Q J Med 2004; 97: 115-126
QJM vol. 97 no. 3 (c) Association of Physicians 2004; all rights reserved.
Review |
Managing malignant disease in patients with porphyria
From the 1Department of Cancer Medicine, Faculty of Medicine, Imperial College London, and 2Department of Clinical Biochemistry, King's College Hospital, London, UK
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Summary |
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Certain types of porphyria have an increased incidence of malignant disease. In addition, patients with all forms of porphyria may develop malignant disease as a ‘normal life event’. The investigation and treatment of porphyric patients with malignant disease requires specific precautions to minimize the risk of an acute porphyric attack, and to ensure optimum treatment of the malignancy. We briefly review the biochemical basis, clinical features and current management of porphyria in cancer patients.
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Biochemical basis of the porphyrias |
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The porphyrias represent a collection of seven disorders due to genetic defects in haem biosynthesis (Table 1). The pathway starts and finishes in the mitochondrial matrix, so that the final product of the pathway, haem, inhibits the first and rate-limiting enzyme reaction, ALA synthase (ALA-S), in haem biosynthesis (Figure 1). In situations of increased hepatic haem demand, ALA-S is de-repressed, leading to the accumulation of
-amino-laevulinate (ALA), the putative neurotoxin responsible for the main features of the acute porphyria attack. This most commonly occurs in acute intermittent porphyria (hydroxmethyl bilane synthase deficiency) and in the extremely rare ALA dehydrative deficiency. Paradoxically, variegate porphyria and hereditary coproporphyria are accompanied by both neurological and dermatological manifestations, although the defects are late in the pathway. This has recently been resolved: protoporphyrinogen and coproporphyrinogen, which accumulate in these porphyrias and cause the photosensitivity, are also inhibitors of hydroxy methyl bilane synthase, thus simulating the defect in acute intermittent porphyria.
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The precise mechanism of the neuropsychiatric toxicity is not clear. ALA, a glutamate analogue, has been implicated in this regard, and its urinary levels correlate well with clinical manifestations and response to treatment. Neuronal haem deficiency, vascular insufficiency, free-radical-mediated reactions and porphobilinogen toxicity are alternate pathogenic mechanisms. The dermatological manifestations are more clearly understood, and relate to the accumulation of porphyrin intermediates within the dermis. Exposure to ultraviolet light activates these compounds, leading to free radical formation and cell damage, probably mediated via lysosomal disruption.
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Clinical features of the porphyrias |
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Clinically the porphyrias may be subdivided into the neuropsychiatric (acute), dermatological or mixed types (Table 1). Acute attacks were the most feared manifestation, and are mainly a consequence of central, peripheral and autonomic nervous damage. Seizures, psychiatric symptoms, disturbed consciousness, muscle weakness and paralysis, vomiting, abdominal pain, constipation, tachycardia and hypertension are well-recognized features of an acute attack. Skin lesions range from a burning sensation on exposure to sunlight (erythropoietic protopoprhyria), vesicle formation with scarring (porphyria cutanea tarda, variegate porphyria, hereditary coproporphyria) to severe tissue damage with loss of digits, facial appendages and major scarring (congenital erythropoietic porphyria). The mixed forms show acute attacks (usually less severe than occurs in acute intermittent porphyria) with vesicle formation and minor scarring in sun-exposed areas.
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Laboratory diagnosis of porphyrias |
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Diagnosis of the different forms of porphyria has been described in detail elsewhere.1 Briefly, investigations are designed to ascertain whether an acute attack is in progress and to establish whether the symptoms experienced such as severe abdominal pain are due to acute porphyria. Assays of urinary amino laevulinic (ALA) and porphobilinogen (PBG) assist in this differential diagnosis. Normal levels of ALA in particular, and of PBG, indicate that the patient is not suffering from an acute attack, but do not exclude an underlying porphyria. Markedly raised excretion of ALA and PBG, which improves following an infusion of the specific treatment haem arginate, confirms the diagnosis of acute porphyria. Intermediate values may cause some diagnostic difficulty, but a therapeutic trial of haem arginate usually proves of value. Differentiation of the four types of acute or mixed porphyria requires specialist biochemical analysis of plasma, red cells, urine and faeces, usually undertaken at a specialist centre. Although the enzyme defects underlying the porphyrias have been identified, molecular genetics are not yet suitable for primary diagnostic purposes. Mutational analysis for the HMBS, COX and PPOX genes underlying acute intermittent, hereditary coproporphyria and variegate porphyrias, respectively, has identified more than 300 different mutations. Analysis of gene mutations is largely used for family studies, allowing pre-symptomatic diagnosis, and when biochemical investigations are equivocal.
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Treatment of porphyrias |
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The mainstay of treatment is the prevention (as far as possible) of acute attacks, and the avoidance of skin lesions. Approximately 75% of acute attacks have identifiable precipitants, e.g. porphyrinogenic drugs, infections, malignancies, alcohol, tobacco, illicit drug use, fasting, pre-menstrual, stress (e.g. anaemia, vigorous exercise, travel), and these should be avoided where possible. Maintenance of a high carbohydrate diet or at least not missing meals may be helpful. In patients with severe regular pre-menstrual attacks, induction of an artificial menopause with a gonadorelin analogue may be helpful. For patients with severe recurrent attacks requiring hospitalization, regular weekly or fortnightly prophylactic haem arginate infusions may be necessary. Erythropoietin is helpful in some patients, and hepatic transplantation has been effective in a severely affected patient with almost continuous attacks. Enzyme replacement therapy should be available in the not too distant future.
Avoidance of porphyrinogenic drugs and treatment of intercurrent disease with drugs on the ‘safe list’ are the most important elements of prevention of attacks. However, in certain situations, e.g. epilepsy, tuberculosis, malignant disease, potentially porphyrinogenic drugs may have to be used. If the patient has fully latent acute porphyria with normal or near-normal urinary PBG levels, these drugs may often be used safely, particularly if the strongly porphyrinogenic drugs are avoided. Monitoring urinary ALA and PBG levels can often give warning of an acute attack, and haem arginate should always be kept locally available.
