illustrated by the observation that keratoacan-
areata. The detrimental thomas may erupt in patients being treated with molecular inhibitors
social impact of hair of mutated BRAF, which is found in approximately 40% of melano-
loss in patients with mas66,67. In patients with the characteristic V600E activating mutation
diseases such as alopecia CHAPTER
in BRAF, molecular inhibitors of BRAF arrest melanoma growth68.
areata cannot be
underestimated. The
disease process targets
However, when wild-type BRAF is inhibited, especially in the presence
of mutated RAS, signaling pathways are enhanced and cellular prolif-
1
eration ensues66,67. Keratoacanthomas and squamous cell carcinomas
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