Treatment Options in Acute Porphyria, Porphyria Cutanea Tarda, and Erythropoietic Protoporphyria Pauline Harper, MD, PhD Staffan Wahlin, MD
Corresponding author Pauline Harper, MD, PhD Porphyria Centre Sweden, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm SE-141 86, Sweden. E-mail:
[email protected] Current Treatment Options in Gastroenterology 2007, 10:444–455 Current Medicine Group LLC ISSN 1092-8472 Copyright © 2007 by Current Medicine Group LLC
Opinion statement The porphyrias are a group of uncommon metabolic diseases caused by enzyme deficiencies within heme biosynthesis that lead to neurotoxic or phototoxic heme precursor accumulation. There are four acute porphyrias characterized by neuropsychiatric symptoms: acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and 5-aminolevulinic acid dehydratase deficiency porphyria. Treatment includes elimination of any porphyrogenic factor and symptomatic treatment. Carbohydrate and intravenous heme administration constitute specific therapies in the disorders’ acute phase. The mainstay treatment in the cutaneous porphyrias is avoidance of sunlight exposure. In porphyria cutanea tarda and the two acute porphyrias with skin manifestations, variegate porphyria and hereditary coproporphyria, care of the vulnerable skin is important. In porphyria cutanea tarda, specific treatment is accomplished by a series of phlebotomies and/or by low-dose chloroquine administration. In erythropoietic protoporphyria, light-protective beta-carotene is prescribed.
Introduction Porphyrias are inherited metabolic diseases secondary to deficiencies in the activity of specific enzymes in the heme biosynthetic pathway. With the exception of the initial enzyme, catalytic deficiency at any of the seven subsequent steps in the heme biosynthetic chain may result in accumulation of toxic heme precursors [1]. Clinically, the porphyrias are divided into two main groups: the acute porphyrias, which present with neuropsychiatric symptoms, and the cutaneous porphyrias, which are characterized by dermal photosensitivity. Two of the acute forms of porphyria also present with photosensitivity. The autosomal dominant porphyrias are acute intermittent porphyria (AIP), familial porphyria cutanea tarda (PCT), hereditary coproporphyria (HCP), variegate porphyria (VP), and erythropoietic protoporphyria (EPP). Two rare forms are inherited in a recessive fashion: 5-aminolevulinic acid dehydra-
tase–deficient porphyria and congenital erythropoietic porphyria. Two mutations for PCT cause hepatoerythropoietic porphyria. Most porphyrias have low clinical penetrance, and symptoms are often triggered by specific endogenous or environmental porphyrogenic factors. Residual enzyme activity usually is enough to satisfy the physiologic heme demands [2••]. However, the recessive conditions exhibit very low residual enzyme activity and high clinical penetrance, often with manifestations from early childhood [2••]. The same is true for the extremely rare homozygous or compound heterozygous conditions of AIP, HCP, and VP. Porphyria symptoms result from the action of neurotoxic or phototoxic metabolites produced in the liver or bone marrow. Liver transplantation [3,4,5••] and/or bone marrow transplantation (BMT) [6,7] may be the final therapeutic alternatives.
Acute Porphyria, Porphyria Cutanea Tarda, and Erythropoietic Protoporphyria A firm porphyria diagnosis requires investigation handled by laboratories equipped with adequate meth-
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odologies. The sample collection procedure and sample type are critical to the investigation’s quality [8].
The acute porphyrias • The autosomal acute porphyrias, AIP, VP, and HCP, have low penetrance and manifest clinically almost exclusively after puberty. • AIP is the most common acute porphyria, with a worldwide prevalence of approximately one to two per 20,000 [1]. AIP’s clinical penetrance, even if limited, is high compared with VP and HCP, and women are affected more than men [9,10•]. • Pathophysiology, diagnostic principles, and acute symptom treatment are the same for all the acute porphyrias; therefore, AIP may serve as a model for the clinical approach to these disorders. • AIP is characterized by acute, basically neurologic, and potentially lifethreatening attacks precipitated by certain therapeutic drugs; reproductive hormones; or factors such as fasting, stress, infection, alcohol, cannabis, and smoking. • The triggering factors in acute porphyria operate via hepatic heme biosynthesis acceleration through induction of the ubiquitous form of 5-aminolevulinic acid synthase (ALAS1), the initial and rate-controlling enzyme of hepatic heme biosynthesis [11••]. Under conditions of strong hepatic ALAS1 induction, the deficient porphobilinogen deaminase (PBGD) catalytic step becomes overloaded by its substrate, porphobilinogen (PBG). Consequently, PBG and the substrate of the previous enzyme, 5-aminolevulinic acid (ALA), accumulate. Thus, the acute attack is invariably accompanied by excess formation and renal excretion of the porphyrin precursors ALA and PBG in which the latter gives rise to a red discoloration of the urine.
