CHAPTER 60
Cutaneous Porphyrias

Robert P. E. Sarkany

St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Introduction

The porphyrias are a group of disorders caused by defects in the biosynthesis of haem. Their relevance to the skin arises from the phototoxic properties of the porphyrins, which accumulate in most porphyrias and cause photosensitivity.

The majority of the porphyrias are inherited. Many of them affect other organs as well as the skin. The recognition and management of both the genetic and internal consequences of porphyrias presenting in the skin are a key challenge for the dermatologist.

Clinical management in these disorders is made easier when the clinician understands their theoretical basis. Thus, this section is divided into two halves. The first provides a theoretical basis for understanding the porphyrias, the general principles of clinical management and a clinician's guide to laboratory testing. The second half covers individual porphyrias in detail.

GENERAL CONSIDERATIONS: THEORETICAL BASIS, CLINICAL FEATURES AND LABORATORY TESTING IN PORPHYRIA

Theoretical basis for understanding the porphyrias

Phototoxicity of porphyrins

The phototoxic properties of porphyrins are responsible for the cutaneous features of the porphyrias. Porphyrins are intermediates in the biosynthesis of haem, and consideration of the chemical features of the haem and porphyrin molecules is necessary to understand the cause of porphyrin phototoxicity.

Chemistry of porphyrins and haem [1]

A pyrrole is a ring composed of four carbon atoms and one nitrogen atom. Four pyrroles linked into a ring create a tetrapyrrole, a remarkable and biologically critical molecular structure found in chlorophyll, haem and vitamin B₁₂. A porphyrin is a special type of tetrapyrrole in which four pyrrole rings are linked by methine bridges into a large ring structure.

Haem is the molecule created by the insertion of ferrous iron into the centre of the porphyrin molecule protoporphyrin IX (Figure 60.1). Essentially, incorporation of iron into the porphyrin molecule enables it to become biologically useful. Iron's capacity to bind to molecular oxygen, and to transfer electrons (by moving between the 2+ and 3+ oxidation states) makes it potentially useful in biological systems, but free iron precipitates in the presence of water. For iron to be useful, it has to be kept soluble by protecting its binding sites against water. In addition, subtle modification of the electronic structure of the iron atom can optimize its ability to transfer electrons and reversibly bind molecular oxygen. Binding of iron to the porphyrin molecule solubilizes iron and also optimizes its electronic structure. The porphyrin's central cavity is the right size to fit an iron atom, and its four central nitrogen atoms occupy four of the iron's coordination binding sites, leaving only two free. A key feature of the porphyrin structure is that each double bond is adjacent to a single bond, so it is ‘aromatic’ with 18 of its electrons being delocalized and free to move around the molecule (Figure 60.1). This electron current results in the central nitrogen atoms tending to donate electrons to the iron atom, as well as other subtler electronic interactions involving transient changes in the porphyrin's electronic state [2].

Image described by surrounding text. — **Figure 60.1** The haem molecule and its key structural features. The alternation of single and double bonds around the tetrapyrrole ring indicates the aromaticity of the molecule, central to its chemical characteristics. The four coordination bonds between iron and nitrogen atoms are shown. The two remaining bonds between the iron and either molecular oxygen or amino acid residues lie perpendicular to the page.

Haem can bind to a variety of proteins, and the nature of this interaction reflects the protein's function. In proteins with electron transport functions, such as respiratory cytochromes, amino acids bind to both remaining coordination binding sites on the iron so that haem can transfer electrons through alterations in the iron's oxidation state. In proteins with oxygen-binding functions, such as haemoglobin, an amino acid binds to one of the iron's remaining coordination binding sites, leaving the sixth site free to bind to oxygen. In summary, the aromatic porphyrin structure is well suited to complexing with iron to form haem, rendering the iron useful for electron transfer (respiratory cytochromes), reversible oxygen binding (haemoglobin and myoglobin) and oxidation and reduction reactions (cytochrome P450, catalase), with fine tuning of the iron's functionality being determined by the apoprotein that binds to the haem.

Photochemistry of the porphyrins [3, 4]

The complex electronic structure of the large aromatic porphyrin molecule results in its 18 delocalized electrons having unusual excitation characteristics. These electrons are excited by relatively long wavelength light. The main absorption peak is at 408 nm (‘Soret band’) [3], and this long wavelength of exciting light predisposes to phototoxic behaviour by the porphyrin. These photons have insufficient energy to chemically alter the porphyrin structure, so that alternative fates for the energy, particularly fluorescence and phosphorescence, become more likely [4]. Thus, following excitation by light around the 408 nm peak, electrons either return to the non-excited ground state by releasing the energy as characteristic red fluorescence, or the porphyrin's excited singlet state transforms (by intersystem crossing) to the longer lived excited triplet state. Transfer of energy from this excited triplet state to neighbouring molecules leads to the phototoxicity responsible for the clinical features of the cutaneous porphyrias. Thus cutaneous disease in the porphyrias can be thought of as a by-product of the unusual porphyrin structure which enables haem proteins to fulfil their biological functions.

Enzyme deficiencies and the porphyrias

The porphyrias all result from a partial deficiency of one of the enzymes required for the biosynthesis of haem, thus causing accumulation of the enzyme's substrate. The toxicity profile of the accumulated molecule determines the clinical features of the resulting porphyria. A basic understanding of the biosynthetic pathway enables the clinician to interpret laboratory results and to predict the clinical features of each porphyria on the basis of each porphyrin's properties.

Biosynthesis of haem [1, 2]

Haem is synthesized from simple biochemicals (glycine and succinyl CoA) via an eight-step pathway, each step being catalysed by an enzyme (Figure 60.2). Synthesis of the pyrrole ring (porphobilinogen (PBG)) is followed by assembly of the tetrapyrrole structure (hydroxymethylbilane). One of the pyrrole rings (the ‘D’ ring) is ‘flipped’ around to create the III isomer (the alternative I isomer forms in the absence of the cosynthase enzyme). Next, the carboxylic acid side chains of uroporphyrinogen III are progressively decarboxylated via coproporphyrinogen III to protoporphyrinogen, which is then oxidized to protoporphyrin IX. It is likely that the progressive decarboxylation to remove six of the eight electron-withdrawing carboxylate groups increases the flux of electrons onto the molecule's central nitrogens to facilitate coordination with iron. Finally, ferrous iron is chelated into the protoporphyrin's central cavity to form haem. Around 80% of haem is synthesized in erythroid cell precursors in the bone marrow (for haemoglobin production). The decarboxylation of uroporphyrinogen to coproporphyrinogen, and thence to protoporphyrinogen, decreases water solubility, so that uroporphyrinogen is only excreted via the kidneys whereas hydrophobic protoporphyrinogen and protoporphyrin are exclusively excreted into the bile. Coproporphyrinogen is excreted by both routes. Physiological concentrations of porphyrins stay low because of the high efficiency of haem synthesis.

Clinical features of the porphyrias: general considerations

Porphyrias present with either skin disease or acute attacks or both.

Classification of the porphyrias [1, 2]

In any porphyria, a partial enzyme deficiency causes the accumulation of porphyrins. The enzyme deficiency associated with each disorder is shown in Figure 60.3. The porphyrias have previously been classified, according to the predominant site of porphyrin accumulation, into the erythropoietic group (congenital erythropoietic porphyria and erythropoietic protoporphyria) and the hepatic group (all the others). This division is not of value clinically. For the clinician, the key division is between porphyrias that cause acute attacks and those that cause skin disease. In this chapter the following classification is used for the six common porphyrias:

Cutaneous disease only:
- Porphyria cutanea tarda (PCT).
- Congenital erythropoietic porphyria (CEP).
- Erythropoietic protoporphyria (EPP).
Cutaneous disease and acute attacks:
- Hereditary coproporphyria (HC).
- Variegate porphyria (VP).
Acute attacks only:
- Acute intermittent porphyria (AIP).

Image described by caption. — **Figure 60.3** The pathway of haem biosynthesis showing the enzyme deficiency associated with each porphyria. Abbreviations of the disease names are defined in the text.

Porphyria and the skin

The cutaneous porphyrias share many features. Consideration of these underlying similarities is necessary for a logical approach to clinical management of patients.

All the cutaneous porphyrias, except EPP, present with fragility and blistering of light-exposed skin; the term ‘bullous porphyrias’ is often used for this group of diseases. Not only can they appear very similar clinically, but the mechanism underlying the skin disease in all cutaneous porphyrias is a local porphyrin phototoxicity reaction. This shared pathogenetic mechanism means that the histopathological appearances in each of these conditions are also similar. As a result, these disorders can only be reliably differentiated by biochemical analysis. The other important similarity between them is that they are all caused by Soret wavelength light (408 nm), so the same strategy for photoprotection applies to them all, as detailed below.

Pathophysiology of skin disease in porphyria [1–3]

Photons of violet light, with a wavelength peak at 408 nm, transform the porphyrin molecule into an excited singlet state (Figure 60.4). This may revert to the unexcited ground state by emission of the characteristic red porphyrin fluorescence, but intersystem crossing can convert it to the excited triplet state, long-lived enough to interact with other molecules, particularly molecular oxygen, converting it to excited singlet oxygen in the process. The singlet oxygen stimulates production of hydroxyl radicals, which damage tissue directly, and also indirectly by stimulating complement activation [4], mast cell degranulation [5] and matrix metalloproteinase activity [6]. The site of this phototoxic reaction in the skin determines the clinical characteristics of the porphyria. In EPP, lipophilic protoporphyrin tends to localize to membranes including endothelial cell membranes, and to remain within erythrocytes, and the phototoxic reaction involves upper dermal blood vessels causing pain. In PCT, the water-soluble uroporphyrin diffuses easily into surrounding tissues and the phototoxic reaction occurs in the upper dermis, causing lysis of cells in the superficial dermis with the formation of membrane-limited vacuoles that merge to produce a blister under the basal lamina, producing the characteristic clinical presentation [7]. In VP, copro- and protoporphyrin accumulate (see Figure 60.3), but patients suffer from PCT-like upper dermal blisters rather than EPP-like acute pain. This is likely to be because, although hydrophobic porphyrins predominate in the plasma in VP, hydrophilic porphyrins, particularly uroporphyrin, predominate in the skin, probably due to secondary local photoinactivation of uroporphyrinogen decarboxylase (UROD) in the skin by coproporphyrin [2]. In addition, the protoporphyrin in VP is conjugated to a peptide which may reduce its phototoxicity.

There is no simple correlation between the plasma porphyrin concentration and the severity of cutaneous disease in porphyria. This is because of the large number of local variables that can alter the extent of the phototoxic reaction in the skin, and because an increased plasma porphyrin concentration is not always associated with cutaneous disease [8].

