How can I be sure that the patient has chronic cutaneous porphyria?
Unlike acute porphyrias, which may be clinically indistinguishable, cutaneous porphyrias may be more easily identified from each other in the clinical setting due to some of their unique properties. Together with the occasional photosensitivity of HCP (hereditary coproporphyria) and VP (variegate porphyria), cutaneous porphyrias manifest cutaneous lesions due to the photosensitizing effects of excess porphyrins in the skin or in the dermal vessels. Skin lesions may manifest as either bullae or vesicles as seen in most cutaneous porphyrias or as acute erythematous painful lesions seen in EPP (erythropoietic protoporphyria). These different manifestations are mainly due to the differing water solubility of various porphyrins, which is a function of the number of carboxylate groups attached to the tetrapyrroles. The presence of these polar functional groups renders porphyrins progressively more water soluble as their numbers increase. In most of the cutaneous porphyrias, the excess hydrophilic porphyrins diffuse throughout the skin up to the dermoepidermal junction, leading to blister formation. In contrasts, the lipid-soluble excess protoporphyrin seen in EPP deposits is up only until the endothelium of small vessels, leading to endothelial necrosis.
Skin photosensitivity is the predominant clinical feature of both types of cutaneous porphyria. The bullous type, as exemplified by PCT (porphyria cutana tarda) may sometimes be accompanied by hypertrichosis and hyperpigmentation or may sometimes occur in the absence of vesicles. Lichenification, scarring, and skin calcification may also be observed. The cutaneous lesions that may be seen in neurocutaneous porphyria (i.e., VP and HCP) are clinically and histologically indistinguishable from those of PCT. Although the cutaneous lesions of CEP (congenital erythropoietic porphyria) and HEP (hepatoerythropoietic porphyria) resemble those of PCT, they are usually more severe and usually occur at a younger age. In some instances, they may be manifest in early infancy.
EPP presents with acute photosensitivity characterized by painful erythema and edema after brief exposure to sunlight. Most patients develop symptoms in early childhood (<1-2 years old). Unlike the other forms of cutaneous porphyria, it usually does not present with blisters, which develop only rarely and after prolonged sun exposure. It may also sometimes present with petechiae and purpuric lesions. Repeated sun exposures lead to chronic changes, giving the skin a waxy, thickened appearance with prominent pores (peau d’ orange appearance). This chronic change is usually prominent in the malar areas of the face in a typical “butterfly” pattern and over the knuckles of the hands. In addition, patients may also present with hemolysis and associated pigmented gallstones. Its most serious complication, however, is the development of pigmentary hepatic cirrhosis thought to be due to the excess protoporphyrin precipitation in hepatocytes and biliary canaliculi.
Cutaneous porphyria primer
Porphyria cutanea tarda (PCT)
PCT is the most common form of porphyria worldwide and in the U.S., with a prevalence of 1 per 25,000. It is associated with an acquired or inherited deficiency of hepatic uroporphyrinogen decarboxylase (UROD) activity, although other factors – especially iron, alcohol, chronic hepatitis C, HIV, and estrogen – are important contributory factors. Symptoms develop when hepatic UROD activity is below ~25% of normal.
The incidence and prevalence of PCT are higher in equatorial nations, where there is more exposure to sunlight of high intensity. It is also found to be more common in regions where iron overload, chronic hepatitis C, HIV, and alcohol abuse are prevalent. Indeed, these conditions should be sought in patients who present with PCT. It is a heterogeneous disease and has been classified into three subtypes.
Type I represents 80% to 90% of PCT and is characterized by decreased hepatic, but normal, erythroid UROD activity. It is not associated with mutations of the UROD gene and is thought to arise from the presence of an inhibitor (uroporphomethene) that binds and inhibits the hepatic enzyme. This inhibitor is formed only in the presence of iron and reactive oxygen species and is probably the main reason why hemochromatosis, alcoholism, hepatitis B and C, HIV, and estrogens are the major risk factors for PCT.
Hepatic UROD can also be inhibited by various environmental chemicals, such as hexachlorobenzene, dioxin, and others. Indeed, the addition of the fungicide hexachlorobenzene to wheat seeds (which were intended for planting, but which were baked into bread) caused a massive disease outbreak in Turkey in the late 1950s.