Clinical manifestations of the acute porphyria attack • Acute porphyria is a neuropsychiatric condition with symptoms from the autonomous, peripheral, and central nervous systems [10•,12••,13•–15•]. • Severe abdominal pain without peritoneal signs is the acute attack’s most common symptom, present in more than 90% of patients and often accompanied by nausea; vomiting; abdominal distention; constipation; or, occasionally, diarrhea. • Muscle pain is usually present. • Involvement of respiratory functions may lead to respiratory failure. • Bladder dysfunction or paresis occurs. • Hypertension and tachycardia are often present. • Sudden death due to cardiac arrhythmia may occur. • Hyponatremia because of sodium loss, overhydration, or hypothalamic involvement (SIADH) is common [16]. • Seizures affect approximately 20% of the patients secondary to hyponatremia, hypomagnesemia, or central nervous system involvement. Psychiatric symptoms such as depression, insomnia, agitation, confusion, and hallucinosis may be present.
Treatment of the attack of acute porphyria • The patient should be hospitalized and given symptomatic relief via nonporphyrogenic drugs. Any possible porphyrogenic medication should be
446 Liver Disease withdrawn, and fluid and electrolyte balance controlled. A urine specimen should be collected for PBG analysis as soon as possible. • Specific treatment should be started and aimed to repress hepatic ALAS1 by administration of glucose, and hemin, if needed. Hemin is clinically more effective than glucose [10•,12••,13•,17••,18]. Drugs for symptomatic treatment may be administered in standard doses unless otherwise specified.
Administration of carbohydrate Carbohydrate-based calories should be provided via oral or intravenous glucose administration at a minimum of 300 to 500 g of carbohydrate daily (eg, 2 L of 10% glucose in saline per 24 hours).
Administration of human hemin In severe or prolonged attacks, hemin should be administered in the form of Normosang (Orphan Europe, Paris, France) or Panhematin (OVATION Pharmaceuticals, Inc., Deerfield, IL), according to manufacturer directives. Thrombophlebitis, the main adverse effect of hemin administration, is avoided by dissolving hemin in human serum albumin (HSA). The required amount of Normosang can be dissolved into a glass vial containing 100 mL of 20% (200 mg/mL) HSA solution [10•,17••,18]. Panhematin is administered in an equimolar albumin solution by reconstituting the 313-mg vial of lyophilized hemin with 132 mL of 25% HSA instead of sterile water [19•]. Consensus favors doses of 3 to 4 mg/kg body weight (up to 250 mg Normosang or 313 mg Panhematin) as a daily albumin solution infused into a large vein for 4 days. The infusion is administered over 40 to 60 minutes [19•], followed by rinsing with physiologic saline. The hemin solution should be filtered before administration and is considered stable for approximately 1 hour. Hift and Meissner [10•] have reported a good clinical effect using a lower standard dose of 125 mg heme arginate, irrespective of body weight, in 20% human albumin solution. Rare side effects are fever, aches, malaise, hemolysis, and transitory renal failure after very high doses.
Symptomatic treatment: pain The patient should be given a private and darkened room and left undisturbed. Nonopioid analgesics are seldom effective. Morphine, 10- to 15-mg intramuscular injections one to three times daily for 1 to 4 days, is preferred. Buprenorphine can be administered between morphine doses as 0.3- to 0.6-mg intramuscular injections or 0.2 to 0.4 mg sublingually four times daily. Pethidine (meperidine) should be avoided due to its neurotoxic metabolite, norpethidine. The addition of a suitable neuroleptic (eg, chlorpromazine, 10–15 mg/dose) decreases analgesic requirements.
Symptomatic treatment: nausea, vomiting Chlorpromazine, droperidol, prochlorperazine, or ondansetron should be administered.
Symptomatic treatment: agitation, insomnia, anxiety, confusion, psychosis Chlorpromazine, fluphenazine, or lorazepam may be administered. The porphyric patient may respond to lower doses than usually recom-
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mended. Psychiatric symptoms fluctuate. Serum sodium and magnesium concentrations should be checked.
Symptomatic treatment: tachycardia and hypertension Propranolol should be administered to control sympaticotonic manifestations. Patients often respond to low doses (eg, 10 mg three times daily), but higher doses may be needed.
Symptomatic treatment: cardiac arrhythmia Serum electrolytes should be monitored and corrected if necessary. Autonomous lability can lead to orthostatic arrhythmia, hypotension, and circulatory collapse.
