A Middle-Aged Man With Summer Rash on His Arms and Hands
AUTHOR:
Ronald N. Rubin, MD—Series Editor
CITATION:
Rubin RN. A middle-aged man with summer rash on his arms and hands. Consultant. 2019;59(12):362-364.
A 56-year-old man presented for evaluation of a rash on his hands, arms, and neck of 2 years’ duration. The rash was characterized by blistering, friability and discoloration in the affected areas. He had noted the rash the previous year, but over the winter the lesions had resolved, only to reappear in the spring and summer.
The lesions were not pruritic or significantly painful. He did not recall having developed a rash like this one earlier in his life. He was otherwise healthy, without major medical diagnoses, and sporadic use of nonsteroidal anti-inflammatory drugs was his only medication. His family history was unremarkable except for coronary artery disease in several relatives. He worked as a landscaper, with the bulk of his work occurring in the warmer months. When he was younger, he consumed heavy amounts of alcohol and had exposure to illicit drugs. He reported consuming far less alcohol in recent years.
Physical examination abnormalities were mainly localized to the skin of the anterior neck, arms, and face, and most dominantly the dorsum of the hands, which revealed blistering lesions with scarification of healed areas and skin friability. There was no hepatosplenomegaly or petechia or purpura.
Laboratory test results included a normal complete blood cell count. Results of a biochemistry panel included a random glucose level of 128 mg/dL and mildly elevated transaminase levels. Results of a porphyria panel revealed a normal urine porphobilinogen level.
Answer: D, attention and adherence to maneuvers to address susceptibility factors result in response rates of 90% or greater.
This clinical vignette completes a duet of cases related to the porphyrias—which are always and at all levels a difficult set of conditions to master. Breaking the 8-step heme synthesis pathway into logical and memorable pieces can be a challenge. A reasonable “lumping” scheme is to group them as porphyrias in which hepatic overproduction is the main pathophysiologic problem (with δ-aminolevulinic acid and porphobilinogen being the precursors overproduced) and porphyrias in which overproduction of photosensitive porphyrins by either the liver or bone marrow (with uroporphyrin and protoporphyrin being the precursors overproduced) are the main problem.
This scheme nicely correlates with clinical events, since the hepatic porphyrins are neurotoxic, and pain is a cardinal manifestation seen clinically, while erythropoietic porphyrins are skin-toxic such that dermatologic lesions are the cardinal manifestation. The classic example of the former is acute intermittent porphyria (AIP), which was addressed in a previous “What’s the ‘Take Home’?” column.1 The most common of the latter is porphyria cutanea tarda (PCT), which will be discussed here. To the purist, this digest is an oversimplification, and overlaps and exceptions exist. Nonetheless, to clinically recognize and manage these two conditions in the framework suggested above can go a long way in the clinic and the emergency department.
In fact, PCT is the most prevalent of the porphyrias (5-10 cases per 100,000 population), and the condition is caused by inhibition of uroporphyrin decarboxylase.2 However, acquired cofactors are essentially required to be present for clinical disease to manifest. Specifically, an increased hepatic iron level related to some form of primary liver disease and/or systemic iron overload states is the key pathophysiologic sign. In particular, several conditions (often comorbid in the same patient) include hepatitis C virus infection (69% prevalence in PCT), alcohol consumption (87%), tobacco use (81%), and genetic hemochromatosis mutations (53%).2 The use of estrogen agonists causes upregulation of hepatic uroporphyrin synthesis and is another acquired cofactor (66% prevalence).3 Because of the requirement for acquired cofactors, genetic lesions do not always result in disease, so family history may be negative, making Answer C incorrect.
The classic presentation of PCT is the appearance of blistering skin lesions on sun-exposed areas, most commonly on the backs of the hands in patients in midlife or older. Interesting and typical cases of PCT that I have seen include postmenopausal women using estrogen replacement, and a man with moderate hepatic disease who was a bridge toll collector at the New Jersey Shore who developed profound symptoms in his exposed money-taking arm and hand, with essentially no symptoms on the side that had been kept protected within the toll booth. The case presented above of a landscaper in midlife is a genuine one and is also very typical. The diagnosis is easily confirmed by porphyrin analysis results showing normal or minimally elevated δ-aminolevulinic acid and porphobilinogen levels but elevated urine/plasma uroporphyrins.2 Elevated porphobilinogens are a marker of AIP but are normal or minimally elevated in PCT, so Answer A is incorrect.