Histopathology of the skin in porphyria [9, 10]

In all the cutaneous porphyrias, homogeneous material is seen within the vessel walls of the upper dermal and papillary vascular plexus. It is periodic acid–Schiff (PAS) positive and diastase resistant, and contains a protein polysaccharide complex, lipids and tryptophan. Immunofluorescence reveals immunoglobulins (mainly IgG) in a similar vascular distribution, and IgG at the dermal–epidermal basement membrane zone, in involved skin. Electron microscopy shows reduplication of the vascular basal lamina and the presence of masses of fine fibrillar material, mainly around these blood vessels and often also at the dermal–epidermal junction. In EPP, the vessel wall changes are more pronounced, whereas the basement membrane zone changes predominate in affected skin in PCT and VP. In bullous porphyrias, bullae are subepidermal with the split occurring in the lamina lucida [11] (Figure 60.5) leaving the dermal papilla protruding into the blister cavity, an appearance called ‘festooning’ [10]. The findings in bullous porphyrias are indistinguishable from those of pseudoporphyria. In EPP, in the acute phase, there is visible endothelial damage in superficial dermal vessels [12]. Electron microscopy shows the ‘amorphous’ material seen in vessel walls on light microscopy in light-exposed skin to be a replicated, layered and fragmented basement membrane, with fine fibrillar material permeating the capillary connective tissue sheath and extending beyond the vessel walls, caused by repeated episodes of damage [13, 14].

General considerations in the management of skin disease in porphyria

Apart from PCT, and to some extent CEP, where effective specific treatments exist, the management of the skin in the other cutaneous porphyrias is based on preventing violet (Soret wavelength) light penetrating the epidermis. The connection between sun exposure and symptoms is obvious in EPP, but is not obvious to patients with the bullous porphyrias where fragility and blistering are not related to individual episodes of sun exposure. It can therefore be difficult to convince these patients of the importance of photoprotection. Basic measures include sun avoidance behaviour, sun protective clothing and hats. Most sunscreens, including UV-absorbent chemical ‘total sunblocks’, do not protect against the visible violet Soret wavelength [15]; any sunscreen providing significant visible light protection will be opaque rather than transparent. Sunscreens containing reflectant particles, particularly large particle size titanium dioxide (pigmentary grade), zinc oxide and iron oxide, can effectively protect against violet light [16]. Cosmetically acceptable sunscreens with reasonable protection up to 430 nm are available commercially, for example Dundee sunscreen (Tayside Pharmaceuticals, Dundee, UK) [15, 16]. Dihydroxyacetone paint induces the formation of a light-absorbing brown pigment in the stratum corneum, and has been used in some patients with EPP [17]. Some reasonably clear window films can absorb some violet light, and are useful on car or home windows, particularly in EPP and CEP [18]. This author generally uses two films which are clear and provide reasonable, though not complete, protection against Soret wavelength light (Dermagard film, Bonwyke, Hants, UK; CLS200XSR film, Madico, USA). The Madico TA81XSR film is yellower but does provide better protection. Clearly, films applied to car windows must comply with local legislation, which varies considerably in different parts of the world.

Acute attacks of porphyria [1, 2]

AIP, HC and VP can all cause acute attacks, and HC and VP may also cause cutaneous disease. (A rare autosomal recessive acute porphyria, aminolaevulinic acid (ALA) dehydratase porphyria, has also been reported but does not cause skin disease, and will not be discussed further.)

Definition

An acute and potentially fatal illness, frequently triggered by drugs and hormones which are metabolized by cytochrome P450. It is characterized by an acute neurotoxic reaction in many tissues.

Epidemiology

The commonest acute porphyria is AIP, followed by VP. HC is rare. The prevalence of clinically overt acute porphyria in Europe is 1–2 per 100 000 inhabitants, but over 90% of individuals possessing AIP or VP gene defects are asymptomatic, so the enzyme deficiencies are common. PBG deaminase deficiency, which causes AIP, is present in 0.2% of all blood donors [3].

Pathophysiology [4]

Impaired activity of PBG deaminase is associated with acute attacks. The deficiency can be primary (as in AIP) or secondary, the latter being due to inhibition of the enzyme by accumulated coproporphyrinogen and protoporphyrinogen (as in HC and VP) [5]. In the liver, haem is mostly incorporated into cytochrome P450 proteins, whose production is induced by many of the drugs and hormones metabolized by the P450 system. When a drug or hormone induces cytochrome P450, and hence acutely increases the hepatic requirement for haem, the inability of the pathway to respond adequately because of the PBG deaminase deficiency is exposed. This acute hepatic haem deficiency in turn causes secondary accumulation of ALA and increased ALA synthase activity due to loss of end-product negative feedback. The symptoms of the acute attack result from neuronal dysfunction, the pathogenesis of which is not fully understood. Postulated mechanisms include disturbed metabolism of neurotransmitters (due to reduced activity of haem-containing hepatic tryptophan dioxygenase), direct neurotoxicity of accumulated ALA (which structurally resembles the neurotransmitter γ-aminobutyric acid) and acute haem deficiency within neurons.

Factors that may precipitate an acute attack [1]

The most common precipitants are drugs and the menstrual cycle, with recurrent attacks often occurring in the late luteal phase. Alcohol, cannabis, fasting, stress and infection may also trigger attacks. It is not possible to predict whether a specific drug will provoke an attack in an individual. Drugs should be prescribed only after reference to an up-to-date drug list. This author recommends using the lists available on the internet from the Welsh Medicines Information Centre [6] or the European Porphyria Initiative [7]. These lists are regularly reviewed and updated by experts, and are lists of drugs, by type, that are known to be safe in acute porphyria; that is, the lists are designed to answer questions such as ‘which antihypertensive can be safely used in a patient with acute porphyria?’. The recommendations on such lists are not absolute and do not substitute for clinical judgement. The risk of a drug provoking an attack is obviously highest where that drug has previously caused an attack in that patient, and in any patients who have previously had symptoms suggestive of an acute attack.

Clinical presentation [1, 2]

Acute attacks are five times more common in females, and most frequently occur between the ages of 10 and 40 years. They are rare before puberty. The severity of acute attacks varies from mild abdominal pain, sometimes accompanied by vomiting and constipation, through to very severe attacks with bulbar palsy and respiratory paralysis. Severe, constant abdominal pain occurs in almost all acute attacks. It can be in any quadrant or even in the back, buttocks and thighs, and may require large amounts of opiate analgesia. There may be guarding but no true peritonism. Vomiting and constipation (due to partial ileus) occur in at least half of attacks. The pulse rate and blood pressure are often moderately raised, dehydration is common and hyponatraemia (probably caused by inappropriate secretion of vasopressin) may be severe enough to cause convulsions. The pain, tachycardia, hypertension and partial ileus are all caused by an acute autonomic neuropathy. Sensory or sympathetic involvement, manifest as severe dysaesthesia or causalgia, is rarer. A motor neuropathy occurs in 5–10% of cases, usually heralded by aching pains in the limbs and sometimes by disappearance of the abdominal pain. It may cause a severe acute Guillain–Barré-type syndrome. The motor neuropathy usually occurs when porphyrinogenic drugs have been administered inadvertently during the developing acute attack. Respiratory paralysis is the commonest cause of death. Confusion, abnormal behaviour, agitation and hallucinations occur in up to 50% of attacks. Porphyria is not related to any chronic psychiatric disease, except generalized anxiety.

Biochemical diagnosis of an acute attack [8, 9]

The diagnostic finding is of increased urinary PBG excretion. Although qualitative screening tests may be useful in an emergency, their low sensitivity makes it essential to also carry out a quantitative assay. Commercially available kits can provide a rapid and reasonably sensitive semiquantitative assay, after which a specific quantitative assay should be carried out (reliable quantitative assay kits are commercially available). A normal urinary PBG concentration excludes an acute porphyric attack (except in ALA dehydratase porphyria). An increased PBG concentration does not necessarily mean that an acute attack is occurring since urinary PBG falls between attacks but does not always return to normal, particularly in AIP. The higher the PBG concentration, the more likely an acute attack, but, in the presence of an increased urinary PBG, an acute attack can only be diagnosed on clinical grounds. Urinary ALA is also increased during an acute attack but to a lesser extent than PBG and is not as useful diagnostically (the only exception being ALA dehydratase porphyria in which only ALA is increased and urinary PBG is normal).

Long-term management of patients with acute porphyria [1, 2]

The dermatologist may diagnose VP (or less commonly HC) on the basis of cutaneous disease before any acute attack has occurred. Once an acute porphyria has been diagnosed, the patient should be given a list of drugs with information about their safety in acute porphyria. Many lists exist both of ‘safe’ drugs and ‘unsafe’ drugs [6, 7]. It is obviously vital for clinicians and patients to be clear about whether they are dealing with a list of ‘safe’ or ‘unsafe’ drugs, and there are advantages to using a ‘safe’ list, as discussed above. It is important to recognize that a list of safe drugs is a guide, and that no drug can be guaranteed to be safe in an individual patient. Conversely, drugs which do not appear on a safe list should not be withheld in patients who need them to treat a serious or life-threatening illness; in that situation expert advice should be sought from a specialist centre.

The patient should also be advised to abstain from alcohol, cannabis and prolonged calorie-restricted diets, and to wear an emergency identification bracelet (e.g. MedicAlert) so that medical staff are aware of the diagnosis if the patient is ever found in an unconscious or confused state. Screening of relatives is essential to identify those with clinically latent disease, who are also at risk of acute attacks. The choice of test and interpretation of results can be complex and details are covered in the laboratory testing section and under each individual disorder in this chapter. Such testing is ideally carried out in a specialist centre. Relatives diagnosed with an acute porphyria need the same advice as the index case. Conversely, patients with PCT, EPP and CEP can be reassured that acute attacks are not part of their disease.

Treatment of the acute attack [1, 2]

The key to managing an acute attack is early diagnosis. Once the diagnosis has been made, avoidance of acute attack-inducing drugs is essential to prevent exacerbation. Supportive treatment includes analgesia, sedatives and antiemetics (in each case using drugs known to be safe in acute porphyria) and careful management of fluid balance with rehydration and correction of hyponatraemia. The specific treatments are intravenous haematin or haem arginate (Normosang, Orphan Pharmaceuticals), which have now replaced carbohydrate as the treatment of choice. These drugs suppress hepatic ALA synthase activity and so reduce ALA and PBG accumulation. Haem arginate is more effective when given earlier during an attack, increasing the importance of early diagnosis. Advice from a specialist centre should be sought when treating an acute attack.

Clinician's guide to laboratory testing in porphyria [1–3]

Although clinical features may raise the possibility of a porphyria, the cutaneous presentations of several porphyrias are very similar. Precise diagnosis is essential in porphyria because of the great differences in clinical management between porphyrias that can be clinically indistinguishable. An accurate diagnosis can only be made on the basis of porphyrin analyses carried out in an experienced laboratory. The clinician's role is to suspect the diagnosis of cutaneous porphyria, and then to use laboratory testing to confirm whether this is the diagnosis, and if so to precisely identify the porphyria. For any porphyria characterized by acute attacks, testing for latent porphyria in relatives will then be necessary.

