D i a g n o s t i c Wor k - u p of t h e

Itchy Patient
Sarina B. Elmariah, MD, PhD*

KEYWORDS
 Pruritus  Itch  Diagnosis  Evaluation  Pruriceptive  Neuropathic  Systemic

KEY POINTS
 Itch is a symptom of many dermatologic, systemic, neurologic, or psychiatric disorders.
 Chronic or severe itch has a negative impact on the quality of life of affected individuals.
 The most important and fundamental factor in ultimately diagnosing the cause of itch remains a
detailed history and physical examination.
 In the absence of primary inflammation, a work-up for other systemic or neurologic causes may be
necessary.

INTRODUCTION singular disease, identifying the cause of a pa-

tient’s pruritus is often challenging. It is thus
Itch, also called pruritus, is defined as a sensation important to have a framework for how to
that provokes the urge to scratch. Pruritus arises approach the diagnostic evaluation of the chroni-
commonly in the setting of numerous dermato- cally itchy patient. This article reviews basic path-
logic, systemic, neurologic, and psychiatric disor- ophysiology of itch signaling, discusses the broad
ders, affecting all age groups, races, and both differential diagnosis for chronic pruritic disorders,
genders. Pruritus is considered chronic when and outlines an approach to the clinical assess-
symptoms arise regularly for more than 6 weeks. ment of patients with chronic itch in the presence
At any given time, approximately 25% to 38% of or absence of primary skin findings.
the general population may be affected by pruri-
tus. Rates of moderate to severe itch may be ANATOMIC ITCH CLASSIFICATION
much higher in specific populations, such as those
with inflammatory or allergic skin disease, or indi- Chronic itch is often classified into several sub-
viduals with chronic medical disorders (eg, chronic types typically reflecting anatomic basis of disease
renal failure, cholestasis, or malignancy).1–3 activity. In one scheme proposed by Twycross and
Chronic pruritus has a significant and negative colleagues,13 pruritus subgroups include prurito-
impact on patient quality of life. Similar to chronic ceptive or dermatologic itch (arising in the skin),
pain, patients with chronic or severe itch neuropathic itch (arising along the neural path-
experience reduction in time and quality of sleep, ways caused by injury or damage), neurogenic
impaired memory and attention, physician- itch (arising from abnormal activation of undam-
diagnosed depression and anxiety, and social aged nerves because of endogenous or exoge-
isolation and withdrawal.4–12 nous agents), and psychogenic itch (arising in the
Because itch is a symptom that may arise in context of psychiatric disease). Building on this
the setting of many conditions and is not itself a scheme, the International Forum for the Study of
derm.theclinics.com

Disclosure Statement: The author has nothing to disclose.

Massachusetts General Hospital, Boston, MA 02114, USA
* Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, 149 Thir-
teenth Street, Charlestown, MA 02129.
E-mail address: [email protected]

Dermatol Clin 36 (2018) 179–188

https://doi.org/10.1016/j.det.2018.02.002
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180 Elmariah

