Photosensitivity and Other Reactions to Sunlight¶
Chapter 64 | Part 2: Cardinal Manifestations and Presentation of Diseases · Part 2 – Cardinal Manifestations & Presentation · Chapter 64
Key Clinical Points¶
- Photosensitivity requires a chromophore (e.g., DNA, proteins, lipids) to absorb photon energy and transfer it to structures or oxygen.
- UV-B (290–320 nm) is the primary driver of erythema; UV-A (320–400 nm) penetrates deeper and causes photoaging.
- Fitzpatrick skin types (I–VI) determine susceptibility based on melanin type (Eumelanin vs. Pheomelanin).
- Polymorphous Light Eruption (PMLE) is the most common photosensitivity disease, often characterized by pruritic erythematous papules.
- Merkel Cell Carcinoma (MCC) is a neuroendocrine carcinoma associated with MCPyV and high mortality in metastatic cases.
- Phototoxic reactions are nonimmunologic; photoallergic reactions are immunologic.
- Immune suppression from UVR involves Langerhans cell depletion and urocanic acid isomerization.
- Vitamin D synthesis occurs via UV-B photolysis of 7-dehydrocholesterol; sunscreens do not significantly reduce these levels.
- NMSC (BCC, SCC) are directly linked to sun exposure; melanoma's link is less direct but significant in childhood.
- Drug-induced photosensitivity can be categorized as phototoxic or photodermatitis based on the timing of the reaction.
DEFINITION & CLASSIFICATION¶
• Definition (Harrison's 22e): Photosensitivity is a reaction where a photon-absorbing chemical (chromophore) present in the skin absorbs incident energy, becomes excited, and transfers the absorbed energy to various structures or to molecular oxygen. • Diagnostic Requirements: ◦ Careful history to define duration of signs/symptoms. ◦ Time between exposure and symptoms. ◦ Visible changes in skin. ◦ Age of onset (e.g., EPP begins in infancy; PCT in 4th–5th decades). • Solar Radiation Dynamics: ◦ UV-B (290–320 nm): Most efficient at producing erythema (sunburn spectrum). ◦ UV-A (320–400 nm): ~1000-fold less efficient at erythema but penetrates to dermis → causes photoaging of structural/matrix proteins. ◦ Absorption Spectrum: Range of wavelengths a molecule absorbs. ◦ Action Spectrum: Range of wavelengths that evoke a specific response. • Skin Anatomy & Chromophores: ◦ Epidermis (stratified squamous) and Dermis (collagen, elastin) both susceptible to damage. ◦ Stratum corneum is major UV-B absorber; <10% of UV-B reaches dermis. ◦ Endogenous chromophores: Nucleic acids, proteins, lipids, 7-dehydrocholesterol. ◦ Porphyrins: Trace amounts normally; increased in porphyrias. Used in photodynamic therapy (PDT) for BCCs and SCCs. • Melanin & Pigmentation: ◦ Synthesis: Tyrosine derivatives in melanocytes → transferred to keratinocytes. ◦ Mechanism: Increased tyrosinase activity via MC1R (melanocortin-1 receptor). ◦ Eumelanin: Brown/black; high MC1R activity; better shielding. ◦ Pheomelanin: Red; low MC1R activity; weaker shielding → higher melanoma risk due to ROS amplification. ◦ Regulation: Controlled by p53; absence of functional p53 attenuates tanning. • Fitzpatrick Classification (Table 64-1): ◦ Type I: Always burn, never tan. ◦ Type II: Always burn, sometimes tan. ◦ Type III: Sometimes burn, sometimes tan. ◦ Type IV: Sometimes burn, always tan. ◦ Type V: Never burn, sometimes tan. ◦ Type VI: Never burn, always tan.
Classification of Photosensitivity Diseases (Table 64-2)¶
• Genetic: Congenital erythropoietic porphyria (CEP), Erythropoietic protoporphyria (EPP), X-linked protoprophyria (XLP), Porphyria cutanea tarda (PCT) —familial, Variegate porphyria (VP), Hepatoerythropoietic porphyria (HEP), Albinism, Xeroderma pigmentosum, Rothmund-Thomson syndrome, Bloom syndrome, Cockayne syndrome, Kindler syndrome, Phenylketonuria. • Phototoxic: Includes reactions to internal drugs and external agents (drugs, plants, food). • Photoaggravated: Lupus erythematosus (Systemic, Subacute cutaneous, Discoid), Dermatomyositis, Herpes simplex, Lichen planus actinicus, Acne vulgaris (aestivale). • Other: Pseudoporphyria.