The familial forms of PCT comprise the remaining portion of the disorder and arise due to heterozygous mutations of the UROD gene. Type II is an autosomal dominant condition of low penetrance that leads to decreased UROD activity in all tissues. Affected individuals have approximately 50% deficiency of UROD and may develop PCT more readily than type I. It is usually accompanied by abnormal liver function tests and is often associated with hepatic steatosis, iron, and inflammation on biopsy.
Type III is a rare familial type of PCT similar to type II; however, UROD activity is deficient only in nonerythroid tissues. It usually presents clinically in the third or fourth decade of life. (See Figure 1. PCT skin manifestations.)
Hepatoerythropoitic porphyria (HEP)
Whereas types II and III PCT are due to heterozygous UROD gene defects, HEP is due to either homozygote or compound heterozygote mutants of the same gene. Although both parental alleles are defective, HEP patients usually have some residual UROD activity (5-10%) and are thought to have unique mutations not usually found in familial PCT. It is a rare form of porphyria; only about 20 cases have been reported. Due to a common enzymatic defect, HEP not surprisingly does not resemble PCT biochemically. Unlike PCT, however, erythrocyte zinc-protoporphyrin is increased in HEP. (See Figure 2. HEP skin lesions.)
Congenital erythropoietic porphyria (CEP)
CEP or Günther’s disease is an autosomal recessive photosensitive condition that arises due to an almost complete absence of uroporphyrinogen III (co)-synthase, which catalyses the formation of uroporphyrinogen III from hydroxymethylbilane (HMB). Most of the estimated 200 reported cases are due to compound heterozygotes. The most common mutations are C73R (33%), L4F (7-8%), and T228M (6-7%), in the order of decreasing prevalence. The degree of UROS activity in CEP may range from undetectable to 35% of the mean expressed by the normal cDNA.
The accumulated HMB can be converted nonenzymatically to uroporphyrinogen I, which in turn can be converted to coproporphyrinogen I by UROD. Thus, it is not surprising that these compounds are found in the urine, plasma, and erythrocytes of patients. Fecal porphyrins, however, are mainly coproporphyrin I. Red cell zinc-chelated protoporphyrin, a marker of increased erythropoiesis may also be increased. (See Figure 3, Gunther’s disease.)
Erythropoietic protoporphyria (EPP)
EPP is the most common erythropoietic porphyria and is the second most common porphyria in adults next to PCT. It is considered prototypic of non-bullous photosensitive porphyria. Although described as an autosomal dominant ferrochelatase-deficient condition with variable penetrance, recent genetic studies revealing different patterns of inheritance consistent with a three-allele system shed doubt on this simplified classical paradigm. The ferrochelatase (FECH) gene is located on chromosome 18q21.3, is 45 kb in length, and contains a total of 11 exons. Despite this uncertainty, EPP is thought to be due to a partial enzymatic deficiency, of which patients typically only have 15% to 25% detectable FECH activity in comparison to controls. The explanation for this discrepancy may be due to the presence of IVS3-48T/C polymorphism that is common in Caucasians and East Asians (but rare in Africans). In combination with a FECH mutation, the IVS3-48T/C gene leads to errors in post-transcriptional modification, which leads to nonsense mediated decay, thereby further reducing FECH expression from an expected 50% to the observed 15% to 25%.
Biochemically, EPP is characterized by elevated protoporphyrin in plasma, erythrocytes, and feces. Unlike other porphyrias, urinary porphyrins and precursors are normal because the lipophilic protoporphyrin is not excreted into the urine at all. Furthermore, unlike all homozygous forms of porphyria, various hemolytic disorders, lead poisoning, and iron deficiency anemia, the increased protoporphyrin is predominantly “free” and not chelated to zinc. Free protoporphyrin is considered to be the hallmark of EPP and thus must be differentiated from those complexed with zinc for proper diagnosis. (See Figure 4 and Figure 5.)
