(2) abnormal mucosal patterns such as mucosal edema,

multiple nodular lesions, coarsened mucosal folds,

or multiple polyps; and (3) motility disturbances. A
biopsy of the GI tract may be indicated for patients
in whom the diagnosis of SM is suspected, but who lack
skin lesions. Histologic sections of jejunal biopsies show
moderate blunting of the villi and may show increased
mast cell numbers in association with vari- able
numbers of eosinophils.19,20
Despite the infrequency of significant hepatic dis-
ease, liver function tests are abnormal in approxi-
mately one-half of all patients with extracutaneous
disease. Other surrogate markers of mastocytosis are
elevated serum IL-6 levels, soluble SCF receptor
(CD117), and IL-2 receptor (CD25) levels.36 The levels
indicate the presence of SM. In contrast, the presence of
noncutaneous signs and symptoms or disease onset in
25
adolescents or adults necessitates a CBC with dif-
ferential, liver function test, total serum tryptase level,
and skeletal X-rays (see Fig. 149-9 and Table 149-3).
Because the presence and type of c-kit mutation may
predict disease longevity as well as a patient’s response
to treatment (see Section “Treatment”), determination
of c-kit mutations in the skin or blood of mastocytosis
patients with systemic disease should be considered.
differential diagnosis
Cutaneous lesions of childhood and adult mastocy-

of the latter receptors are highly correlated with the
severity of bone marrow pathology.37
The initial evaluation of a prepubertal child with
mastocytosis generally does not require extensive eval-
uation if the history and physical examination do not
Chapter 149
tosis are very characteristic, and thus are rarely con-
fused with other skin disorders. Since UP lesions may
urticate, they could initially be mistaken for urticaria.
However, individual urticaria lesions last only a few
hours and lack the associated hyperpigmentation seen

::
Mastocytosis
Algorithm for a diagnostic evaluation of new-onset mastocytosisa

Mast cell mediator symptoms

No skin findings plus unexplained ulcer

Hyperpigmented papules, macules or malabsorption hepatosplenomegaly,
or solitary nodule and/or skeletal or hematologic
abnormalities

Skin biopsy of lesion, CBC with diff, LFTs,

CBC with diff LFTs, serum tryptase, 24 hr
Serum tryptase level urinary histamine metablolite
Skeletal x-rays levels, vasoactiveamines

Elevated serum tryptase Elevated tryptase and/or Normal tryptase

Normal tryptase, CBC, plus hepatosplenomegaly urinary histamine urinary histamine
No hepatosplenomegaly or hematologic, LFTs, metabolites metabolite levels
bone abnormalities

Repeat serum tryptase Bone marrow biopsy CBC with diff, LFTs,
Explore other diagnoses
CBC, LFTs annually Skeletal x-rays, possible
GI or bone marrow biopsy

Abnormal bone marrow Normal Bone marrow

1 major + 1 minor or follow clinically
3 minor criteria

Systemic mastocytosis
WHO criteria for
classification

Figure 149-9 Algorithm for a diagnostic evaluation of new-onset mastocytosis (especially in adolescents and adults).
CBC = complete blood cell count; Tc = technetium; WHO = World Health Organization. aFor details of the WHO classification
of mastocytosis, see Valent P et al: World Health Organization Classification of Tumours: Pathology and Genetics of Tumours
of the Haematopoietic and Lymphoid Tissues, edited by Jaffe ES et al. Lyon, IARC Press, 2001. 1815
25 in UP. Some childhood mastocytosis patients may
develop bullae. Therefore, the differential diagnosis BOX 149-2 DIFFERENTIAL DIAGNOSIS
for blisters in infants such as bullous impetigo, bullous OF SYSTEMIC MASTOCYTOSIS WITHOUT
arthropod bites, linear IgA bullous dermatosis, bullous
pemphigoid, epidermolysis bullosa, toxic epidermal SKIN LESIONSa
necrolysis, and incontinentia pigmenti should be con-
Gastrointestinal
sidered. Rarely, nodular scabies lesions have been con-
fused with UP (see Box 149-1). The differential diag- Peptic ulcer disease
nosis of mastocytomas in children includes juvenile Ulcerative colitis
xanthogranulomas, Spitz nevi, pseudolymphomas or Gluten-sensitive enteropathy
rarely in resolving lesions, a café au lait macule. Adult Hepatitis
UP lesions might initially appear as lentigines or atypi-
Parasitic disease
cal melanocytic nevi; however, they usually have an
associated erythema (telangiectasia) not seen in these Cardiovascular
melanocytic lesions. Allergy
Mastocytosis should be suspected in patients with- Idiopathic anaphylaxis
Section 25 ::

out skin lesions if they have symptoms suggesting Cardiac disease

mast cell mediator release and one or more of the
Endocrine
following: peptic ulcer disease or malabsorption,
radiographic or 99technetium bone scan abnormali- Adrenal tumor
ties, hepatomegaly, splenomegaly, lymphadenopathy, Vasoactive intestinal polypeptide tumor
and/or peripheral blood abnormalities (Box 149-2). Carcinoid syndrome
Skin Manifestations of Bone Marrow or Blood Chemistry Disorders