Symptomatic treatment: seizures Possible hyponatremia or hypomagnesemia should be controlled and corrected if necessary. Most antiseizure drugs can exacerbate acute porphyria. Intravenous diazepam is used for acute treatment, clonazepam or gabapentin for maintenance treatment.
Symptomatic treatment: hypomagnesemia Daily infusions of magnesium sulfate, 30 to 40 mmol, should be administered until resolved, followed by a daily maintenance dose of 10 mmol if needed.
Symptomatic treatment: hyponatremia Hyponatremia presents secondary to fluid loss, low intake, iatrogenic overhydration, or renal loss secondary to porphyria-induced renal lesion. It also may be caused by inappropriate hypophyseal secretion of antidiuretic hormone (SIADH). Depending on cause, hyponatremia should be corrected with fluid restriction or sodium chloride infusion according to standard protocol, with a maximum correction rate of 8 to 10 mmol/L/d.
Symptomatic treatment: muscle weakness Muscle weakness is treated via early-activating physiotherapy. One should be alert to respiratory failure.
Symptomatic treatment: respiratory muscle paresis Respiratory muscle paresis is treated via mechanical ventilator.
Symptomatic treatment: dysphagia Dysphagia is treated via nasogastric tube for peroral administration of fluid and nutrients.
Symptomatic treatment: bladder paresis A urethral catheter should be inserted. Xylocaine (Abraxis Pharmaceutical Products, Schaumburg, IL) gel is safe to use.
Symptomatic treatment: constipation Sorbitol, senna, or lactulose should be administered.
Symptomatic treatment: bowel paresis (ileus) Neostigmine should be administered.
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Symptomatic treatment: diarrhea Loperamide should be administered.
Recurrent acute attacks Patients with recurrent acute attacks should be evaluated on each occasion to rule out disorders that may mimic acute porphyria. Urinary PBG should be monitored. In patients receiving hemin repeatedly, serum ferritin levels should be monitored for control of iron overloading. Prolonged, repeated hemin therapy may lead to apparent decline in therapeutic efficacy, suggesting tolerance [10•].
Prevention of recurrent attacks Prophylactic hemin treatment (eg, 1 ampoule of hemin) every 1 or 2 weeks should be tried in patients with repeated acute attacks [10•,12••,13•]. If effective, this treatment has considerable advantages, as it can be administered without hospitalization, lessens the need for opiates or other analgesics, and probably also reduces the total amount of administered exogenous heme.
Recurrent premenstrual acute attacks Prophylactic heme therapy should be tried before considering hormonal treatment of women with predictable, recurrent acute attacks in connection with the menstrual cycle. In some women, premenstrual attacks may be prevented by lowdose gestagen oral contraceptive or by a low-dose combination of estrogen and gestagen, as it may stabilize the endogenous steroid production at a low level. Gonadotropin-releasing hormone analogues (GnRHas) to suppress the menstrual cycle can be considered [1,12••]. The treatment should begin within the first 2 days after menstruation onset. Buserelin as nasal spray, 0.9 to 1.2 mg/d administered as 0.15 mg in each nostril three or four times daily, or triptorelin depot, 3.75 mg subcutaneously once every month [20], is administered to achieve and maintain medical oophorectomy with amenorrhea. After induction of menopause, estrogen deficiency symptoms are blocked by administration of estradiol combined with the gestagen norethisterone in lowest available dose, preferably as percutaneous patch. Bone mineral density should be tested for early detection of osteoporosis. Bisfosfonate therapy is added if indicated [12••,20]. Not all women benefit from the GnRHa therapy, and treatment advantages must be balanced against side effect risks.
Subacute/subchronic symptoms Minor symptoms often can be handled at home by carbohydrate supplementation; rest; and analgesics such as acetylsalicylic acid, paracetamol, or sublingual buprenorphine. Any suspected precipitating factor, including stress, is eliminated.
Clinically asymptomatic but biochemically active AIP carriers This is a condition characterized by permanently increased concentrations of ALA and PBG in urine and plasma in the absence of clinical symptoms [21]. No specific treatment is needed, but the patient should be submitted to a surveillance program for timely detection of the late complications of acute porphyrias.
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Hormonal contraceptives and acute porphyria Birth control pills, although potentially porphyrogenic, are widely used. In several patients, contraceptive pill use has precipitated their first acute attack, whereas others have remained asymptomatic. Occasionally, patients experience relief from AIP symptoms [9,12••]. Natural estrogens are less porphyrogenic than synthetic hormones. Gestagen is the more porphyrogenic component of combination pills. The modern low-dose hormonal oral contraceptives probably are less porphyrogenic than the older varieties. Combinations of norethisterone and ethinylestradiol have been welltolerated in AIP carriers, as have intrauterine, low-dose, progesterone anticonceptive devices (levonorgestrel) that limit hepatic exposure to the potentially porphyrogenic gestagen component [9]. Intrauterine devices such as copper spiral are an alternative to consider. The patient should be monitored carefully with regard to clinical status and urinary excretion of PBG, at least during the first months after the prescription of an oral contraceptive. The patient should avoid other precipitating factors, such as stress, alcohol ingestion, fasting, and smoking. The treatment should be interrupted in case of porphyria symptoms.