Skin lesions can usually be avoided by avoiding exposure to UV light, rigorous use of UV-blocking creams, and in the case of porphyria cutanea tarda, use of oral ß-carotene. Porphyria cutanea tarda usually occurs in susceptible individuals who are exposed to one or more hepatotoxins, e.g. hepatitis C, iron overload due to genetic haemochromatosis, alcohol misuse, oral contraceptives, cancer chemotherapy. Again, avoidance is the best preventative strategy. It should be remembered that patients with known porphyria are equally liable to other diseases, and these should be identified and vigorously treated. Eczema, psoriasis and skin infections all occur in acute porphyrias, and should not be dismissed as dermatological manifestations of porphyria. Similarly, abdominal pain due to acute appendicitis, twisted ovarian cysts or peritonitis, has often been dismissed as an attack of porphyria, sometimes with fatal consequences. The patients themselves are often the best judges of non-porphyric attacks of abdominal pain.
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Malignant disease in porphyria |
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Hepatocellular carcinoma (HCC) appears to occur with a higher prevalence in both acute intermittent porphyria and in porphyria cutanea tarda. Scandinavian studies2 report a relative risk of HCC in acute porphyria of 30–55, and 5% of patients with porphyria cutanea tarda die of primary liver cancer. Whether this is due to the porphyria, or to the associated precipitants, hepatitis, iron overload or hepatotoxins, is uncertain. Conversely, 5–10% of patients with HCC have porphyria cutanea tarda. In one reported case, porphyria cutanea tarda resolved following surgical excision of a hepatic adenoma containing uroporphyrin, coproporphyrin and protoporphyrin.3 Perhaps somewhat surprisingly, as far as we are aware, there is no association between the dermatological porphyrias and cutaneous malignancy. Indeed, photosensitization with systemic aminolaevulinic acid has been used for photodynamic therapy of superficial cancers, and photoactive porphyrins may have a protective effect against cutaneous malignancies. Patients suffering from a cutaneous porphyria usually avoid exposure of the skin to sunlight or other forms of ultraviolet radiation, and may thereby reduce their risk of developing actinic skin tumours.
Intercurrent malignant disease in acute porphyria, particularly if there is hepatic metastatic spread, can precipitate an acute attack which often recurs in spite of a course of haem arginate. Malignancy of the breast, pancreas or colon should be considered in patients presenting with an acute porphyric attack in their late thirties/forties, especially if male.
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Drugs |
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The identification of potentially porphyrinogenic drugs may be difficult, and in most cases is based only on case reports or anecdotal experience. Cell culture techniques can be used to test substances for the ability to induce ALA synthase activity, or for effects on porphyrin synthesis. Animal models of porphyria rely on the administration of a porphyrinogenic agent such as dicarbethoxy-dihydrocollidine prior to administering the drug in question.
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Investigation of porphyric patients suspected of malignant disease |
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Certain solid tumours produce substances that can be measured quantitatively by biochemical or immunochemical means in body fluids or tissues. In practice, tumour markers may be useful for detection and localization of malignancy, quantification of tumour burden and response to treatment. However, most tumour markers are not sufficiently sensitive or specific to be used for screening or diagnosis of cancer, and levels may be elevated in other malignant or benign conditions. In one reported case of a patient with acute intermittent porphyria, circulating levels of carcinoembryonic antigen (CEA), but not
-fetoprotein (AFP), were markedly elevated during haem arginate treatment of acute attacks.4 The effect of haem arginate on CEA concentration in vitro was investigated by adding haem arginate to the serum of two healthy controls. In both cases, CEA levels were raised, but other tumour markers including AFP, CA-125, CA-15.3, CA-19.9 and prostate specific antigen were not elevated. Therefore, measurements of CEA should not be relied upon in patients undergoing treatment with haem arginate. |
Treatment of malignant disease in porphyric patients |
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Surgery
Surgery has a key role in the management of patients with malignant disease. Given that anaesthesia in some form is therefore unavoidable, attention to the anaesthetic management of porphyric patients is important if an acute crisis is to be avoided. Optimal and safe anaesthesia is dependent on the identification of susceptible individuals and avoidance of porphyrinogenic agents whenever possible.
Pre-operative assessment and management
In the pre-operative assessment, a full history and physical examination are important. Particular attention should be paid to the neurological examination and signs of peripheral and/or autonomic neuropathy. Examination may also reveal cutaneous manifestations of the hepatic porphyrias. If skin lesions are present, these must be protected peri-operatively to prevent skin damage. Particular care should be taken with facemasks and with adhesive tape used to affix intravenous lines and other enteral or parenteral devices.
Premedication
Caloric restriction is associated with precipitation of acute attacks, and prolonged fasting in the pre-operative period should be avoided where possible. Glucose-saline should be administered by infusion; 5% dextrose is hypotonic and is best avoided, since hyponatraemia is associated with acute attacks and a risk of further electrolyte imbalance. Most benzodiazepines used for premedication are considered safe. Phenothiazines may have particular advantage. Given that stress may precipitate an acute porphyric attack, it is often beneficial to administer an anxiolytic or sedative premedication, although all barbiturates must be strictly avoided.
Regional anaesthesia
Regional anaesthesia may be used in porphyric patients, but certain precautions need to be taken. Firstly, mental state must be assessed in the preoperative neurological examination. It is important to bear in mind that neuropsychiatric disorders, including porphyria, may preclude patient co-operation and make regional anaesthesia inappropriate. In addition, if an acute attack occurs during a regional technique or nerve block, a sudden deterioration in cardiovascular or haemodynamic status may rapidly become difficult to manage. At this point, administration of a general anaesthetic should be considered. An acute porphyric attack should be considered in any patient who suddenly becomes confused during regional anaesthesia. Hypovolaemia and autonomic neuropathy increase the risk of cardiovascular instability and may contraindicate regional anaesthesia in such patients.