In adults suspected of having SM without cutaneous Medullary thyroid carcinoma

lesions, the diagnosis of a carcinoid tumor or pheo-
Gastrinoma
chromocytoma should be considered. Patients with
mastocytosis do not excrete increased amounts of Diabetes mellitus
5-hydroxyindoleacetic acid, and patients with carci- Neoplastic/oncologic
noid tumor or pheochromocytoma do not have his- Hypereosinophilic syndrome
tologic evidence of mast cell proliferation or elevated Lymphoma
serum tryptase levels.38
Myeloma
Histiocytosis
Bone tumor metastases
a
Some forms of mast cell disease may not show cutaneous
manifestations. These include aggressive systemic mastocytosis,
BOX 149-1 DIFFERENTIAL DIAGNOSIS mast cell leukemia, systemic mastocytosis with an associated
OF CUTANEOUS MAST CELL DISEASE clonal hematologic nonmast cell lineage disease, and isolated
bone marrow mastocytosis.
Most Likely
Diffuse or localized hyperpigmented papules/
macules
Urticaria
Multiple nevi prognosis
Langerhans cell histiocytosis
Juvenile xanthogranulomas Pediatric-onset cutaneous disease has a favorable
Nodular scabies prognosis with at least 50% of cases of childhood UP
resolving by adulthood.1,16 Furthermore, children born
Café-au-lait spots
of mothers with ISM reportedly are free of disease.17 It
Multiple cutaneous lentiginosis has been postulated that children with activating c-kit
Postinflammatory hyperpigmentation mutations may represent the 10%–15% of those whose
Bullous lesions disease persists into adulthood2,12; however, with the
Linear immunoglobulin A dermatosis recent report of detectable activating c-kit mutations in
84% of children with mastocytosis, the prognostic sig-
Bullous impetigo
nificance of this abnormality is unclear.
Epidermolysis bullosa Most adults with UP have only CM or ISM and rarely
Arthropod bite reaction develop more advanced disease. Patients with ISM
Toxic epidermal necrolysis appear to have a good prognosis with limited potential
Incontinentia pigmenti to progression to more severe forms of SM.3,19
Older patients with UP who experience fading of their
Solitary papule or nodule
lesions continue to exhibit bone marrow lesions typi-
Congenital nevus cal of their diagnosis, whether ISM or SM-AHNMD.18
Juvenile xanthogranuloma Patients with SM-AHNMD have a variable course,
Pseudolymphoma which is dependent on the prognosis of their hema-
tologic disorder. In patients with ASM, the mean sur-
vival is 2–4 years, but the prognosis may improve with

1816
 TABLE 149-4
25
treatment for Cutaneous mastocytosis

topical physical systemic

First line Emollients H1 ±H2 antihistamines
Second line Topical glucocorticoids Psoralen and ultraviolet A light (adults Leukotriene antagonists
Calcineurin inhibitors only) Oral cromolyn sodium
Pulsed dye laser for telangiectasia
macularis eruptiva perstans
Third line Intralesional corticosteroids or Glucocorticoids

Chapter 149
Surgical excision (mastocytoma)

Note: Avoidance of triggering factors such as heat, friction, or drugs.

aggressive symptomatic management. The prognosis are safe alternative systemic anesthetics for masto-
for MCL is poor with a mean survival of less than 6 cytosis patients. It has been recommended that mas-
months.19,28 tocytosis patients undergoing general anesthesia be

::
monitored postoperatively for 24 hours since delayed

treatment
The management of patients with mastocytosis
includes counseling patients and care providers as to
the features of the disease, avoidance of factors that
provoke mast cell mediator release, and management
of symptoms associated with these released mediators
(Tables 149-4 and 149-5). Mastocytosis patients should
be cautioned to avoid potential mast cell degranulat-
ing agents such as ingested alcohol, anticholinergic
preparations, aspirin and other NSAIDs, narcotics,
and polymyxin B sulfate. In addition, heat and friction
can induce local or systemic symptoms and should
be avoided whenever possible. A number of sys-
temic anesthetic agents, including systemic lidocaine,
d-tubocurarine, metocurine, etomidate, thiopental,
succinylcholine hydrochloride (suxamethonium chlo-
ride), enflurane, and isoflurane, have been directly
or indirectly implicated in precipitating symptoms of
mastocytosis. Recent reports indicate that fentanyl,
sufentanil, remifentanil, paracetamol, midazolam,
propofol, ketamine, desflurane, sevoflurane, cis-
atracurium, pancuronium, and vecuronium bromide,
Mastocytosis
anaphylaxis can occur hours after surgery. In contrast
to systemic anesthetics, local injections of lidocaine can
be used safely in these patients.23
There is currently no generally recognized safe
and effective mast cell ablative therapy, nor are there
effective mast cell stabilizing drugs. Thus, treatment
of milder forms of mastocytosis is focused, in great part,
on symptomatic relief. In children with asymp- tomatic
mastocytomas or UP lesions, no therapy is needed.
Chronic administration of H1 antihistamines
(hydroxyzine, cetirizine, and fexofenadine) is often
helpful in reducing pruritus and flushing associated
with histamine release.19 Both ketotifen and azelastine,
antihistamines with mast cell-stabilizing properties
may help relieve the pruritus and whealing associated
with mastocytosis, but neither drug offers a significant
advantage over a standard antihistamines.39 H2 anti-
histamines (cimetidine or ranitidine) are most useful
in the management of excess gastric acid secretion, but
may assist in controlling pruritus, flushing, and wheal
formation when administered with an H1 blocker. If GI
symptoms persist with the use of H2 antihistamines,
then proton pump inhibitors may be effective, second-
ary treatments.19,20

