PORPHYRIAS
The various porphyrias occur as the result of inherited enzyme deficiencies of the heme biosythetic pathway. These deficiencies then result in the accumulation of excessive amounts of porphyrin precursors which manifest in various clinical abnormalities. There are various types of porphyrias to include: porphyria cutanea tarda, erythropoietic protoporphyria, acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, congenital erythropoietic porphyria, and a rare form of disease called ALA (aminolevulinec acid) dehydratase-deficient porphyria. Lead poisoning should be included in the differential diagnosis and should be excluded as a part of the work-up. Clinically, porphyria cutanea tarda and erythropoietic protoporphyria present as photosensivity reactions; whereas, acute intermittent porphyria, variegate porphyria and hereditary coproporphyria present as neurologic dysfunction. When porphyria presents as neurologic and abdominal symptoms, screening with urinary aminolevulinic acid and porphobilinogen is warranted. Plasma porphyrin determinations should be performed when patients present with cutaneous symptoms.
PORPHYRIA CUTANEA TARDA (PCT)
This is the most common form of porphyria and results from a deficiency of hepatic uroporphyrinogen decarboxylase (UROD). Clinical symptoms include vesiculo/bullous photosensitivity, hyperpigmentation, the formation of white cutaneous plaques (milia), cutaneous scarring and calcification (pseudoscleroderma), and excessive facial hair growth (hypertrichosis). Patients may relate that their urine is initially normal in color but becomes darkened over time. Liver disease to include cirrhosis can be a potential manifestation. The disease may be either familial or sporadic. The sporadic form of disease may be secondary to alcohol, iron, estrogens, or certain chemicals. There is an association with hemochromatosis and chronic hepatitis C with this form of porphyria.
Measurement of serum porphyrins is an effective screening test. Diagnosis is established by demonstrating elevated levels of urine uroporphyrinogens I and III along with coproporphyrinogen. Testing of the feces will demonstrate an elevated isocoproporphyrin level. The urinary levels of delta aminolevulinic acid and porphobilinogen are never elevated with this form of disease. An assay to measure levels of erythrocyte UROD is available. Laboratory evaluation should include liver function studies, serum ferritin, iron studies, and hepatitis C serologies. Liver biopsy may be necessary to evaluate hepatic iron stores and tissue damage.
Therapy consists of phlebotomy in patients with evidence of cirrhosis and excessive tissue iron stores. Phlebotomy to remove one pint every one to two weeks until a total of five to six pints have been removed. Low dose chloroquine (125 mg given twice/week) or hydroxychloroquine (100 mg weekly) may also prove beneficial. Alcohol consumption should be strongly discouraged. Avoidance of sunlight should be strongly encouraged.
ERYTHROPOIETIC PROTOPORPHYRIA (Erythrohepatic porphyria/protoporphyria)
Patients afflicted with this form of disease present during childhood complaining of pruritis, burning and pain on sun exposed areas. These symptoms then progress to erythema, ecchymosis and cutaneous edema usually without vesicular or bullous lesions. Eventually the lesions will heal and may result in residual scars. Thickening of the skin over the knuckles often develops. Other complications may include gallstones and rarely liver failure. This disorder is the result of a deficiency in the enzyme ferrochelatase. The diagnosis is established in the presence of elevated levels of red blood cell, plasma, and fecal protoporphyrins. The red blood cells of a peripheral smear will display fluorescence under fluorescent light.
Protection from direct sunlight helps prevent symptoms in children. Patients may benefit from beta carotene (Lumitene) in doses of 120 to 300 mg daily with a goal of maintaining serum levels at 800 mg/dL. For prophylaxis, standard sunscreens are ineffective. Only sunscreens that filter the ultraviolet A spectrum of light and those with physical barriers (titanium dioxide and zinc oxide) are effective.
ACUTE INTERMITTENT PORPHYRIA
This common form of porphyria results from a deficiency of porphobilinogen deaminase. Classically, this disorder presents as recurrent episodes of diffuse abdominal pain that may mimic a surgical abdomen. Other symptoms include proximal motor neuropathies, loss of reflexes, cranial nerve deficits, bulbar paralysis, seizures,nausea, vomiting,, constipation, palpitations, tachycardia, hypertension, and acute psychotic episodes. This disorder is more common in women and symptoms do not appear until after puberty. Certain medications (high progersterone birth control pills, anticonvulsants, barbiturates, and sulfonamide antibiotics), alcohol ingestion, pregnancy, menstrual periods, infections, acidosis and decreased caloric intake can induce attacks.
Diagnosis of an acute porphyria is established by demonstrating markedly elevated levels of urinary delta aminolevulinic acid and porphobilinogen. Urine samples should be collected while the patient is symptomatic. Once urine tests demonstrate elevated levels of the above porphyrins, further testing should include testing for red blood cell porphobilinogen deaminase (RBC PBGD). A deficient level establishes the diagnosis. A normal level of RBC PBGD does not exclude the diagnosis as some AIP patients may have a normal RBC level. If a patient is diagnosed with AIP and demonstrates a low RBC PBGD level, then family members may be screened by measuring the RBC PBGD level as all patients who inheritied this form of AIP will have deficient RBC PBGD levels. Some research laboratories offer testing to identify the gene abnormality in the DNA of patients with AIP. Different families with AIP each display their own DNA mutation; however, members of the same family will all have the same mutation. Therefore, DNA testing for the specific mutation may offer an effective screening method among family members.