X-linked dominant erythropoietic protoporphyria (X-EPP)
Stimulated by the observation that some individuals with wild-type homozygous FECH alleles nevertheless manifested EPP-like symptoms, Whatley and colleagues first described X-EPP in 2008. X-EPP results from a gain-of-function mutation of the ALAS2 gene, leading to excess porphyrins despite normal mitochondrial FECH activity. Two-frame shift mutations have been identified in chromosome Xp11.21 in eight families. Its clinical presentation is very similar to EPP due to defective FECH activity. A difference is that subjects with X-EPP demonstrate higher concentrations of RBC zinc-chelated porphyrins, comprising at least 40% of the total erythrocyte protoporphyrins.
Pathophysiology of cutaneous porphyrias
At the molecular level, the cutaneous manifestations are due to the readily absorbed energy of violet light by the delocalized electrons or aromatic porphyrins. Absorption of this energy leads to a higher energy state, referred to as a “singlet state.” The singlet-state porphyrin then transfers this energy onto molecular oxygen, which in turn brings it to a higher energy state. Depending on location, this highly reactive singlet oxygen species then directly results in lipid peroxidation of cell membranes, resulting in lysis of cells and eventual cutaneous manifestations observed.
The skin lesion of PCT, HCP, and VP usually manifest days after sun exposure and are clinically indistinguishable, whereas those of HEP and CEP are more severe and present earlier in life. Because immediate painful erythema and urticarial lesions are found in EPP and X-EPP, some investigators have suggested that mast cell-derived mediators play a significant and contributory role to the various clinical manifestations of EPP and X-EPP. Indeed, protoporphyrin has been shown to induce the release of mast cell-derived mediators when exposed to the Soret band, in contrast to the lack of direct effect of uroporphyrins.
A tabular listing of features and signs and symptoms
There are no pathognomonic skin lesions per se that will completely differentiate cutaneous porphyrias from other photodermatoses (Table I). Like other light-induced skin lesions, cutaneous porphyrias manifest with skin photosensitvity and may be either bullous or erythematous in presentation. Some overlap between the two forms is possible but is unusual and is typically distinguishable on careful review of the history and physical exam.
|Conditions that may be confused||Usually confused with what prototypic cutaneous porphyria?||Key features|
|Secondary porphyrinuria + nonspecific photodermatoses||Both PCT and EPP||Urinary porphyrins <3x the upper limit of normal, mainly coproporphyrins; normal or minimal increased fecal porphyrins (rules out HCP and VP); absence of elevated urinary PBG early in remission; and lack of correlation between symptoms and porphyrin levels on repeat measurement. Typically without genetic mutation in any enzymes involved in heme biosynthesis (except for PCT type I).|
|PMLE, solar angioedema, solar urticaria||EPP|
As with acute porphyrias, secondary porphyrinurias concomitant with nonspecific signs and symptoms may confuse the clinical picture. However, careful observation of the suggested diagnostic algorithm shown in the chapter Acute Porphyrias prevents this common pitfall.
Differential diagnoses of erythematous chronic-cutaneous porphyria include polymorphous light eruption (PMLE), drug-induced photosensitivity, solar urticaria, and/or solar angioedema.
PMLE is the most common photodermatosis and is acquired after exposure to UVA/UVB radiation. In most series, UVA (320-400 nm) has been more effective than UVB (280-320 nm) for PMLE induction. It is so named due to its many morphologic variants but is generally pruritic, grouped, erythematous, or skin-colored papules of varied sizes. Papulovesicles, as well as confluent edema, are also possible, although they rarely may present with blisters. Also rare is the appearance of erythema and pruritus alone. PMLE is usually diagnosed clinically, based on the typical morphology of eruption. Laboratory examinations are usually performed to exclude other dermatoses, such as EPP and lupus.
Drug-induced photosensitivity, likewise, is diagnosed through careful history and physical exam. Although solar urticaria alone is unlikely to be confused with EPP, it has been associated with solar angioedema. There are also some reports of angioedema alone developing after sun exposure. All these conditions are easily differentiated from EPP due to their normal porphyrin profiles, most especially, protoporphyrin.
