Are You Confident of the Diagnosis?
What you should be alert for in the history
Mechanical fragility and blistering of sunlight-exposed skin, typically appearing for the first time during spring or summer, are the usual chief complaints. Painful, slowly-healing erosions that leave scars, hypertrichosis and dyspigmentation may be reported in more chronic cases. Discolored urine, sometimes darker in the first morning void, may be reported. Rarely, scleroderma-like changes are the initial complaint. A positive family history may be elicited in a minority (<20%) of cases.
Symptoms usually appear for the first time in adults, Childhood onset is uncommon, and strongly suggests an inherited disease or exposure to a chemical hepatotoxin. One or more behavioral or constitutional inducing factors is typically present. Chief among these are heavy alcohol intake, estrogen therapies, viral hepatitis, human immunodeficiency viral exposure, hemochromatosis, end-stage renal disease treated by chronic dialysis regimens, environmental chemical hepatotoxin exposure and/or tobacco smoking.
Characteristic findings on physical examination
Blisters and open or crusted erosions on dorsal hands and forearms, sometimes on face and/or sun-exposed feet, which heal with atrophic scars, are most typical (Figure 1). Hyper- and hypopigmented patches and milia may be present (Figure 2). Hypertrichosis of temporal and malar facial areas is often observed. Heavier growth of eyebrow, beard and limb hair may also occur.
Melasma-like mottled facial hyperpigmentation and a reddish suffusion of the central face, shoulders and upper chest are less often noted, but may be florid. Scarring alopecia, calcified sclerodermoid plaques, digital shortening and contractures, and loss of nail plates may develop in severe long-standing cases. Rarely, sclerodermoid changes are the only cutaneous finding. Urine may be reddish or tea-colored, and exhibit pink fluorescence with Wood’s lamp illumination.
Expected results of diagnostic studies
Urinary and plasma porphyrin levels are abnormally high; a predominance of polycarboxylated porphyrins, chiefly uroporphyrin and heptacarboxylic porphyrin, is evident upon chromatographic separation (Figure 3). Fecal porphyrins may be elevated, with a predominance of coproporphyrin fractions, especially isocoproporphyrin.
Molecular analysis (DNA testing) of the uroporphyrinogen decarboxylase gene in familial cases most often reveals one mutant allele; rarely, two mutated alleles are found (hepatoerythropoietic porphyria). Erythrocyte porphyrins are normal, except in hepatoerythropoietic porphyria, in which elevated levels of zinc-protoporphyrin are found. Measurement of activity levels of the enzyme uroporphyrinogen decarboxylase in red blood cells is normal in acquired (sporadic) cases, but reduced to ~50% of normal in most familial cases harboring one mutant uroporphyrinogen decarboxylase gene allele, and to <30% in cases harboring two mutant alleles.
Liver function panels may reveal abnormalities. Serologic testing for hepatitis viruses, particularly hepatitis C, may be positive, as may be human immunodeficiency viral testing. A hematologic profile often reveals elevated hemoglobin and hematocrit and a high serum ferritin level, indicating excess tissue iron stores. Evaluation for mutant hemochromatosis genes may discover the presence of one or two mutations.
Individuals with long-standing active disease may develop hepatocellular carcinoma signaled by abnormal serum alpha-fetoprotein levels. Siderosis may be present in liver biopsy specimens, or detected by non-invasive methods such as magnetic resonance imaging. Cirrhosis or hepatocellular carcinoma may be suggested by various imaging methods and confirmed by biopsy. Abnormal glucose tolerance and serum antinuclear antibodies are occasionally noted. Serum ascorbate (vitamin C) may be low.
Histologic studies of cutaneous vesicles or bullae reveal a subepidermal cleavage plane, “festooning” (protrusion of dermal rete ridges upward into the blister cavity), little or no inflammatory infiltrate, and thickened upper dermal capillary walls and dermoepidermal basement membrane zones (Figure 4). Dermal elastosis, collagen sclerosis and hyaline deposits may be present.
“Caterpillar bodies” – linear, eosinophilic, periodic acid-Schiff positive globules of fragmented basement membrane and degenerating keratinocyte material may be seen in the blister roof. Direct immunofluorescence examination of perivascular and basement membrane zones shows deposition of immunoglobulins and complement. These findings, while consistent with porphyria cutanea tarda, are not diagnostic, as similar findings may be observed in other porphyrias or in “pseudoporphyria”.