Lidocaine may be porphyrinogenic in animal models, but there is little evidence that any local anaesthetic agent has induced an acute attack or neurological pathology in porphyric subjects, and there is insufficient evidence to argue against their use in porphyric patients. The preferred local anaesthetic is bupivacaine (Marcaine). Regional anaesthesia has been safely performed in pregnant patients with acute intermittent porphyria.5 Epidural procaine/fentanyl,6 epidural bupivacaine followed by Caesarean section under spinal anaesthesia,7 and local and regional anaesthesia with bupivacaine, prilocaine, tetracaine or procaine8 have all been used successfully in pregnant women without precipitating an acute porphyric crisis or neurological deterioration. However, in an acute porphyric crisis, mental confusion, haemodynamic instability and neuropathy preclude the use of regional anaesthesia.9
General anaesthesia
Barbiturates are well known inducers of ALA synthtase. All barbiturates, including thiopental, are potentially unsafe and should be avoided.
Of the halogenated inhalational agents available, halothane and isoflurane are thought to be safe, with enflurane labelled as ‘use with caution’. Sevoflurane has been safely administered to two patients with acute intermittent porphyria.10 However, both were short procedures of under 1 h, and the safety of repeated and prolonged exposure to sevoflurane is not yet certain. With rapid elimination and minimal metabolism, all modern inhalational agents, with the possible exception of enflurane, should be safe. Propofol is reported to be safe in the acute porphyrias, and is probably the preferred anaesthetic agent.11
Post-operative management
In the post-operative period, known porphyric patients should be carefully monitored. Attention should be paid to pain control, fluid balance and haemodynamic stability, and the avoidance of postoperative complications such as infection. Haem arginate should be available in the case of an acute attack.
Radiotherapy
Photosensitivity is a well-recognized feature of porphyria that results from activation of porphyrins by light, particularly at wavelengths of 350–700 nm. Ionizing radiation appears to be safe, and there are reports of radiotherapy administered to patients with acute intermittent porphyria,12 porphyria cutanea tarda12,13 and variegate porphyria,14 without precipitation of acute attacks or severe skin reactions. Ionizing radiation is used therapeutically at wavelengths of 1 pm for electrons and 3 pm for photons, which are far shorter than the wavelengths known to activate porphyrins. On the basis of the clinical evidence and known activating wavelength of porphyrins, it is reasonable to presume that patients suffering from porphyria can be treated safely with radiotherapy, and any adverse effects are unlikely to differ from non-porphyric patients. Areas of skin in the planned radiation field should be examined for any pre-existing lesions that may be exacerbated by radiotherapy. If possible, these should be allowed to heal first and monitored carefully during radiotherapy.
Radiation recall reactions have been noted in breast cancer patients treated with tamoxifen or cytotoxic chemotherapy drugs. Manifestations include a photosensitive rash, erythema, hypertrichosis and bullae in the irradiated area as well as outside the radiation fields such as on the trunk and extremities. Radiation recall reactions have only been reported with tamoxifen and not toremifene, which has less oestrogen receptor -agonist activity.15 Given the known association of tamoxifen with porphyria cutanea tarda,16 these observations suggest that radiation recall reactions may be a manifestation of PCT, although there is no supporting literature for this hypothesis.
Cytotoxic drugs
Cytotoxic drugs are the mainstay of therapy in the treatment of malignant disease, and several have been implicated in the precipitation of acute porphyric attacks. The effect of cytotoxic drugs on the haem metabolic pathway is difficult to measure and, since precipitation of an acute porphyric attack can be fatal, it is important to establish which cytotoxic drugs carry a porphyrinogenic risk. Chick embryos or mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DCC) develop a hepatic porphyria that resembles human variegate porphyria in its latent phase.17 Co-administration of small doses of DCC with the drug of interest can be used to study the porphyrinogenic potential of drugs. However, a given drug may induce porphyrin accumulation in one species, but not in another. For instance, methsuximide is known to produce acute porphyric attacks in man, and is active in intact chick embryos, but not in mice.18 It has been suggested that chick embryos may better reflect the human susceptibility to drug exacerbation of porphyria than other mammalian species. In one study, the porphyrinogenic potentials of nine cytotoxic agents were evaluated using chick embryos.19 The results suggest that cyclophosphamide, azathioprine, 5-fluorouracil, busulphan, procarbazine and hexamethylmelamine should be avoided in patients with porphyria, but dacarbazine, chlorambucil and melphalan are non-porphyrinogenic. Cyclophosphamide was not found to be porphyrinogenic in mice. In previous studies, the effect of cyclophosphamide on the haem metabolic pathway in rats and rabbits was inconsistent.20,21
Cyclophosphamide, chlorambucil and melphalan all contain the same alkylating group ((CL–CH2–CH2–CH2)2N–) and have the same cytotoxic mechanism of action, indicating that the porphyrinogenicity of cyclophosphamide is not common to the mustard group of alkylating agents. Both cyclophosphamide and the sulphur-containing alkylating agent busulfan have been implicated in development of porphyria cutanea tarda.22–24
There are reports of porphyria cutanea tarda in association with methotrexate use, although clear causality has not been shown.25,26 Given its porphyrinogenic properties in vitro, methotrexate should be administered with care in patients with a history or family history of porphyria.
A number of patients with variegate porphyria have received cytotoxic chemotherapy without suffering a porphyric crisis.27–29 The drugs administered included mitomycin C, cyclophosphamide, mitoxantrone, 5-fluorouracil, cytosine arabinoside, doxorubicin, 6-thioguanine, vincristine, procarbazine and methotrexate. There are also reports of patients with porphyria cutanea tarda12,30 and acute intermittent porphyria31 who received cytotoxic chemotherapy without complication. It has even been suggested that dactinomycin may have a role in the treatment of an attack of AIP.32 However, there is a theoretical risk of increased toxicity from doxorubicin in patients suffering from hepatic porphyria, who have reduced activity of the cytochrome P450 enzymes33,34 that catalyse hepatic conversion of doxorubicin and its active metabolite doxorubinol into inactive species. Doxorubicin should therefore be administered with care in porphyric patients.
