Acute porphyric disorders

Vol. 90 No. 3 September 2000

ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY REVIEW ARTICLE Acute porphyric disorders Arthur W. Moore III, DMD,a and John M. Coke, DDS,b Gainesville, Fla UNIVERSITY OF FLORIDA COLLEGE OF DENTISTRY

Acute porphyrias are classified into 3 distinct groups of rare genetic disorders of metabolic enzyme biosynthesis. Acute porphyrias can significantly impact multiple organ systems, which often provides a challenge to the dentist presented with such a patient. A case of hereditary coproporphyria is reported in a patient with many of the classical signs and symptoms. The patient also had complex dental needs that required special medical and pharmacotherapeutic modifications. The acute porphyrias are reviewed by the authors with presentation of this challenging case. Recommendations for other dental health care professionals encountering these patients are then presented. (Oral Surg Oral Med Oral Pathol Oral Radiol

Endod 2000;90:257-62)

The group of metabolic disorders collectively referred to as the hepatic porphyrias is a diverse group of diseases characterized by enzymatic defects in the heme metabolic pathway. The human porphyrias differ greatly in their clinical manifestations and management; therefore, proper therapy requires establishment and understanding of the precise disorder present. Porphyrias are classified as either erythropoietic or hepatic depending on the primary organ in which overproduction of porphyrins or precursors takes place.1 Porphyrias may be further classified according to clinical features and patterns of excretion of porphyrins and their precursors. Those acute porphyric conditions associated with neurovisceral manifestations are acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP).

BIOSYNTHETIC PATHWAY AND CYTOCHROME P-450 Heme is a necessary component of vital cellular hemoproteins. More heme is produced in the bone marrow and the liver than in other organs. In marrow, heme is used primarily to make hemoglobin. In the aChief Resident, General Practice Residency and Fellow, Parker E. Mahan, Facial Pain Center. bAssociate Professor, Division of Oral Medicine, Director, Advanced Programs in General Dentistry. Received for publication July 21, 1999; returned for revision Sept 1, 1999; accepted for publication Mar 20, 2000. Copyright © 2000 by Mosby, Inc. 1079-2104/2000/$12.00 + 0 7/13/107976 doi:10.1067/moe.2000.107976

liver, most newly formed heme is used to synthesize cytochrome P-450, a key component of the microsomal mixed-function oxidase system, commonly used in drug metabolism. The heme biosynthetic pathway involves 11 reactions, which occur in 2 different cellular compartments, the mitochondrial and cytosolic compartments (Fig 1). The first reaction involves the formation of gamma-aminolevulinic acid (ALA). The mitochondrial enzyme responsible for this reaction is called ALA synthase, the first and inducible enzyme of the pathway. The remainder of the porphyrin synthetic pathway involves 3 distinct processes: (1) synthesis of a substituted pyrrole compound, porphobilinogen; (2) condensation of 4 porphobilinogen molecules to yield porphyrinogen; and (3) modification of the side chains, dehydrogenatin of the ring system, and introduction of iron, to form the product heme.2 ALA production and subsequent heme biosynthesis in the liver are tightly regulated by ALA synthase. ALA synthase, in turn, is regulated by heme, the end product of the pathway. Heme also inhibits the ferrochelatase reaction.3 Normally, ALA synthase activity in the liver is very low; however, when the demand for heme escalates, ALA synthase can be markedly induced. A number of drugs, hormones, and exogenous compounds increase the need for hepatic heme. In some cases, this results from stimulation of cytochrome P-450 synthesis. Cytochrome P-450, a hemoprotein (actually a group of closely related isoenzymes), is the component of the microsomal oxidation system that binds to drugs during 257

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Fig 1. Heme biosynthetic pathway. *, Enzymatic defect associated with AIP; **, enzymatic defect associated with HCP; ***, enzymatic defect associated with VP.

their metabolism.4 Cytochrome P-450s lack specificity and, therefore, collectively react with and are induced (increased in number, function, or both) by a diverse array of chemicals. Because cytochrome P-450s are hemoproteins, patients with porphyrias may experience problems associated with enzyme induction because there will be a greater demand for heme synthesis.