Pseudoporphyria is a photodistributed vesiculo-bullous disorder that is difficult to distinguish from PCT, based on its presentation and histological findings. Unlike PCT, however, the following symptoms are usually not present: hypertrichosis, sclerodermal changes, hyperpigmentation, and dystrophic calcification. It has varied proposed pathogenic factors, including chronic renal failure in the setting of hemodialysis, diuretics, aluminum hydroxide, polyvinyl chloride dialysis tubing, hemosiderosis, silicone, erythropoietin, susceptibility to oxygen-free radicals, voriconazole, NSAIDs, tetracycline, estrogen, retinoids, cyclosporine, flutamide, amiodarone, carisoprodol/aspirin therapy, pyridoxine, 5-fluorouracil, ephedrine, caffeine, L-carnitine, chromium, excessive cola consumption, and UVA radiation. It is usually treated with the administration of N-acetylcysteine and discontinuation of suspected precipitating agents. As in other nonporphyric dermatoses, porphyrin profile (especially in plasma) is usually normal (although it may be mildly elevated in the setting of renal failure).
How can I confirm the diagnosis?
The preferred first-line test for cutaneous porphyrias is the measurement of total plasma porphyrins via direct fluorometric method. The following table summarizes the data for suspected cutaneous porphyrias (Table II).
|Maximal excitation wave length (nm)||Maximal emission wave length (nm)||Type of porphyria|
|398||619-620||PCT, HCP, or CEP (may also be seen in AIP)|
Source: Adapted from Bonkovsky HL, Barnard GF. Diagnosis of porphyric syndromes: a practical approach in the era of molecular biology. Semin Liver Dis 1998;18(1):57-65.
As is true for acute porphyrias, chronic porphyrias have similar second-line tests that characterize the disease process through its biochemical profile. Once again, 24-hour urinary ALA, PBG, and total porphyrin levels are ordered. Urinary assays should be sent along with spot total fecal porphyrins and erythrocyte porphyrins to further differentiate the various cutaneous porphyrias. Thus, erythrocyte porphyrins are ordered as a second-line test in bullous porphyrias, whereas it is considered first-line when EPP and/or X-EPP are strongly suspected. (First- and second-line tests for acute porphyrias and biochemical finding in porphyrias are summarized in Tables IV and V, respectively, of the chapter “Acute porphyrias” [by Bonkovsky H and Caballes FR].
What other diseases, conditions, or complications should I look for in patients with cutaneous porphyrias?
Porphyria cutanea tarda (PCT)
When PCT is diagnosed, it is important to rule out iron overload, hemochromatosis, estrogen use, HIV, chronic hepatitis C, and alcohol abuse as precipitating factors. A minority of patients (~10%) have either advanced hepatic fibrosis or cirrhosis. It is unclear whether porphyrins contribute to the liver damage that may have precipitated PCT. Similar to acute porphyrias, however, PCT is a risk factor for hepatocellular carcinoma. Furthermore, the frequency of hepatic cancer is higher in patients with PCT than in those with cirrhosis alone.
Table III summarizes the complications and manifestations of various cutaneous porphyrias.
|PCT||Scarring, alopecia, and sclerodermatous changes (15-20%); advanced fibrosis or cirrhosis (10-15%), rare widespread melanosis, dystrophic calcification, nonhealing ulcers in areas of sclerodermatous plaques, calcium deposits usually in the pre-auricular regions of the face, scalp, or neck.|
|EPP and X-EPP||Burning (97%), edema (94%), pruritus (88%), erythema (69%), scarring (19%), vesicles (3%), anemia (27%), gallstones (4-20%), live disease, and/or cirrhosis (<5-10%).|
|CEP and HEP||Red urine, hypertrichosis, and scarring, lifelong hemolytic anemia resulting in compensatory marrow expansion, which leads to pathological fractures, vertebral compression, and short stature. Hemolysis also results in splenomegaly and pigmented gallstones.|
Hepatoerythropoitic porphyria (HEP)
HEP clinically resembles CEP by presenting early in infancy or childhood with red urine, severe photosensitivity, fragile skin, blistering skin lesion, erythrodontia, hypertrichosis, sclerodermoid skin changes, and scarring. Hepatosplenomegaly, elevated liver enzymes, hemolytic anemia, and eventual hepatic disease have also been described. Its prognosis is poor due to the profound deficiency of UROD activity. Mild cases understandably resemble PCT.
