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Dr Dimple Doda

Introduction :

Introduction The Porphyrias are a clinically and genetically heterogeneous group of metabolic diseases that result from either an inherited or an acquired dysfunction of enzymes crucial for heme biosynthesis . Porphyrins are intermediates in the biosynthesis of Heme which is essential for oxygen binding and transport (as in hemoglobin and myoglobin ), for electron transport (as in cytochromes ). Heme synthesis is controlled by eight enzymes along the heme biosynthetic pathway . The human porphyrias arise from deficient activity of the second to eighth enzymes in this pathway


PORPHYRIN-HEME BIOSYNTHESIS The major sites of heme synthesis in the body are the bone marrow and the liver . Heme is the prosthetic group for a number of proteins, including among others hemoglobin, myoglobin , mitochondrial cytochromes , microsomal cytochromes (including cytochrome P 450 ). Approximately 85 percent of heme synthesis occurs in the bone marrow, where heme is used for the production of hemoglobin.


` Patients with all forms of non-acute porphyria manifest cutaneous findings predominantly on sun-exposed body areas . The non-acute porphyrias include : Porphyria cutanea tarda (PCT), the most prevalent type of porphyria Hepatoerythropoietic porphyria (HEP), the homozygous variant of PCT. Erythropoietic protoporphyria (EPP); Congenital erythropoietic porphyria (CEP);

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The non-acute porphyrias can present with variable cutaneous features: Symptoms Mild to severe photosensitivity Burning and stinging Edema Pruritus Signs: Vesicles and bullae Hypertrichosis Increased skin fragility Scarring Hyperpigmentation Scleroderma like changes

Pathophysiology of Cutaneous Signs and Symptoms in the Non-Acute Porphyrias :

Pathophysiology of Cutaneous Signs and Symptoms in the Non-Acute Porphyrias The most common cutaneous manifestation of the non-acute porphyrias is photosensitivity . The sine qua non of photosensitivity in porphyria is increased levels of plasma and tissue porphyrins . It is observed in patients with several of these disorders (PCT, EPP, CEP, HEP) as well as in patients with VP and HCP, who have both cutaneous and neurovisceral findings .

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Patients with the erythropoietic types of porphyria frequently complain of a painful and intense burning sensation and pruritus during or after sun exposure . A “priming” effect of sun exposure on cutaneous photosensitivity in EPP has been described in which a threshold exposure on one day that evokes virtually no reaction seems to augment the response to subsequent exposure on the following day. These subjective symptoms are notably absent in patients with the chronic hepatic porphyrias such as PCT and VP.

Factors Contributing to the Development of Cutaneous Lesions in Porphyrias:

Factors Contributing to the Development of Cutaneous Lesions in Porphyrias Sunlight, especially blue and red light (380-760 nm) Reactive oxygen species ( 1 O 2 , O 2 ·-, H 2 O 2 , ·OH). Cells Erythrocytes Mast cells Polymorphonuclear leukocytes Fibroblasts Soluble mediators The complement system Factor XIII-dependent pathways The eicosanoids Matrix metalloproteinases

Cellular and Soluble Factors Contributing to Photosensitivity :

Cellular and Soluble Factors Contributing to Photosensitivity Porphyrins such as URO, COPRO, and PROTO Absorb light intensely around 400 nm and in the longer visible spectrum between 580 and 650 nm. Absorption results in the generation of excited state porphyrin molecules. The initial excited state porphyrin generated has an extremely short half-life of less than 0.01 µs. Singlet excited state porphyrins may spontaneously convert to a triplet, another excited state. Because of their long half-life, triplet state porphyrins are more likely to react with biologic substrates and mediate most porphyrin -associated photobiologic reactions. Excited state porphyrin molecules ultimately return to their normal ground states by releasing their absorbed energy in the form of light (fluorescence is emitted by singlet state molecules

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Excited porphyrins in their singlet and triplet states can also transfer their absorbed energy to oxygen molecules, thereby creating reactive excited oxygen states. Cellular and tissue damage induced by photoactivated porphyrins is believed to occur primarily as a result of the formation of reactive singlet oxygen ( 1 O 2 ). Those processes in which activated oxygen species play a role in photosensitization are referred to as photodynamic reactions . Most of the porphyrin -mediated cutaneous photosensitization reactions are essentially photodynamic and can be minimized or prevented if reactive oxygen is eliminated by inactivation processes known as quenching or scavenging.