Pregnancy and acute porphyria Pregnancy is usually well-tolerated, but the hormonal changes occasionally may exacerbate the disease [9,12••]. Proper nutrition and hydration are important in hyperemesis, during labor, postpartum, and in the puerperium. Metoclopramide for treating hyperemesis should be avoided. Only drugs or anesthetics classified as safe in porphyria should be used. Acute attacks should be treated in the standard way. No evidence of adverse effects exists for heme therapy on mother or child [22].
Hormone treatment in infertility Ovarian stimulation with gonadotropins has been reported to precipitate acute porphyric attacks [23,24] or to be well-tolerated [9]. Caution is warranted.
Hormone replacement in menopause Postmenopausal women are less prone to AIP morbidity. Hormone replacement therapy in the form of estradiol–norethisterone percutaneous patch, estradiol patch combined with progesterone tablets, or estradiol–progesterone pills and vaginal estradiol tablets is well-tolerated [9].
Drugs in acute porphyria The international drug list should be consulted before any drug is prescribed [25••]. If no safe alternative is available, protective measures are needed. These include attentiveness to other precipitating factors acting in parallel, close clinical observance, monitoring of urine color and PBG excretion, and readiness to treat an acute attack [11••,12••,18,26••].
Preventive measures The patient should be fully aware of the genetic predisposition, informed about precipitating factors, and provided with guidelines concerning treatment and which drugs to use and to avoid. Warning cards or bracelets are valuable when the patient seeks health care [12••,18]. Available website resources with accurate information about porphyria disorders should be propagated extensively [17••,27–29,30•].
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Early recognition and treatment of late complications Hepatocellular carcinoma (HCC) incidence in acute porphyrias is high [31]. We advocate biannual surveillance with contrast-enhanced liver ultrasonography after age 50. Early tumor detection is critical to outcome in HCC. Hypertension is treated actively with safe drugs. Patients with evidence of impaired renal function should be referred to nephrologists.
Liver transplantation The recent report on successful liver transplantation in a young AIP patient with recurrent acute porphyria attacks [3] points to a new therapeutic option for seriously afflicted patients. The decision to transplant may be problematic in this disease with unpredictable clinical course and instances of spontaneous remission. For the patient with HCC, liver transplantation is a good option.
Renal transplantation Patients with active disease and terminal renal failure should be considered for kidney transplantation. In our experience, progression of pre-existing neuropathies is common after starting dialysis. Due to uroporphyrin-I accumulation in plasma, which derives from condensation of accumulated PBG, a risk also exists for painful and disabling skin symptoms resembling severe PCT [32].
Enzyme therapy Enzyme therapy with recombinant human PBGD (Zymenex A/S, Hillerod, Denmark) administered intravenously was demonstrated to be safe, welltolerated, and effective in reducing plasma and urinary PBG concentrations [33] but did not affect clinical endpoints in acute AIP attacks [34].
Cell therapy Repeated portal hepatocyte administration ameliorated the metabolic abnormality in a mouse model for AIP [35].
Gene therapy The hepatic gene defect causing PBGD deficiency in AIP has been corrected in animal models using adenovirus vectors [36], and long-term expression has been achieved using adeno-associated virus vectors that are less harmful to the liver [37].
PCT • With a prevalence of approximately one in 10,000, PCT is one of the two most common porphyrias. This cutaneous hepatic porphyria is caused by reduced hepatic activity of uroporphyrinogen decarboxylase (UROD), which generates polycarboxylated porphyrin overproduction and excretion in urine [15•,38,39•]. Skin manifestations include fragility, blisters, hyperpigmentation, and hypertrichosis due to phototoxic porphyrins accumulated in the skin. • In familial PCT, a genetic defect causes partial deficiency of UROD activity in all cells [38]. The more common sporadic form of PCT has no recognized genetic background. Alcohol consumption, viral hepatitis, and estrogen administration are main factors associated with clinically overt PCT’s emergence. Hepatic siderosis and carrier state for hereditary hemochromatosis are predisposing factors, and hepatic iron store reduction is a basic treatment strategy [39•,40].
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Treatment of PCT, sporadic and familial forms Treatment of skin lesions Treatment is restricted to avoidance of sun by protective clothing and opaque sunscreens, avoidance of skin trauma, and infection care.