Porphyria cutanea tarda may be confused with several other porphyrias that can present with similar vesiculobullous photocutaneous lesions:
-Variegate porphyria can be distinguished by finding urinary coproporphyrin > uroporphryin, elevated fecal Protoporphyrin ≥ coproporphyrin, and a distinctive plasma porphyrin fluorescence emission maximum at 627+1nm. Urinary porphobilinogen is elevated when neurovisceral symptoms are present, but may normalize between symptomatic episodes.
– Hereditary coproporphyria can be distinguished by finding coproporphryin III predominance in urinary and fecal excreta. Urinary porphobilinogen is elevated when neurovisceral symptoms are present, but may normalize between symptomatic episodes.
-Late-onset congenital erythropoietic porphyria can be distinguished by abnormally high levels of isomer I uro- and coproporphyrins in urine, feces and plasma. Erythrocytes will contain abnormally high levels of isomer I uro- and coproporphyrins and/or zinc-protoporphyrin.
Porphyria cutanea tarda can be confused with “pseudoporphyria” associated with photosensitizing drugs, maintenance dialysis programs or chronic intense artificial tanning lamp exposure. It can also be confused with photoaggravated bullous dermatoses such as epidermolysis bullosa acquisita or lupus erythematosus. Such differential diagnoses can readily be eliminated by the absence of abnormal porphyrin accumulation and excretion in all of them.
Plasma porphyrin levels are always abnormally high in true porphyrias with active photocutaneous symptoms, but normal in these other differential diagnoses. Urinary and fecal porphyrin levels are also normal in all forms of “pseudoporphyria.”
Who is at Risk for Developing this Disease?
Individuals harboring a deleterious mutant uroporphyrinogen decarboxylase gene, or two such genes, are at risk for expressing typical familial porphyria cutanea tarda or hepatoerythropoietic porphyria, respectively. A currently unidentified but inheritable defect that somehow impairs hepatic uroporphyrinogen decarboxylase enzyme activity is the postulated cause of an uncommon form of the disease in which no uroporphyrinogen decarboxylase mutations have been identified to date, but which affects multiple family members. Individuals who develop “sporadic” porphyria cutanea tarda are hypothesized to have some genetically determined predisposition that has not yet been elucidated.
Individuals harboring either a mutation or predisposition associated with porphyria cutanea tarda may never develop any symptoms unless also exposed to one or more factors that, in concert with the deleterious effects of such an underlying condition, lead to reduction of hepatic uroporphyrin decarboxylase enzyme activity to approximately 25% of normal. Known or suspected factors include excess alcohol intake, medicinal estrogen usage, coincident hemochromatosis genes, hepatitis and/or human immunodeficiency viral infections, chronic dialysis regimens, and tobacco smoking. Sufficient exposure to polyhalogenated aromatic hydrocarbon hepatotoxins may produce the “epidemic” form of the disease without any genetic predisposition.
What is the Cause of the Disease?
In all forms of porphyria cutanea tarda, activity of the heme synthetic pathway enzyme uroporphyrinogen decarboxylase is deficient in hepatocytes. About 80% of all cases are acquired, the remainder being one of the familial forms.
When hepatic uroporphyrinogen decarboxylase activity drops to about 25% of normal, porphyrin by-products of the heme synthetic pathway begin to accumulate in abnormal amounts in the liver. These polycarboxylated photoactive molecules are then disseminated by the blood plasma to other organs, including the skin and kidneys. Excretion of the 8- and 7-carboxylic porphyrins is primarily renal, while the 4-carboxylic coproporphyrins are excreted in both urine and feces. Porphyrins reaching the skin can absorb radiant energy from sunlight, becoming excited state molecules that can then mediate oxidative damage to skin biomolecules, producing the cutaneous lesions observed.
Reduction of uroporphyrinogen decarboxylase activity to this critical threshold for disease expression appears to occur by an iron-dependent mechanism activated by the contributory factors noted above, which have in common the propensity to cause hepatic siderosis or to elicit induction of cytochrome P450 enzymes. Iron overload facilitates formation of toxic oxygen species and increases oxidative stress, enhancing porphyrin production by mediating the formation of oxidation products that inhibit uroporphyrinogen decarboxylase.