ACUTE PORPHYRIC CONDITIONS Acute intermittent porphyria AIP, an autosomal dominant disease, is probably the most common type of the hereditary hepatic porphyrias. Although a relatively rare condition found globally, AIP is perhaps most common in Scandanavia and the British Isles. Accordingly, descendants of Scandinavian, Anglo-Saxon, and German ancestry appear to be at highest risk.5 In AIP the basic defect involves an inherited deficiency of porphobilinogen (PBG) deaminase, also known as uroporphyrinogen (UROgen) I synthase (Fig 1). Consequently, there is potential for the excess accumulation of porphyrin precursors with associated clinical manifestations. Because the disorder is inherited in an autosomal dominant fashion, it is transmitted as commonly to males as to females. However, symptoms develop after puberty more frequently in women than in men, and they often occur in the luteal phase of the menstrual cycle and sometimes during pregnancy.1 The age at onset and the clinical expressions of AIP are highly variable. The majority of gene carriers remain

clinically latent throughout their lives, whereas others generally manifest with symptoms after puberty.6 All symptoms of AIP can be related to neurologic disturbances involving the autonomic, peripheral, and central nervous systems.6,7 Many patients have a long history of intermittent abdominal and neurologic manifestations of variable severity that remain unexplained until an acute attack occurs. Abdominal symptoms are often the first complaint of an acute attack. These may be mild, such as nausea, vomiting, constipation, or colicky pain, but frequently they are severe enough to occur as acute abdominal pain without fever or leukocytosis, although either or both may sometimes accompany an acute attack. Neurologic findings are just as variable and include abnormal sensory and motor phenomena, seizure, hypothalamic involvement with inappropriate antidiuretic hormone secretion, and neuropsychiatric manifestations.5,6,8 Neuropsychiatric manifestations of AIP include hysteria, anxiety, depression, phobias, psychoses, organic disorders, agitation, delusions, and altered consciousness ranging from somnolence to coma. Respiratory paralysis may accompany the most severe cases; however, fatal attacks are quite rare unless relatively harmful medications are administered before proper diagnosis. During an acute attack of AIP, the patient’s urine may become dark red-brown, especially if exposed to light, because of the excretion of large amounts of ALA and PBG. Accordingly, a urine specimen should be qualita-

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tively screened for PBG. If the screen is positive, then a quantitative analysis for PBG and porphyrins in a 24hour urine specimen should be performed.9

Hereditary coproporphyria HCP is considered the least common of the acute porphyrias. However, HCP may be more prevalent than was once thought because disordered heme metabolism and differing tissue sensitivity may lead to atypical clinical presentations; thus, many cases may go unrecognized or are perhaps defined as another entity, such as fibromyalgia. As in AIP, the disorder is inherited in an autosomal dominant fashion with greater propensity for expressivity seen in the female population. The enzymatic defect in HCP is a 50% deficiency of the mitochondrial enzyme coproporphyrinogen (COPROgen) oxidase (Fig 1). Inheritance is associated with high penetrance and variable expressivity because latent carriers are common and few ever experience acute episodes; however, homozygous HCP has also been described.1,6,10 The same factors that precipitate acute episodes of AIP (eg, porphyrogenic drugs, hormones, stress) may also provoke acute attacks of HCP. However, attacks occur less readily in HCP than in AIP, and HCP is considered to be a less severe and debilitating disease.1 Regarding clinical symptomology, HCP and AIP are quite similar, with gastrointestinal, mental, and neurologic manifestations in both. It is important to note that, unlike patients with AIP, those with HCP may also manifest cutaneous photosensitivity. Photosensitivity is caused by the oxidation of excess porphyrinogens to photosensitizing porphyrins. Diagnosis of HCP requires analysis of stool for a marked increase of coproporphyrins. Variegate porphyria VP is sometimes called protocoproporphyria hereditaria or South African porphyria, because it is most prevalent in the white population of South Africa.1 As with AIP and HCP, VP is inherited in an autosomal dominant fashion. The enzyme defect in VP is a 50% deficiency of the mitochemical enzyme protoporphyrinogen (PROTOgen) oxidase, which may result in the accumulation of protoporphyrin (Fig 1). Homozygous cases of VP have been reported. The same factors that provoke acute episodes in AIP and HCP may precipitate acute attacks of VP. Attacks are characterized by symptoms very similar to those of AIP and HCP. The disease is called “variegate” porphyria because it can be manifested by an acute attack with neurovisceral symptoms, cutaneous photosensitivity, or both, and can also be completely latent clinically.1 Diagnosis of VP requires analysis of stool for a marked increase of protoporphyrin.