Removal of precipitating factors Exposures to alcohol, estrogens, iron supplementation, or certain herbicides should be interrupted, and viral hepatitis treated.
Iron depletion therapy Phlebotomy invariably leads to clinical and biochemical remission and is the treatment of choice for patients with hemosiderosis and hemochromatosis gene mutations. Repeated venesections of 300 to 400 mL over 1- to 3-week intervals influence the basic pathogenic mechanisms by mobilizing hepatic iron for de novo hemoglobin biosynthesis. Therapy is monitored with hemoglobin concentration and serum ferritin. The number of phlebotomies required for remission depends on the individual. Adding low-dose oral chloroquine to the phlebotomy regimen accelerates treatment response.
Chloroquine therapy Low-dose oral chloroquine, 125 mg twice weekly, reduces hepatic concentrations of porphyrins by forming water-soluble complexes facilitating renal excretion. Clinical effect generally is seen within approximately 6 months, and therapy should continue until full biochemical remission, usually more than 1 year.
Desferrioxamine As an alternative to phlebotomy, subcutaneous desferrioxamine infusions can reduce hepatic iron stores. The complexed iron is excreted in urine and cleared by dialysis.
Coexistence of hepatitis C Patients with overt PCT suffering from hepatitis C virus infection should receive antiviral therapy. Iron depletion augments treatment response.
PCT in childhood In familiar PCT, especially in carriers of the HFE genotype, cutaneous symptoms may present in early childhood. Preferred therapy consists of a series of small-volume phlebotomies or chloroquine dosed according to body weight.
PCT during pregnancy Cutaneous symptoms may appear in early pregnancy and are preferentially treated by phlebotomy. In refractory cases, low-dose chloroquine may be added, as no fetal risk has been recognized. Due to hemodilution and iron depletion, symptoms typically improve with advancing pregnancy.
PCT in women taking contraceptive pills or under estrogen supplementation Stopping female sex hormone therapy often is sufficient for remission. Upon reintroduction after remission, intrauterine or transdermal therapy should be considered to reduce porphyrogenic hepatic metabolism.
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PCT in patients with end-stage renal disease undergoing dialysis Iron removal by phlebotomy or subcutaneous desferrioxamine is seldom a realistic option considering the anemia associated with chronic kidney failure. Chloroquine is unsuitable in kidney failure. Symptoms may improve by mobilizing hepatic iron stores for hemoglobin biosynthesis with erythropoietin without simultaneous iron administration. Small phlebotomies (50–100 mL) may be tried. Porphyrins are poorly filtrated via ordinary dialysis membranes and accumulate in blood. Dialyzers with ultrapermeable membranes and with blood flow rates higher than those routinely used effectively reduce plasma porphyrin concentrations. In extreme cases, plasmapheresis should be considered. The only curative alternative in PCT associated with renal failure is renal transplantation.
Monitoring of therapy Urinary (or plasma) porphyrin concentrations are followed every other month until normalization.
Late complications PCT is associated with liver damage. Untreated or insufficiently treated individuals with longstanding active PCT are at risk of developing HCC, especially in PCT associated with hepatitis C or alcoholic liver disease [39•,40].
EPP • In EPP, deficient function of ferrochelatase, the last enzyme in heme biosynthesis, causes protoporphyrin accumulation. EPP’s prevalence is one in 75,000 to one in 200,000, and the inheritance pattern is complex. A deleterious mutation on one allele together with a polymorphism, present in approximately 10% of the population [41], on the other allele explains a residual enzyme activity below 35% of normal, which is required for the EPP phenotype [2••]. The accumulated protoporphyrin mainly originates in bone marrow and leaves the body via the hepatobiliary route. The photoreactivity and hydrophobicity of protoporphyrin explain the main clinical manifestations: severe acute photosensitivity and liver disease. One quarter to one third of EPP individuals have some kind of liver involvement, and approximately 5% develop advanced liver disease [42]. Gallstones are common. • The diagnosis is based on elevated concentrations of erythrocyte-free protoporphyrin and the presence of a characteristic plasma fluorescence marker at 635 nm [8].
Treatment of cutaneous photosensitivity Avoidance of direct exposure to sunlight The cornerstone of treatment is avoidance of direct sunlight exposure and use of protective clothing. Visible skin damage seldom accompanies the severe pain. The patient should be given medical information to help achieve better understanding at school, work, etc. Lifestyle counseling and psychosocial support should be provided, if suitable.
Treatment of acute skin pain and/or erythema Cold bath or cold compress, oral analgesics, and antihistaminics are recommended to mitigate the skin symptoms.