TABLE 149-5
treatment of noncutaneous mastocytosis symptoms

gastrointestinal Cardiovascular musculoskeletal Hematologic

First line H2 antihistamines, oral H1 and H2 antihistamines Calcium supplement ± vitamin Systemic chemotherapy
cromolyn (children) Subcutaneous epinephrine D supplement appropriate for
(anaphylaxis) hematologic disorder
Second line Proton pump inhibitors Glucocorticoids Bisphosphonates
Leukotriene antagonist (prophylaxis) Nonsteroidal anti-inflammatory
Anticholinergics drugs with caution
Third line Glucocorticoids Local radiation to bony lesions
Note: Cytoreductive therapy is restricted to patients with aggressive variants of mastocytosis (systemic mastocytosis with an associated clonal
hematologic nonmast cell lineage disease, aggressive systemic mastocytosis, and mast cell leukemia). 1817
25 Disodium cromoglycate (cromolyn sodium) inhib-
its degranulation of mast cells and may have some
efficacy in the treatment of mastocytosis, particularly
in relieving GI complaints in children.40 Cromolyn
sodium, however, does not lower plasma or urinary
histamine levels in patients with mastocytosis. Low-
dose aspirin has been used in some patients to reduce
flushing, tachycardia, and syncope. However, aspirin
must be used with extreme caution, as it may cause
vascular collapse in some patients with mastocytosis
and exacerbate peptic ulcer disease. Antileukotrienes
have proven effective in controlling symptoms of
flushing, diarrhea, and abdominal cramping in some
mastocytosis patients.19,20
Potent topical glucocorticoids under occlusion for
Section 25 ::
8 h/day for 8–12 weeks reduces the number of UP
lesions. However, these lesions eventually recur after
discontinuation of therapy within the year.41,42 Oral
glucocorticoids have some efficacy in patients with
malabsorption and ascites. After control is achieved,
glucocorticoid therapy should be tapered to the lowest
Skin Manifestations of Bone Marrow or Blood Chemistry Disorders
effective dose.17,19 Osteoporosis should be treated with
calcium and vitamin D supplementation and, when
appropriate, the addition of estrogen replacement or
bisphosphonates as determined by monitoring bone
density.
Epinephrine should be used to treat episodes of ana-
phylaxis. Patients with such episodes should carry epi-
nephrine, be prepared to self-administer this drug, and
have a plan for emergency management. If subcutane-
ous epinephrine is insufficient, intensive therapy for
vascular collapse should be instituted. Patients with
recurrent episodes of anaphylaxis should receive con-
tinuous H1 and H2 antihistamines to lessen the severity
of attacks. Episodes of vascular collapse in masto-
cytosis patients may be spontaneous, but have also
occurred after insect stings or after administration of
iodinated contrast media. In the latter case, premedica-
tion with corticosteroids and antihistamines is recom-
mended before such procedures.
Methoxypsoralen with ultraviolet A (PUVA) light
can relieve pruritus and whealing after 1–2 months
of treatment.43,44 However, pruritus usually recurs
within 3–6 months after PUVA is stopped. Pigmenta-
tion induced by PUVA also may camouflage lesions of
UP in some adult patients; however, this benefit must
be weighed against the increased risk of skin cancers
associated with long-term treatment.
Cytoreductive therapy should be considered in
patients with SM-AHNMD, ASM, or MCL. The risk-
benefit must be carefully considered due to the dose-
limiting toxicities of the various drugs. IFN-α may
be considered for ASM with and without associated
hematologic malignancy. In a prospective study,
IFN-α was most efficacious in ameliorating the signs
1818
and symptoms mast cell disease; however, improve-
ment was only transitory.45 2-Chlorodeoxyadenosine
has been shown to be efficacious in reducing ascites,
mediator-associated symptoms, and BMMC burden in
patients with more advance mastocytosis, and appears
to be the treatment of choice in this patient group.
However, its use is restricted by the associated myelo-
suppression.46,47
Tyrosine kinase inhibitors, such as imatinib mesyl-
ate, inhibit growth of neoplastic cells through recep-
tors such as KIT, ABL, and PDGFR tyrosine kinases and
have been successful in the treatment of a patient with
a transmembrane mutation of KIT at the F522C
position.48,49 Imatinib, however, does not inhibit the
growth of mast cells expressing D816 mutation, and
thus is ineffective in the treatment of mastocytosis
patients with this KIT abnormality.50 Disatinib has
been demonstrated to inhibit the in vitro growth of
mast cell lines expressing D816V; however, this agent
has not been effective in reducing the signs or symp-
toms of mast cell disease in SM patients with this c-kit
mutation.51
Splenectomy may improve survival in patients with
ASM that has a poor prognosis.52 Radiotherapy has
been used to treat refractory bone pain in advanced dis-
ease.53 Nonmyeloablative bone marrow transplantation
may be considered for gravely ill patients, although a
recent report using this therapy in three patients with
advanced SM showed no sustained improvement
despite inducing a graft-versus-mast cell state.54
KeY referenCes
Full reference list available at www.DIGM8.com
DVD contains references and additional content
2. Heide R, Tank B, Oranje AP: Mastocytosis in childhood.
Ped Dermatol 19:375, 2002
12. Longley BJ et al: Activating and dominant inactivating c-
kit catalytic domain mutations in distinct clinical forms of
human mastocytosis. Proc Natl Acad Sci U S A 96:1609, 1999
14. Bodemer C et al: Pediatric mastocytosis is a clonal disease
associated with D816V c-KIT mutations. J Invest Dermatol
130:804, 2010
19. Valent P et al: Mastocytosis: Pathology, genetics and cur-
rent options for therapy. Leukemia Lymphoma 46:35, 2005
23. Konrad FM, Schroeder TH: Anaesthesia in patients with
mastocytosis. Acta Anaesthesiol Scand 53;207, 2009
28. Escribano L et al: Prognosis in adult indolent systemic
mastocytosis: a long-term study of the Spanish newtwork
on mastocytosis in a series of 145 patients. J Allergy Clin
Immunol 124:514, 2009
47. Pardanani A et al. Treatment of systemic mast cell disease
with 2-chlorodeoxyadenosine. Leuk Res 28:127-131, 2004
50. Vega-Ruiz A et al: Phase II study of imatinib mesylate as
therapy for patients with systemic mastocytosis. Leuk Res
33;1481, 2009
 Skin Manifestations of Internal
Organ Disorders