Itch (IFSI) designed a two-tiered classification sys- mechanism by which such disorders provoke
tem that allows a physician to categorize itch itch is unknown. In general, it is believed that
based on clinical features alone (in the absence damage, dysfunction, or neoplasia of specific or-
of a known or definitive anatomic target) or once gans results in the production of one or more by-
diagnostic data have been obtained that suggest products that function as pruritogens that directly
the underlying cause.14 In the first tier, the IFSI activate peripheral or central nerves. In some
scheme divides itch into three major types based scenarios, acquired dysfunction of the nerves or
on patient history and physical examination neuropathy may lead to abnormal sensations of
including Group I (pruritus on diseased skin itch, similar to pain. Because of the highly vari-
including autoimmune or allergic disorders, drug able nature of how pruritus arises in systemic dis-
rashes), Group II (pruritus on nondiseased or non- ease, itch may manifest early in disease and can
inflamed skin including itch caused by systemic, precede other systemic symptoms (eg, paraneo-
neurologic, or psychiatric disorders, diseases of plastic itch in Hodgkin lymphoma), or may arise
pregnancy, and drug-induced itch without a late in disease (eg, in chronic kidney disease).
rash), or Group III (pruritus presenting with sec- When chronic pruritus arises in the setting of sys-
ondary scratch lesions, such as prurigo nodularis, temic disease, only secondary lesions, such as
lichen simplex chronicus, or hyperpigmentation). If excoriations, lichenification, prurigo nodules,
clinical evaluation and diagnostic tests suggest a and hyperpigmentation are observed on exami-
cause for the patient’s pruritus, further categoriza- nation. Occasionally, other cutaneous stigmata
tion into one of the following six groups may be of disease may be present and help the clinician
possible: (1) dermatologic diseases; (2) systemic hone in on a possible diagnosis (eg, jaundice,
diseases including diseases of pregnancy and palmar erythema, and periumbilical varicosities
drug-induced pruritus; (3) neurologic; (4) psychiat- in the setting of liver failure; acanthosis nigracans
ric/psychosomatic diseases; (5) mixed, when in diabetes or metabolic disorders; diffuse pete-
more than one underlying disease may contribute chiae or purpura in the setting of various hemato-
to itch; and (6) other, when no cause is identified.14 logic malignancies; nail changes in liver or kidney
disease).
DIFFERENTIAL DIAGNOSIS OF ITCH Itch that results from injury, degeneration, or ac-
quired dysfunction of the afferent pruritoceptive
Itch in dermatologic disease or pruritoceptive itch pathways is considered neuropathic in origin
results from the elaboration of inflammatory medi- (Table 2). Examples of neuropathic pruritus
ators in the skin in the setting of allergic diseases, include localized pruritus syndromes, such as bra-
infections, autoimmune or connective tissue chioradialis pruritus, notalgia or meralgia pares-
diseases, cutaneous neoplasms, and genoderma- thetica, and postherpetic itch. Widespread or
toses. Commonly encountered primary inflamma- generalized neuropathic itch may develop in the
tory dermatoses that are associated with itch context of neurodegenerative disorders, such as
include atopic dermatitis, psoriasis, allergic or multiple sclerosis or because of small fiber
irritant contact dermatitis, urticaria, bullous pem- neuropathies. Similar to what is observed in sys-
phigoid, dermatophytosis, scabies and other in- temic itch, clinical findings in patients with neuro-
festations, xerosis, and many other conditions. pathic itch conditions consist of secondary
Itch may be localized (as in the case of allergic lesions including excoriations, hyperpigmentation,
contact dermatitis) or widespread (as in the case and lichenification. Some systemic diseases may
of scabies, atopic dermatitis). In many of the previ- compromise neural pathways resulting in itch
ously mentioned conditions, the presence of pri- and may thus reflect a neuropathic cause. How-
mary inflammatory lesions allows for immediate ever, because neural compromise in these situa-
diagnosis by the trained clinician. In some cases, tions is secondary to another underlying
however, secondary changes of the skin may disorder, such itches are currently classified under
obscure primary lesions and further evaluation the systemic rubric.
may be required. Individuals with psychiatric or psychosomatic
Generalized pruritus may manifest in the diseases may experience itch, formication and
context of numerous systemic diseases, other tactile hallucinations, self-injurious or pick-
including malignancy, renal and hepatic dysfunc- ing behaviors, and neurotic excoriations. One
tion, metabolic and endocrine disorders, infec- study estimated that approximately 40% of indi-
tious syndromes, and as a side effect of viduals admitted for inpatient psychiatric care
systemic medications (Table 1). In the IFSI experienced generalized itch.15 Although skin
classification, pruritic disorders of pregnancy picking is common in the general population,
are also included in this category. The exact it frequently accompanies affective and anxiety

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 Diagnostic Work-up of the Itchy Patient 181