EPIDEMIOLOGY¶
• General Trends: ◦ High geographic variation based on skin phototype and UVR intensity. ◦ NMSC incidence increasing 2–3% per year due to detection/outdoor activity. ◦ Risk of NMSC: ~15% lifetime risk for fair-skinned individuals. • Non-Melanoma Skin Cancer (NMSC): ◦ 80% develop on face, neck, hands. ◦ Risk factors: Male sex, childhood sun exposure, older age, fair skin, low latitude. • Merkel Cell Carcinoma (MCC): ◦ Incidence: ~1 in 100,000. ◦ Profile: Neuroendocrine; predominantly fair-skinned males in 6th–8th decades. ◦ Survival Rates: ◦ Local disease: ~50% at 5 years. ◦ Nodal disease: ~35% at 5 years. ◦ Metastatic disease: ~15% at 5 years. ◦ Pathogenesis: Linked to Merkel cell polyoma virus (MCPyV). ◦ MCPyV-negative cases: High levels of UV-induced signature mutations (C → T, CC → TT) and p53 inactivation. ◦ Treatment: Metastatic MCC successfully treated with PD-1/PD-L1 inhibitors.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Carcinogenesis Mechanisms: ◦ UV-B is a complete carcinogen (initiator and promoter). ◦ Mutation Accumulation: Transition from precancerous clones to cancer requires additional mutations in genes like CDKN2A. ◦ SCC vs. BCC Differentiation: ◦ SCC: High mutation rates in NOTCH1 (~60% of SCCs) and p53. ◦ BCC: Distinct profile; inactivating mutations in patched or activating mutations in smoothened → activation of sonic hedgehog pathway. ◦ Signaling Pathways: Wnt/β-catenin and Hedgehog pathways are critical for hair follicle development and skin cancer. • Photoimmunology & Immunosuppression: ◦ Local Suppression: UV-B depletes epidermal Langerhans cells → reduced allergic sensitization to contact allergens (e.g., dinitrochlorobenzene). ◦ Systemic Suppression: High doses of UVR; involves T-cells, B-cells, and cytokines (TNF-α, IL-4, IL-10). ◦ Molecular Drivers: ◦ DNA & Urocanic acid: Urocanic acid trans-isomer → UV-induced trans-cis isomerization → immunosuppression. ◦ DAMPs: From necrotic keratinocytes → Type I interferon response via Toll-like receptor signaling. ◦ Clinical Impact: Chronic sun exposure leads to higher NMSC risk due to T-cell suppression of antitumor responses.
CLINICAL FEATURES¶
• Diagnostic Clues: ◦ Age of onset (e.g., EPP in infancy vs. PCT in 4th–5th decades). ◦ Timing: Time between exposure and symptom development. ◦ Location: Areas protected from sun (scalp, eyelids) may be spared; exposed areas show photoaging. • Polymorphous Light Eruption (PMLE): ◦ Prevalence: More common in women. ◦ Juvenile variant: Known as juvenile spring eruption. ◦ Clinical Presentation: Pruritic erythemated papules/plaques on trunk and forearms; face less affected. ◦ "Hardening": Symptoms may subside with continued exposure. • Other Conditions: ◦ Actinic prurigo, Hydroa vacciniforme, Sunburn, Acne vulgaris (aestivale). ◦ Role of genetics: Xeroderma pigmentosum (DNA repair defect), Porphyrias (heme synthesis defects).
DIFFERENTIAL DIAGNOSIS¶
• Classification of Photosensitivity: ◦ Phototoxic (nonimmunologic, e.g., fluoroquinolones). ◦ Photoallergic (immunologic, e.g., chlorpromazine, piroxicam). ◦ Systemic conditions: SLE, Dermatomyositis. ◦ Genetic disorders: Porphyrias, Xeroderma pigmentosum.
DIAGNOSTIC APPROACH¶
- Initial Presentation: Patient presents with photosensitivity.
- Laboratory Screening: a. ANA Test → If Positive → Diagnosis: Systemic Lupus Erythematosus (SLE). b. Plasma Porphyrin → If High → Diagnosis: Porphyria (further differentiated as Lupus erythematosus or Porphyria cutanea tarda).
- History of Exposure to Photosensitizing Drug: a. If "Chronic drug" → Diagnosis: Drug photosensitivity. b. If "Rash drug" → Determine timing: i. Immediate → Diagnosis: Phototoxic (e.g., acetone, chemicals). ii. Delayed → Diagnosis: Photodermatitis (e.g., sulfonamides, tetracyclines). iii. Unrelated → Other considerations.
- Specific Testing for "Rash drug": a. Perform Photo Patch Test. b. If Positive → Diagnosis: Phototoxic or Photodermatitis. c. If Negative → Diagnosis: Polymorphism/Systemic Lupus Erythematatus.
MANAGEMENT & TREATMENT¶
- Photoprotection: a. Use high-SPF broad-spectrum sunscreens. b. Use protective clothing and sun avoidance.
- Drug Management: a. Identify and remove offending agents (e.g., fluoroquinolones, sulfonamides). b. For acute flares of PMLE: Topical or systemic glucocorticoids.
- Vitamin D Maintenance: a. Supplementation is preferred to sun exposure for Vitamin D deficiency. b. Note: Sunscreens do not significantly reduce Vitamin D levels; they are not a justification for increased cancer risk.
- Special Populations (Organ Transplant): a. Monitor closely and use rigorous photoprotection. b. Note: mTOR inhibitors (sirolimus, everolimus) may reduce NMSC risk compared to calcineurin inhibitors (cyclosporine, tacrolimus).