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Sunscreens and protective pigmentation Topical UV sunscreens offer only partial blockage of exciting wavelengths. Reflecting and pigmented blocking agents such as topical zinc or titanium oxide or tanning agents containing dihydroxyacetone may be of some benefit [42,43].
Systemic beta-carotene A frequently used tolerance-enhancing agent is oral beta-carotene. Daily doses of 180 to 300 mg may be required in adults to maintain recommended serum concentrations of 11 to 15 μmol/L [15•,42]. Recommended daily doses in children are 60 to 90 mg (aged 1–4 years), 90 to 120 mg (aged 5–8 years), 120 to 150 mg (aged 9–12 years), and 150 to 180 mg (aged 13–16 years). Blood concentration reaches steady state after approximately 3 weeks.
Protection from medical light sources The risk for phototoxic injury in endoscopy, laparoscopy, and nontransplant surgery is negligible. Protective filters to avoid serious phototoxic injuries to abdominal organs are needed during liver transplantation. Light sources should be covered with filters that block wavelengths below 470 nm [44].
Treatment of hepatobiliary complications • The most serious liver complication is cholestatic liver failure with accelerating hepatic protoporphyrin accumulation. In most cases, underlying cirrhosis is already present. At an advanced stage, extreme abdominal pain, neuropathy, and marked photosensitivity arise. Prophylactic treatment’s value is unclear, but in overt liver disease, several treatment targets are possible [7,45••].
Reducing protoporphyrin in transit Erythrocyte transfusion reduces protoporphyrin production by negative feedback. Plasma or erythrocyte aphaeresis removes circulating protoporphyrin [7,45••].
Heme therapy Exogenous heme may restore the hepatocyte heme pool and improve liver function tests [6], but it has no proven effect on erythroid heme synthesis.
Increasing protoporphyrin excretion Ursodeoxycholic acid or chenodeoxycholic acid may have positive effects in altering bile composition, protecting cholangiocytes and hepatocytes from the cytotoxic effect of hydrophobic bile acids, and stimulating biliary secretion [7,45••]. Alpha-tocopherol may counter a lack of endogenous scavengers, and oral charcoal and cationic exchange resins stop enterohepatic protoporphyrin recirculation.
Liver transplantation Lifesaving liver transplantation has been done in more than 40 cases since 1983. Patient survival is similar to that of other indications, but recurrent graft disease is common [5••], as the excess production by the erythroid tissue remains unchanged.
BMT BMT corrects the tissue primarily responsible for protoporphyrin overproduction. It has been done after medical reversal of liver failure
454 Liver Disease [7] and after liver transplantation for recurrent graft disease [6]. The inherent risks make BMT unsuitable for the majority of EPP patients who merely suffer from photosensitivity. In liver cirrhosis, even if compensated, BMT risks are likely to be unacceptable. In graft disease and in recurrence after liver transplantation, or if medical reversal of cholestasis without underlying cirrhosis can be achieved, BMT should be considered.
Surveillance program • Annual follow-ups including porphyrin metabolism, blood, and standard liver function tests are recommended. Monitoring the liver function tests is mandatory, and elevated results should incite liver biopsy with the aim of identifying progressive liver disease. EPP patients should be vaccinated against hepatitis A and B. Avoidance of alcohol consumption and fasting are important [45••].
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance Anderson KE, Sassa S, Bishop DF, Desnick RJ: Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias. In The Metabolic and Molecular Bases of Inherited Disease, edn 8. Edited by Scriver CR, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 2001:2991–3062. 2.•• Badminton MN, Elder GH: Molecular mechanisms of dominant expression in porphyria. J Inherit Metab Dis 2005, 28:277–286. Relevant for understanding the relationship between genotype and phenotype in the porphyrias. 3. Soonawalla ZF, Orug T, Badminton MN, et al.: Liver transplantation as a cure for acute intermittent porphyria. Lancet 2004, 363:705–706. 4. Stojeba N, Meyer C, Jeanpierre C, et al.: Recovery from a variegate porphyria by a liver transplantation. Liver Transpl 2004, 10:935–938. 5.•• McGuire BM, Bonkovsky HL, Carithers RL, Jr, et al.: Liver transplantation for erythropoietic protoporphyria liver disease. Liver Transpl 2005, 11:1590–1596. This article reviews post–liver transplant survival, the risk of recurrent liver disease, and other clinical aspects in a large group of EPP patients. 6. Rand EB, Bunin N, Cochran W, et al.: Sequential liver and bone marrow transplantation for treatment of erythropoietic protoporphyria. Pediatrics 2006, 118:e1896–e1899. 7. Wahlin S, Aschan J, Bjornstedt M, et al.: Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis. J Hepatol 2007, 46:174–179. 8. Deacon AC, Elder GH: ACP Best Practice No 165: front line tests for the investigation of suspected porphyria. J Clin Pathol 2001, 54:500–507. 9. Andersson C, Innala E, Bäckström T. Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population-based study in northern Sweden. J Intern Med 2003, 254:176–183. 10.• Hift RJ, Meissner PN: An analysis of 112 acute porphyric attacks in Cape Town, South Africa: evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Medicine 2005, 84:48–60. A comprehensive article including a large group of AIP and VP patients, comparing clinical aspects and treatment outcome. 1.