There are reports of several combination chemotherapy regimens being administered safely to patients with porphyria. Five patients with hepatic porphyria received combination chemotherapy without incident,27 including three women with breast cancer treated with cyclophosphamide, methotrexate and 5-FU (CMF), one of whom subsequently received vincristine and doxorubicin, a patient with follicular lymphoma treated with vincristine, cyclophosphamide and procarbazine, and another patient with acute lymphoblastic leukaemia treated with vincristine, doxorubicin, intrathecal methotrexate, cytarabine, thioguanine, BCNU and L-asparaginase who later had an acute attack precipitated by sepsis. A group of patients with lymphoma-associated porphyria cutanea tarda were safely treated with cyclophosphamide, vincristine, procarbazine and topical nitrogen mustard.35 A patient with testicular cancer and acute intermittent porphyria was treated with cyclophosphamide, vinblastine, dactinomycin, bleomycin and cisplatin without apparent exacerbation of porphyria.31
However, the literature on the use of chemotherapeutic agents in patients suffering from porphyria is limited to a small number of patients, and any recommendations cannot therefore be based on a large body of evidence. In a number of cases where a chemotherapeutic drug was implicated as the causative agent in an acute porphyric attack, the evidence was not clear-cut and there were other possible precipitating factors.27,36 Further, where there was precipitation of an acute porphyric attack, in all cases the episode appears to have been mild and managed successfully, with no reported deaths in any of the case histories reviewed.
Successful treatment of haematological and solid malignancies requires specific cytotoxic chemotherapy regimens that have proven efficacy in large clinical studies. To ensure that patients receive the most efficacious treatment, occasions may arise where it may be difficult if not impossible not to use a potentially porphyrinogenic drug. In such circumstances, certain precautions will minimize the risk to the patient, including admission to hospital for the first administration of the drug, careful observation for any signs and symptoms of an acute porphyric attack, monitoring of urinary ALA and PBG levels and ensuring that haem arginate is immediately available.
Table 2 summarizes the chemotherapeutic drugs that are potentially porphyrinogenic, based on animal studies and case reports. These should be used with caution in patients with porphyria.
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Administration of chemotherapy
Given the well-recognized fragility of the skin in the cutaneous porphyrias, it is prudent to establish intravenous access via an indwelling central venous cannula prior to the commencement of a course of chemotherapy. This will help to prevent repeated mechanical trauma to the skin which may lead to severe damage and scarring. Many chemotherapeutic agents are photosensitizing, and patients should be advised to avoid exposure to the sun or sunlamps throughout their treatment.
Tyrosine kinase inhibitors
Imatinib mesylate targets the ATP binding domain of the BCR-ABL tyrosine kinase and also inhibits platelet derived growth factor ß and c-kit tyrosine kinases. Imatinib is effective in the treatment of chronic myeloid leukaemia with a reciprocal translocation between chromosomes 9 and 22 (Philadelphia chromosome) that produces a BCR-ABL fusion gene, and in gastrointestinal stromal tumours expressing c-kit. In a recent case, a patient with transfusion-dependent proliferative-phase myelofibrosis developed porphyria cutanea tarda following 6 weeks of imatinib treatment in a clinical trial.37 However, repeated blood transfusion is a well-recognized precipitant of PCT, and imatinib may not have played a causal role. Until further data become available, imatinib should be administered with caution in patients with a history or family history of porphyria.
Endocrine therapy
Approximately 70% of human breast cancers express the oestrogen receptor (ER), and the majority of ER-positive cancers respond to direct inhibition of ER function, or to reduction of circulating oestrogen levels. Tamoxifen, an oral non-steroidal competitive ER antagonist, has been the hormonal agent of choice for over 20 years both in the adjuvant setting and for metastatic disease, and is also active in the prevention of breast cancer. At least three cases of tamoxifen-associated porphyria cutanea tarda have described.16,38,39 Porphyria cutanea tarda can be precipitated by oestrogens, and tamoxifen may have induced porphyria in these patients because of its partial oestrogenic activity. However, the mechanism of oestrogen-induced porphyria cutanea tarda is not well understood and there may be a latent period from 6 months to 10 years between exposure to the drug and development of porphyria. Another mechanism may be the hepatotoxicity of tamoxifen. Tamoxifen undergoes N-demethylation in the liver to form reactive metabolites that may inactivate proteins and/or DNA, including uroporphyrinogen decarboxylase that could account for development of porphyria cutanea tarda.16 Approximately 25% of patients receiving tamoxifen have fatty liver as identified by liver ultrasound.40 Tamoxifen is widely used in the treatment of breast cancer, and the benefits far outweigh the potential risk of hepatotoxicity, but regular monitoring of liver function is recommended. In most cases hepatotoxicity is reversible on discontinuation of tamoxifen treatment, but there are reports of tamoxifen-induced non-alcoholic steatohepatitis progressing to cirrhosis. Although oestrogens are considered porphyrinogenic, hormone replacement therapy appears to be safe, at least in a small study of patients with porphyria cutanea tarda treated with transdermal oestrogens.
Nucleoside analogue reverse transcriptase inhibitors
There is one report of a patient with HTLV-I-associated T-cell leukaemia/lymphoma treated with chemotherapy and zidovudine who developed an axonal neuropathy, and was found to have increased circulating concentrations of coproporphyrin and uroporphyrin but normal 5-ALA and PBG levels.41 The level of coproporphyrin remained elevated for 3 months. It is therefore possible that nucleoside analogue reverse transcriptase inhibitors such as zidovudine might inhibit the activity of certain mitochondrial enzymes and lead to a disturbance in haem biosynthesis. Although this is an isolated case report, care should be taken in prescribing such drugs to patients with a history of porphyria. Furthermore, in any patients developing peripheral neuropathy while receiving nucleoside analogue reverse transcriptase inhibitors, a possible effect on the haem pathway should be suspected and appropriate testing carried out. However, there is one report of a patient with pre-existing hereditary coproporphyria who was treated safely with zidovudine.42
Infections
It is well recognized that bacterial infection can precipitate a porphyric crisis. Chemotherapy-induced myelosuppression carries an increased risk of bacterial sepsis, and extra care must be taken to protect against infection in porphyric patients receiving cytotoxic chemotherapy. Neutropenic sepsis has been documented or implicated as the precipitating cause of acute porphyria in a number of cases.27,33 Porphyric skin lesions are potential portals of entry for infection, and against a background of immune suppression by underlying malignancy and/or cytotoxic chemotherapy treatment, there is a risk of serious life-threatening infection. There is one reported case of cellulitis and fatal septicaemia with a vancomycin-resistant strain of Aureobacterium sp. in a patient with porphyria cutanea tarda undergoing treatment for acute myeloid leukaemia, where bullous skin lesions were the likely site of primary infection.43 Any cutaneous lesions associated with porphyria should ideally be allowed to heal prior to commencement of chemotherapy, but if this is not possible, lesions must be kept clean and monitored closely for early signs of infection. All currently used antibiotics appear to be safe in porphyria. Porphyric patients who develop febrile neutropenia should receive standard antimicrobial therapy. There is no literature on colony-stimulating factors in porphyric patients, and it is not possible to make any specific evidence-based recommendation on their safety.