Congenital erythropoietic porphyria (CEP)
The variable clinical manifestations of CEP are likely related to the severity of UROD deficiency afforded by different combinations of mutant alleles. Other factors such as degree of hemolysis, extent of reactive erythropoiesis, and degree of exposure to ultraviolet light may also modulate disease severity. Indeed, homozygozity for C73R correlates with the most severe manifestation of CEP, resulting in non-immune hydrops and/or early transfusion dependency from birth. In most cases, however, severe photosensitivity develops soon after birth and is manifested by increased friability and blistering of the epidermis on sun-exposed areas. In addition, pink or red-brown staining diapers (due to the markedly increased uroporphyrin I in urine), hypertrichosis of face and extremities, erythrodontia, and other hemolytic complications characterize this condition.
Erythropoietic protoporphyria/X-linked dominant erythropoietic protoporphyria
EPP and X-EPP present with the classical acute photosensitivity characterized by painful erythema and edema after brief exposure to sunlight. Most patients present with early childhood photosensitivity (<1-2 years old) but the condition may develop in infants as well. Unlike other forms of cutaneous porphyria, it usually does not present with blisters, which develop only rarely and after prolonged sun exposure. It may also sometimes present with petechiae and purpuric lesions. Repeated sun exposures lead to chronic changes, giving the skin a waxy, thickened appearance with faint linear scars. This chronic change is usually prominent in the malar areas of the face in a typical “butterfly” pattern and over the knuckles of the hands. In addition, patients may also present with hemolysis and associated pigmented gallstones. Their most serious complication, however, is the development of pigmentary hepatic cirrhosis, thought to be due to the excess protoporphyrin precipitation in hepatocytes and biliary canalicul
What is the right therapy for the patient with cutaneous porphyria?
Because the manifestations of cutaneous porphyrias are due to the interaction of sunlight with accumulated porphyrins, avoidance of sunlight and wearing of protective clothing are paramount in ameliorating or preventing symptoms. However, the different complications and manifestations of each cutaneous porphyria dictates that subsequent treatments be individualized.
Unlike acute porphyria, additional treatment options of cutaneous symptoms, more often than not, depend on the type of porphyria (Table IV).
|Cutaneous porphyria||Additional treatment options from limiting light exposure||Comments|
|PCT||Phlebotomy,chloroquine therapy,desferrioxamine||(Refer to Table V, Therapeutic algorithm.)|
|Coexistence of hepatitis C||Should receive antiviral therapy if possible. Iron depletion augments treatment response.|
|PCT in childhood||Series of small-volume phlebotomies or chloroquine, dosed per body weight. (Refer to Table V, Therapeutic algorithm.)|
|PCT in pregnancy||Preferably treated with phlebotomy. Low-dose chloroquine may be added in refractory cases, without known reported fetal risk. Due to hemodilution and iron depletion, symptoms are usually improved during pregnancy.|
|PCT and hormone supplementation or contraception||Discontinue hormone therapy.|
|EPP||Cold bath or cold compress, oral analgesics, and antihistamines||Treatment of acute skin pain, pruritus, and/or erythema.|
|Systemic beta-carotene and possibly afamelanotide in the near future||(Refer to Table V, Therapeutic algorithm.)|
|Exchange transfusion and plasmapheresis||Reduction of circulating protoporphyrins. (Refer to Table V, Therapeutic algorithm.)|
|IV Hemin of PRBC transfusion||ALAS2 suppression and subsequent decrease of hepatic heme.|
|Orthotopic liver transplant (OLT)||Has been done in more than 40 cases since 1983.|
|Bone marrow transplant||(Refer to Table V, Therapeutic algorithm.)|
|HEP and CEP||Hematological support (including transfusion)||To correct for hemolytic anemia.|
|Hydroxyurea||To reduce porphyrin synthesis.|
|Oral charcoal||To facilitate fecal porphyrin excretion.|
See treatment algorithm (Table V).