11.•• Thunell S: (Far) outside the box: genomic approach to acute porphyria. Physiol Res 2006, 55(Suppl 2):S43–S66. An excellent article discussing mechanisms by which different endogenous and exogenous porphyrogenic factors provoke an induction of hepatic ALAS1. 12.•• Anderson KE, Bloomer JR, Bonkovsky HL, et al.: Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med 2005, 142:439–450. Excellent review discussing diagnosis, symptoms, treatment, and counseling aspects of the acute porphyrias. 13.• Kauppinen R: Porphyrias. Lancet 2005, 365:241–252. Excellent and concise article discussing important diagnostic, clinical, and therapeutic aspects of all the porphyrias. 14.• Bonkovsky HL: Neurovisceral porphyrias: what a hematologist needs to know. Hematology Am Soc Hematol Educ Program 2005:24–30. A short and didactic paper considering relevant biochemical, clinical, and therapeutic aspects of the acute porphyrias. 15.• Sassa S: Modern diagnosis and management of the porphyrias. Br J Haematol 2006, 135:281–292. Excellent and concise article discussing important diagnostic, clinical, and therapeutic aspects of all the porphyrias. 16. Schreiber A, Elitok S, Kettritz R: Solving electrolyte disturbances with the Ehrlich reagent. Nephrol Dial Transplant 2003, 18:1217–1219. 17.•• The European Porphyria Initiative website. http://www. porphyria-europe.org/. Accessed July 10, 2007. A multilingual website providing accurate information on porphyrias for doctors and patients. 18. Thunell S, Bjernevik K, Thunell G, Harper P: Patient’s and Doctor’s Guide to Medication in Acute Porphyria 2005. Stockholm: Swedish Porphyria Association; 2005. 19.• Anderson KE, Bonkovsky HL, Bloomer JR, Shedlofsky SI: Reconstitution of hematin for intravenous infusion. Ann Intern Med 2006, 144:537–538. A practical description of reconstituting hemin for injection with 25% HSA. 20. Castelo-Branco C, Vicente JJ, Vanrell JA: Use of gonadotropin-releasing hormone analog with tibolone to prevent cyclic attacks of acute intermittent porphyria. Metabolism 2001, 50:995–996.
Acute Porphyria, Porphyria Cutanea Tarda, and Erythropoietic Protoporphyria Floderus Y, Sardh E, Moller C, et al.: Variations in porphobilinogen and 5-aminolevulinic acid concentrations in plasma and urine from asymptomatic carriers of the acute intermittent porphyria gene with increased porphyrin precursor excretion. Clin Chem 2006, 52:701–707. 22. Badminton MN, Deybach JC: Treatment of an acute attack of porphyria during pregnancy. Eur J Neurol 2006, 13:668–669. 23. Seiden WB, Kelly LP, Ali R: Acute intermittent porphyria associated with ovarian stimulation. A case report. J Reprod Med 2003, 48:201–203. 24. Wang JG, Guarnaccia M, Weiss SF, et al.: Initial presentation of undiagnosed acute intermittent porphyria as a rare complication of ovulation induction. Fertil Steril 2006, 86:462.e1–462.e3. 25.•• The Drug Database for Acute Porphyria website. http:// www.drugs-porphyria.org/. Accessed July 10, 2007. The Drug Database for Acute Porphyria is a searchable system developed to provide evidence-based information about selecting safe drugs for patients with acute porphyria. 26.•• Thunell S, Pomp E, Brun A: Guide to drug porphyrogenicity prediction and drug prescription in the acute porphyrias. Br J Clin Pharmacol 2007 [Epub ahead of print]. This is an outstanding work describing evidence-based techniques for assessment of drug porphyrogenicity and nonporphyrogenicity in acute porphyrias. Used in the Scandinavian drugs-porphyria website. 27. Porphyria South Africa website. http://www.uct.ac.za/ depts/porphyria/. Accessed July 10, 2007. 28. The American Porphyria Foundation website. http://www. porphyriafoundation.com/. Accessed July 10, 2007. 29. The Canadian Porphyria Foundation. http://www.cpf-inc. ca. Accessed July 10, 2007. 30.• Deybach JC, Badminton M, Puy H, et al.: European porphyria initiative (EPI): a platform to develop a common approach to the management of porphyrias and to promote research in the field. Physiol Res 2006, 55(Suppl 2):S67–S73. Describes the European Porphyria Initiative, an international collaborative network of porphyria experts. 31. Andant C, Puy H, Bogard C, et al.: Hepatocellular carcinoma in patients with acute hepatic porphyria: frequency of occurrence and related factors. J Hepatol 2000, 32:933–939. 32. Harper P, Sardh E, Henrichson A, et al.: Plasma porphyrin precursors and porphyrins in AIP-patients with chronic renal failure [abstract S06-3]. Paper presented at the Porphyrins and Porphyrias International Meeting. Rotterdam, The Netherlands; April 29–May 3, 2007. http://www2.eur. nl/fgg/emco/porphyrias2007/downloads/abstractbook.pdf. Accessed September 26, 2007. 33. Sardh E, Rejkjaer L, Andersson DE, Harper P: Safety, pharmacokinetics and pharmocodynamics of recombinant human porphobilinogen deaminase in healthy subjects and asymptomatic carriers of the acute intermittent porphyria gene who have increased porphyrin precursor excretion. Clin Pharmacokinet 2007, 46:335–349. 21.