What samples to send

In an adult with suspected bullous porphyria, it is generally sufficient to analyse the urine and either plasma (where fluorimetry is available) or faeces (where it is not). However, urine, plasma and faeces all need to be analysed in children because of the increased complexity of the differential diagnosis. Faecal analysis is also necessary in instances when urine and plasma results do not differentiate HC from CEP, and in renal failure, where urine may be unavailable and plasma analysis unhelpful because renal failure increases plasma porphyrins. In suspected EPP, red cells and either plasma or faeces should be analysed.

Handling of samples

Laboratory testing of body fluids measures porphyrins since porphyrinogens are spontaneously oxidized to their respective porphyrins outside the body. PBG has a tendency to polymerize to other molecules but porphyrins are reasonably stable when protected from light and oxidants. Thus, all specimens should be kept at room temperature or at 4°C in the dark and ideally should be analysed within 48 h of collection.

For urine and faecal analysis, fresh random specimens (10–20 mL urine or 5–10 g dry weight faeces) are preferable to 24 h collections. Random specimens yield equally useful results, and 24 h collections delay samples reaching the laboratory. Very dilute urine (creatinine <4 mmol/L) is unsuitable.

Laboratory analysis of porphyrins

Old-fashioned qualitative screening methods for detecting porphyrins in specimens (often involving a Wood's light) are insensitive, and negative results from such tests are not of value. Whether testing urine, faeces, red cells or whole blood, quantitative screening using spectrophotometric or fluorimetric techniques is necessary and yields results as a total porphyrin concentration. Whole blood or red cell porphyrin testing measures both the total and free protoporphyrin concentrations. Plasma is analysed by fluorimetric scanning – a diagnostically powerful and simple qualitative technique. In urine and faeces, the finding of an increased porphyrin concentration will lead on to high-performance liquid chromatography (HPLC), which can be used to rapidly identify the accumulated porphyrins (Figure 60.6). For PBG measurement in urine, qualitative tests are insensitive, and quantitative measurement, usually using a kit, is required. Semiquantitative test kits are useful in emergencies where a result is needed quickly.

Interpretation of results [4]

In cutaneous porphyrias, the accumulated porphyrin can usually be detected in plasma as an emission peak on spectrofluorimetry (Table 60.1). Uro- and coproporphyrin are excreted into the urine and copro- and protoporphyrin into the faeces. Protoporphyrin accumulates in red cells in EPP.

Plasma spectrofluorimetry. In plasma spectrofluorimetry, the sample is excited by 410 nm light, and fluorescent emissions detected. An emission peak at 615–620 nm indicates the presence of uro- or coproporphyrin and suggests a diagnosis of PCT, HC, CEP or HEP (urine analysis will differentiate PCT and HEP from the other two conditions). A peak at 624–626 nm indicates the presence of a porphyrin–peptide conjugate diagnostic of VP. This 624–626 nm peak is a sensitive indicator of VP and may even persist during periods of clinical remission when faecal excretion becomes normal. It is also positive in most cases of latent VP (in relatives) [5, 6]. A peak around 633 nm (it can lie between 626 and 634 nm) is caused by protoporphyrin and suggests EPP, and EPP is an unlikely diagnosis in the absence of this peak. Plasma porphyrin concentrations, particularly uroporphyrin, increase in renal failure and can be as high as those found in patients with PCT.
Whole blood/red cell. An increased free protoporphyrin concentration is the diagnostic finding in EPP. The total protoporphyrin concentration includes both free and zinc-protoporphyrin. Zinc-protoporphyrin is also increased in iron deficiency, lead poisoning and certain anaemias. In a child with plasma, urine and faecal results typical of PCT, red cell UROD activity needs to be measured to exclude hepatoerythropoietic porphyria (HEP).
Urinary and faecal analysis. An increased total porphyrin concentration suggests a diagnosis of cutaneous porphyria. The total urinary porphyrin concentration is used to monitor disease activity in PCT. HPLC analysis is used to identify the porphyrins once an increased concentration has been found.
- In urine. An increase in uroporphyrin (and other highly carboxylated porphyrins especially heptacarboxyporphyrin) is typical of PCT though this does not exclude VP. Plasma spectrofluorimetry differentiates these two conditions and faecal analysis is required where this is unavailable. When PCT goes into remission and the total urinary porphyrin concentration returns to normal, it may still be possible to diagnose PCT from the characteristic urinary HPLC pattern. Coproporphyrinuria, in the presence of normal faecal porphyrin levels, does not indicate porphyria and can be caused by certain drugs, lead toxicity and hepatobiliary disease.
- In urine and faeces. Increased coproporphyrin suggests VP, but does not exclude HC. Isomer III to isomer I ratios are increased in every porphyria except CEP (where they are decreased). In CEP, excess type I isomers of uro- and coproporphyrin are present in urine and type I coproporphyrin in faeces.
- In faeces. In the presence of a plasma spectrofluorimetry peak at 615–620 nm, if urine HPLC does not show the PCT pattern, faecal analysis is required to differentiate HC (increased coproporphyrin III concentration) from CEP (increased coproporphyrin I concentration). Increased faecal isocoproporphyrin is characteristic of PCT. In renal failure, faecal analysis is vital since urine may be unavailable and plasma porphyrins are increased (PCT is the porphyria most commonly associated with renal failure). Increased faecal protoporphyrin is suggestive but not diagnostic of EPP, since it can also derive from bacterial degradation of haem in the gut and may indicate gastrointestinal haemorrhage when porphyrin concentrations are normal elsewhere.

Table 60.1 The major biochemical findings in the cutaneous porphyrias.

	Urine	Faeces	Red cell	Plasma fluorimetry
Congenital erythropoietic porphyria	Uroporphyrin I; coproporphyrin I	Coproporphyrin I	Zinc- and free protoporphyrin; uroporphyrin I; coproporphyrin I	Peak at 615–620 nm
Porphyria cutanea tarda	Uroporphyrin III; heptacarboxy-porphyrin	Isocoproporphyrin; heptacarboxy-porphyrin	Normal	Peak at 615–620 nm
Hereditary coproporphyria	Coproporphyrin III	Coproporphyrin III	Normal	Peak at 615–620 nm
Variegate porphyria	Coproporphyrin III	Protoporphyrin; coproporphyrin III; X-porphyrin	Normal	Peak at 624–627 nm
Erythropoietic protoporphyria	Normal	Protoporphyrin (not diagnostically helpful)	Free protoporphyrin	Peak at 626–634 nm

Adapted from Deacon and Elder 2001 [4].

Biochemical diagnosis of an acute attack of porphyria [3, 4]

This is discussed earlier in this chapter. A definitive diagnosis of VP or HC can usually be made on the basis of detailed porphyrin analysis. A definitive diagnosis of AIP requires enzyme or genetic tests.

Screening of relatives

In VP and HC, porphyrin levels are normal before puberty. Over the age of 15 years, a plasma fluorimetry scan is a reasonably sensitive biochemical test for latent VP in asymptomatic relatives of patients, picking up most cases. A positive scan is diagnostic of latent VP but a negative result is uninformative [5, 6]. Faecal analysis, to measure the ratio of coproporphyrin isomers, will pick up some cases of latent HC after puberty [7]. In VP and HC, a negative porphyrin screening test in a relative needs to be followed by DNA analysis before latent disease can be excluded. The lack of any common mutations in porphyria (apart from South African VP) means that the causative mutation usually has to be identified for each family.

INDIVIDUAL PORPHYRIAS

PORPHYRIAS THAT CAUSE CUTANEOUS DISEASE BUT DO NOT CAUSE ACUTE ATTACKS

Congenital erythropoietic porphyria

Definition and nomenclature

This is a severe and rare childhood porphyria causing lifelong mutilating photosensitivity and haematological disease.

Introduction, epidemiology and pathophysiology

Congenital erythropoietic porphyria (CEP) is caused by an autosomal recessive inherited deficiency of the uroporphyrinogen III cosynthase enzyme. Since this enzyme is required to form the biologically useful type III porphyrin isomers, its absence results in non-enzymatic reactions producing large amounts of type I isomer porphyrins which cannot participate in haem formation, and which massively accumulate in erythroid cells and then gradually leak into the plasma.

It is a rare disease: the incidence in Europe is 0.007 per year per 10 million population [1], and roughly 200 cases have ever been reported worldwide. Rare adult-onset cases of acquired CEP have been reported secondary to myelodysplasia [2].

Clinical features [3–5]

Presentation

CEP has a wide spectrum of presentation, from hydrops fetalis through to severe disease starting in infancy and also mild forms presenting later in life. The first sign of CEP is often the child's mother noting brown discoloration of amniotic fluid at the onset of labour, or observing pink or brown porphyrin staining of nappies (which fluoresce red-orange under Wood's light).

Severe photosensitivity begins in infancy, often in the neonatal period, with blisters developing in light-exposed skin on minimal light exposure [3–5]. Phototherapy for neonatal jaundice may trigger lesions. Most children are so sensitive to the light that they have problems throughout the year. Exposed (and sometimes non-exposed) skin is fragile. The repeated bouts of inflammation with vesicles and bullae, often complicated by secondary infection, cause mutilating scarring, particularly of the face and hands (Figure 60.7). This photomutilation is associated with erosion of the terminal phalanges, onycholysis and destructive changes affecting the pinnae and nose. A diffuse pseudosclerodermatous thickening of exposed skin often gradually develops, with microstomia and sclerodactyly-like changes. Hypertrichosis is found in most patients, particularly on the upper arms, temples and malar region. Patchy hypo- and hyperpigmentation occur even in minimally exposed areas.

A milder late onset form, presenting at any age from the third decade onward, has been described; this presents in a manner similar to PCT, and occurs either as a result of mild inherited gene mutations [6] or as an acquired disease secondary to bone marrow myelodysplasia [2].

The eyes and internal organs are frequently involved [4, 5].

Eyes. Keratoconjunctivitis, blepharitis, cataracts, corneal ulcers, scars, cicatricial ectropion and scarring alopecia of eyelashes and eyebrows may all occur. Scleromalacia, pterygium formation, optic atrophy, retinal haemorrhage and scleral necrosis are less common.
Bones and teeth. When teeth emerge, they are almost always stained brown (and fluoresce under Wood's light). Decreased bone density, osteopenia and osteolytic lesions secondary to erosion by hyperplastic bone marrow are seen on X-ray and are associated with vertebral compression and collapse, and with pathological fractures. In the hands there is resorption of terminal phalanges with acro-osteolysis and cortical bone rarefaction. Occasionally, strict avoidance of the sun may impair vitamin D metabolism.
Haematology [4, 5]. The high concentrations of porphyrins in red cells cause haemolytic anaemia, severe enough to induce marrow hyperplasia often with visible expansion of the maxillary bones in the face. Hypersplenism is common. The haemolysis can be fully compensated or may cause a severe anaemia, and is occasionally so severe that some patients become transfusion dependent. The severity of the anaemia often fluctuates strikingly over time. Very severe haemolytic anaemia may even cause hydrops fetalis. Bone marrow examination reveals normoblastic hyperplasia. Under violet illumination most normoblasts have persistent red fluorescence localized to their nuclei, with haem-containing inclusion bodies being seen in the nuclei of these fluorescent cells.