|All cutaneous porphyria||1. Sunlight avoidance.2. Use of opaque sunscreen containing zinc or titanium oxide and use of protective clothing.3. Avoidance of porphyrinogenic substances or precipitating factors.||Clinical|
|PCT||1. Phlebotomy is the preferred treatment in patients with iron overload or hemochromatosis gene mutations. 300-450 mL of blood is removed either once or twice per week or within 1- to 3-week intervals until serum transferrin saturation is <16%, Hct <35%, and serum ferritin <10 ng/mL. Usually accomplished by removal of 12-16 units or 2.5-7 L of blood.2. Chloroquine may be added to phlebotomy regimen to accelerate treatment response. Alternatively, it may be used when phlebotomy is contraindicated due to presence of anemia. It is dosed at 125 mg twice a week. Clinical effect is generally seen within ~6 months. Therapy should continue until full biochemical remission, usually more than 1 year.3. Desferoxamine, SQ is another alternative to phlebotomy.4. If with renal disease (options): a. Mobilization of iron stores via erythropoietin combined with small phlebotomies (5-100 mL) is preferred. b. Use of dialyzers with ultra-permeable membranes with blood flow rates higher than routine may reduce plasma porphyrins. c. Plasmapheresis should be considered in severe cases. d. Renal transplantation is curative in severe cases, refractory to above modalities in PCT associated with renal failure.||Urinary or plasma porphyrins may be followed every 2-3 months and should become normal after the target ferritin is reached.|
|EPP/X-EPP||1. Systemic beta carotene: a. Adults: 180-300 mg/day b. Children: 60-90 mg (1-4 years old); 90-120 mg (5-8 years old); 120-150 mg (9-12 years old); 150-180 mg (13-16 years old).2. Afamelanotide: An alpha-melanocyte-stimulating hormone analogue, currently undergoing Phase III trial shows promise.3. Liver transplant.4. Bone marrow transplant (BMT): Strongly consider only after recurrence of liver disease post-OLT or persistent cholestasis of graft without underlying cirrhosis.5. Ursodeoxycholic acid or chenodeoxycholic acid may alter bile composition to protect cholangiocytes and hepatocytes. Vitamin E acts as a free radical scavenger, while oral charcoal and cationic exchange resins may interfere the enterohepatic circulation of protoporphyrins.6. Intravenous hemin and erythrocyte transfusions is thought to suppress ALAS1 and improve LFTs but has no proven effect on erythroid heme synthesis.7. Exchange transfusions and plasmapheresis have been used to remove protoporphyrin as a bridge to OLT.||1. Recommended serum levels of beta-carotene11-15 µmol/L. Blood concentration reaches steady state in ~3 weeks.2. Unclear whether afamelanotide needs monitoring.3. Patient survival is similar to other indications for OLT. However, cirrhosis my recur on graft due to accumulation of protoporphyrins.|
|CEP & HEP||Hematological support (including transfusion), hydroxyurea to reduce porphyrin synthesis, splenectomy for hypersplenism, oral charcoal treatment to facilitate fecal porphyrin excretion, and curative bone marrow transplant.||No established guidelines on need for supportive treatment and BMT; mainly clinical.|
What is the most effective initial therapy?
The most effective initial therapy is the avoidance of sun exposure and/or strong light of ~400 to 410 nm wavelengths (Soret band) to prevent cutaneous manifestations.
Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.
Because the Soret band of light (400-410 nm) is within the visible spectrum, most sunblocks (which screen out only UV light) are not protective. For the same reason, window glass offers no protection – whereas it absorbs UV wavelengths that lead to the typical sunburn reaction (290-320 nm), it is transparent to the visible spectrum. Although less cosmetically appealing, opaque sunscreens containing zinc oxide or titanium dioxide are more effective means of protection. In addition, use of opaque clothing (e.g., Solumbrex
®) may also be beneficial. Therapeutic failure is evidenced by skin manifestations or the appearance of symptoms.