Chapter 150 :: The Skin and Disorders of the

Alimentary Tract, the Hepatobiliary
System, the Kidney, and the
Cardiopulmonary System
:: Graham A. Johnston &
Robin A.C. Graham-Brown
DISORDERS OF THE ALIMENTARY TRACT, THE HEPATOBILIARY SYSTEM, THE
KIDNEY AND THE CARDIOPULMONARY SYSTEM AT A GLANCE
A full physical examination should be part of In both abdominal pain and gastrointestinal
a full dermatologic assessment. bleeding there can be cutaneous findings that
suggest the underlying cause.
It is important to examine the skin in a
patient presenting with a systemic problem. Some cardiopulmonary syndromes have specific
dermatologic clues.
Look for generalized changes in skin quality first.
Remember dermatologic drugs as a cause of
Then examine specific organ systems systematically. systemic symptoms.

The majority of causes of jaundice can be

found on clinical history and examination.

Diseases of the skin frequently indicate, or associate
with, diseases of the alimentary tract, the hepatobiliary
system, the kidneys, and the cardiopulmonary system.
Just as a full physical examination should be part of a
full dermatologic assessment, it is important to exam-
ine the skin in a patient presenting with a systemic
problem. This chapter is presented in the same order
that a physician performing a full physical examina-
tion might approach the patient. The cutaneous mani-
festations that indicate internal disease are discussed
for each step of the examination.
GENERAL SKIN CHANGES
ALTERATIONS IN SKIN QUALITY
renal disease, or chronic hepatic disease is nonspecific.
Asteatotic eczema may develop. Some patients itch
without any visible abnormality of their skin.
CARDIAC DISEASE
EHLERS–DANLOS SYNDROME. Hyperelastic
velvety skin that rebounds to the original position after
being stretched, “cigarette-paper” scars, and hyperex-
tensible joints are characteristic of the Ehlers–Danlos
syndrome. Mitral and tricuspid prolapse, dilatation of
the aorta and pulmonary artery, arterial rupture, myo-
cardial infarction, and emphysema may accompany
this syndrome (see Chapter 137).1