PROGNOSIS & COMPLICATIONS¶
• Skin Cancer Survival: ◦ Melanoma: Risk linked to childhood exposure; can occur in non-sun-exposed skin. ◦ MCC: 50% survival (local), 35% (nodal), 15% (metastatic). • Complications of Photosensitivity: ◦ Chronic sun exposure → Photoaging, Actinic keratosis, NMSC (BCC, SCC, MCC). ◦ Systemic issues: SLE exacerbation by UVR.
SPECIAL POPULATIONS¶
• Organ Transplant Recipients: ◦ >50% develop BCCs and SCCs due to immunosuppression. ◦ Risk correlates with duration/degree of immunosuppression. ◦ Calcinerin inhibitors (cyclosporine, tacrolimus) may suppress p53-dependent senescence pathways. • Systemic Lupus Erythematosus (SLE): ◦ UVR-induced DNA damage may promote autoantibody formation. ◦ Clinical forms: Systemic, Subacute cutaneous, Discoid.
KEY PEARLS & HIGH-YIELD POINTS¶
• Phototoxic vs. Photoallergic: Phototoxic is nonimmunologic; Photoallergic is immunologic. • Urocanic Acid: Key mediator of UV-induced immunosuppression via trans-to-cis isomerization. • Vitamin D: Sunscreen use does not significantly impact Vitamin D levels; supplementation is the preferred method for deficiency. • Merkel Cell Carcinoma: High suspicion in fair-skinned patients with head/neck lesions; associated with MCPyV. • Drug Identification: Fluoroquinolones and Sulfonamides are common culprits for drug-induced photosensitivity (Table 64-3, Table 64-4). • Sunscreen Ingredients (Table 64-5): Includes PABA (15%), Avobenzone, Cinoxate (3%), etc.
Reference Tables¶
TABLE 64-1 Skin Type and Sunburn Sensitivity (Fitzpatrick Classification) TYPE I II III IV V VI¶
Harrison's 22e, p.430
| TYPE | DESCRIPTION |
|---|---|
| I | Always burn, never tan |
| III | Sometimes burn, sometimes tan |
| V | Never burn, sometimes tan |
TABLE 64-2 Classification of Photosensitivity Diseases TYPE Genetic¶
Harrison's 22e, p.433
| TYPE | DISEASE |
|---|---|
| Genetic | Congenital erythropoietic porphyria (CEP) |
| Erythropoietic protoporphyria (EPP) X-linked protoprophyria (XLP) |
|
| Porphyria cutanea tarda (PCT) —familial | |
| Variegate porphyria (VP) | |
| Hepatoerythropoietic porphyria (HEP) | |
| Albinism | |
| Xeroderma pigmentosum | |
| Rothmund-Thomson syndrome | |
| Bloom syndrome | |
| Cockayne syndrome | |
| Kindler syndrome | |
| Phenylketonuria | |
| Phototoxic | |
| Internal | Drugs |
| External | Drugs, plants, food |
| Neoplastic and degenerative | Photoaging |
| Actinic keratosis | |
| Melanoma and nonmelanoma skin cancer | |
| Photoaggravated | Lupus erythematosus |
| Systemic | |
| Subacute cutaneous | |
| Discoid | |
| Dermatomyositis | |
| Herpes simplex | |
| Lichen planus actinicus | |
| Acne vulgaris (aestivale) Pseudoporphyria |
TABLE 64-4 Drugs That May Cause a Photoallergic Reaction DRUG 6-Methylcoumarin Aminobenzoic acid and esters Bithionol…¶
Harrison's 22e, p.434
| DRUG | TOPICAL | SYSTEMIC |
|---|---|---|
| 6-Methylcoumarin | + | |
| + | ||
| Bithionol | + | |
| Diclofenac | + | |
| Halogenated salicylanilides | + | |
| + | ||
| Musk ambrette | + | |
| Promethazine | + | |
| Sulfonylureas | + |
TABLE 64-3 Drugs That May Cause a Phototoxic Reaction DRUG Amiodarone Dacarbazine Fluoroquinolones 5-Fluorouracil…¶
Harrison's 22e, p.434
| DRUG | TOPICAL | SYSTEMIC |
|---|---|---|
| Amiodarone | + | |
| Fluoroquinolones | + | |
| + | ||
| Furosemide | + | |
| Phenothiazines | + | |
| + | ||
| Retinoids | +/− | + |
| Sulfonylureas | + | |
| Thiazides | + |
TABLE 64-5 FDA Category I Monographed Sunscreen Active Ingredients INGREDIENTS p -Aminobenzoic acid (PABA) Avobenzone…¶
Harrison's 22e, p.436
| INGREDIENTS | MAXIMUM CONCENTRATION, % |
|---|---|
| p-Aminobenzoic acid (PABA) | 15 |
| Cinoxate | 3 |
| Ecamsule | 15 |
| Meradimate | 5 |
| Octinoxate | 7.5 |
| Oxybenzone (benzophenone-3) | 6 |
| Ensulizole | 4 |
| Titanium dioxide | 25 |
| Zinc oxide | 25 |