Differential diagnosis

The photosensitivity differentiates CEP from other scarring, blistering disorders of childhood, including epidermolysis bullosa dystrophica. The cutaneous changes may resemble HEP (the homozygous form of familial PCT) or homozygous VP. The cutaneous disease in late-onset CEP is clinically indistinguishable from PCT or VP.

Disease course and prognosis

In the past, most patients died by the age of 40 years but improvements in supportive care (particularly use of antibiotics) have improved the prognosis, though the haematological complications may be fatal [7]. Long-term hypertransfusion causes significant problems with iron overload as patients reach adulthood, even when iron chelation has been used. Bone marrow transplantation now holds out the promise of cure for these patients (see below). The key markers of poor prognosis in CEP are early onset of disease (especially in the first year of life) and significant haematological involvement [7].

Investigations

The uroporphyrinogen III cosynthase enzyme deficiency results in the massive accumulation in all tissues of type I isomers of porphyrins, mainly uroporphyrin, along with coproporphyrin and smaller amounts of 7-, 6- and 5-carboxylic acid porphyrins [3]. Red cells and urine contain large amounts of uro- and coproporphyrin (mainly type I) and faeces contain increased concentrations of coproporphyrin (mainly type I). A plasma spectrofluorimetry peak is seen at 615–620 nm. The absence of isocoproporphyrins and the normal level of 5-carboxylic porphyrin excretion in faeces distinguish CEP from HEP.

Management [7]

Treatment

The photosensitivity is so severe that photoprotection is crucial. Sun avoidance and use of sun protective clothing and hats are essential. Opaque sunscreens containing pigmentary grade titanium dioxide or zinc oxide, possibly with added iron oxide, may be of limited value [8, 9], and amber window films on home or car windows can reduce exposure to Soret wavelength light (TA81XSR, Madico, USA) [10], though more opaque films may be necessary (which are obviously not allowed on car windows).

Prompt treatment of secondary infection is important. Many therapies reduce the porphyrin concentrations by suppressing erythropoiesis. Hypertransfusion with regular blood transfusions to maintain a polycythaemia inhibits endogenous haemoglobin production and decreases porphyrin formation, and may reduce haemolysis and cutaneous symptoms in moderately affected patients. However, splenomegaly may increase transfusion requirements and the value of hypertransfusion often decreases at puberty [6]. Hypertransfusion is frequently complicated by iron overload, even when desferrioxamine has been used, and blood-borne infections can be a complication. Intravenous haematin has been tried in late-onset disease [11]. Haemolysis worsens the porphyria by causing anaemia and usually necessitates blood transfusion. Splenectomy may reduce haemolysis though the improvement may be temporary. Lights during surgical procedures may cause phototoxic reactions and filters should be used over the operation lights during any unavoidable surgery, preferably a yellow filter (e.g. Madico TA81XSR). Overall, the results from all systemic therapies in CEP are disappointing [7] and the mainstay of treatment is strict photoprotection and treatment of haemolytic anaemia by hypertransfusion.

Since 1991, allogeneic bone marrow transplantation (bone marrow or umbilical cord blood stem cells) from an HLA-compatible donor has emerged as the treatment of choice in severe CEP. It provides a long-term cure [7, 12] though the difficulties of finding a tissue-matched donor, and the dangers of marrow transplantation, mean that it should be reserved for the most severely affected patients and in children with markers of poor prognosis [4, 7]. Gene therapy has been successfully used in vitro, but no in vivo studies have been carried out yet [13].

Genetic counselling

Since CEP is autosomal recessive, parents will be unaware of the risk until an affected child has been born, and the risk of disease is in further offspring rather than subsequent generations. For parents of an affected child, the chance of each future offspring suffering from the disease is 25%. The diagnosis may be made before birth by measuring the uroporphyrin I concentration in amniotic fluid, which is increased as early as 16 weeks in utero. If the mutations in the index case have been identified, or the fetus is homozygous for the common C73R mutation, prenatal diagnosis from chorionic villous biopsy is possible [14].

Porphyria cutanea tarda

Definition

Porphyria cutanea tarda (PCT) is the commonest of all the porphyrias [1, 2]. It is characterized by fragility and blistering of exposed skin. It is usually acquired and is often associated with liver disease. It does not cause acute attacks.

Introduction, epidemiology and pathophysioloogy

Porphyria cutanea tarda results from deficiency of UROD [3]. This causes an accumulation of uroporphyrin and other highly carboxylated porphyrins. Seventy-five per cent of patients have the type I (sporadic) form in which the enzyme deficiency is acquired and restricted to hepatocytes, due to inhibition of a normal UROD enzyme [3]. Twenty-five per cent have type II (familial) disease where the enzyme deficiency is hereditary, present in all tissues and associated with a UROD gene mutation. The penetrance of this autosomal dominant inherited form is so low that a family history is present in under 7% of cases, and since at least a 75% reduction in enzyme activity is required for clinical expression, some enzyme inhibition in the liver also occurs in familial PCT. Thus, UROD mutations are increasingly thought of as a risk factor for the development of PCT, rather than as representing a completely separate familial form of the disease. Type III disease is rare and characterized by a hereditary enzyme deficiency localized to the liver. Toxic porphyria, in which halogenated aromatic hydrocarbons inhibit the enzyme, is rare and mainly affects workers making herbicides [4]. A major epidemic of toxic porphyria in the 1950s in Turkey was caused by hexachlorobenzene added as a fungicide to seed wheat [5].

In PCT, the UROD enzyme is inactivated by uroporphomethene, a competitive inhibitor of UROD, which is formed by the oxidation of uroporphyrinogen [6]. The inhibitor is generated in the liver by reactive oxygen species in the presence of iron (Figure 60.8) [7]. The accumulated uroporphyrin diffuses from the plasma into the surrounding tissues, causing a phototoxic reaction in the upper dermis in sun-exposed skin. This leads to lysis of cells in the superficial dermis with the formation of membrane-limited vacuoles which merge to produce a blister cavity under the basal lamina [8].

The prevalence varies but in most countries is around 1 in 10 000 [2].

Clinical features [9]

Presentation

Sporadic PCT usually presents in middle age whilst the familial form can occur at a younger age. Almost all patients notice increased fragility on light-exposed skin, particularly the backs of the hands and forearms, with minor trauma shearing the skin away to leave sharply marginated erosions (Figure 60.9). Most patients suffer from bullae, which can be over 1 cm in diameter and may be painful. They crust and resolve over a few weeks, leaving atrophic scars, milia and often mottled hyper- or hypopigmentation. Patients rarely associate the development of new lesions with sun exposure, but symptoms are generally worse in the summer. Other common features are: patches of scarring alopecia following resolution of bullae on the scalp; hypertrichosis, usually on the upper face and forehead, sometimes on the ears or arms [10] and occasionally affecting the whole body; and hyperpigmentation in a melasma-like pattern on the cheeks and around the eyes, or in a diffuse pattern on light-exposed skin, or occasionally in a reticulate distribution [9, 10]. Photo-induced onycholysis [11] and accelerated solar elastosis [10] may also occur. Morphoea-like plaques may develop, particularly on the head and upper trunk. They are histologically indistinguishable from true scleroderma and mainly occur in longstanding untreated disease. It has been postulated that they arise as a result of the induction of collagen synthesis by uroporphyrin I [12]. These plaques may calcify, and may require excision and grafting if they ulcerate [13].

On the scalp, the morphoea-like change may cause a slowly expanding scarring alopecia starting in the frontoparietal and occipital areas [9, 10, 14]. Even sclerodactyly or the facial changes of systemic sclerosis have been reported. Rare presentations of PCT include cicatricial conjunctivitis [15] and hair darkening [16].

Clinical variants

The homozygous form of familial PCT, hepatoerythropoietic porphyria (HEP), is associated with over 90% reduction in UROD activity [10, 17]. It usually causes a severe disease clinically similar to CEP, with photosensitivity during infancy causing immediate pain on sun exposure, blisters on sun-exposed skin and mutilating scarring of the face and fingers. Prominent hypertrichosis, fluorescent teeth, eye involvement and shortened distal phalanges also occur. Haemolysis is milder than in CEP, and life expectancy is normal. HEP can occasionally present with a milder disease similar to PCT. Since the mutated alleles in HEP have to be associated with some residual enzyme activity to be compatible with life, the UROD gene mutations in HEP patients are different to those found in type II PCT [18].

Differential diagnosis

Porphyria cutanea tarda can be clinically indistinguishable from VP, drug-induced pseudoporphyria, renal pseudoporphyria, HC, late-onset Günther disease or mild HEP. Biochemical analysis is necessary to diagnose PCT, and it is particularly important to exclude VP and HC among the differential diagnoses since they can cause acute attacks.

Investigations

Porphyria cutanea tarda is essentially a liver disorder with secondary effects in the skin. It is crucial to investigate patients thoroughly both regarding other systemic diseases predisposing to the development of PCT, and in order to assess the severity of any liver disease.

Biochemical findings [2]

In PCT, the urinary porphyrin concentration is increased, consisting mainly of uroporphyrin, some heptacarboxylic acid porphyrin, and sometimes also hexa- and pentacarboxylic acid porphyrins. A plasma spectrofluorimetry peak is seen at 615–620 nm. Isocoproporphyrin accumulates in the faeces. Urine analysis alone is insufficient to diagnose PCT, since a few patients with VP have the PCT urine pattern (‘dual porphyria’) [19]. In patients with renal failure, faecal analysis is essential, since plasma porphyrins are increased by haemodialysis and urine collection may not be possible. The biochemical marker of disease activity and response to treatment is quantitative urinary porphyrin excretion measured in a random urine sample. In HEP, the findings are as in PCT, but with the additional finding of a raised red cell zinc-protoporphyrin, and lower red cell UROD activity than occurs in type II PCT.

Histopathology [20]

The bullae in PCT are subepidermal with a sparse inflammatory infiltrate and ‘festooning’ of dermal papillae into the bullae. There is deposition of PAS-positive diastase-resistant fibrillar glycoprotein material in and around the upper dermal blood vessel walls, and reduplication of the basement membrane. Immunofluorescence reveals IgG, a little IgM, fibrinogen and complement at the epidermal–dermal junction. Morphoea-like lesions in PCT are histologically indistinguishable from other forms of morphoea.