The presence of pallid, dry, rough, and scaly skin that CUTIS LAXA. Progressive looseness of the skin with
is usually itchy in patients with malabsorption, chronic pendulous folds and droopy eyelids may be associ-
ated with generalized hyperelastosis leading to aortic
26 dilatation and rupture, congestive heart failure, or cor
pulmonale with pulmonary artery stenosis and pro-
gressive emphysema (see Chapter 137).
PSEUDOXANTHOMA ELASTICUM. The skin
of patients with pseudoxanthoma elasticum (PXE) is
thick, lax, and yellowish, especially over the axillae,
antecubital area, and neck. Yellow patches may occur
on mucous membranes, especially the labia. The alter-
ations in the ABCC6 gene responsible for PXE may also
lead to arteries becoming calcified, the aortic and mitral
valves thickened, and cardiovascular symptoms, such
as angina pectoris and claudication are frequent symp-
toms (see Chapter 137).2
Section 26 ::
PROGERIA. In Hutchinson–Gilford syndrome (pro-
geria) and progeroid states such as Werner ’s syndrome,
the skin appears atrophic and tight from a very early
age. There is marked loss of subcutaneous tissue, with
leg ulceration. Coronary atherosclerosis frequently
leads to premature death by myocardial infarction (see
Skin Manifestations of Internal Organ Disorders
Chapter 139).
LIVER DISEASE
Skin changes are very common in chronic liver dis-
ease.3 Hormone-induced changes of the skin include
loss of forearm, axillary, and pubic hair in both sexes.
Men may experience a decreased rate of growth of
facial hair, pectoral alopecia, and a female pubic hair
distribution, as well as loss of libido, testicular atrophy,
and oligospermia. Striae distensae occur in both men
and women (Fig. 150-1). Gynecomastia, together with
Dupuytren contracture and swelling of the parotid
gland, is associated with cirrhosis.
Many of these changes occur more commonly in those
where alcohol is the underlying cause. Patients with
chronic alcoholism also develop a “pseudo-Cushing
syndrome,” even in the absence of liver disease; signs
include facial mooning, truncal obesity, and proximal
Figure 150-1 Widespread striae in a 16-year-old boy with
chronic active hepatitis.
1820
muscle wasting. These changes may regress if the patient
discontinues alcohol.
Patients with chronic liver disease often have tel-
angiectatic changes, mainly on light-exposed skin.
Numerous tiny telangiectases sometimes give the
impression of a diffuse, almost exanthematic redness.
They are known as “dollar paper markings” after the
small threads visible in paper money held up against
the light. They fade on pressure with a glass slide and
rarely pulsate.
RENAL DISEASE
The skin of patients with chronic renal failure (CRF) is
frequently dry, often with ichthyosis-like scaling,4 pos-
sibly resulting in part from altered vitamin A metabo-
lism.5 The fluid volume shifts of dialysis may exagger-
ate this.
COLOR CHANGES
Skin color is altered in CRF. The skin is pale due to ane-
mia and often exhibits a distinctive muddy hue, due to
accumulation of carotenoid and nitrogenous pigments
(urochromes) in the dermis, although its etiology is
complicated and may depend in part on treatment
modalities used.6
CYANOSIS
An increase in the absolute amount of desaturated
(reduced) hemoglobin results in a purple–blue dis-
coloration of the skin. Cyanosis is classified into
“central” and “peripheral” types: the terms referring to
the level of arterial oxygen saturation rather than the
anatomic source of cyanosis. Thus, central cya- nosis
occurs in states that produce low arterial oxy- gen
saturation, such as congenital heart disease with
intracardiac or intrapulmonary right-to-left shunting,
or severe lung disease. Peripheral cyanosis develops
when there is normal arterial oxygen saturation but
reduced blood flow, such as low-output cardiac fail-
ure and local vasoconstriction. Pulmonary embolism
may result in a combination of central cyanosis and
peripheral cyanosis.
Central cyanosis is usually visible on warm areas of
the skin like the tongue, oral mucosae, and conjuncti-
vae. Peripheral cyanosis is seen on cooler areas such
as the nose, lips, earlobes, and fingertips. In the ane-
mic patient, detection of cyanosis may be impossible
because the absolute amount of reduced hemoglobin is
not increased. Cyanosis fades when pressure is applied
because the coloration is within the blood vessels.
ERYTHEMA
Redness of the skin is caused by an increase in the
amount of saturated hemoglobin, an increase in the
diameter or actual number of skin capillaries, or a com-
bination of these factors. Edema of the face, arms, and
hands associated with redness and/or cyanosis may
indicate obstruction of the superior vena cava due to
mediastinal disease.
Primary polycythemia may produce a character-
istic “ruddy” complexion but, in secondary disease
especially, may also cause a peculiar ruddy cyano-
sis. This is most pronounced on the tongue, lips,
nose, earlobes, conjunctivae, and fingertips. It is due
to increased amounts of saturated hemoglobin pro-
ducing erythema with increased amounts of desatu-
rated hemoglobin producing cyanosis because of the
inability of the body to fully oxygenate the increased
absolute amounts of hemoglobin. The absence of nail
clubbing in polycythemia vera may help differentiate
patients with from those patients with cardiopulmo-
nary disease who develop secondary polycythemia.
In addition, the hypervolemic state of polycythemia
vera is associated with increased stroke volume and
may lead to high-output cardiac failure. Pulmonary
emboli may result from venous thrombosis secondary