Table I. Drug recommendations for patients with acute porphyric disorders Indicated (safe) Acetaminophen Acetylsalicylic acid Acyclovir Amphotericin Ascorbic acid Atropine Azathioprine Beclomethasone Bupivacaine Cephalosporins Chloral hydrate Chlorpromazine Codeine Dexamethasone Diazepam Diflunisal Diphenhydramine Fentanyl Folic acid Gentamicin Guanethidine Ibuprofen Iron Lithium Meperidine Morphine Neostigmine Nitrous oxide Nortriptyline Penicillins Phenothiazines Procaine Propranolol Reserpine Streptomycin Succinylcholine Tetracaine Trifluoperazine

Contraindicated (unsafe) Alcohol Amitriptyline Amphetamine Barbiturates Carbamazepine Chloroform Chlordiazepoxide HCL Clonazepam Clonidine Dapsone Erythromycin Estrogen Etidocaine Flurazepam Hydantoin Glutethimide Imipramine Lidocaine Mepivacaine Meprobamate Methyldopa Metoclopramide Miconazole Oral contraceptives (some) Oxazepam Oxycodone Pentazocine Phenacetin Phenobarbital Phenytoin sodium (Dilantin) Sulfonamides Thiopental sodium Tranylcypromine Trazodone HCL Valproate

References 1,6-9.

MEDICAL MANAGEMENT OF ACUTE PORPHYRIAS Prevention is an important aspect of therapy. All drugs known to provoke acute episodes should be avoided (Table I). Clinical judgement (risk versus benefit) must be used with many medications; however, barbiturates are absolutely contraindicated. For other medications, when no alternatives are available, administration should ideally correspond with the minimal therapeutic dosages. Patients with acute porphyric disorders should avoid fasting and crash dieting. An adequate caloric intake, preferably high in carbohydrates, should be ensured, by intravenous infusion if necessary of at least 300 grams of glucose daily. Elevated plasma glucose

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concentrations prevent the induction of ALA synthase.1 Infections can precipitate acute porphyric episodes, and when appropriate, compatible antibiotics (Table I) should be administered. The daily administration of luteinizing hormonereleasing hormone (LH-RH) analog to suppress cyclical ovarian hormone production may prove effective in preventing frequent premenstrual attacks of AIP.1,11 Vitamin B6 and antioxidant supplementation have also been recommended for the management of the acute porphyric conditions. Sunscreens and Bcarotene may be beneficial for those patients with cutaneous photosensitivity.1 Patients with acute porphyric disorders may be seen with abdominal pain unrelated to porphyric disorders, such as appendicitis; therefore, other causes should be sought and ruled out before dismissing abdominal pain as a manifestation of an acute porphyric attack. For patients who are apparently suffering from an acute porphyric attack, ingestion or infusion of glucose at a rate of 10 to 20 grams per hour for 24 hours should be instituted. When attacks are nonresponsive to conventional therapy after 24 hours or when the patient is severely ill, 3 to 4 mg/kg of hematin (heme hydroxide) can be given intravenously. Continuous maintenance of fluid and electrolyte balance is vital. Codeine or morphine is commonly used for pain relief; phenothiazines for nausea and anxiety; propranolol for tachycardia and hypertension; neostigmine for obstipation; chloral hydrate for sedation; and bromide and magnesium for seizures.1,8,12 Continued treatment between attacks is seldom necessary.