Table 1
Common systemic diseases that cause itch

Cutaneous Manifestations of
Condition Underlying Disease Diagnostic Findings
Renal disorders
End-stage chronic Skin findings: butterfly sign (sparing Clinical history/physical examination:
renal failure of central back surrounded by suggestive, but need pathologic
hyperpigmentation and and/or serologic confirmation of
excoriations on “reachable” areas underlying disease
of back) Pathology (skin): nondiagnostic
Systemic findings/association: N/A Diagnostic work-up: BUN/Cr, CBC,
ferritin
Reactive perforating Skin findings: dome-shaped Clinical history/physical examination:
collagenosis flesh-colored or hyperpigmented suggestive, but need pathologic
papules with an adherent keratotic and/or serologic confirmation of
plug skin lesions
Systemic findings/association: chronic Pathology (skin): epidermal
renal insufficiency, anemia hyperplasia or cup-shaped
depression with keratin plug
containing parakeratosis,
inflammatory debris, and
basophilic collagen fibers in dermis
and extruding through epidermis
Diagnostic work-up: BUN/Cr, ferritin,
fasting serum glucose
Hepatobiliary disease
Primary biliary Skin findings: palmar pruritus with or Clinical history/physical examination:
cirrhosis without erythema, suggestive, but need pathologic
hyperpigmentation, xanthelasma/ and/or serologic confirmation of
xanthomas, spider nevi, jaundice underlying disease
Systemic findings/association: Pathology (skin): nondiagnostic
HSM  ascites, peripheral edema, Diagnostic work-up: elevated alkaline
fatigue, abdominal discomfort phosphatase, g-glutamyl
transpeptidase, IgM, AST/ALT,
elevated bilirubin, 
thrombocytopenia, 1 antinuclear
antibodies and antimitochondrial
antibodies
Hepatitis C Skin findings: xerosis, jaundice, Clinical history/physical examination:
peripheral edema, spider nevi, suggestive, but need pathologic
purpura, lichen planus, porphyria and/or serologic confirmation of
cutanea tarda underlying disease
Systemic findings/association: Pathology (skin): nondiagnostic
HSM  ascites, peripheral edema, Diagnostic work-up: Hepatitis C
fatigue, abdominal discomfort, antibody, qualitative and
Raynaud disease quantitative assays for hepatitis C
virus RNA, genotyping, hepatitis B
Ag/Ab, HIV, CBC, TSH, LFTs
Cholestatic jaundice, Skin findings: jaundice, Clinical history/physical examination:
also cholestasis of telangiectasia/spider angiomas, suggestive, but need pathologic
pregnancy palmar erythema, xanthelasma; and/or serologic confirmation of
alopecia underlying disease
Systemic findings/association: chronic Pathology (skin): nondiagnostic
hepatic insufficiency, peripheral Diagnostic work-up: elevated alkaline
edema, numerous sequelae phosphatase, g-glutamyl
depending on the cause of transpeptidase, AST/ALT, elevated
cholestasis bilirubin; cholangiography to help
discern potential causes
(continued on next page)

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182 Elmariah

Table 1
(continued )

Cutaneous Manifestations of
Condition Underlying Disease Diagnostic Findings
Hematopoeitic disease
Polycythemia vera Skin findings: ecchymoses, mucosal Clinical history/physical examination:
bleeding suggestive, but diagnosis of
Systemic findings/association: exclusion
headache, splenomegaly, Pathology (skin): nondiagnostic
hepatomegaly, hypertension Diagnostic work-up:
hemoglobin >16.5; bone marrow
biopsy showing hypercellularity
with trilinear growth; JAK2V617F
or JAK2 exon 12 mutation
Iron-deficiency Skin findings: pallor, nail bed pallor Clinical history/physical examination:
anemia and spoon-shaped nail suggestive, but diagnosis of
(koilonychia) atrophy of the lingual exclusion after serologic
papillae on tongue, angular confirmation of underlying anemia
stomatitis Pathology (skin): nondiagnostic
Systemic findings/association: fatigue, Diagnostic work-up: low hemoglobin,
cold intolerance, muscle cramps, hematocrit, MCV, and MCHC; low
splenomegaly, rarely pseudotumor serum iron and ferritin, elevated
cerebri TIBC; stool Hemoccult test; bone
marrow aspiration
Hodgkin lymphoma Skin findings: excoriations secondary Clinical history/physical examination:
to pruritus, new onset of eczema, suggestive, but need pathologic
xerosis and/or serologic confirmation of
Systemic findings/association: weight underlying disease
loss, fatigue, fever, sweats, Pathology (skin): nondiagnostic
asymptomatic lymphadenopathy, Diagnostic work-up: CBC with diff,
splenomegaly, hepatomegaly ESR, LDH; chest, abdomen, pelvic
CT 1 PET; lymph node biopsy
needed to confirm
Non-Hodgkin Skin findings: in some cases, primary Clinical history/physical examination:
lymphoma cutaneous papules, nodules, suggestive but need pathologic
patches, plaques or tumors; pallor, and/or serologic confirmation of
purpura, ecchymoses underlying disease
Systemic findings/association: bulky Pathology (skin): nondiagnostic
lymphadenopathy, splenomegaly, Diagnostic work-up: CBC with diff
hepatomegaly, abdominal or may show abnormalities, elevated
testicular masses b2-microglobulin, LDH; chest,
abdomen, pelvic CT 1 PET; lymph
node or bone marrow biopsy
needed to confirm
Multiple myeloma Skin findings: pallor, purpura, Clinical history/physical examination:
ecchymoses suggestive, but need pathologic
Systemic findings/association: bone and/or serologic confirmation of
tenderness, neuropathy, underlying disease
hepatomegaly, splenomegaly, Pathology (skin): nondiagnostic
cardiomegaly Diagnostic work-up: SPEP and UPEP
with immunofixation; bone
marrow biopsy; CBC with diff may
show abnormalities, elevated
b2-microglobulin, LDH; spine MRI
(continued on next page)