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1 Cutaneous disease only: Porphyria cutanea tarda (PCT) Congenital erythropoietic porphyria (CEP) Erythropoietic protoporphyria (EPP). 2 Cutaneous disease and acute attacks: Hereditary coproporphyria (HC) Variegate porphyria (VP). 3 Acute attacks only: Acute intermittent porphyria (AIP)


PORPHYRIA CUTANEA TARDA AT A GLANCE Most frequently occurring type of porphyria worldwide. Sporadic and inherited ( autosomal dominant) forms of the disease arise due to deficiency of uroporphyrinogen decarboxylase . Age of onset is usually in the third to fourth decade of life; the disorder is unusual before puberty. Characterized by moderate to severe photosensitivity; cutaneous signs include vesicles and bullae , erosions, crusts, milia , scarring, hyperpigmentation , and hypertrichosis .


ETIOLOGY AND PATHOGENESIS PCT is due to either an inherited or an acquired deficiency of UROGEN decarboxylase , the fifth enzyme in the heme pathway. PCT is further subdivided into two types: Acquired PCT , also referred to as sporadic or type I PCT ; the enzyme is deficient only in the liver . Hereditary PCT , also referred to as familial or type II PCT, the residual UROGEN decarboxylase activity is decreased approximately 50 percent in all tissues, including RBCs and cultured skin fibroblasts.

pathogenesis :

pathogenesis In PCT, the UROD enzyme is inactivated by an inhibitor which binds to its catalytic site. The inhibitor is generated in the liver by reactive oxygen species in the presence of iron. The accumulated uroporphyrin diffuses from the plasma into 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 .


CLINICAL MANIFESTATIONS Vesicles and bullae followed by erosions and crusting occur predominantly in areas subject to repeated trauma . There is increased skin fragility, usually on the dorsa of the hands . The traumatized skin becomes crusted , and as the lesions resolve, areas of scarring may ensue. Numerous small milia can develop, particularly on the fingers and hands .

vesicles and bulla present over dorsum of hand:

vesicles and bulla present over dorsum of hand

Erosions and crusting following ruptured vesicles and bullae:

Erosions and crusting following ruptured vesicles and bullae

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Facial hypertrichosis develops gradually and is more apparent in females. The hair may vary in texture from fine to coarse and are seen along the temples and the cheeks . Hypertrichosis may be the presenting symptom in women. Sclerodermoid plaques can occur in PCT and in HEP and typically develop on both light-exposed and light-protected body areas . These are usually scattered, waxy yellow to white, indurated plaques that closely resemble morphea or scleroderma both clinically and histopathologically .

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Hypertrichosis Scleroderma like changes


HISTOPATHOLOGY The characteristic histopathologic finding in PCT is a sub-epidermal blister. Bullae typically show a corrugated, undulating base that has been termed festooned. There is little or no inflammatory infiltrate.

biochemical findings :

biochemical findings In PCT, the urinary porphyrin concentration is increased , consisting mainly of uroporphyrin . 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 ’)


HEPATO-ERYTHROPOIETIC PORPHYRIA AT A GLANCE Extremely rare. Autosomal recessive disorder due to homozygous deficiency of uroporphyrinogen decarboxylase . Age of onset is early infancy (1 to 4 years). Characterized by severe photosensitivity, including vesicles and bullae , erosions, excoriations, crusts, and milia ; mutilating scarring; and hypertrichosis .


CLINICAL MANIFESTATIONS The disease typically manifests in early childhood , and dark red urine is often the first sign . Severe cutaneous photosensitivity with blistering and pruritus then ensues. The photosensitivity may diminish with age and is followed by hypertrichosis , hyperpigmentation , and scleroderma-like scarring similar to that seen in CEP. Ocular manifestations include ectropion associated with cutaneous sclerosis and scleromalacia perforans .

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Hypertrichosis , hyperpigmentation and scleroderma like changes


LABORATORY FINDINGS The urinary porphyrin pattern is similar to that found in PCT . However , elevated RBC PROTO levels in HEP helps to distinguish it from PCT. These findings suggest that there is abnormal porphyrin synthesis in both the liver and the bone marrow. Unlike in PCT patients, serum iron concentrations are usually normal in those with HEP.