Anaemia
Repeated blood transfusions lead to an increase in iron stores, and iron overload is a known precipitating factor for PCT. One patient with myelodysplastic syndrome and refractory anaemia who had no previous history of porphyria developed porphyria cutanea tarda following multiple blood transfusions. The serum ferritin concentration was markedly elevated, suggesting that an increased iron store was the precipitating factor.44
Nausea and vomiting
Oncology patients commonly suffer from nausea and vomiting and the causes of emesis in the cancer patient are protean. Nausea and/or vomiting commonly complicate administration of anaesthetic drugs, cytotoxic chemotherapy or opioid analgesia, or may be related to the underlying malignancy such as in gastric carcinoma, hepatic or cerebral metastasis, or malignant bowel obstruction. Among the anti-emetics commonly prescribed, promethazine, droperidol, and the 5-HT3 receptor antagonist ondansetron are considered safe in porphyria.45
Opiates and analgesics
Control of pain and alleviation of suffering are principal objectives of cancer therapy. In palliative care, quality of life is paramount, and the prevention of acute porphyric attacks is therefore especially important in this setting. Fortunately, most of the major analgesics are considered safe in porphyria, including morphine, fentanyl, paracetamol, aspirin, indomethacin and naproxen. Ibuprofen and diclofenac (anthranic acid derivatives) and pyrazalone derivatives such as phenylbutazone are considered unsafe, and there is no safety information regarding ketorolac.46 Fentanyl has been shown to be safe in both chick embryo models and in clinical practice. In addition, pethidine is widely used in the treatment of acute porphyric attacks, although it is considered unsuitable for chronic analgesia due to the accumulation of the neurotoxic metabolite nor-pethidine.
Bone marrow transplantation
Porphyria cutanea tarda has been reported following allogeneic bone-marrow transplantation for chronic myeloid leukaemia, but the precipitating factor/s were not identified with certainty. Possible precipitants were cyclophosphamide or total body irradiation used in the conditioning regimen, intrathecal methotrexate administered for prophylaxis of central nervous system involvement, immunosuppressants used to prevent graft versus host disease, or repeated blood transfusions.44,46,47 Other factors that may precipitate or exacerbate porphyria in patients undergoing bone marrow, peripheral progenitor cell, or solid organ transplantation include opportunistic infections, particularly cytomegalovirus infection, intensive anti-emetic treatment, fluid and electrolyte imbalance, haemodynamic instability and possibly total parenteral nutrition.36,44 It should be noted that cutaneous manifestations of graft versus host disease following transplantation are likely to be particular severe in patients with cutaneous porphyria.
Transplant patients can become non-specifically unwell for a variety of reasons, and a porphyric attack might easily be mistaken for a more common adverse effect associated with the transplantation procedure. It is important to remain vigilant and aware of the possibility of porphyria in these patients, recognize the symptoms and signs of the disease, and undertake the necessary diagnostic investigations without delay so that appropriate and effective treatment can be provided.
Anticonvulsant medication
The central nervous system is not uncommonly the site of primary or metastatic tumours and affected patients are at risk of developing seizures. Surgical resection of intracranial deposits or radiotherapy may result in epileptogenic foci. As a result, a number of cancer patients will require anticonvulsant medication for prophylaxis or treatment of seizures.
Most anticonvulsant drugs are metabolized in the liver and can potentially exacerbate porphyria. The barbiturates are the drugs most likely to precipitate an acute porphyric attack in a susceptible individual. Phenytoin, valproate, carbamazepine and primidone may also potentially precipitate attacks.48–50 Gabapentin is a newer anticonvulsant which does not induce hepatic oxidative metabolism, and therefore carries a low risk of precipitating an acute porphyric attack. Gabapentin and clonazepam have been safely administered to patients with porphyria and poorly controlled epilepsy.51,52
Pseudoporphyria
Pseudoporphyria is a bullous skin condition that mimics porphyria cutanea tarda both clinically and histopathologically. The presence of abnormal urine porphyrins distinguishes true porphyria from pseudoporphyria. Pseudoporphyria cutanea tarda is rare but has been reported in association with 5-fluorouracil.53 5-Fluorouracil is a known photosensitizer54 and non-bullous reactions on sun-exposed skin are not uncommon. Other drugs prescribed to oncology patients that have been reported to cause pseudoporphyria include flutamide,55,56 etretinate,57 non-steroidal anti-inflammatory drugs58 and COX-2 inhibitors.59 Any suspected case of porphyria must be confirmed on analysis of the urine, faecal and blood porphyrins.
Haemodialysis-related porphyria cutanea tarda is a rare but important cause of pseudoporphyria resulting from extremely high levels of plasma porphyrins due to inadequate clearance by haemodialysis. The condition is difficult to treat, since chloroquine is ineffective and venesection is contraindicated in anaemia of end-stage renal disease. However, isolated reports indicate successful treatment with recombinant erythropoietin.60–62
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Guidelines for the use of drugs in porphyric patients with cancer |
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TopSummaryBiochemical basis of the...Clinical features of the...Laboratory diagnosis of...Treatment of porphyriasMalignant disease in porphyriaDrugsInvestigation of porphyric...Treatment of malignant disease...Guidelines for the use...Management of an acute...Search strategyReferences |
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Oncology is a rapidly evolving speciality with new agents constantly being developed and used. As a result, it is not always possible to determine the safety of new drugs in porphyric patients prior to their administration. It is therefore important that patients with a known history of porphyria are monitored carefully to ensure the early detection and treatment of any porphyric attacks.