Systemic Implications and Complications
Long-standing active porphyria cutanea tarda may eventuate in cirrhosis and hepatocellular carcinoma. Liver biopsies done in earlier stages of the disease may exhibit fatty changes, chronic inflammatory infiltrates, increased iron deposition, fibrosis and necrosis. Alcohol abuse calls for appropriate referrals for evaluation of liver pathology and for an abstinence support program.
Use of medicinal estrogens for birth control, menopausal symptoms. or treatment of prostatic carcinoma warrants consultation with treating physicians to determine if they may be discontinued or not.
Potential complications due to hemachromatosis should be investigated byHFE gene testing, as well as hematological and serum ferritin evaluations. Referral to appropriate consultants for management of problems arising from excess tissue iron due to HFEgene mutations may be required.
Serological testing may reveal hepatitis C, B or A viral infection and/or human immunodeficiency viral infection, which justify referral for further investigation and management by infectious disease and/or hepatology specialists.
The numerous health concerns related to smoking should be considered and appropriate referrals made. A smoking cessation program may be helpful. Porphyria due to environmental exposure to hepatotoxic organic chemicals, such as hexachlorobenzene or dioxin, calls for epidemiologic investigation and for evaluation of other individuals similarly exposed.
Rarely, porphyria cutanea tarda-like disorders arise from hepatic tumors that secrete abnormal amounts of polycarboxylated porphyrins. Especially when other contributory factors are not in evidence, imaging of the liver to search for tumors may be warranted.
Eliminate aggravating factors
Environmental hepatotoxin exposure
Protection from sunlight exposure
– Lifestyle changes
– Protective clothing
Alternative means of ferrodepletion
– Novel oral agents
Treat associated disorders
Hepatitis C or B
Human Immunodeficiency viral infection
Vitamin C deficiency
Optimal Therapeutic Approach for this Disease
Elimination of alcohol use and tobacco smoking are mandatory. Iron supplements should be discontinued. Any potentially hepatotoxic chemical agents identified must be removed from the patient’s environment. Medicinal estrogens should be discontinued, if possible.
Photoprotection is required until clinical remission can be induced. Lifestyle adjustments and protective clothing are the most helpful means of reducing sunlight exposure. Topical sunscreens and sunblockers will not be effective unless formulated with agents that scatter or block long ultraviolet A and visible light radiation, the spectra most efficient at photoexciting porphyrin molecules.
Serial phlebotomy is usually the preferred treatment for individuals with increased tissue iron stores. Removal of ~500 ml whole blood at judicious intervals, most often weekly or biweekly as tolerated, should be pursued until the serum ferritin level is reduced to the low normal range. Venesection mobilizes excess tissue iron, removing its inhibitory effect on uroporphyrinogen decarboxylase catalytic activity, thus normalizing hepatic heme synthesis and porphyrin overproduction. Care should be taken not to produce iatrogenic anemia (hemoglobin < 10-11 g/dL) by overly aggressive schedules. Hepatitis C therapy appears to be more successful if iron stores are first reduced by phlebotomy.
When patients are poor candidates for venesection, or have little or no evidence of iron overload, low doses of chloroquine phosphate 125-250 mg twice weekly or hydroxychloroquine sulfate 100-200 mg twice/thrice weekly may suffice to induce biochemical and clinical remissions over several months. Standard larger doses for antimalarial or photoprotective indications should be avoided due to risk of hepatotoxicity. Even low doses may cause hepatotoxicity, so monitoring liver function at the outset of treatment is recommended. Initial rises in hepatic transaminases and in urinary porphyrin levels often normalize with continued treatment. Although retinopathy is unlikely to develop at such low doses, ophthalmological clearance and monitoring is recommended.
In selected patients, antimalarial and phlebotomy therapies may be combined to speed onset of remissions. Antimalarials are contraindicated in patients with kidney dysfunction; these drugs cause porphyrins to be discharged from hepatocytes into the blood stream from which they are normally cleared by renal mechanisms. Since porphyrins are not cleared through standard hemodialysis membranes, they can rise to extraordinarily high blood levels in patients with poor kidney function, increasing cutaneous photosensitivity.
Alternative means of ferrodepletion, such as desferrioxamine chelation, may be required if phlebotomy is contraindicated. Human recombinant erythropoietin achieves ferrodepletion by stimulating erythropoiesis, which drives iron mobilization. If erythropoietin increases circulating red cell volume, small-volume phlebotomy may become sustainable at judicious intervals, thereby accelerating reduction of iron stores. Novel oral ferrodepleting agents are under study for efficacy as alternative agents.