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Andersson C, Peterson J, Anderson K, et al.: Randomized clinical trial of recombinant human porphobilinogen deaminase (rhPBGD) in acute attacks of porphyria [abstract S06-5]. Paper presented at the Porphyrins and Porphyrias International Meeting. Rotterdam, The Netherlands; April 29–May 3, 2007. http://www2.eur.nl/fgg/emco/porphyrias2007/downloads/abstractbook.pdf. Accessed September 26, 2007. 35. Nowak G, Yin Z, Ellis EC, et al.: Hepatocyte transplantation ameliorates the metabolic abnormality in a mouse model of acute intermittent porphyria. Transplantation 2006, 82(Suppl 2):216–217. 36. Johansson A, Nowak G, Möller C, et al.: Adenoviral-mediated expression of porphobilinogen deaminase in liver restores the metabolic defect in a mouse model of acute intermittent porphyria. Mol Ther 2004, 10:337–343. 37. González-Aseguinolaza G, Prieto J, Rodríguez-Pena M, et al.: AAV-mediated liver-specific expression of porphobilinogen deaminase protects against acute attack induced by phenobarbital injection in a mouse model of acute intermittent porphyria [abstract S05-5]. Paper presented at the Porphyrins and Porphyrias International Meeting. Rotterdam, The Netherlands; April 29–May 3, 2007. http://www2.eur.nl/fgg/ emco/porphyrias2007/downloads/abstractbook.pdf. Accessed September 26, 2007. 38. Badminton MN, Elder GH: Management of acute and cutaneous porphyrias. Int J Clin Pract 2002, 56:272–278. 39.• Kostler E, Wollina U: Therapy of porphyria cutanea tarda. Expert Opin Pharmacother 2005, 6:377–383. The article covers most of PCT’s clinical aspects and has a good selection of references. 40. Thunell S, Harper P: Porphyrins, porphyrin metabolism, porphyrias. III. Diagnosis, care and monitoring in porphyria cutanea tarda--suggestions for a handling programme. Scand J Clin Lab Invest 2000, 60:561–579. 41. Wiman A, Floderus Y, Harper P: Novel mutations and phenotypic effect of the splice site modulator IVS3-48C in nine Swedish families with erythropoietic protoporphyria. J Hum Genet 2003, 48:70–76. 42. Thunell S, Harper P, Brun A: Porphyrins, porphyrin metabolism and porphyrias. IV. Pathophysiology of erythyropoietic protoporphyria--diagnosis, care and monitoring of the patient. Scand J Clin Lab Invest 2000, 60:581–604. 43. Holme SA, Anstey AV, Finlay AY, et al.: Erythropoietic protoporphyria in the U.K.: clinical features and effect on quality of life. Br J Dermatol 2006, 155:574–581. 44. Wahlin S, Harper P, Brun A: Protection from phototoxic injury in erythropoietic protoporphyria [abstract S07-3]. Paper presented at the Porphyrins and Porphyrias International Meeting. Rotterdam, The Netherlands; April 29–May 3, 2007. http://www2.eur.nl/fgg/emco/porphyrias2007/downloads/ abstractbook.pdf. Accessed September 26, 2007. 45.•• Anstey AV, Hift RJ: Liver disease in erythropoietic protoporphyria: insights and implications for management. Gut 2007, 56:1009–1018. An exhaustive review on hepatic complications in EPP. 34.