Risk factors for the development of PCT

The major risk factors for developing PCT are subclinical genetic haemochromatosis, hepatitis C infection, alcohol and oestrogens [21]. They all predispose to the inhibition of the UROD enzyme in the liver. Since some inhibition of the hepatic enzyme is also required for clinical expression of familial PCT, the same risk factors apply to sporadic and familial PCT. Since most of the risk factors have significant implications both for treatment and for the patient's general health, it is essential to investigate for risk factors in all patients diagnosed with PCT.

Haemochromatosis: As expected in a disorder where hepatic iron plays a key role, almost all patients have increased stainable iron in the liver, and total body iron stores are increased in at least 60% of patients [2, 21, 22]. In the USA and northern Europe, around 20% of PCT patients have true hereditary haemochromatosis [21, 23] with homozygosity for the Cys282Tyr haemochromatosis mutation. Homozygosity for this mutation increases the risk of developing PCT 60-fold [21]. The clinical relevance of heterozygosity for the mutation is unclear. In southern Europe, haemochromatosis is a less important risk factor. The iron overload found in PCT patients who do not have haemochromatosis is milder, and its cause obscure.
Hepatitis C infection: In southern Europe, 70–90% of all PCT patients are infected with the hepatitis C virus [24, 25], compared with around 60% of patients in the USA [21] and 7–36% in northern Europe [26, 27].
Alcohol: Between 30% and 90% of PCT patients consume over 40 g of alcohol daily, and 2% of all alcoholics with cirrhosis develop PCT [7].
Oestrogens: Ingested oestrogens, in the oral contraceptive pill or in hormone replacement therapy, are the sole risk factor in over a quarter of female patients [21]. Stopping the hormone may be sufficient to induce remission if the duration of therapy has been short [28]. If it is not possible to stop the hormone therapy, transdermal drug delivery is a safer alternative than the oral route [29].

There are other less common risk factors for developing PCT. Haemodialysis predisposes to PCT [11], though PCT is less common in renal failure than pseudoporphyria – faecal porphyrin analysis differentiates these disorders. Human immunodeficiency virus (HIV) infection predisposes to PCT [30], an association which may be due to co-infection with the hepatitis C virus [31]. Non-insulin-dependent diabetes, systemic lupus erythematosus, dermatomyositis, hepatitis A and B infection, haematological malignancy, sideroblastic anaemia, thalassaemia and the drug tamoxifen have also all been reported to be associated with PCT [2, 10, 32, 33].

Most patients possess more than one risk factor for developing PCT, with hepatitis C infection and alcohol being strongly linked in men.

Liver disease in PCT

Since PCT is primarily a liver disorder with secondary effects in the skin, liver disease is a major concern [22]. In almost all cases, liver biopsy reveals increased stainable iron, fatty change and intracellular porphyrin crystals. Fifty per cent of patients have more severe changes (lobular necrosis or inflamed fibrotic portal tracts), and cirrhosis occurs in 15% [22]. As one would expect, the most severe liver disease tends to occur in patients who have alcoholism, hepatitis C infection and iron overload [21]. The accumulated porphyrins are carcinogenic to the liver, so PCT confers an additional risk for developing hepatocellular carcinoma on top of the risk conferred by the hepatitis C infection present in many patients [34]. In southern Europe around 3% of PCT patients develop hepatocellular carcinoma during the decade after presentation [35], though the incidence of hepatic malignancy is probably lower than this in countries with lower hepatitis C infection rates. Risk factors for developing hepatocellular carcinoma are thought to be a symptomatic period longer than 10 years prior to treatment, severe changes on hepatic histology at presentation, hepatitis C infection, male sex and age over 50 years at presentation [36, 37]. The converse situation, where a primary hepatic tumour secretes porphyrins to cause a PCT-like skin disease, is rare [38]. Hepatic function must be assessed at presentation in all PCT patients, and patients at high risk of hepatic malignancy require regular ultrasounds and serum α-fetoprotein measurement to detect carcinoma at a treatable stage [36]. PCT should be managed as a liver disorder, and the threshold for referral to a hepatologist should be low.

Management

Photoprotection

Visible light sunscreens containing pigmentary grade titanium dioxide or zinc oxide, sometimes with added iron oxide [39, 40], filter films for car and home windows, gloves, hats and clothes play an important role in controlling symptoms during the period of several months before specific therapies take effect.

Elimination of risk factors

Stopping oestrogen therapy [28], if it has not been used for more than 2 years, can induce remission. However, elimination of the underlying cause by abstaining from alcohol, or by treating hepatitis C with interferon α [41], does not always induce remission. All patients should be advised to abstain from alcohol or oestrogen therapy to prevent exacerbation of the disease.

Specific treatments

Definitive treatment with venesection or low-dose antimalarials is required in almost all cases. Venesection depletes iron stores and eliminates hepatic iron overload, thus restoring normal enzyme activity. Around 500 mL of blood is removed every week or every 2 weeks, aiming to decrease transferrin saturation to 15%, haemoglobin to 11–12 g/dL and plasma ferritin to below 25 μg/L [42, 43]. Blistering usually resolves within 2–3 months, skin fragility within 6–9 months [44], and porphyrin concentrations generally normalize within 13 months or so [10], at which point treatment should be stopped. Hypertrichosis [10] and sclerodermoid lesions [15] respond more slowly during the years after treatment has stopped. Excision and grafting may be needed for ulcerated sclerodermoid lesions [10]. Desferrioxamine leads to earlier remission than venesection because it rapidly chelates hepatic iron, and it may be of value in PCT with renal failure but it is expensive and requires the use of a subcutaneous pump at night [45, 46]. Erythropoietin mobilizes hepatic iron into haemoglobin and is the treatment of choice for PCT in renal failure where patients are too anaemic for venesection and cannot excrete chloroquine [47]. Low-dose antimalarials are a very effective treatment for PCT. They work by complexing with uroporphyrin and promoting its excretion into the bile [48]. Daily doses of chloroquine cause a potentially dangerous acute hepatitis, but chloroquine at the low dose of 125 mg [49, 50] or 250 mg [51, 52] taken twice a week is safe and effective. It leads to clinical remission within 6 months or so and biochemical remission after 6–15 months, at which point treatment is stopped [49–52]. Retinopathy does not seem to occur with such low doses of chloroquine [51]. Hydroxychloroquine (100 mg twice weekly) is also effective [53].

Low-dose chloroquine is the treatment of choice except in the following situations, in which venesection is preferable: (i) patients who do not respond to chloroquine; (ii) patients with a pathologically high serum ferritin concentration or homozygous for the Cys282Tyr mutation (if genetic analysis is available), who require iron depletion to protect internal organs; and (iii) patients with significant hepatitis C liver disease, who require iron depletion since hepatic siderosis increases their virally induced liver damage [54] and reduces the effectiveness of interferon [55]. Anyway, chloroquine is usually less effective in patients with haemochromatosis [56]. However, chloroquine is not contraindicated in these situations, and may be needed when venesection is not possible, particularly in patients with hepatitis C liver disease where venous access is impaired by previous intravenous drug abuse. Remission with low-dose chloroquine generally lasts 17–24 months [49, 50]. With venesection, relapse generally occurs around 2.5 years after the end of treatment [9, 48]. Long-term follow-up is necessary for all patients to monitor for relapse (by measuring urinary porphyrin excretion) and for the management of coexisting liver disease.

Genetic counselling [57]

Familial and sporadic PCT can be differentiated by measuring red cell UROD activity. Since additional inhibition of the hepatic enzyme is required for clinical expression of disease in familial PCT, UROD mutations can be considered as a risk factor for developing the disease rather than as a different form of PCT. In view of the identical management of sporadic and familial PCT, the lack of evidence that identifying latent PCT in relatives alters outcomes, and the very low penetrance of familial PCT, it is difficult to justify family screening in familial PCT. It is therefore of little value to measure red cell UROD activity unless one is trying to differentiate HEP from PCT.

Erythropoietic protoporphyria

Definition

Erythropoietic protoporphyria (EPP) is a hereditary porphyria characterized by painful, lifelong photosensitivity and occasionally liver disease.

Introduction, epidemiology and pathophysiology

The incidence of EPP in Europe varies between countries (from 0.03 new cases/million per year in Spain to 0.36 in the UK) [1].

EPP usually results from deficient activity of ferrochelatase, the final enzyme of haem biosynthesis. In a minority of cases it is caused by gain-of-function mutations in ALAS-2 (the first enzyme in the pathway) [2]. This causes the accumulation of protoporphyrin predominantly in cells of the erythroid series, which causes a phototoxic reaction as the porphyrin-laden cells pass through the small upper dermal blood vessels and are exposed to the Soret wavelength in sunlight. The photoactivated porphyrin from red cells and plasma causes an acute injury to the endothelium mediated by singlet oxygen and the hydroxyl radical [3, 4]. Many ferrochelatase gene mutations have been identified in EPP patients and none are particularly common [5]. A few adult-onset cases have been reported that are associated with haematological malignancy and may be associated with chromosomal deletions involving the ferrochelatase gene [6].

Clinical features [7, 8]

Unlike the other cutaneous porphyrias, EPP causes immediate pain on exposure to bright sunlight. It presents most commonly in the first year, quite often in babies who usually present with crying in their prams in sunny weather, or crying for no obvious reason at night in the summer. Onset later in childhood does occur but onset in adulthood is rare. In spring and summer, after anything from a few minutes to an hour or two of sun exposure, patients describe discomfort, tingling or itching in exposed skin, particularly the dorsae of the hands and the face. If exposure continues, severe burning pain follows which can last anything between an hour and several days. Children often find partial relief with cold water and wet cloths, and this feature may be diagnostically useful. Usually the only physical sign during an attack is oedema, which may be subtle (Figure 60.10). Erythema is less common. The lack of physical signs often leads to delay in diagnosis, with some patients initially being labelled as malingerers.

Many patients experience a ‘priming phenomenon’ in which sunlight tolerance is reduced on the day after significant sun exposure [9]. In severe attacks, purpuric lesions and crusted erosions or vesicles may occur; these take a week or two to resolve after the attack settles down, and the pain may be severe enough to require hospital admission. Rare cases of EPP with prominent purpura and histological changes resembling a leukocytoclastic vasculitis [10], acute photo-onycholysis [11] or erythematous plaques [12] have been described. Physical signs may develop during childhood, with slight thickening of skin over the metacarpophalangeal and interphalangeal joints, superficial vermicular waxy scarring on the nose, shallow linear, punctate or small circular scars on the cheeks and forehead and radial scars around the lips (Figure 60.11). The skin over the nose, cheeks and forehead can become roughened and ‘pebbly’ in texture. Fifteen per cent of patients have no physical signs at all [7].