MANAGEMENT Photoprotection (e.g., with broad-band sunscreens and/or protective clothing) Avoidance of sun exposure and trauma Discontinuation of alcohol ingestion and estrogen therapy Phlebotomy ( venesection ): 400-500 mL every 2 wk over 3-6 mo Low-dose chloroquine treatment: 125 mg twice weekly for 6-12 mo until porphyrin excretion is within normal range. Measurement of urinary porphyrin excretion and plasma porphyrins quarterly to monitor progress


Pseudoporphyria The term Pseudoporphyria is used to describe patients who clinically exhibit cutaneous manifestations resembling those of PCT without the characteristic abnormal porphyrin profile . This disorder may develop in association with ingestion of certain drugs such as Furosemide , Nalidixic acid, Tetracycline, Naproxen, Pyridoxine and Isotretinoin .

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In the drug-induced type of pseudoporphyria , the blistering process is sub-epidermal with little or no dermal inflammation. Staining with PAS reveals little or no deposition around upper dermal blood vessels and capillary walls . Direct immunofluorescence studies have shown patchy granular deposition of immunoglobulin G and C3 at the basement membrane zone Has also been associated with chronic renal failure treated with long-term hemodialysis

Dialysis-associated pseudoporphyria. Vesicles formed on the dorsal aspects of the hands in this patient with chronic renal failure.:

Dialysis-associated pseudoporphyria . Vesicles formed on the dorsal aspects of the hands in this patient with chronic renal failure.


ERYTHROPOIETIC PROTOPORPHYRIA AT A GLANCE Second most common of the cutaneous porphyrias . Autosomal dominant disorder involving a deficiency of ferrochelatase . Age of onset in early childhood (1 to 4 years); rarely late onset can occur. Symptoms include acute burning and stinging of the skin that may be severe. Cutaneous findings include erythema , edema, purpura , skin thickening, and waxy scars ; blistering is rare.


ETIOLOGY The specific defective enzyme in EPP is ferrochelatase , which is decreased in various tissues of affected patients, including RBCs . Ferrochelatase catalyzes the final step in the formation of heme , the incorporation of ferrous iron (Fe 2+ ) into PROTO. The end product of the pathway, ferrous PROTO or heme is available to function as a prosthetic group by combining with appropriate apoproteins .


CLINICAL MANIFESTATIONS Skin Typically the disease begins early in life and is characterized by Acute episodes of cutaneous photosensitivity , burning, stinging (smarting) pruritus particularly the nose, cheeks dorsal aspects of the hands. Symptoms may occur within minutes of sun exposure . The skin lesions often resolve slowly, leaving small, atrophic, waxy or pitted scars .

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Pursing of perioral skin ( pseudorhagades ). The skin of the knuckles and fingers particularly over the MCP and IP joints , often appears thickened, wrinkled and waxy, suggesting a premature aging (so-called old knuckles in a child). This change is pathognomonic . Superficial scarring over the bridge of the nose Small annular shallow scars occur on the face.


Liver Severe life-threatening hepatotoxicity occurs in a small percentage of patients with EPP. Affected individuals become severely jaundiced, develop hepatic cirrhosis , and may go into hepatic coma and die. Some EPP patients with end-stage liver disease may develop axonal neuropathy resembling that in the acute hepatic porphyrias despite having normal serum ALA and PBG levels.

biochemical findings :

biochemical findings The diagnosis of EPP is based on the detection of elevated levels of free PROTO in the RBCs and/or feces . In addition, there may be increased plasma PROTO levels , increased fecal COPRO levels. Examination of a blood smear under a fluorescent microscope reveals red-fluorescing RBCs (5 percent to 30 percent).


HISTOPATHOLOGY Marked eosinophilic homogenization Thickening of vessels in the papillary dermis due to the accumulation of amorphous, homogeneous, slightly basophilic (hyaline-like) substance in and around the vessel walls . The perivascular deposits of concentric eosinophilic layers of hyaline-like material stain strongly positive with PAS.

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Perivascular hyaline material deposition


CONGENITAL ERYTHROPOIETIC PORPHYRIA AT A GLANCE ( gunther’s disease) Autosomal recessive disorder involving a deficiency of uroporphyrinogen III synthase . Age of onset in infancy or first decade of life. Cutaneous manifestations include vesicles and bullae , erosions, crusting, milia , mutilating scarring, hyperpigmentation , and hypertrichosis . Systemic findings include hemolytic anemia and hepatosplenomegaly . Porphyrin deposition occurs in bones and teeth ( erythrodontia ) .