to hyperviscosity.
FLUSHING
Paroxysmal intense flushing of the face, neck, chest,
and abdomen, often with telangiectases of the face and
neck, may occur in patients with carcinoid tumors, sys-
temic mastocytosis, and pheochromocytoma, alone or
in Sipple syndrome.
PIGMENTARY CHANGES
In addition to jaundice (see below), both diffuse and
circumscribed pigmentary changes may occur in
chronic liver disease. A diffuse muddy gray color in
patients with long-standing cirrhosis is due to basal cell
melanin.
CIRRHOSIS. Melanosis is common in primary bili-
ary cirrhosis (PBC) and may be an early presenting
sign. It initially involves exposed areas, but gradually
becomes generalized. Blotchy, circumscribed areas of
dirty brown pigmentation are also occasionally evi-
dent. Accentuation of normal freckling and areolar
pigmentation can occur. Localized linear pigmentation
may appear in the creases of the fingers and palms.
Pigmentation resembling chloasma may localize to the
perioral and periorbital areas. Guttate hypomelanosis,
a condition in which small white macules, sometimes
with a central spider, appear on the skin of the but-
tocks, back, thighs, and forearms, may occur in cirrho-
sis and, rarely, in PBC.7 The yellow and orange lesions
of dermal, subcutaneous, and tendon xanthomas and
also xanthelasma are common in PBC and can be
extensive (see Chapter 135).
HEMOCHROMATOSIS. The generalized metallic
gray or bronze-brown color of the skin in hemochro-
matosis can be striking. There is accentuation in sun-
exposed and traumatized skin, and occasionally there
is buccal and conjunctival pigmentation.8
The etiology and pathogenesis of hyperpigmenta-
tion in chronic liver disease remains obscure and var-
26
ies from disease to disease. The pigmentation in PBC is
due predominantly to excess melanin with no stainable
iron, while in hemochromatosis, pigmentation results
both from the presence of hemosiderin in the skin and
excess melanin. After phlebotomy, histologic siderosis
and pigmentation decrease, even though melanosis
remains histologically.
VITAMIN DEFICIENCY. Pellagra gives rises to
lichenified, and often deeply pigmented skin in sun-
exposed sites and can develop in patients with alcoholic
liver disease. Vitamin B12 deficiency causes pigmenta-
tion of the distal extremities in a glove and stocking dis-
Chapter 150 :: The Skin and Disorders of the Alimentary Tract, the Hepatobiliary System
tribution. Diffuse hyperpigmentation occurs in folate
deficiency. Kwashiorkor produces generalized depig-
mentation (see Chapter 130).
JAUNDICE
(Box 150-1)
In jaundice, raised plasma bilirubin produces a gen-
eralized coloration of the skin, mucous membranes,
and other body tissues varying in hue from faint
golden to dark green–yellow. Both jaundice and pig-
mentation are most prominent in extrahepatic biliary
obstruction and in PBC.
Jaundice results from increased cellular or connec-
tive tissue binding of bilirubin and its metabolites in
the skin. Bilirubin has an affinity for elastin, but cir-
culates almost exclusively as a tightly bound complex
with albumin. Eighty-five percent of bilirubin comes
from the degradation of heme, the remainder from
other heme-containing proteins, such as myoglobin
and cytochromes. Jaundice results from an imbalance
between tissue production and hepatic clearance of
bilirubin.
Tissue-serum equilibration is slow, and so the inten-
sity of clinical jaundice often fails to reflect the con-
current serum bilirubin level. Hyperbilirubinemia
may, therefore, antedate the onset of detectable jaun-
dice, and jaundice may persist despite falling or nor-
mal serum bilirubin levels. The correlation between
skin color and serum pigment levels is especially
poor in newborns. The intensity of jaundice and lev-
els of serum bilirubin in patients with biliary atresia,
acquired bile duct obstruction, or defective bilirubin
conjugation tend to stabilize despite continued pig-
ment production. Congestive cardiac failure may
cause hyperbilirubinemia and jaundice secondary to
raised intrahepatic pressure.
CLINICAL FEATURES. Clinically detectable jaun-
dice appears when sufficient amounts of bilirubin
become tissue bound. Involvement of the sclerae dif-
ferentiates jaundice from other causes of skin pig-
mentation, including carotenemia, the yellow skin
pigmentation produced by quinacrine and busulfan,
and lycopenemia due to the ingestion of tomato juice.
The urine becomes dark yellow and even brown
in color as conjugated serum bilirubin rises. Because 1821
26 BOX 150-1 A FUNCTIONAL
most of the brown color of normal feces is due to uro-
bilins derived from degradation of bilirubin in the
CLASSIFICATION OF JAUNDICE intestine, the jaundice of impaired bilirubin excretion or
bile obstruction is associated with “clay-colored” stools.
Unconjugated hyperbilirubinemia Ultraviolet radiation enhances degradation of bilirubin;
New and infant this is the rationale for phototherapy to pre- vent
kernicterus in severe neonatal jaundice.
“Physiologic”—functional hepatic immaturity
The jaundice of biliary obstruction resolves after
Hemolysis—Rh, ABO, sepsis, drug factors the obstruction is relieved. Jaundice in patients with
Prematurity acute hepatitis resolves spontaneously. The jaundice of
Transient familial hyperbilirubinemia—maternal chronic liver disease may improve after transplanta-
steroid inhibitors tion. Jaundice in chronic active hepatitis can decrease
after glucocorticoid therapy. Neonatal jaundice may
Crigler–Najjar syndrome—glucuronyl transferase
respond to phototherapy (see Chapter 237).
deficiency (hereditary)
Adult
Section 26 ::