The diagnosis of PCT is important on 2 levels—first to be able to reduce skin manifestations and toxicity, and second because PCT may expose the presence of important treatable susceptibility factors such as hepatic disease and/or iron overload. In fact, in any patient with PCT, a measurement of ferritin is indicated and in almost all cases will yield increased levels regardless of whether due to intrinsic liver disease or systemic iron overload. And, the first order of therapy is phlebotomy to reduce ferritin levels to the low ranges of normal. If genetic hemochromatosis is demonstrated, periodic phlebotomy, perhaps lifelong, may be required.2,4 Clearly, adding iron to these patients is opposite to the goal, and Answer B is thus very wrong.
Other susceptibility factors also need be probed, addressed, and treated. Thus, alcohol intake must be diminished even to the point of abstinence, and hepatitis C screening and antiviral therapy evaluated when present. When these maneuvers are undertaken and successful, the prognosis for symptom relief is excellent, with responses in the 90% or higher range, such that Answer D is the correct one here. Along the way, periodic monitoring of urine/plasma uroporphyrin levels, serum ferritin levels, and general liver function biochemistries is recommended for early detection of recurrence and the need for retreatment.2
A variety of skin protective maneuvers are also helpful, the main one being covering exposed areas with hats, long-sleeved garments, and gloves when working or playing outdoors. Most topical sunscreens are quite ineffective, since not all wavelengths are blocked (nontransparent zinc oxide is an exception). A novel melanocyte-stimulating hormone, afamelanotide, seems to have efficacy in the more severe erythropoietic protoporphyria, but for now it remains untested and likely unnecessary in PCT cases.4
PATIENT FOLLOW-UP
Urine porphyria studies were sent, the results of which showed normal values for porphobilinogen but a significantly elevated uroporphyrin level (>500 µmol/mol of creatinine; reference range, 0-30 µmol/mol of creatinine). Thus, the diagnosis of PCT was confirmed. Additionally, the ferritin level was elevated at 430 ng/mL (reference range, 15-300 ng/mL), and the results of hepatitis C virus testing were negative.
The patient was advised to take care in protecting his skin from sunlight as best possible, such as by wearing a hat and gloves and using sunscreen at all times. Abstinence from alcohol also was stressed, and a program of phlebotomy was initiated. He was seen periodically, and by the following spring, his ferritin level was 50 ng/mL, and his transaminase levels had normalized. He was in the summer mode of outdoor activity and work, but his reports and physical examination revealed essentially clear skin without lesions.
TAKE-HOME MESSAGE
PCT is the most prevalent of the porphyrias, affecting 5 to 10 persons per 100,000. Most people with PCT, if tested, will demonstrate some degree of deficiency or inhibition of the uroporphyrin decarboxylase enzyme in the heme synthesis pathway. However, it seems that other acquired conditions are required to generate clinical symptoms, namely photosensitivity and blistering of skin in sun-exposed areas due to the elevated uroporphyrins that accrue and that are skin-trophic. In fact, usually 2 or more of these cofactors will be present in symptomatic cases, with excessive alcohol use, hepatitis C, estrogen use in women, heavy tobacco use, and genetic hemochromatosis being the major susceptibility factors. A common finding in all cases is elevated hepatic iron with a laboratory finding of high ferritin. When these cofactors are effectively reversed (eg, abstinence from alcohol, treatment of hepatitis C) and ferritin levels are lowered by phlebotomy, symptomatic improvement is almost universal.
Ronald N. Rubin, MD, is a professor of medicine at the Lewis Katz School of Medicine at Temple University and is chief of clinical hematology in the Department of Medicine at Temple University Hospital in Philadelphia, Pennsylvania.
REFERENCES:
- Rubin RN. A 30-year-old woman with a reported history of porphyria. Consultant. 2019;59(10):308-310. https://www.consultant360.com/article/consultant360/30-year-old-woman-reported-history-porphyria. Accessed November 14, 2019.
- Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017;377(9):862-872.
- Ippen H. Treatment of porphyria cutanea tarda by phlebotomy. Semin Hematol. 1977;14(2):253-259.
- Lagendonk JG, Balwani M, Anderson KE, et al. Afamelanetide for erythropoietic protoporphyria. N Engl J Med. 2015;373(1):48-59.