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 Diagnostic Work-up of the Itchy Patient 183

Table 1
(continued )

Cutaneous Manifestations of
Condition Underlying Disease Diagnostic Findings
Endocrine and metabolic syndromes
Hyperthyroidism Skin findings: pretibial myxedema, Clinical history/physical examination:
erythema, edema, velvety skin, suggestive, but need pathologic
flushing and hyperhidrosis and/or serologic confirmation of
Systemic findings/association: anxiety, underlying disease
heat intolerance, palpitations, Pathology (skin): nondiagnostic
tachycardia, hypertension, tremors, Diagnostic work-up: suppressed TSH,
muscle weakness elevated T3, T4; 1 autoantibodies -
anti-TPO, anti-TSab
Hypothyroidism Skin findings: xerosis, rough skin, Clinical history/physical examination:
coarse or brittle hair, alopecia, suggestive, but need pathologic
macroglossia, periorbital edema, and/or serologic confirmation of
pallor, jaundice underlying disease
Systemic findings/association: weight Pathology (skin): nondiagnostic
gain, fatigue, depression, Diagnostic work-up: elevated TSH,
bradycardia, altered blood pressure decreased T3, T4; 1 autoantibodies
-anti-thyroid peroxidase and
antithyroglobulin antibodies;
thyroid imaging
Diabetes Skin findings: acanthosis nigricans, Clinical history/physical examination:
necrobiosis lipoidica diabeticorum, suggestive, but need pathologic
granuloma annulare, diabetic and/or serologic confirmation of
dermopathy, waxy skin syndrome, underlying disease
diabetic bullae, xerosis Pathology (skin): nondiagnostic for
Systemic findings/association: itch, but may have reduced IENF
retinopathy, neuropathy, chronic density
kidney disease, increased Diagnostic work-up: elevated fasting
cardiovascular morbidity and glucose, 2-h oral tolerance test, and
mortality HgbA1c; UA; may have altered QST
or QSART
Infectious disease
HIV infection Skin findings: coarse or xerotic skin, Clinical history/physical examination:
erythematous papules or folliculitis, suggestive, but need pathologic
history of recurrent infections, and/or serologic confirmation of
eczema underlying disease
Systemic findings/association: flulike Pathology (skin): eosinophilic
illness, generalized folliculitis reveals dermal
lymphadenopathy, opportunistic eosinophils around the hair follicles
infections, weight loss, dementia if and sebaceous glands
severe Diagnostic work-up: ELISA or Western
blot for HIV 1/2; p24 antigen
detection; viral load; CD4 T-cell
count

Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; BUN/Cr, blood, urea, nitrogen, creatinine; CBC,
complete blood count; CSF, cerebrospinal fluid; CT, computed tomography; CVA, cerebrovascular incident; ELISA,
enzyme-linked immunosorbent assay; ESR, erythrocyte sedimentation rate; HgbA1c, hemoglobulin A1c; HIV, human immu-
nodeficiency virus; HSM, hepatosplenomegaly; IENF, intraepidermal nerve fiber; IF, immunofluorescence; LDH, lactate de-
hydrogenase; LFT, liver function tests; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular
volume; QSART, quantitative pseudomotor axon reflex testing; QST, quantitative sensory testing; SPEP, protein electro-
phoresis study from serum; TIBC, total iron binding capacity; TPO, thyroperoxidase; TSAB, thyroid-stimulating antibody;
TSH, thyroid-stimulating hormone; UA, urine analysis; UPEP, protein electrophoresis study from urine.

disorders, eating and substance abuse disorders, or neurologic causes of itch have been excluded.
and impulse control disorders. Psychiatric or psy- It is important to recognize that itch may result
chogenic itch is a diagnosis of exclusion, and from medications used to treat psychiatric or
must be rendered once dermatologic, systemic, neurologic diseases and that emotional stress