Excess bilirubin production

PRURITUS
Hemolysis
Congenital CHOLESTATIC PRURITUS
Acquired
Dyserythropoietic—“shunt” hyperbilirubinemia
PATHOGENESIS OF CHOLESTATIC PRURITUS.
One of the most common and distressing symptoms of
Skin Manifestations of Internal Organ Disorders

Deficient conjugation hepatobiliary disease is pruritus. Although retained cuta-

Familial
Constitutional hepatic dysfunction (Gilbert
syndrome)
Crigler–Najjar syndrome type II
Acquired
Posthepatic
Associated disease—cardiac, enteric, metabolic
Drug-induced
Diagnostic features
Serum-conjugated bilirubin less than 15% of total
Absence of bilirubinuria
Low to normal urine urobilinogen
Absence of other liver function disturbances
Normal morphologic features of liver
Conjugated hyperbilirubinemia
Hepatic cell damage
Acute—viral, toxic, anoxic, metabolic
Chronic—cirrhosis, metabolic
Impaired bile excretion
Extrahepatic obstruction
Intrahepatic cholestasis—atresia, viral, drugs,
hormones, pregnancy, benign recurrent cholestasis
Familial (defect confined to bilirubin excretion)
Dubin–Johnson syndrome—excretory defect and
cell pigment
Rotor’s syndrome—excretory defect and no
pigment
Diagnostic features
Serum-conjugated bilirubin more than 15% of total
Bilirubinuria common
Urine urobilinogen often elevated
Other liver functions often abnormal in hepatic cell
damage and impaired bile excretion
Characteristic morphologic abnormalities of liver
1822
neous bile acids have been implicated, there is a poor cor-
relation between the plasma bilirubin and the severity of
pruritus. However, the partial relief of itching by bile salt-
chelating resins and the disappearance of pruritus when
liver cells fail strongly indicates that the liver must manu-
facture at least one of the contributing agents.
Opiate agonists, such as morphine, induce pruritus.
Animal studies show that the intracerebral presence
of morphine induces pruritus that is reversed by the
opiate antagonist nalaxone,9 demonstrating that opi-
ate agonists induce itching centrally. In addition, the
administration of the opioid antagonist nalmefene to
patients with PBC produces a reaction similar to that
of opiate withdrawal, and the injection of plasma from
patients with PBC into monkeys produces pruritus.
Taken together, these studies suggest that opioidergic
tone increases in cholestasis.9 These studies do not, of
course, tell us which agent(s) cause the pruritus of cho-
lestasis, nor whether it originates peripherally (e.g., in
the liver) or centrally.10
CLINICAL FEATURES. Pruritus more commonly
occurs in conditions causing cholestasis and ranges
from mild and transient to severe and prolonged. Pru-
ritus may be debilitating in patients with PBC, mechan-
ical biliary obstruction, or intrahepatic obstruction.
Drugs, especially erythromycin, oral contraceptives,
phenothiazines, chlorpropamide, para-aminosalicylic
acid, and nitrofurantoin, induce cholestasis accompa-
nied by pruritus. Pruritus is the presenting symptom in
more than 50% of cases of PBC and may precede
jaundice by months or even years. However, in viral
hepatitis, itching is frequently missed as an early sign
of the disease until it occurs in the later, icteric phase.
Pruritus is usually most marked on the extremities
and only rarely involves the neck and face, and geni-
talia. There is little correlation between the severity of
cholestasis and the severity of perceived pruritus: a
spontaneous decrease in the intensity of pruritus may
signal the development of hepatocellular failure rather
than improvement. Scratching gives only very tempo-
rary relief in the pruritus of cholestasis. There may be
no visible skin changes except excoriations, although
lichenified plaques, nodular prurigo or peforating col-
lagenoses may be seen (see Chapter 69).
MANAGEMENT. Pruritus rapidly decreases when
cholestasis secondary to mechanical bile duct obstruc-
tion is relieved. Drugs to relieve cholestasis such as
ursodeoxycholic acid do not consistently relieve pru-
ritus, nor do the anion exchange resins cholestyramine
and cholestipol, which are thought to bind intestinal
pruritogens and prevent them making their way to the
skin. Neurotransmitter receptor antagonists such as
oral nalmefene have been advocated for the pruritus of
cholestasis11 Intravenous naloxone has short-term effi-
cacy12 as has oral naltrexone.13 However, while these,
together with sedating antihistamines or ultraviolet
light can help, long-term results with any approach,
including plasmapheresis, charcoal hemoperfusion,
and hepatic enzyme inducers (such as rifampicin)
have been disappointing.14
RENAL PRURITUS
Renal pruritus is a major problem4 and reported to be as
high as 90% in patients undergoing hemodialysis.15–17
PATHOGENESIS OF RENAL PRURITUS. Renal
pruritus has been thought to be caused by a combi-
nation of increased serum histamine, vitamin A, and
parathyroid hormone (PTH); mast cell hyperplasia;
peripheral polyneuropathy; xerosis.16,18; and inflamma-
tory factors.19 Clinically, the skin may appear normal
or demonstrate a variety of lichenified or hyperkera-
totic lesions.20
MANAGEMENT. Topical moisturizers alleviate
pruritus associated with xerotic skin. Topical gluco-
corticoids and ultraviolet phototherapy21,22 are often
used to suppress inflammation in treated areas. Topi-
cal capsaicin depletes substance P from nerve endings,
thereby suppressing itch sensation.23 Gabapentin and
the κ-opioid-receptor-agonist nalfurafine have also
been found useful.19 Improving the efficacy of dialysis
and/or changing the dialysate concentration may help
to alleviate pruritus.24 Some patients have responded
to treatments with intravenous lidocaine, heparin, and
cholestyramine.22 Surgical options include subtotal
parathyroidectomy, electric needle stimulation, and
renal transplantation. Erythropoietin lowers plasma
histamine concentrations with subsequent improve-
ment in pruritus.25 There are reports of success with
oral evening primrose oil,26 and endocannibinnoids.27
Thalidomide, pentoxiphylline, and topical tacrolimus
ointment may help some patients.19,28
ALTERATIONS IN SWEATING
Sweating may be prominent in a number of cardio-