A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies
Apart from limiting light exposure, each cutaneous porphyria may be treated in a variety of ways. In fact, treatment of the cutaneous lesions of VP and HCP with phlebotomies and chloroquine are ineffective, although useful in PCT. In addition, treatment of the neurocutaneous porphyria with chloroquine may induce an acute attack since chloroquine and its derivatives are known to be porphyrinogenic. Cholestyramine, however, may decrease the photosensitivity associated with liver dysfunction for both of the neurocutaneous porphyrias. Unlike VP, the skin lesions of HCP may obtain some benefit from beta-carotene therapy. Similarly, CEP is treated by a plethora of ways apart from sunlight avoidance, including intensive skin care, hematological support (including transfusion), hydroxyurea to reduce porphyrin synthesis, splenectomy in hypersplenism, oral charcoal treatment to facilitate fecal porphyrin excretion, and through a curative allogeneic bone marrow transplant. HEP may be treated similarly as CEP due to their shared clinical manifestations, but HEP is primarily treated by avoidance of the sun.
EPP may benefit from beta-carotene in doses of 75 to 300 mg per day. Usual serum levels range from 11 to 15 μmol/L. Effects are modest at best and only about one-third of patients improve from pro-vitamin A and is contraindicated in smokers. Thus, carotene should be discontinued if no increase in sunlight tolerance is apparent 3 months after attaining optimum levels.
As liver function deteriorates, EPP may be treated with cholestyramine and activated charcoal. Although with still unproven benefits, cholestyramine is thought to deplete hepatic protoporphyrin production, while activated charcoal binds protoporphyrin in the gut. An alpha-melanocyte-stimulating hormone analogue, afamelanotide, shows promise by induction of eu-melanin production.
As in the three most common acute porphyrias, transplantation may be initiated in EPP in the setting of advanced liver failure. During transplantation or any surgical procedures on EPP patients, yellow filters should be applied to surgical lighting to reduce the potential phototoxic injury to intra-abdominal organs. Protoporphyrins may reaccumulate in the donor liver due to the erythroid protoporphyrin production. Thus, combined liver and bone marrow transplantation is ideal to prevent relapse of end-stage liver disease. Similar supportive and preventive treatments are implemented for X-EPP.
After stopping precipitating factors, such as alcohol or estrogens, PCT is preferably treated with phlebotomy. Remission may occur after only 5 to 6 pints of blood have been removed. A unit (450 mL) of blood is removed either once or twice per week until depletion has been achieved, as shown by transferrin saturation of less than 16%, hematocrit of less than 35%, and serum ferritin of less than 10 ng/mL. This is usually accomplished by the removal of 12 to 16 units or 2.5 to 7 L of blood. Urinary or plasma porphyrins may be followed every 3 months and become normal some time after the target ferritin is reached, in most cases within 6 months.
If phlebotomy is ineffective or contraindicated due to the presence of anemia, low-dose chloroquine provides a therapeutic option. It forms complexes with porphyrins in lysosomes, leading to hepatic mobilization and increased urinary excretion. In severe cases, a combination of phlebotomy and antimalarials results in faster remission than does either treatment alone. On the other hand, patients with PCT and chronic hepatitis C may benefit after the treatment of hepatitis C. In patients with end-stage renal disease with concomitant anemia, where phlebotomy is contraindicated and chloroquine is ineffective, concomitant treatment with recombinant erythropoietin and phlebotomy may be required.
Listing of these, including any guidelines for monitoring side effects.
First- and second-line diagnostic tests are discussed the chapter “Acute porphyrias” (by Bonkovsky H and Caballes FR).
How should I monitor the patient with cutaneous porphyria?
Monitoring of the neurocutaneous porphyrias, such as VP and HCP, follow the guidelines already described for acute porphyrias. Although monitoring of PCT and EPP are more standardized than other cutaneous porphyria, surveillance of the less common chronic cutaneous porphyrias involving porphyrin metabolism and blood and liver function tests is likely prudent. With EPP, it is recommended that these tests be done annually and any elevated liver chemistries should prompt a low threshold for liver biopsy. As with patients at risk for or who have chronic liver disease, EPP patients should be vaccinated against hepatitis A and B. Depending on the etiology of PCT, more frequent monitoring may be necessary. Although CEP and HEP may also present with liver damage, it is unclear whether extrapolation of the above recommendations improve survival or decrease morbidity.