A diet including vitamin C-rich fruits and vegetables or oral vitamin C supplements should be prescribed to replete any deficiency. A rigorous low-iron diet is not necessary if iron-rich foods are consumed in moderation.
Treatment of associated disorders, such as hepatitis and human immunodeficiency viral infections, hemochromatosis, or hepatic tumors, should be carried out by appropriate consultants. Vaccination for hepatitis B is recommended. Discovery of an hepatic tumor will necessitate referral for its surgical care.
Patients should be advised that clinical remission may lag biochemical improvement; photosensitivity may continue to diminish after therapy has reached an end-point and is discontinued. Plasma or urinary porphyrin levels and serum ferritin levels should be tracked while ferrodepletion is in progress, treatment being halted when ferritin is reduced to a low normal level. Hemoglobin levels obtained prior to each venesection should guide the frequency of bloodletting. Porphyrin levels may continue to decrease without further treatment, and become normal, but may stabilize at slightly abnormal levels that cause no clinical symptoms.
After biochemical and clinical remission has been achieved, patients remain at risk for recurrence of active disease. While many patients enjoy years of remission without any maintenance therapy, others may relapse within months to a few years, particularly if contributory factors have not been eliminated. Recurrences often respond again to the initially successful therapy.
Monitoring laboratory values in patients in remission allows early detection of recurrence, permitting timely reinstitution of therapy. Plasma or urinary porphyrin levels obtained every 3 months for the first year of remission, then every 6-12 months, will indicate any trend toward steadily rising porphyrin production. Progressively rising serum ferritin values over the same time may also signal that the patient is headed toward relapse. Reinstitution of ferrodepletion may then return the patient to biochemical remission before any clinical symptoms have a chance to reappear.
It may be possible to reinstitute estrogen therapies after remissions are achieved without precipitating relapse. Estrogen patch delivery may be less hazardous than oral administration, since “first-pass” effects on hepatocytes is reduced by transcutaneous delivery. Patients electing to restart medicinal estrogens should be monitored more closely for rising porphyrin levels warning of impending relapse.
Individuals who wish to know whether they have a familial form of porphyria cutanea tarda can obtain molecular analysis of their uroporphyrinogen decarboxylase genes. Once a mutation is identified in a proband, the DNA of family members can be screened for the same mutation. Although most carriers do remain silent, they are at risk of developing active disease if exposed to known contributory factors. Avoidance of the well-known factors outlined above should be recommended to confirmed carriers.
Unusual Clinical Scenarios to Consider in Patient Management
Rarely, familial porphyria cutanea tarda presents in children harboring one uroporphryinogen decarboxylase mutant allele, or in children with two such mutant alleles (hepatoerythropoietic porphyria). It is important to establish the genotype of each childhood case correctly, as treatment with serial phlebotomy or with antimalarials can be expected to induce remissions only in those with one mutation, not in recessive hepatoerythropoietic porphyria.
DNA molecular analysis most accurately genotypes childhood porphyria cutanea tarda; however, that erythrocyte zinc protoporphyin levels are abnormally elevated in the recessive disease, but normal in the autosomal dominant form, can suggest the genotype.
Active porphyria cutanea tarda in pregnant women is not harmful to the fetus. Fetal demand for iron may actually benefit iron-loaded mothers by reducing iron stores. Iron supplementation during pregnancy should be avoided, unless warranted by unusual circumstances.
Persons treated with hemodialysis or chronic peritoneal dialysis for end-stage renal disease may develop a bullous dermatosis that is not a true porphyria, even though plasma or serum porphyrin levels are often mildly elevated in dialysis populations. Dialysis patients may also develop true porphyria cutanea tarda, in which case their plasma/serum porphyrin levels are grossly abnormal. Fecal isocoproporphyrin levels may be high in those with true porphyria cutanea tarda, but not in those with dialysis-associated “pseudoporphyria”.
It is important to distinguish these groups, as erythropoietin alone, or in conjunction with low-volume phlebotomies, may help those with true porphyria cutanea tarda, but are not expected to benefit those with non-porphyric bullous dermatosis of dialysis. Antimalarial therapies are contraindicated in patients with end-stage renal disease and porphyria cutanea tarda.
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