There is a limited literature on the safety of drugs used in the treatment of porphyric patients with malignant disease. We propose that a central database should be established to collect prospective data on malignant disease and its treatment in porphyric patients. This would provide a valuable resource for oncologists and other medical practitioners caring for porphyric patients. A large evidence base would enable informed decisions to be made in the treatment of this group of patients, rather than the current practice of relying on a small number of isolated case reports or anecdotal evidence.
If an acute attack of porphyria is suspected, expert advice should be sought to ensure that a correct diagnosis is made, and that causes other than porphyria are excluded. This will prevent drugs being incorrectly labelled as porphyrinogenic. In practice, it may be difficult to pinpoint the precipitating agent, since chemotherapy regimens often make use of combinations of drugs, in addition to adjunctive treatments such as anti-emetics, and any other concurrent medication the patient may be taking.
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Management of an acute porphyric attack |
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TopSummaryBiochemical basis of the...Clinical features of the...Laboratory diagnosis of...Treatment of porphyriasMalignant disease in porphyriaDrugsInvestigation of porphyric...Treatment of malignant disease...Guidelines for the use...Management of an acute...Search strategyReferences |
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In an acute attack, management is mainly supportive, with specific treatments aimed at reversing factors that increase ALA synthase activity. The first step should be to withdraw the drug concerned. Intravenous fluids should be administered to ensure adequate hydration. Carbohydrates should be administered, which may require a nasogastric tube, given the nausea and vomiting that often accompanies an acute attack. Alternatively, a dextrose-saline infusion can be given intravenously. Carbohydrates down-regulate the rate-limiting enzyme in haem biosynthesis, ALA synthase, and also have an indirect effect in decreasing the production of porphyrins by preventing the induction of cytochrome P450 by starvation. The aim should be a caloric intake of 2000 kcal/24 h. Opiates should be administered for pain control, and where sedation is required, phenothiazines may be used safely. The tachycardia and hypertension that often accompanies an acute crisis should be controlled with a ß-adrenergic antagonist, which may also decrease the activity of ALA synthase. Convulsions may be treated with diazepam or clonazepam, but with the exception of gabapentin, most other anticonvulsants are largely contraindicated. In crises associated with seizures and magnesium deficiency, magnesium sulphate may be infused.63
The only specific form of therapy is haematin, which is thought to supplement the intracellular pool of haem, thus leading to repression of ALA synthase. However, haematin is unstable and may cause renal failure, dose-related coagulopathy, and thrombophlebitis.64,65 Haem arginate, which has fewer side-effects and is more stable than haematin, may be administered during an acute attack.66 Although cimetidine has been reported to have clinical utility in the treatment of acute porphyria by inhibiting haem oxidase activity,67,68 it also induces cytochrome P450 enzymes and may potentially exacerbate porphyria by increasing haem turnover. Other treatments reported in the literature that might be considered include somatostatin, which decreases the rate of formation of ALA synthase, combined with plasmapheresis,69 haem oxygenase inhibitors such as tin mesoporphyrin,70 which have been used extensively in genetic hyperbilirubinaemias, although they are not in current use in the treatment of porphyria, and erythropoietin.52,60–62
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Search strategy |
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TopSummaryBiochemical basis of the...Clinical features of the...Laboratory diagnosis of...Treatment of porphyriasMalignant disease in porphyriaDrugsInvestigation of porphyric...Treatment of malignant disease...Guidelines for the use...Management of an acute...Search strategyReferences |
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Literature for this review was identified by searches of PubMed and Web of Science. Search terms used included ‘malignancy’, ‘cancer’, ‘porphyria’, ‘porphyria cutanea tarda’ and ‘acute intermittent porphyria’. In addition, any relevant references in the reviewed literature were included.
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Acknowledgments |
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We are grateful to the Stone Foundation for financial support.
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Footnotes |
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Address correspondence to Dr C. Palmieri, Department of Cancer Medicine, 6th Floor MRC Cyclotron Building, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 ONN. e-mail: c.palmieri{at}imperial.ac.uk
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References |
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TopSummaryBiochemical basis of the...Clinical features of the...Laboratory diagnosis of...Treatment of porphyriasMalignant disease in porphyriaDrugsInvestigation of porphyric...Treatment of malignant disease...Guidelines for the use...Management of an acute...Search strategyReferences |
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1. Thadani H, Deacon A, Peters T. Diagnosis and management of porphyria. Br Med J 2000; 320:1647–51.
2. Kaczynski J, Hansson G, Thunell S, Watterberg L, Wallerstedt S. Erythrocyte porphobilinogen deaminase activity and primary liver cancer. J Int Med 1995; 237:309–313.[Web of Science][Medline]
3. Tio TH, Leijnse B, Jarrett A, Rimington C. Acquired porphyria from a liver tumour. Clin Sci 1957; 16:517–27.[Web of Science][Medline]
4. Gross U, Schurek JO, Doss M, Doss MO. Haem arginate interferes with estimation of carcinoembryonic antigen. Ann Clin Biochem 2001; 38:275–6.[CrossRef][Web of Science][Medline]
5. McNeill MJ, Bennet A. Use of regional anaesthesia in a patient with acute porphyria. Br J Anaesth 1990; 64:371–3.
6. Joyau M, Deybach JC, Durand M, Parmentier G, Nordmann Y. Peridural anaesthesia with procaine and fentanyl in a parturient with acute intermittent prophyria. Ann Franc Anesthes Reanimat 1986; 5:453–5.