What's the evidence?
Anderson, E, Goldman, L, Ausiollo, D. “The porphyrias”. 2007. (The author is a renowned expert in porphyria. The article provides a brief description of the prototypic porphyrias and proceeds to discuss each type in some detail. The article further stresses a simplified algorithm in the diagnosis of both acute and cutaneous porphyrias.)
Bonkovsky, HL, Lambrecht, RW, Barton, JC. “Hemochromatosis, iron-overload, and porphyria cutanea tarda”. Cambridge University. 2000. (The authors have expertise on both hemochromatosis and porphyria. The work reviews the history, genetics, clinical features, physical findings, laboratory features, hepatic histology, and management of PCT. The role of iron in uroporphyrin overproduction, along with alcohol, estrogens, and viral hepatitis is also discussed.)
De Salamanca, RE, Sepulveda, P, Moran, MJ. “Clinical utility of fluorometric scanning of plasma porphyrins for the diagnosis and typing of porphyrias”. Clin Exp Dermatol. vol. 18. 1993. pp. 128-30. (The article is the basis of the fluorometric scanning of plasma porphyrins to identify specific porphyrias.)
Harper, P, Wahlin, S. “Treatment options in acute porphyria, porphyria cutanea tarda, and erythropoietic protoporphyria”. Curr Treat Options Gastroenterol. vol. 10. 2007. pp. 444-5. The authors provide a brief description of acute porphyria, PCT, and EPP. In a simple list format, the authors suggest the treatment options for each of the common complications of porphyria.)
Lecha, M, Puy, H, Deybach, JC. “Erythropoietic protoporphyria”. Orphanet J Rare Dis. vol. 4. 2009. pp. 19(The article is written by authors who are renowned for their work in porphyria. A comprehensive review and demonstration of the cutaneous lesions of EPP.)
McGuire, BM, Bonkovsky, HL, Carithers, RL. “Liver transplantation of erythropoietic protoporphyria liver disease”. Liver Transplant. vol. 11. 2005. pp. 1590-6. (The authors performed the study to define post-transplant survival, risk of recurrent disease, and specific management issues in patients transplanted for EPP liver disease.The study found that a 5-year patient survival rate in EPP patients who received liver transplants is good: howerver, the recurrence of EPP liver disease appeared to diminish long-term graft and patient survival.)
Phillips, JD, Bergonia, HA, Reilly, CA. “A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda”. P Natl Acad Sci USA. vol. 104. 2007. pp. 5079-84. (The work is the landmark study that identified a specific inhibitor that underlies PCT.)
Sarkany, RPE. “Making sense of the porphyrias”. Photodermatol Photoimmunol Photomed . vol. 24. 2008. pp. 102-8. The article describes the pathophysiology behind the two skin manifestations of cutaneous porphyrias. It suggests a simplified checklist for patients following up with known cutaneous porphyrias.)
Thapar, M, Bonkovsky, H. “The diagnosis and management of erythropoeitic protoporphyria.”. Gastroenterol Hepatol. vol. 4. 2008. pp. 561-6. (The authors briefly review the enzymatic defects, genetics, epidemiology, clinical presentation, diagnosis, and management of EPP.)
Whatley, SD, Ducamp, S, Gouya, L. “C-Terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload”. Ame J Hum Genet. vol. 83. 2008. pp. 1-7. (The authors provided the seminal work explaining some of the complexities of the genetics of EPP. In this seminal article, the investigators showed that a different mutation can cause similar symptoms as those seen in classical EPP.)
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- How can I be sure that the patient has chronic cutaneous porphyria?
- A tabular listing of features and signs and symptoms
- How can I confirm the diagnosis?
- What other diseases, conditions, or complications should I look for in patients with cutaneous porphyrias?
- What is the right therapy for the patient with cutaneous porphyria?
- What is the most effective initial therapy?
- Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.
- A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies
- Listing of these, including any guidelines for monitoring side effects.
- How should I monitor the patient with cutaneous porphyria?