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184 Elmariah

Table 2
Neuropathic itch

Cutaneous Manifestations of Underlying

Condition Disease Diagnostic Findings
Brachioradial Skin findings: excoriations on lateral Clinical history/physical examination:
pruritus aspect of arms and shoulders; may be sufficient for diagnosis in some cases
generalized Pathology (skin): nondiagnostic
Systemic findings/association: neck, Diagnostic work-up: radiograph, CT, or
shoulder injury, photosensitivity MRI of cervical spine may demonstrate
abnormalities
Notalgia or Skin findings: hyperpigmented patches Clinical history/physical examination:
meralgia on upper middle aspect of back, T2-T6 sufficient for diagnosis in most of cases
paresthetica (notalgia), or outer thigh, lateral Pathology (skin): nondiagnostic
femoral cutaneous (meralgia); Diagnostic work-up: radiograph, CT, or
frequently unilateral MRI of spine may demonstrate
Systemic findings/association: obesity, abnormalities
pregnancy
Postherpetic Skin findings: hyperpigmentation, Clinical history/physical examination:
neuralgia lichenification or excoriations limited
sufficient for diagnosis in most cases
to previously affected dermatomes Pathology (skin): nondiagnostic
Systemic findings/association: prior Diagnostic work-up: CSF may show
herpes zoster eruption pleocytosis, elevated protein, or VZV
DNA; increased anti-VZV antibody
titers may be present
Multiple Skin findings: xerosis, localized or Clinical history/physical examination:
sclerosis widespread secondary skin changes suggestive, but diagnosis of exclusion
(hyperpigmentation, lichenification, Pathology (skin): may have reduced IENF
excoriatons) density on protein gene product 9.5
Systemic findings/association: ataxia, biopsy
double vision, Lhermitte sign (electrical Diagnostic work-up: MRI of brain and
spine pain when bending neck), spinal cord, CSF electrophoresis, visual
sensory loss, parasthesias, dysesthesia and sensory evoked potentials; may
observe altered QST and QSART
Cerebrovascular Skin findings: localized or widespread Clinical history/physical examination:
accident secondary skin changes suggestive, but diagnosis of exclusion
(hyperpigmentation, lichenification, Pathology (skin): nondiagnostic
excoriatons); may also have cutaneous Diagnostic work-up: imaging as part of
findings of purpura, petechia, Janeway CVA assessment
lesions, Osler nodes
Systemic findings/association: sensory
loss, weakness, ataxia

Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; CVA, cerebrovascular incident; IENF, intraepidermal
nerve fiber; QSART, quantitative pseudomotor axon reflex testing; QST, quantitative sensory testing; VZV, varicella zoster
virus.

and psychological factors may impact itch (localized vs generalized), and progression of
severity in the setting of pre-existing dermatologic symptoms and whether symptoms are accompa-
or systemic disease. nied by a rash. The quality of the sensory distur-
bance may also be helpful. For example, burning
DIAGNOSTIC EVALUATION OF THE ITCHY in association with itch is characteristic of hives,
PATIENT but may also manifest with patients with atopic
dermatitis, photodermatoses, or peripheral neu-
Because the differential diagnosis is so broad, it is ropathy. Identifying exposures, locations, or activ-
necessary to take a systematic approach to evalu- ities that provoke or aggravate itch may help
ating the patient with chronic pruritus. The founda- narrow the differential diagnosis (eg, as in the
tion of any successful diagnostic evaluation is a case of an environmental or contact allergy, aqua-
detailed history that elicits the onset, distribution genic pruritus, or cholinergic urticaria). Eliciting a

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 Diagnostic Work-up of the Itchy Patient 185