7. Brennan L, Halfacre JA, Woods SD. Regional anaesthesia in porphyria. Br J Anaesth 1990; 65:594.
8. Bohrer H, Schmidt H. Regional anesthesia as anesthetic technique of choice in acute hepatic porphyria. J Clin Anesth 1992; 4:259.[Medline]
9. Jensen NF, Fiddler DS, Striepe V. Anaesthetic considerations in porphyrias. Anesth Analg 1995; 80:591–9.[Abstract]
10. Evans PR, Graham S, Kumar CM. The use of sevoflurane in acute intermittent porphyria. Anaesthesia 2001; 56:388–9.[CrossRef][Web of Science][Medline]
11. James MF, Hift RJ. Porphyrias. Br J Anaesth 2000; 85:143–53.
12. Schaffer M, Schaffer P, Panzer M, Wilkowski R, Duhmke E. Porphyrias associated with malignant tumours: results of treatment with ionizing irradiation. Onkologie 2001; 24:170–2.[CrossRef][Web of Science][Medline]
13. Maughan WZ, Muller SA, Perry HO. Porphyria cutanea tarda associated with lymphoma. Acta Dermato Venereol 1979; 59:55–8.[Web of Science][Medline]
14. Scarlett JD, Corry J, Jeal PN. Cytotoxic chemotherapy and a radiotherapy in a patient with breast cancer and variegate porphyria. Aust NZ J Med 1995; 25:742–3.[Web of Science][Medline]
15. Bostrom A, Sjolin-Forsberg G, Wilking N, Bergh J. Radiation recall–another call with tamoxifen. Acta Oncol 1999; 38:955–9.[CrossRef][Web of Science][Medline]
16. Agarwal R, Peters TJ, Coombes RC, Vigushin DM. Tamoxifen-related porphyria cutanea tarda. Med Oncol 2002; 19:121–3.[CrossRef][Web of Science][Medline]
17. De Matteis F. Disturbances of liver porphyrin metabolism caused by drugs. Pharmacol Rev 1967; 19:523–57.
18. Racz WJ, Marks GS. Drug-induced porphyrin biosynthesis. II. Simple procedure for screening drugs for porphyria-inducing activity. Biochem Pharmacol 1969; 18:2009–18.[CrossRef][Web of Science][Medline]
19. Cochon AC, Aldonatti C, San Martin de Viale LC, De Calmanovici RW. Evaluation of the porphyrinogenic risk of antineoplastics. J Appl Toxicol 1997; 17:171–7.[CrossRef][Web of Science][Medline]
20. Palma-Carlos AG, Palma-Carlos ML, Lourenco MG, Martins-Silva JA. Effect of alkylating agents on haem metabolism. S Af J Lab Clin Med 1971; 25:81–4.
21. Rizzardini M, Ferraroli A, Dal Fiume D, Cantoni L. Cyclophosphamide impaired regulation of hepatic heme metabolism. Experientia 1984; 40:1390–2.[CrossRef][Web of Science][Medline]
22. Kyle R, Dameshek W. Porphyria cutanea tarda associated with chronic granulocytic leukemia treated with busulfan. Blood 1961; 23:776–85.
23. Gonzalez A, Roman P, Garcia FJ, Gonzalez Q. Case of porphyria after treatment with cisplatin. Med Clin 1986; 97:738–9.
24. Manzione NC, Wolkoff AW, Sassa S. Development of porpohyria cutanea tarda after treatment with cyclophosphamide. Gastroenterology 1988; 95:1119–22.[Web of Science][Medline]
25. Malina L, Chlumsky J, Chlumska A, Krtek V. Porphyria cutanea tarda (PCT) als folge der methotrexat-und buthiopurin-therapie. Z Hautkr 1983; 58:645–63.
26. O’Neill T, Simpson J, Smyth SJ, Lovell C, Calin A. Porphyria cutanea tarda associated with methotrexate therapy. Br J Rheum 1993; 32:411–12.
27. Samuels B, Bezwoda WR, Derman DP, Goss G. Chemotherapy in porphyria. S Afr Med J 1984; 65:924–6.[Web of Science][Medline]
28. Scarlett JD, Corry J, Jeal PN. Cytotoxic chemotherapy and radiotherapy in a patient with breast cancer and variegate porphyria (VP). Aust N Z J Med 1995; 25:742–3.[Web of Science][Medline]
29. Wehmeier A, Fitcher J, Goerz G, Schneider W. Polychemotherapy of acute myelogenous leukemia in a patient with acute intermittent porphyria. Klin Wochenschr 1987; 65:338–40.[CrossRef][Web of Science][Medline]
30. Rayhanzadeh S, Shoss RG, Noyes J. Porphyria cutanea tarda associated with lymphosarcoma. Arch Dermatol 1975; 111:129.
31. Arbus M. Relationship between porphyria and the use of antineoplastics. Am J Hosp Pharm 1981; 38:631.[Medline]
32. Yull G. Actinomycin-D treatment in a case of acute intermittent porphyria. Lancet 1970; 2:216–17.[CrossRef][Web of Science][Medline]
33. Forget F, Awada A, Klastersky J. Anticancer chemotherapy in a patient with a prior history of acute intermittent porphyria. Support Care Cancer 2001; 9:465–6.[CrossRef][Web of Science][Medline]
34. Meyer U, Schuurmans M, Lindberg R. Acute porphyrias:pathogenesis of neurological manifestations. Semin Liver Dis 1998; 18:43–52.[Web of Science][Medline]
35. Rayhanzadeh S, Shoss RG, Noyes J. Porphyria cutanea tarda associated with lymphosarcoma. Arch Dermatol 1975; 111:129.
36. Dopfer R, Doss M, Ehninger G, Ostendorf P, Niethammer D. Appearance of an inherited porphyria cutanea tarda in a child after allogenic bone marrow transplantation for chronic myelogenous leukaemia. Bone Marrow Transplant 1986; 1:95–9.[Web of Science][Medline]
37. Ho AY, Deacon A, Osborne G, Mufti GJ. Precipitation of porphyria cutanea tarda by Imatinib Mesylate? Br J Haem 2003; 121:375.[CrossRef][Web of Science][Medline]
38. Malina L, Michalikova H, Hussarova L. Porphyria cutanea tarda after antineoplastic drugs. Casopis Lekaru Ceskych 1999; 138:536–8.[Medline]
39. Claus A, Gail P. Tamoxifen and porphyria. In: Millenium meeting on porphyrins and porphyrias 2000. Paris, Institut Pasteur, 2000.
40. Murata Y, Ogawa Y, Saibara T, Nishioka A, Fujiwara Y, Fukumont Inoma T, Enzan H, Onishi S, Yoshida S. Unrecognized heaptic steatosis and non-alcoholic steatohepatitis in adjuvant tamoxifen for breast cancer patients. Obcol Rep 2000; 7:1299–304.