Mild variants of EPP may cause diagnostic confusion because of delayed onset of symptoms, shortened duration of attacks, and occasionally absence of pain. Oedema and predilection of the reaction to the face and dorsal hands and feet are diagnostic clues. There is an occasional association between EPP and a seasonal palmar keratoderma. The keratoderma is more commonly seen in autosomal recessive EPP [13].

Children with EPP suffer from social isolation due to difficulty joining friends to play outside, and sensitivity to psychosocial issues is important for clinicians. Although EPP is lifelong, childhood and adolescence are frequently the most difficult times because it is easier for adults to organize their lives to reduce sun exposure, but it is not surprising that the disease has such a profound impact on quality of life [7].

Symptoms often improve and porphyrin levels fall during pregnancy [7, 14]. Patients may develop a mild hypochromic microcytic or normocytic anaemia, which can be associated with decreased serum iron levels and increased serum iron binding capacity [8].

With the exception of patients with EPP liver failure, operating theatre lights do not cause any problems during or after surgery in EPP patients [15]. Anaesthetists can also be reassured that acute attacks do not occur in EPP. In contrast, operating theatre lights can cause a devastating and potentially fatal phototoxic reaction in patients undergoing liver transplantation for protoporphyric liver failure.

Vitamin D deficiency associated with osteoporosis is common in EPP and vitamin D levels need to be monitored and supplemented as required [16, 17].

Investigations

Biochemical investigation [18]

The diagnostic finding is of an increased red cell-free protoporphyrin concentration. Protoporphyrin is seen as a peak at 633 nm on plasma fluorimetric scanning. Sixty per cent of EPP patients have an increased faecal protoporphyrin concentration, though this is not very useful diagnostically because of its lack of specificity. Urinary porphyrins are normal except in biliary impairment, when coproporphyrinuria develops. Umbilical cord protoporphyrin concentration is not a useful test to identify EPP in newborns [19].

Histopathology [20, 21]

In the acute phase there is visible endothelial damage in superficial dermal vessels [22]. In the chronic phase, in exposed areas of skin, the repeated episodes of damage to small vessels in the upper dermis cause deposition of PAS-positive diastase-resistant hyaline material in the walls of blood vessels of the upper dermal and papillary vascular plexuses. Immunofluorescence shows immunoglobulins (mainly IgG) in a similar distribution. On electron microscopy the hyaline material can be seen to be a greatly replicated, layered and fragmented basement membrane, with fine fibrillar material permeating the capillary connective tissue sheath and extending beyond the vessel walls [20, 23].

Management [7]

No therapy has ever been proven to be effective in EPP mainly because of the lack of an objective test for disease activity in EPP, and high placebo rates make useful clinical trials difficult. This author's experience is that results with the specific therapies are generally fairly disappointing, and that attention to sunlight protection is the key to management.

Photoprotection

Basic measures include sun avoidance behaviour, sun protective clothing and hats. It is important to use correct sunscreens [24, 25]. Dihydroxyacetone paint has been used in some patients with EPP [26], and window films, which absorb violet light, can be useful for car or home windows, particularly in severely affected patients; all of these are discussed in detail in the general management section earlier in this chapter.

Acute reactions

For an acute reaction, complete sun avoidance (even through windows) leads to earlier resolution, and fans and cold water provide some pain relief. Antihistamines and most analgesics are of little value. For severe attacks, hospital admission may be necessary – for light avoidance and analgesia (usually opiate).

Specific therapies

Oral β-carotene is the most widely used treatment, usually at a dose around 180 mg daily in adults (90 mg daily in children) taken throughout the spring and summer. It is postulated to scavenge free radicals involved in the acute phototoxic reaction. Although some patients report that it reduces symptoms, others do not, and proof of efficacy from controlled trials is lacking. Patients may need to take it for several months before any effect is observed. The most common adverse effect of β-carotene is reversible skin discoloration. Controlled trials of N-acetyl cysteine and colestyramine have been shown to be of no benefit [27, 28]. Short courses of a few weeks of psoralen and long-wave UVA radiation (PUVA) [29] and narrow-band UVB [30] used in the early spring may be valuable, particularly in milder cases. These probably increase photoprotection by inducing epidermal thickening and pigmentation. Unlike PUVA, narrow-band UVB does not overlap with the EPP action spectrum and so cannot trigger attacks of pain. Many other systemic treatments with antioxidant or free radical scavenging properties have been used in EPP in an uncontrolled way on small numbers of patients, with conflicting and generally unconvincing results. Afamelanotide, the α-melanocyte-stimulating hormone analogue, has shown promising results in initial trials in EPP patients [31].

Genetic counselling

Although rare cases of autosomal recessive inheritance have been reported [32, 33], EPP is generally an autosomal dominant disorder with incomplete penetrance. The disease results from co-inheritance of a gene mutation on one ferrochelatase allele with a low expression variant on the other allele. This low expression variant is present in around 10% of the white population and is associated with reduced ferrochelatase mRNA levels resulting from the presence of the polymorphic variant IVS3-48C [34]. This low expression variant is common in Japan and South-East Asia and rare in Africa, which may explain the observed variations between continents [35]. Overall, the probability of each offspring of an EPP patient suffering from the disease is under 10%, but testing for the IVS3-48C polymorphism in a patient's partner is now available and can indicate more precisely whether there is a significant probability of future offspring being affected. This is useful for patients who would not consider having children if there were a significant likelihood of them having the disease. For a disorder which is rarely life-threatening, termination of pregnancy and thus antenatal diagnosis are not relevant.

Liver disease in EPP [32, 36]

Protoporphyrin is excreted exclusively into the bile. It precipitates to form gallstones in around 12% of patients. It is also hepatotoxic, particularly to bile canaliculi, and severe liver damage occurs in around 1% of patients. EPP liver failure requiring transplantation may occur at almost any age [36]. Usually a patient develops jaundice, worsening photosensitivity and often upper abdominal pain over a period of weeks or months. Investigation shows severe or total cholestasis, and a dramatically high red cell protoporphyrin concentration (due to its impaired excretion), which causes the worsening photosensitivity. Liver histology reveals deposition of protoporphyrin in vacuoles within bile canaliculi and hepatocytes, which may be accompanied by cirrhosis (Figure 60.12). Although such acute episodes may resolve spontaneously, the porphyrin-induced cholestasis may become increasingly severe and itself further increase the protoporphyrin concentration in a vicious cycle, in which case the patient will die unless a liver transplant can be performed. Unless filter films are used over operating theatre lights [15], the very high protoporphyrin concentration may result in a severe phototoxic reaction with postoperative burns. A severe and prolonged neuropathy may also occur after liver transplant [36]. Even if these immediate postoperative complications are avoided, protoporphyric liver disease recurs in the graft in 69% of patients over several years, severe enough to require retransplantation in a minority. Patients with severe liver disease have been treated by bone marrow transplantation (in one of them with a liver transplant). Although the marrow transplantation does cure the EPP, the dangers of the procedure mean that it is reserved for these rare, life-threatening situations [37, 38].

It is vital to recognize impending protoporphyric liver failure early enough that arrangements can be made for a liver transplant if it should become necessary. Thus, all EPP patients should have liver function tests and red cell protoporphyrin concentration checked at least once a year. The appearance of coproporphyrin in the urine has been proposed as an indicator of significant liver disease in EPP [39]. Worsening photosensitivity may be the only clinical indication of the development of severe liver disease. Although protoporphyric liver failure is rare, mild abnormalities of liver function tests are common in EPP [39]. Since the significance of these abnormalities is unclear, it is advisable to monitor them closely in these patients, and to refer the patient to a hepatologist if the abnormality is persistent or deteriorating. In such patients, an ion exchange resin such as cholestyramine may protect the liver against further porphyrin toxicity. The major difficulty for the dermatologist is the lack of any means of identifying those EPP patients at risk of liver failure. Since several cases have been described in siblings, patients with a relative who has suffered protoporphyric liver failure should be treated as being at increased risk of developing it themselves. Recessive inheritance of EPP may increase the risk of severe hepatic disease, though it is not clear how significant an association this is [32].

Iron deficiency anaemia may trigger or exacerbate hepatic disease by increasing porphyrin accumulation [32], and subsequent iron replacement may make the situation temporarily worse by acutely stimulating haem biosynthesis.

PORPHYRIAS THAT CAUSE CUTANEOUS DISEASE AND ACUTE ATTACKS

Hereditary coproporphyria

Definition

This is a rare inherited disease usually characterized by acute attacks, which involves the skin as well in a minority of patients.

Clinical features

Like VP, this porphyria presents from puberty onwards. The skin is not affected in most patients suffering from this rare acute porphyria but around 10–20% [1] of patients have cutaneous involvement with fragility and blistering in sun-exposed areas, indistinguishable from that seen in PCT or VP. The skin disease may be triggered or exacerbated by intercurrent liver disease [2]. Rare variants include a homozygous form characterized by short stature, acute attacks and skin changes with prominent hypertrichosis and pigmentation [3], and harderoporphyria which causes haemolysis in the neonate or bullae. HC is caused by an autosomal dominant inherited deficiency of coproporphyrinogen oxidase.

Investigations

The biochemical findings are of a 615–620 nm peak on plasma spectrofluorimetry, increased uro- and coproporphyrin concentrations in urine, and increased coproporphyrin in faeces. Predominance of the type III isomer in faeces is a sensitive indicator of HC [1].

Variegate porphyria

Definition

This is a rare inherited disease usually characterized by photo-induced skin fragility and blistering, which may cause acute attacks.

Introduction, epidemiology and pathophysiology

Variegate porphyria is caused by an autosomal dominant inherited deficiency of protoporphyrinogen oxidase. In addition to causing photosensitization, accumulated coproporphyrinogen and protoporphyrinogen also inhibit PBG deaminase, the probable mechanism for acute attacks in VP [1]. In South Africa, VP is common (due to a founder effect [2]) with a prevalence in whites and Afrikaner-descended non-whites of 1/200. The incidence of VP in Europe varies between countries in the range 0.01–0.26 new cases/million/year [3]. Elsewhere the prevalence is around 0.5–1/100 000 [2]. At least 80% of South African carriers of a pathogenic VP mutation are completely asymptomatic [4].

It is perhaps unexpected that the accumulated copro- and protoporphyrin should cause PCT-like upper dermal blistering rather than EPP-like acute pain. This is likely to be because, although hydrophobic porphyrins predominate in the plasma, hydrophilic porphyrins, especially uroporphyrin, predominate in the skin. This local accumulation is thought to result from secondary local photo-inactivation of UROD in the skin by coproporphyrin [4]. In addition, the protoporphyrin in VP is conjugated to a peptide which may reduce its phototoxicity.