history of new topical or systemic medications, stimulus could be performed with the edge of
personal care items (eg, detergents, fragrances, single-use, disposable needle (26–30 gauge)
lotions), household items (eg, furniture, carpets, or the broken edge of a wooden swab stick or
mattresses), or new household pets may suggest tongue depressor. Temperature sensation may
an allergy. A recent history of travel might suggest be assessed using the end of any metal instrument
exposure to scabies, lice, or other parasitic infec- kept at room temperate. Sensory testing should
tions. To elicit symptoms of systemic, neurologic, begin on the distal first toe if a widespread neurop-
or psychiatric disease, a detailed review of symp- athy is suspected and then work proximally up the
toms should also be performed. Patients should leg to assess the extent of sensory loss. If localized
be questioned about recent emotional stress, or dermatomal sensory disturbance is suspected,
febrile illness, weight loss, abdominal discomfort, test at the distal and then proximal aspect of the
diarrhea or other gastrointestinal symptoms, area of concern and the corresponding contralat-
numbness or paresthesias, dizziness, weakness, eral area of the body for comparison. In general,
arthritis, allergic symptoms (conjunctivitis, rhinitis, it is helpful to have patients close their eyes during
angioedema), or other constitutional symptoms. neurologic evaluation.
A comprehensive physical examination should If a diagnosis is made following history and
be performed at the initial evaluation and should physical examination, further evaluation may or
be repeated at subsequent visits as symptoms may not be necessary. When a nonspecific derma-
persist or evolve. The presence of primary lesions titis or heavily excoriated primary lesions are
including xerosis, ichthyosis, macular or papular observed on the initial examination, a skin biopsy
erythema, vesicles, bullae, or wheals suggests may be helpful to confirm a suspected diagnosis.
an underlying dermatologic disease. When pruri- In the absence of an obvious primary dermatitis,
tus is severe, primary lesions may be deeply when an immediate diagnosis cannot be made,
excoriated or lichenified, obscuring characteristic the author suggests a trial of empiric therapy for
lesional architecture and making a clinical 2 to 3 weeks. This effort may consist of regular
diagnosis based on lesion morphology more use of bland emollients and midpotency topical
challenging. Scratching the skin to elicit corticosteroids, and avoidance of harsh deter-
dermatographism may be helpful when allergic gents, fragrances, and any identifiable triggers
conditions, atopy, urticarial, or hypersensitivity (Fig. 1). In patients who are dermatographic or in
reactions are suspected. Moreover, if the patient whom the clinician is suspecting an allergic trigger,
history suggests that exercise, heat, or cold can a trial of long-acting, oral antihistamines should be
induce pruritus, consideration should be given pursued. If a hypersensitivity reaction to a partic-
to examining the patient for potential skin ular medication or supplement is suspected, then
changes (eg, urticaria) following physical activity a trial of drug avoidance for a minimum of 2 to
(eg, running in place for 1 minute), and applica- 3 months should be pursued if possible.
tion of a warm wash cloth or an ice cube. Exam- When a patient with chronic itch has failed a
ination of ocular, oral, and if symptomatic genital reasonable trial of empiric therapy, further diag-
mucosa may also reveal inflammation, dehydra- nostic evaluation should be pursued (see Fig. 1).
tion, or evidence of systemic or autoimmune dis- First, the clinician should perform a skin biopsy
eases. In addition, physicians should seek out of lesional or actively pruritic skin for standard he-
cutaneous signs of systemic diseases that might matoxylin and eosin staining to evaluate for sub-
contribute to the patient’s itch (eg, acanthosis clinical inflammation. Special stains to evaluate
nigricans in the undiagnosed patients with dia- for an increase in the number of specific inflamma-
betes; jaundice, spider angioma, xanthelasma, tory cells (eg, mast cells, eosinophils) or the
purpura, or nail changes in a patient with chronic presence of fungal elements may be necessary.
hepatic failure). Palpation of the thyroid for thyro- An additional biopsy may be sent for direct
megaly, nodularity, or tenderness (suggestive of immunofluorescence to assess for autoimmune
Graves disease or Hashimoto thyroiditis); abdom- inflammation (eg, bullous pemphigoid, dermatitis
inal tenderness or organ enlargement (suggestive herpetiformis) if clinical suspicion warrants.
of hepatobiliary or splenic disease); and evalua- If an allergic reaction is suspected based on
tion for lymphadenopathy (suggestive of malig- clinical examination or suggested by skin biopsy,
nancy or infection) should be performed. patch testing for type IV delayed hypersensitivity
If neuropathic disease is suspected, evaluation reactions should be performed to common aller-
for abnormalities in pain or temperature (pathways gens including preservatives, fragrances, metals,
that parallel and interact with itch pathways) and to the patient’s own personal care products
should be performed. In a typical dermatology (eg, soaps, detergents, lotions). The relevance of
clinic setting, testing pain responses to a pinprick any identified allergens must then be determined