Prophylactic therapy entails avoidance of inciting factors as listed above and adequate daily caloric intake high in carbohydrates. Dieting and fasting should be strictly avoided. During an acute attack, pain may be contolled with narcotics or phenothiazines. Nausea and vomiting may respond to valium or chlorpromazine. Treatment to abort an acute attack includes therapy with intravenous panhematin (1-4 mg/kg QD to BID but no more than 6 mg/kg/day). Therapy for an acute attack should also include 400 gm of glucose daily either orally or intravenously. If symptoms persist after glucose supplementation, then therapy with panhematin should be considered; however, this may result in a prolonged delay (two days) before initiating panhematin therapy. Therefore, if an attack is moderate to severe, panhematin may be initiated during intravenous glucose therapy, but may be delayed in mild attacks. Conventional anticonvulsants may worsen an acute attack; however, gabapentin and vigabatrin may be effective in treating seizures associated with this disease.
VARIEGATE PORPHYRIA
This form of disease is secondary to a deficiency of protoporphyrinogen oxidase. Variegate porphyria is not as common as other forms of porphyria and is seen mostly in persons of Finnish and South African descent. Clinical symptoms range from skin manifestations similar to porphyria cutanea tarda or abdominal pain and neurologic abnormalities similar to acute intermittent porphyria. Diagnosis is established by demonstrating elevated levels of porphyrin precursors in stool samples. Levels of protoporphyrin and coproporphyrinogen are persistently elevated; whereas, levels of delta aminolevulinic acid, porphobilinogen and uroporphyrinogen are only elevated during acute attacks of abdominal pain. Complete lack of direct contact with sunlight is the only effective means of treatment for photosensitive symptoms. Intravenous heme (panhematin) at a dosage of 1 to 4 mg/kg QD to BID (but no more than 6 mg/kg/day) may be beneficial during an acute attack.
HEREDITARY COPROPORPHYRIA
This form of disease is secondary to a deficiency of coproporphyrinogen oxidase. This is an uncommon form of porphyria. Clinical symptoms are milder but similar to acute intermittent porphyria. There may also be symptoms of mild photosensitivity reactions. Elevated urinary levels of coproporphyrinogen III, delta aminolevulinic acid and porphobilinogen during attacks of abdominal pain establishes the diagnosis.
CONGENITAL ERYTHROPOIETIC PORPHYRIA
(Gunther’s Disease/ congenital hematoporphyria/ erythropoietic uroporphyria)
This form of disease is an autosomal recessive disorder which is secondary to a deficiency of uroporphyrinogen III synthase. Clinical manifestations include hydrops fetalis, cutaneous photosensitivity (blistering, erosions, and infections) and hypertrichosis. Ocular changes include keratoconjunctivitis, ectropion, symblepharon which may result in blindness. Hemolytic anemia and splenomegaly are common findings in this disorder. A unique feature of this form of disease is the appearance of reddish depositions of porphyrins in the teeth, a finding known as erythrodontia. Skeletal pathology includes fractures, vertebral collapse, osteopenia/osteoporosis, and osteolytic lesions. Symptoms usually begin during infancy. The diagnosis is established by measuring total and fractionated porphyrins in both the urine and erythrocytes. Also, measurement of erythrocyte uroporphyrinogen III synthase levels should be performed.
Avoidance of ultraviolet light is the most effective form of therapy. Blood transfusions and splenectomy may be effective in decreasing symptoms. Oral activated charcoal (60 gm TID) may also be effective.
ALAD-DEFICIENCY PORPHYRIA
This rare form of porphyria occurs secondary to a deficiency of delta-aminolevulinic acid dehydratase. Clinical symptoms are similar to acute intermittent porphyria (AIP). Diagnosis is inferred by the finding of increased levels of urinary delta-aminolevulinic acid.
HEPATOERYTHROPOIETIC PORPHYRIA
This is a rare form of disease which results from a severe UROD deficiency. Diagnostic testing is the same as for PCT. No effective therapeutic regimens exist.
PSEUDOPORPHYRIA
This cutaneous disorder is characterized by the development of vesicobullous lesions which occur without any biochemical porphyrin abnormalities. Bullae form on sun exposed areas of skin and are otherwise asymptomatic. Histologic examination of lesions reveals cell-poor subepidermal bullae, thickening and hyalinization of the dermal vessel walls plus dermal sclerosis, along with infiltration of mononuclear cells in the perivascular regions of the upper dermis. This disorder generally occurs as a side effect of certain medications such as amiodarone, bumetanide, etretinate, isotretinoin, dapsone, colchicine, furosemide, nalidixic acid, naproxen, pyridoxine, chlorthalidone and tetracycline. This disorder is also seen in patients who frequent tanning beds or require hemodialysis. Discontinuation of the inciting drug is generally curative.