41. Aramideh M, Koopsmans RP, Koelman JHTM, Stam J. Rapidly progressing peripheral neuropathy with lactic acidosis and coproporphyria in a patient with with HTLV-I associated T-cell leukaemia treated with zidovudine. J Neurol 2001; 248:621–2.[CrossRef][Web of Science][Medline]
42. Herrero C, Bassas S, Azon A, Masxaro JM, Miro J. Acquired immunodeficiency syndrome in a patient affected by hereditary coproprohyria: safety of zidovudine treatment. Arch Dermatol 1990; 126:122–3.[Medline]
43. Nolte FS, Arnold KE, Sweat H, Winston EF, Funke G. Vancomycin-resistant Aureobacterium species cellulitis and bacteremia in a pateint with acute myelogenous leukemia. J Clin Microbiol 1996; 34:1992–4.[Abstract]
44. Oubre D, Cruz J, Keung Y. Porphyria cutanea tarda in a patient with post transplant MDS. Bone Marrow Transplantation 2001; 27:219–20.[CrossRef][Web of Science][Medline]
45. De Wet J, Coccia-Portugal MA, Falkson G. Ondansetron in a patient with porphyria. SAMJ 1992; 82:480.
46. Disler PB, Moore MR. Drug therapy in the acute porphyria. Clin Dermatol 1985; 3:112–24.[CrossRef][Medline]
47. Ramsey CA, Magnus IA, Turnbull A, Baker H. The treatment of porphyria cutanea tarda by venesection. Q J Med 1974; 43:1–24.[Web of Science][Medline]
48. Reynolds NC, Miska RM. Safety of anticonvulsants in hepatic porphyrias. Neurology 1981; 31:480–4.
49. Yandel ML, Watters MR. Treatment of complex partial status epilepticus unmasking acute intermittent porphyria in a patient with resceted anaplastic glioma. Clinical Neurol Neurosurg 1995; 97:261–3.[CrossRef]
50. Peters H. Acute hepatic porphyria. In: Johnston R, ed. Current therapy in neurologic disease. BC Decker, 1985.
51. Labiner DM, Ahern GL, Kolb MA, Johnston DS, Vengrow MI. Gabapetin is both safe and effective in treating seizures associated with porphyria. Epilepsia 1994; 35(Suppl.):53.
52. Winkler AS, Marsden J, Deacon A, Wilson S, Chandler G, Macdougall IC, Peters TJ. Serum erythropoietin levels may be inappropriately low in the acute neuropsychiatric porphyrias. Clin Chim Acta 2002; 317:93–100.[CrossRef][Web of Science][Medline]
53. Laidman PJ, Gabauer K, Trotter J. 5-flouorouracil-induced pseudoporphyria. Aust NZ J Med 1992; 22:385.[Web of Science][Medline]
54. Falkson G, Schultz FJ. Skin changes in a patient with 5-fluorouracil. Br J Dermatol 1962; 74:229–36.[CrossRef][Web of Science][Medline]
55. Borroni G, Brazzelli V, Baldini F, Borghini F, Gaviglio MR, Beltrami B, et al. Flutamide-induced pseudoporphyria. Br J Dermatol 1998; 138:711–12.[CrossRef][Web of Science][Medline]
56. Mantoux F, Bahadoran P, Perrin C, Bermon C, Lacour JP, Ortonne JP. Flutamide induced late cutaneous psuedoporphyria. Ann Dermatol Venerol 1999; 126:150–2.[Web of Science][Medline]
57. McDonagh AJ, Harrington CI. Pseudoporphyria complicating etreinate therapy. Clin Exp Dermatol 1989; 14:437–8.[CrossRef][Web of Science][Medline]
58. LaDuca JR, Bouman PH, Gaspari AA. Nonsteroidal antiinflammatory drug induced pseudoporphyria: a case series. J Cutan Med Surg 2002; 6:320–6.[Web of Science][Medline]
59. Cummins R, Wagner-Weiner L, Paller A. Psedoporphyria induced by celecoxib in a patient with juvenile rheumatoid arthritis. J Rheumatol 2000; 12:2938–40.
60. Anderson KE, Goeger DE, Carson RW, Lee SM, Stead RB. Erythropoietin for the treatment of porphyria cutanea tarda in a patient on long term hemodialysis. N Engl J Med 1990; 322:315–17.[Web of Science][Medline]
61. Yaqoob M, Smyth J, Ahmad R, McClelland P, Fahal I, Kumar KAR, Verbov J. Haemodialysis-related porphyria cutanea tarda and treatment by recombinant human erythropoietin. Nephron 1992; 60:428–31.[Web of Science][Medline]
62. Peces R, Enriquez de Salamanca R, Fontanellas A, Sanchez A, de la Torre M, Capparros G, Ferreras I, Nieto J. Successful treatment of haemodialysis-realted porphyria cutanea tarda with erythropoietin. Nephrol Dial Transplant 1994; 4:433–5.
63. Taylor RL. Magnesium sulfate for AIP seizures. Neurology 1981; 31:1371–2.
64. Morris DL, Dudley MD, Pearson RD. Coagulopathy associated with hematin treatment for acute intermittent porphyria. Ann Intern Med 1981; 95:700–1.
65. Ashley EM. Anaesthesia for porphyria. Br J Hosp Med 1996; 56:37–42.[Web of Science][Medline]
66. Mustajoki P, Nordmann Y. Early administration of heme arginate for acute porphyric attacks. Arch Int Med 1993; 153:2004–8.
67. Horie Y, Tanaka K, Okano J, Kawasaki H, Yamamoto S, Kondo M, Sassa S. Cimetidine in the treatment of porphyria cutanea tarda. Intern Med 1996; 35:717–19.[Web of Science][Medline]
68. Rogers PD. Cimetidine in the treatment of acute intermittent porphyria. Ann Pharmacother 1997; 31:365–7.[Abstract]
69. Medenica R, Lazovic G, Long P, Corbitt W, Powell D. Plasmapheresis combined with somatostatin is a successful treatment of porphyrias. Ther Apher 1997; 1:159–64.[Medline]
70. Galbraith RA, Kappas A. Pharmokinetics of tin-mesoporphyrin in man and the effects on tin-chelated porphyrins on hyperexcretion of heme pathway precursors in patients with acute inducible porphyria. Hepatology 1989; 9:882–8.[Web of Science][Medline]
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