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186 Elmariah

Fig. 1. Diagnostic approach to the itchy patient. BUN/Cr, blood, urea, nitrogen, creatinine; C/A/P CT, chest,
abdomen, pelvis computed tomography; CBC, complete blood count; CXR, chest radiograph; DIF, direct immuno-
fluorescence; GI, gastrointestinal; H&E, hematoxylin and eosin; HPI, history of present illness; ID, infectious dis-
ease; IENF, intraepidermal nerve fiber quantitation; LFT, liver function tests; NCS, nerve conduction studies;
Onc, oncology; PE, physical exam; QSART, quantitative sudomotor axon reflex testing; QST, quantitative sensory
testing; ROS, review of systems; SPEP, protein electrophoresis study from serum; TSH, thyroid stimulating
hormone. (Adapted from Fleurant A, Elmariah SB. Evaluation of the itchy patient. Curr Dermatol Rep 2018;8.
https://doi.org/10.1007/s13671-018-0208-y; with permission.)

by having the patient avoid them for at least detection of antigens directly in the stool using
3 months. Additional allergy testing for type I IgE- such techniques as enzyme-linked immunosor-
mediated hypersensitivity reactions performed by bent assay, immunoblot, or polymerase chain re-
an allergist may be warranted in patients who fail action assays may be helpful to evaluate for
patch testing or have chronic or seasonal urticarial helminths that are not readily identified in stool
dermatoses. samples (eg, Toxocara sp, schistosomes, filariae,
When chronic itch arises in the setting of urti- and trichinella).17 When the clinical suspicion for
caria, new-onset dermatographism, or pathologic a parasitic infection is high, empiric antihelminthic
evidence of eosinophils and/or blood eosinophilia therapy may be considered and the patient should
in the absence of an identifiable allergic cause, pa- be referred to an infectious disease specialist.
tients should undergo evaluation for intestinal In the absence of clinical or pathologic inflamma-
parasitic infection by helminths and/or protozoa. tion of the skin, patients with chronic pruritus
Such studies are also indicated when patients should undergo diagnostic work-up for systemic
with chronic pruritus report having traveled or neurologic causes of itch. The initial serologic
outside of the United States or been camping screening should include complete blood count
before the onset of their symptoms; after with differential; liver function tests including aspar-
consuming undercooked meats; and in any patient tate transaminase, alanine transaminase, alkaline
who reports having abdominal symptoms, phosphatase, and total and direct bilirubin; lactate
diarrhea, and/or has evidence of unexplained dehydrogenase; thyroid-stimulating hormone; and
nutritional deficiencies (eg, vitamin B12 or iron defi- a total IgE level.3 Further serologic testing should
ciency). Initial screening consists of examination of be performed based on individual risk factors or
stool smears collected over 3 days for ova or par- concomitant symptoms. For example, in sexually
asites.16 Serologic screening for antibodies to active individuals and/or those with intravenous
strongyloides is advised by some experts. Simi- drug use or transfusion history, unexplained weight
larly, screening for peripheral blood antibodies or loss, or febrile illness, screening for infectious

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 Diagnostic Work-up of the Itchy Patient 187