Clinical features [4–6]

Skin

Of those patients with symptomatic VP, around 70% of patients have cutaneous involvement, and only around 17% of these patients will ever suffer an acute attack [7]. VP only very rarely presents before puberty, and usually the skin disease begins in adolescence or young adulthood. Patients describe skin fragility, usually fairly mild, affecting sun-exposed skin particularly on the backs of the hands [4, 5]. The skin disease is generally indistinguishable from PCT, with painful tense bullae occurring in sun-exposed skin, as well as scarring, pigmentary abnormalities, sometimes pseudosclerodermatous changes of the hands and fingers, and occasionally photo-onycholysis. However, a significant number of patients do not describe worsening in the summer, and the patients who do describe seasonal variation often have their worst problems in late summer and autumn. In addition, around half of patients with VP describe mild, transient, light-related eruptions in the early summer. The examination findings of scarring, patches of hypo- and hyperpigmentation at the sites of blisters, milia and mild hypertrichosis, particularly around the eyes, are indistinguishable from PCT. Intercurrent biliary obstruction exacerbates the cutaneous disease since the accumulated porphyrins are excreted into the bile. Acute photosensitivity can occur in patients with disturbed liver function. Hormonally induced hepatic dysfunction may explain the exacerbations of skin disease seen in females taking oral contraceptives and during pregnancy. VP sometimes goes into clinical and biochemical remission in old age. Patients with VP have recently been shown to be at increased lifetime risk of hepatocellular carcinoma [8]

Acute attacks [4, 5, 7, 9]

As in other acute porphyrias, women are three times as frequently affected as men, and 70% of acute attacks occur between the ages of 20 and 40 years. Around 17% of patients with cutaneous VP ever suffer an acute attack; the number has declined recently due to improved use of prophylactic measures. The severity of acute attacks varies from mild abdominal pain, sometimes accompanied by vomiting and constipation, through to very severe attacks with bulbar palsy and respiratory paralysis. The presentation, diagnosis and management of acute attacks is covered in the section on acute attacks of porphyria earlier in this chapter.

Clinical variants

In homozygous VP a mutation on both protoporphyrinogen oxidase alleles results in an enzyme activity less than 20% of normal, compared with the 50% in other VP patients [10]. Fragility, bullae and often hypertrichosis develop in exposed (and sometimes non-exposed) skin in neonates or infants and the skin disease may be severe. Delayed development, epilepsy, sensory neuropathy, nystagmus, various hand deformities and growth retardation also commonly occur. Acute attacks do not occur in these patients. The biochemical findings are the same as in VP, except for the lower enzyme activity.

Differential diagnosis

VP cutaneous disease is easily distinguished from non-photosensitive blistering disorders. It can be clinically very similar to PCT, late-onset CEP, HC and pseudoporphyria. Biochemical analysis is required to diagnose VP.

Investigations

A plasma spectrofluorimetry peak around 626 nm (caused by a porphyrin–protein complex) is diagnostic of VP in the absence of a raised free red cell protoporphyrin level, and is present in virtually all symptomatic cases of VP. It may persist during periods of clinical remission when faecal excretion becomes normal and is a more sensitive test than measurement of faecal porphyrins [11]. A persistently normal faecal protoporphyrin concentration in adulthood in patients with the VP genetic defect has been proposed as a prognostic marker indicating a greater likelihood of the VP never causing any clinical problems and staying clinically latent [9]. The urine contains increased levels of coproporphyrin, and increased concentrations of copro- and protoporphyrin are found in the faeces. In a few patients, the urine shows the typical PCT pattern of uroporphyrin accompanied by hepta- and sometimes hexa- and pentacarboxylic acid porphyrins, a situation known as ‘dual porphyria’ [12]. Thus, urinary analysis alone can result in the misdiagnosis of VP as PCT, with potentially disastrous consequences. During acute attacks, urinary PBG (and ALA) are raised. The urinary PBG usually falls to normal within weeks of the attack resolving, but may stay a little increased outside the context of an acute attack [13].

Management

Treatment

The key to successful management of the skin disease is photoprotection with sun avoidance using clothes, hats and gloves. Opaque sunscreens, containing pigmentary grade titanium dioxide or zinc oxide sometimes with the addition of iron oxide, are protective against Soret wavelength light [14, 15]. The skin disease is rarely severe enough to require filter films for car and home windows. Since the relationship between sun exposure and skin lesions is not obvious, the role of light in producing the skin lesions should be explained to the patient. β-Carotene and canthaxanthin have also been claimed to provide limited protection in some patients, and UVB phototherapy may also be of value [4]. If liver function tests indicate biliary obstruction, relief of this will reduce cutaneous symptoms.

The risk of acute attacks is the key issue for the safe management of patients and their families. Patients should be directed to a list of drugs to avoid [16], including those that can induce attacks, and also those known to induce cholestasis, as well as cannabis. They should also be advised to wear an emergency identification bracelet, to avoid low calorie diets and to become teetotal. Liver transplantation has been successfully used to cure variegate porphyria (and acute intermittent porphyria) in cases where acute attacks are frequent, severe and uncontrollable by medical means [17].

Genetic counselling

It is important to identify relatives who have latent VP because of the risk of acute attacks. The plasma 624–626 nm peak is found in the majority of cases of latent VP but only from teenage onwards. A positive plasma fluorimetry result is diagnostic of latent VP, but a negative result is uninformative [18, 19]. The only completely reliable way to identify those carrying the VP gene defect if the plasma scan is negative is to identify the protoporphyrinogen oxidase gene mutation in the index case and then assess its presence or absence in relatives. This is labour intensive because, outside South Africa, most families have their own private mutation. Relatives found to have the gene defect are at a low risk (roughly 5–10%) of acute attacks and should take all the precautions taken by any patient diagnosed with an acute porphyria. The risk of a patient passing the mutated gene on to each offspring is 50%, and around 20% of those carrying the mutation will eventually develop symptoms of some sort.

MISCELLANEOUS

Pseudoporphyria

Definition

Pseudoporphyria is a non-porphyric dermatosis clinically and histologically indistinguishable from porphyria cutanea tarda. Porphyrin concentrations are entirely normal. Pseudoporphyria is one of the clinical presentations of drug-induced photosensitivity, and there are other non-drug-related causes.

Introduction, epidemiology and pathophysiology [1]

The causes of pseudoporphyria are photosensitizing drugs, haemodialysis and sunbeds. Since pseudoporphyria is one of the presentations of drug photosensitivity, it is unsurprising that the relevant drugs are generally recognized photosensitizers. The most common causes of pseudoporphyria are non-steroidal anti-inflammatory drugs (NSAIDs), especially naproxen and nabumetone. Oxaprozin, ketoprofen, mefenamic acid and diflunisal are also reported causes. NSAID-induced pseudoporphyria is common: in one group of patients treated with naproxen for juvenile rheumatoid arthritis, 12% developed pseudoporphyria [2]. Other drugs reported to induce pseudoporphyria include nalidixic acid, tetracyclines including minocycline, bumetanide, furosemide, isotretinoin and dapsone. There are isolated reports with other drugs.

Another situation in which pseudoporphyria is common is in patients with chronic renal failure undergoing haemodialysis (or less commonly peritoneal dialysis).

The third group of patients are those whose pseudoporphyria is induced by UVA tanning beds. This group are predominantly female. Although some of the reported cases were of patients also taking photosensitizing medications, in some patients use of UVA sunbeds appears to be the sole causative factor [3].

Clinical features

Presentation

The clinical features in the skin are indistinguishable from porphyria cutanea tarda [1]: vesicles, bullae, fragility, milia and scarring on exposed skin, particularly the dorsal hands, but also the face, chest and occasionally other sites. However, hypertrichosis, hyperpigmentation, sclerodermoid changes and dystrophic calcification are much less commonly seen than in PCT. In children, the facial scarring can resemble that seen in EPP, but without the painful bouts of photosensitivity seen in that disease. Unlike the porphyrias, pseudoporphyria has no manifestations except in the skin.

Differential diagnosis

The main differential diagnoses are PCT, and EPP where there is EPP-type scarring. The diagnosis requires the presence of clinical features of PCT in the skin, with normal urine, faecal and plasma porphyrin concentrations reported by an experienced porphyrin laboratory. It is preferable though not essential to identify a recognized cause of pseudoporphyria in the patient. Other relevant diseases also need to be excluded (epidermolysis bullosa acquisita, bullous pemphigoid, etc.). The situation is more complex in patients in renal failure. Haemodialysis is associated with increased plasma porphyrin concentrations anyway [4], and urine may be unavailable to test in these patients. The situation is further complicated by the fact that PCT can also be induced by chronic renal failure. Conclusive differentiation of PCT from pseudoporphyria in the context of renal failure and dialysis is not always possible, but can sometimes be achieved on the basis of the degree of increase in porphyrin concentrations in plasma, faeces and (where available) urine. It is important to try to differentiate the two diseases in renal failure, because of the implications regarding aetiological factors and treatment options.

Investigations

By definition, the porphyrin concentrations in urine, plasma, red cells and faeces must be normal for a diagnosis of pseudoporphyria to be made. The histopathological and immunofluorescent appearances of affected skin are essentially identical in pseudoporphyria and PCT. Blood vessel thickening and sclerosis of collagen are less common in pseudoporphyria, but the two diseases cannot be reliably differentiated from skin biopsies [5].

Management

In drug-induced and sunbed-related pseudoporphyria, the key to management is to remove the provoking factor by stopping the relevant drug or sunbed usage. However, symptoms may continue for several months after the discontinuation of a causative drug [6], and scarring persists. Dialysis-related pseudoporphyria generally persists until renal transplantation removes the need for dialysis. UV, especially UVA, causes the photosensitive reaction in pseudoporphyria (in contrast to the situation in PCT). Hence, broad spectrum UV protection is vital until the disease resolves. The treatments of PCT (antimalarials, venesection) are obviously not effective in pseudoporphyria.

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Singal AK, Kormos-Hallberg C, Lee C, et al. Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda. Clin Gastroenterol Hepatol 2012;10:1402–9.
Farinati F, Cardin R, DeMaria N, et al. Iron storage, lipid peroxidation and glutathione turnover in chronic HCV-positive hepatitis. J Hepatol 1995;22:449–56.
Roeckel IE. Commentary: iron metabolism in hepatitis C infection. Ann Clin Lab Sci 2000;30:163–5.
Stolzel U, Kostler E, Schuppan D, et al. Hemochromatosis (HFE) gene mutations and response to chloroquine in porphyria cutanea tarda. Arch Dermatol 2003;139:309–13.
Elder GH. The cutaneous porphyrias. In: Hawk JLM, ed. Photodermatology. London: Arnold, 1999:171–99.