pulmonary states such as acute myocardial infarction,
cardiogenic shock, left ventricular failure, massive
pulmonary emboli, and pulmonary edema. Pallor and
26
clamminess/coldness of the extremities and exposed
surfaces are also often found. Excessive sweating may
suggest pheochromocytoma when associated with
hypertension.
The sodium and chloride content of sweat is
increased in patients with cystic fibrosis and may lead
to an increase in skin wrinkling after immersion, as
when bathing.29
SKIN CHANGES IN MALIGNANCY
(See also Chapter 153)
Chapter 150 :: The Skin and Disorders of the Alimentary Tract, the Hepatobiliary System
Many skin changes occur in association with malig-
nancies.
Dry skin (acquired ichthyosis) with asteatotic der-
matitis as well as hyperpigmentation is not uncom-
mon.
DERMATOMYOSITIS
(See Chapter 156)
Adult onset dermatomyositis is associated with
underlying malignant disease in a significant minor-
ity of cases.30 Blind CT scans may help uncover occult
malignancy in these patients.31 Pancreatic, gastric,
and colorectal cancers are the third most common
after bronchogenic and ovarian cancers in Europe and
North America. In China, nasopharyngeal carcinoma
is common. The rash and myopathy can regress after
removal of the tumor.
Interstitial lung disease occurs32 with bronchiolitis
obliterans, subcutaneous emphysema, and spontane-
ous pneumothorax. Upper pharyngeal weakness can
lead to chronic aspiration an, exertional dyspnea can
occur because of weakness of the respiratory muscles.
Lung disease is associated with anti-Jo-1 antibodies.
ACANTHOSIS NIGRICANS
(See Chapter 151 and 153)
In two-thirds of patients with acanthosis nigricans
and cancer, the tumor is gastric. The changes may
regress if the tumor, usually an adenocarcinoma of the
stomach or bowel, is removed.
HYPERTRICHOSIS LANUGINOSA
Excessive growth of lanugo hair is a rare complication
of gastrointestinal cancer.
OTHER SKIN CHANGES IN
MALIGNANCY
Diverse cutaneous paraneoplastic syndromes may
arise from underlying tumors.33 They may precede,
coincide with, or follow the diagnosis of cancer
and usually indicate a poor prognosis. They include 1823
26
Section 26 ::
Figure 150-2 Patient with “tripe hands” due to adenocar-
cinoma of the jejunum.
reactive erythemas, such as erythema gyratum repens
and necrolytic migratory erythema; the vascular der-
matoses (trousseau syndrome); and papulosquamous
Skin Manifestations of Internal Organ Disorders
disorders, including tripe palms (Fig. 150-2), palmar
hyperkeratosis, acquired ichthyosis, pityriasis rotunda,
Bazex syndrome, florid cutaneous papillomatosis, the
sign of Leser–Trélat, and extramammary Paget disease.
Migratory superficial thrombophlebitis occurs in asso-
ciation with neoplasia, particularly carcinoma of the
pancreas. Glucagonoma, one of the amine precursor
uptake and decarboxylation (APUD) cell tumors, usu-
ally arises in the islet cells of the pancreas, and occurs
in association with a distinctive necrolytic migratory
erythema (see Chapter 153).
Any tumor may metastasize to the skin. The scalp
is a common site. Metastases at the umbilicus (Sister
Joseph nodules) occur particularly with carcinoma of
the stomach, colon, or ovary (Fig. 150-3).
ERYTHRODERMA
(See Chapter 23)
The systemic effects of erythroderma can be consid-
erable. Patients can develop hypothermia, hypoalbu-
minemia, hypovolemia, secondary sepsis, the initial
stages of renal failure, and high-output cardiac failure
Figure 150-3 Umbilical metastasis (Sister Joseph nodule)
from intraabdominal adenocarcinoma.
1824
with secondary effects on hepatic function. Death from
sepsis, cardiac failure, adult respiratory distress syn-
drome, and capillary leak syndrome occur.34
SPECIFIC ORGAN AND
SYSTEM CHANGES
NAILS
(See Chapter 89)
Lindsey, or half-and-half, nails are normal in their
distal 50% and white in the proximal 50% and found
in CRF.
In malabsorption or malnutrition, nails grow more
slowly, become brittle, and may develop fissures.35,36
Multiple pigmented bands can appear. Koilonychia
usually indicates iron deficiency, even without anemia
(see below). White nails, thought to be due to selenium
deficiency, have occurred with total parenteral nutri-
tion.
Flushing of the nail beds that is synchronous with
the heartbeat is a sign of aortic regurgitation called
Quincke pulsation.
NAIL CHANGES IN LIVER DISEASE
Nail abnormalities are a less constant physical sign than
spider nevi or liver palms. In cirrhosis, however, a
number of changes may occur: clubbing, curved nails,
thickened nails, longitudinally ridged nails, white nails,
watch-glass deformity, flattened nails, white bands,
striations, and brittleness.36
White nails may occasionally be seen in healthy
individuals or in association with systemic disease,
including congestive heart failure, diabetes, cryoglob-
ulinemia, Raynaud syndrome, and systemic sclerosis.
Intensely white nails (Terry nails) are characteristic
of cirrhosis (Fig. 150-4).37 Thumbs and forefingers are
often most affected. The whiteness does not alter with
nail growth or with compression of digital vessels and
is thought to be due to the opacity of the nail plate itself.
The so-called watch-glass deformity may accom- pany
white nails (see Fig. 150-5).
Azure lunulae, a bluish color of the lunular por-
tion of nails, occurs in hepatolenticular degeneration
(Wilson disease). Azure lunulae and corneal changes
resembling Kayser–Fleischer rings may also be evident
in patients with argyria or following treatment with
busulfan or antimalarials.36
The characteristic nail changes of lichen planus,
including longitudinal ridging, pterygium formation,
and permanent nail loss, occur both with and without
skin changes in PBC (see Section “Cutaneous Manifes-
tations of Primary Biliary Cirrhosis”).
Splinter hemorrhages also occur in cirrhosis. Flat or
spoon nails are less common in patients with liver dis-
ease. The nails are flat or concave, pale in color, and
frequently show longitudinal ridging. In hemochro-
matosis, koilonychia is probably the most common of
the nail abnormalities, but it is not related to anemia.36