causes, such as human immunodeficiency virus systemic work-up has been unrevealing. If clinical
(HIV), hepatitis B or C, or syphilis, may be war- suspicion for neuropathy is high, a trial of treat-
ranted. In patients with an exposure history and ment with neuromodulators may be attempted.
systemic complaints, screening for Lyme disease When pruritus is limited to a localized area of
or tuberculosis should be pursued because late or skin, mononeuropathy or multifocal neuropathy
latent stages of these diseases may be accompa- of a local cause (eg, trauma, compression, or
nied by itch with or without a rash. Protein electro- entrapment) may be confirmed by computed to-
phoresis studies from serum or urine with mography or MRI of the corresponding area of
immunofixation, peripheral blood smear, chest the spine or proximal joint. If pruritus is general-
radiograph, colonoscopy, and prostate or breast ized and/or accompanied by other sensory symp-
examination (as appropriate) may be indicated in toms (eg, burning, pain, tingling, prickling, or
chronically itchy patients that are older or experi- sensory loss), the patient should undergo evalua-
encing constitutional symptoms.18 Serologic or tion for a polyneuropathy that affects multiple pe-
stool studies if parasite infection is suspected ripheral nerves simultaneously. A reasonable first
may be performed as outlined previously. step in this scenario is to evaluate the intraepider-
When the initial systemic work-up suggests an mal nerve fiber density and patterns of cutaneous
underlying cause, a referral to one or more special- innervation by examining skin obtained from the
ists in the indicated fields should be made. Most distal lower leg. Skin samples intended for this
commonly, patients with chronic itch may benefit type of study require that the tissue be preserved
from being seen by allergy/immunology, rheuma- in a paraformaldehyde-based fixative, that the pa-
tology, hematology/oncology, endocrinology, thology service can perform immunofixation or
and/or infectious disease specialists for further immunohistochemistry for protein gene product
diagnostic evaluation. An allergist may perform a 9.5 to identify neural processes, and a pathologist
series of tests to evaluate ingested, inhaled, or who is familiar with reading such samples.21 A
other environmental allergens and the potential reduction in intraepidermal nerve fiber density
for a mast cell disorder. Allergy skin tests including suggests a small fiber polyneuropathy and war-
prick, puncture, or intradermal testing or serologic rants referral to a neurologist for quantitative sen-
radioallergosorbent tests is highly recommended sory and/or sudomotor reflex testing.22 Similar to
when an environmental trigger is suspected. Pa- pruritus, polyneuropathy is associated with a
tients with refractory pruritus who also experience large number of systemic and/or neurologic pro-
hives, angioedema, heat intolerance, flushing, cesses. Screening for some of the more common
dizziness, gastrointestinal upset, pulmonary, or causes (eg, diabetes, HIV, nutritional deficiencies,
cardiac symptoms, or have a history of anaphy- alcohol abuse or drug toxicities, autoimmune dis-
laxis should undergo further evaluation for ease) should include fasting serum glucose,
mast cell disease. Screening consists of evalu- glucose tolerance testing or HgbA1c, vitamin B12
ating total serum tryptase and histamine levels, levels, protein electrophoresis studies from serum
24-hour urinary excretion of histamine, N-methyl- or urine with immunofixation, thyroid-stimulating
histamine or N-methylimidazoleacetic acid, hormone, antinuclear antibodies, erythrocyte
leukotrienes, or prostaglandin isoforms (eg, leuko- sedimentation rate, rheumatoid factor, and
triene E4, prostaglandin D2, 11-beta-prostaglandin HIV.22 Screening for Lyme disease and more spe-
F2).19,20 Screening for genetic mutations in c-kit cific testing for autoimmune disorders or infec-
from peripheral blood or bone marrow may be tious agents may also be performed if indicated
helpful in working up a possible proliferative disor- by history or physical examination.
der involving mast cells.19,20 If the diagnostic work-up suggested previously
When a patient with chronic itch has evidence of is unrevealing, the author advocates a trial of
hematologic disease including anemia or polycy- empiric neuromodulator therapy if it has not previ-
themia, thrombocytopenia or thrombocytosis, ously been attempted. If such an intervention at-
leukocytosis, unexplained eosinophilia, or a pro- tenuates pruritus, it is up to the clinician’s
tein electrophoresis study from serum suggestive discretion as to whether a diagnosis of neuro-
of a gammopathy on his or her initial screening, pathic or psychogenic itch may be appropriate.
the patient should be referred to a hematologist Whether the patient’s itch is psychiatric in nature
for bone marrow examination. In some cases, ge- or simply exacerbated by stress, the influence of
netic screening for malignancy-associated muta- chronic and severe pruritus on an individual’s
tions may be performed using peripheral blood. quality of life should not be underestimated. The
Several different options exist when approach- author advocates that all patients with chronic
ing the diagnostic evaluation of pruritus in a pa- itch who are suffering from associated anxiety,
tient in whom neuropathic itch is suspected or depression, or social isolation may benefit from

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188 Elmariah

seeing a psychiatrist, psychologist, or mind-body women: women are more anxious than men. Br J
specialist, and/or taking part in a support group. Dermatol 2015;172:1323–8.
7. Kini SP, DeLong LK, Veledar E, et al. The impact of
SUMMARY pruritus on quality of life: the skin equivalent of
pain. Arch Dermatol 2011;147:1153–6.
Pruritus is a common and at times disabling 8. Ross SE, Hachisuka J, Todd AJ. Spinal Microcircuits
symptom that arises in the setting of countless and the Regulation of Itch. In: Carstens E,
dermatologic, systemic, neurologic, or psychiatric Akiyama T, editors. Itch: Mechanisms and Treat-
disorders. Although it may be trivial to diagnose ment. Boca Raton (FL): CRC Press/Taylor & Francis;
the cause of pruritus in cases of primary dermato- 2014. Chapter 20.
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tus in the absence of an eruption may be far itch. Curr Probl Dermatol 2016;50:18–23.
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view of systems, and performing a complete phys- derived atopic dermatitis cytokine TSLP activates
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of actively itchy skin is helpful when trying lergy Asthma Proc 2017;38:401–8.
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inflammation is observed, patients may undergo vated receptors and itch. Handb Exp Pharmacol
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