Laboratory Studies

Protoporphyrin concentration is elevated in red blood cells, plasma, bile, and feces. The diagnosis is usually made by finding the abnormal levels in erythrocytes and plasma. Urinary porphyrin levels are normal in patients without liver dysfunction. Abnormal coproporphyrinuria develops when liver function is deteriorating.^{[48, 49]}

The screening test for either type of protoporphyria is measurement of total blood porphyrin, which includes both metal-free protoporphyrin and zinc protoporphyrin. Levels that are 5-50 times the upper limit of the normal range are diagnostic. Separate determination of zinc protoporphyrin as a fraction of the total is helpful for a preliminary differentiation between erythropoietic protoporphyria (EPP) and X-linked protoporphyria. In EPP, zinc protoporphyrin constitutes approximately 5% of the total protoporphyrin in blood, whereas in X-linked protoporphyria, it constitutes 20-40%. The determination directs attention to the appropriate gene for mutation analysis. Some reference laboratories measure only zinc protoporphyrin but label it, misleadingly, as “free protoporphyrin.” The level of zinc protoporphyrin is elevated in patients with iron deficiency and lead poisoning. The test is not useful in screening for protoporphyria.

Obtain a serum liver function panel at diagnosis. Monitor indices of liver function at 6- to 12-month intervals if baseline values are normal. If liver function is abnormal, complicating factors (eg, gallstones, viral hepatitis, alcohol or drug abuse, other toxic, infectious, immunologic, or metabolic storage disorders) should be excluded by appropriate testing.

Perform a hematological assessment. Microcytic anemia, which may occur in 20-60% of individuals with protoporphyria,^[50]often associated with mild iron deficiency, may be found.^{[1, 51]}Iron therapies have resulted in both beneficial^{[52, 53, 54]}and adverse^{[55, 56]}effects in EPP. Iron supplementation has been beneficial in some cases of XLP.^[35]

A lifetime of sunlight avoidance predisposes to vitamin D deficiency among individuals with protoporphyria.^{[57, 58]}Determine serum 25-hydroxyvitamin D level at diagnosis and at intervals as needed to monitor response to supplementation, if indicated.

Imaging Studies

If cholelithiasis is suspected, abdominal ultrasonography or other imaging procedures are indicated.

Bone mineral density studies may reveal osteopenic or osteoporotic changes due to vitamin D deficiency as a result of chronic sunlight avoidance.^[58]

Other Tests

Impending liver failure may be signaled by progressively rising levels of urinary coproporphyrin.^[49]Urinary porphyrin levels are within normal limits in persons with uncomplicated protoporphyria. Protoporphyrin, being lipophilic, is not excreted by renal mechanisms and does not normally appear in urine. Coproporphyrin, which accumulates as a result of liver disease, has intermediate water solubility, and levels become abnormally elevated in the urine of patients developing protoporphyrin-induced hepatotoxicity.^[48]

Procedures

In the event of overt liver dysfunction, liver biopsy is indicated. Some experts suggest that individuals with genotypes associated with higher risk of liver disease, such as a "null-allele" FECH mutation that encodes an enzyme with essentially no residual activity, biallelic FECH mutations, one of the ALAS2 increased-function mutations, or a family history of protoporphyric liver disease, should undergo liver biopsy even before liver function tests become abnormal.^{[24, 36]}The presence of other risk factors for liver disease, such as viral hepatitis, hemochromatosis, or alcoholic or nonalcoholic fatty liver, increases the weight of argument for earlier liver biopsy.

Liver transplantation may be life-saving, but does not cure protoporphyria because the source of most of the excess protoporphyrin is bone marrow erythropoiesis. Continued overproduction of protoporphyrin eventually leads to its deposition in the engrafted liver, which may again become dysfunctional.^[42]Bone marrow or peripheral stem cell transplantation can be curative, but attendant risks have restricted use of these procedures to a limited number of highly selected cases.^{[15, 35, 41, 59, 60]}Research in animal models has shown promising developments in gene therapy strategies that may eventually be transferrable to humans.

Histologic Findings

Light microscopy examination of the acute skin reaction shows nonspecific perivascular and interstitial neutrophilic dermal infiltrates. Subepidermal blisters similar to those seen in porphyria cutanea tarda can be seen in early lesions of erythropoietic protoporphyria (EPP). These blisters are cell-poor and inflammatory infiltrate is sparse. “Caterpillar bodies” may be seen in the basal layer epidermis overlying blisters. Ultrastructural findings in the acute reaction include damage of endothelial cells with extravasation of intravascular contents and degranulated mast cells.^[61]

Biopsy specimens of chronically damaged skin show deposition of hyaline masses in the upper dermis and markedly thickened walls of upper dermal capillaries.^[62]The deposition can be extensive and involve the surrounding dermis to mimic a colloid milium. The hyaline material surrounding blood vessels is periodic acid-Schiff–positive and diastase-resistant. Ultrastructural findings in chronically damaged skin include replicated basal laminae around dermal vessels, degranulated mast cells, and amorphous dermal deposits.^[62]Direct immunofluorescence studies show deposition of immunoglobulins and complement in and around upper dermal vessel walls and, to a lesser extent, at the dermoepidermal junction.^[62]

Liver biopsy typically reveals brown pigment in hepatocytes, Kupffer cells, portal macrophages, and small biliary structures.^{[22, 42]}Many of these protoporphyrin deposits are crystalline when examined under electron microscopy and birefringent when examined under polarization microscopy.^{[22, 42]}Cirrhotic changes are seen in advanced disease, including fibrous expansion of portal areas and regenerative nodules.^{[22, 42]}

Treatment & Management

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Author

Jose A Plaza, MD Director of Dermatopathology, Professor of Pathology and Dermatology, The Ohio State University Wexner Medical Center

Jose A Plaza, MD is a member of the following medical societies: American Medical Association, American Society for Clinical Pathology, American Society of Dermatopathology, International Society of Dermatopathology

Disclosure: Nothing to disclose.

Specialty Editor Board

David F Butler, MD Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Military Dermatologists, Phi Beta Kappa, Texas Dermatological Society

Disclosure: Nothing to disclose.

Edward F Chan, MD Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Edward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Additional Contributors

Maureen B Poh-Fitzpatrick, MD Professor Emerita of Dermatology and Special Lecturer, Columbia University College of Physicians and Surgeons

Maureen B Poh-Fitzpatrick, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, New York Academy of Medicine, New York Dermatological Society

Disclosure: Nothing to disclose.

Acknowledgements

Günter Burg, MD Professor and Chairman Emeritus, Department of Dermatology, University of Zürich School of Medicine; Delegate of The Foundation for Modern Teaching and Learning in Medicine Faculty of Medicine, University of Zürich, Switzerland

Günter Burg, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, International Society for Dermatologic Surgery, North American Clinical Dermatologic Society, and Pacific Dermatologic Association

Disclosure: Nothing to disclose.