Erythropoietic protoporphyria

Elder G, Harper P, Badminton M, et al. The incidence of inherited porphyrias in Europe. J Inherit Metab Dis 2013;36:849–57.
Whatley SD, Ducamp S, Gouya L, et al. C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. Am J Hum Genet 2008;83:408–14.
Brun A, Sandberg S. Mechanisms of photosensitivity in porphyric patients with special emphasis on erythropoietic protoporphyria. J Photochem Photobiol B 1991;10:285–302.
Takeshita K, Takajo T, Hirata H, et al. In vivo oxygen radical generation in the skin of the protoporphyria model mouse with visible light exposure: an L-band ESR study. J Invest Dermatol 2004;122:1463–70.
Minder EI, Gouya L, Schneider-Yin X, Deybach JC. A genotype–phenotype correlation between null-allele mutations in the ferrochelatase gene and liver complication in patients with erythropoietic protoporphyria. Cell Mol Biol (Noisy-le-grand) 2002;48:91–6.
Sarkany RP, Ross G, Willis F. Acquired erythropoietic protoporphyria as a result of myelodysplasia causing loss of chromosome 18. Br J Dermatol 2006;155:464–6.
Holme SA, Anstey AV, Finlay AY, et al. Erythropoietic protoporphyria in the UK: clinical features and effect on quality of life. Br J Dermatol 2006;155:574–81.
Deleo VA, Poh-Fitzpatrick M, Mathews-Roth M, Harber LC. Erythropoietic protoporphyria. Ten years experience. Am J Med 1976;60:8–22.
Poh-Fitzpatrick MB. The ‘priming phenomenon’ in the acute phototoxicity of erythropoietic protoporphyria. J Am Acad Dermatol 1989;21:311.
Patel GK, Weston J, Derrick EK, Hawk JL. An unusual case of purpuric erythropoietic protoporphyria. Clin Exp Dermatol 2000;25:406–8.
Marsden RA, Dawber RP. Erythropoietic protoporphyria with onycholysis. Proc R Soc Med 1977;70:572–4.
Murphy GM, Hawk JL, Magnus IA. Late-onset erythropoietic protoporphyria with unusual cutaneous features. Arch Dermatol 1985;121:1309–12.
Holme SA, Whatley SD, Roberts AG, et al. Seasonal palmar keratoderma in erythropoietic protoporphyria indicates autosomal recessive inheritance. J Invest Dermatol 2009;129:599–605.
Poh-Fitzpatrick MB. Human protoporphyria: reduced cutaneous photosensitivity and lower erythrocyte porphyrin levels during pregnancy. J Am Acad Dermatol 1997;36:40–3.
Wahlin S, Srikanthan N, Hamre B, et al. Protection from phototoxic injury during surgery and endoscopy in erythropoietic protoporphyria. Liver Transpl 2008;14:1340–6.
Holme SA, Anstey AV, Badminton MN, et al. Serum 25-hydroxyvitamin D in erythropoietic protoporphyria. Br J Dermatol 2008;159:211–13.
Allo G, Del Carmen Garrido-Astray M, De Salamanca RE, et al. Bone mineral density and vitamin D levels in erythropoietic protoporphyria. Endocrine 2013;44:803–7.
Deacon A. The porphyrias and their investigation. CPD Bull Clin Biochem 1999;1:122–6.
Hanneken S, Siegesmund M, Bolsen K, et al. The prognostic value of cord blood analysis in erythropoietic protoporphyria: the ‘Duesseldorf Cord Blood Study’. Photodermatol Photoimmunol Photomed 2010;26:7–9.
Ryan EA, Madill GT. Electron microscopy of the skin in erythropoietic protoporphyria. Br J Dermatol 1968;80:561–70.
Epstein JH, Tuffanelli DL, Epstein WL. Cutaneous changes in the porphyrias. A microscopic study. Arch Dermatol 1973;107:689–98.
Gschnait FG, Wolff K, Konrad K. Erythropoietic protoprophyria – submicroscopic events during the acute photosensitivity flare. Br J Dermatol 1975;92:545–57.
Wick G, Honigsmann H, Timpl R. Immunofluorescence demonstration of type IV collagen and a noncollagenous glycoprotein in thickened vascular basal membranes in protoporphyria. J Invest Dermatol 1979;73:335–8.
Moseley H, Cameron H, MacLeod T, et al. New sunscreens confer improved protection for photosensitive patients in the blue light region. Br J Dermatol 2001;145:789–94.
Kaye ET, Levin JA, Blank IH, et al. Efficiency of opaque photoprotective agents in the visible light range. Arch Dermatol 1991;127:351–5.
Johnson JA. Durable protection against long-wavelength UV-A radiation and blue light. Arch Dermatol 1992;128:409.
Norris PG, Baker CS, Roberts JE, Hawk JL. Treatment of erythropoietic protoporphyria with N-acetylcysteine. Arch Dermatol 1995;131:354–5.
Tewari A, Marsden J, Naik H, et al. Oral cholestyramine is not an effective treatment for uncomplicated erythropoietic protoporphyria. J Am Acad Dermatol 2012;67:1383–4.
Roelandts R. Photo (chemo) therapy and general management of erythropoietic protoporphyria. Dermatology 1995;190:330–1.
Collins P, Ferguson J. Narrow-band UVB (TL-01) phototherapy. An effective preventative treatment for the photodermatoses. Br J Dermatol 1995;132:956–63.
Harms J, Lautenschlager S, Minder CE, et al. An alpha-melanocyte-stimulating hormone analogue in erythropoietic protoporphyria. N Engl J Med 2009;360:306–7.
Sarkany RPE, Cox TM. Autosomal recessive erythropoietic protoporphyria: a syndrome of severe photosensitivity and hepatic failure. Q J Med 1995;88:541–9.
Whatley SD, Mason NG, Khan M, et al. Autosomal recessive erythropoietic protoporphyria in the United Kingdom: prevalence and relationship to liver disease. J Med Genet 2004;41:e105.
Gouya L, Puy H, Robreau AM, et al. The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH. Nat Genet 2002;30:27–8.
Gouya L, Martin-Schmitt C, Robreau AM, et al. Contribution of a common single-nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria. Am J Hum Genet 2006;78:2–14.
Wahlin S, Stal P, Adam R, et al. Liver transplantation for erythropoietic protoporphyria in Europe. Liver Transpl 2011;17:1021–6.
Wahlin S, Aschan J, Bjornstedt M, et al. Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis. J Hepatol 2007;46:174–9.
Rand EB, Bunin N, Cochran W, Ruchelli E, et al. Sequential liver and bone marrow transplantation for treatment of erythropoietic protoporphyria. Pediatrics 2006;118:e1896–9.
Doss MO, Frank M. Hepatobiliary implications and complications in protoporphyria, a 20-year study. Clin Biochem 1989;22:223–9.

Porphyrias that cause cutaneous disease and acute attacks

Hereditary coproporphyria

Kuhnel A, Gross U, Doss MO. Hereditary coproporphyria in Germany: clinical-biochemical studies in 53 patients. Clin Biochem 2000;33:465–73.
Hawk JL, Magnus IA, Parkes A, et al. Deficiency of hepatic coproporphyrinogen oxidase in hereditary coproporphyria. J R Soc Med 1978;71:775–7.
Grandchamp B, Phung N, Nordmann Y. Homozygous case of hereditary coproporphyria. Lancet 1977;2:1348–9.

Variegate porphyria

Van Tuyll van Serooskerken AM, Drögemöller BI, te Velde K, et al. Extended haplotype studies in South African and Dutch variegate porphyria families carrying the recurrent p.R59W mutation confirm a common ancestry. Br J Dermatol 2012;166:261–5.

Elder G, Harper P, Badminton M, et al. The incidence of inherited porphyrias in Europe. J Inherit Metab Dis 2013;36:849–57.

Day RS. Variegate porphyria. Semin Dermatol 1986;5:138–54.

Mustajoki P. Variegate porphyria. Twelve years' experience in Finland. Q J Med 1980;49:191–203.

Timonen K, Niemi KM, Mustajoki P, Tenhunen R. Skin changes in variegate porphyria. Clinical, histopathological, and ultrastructural study. Arch Dermatol Res 1990;282:108–14.

Elder GH, Hift RJ, Meissner PN. The acute porphyrias. Lancet 1997;349:1613–17.

Schneider-Yin X, van Tuyll van Serooskerken AM, Went P, et al. Hepatocellular carcinoma in variegate porphyria: a serious complication. Acta Derm Venereol 201;90:512–15.

Von und zu Fraunberg M, Timonen K, Mustajoki P, Kauppinen R. Clinical and biochemical characteristics and genotype-phenotype correlation in Finnish variegate porphyria patients. Eur J Hum Genet 2002;10:649–57.

Hift RJ, Meissner PN, Todd G, et al. Homozygous variegate porphyria: an evolving clinical syndrome. Postgrad Med J 1993;69:781–6.

Hift RJ, Davidson BP, van der Hooft C, et al. Plasma fluorescence scanning and fecal porphyrin analysis for the diagnosis of variegate porphyria: precise determination of sensitivity and specificity with detection of protoporphyrinogen oxidase mutations as a reference standard. Clin Chem 2004;50:915–23.

Sturrock ED, Meissner PN, Maeder DL, Kirsch RE. Uroporphyrinogen decarboxylase and protoporphyrinogen oxidase in dual porphyria. S Afr Med J 1989;76:405–8.

Deacon A. The porphyrias and their investigation. CPD Bull Clin Biochem 1999;1:122–6.

Moseley H, Cameron H, MacLeod T, et al. New sunscreens confer improved protection for photosensitive patients in the blue light region. Br J Dermatol 2001;145:789–94.

Kaye ET, Levin JA, Blank IH, et al. Efficiency of opaque photoprotective agents in the visible light range. Arch Dermatol 1991;127:351–5.

The European Porphyria Network. http://www.porphyria-europe.org/ (last accessed May2014).
Stojeba N, Meyer C, Jeanpierre C, et al. Recovery from a variegate porphyria by a liver transplantation. Liver Transpl 2004;10:935–8.
Long C, Smyth SJ, Woolf J, et al. Detection of latent variegate porphyria by fluorescence emission spectroscopy of plasma. Br J Dermatol 1993;129:9–13.
Da Silva V, Simonin S, Deybach JC, et al. Variegate porphyria: diagnostic value of fluorometric scanning of plasma porphyrins. Clin Chim Acta 1995;238:163–8.

Miscellaneous

Pseudoporphyria

Green JJ, Manders SM. Pseudoporphyria. J Am Acad Dermatol 2001;44:100–8.
Lang BA, Finlayson LA. Naproxen-induced pseudoporphyria in patients with juvenile rheumatoid arthritis. J Pediatr 1994;124:639–42.
Stenberg A. Pseudoporphyria and sunbeds. Acta Derm Venereol 1990;70:354–6.
Day RS, Eales L. Porphyrins in chronic renal failure. Nephron 1980;26:90–5.
Maynard B, Peters MS. Histologic and immunofluorescence study of cutaneous porphyrias. J Cutan Pathol 1992;19:40–7.
Girschick HJ, Hamm H, Ganser G, Huppertz HI. Naproxen-induced pseudoporphyria: appearance of new skin lesions after discontinuation of treatment. Scand J Rheumatol 1995;24:108–11.