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CLINICAL MANIFESTATIONS The disease usually develops during the first few months of life with moderate to severe cutaneous photosensitivity associated with pinkish red urine . CEP is the most mutilating of the cutaneous porphyrias . Cutaneous manifestations include skin fragility and vesicles and bullae , which may contain pink fluorescent fluid. This may lead to loss of acral tissue, such as the tips of the ears, the nose, and the fingers and facial mutilation .

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Erythrodontia (red-stained teeth) is a common finding in both deciduous and permanent teeth and is virtually pathognomonic of CEP . The urine may also fluoresce reddish pink. Hemolytic anemia associated with shortened erythrocyte life span (36 vs. 120 days) and hypersplenism occurs. Hirsutism with long, dark, lanugolike hair may occur and is particularly evident in light-exposed areas such as the face, neck, and extremities.

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LABORATORY FINDINGS The primary defect in CEP is decreased UROGEN III synthase activity , which results in accumulation of predominantly type I porphyrins in the tissues . The pink to burgundy red color of the urine from excess URO I is often visible on inspection.

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The Acute porphyrias include : Acute intermittent porphyria (AIP) Variegate Porphyria Herditary Coproporpyria ALA dehydratase deficiency porphyria or plumboporphyria .


ACUTE INTERMITTENT PORPHYRIA AT A GLANCE Most common of the acute porphyrias Autosomal dominant disorder involving deficiency of porphobilinogen deaminase Age of onset in second to fourth decade of life; rare before puberty Acute neurologic attacks but no photosensitivity or cutaneous findings

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CLINICAL MANIFESTATIONS An acute porphyric attack is characterized by abdominal pain (in 80 percent to 90 percent of AIP patients) and neurologic and psychiatric symptoms that can mimic those of numerous disorders . The pain may be diffuse or localized and is often intermittent and spastic. Vomiting and constipation are frequently associated. Between attacks patients are often remarkably symptom free. Attacks are often precipitated by ingestion of drugs .

Drugs precipitating AIP:

Drugs precipitating AIP Barbiturates Carbamazepine Chlorpropamide Chloroquine Danazol Dapsone Erythromycin Ethyl alcohol Furosemide Griseofulvin Methyldopa Nalidixic acid Phenylbutazone Primidone Pyrazinamide Rifampin

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Acute attacks of AIP may be accompanied by seizures, especially in patients with hyponatremia resulting from vomiting and inappropriate fluid therapy. Peripheral neuropathy is a major part of the clinical syndrome in many patients, varying from sensory (localized pain) to motor (weakness progressing to generalized flaccid paralysis). Patients may succumb to the disease, usually due to respiratory failure, or may improve slowly, although residual muscle weakness frequently persists for extended periods.

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LABORATORY FINDINGS The primary gene defect in AIP results in PBG deaminase deficiency, which causes excessive urinary excretion of ALA and PBG . Urinary porphyrin levels may also be slightly elevated. Urinary excretion of ALA and PBG may be as high as 100 mg/24 hours in an acute attack .

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TREATMENT 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 and careful management of fluid balance with rehydration and correction of hyponatraemia . The specific treatments are intravenous haematin or haem arginate , 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 arginate in a dose of 3 mg/kg body weight once daily over 4 consecutive days

Variegate Porphyria:

Variegate Porphyria Autosomal dominant disorder involving deficiency of protoporphyrinogen oxidase . Age of onset in second to third decade of life ; rare before puberty. Skin manifestations are indistinguishable from those of porphyria cutanea tarda Acute attacks similar to those in acute intermittent porphyria can occur ( neurocutaneous porphyria ).

Skin Lesions:

Skin Lesions These include bullae and erosions on light-exposed skin Hyperpigmentation , milia , hypertrichosis , and increased skin fragility are also seen. Blisters are often blood tinged, heal slowly, and heal with scarring and milia formation . In the chronic state, the skin changes may include thickening and scarring.

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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 . 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

Hereditary Coproporphyria :

Hereditary Coproporphyria HCP is an autosomal dominant disorder resulting from a decrease in the residual catalytic activity of COPROGEN oxidase . Age of onset in second to third decade of life; rare before puberty. Skin findings that are indistinguishable from those of porphyria cutanea tarda occur in fewer than 10 percent of patients; acute attacks similar to those of acute intermittent porphyria are the most common feature ( neurocutaneous porphyria )

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