cardiologist confirmed this extensive medical history. At the time of her presentation to the Oral Medicine Clinic she had been “clean and sober” for 4 years. Her dental needs were extensive because “necessary” carbohydrates presented a large proportion of the dietary intake and she had rarely received routine or preventive dental care. After a complete clinical and radiographic orofacial examination, diagnoses included (1) perioral hyperpigmentation and hypertrichosis; (2) irreversible pulpitis and acute apical periodontitis consistent with the left maxillary second premolar; (3) generalized mild periodontitis with less than 20% bone loss noted in all 4 quadrants; (4) multiple class I, class II, and class V carious lesions on posterior teeth; (5) bilateral (left greater than right) temporomandibular arthralgia, and (6) bilateral internal derangement of the temporomandibular joints consistent with anterior displacement of the articular disks with reduction. Before initiating dental therapy, the primary care physician and cardiologist were consulted. Some of the planned dental procedures required antibiotic premedication as recommended by the American Heart Association guidelines.13 It was also noted that the patient has a neuropsychiatric history of becoming quite combative when stressed. It was decided that she be preoperatively and postoperatively medicated with the following medications intravenously: (1) diazepam, 20 mg, (2) promethazine, 50 mg, (3) diphenhydramine, 100 mg, and (4) clindamycin, 900 mg. Diazepam, promethazine, and diphenhydramine were used as anxiolytics, antiallergics, antinauseants, and conscious sedatives. Intravenous clindamycin was the only antibiotic that she had been able to tolerate in the past and was therefore the choice antibiotic in this situation. The patient was prescribed an alcohol-free chlorhexidine gluconate 0.12% rinse to aid in the reduction of gingival inflammation and was appointed for outpatient ambulatory surgery where the more invasive dental therapy would be rendered in one appointment. Those procedures not associated with mucosal hemorrhage, gingival hemorrhage, or both would be completed during a subsequent appointment. At the second appointment, the patient arrived early to begin receiving the intravenous administration of the prescribed medication regimen. Each medication was administered in turn, beginning first with diazepam, followed by promethazine, and then diphenhydramine. Ten minutes passed before the administration of clindamycin to allow for adequate blood levels of the preceding medications. Infusion was timed such that clindamycin 900 mg was administered 30 minutes before the initiation of dental therapy. Vital signs and arterial blood gases were monitored throughout the entire procedure. Routine local anesthesia consisting of 2% mepiva-

ILLUSTRATIVE CASE In December of 1998, a 32-year-old white woman reported to the University of Florida College of Dentistry Oral Medicine Clinic with a chief complaint of “multiple problems with teeth and jaw and local dentists won’t treat me because of my illness.” Her medical history was significant for (1) hereditary coproporphyria (HCP) diagnosed at age 28, (2) 3 prolapsed cardiac valves with regurgitation, (3) liver disease, (4) multiple anaphylactic drug reactions including “most antibiotics” and opioid analgesics, (5) alcohol and drug abuse, and (6) photosensitivity. She also reported multiple hospitalizations in the previous 10 years for recurrent abdominal pain, migraine episodes, other unexplained somatic complaints, and psychiatric disease. Included in these admissions were a splenectomy for chronic thrombocytopenia, tubal ligation, complete hysterectomy, a laparotomy, and removal of substernal benign lymph nodes. Current medications included chlorpromazine and diazepam daily. A thorough consultation with her primary care physician and

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caine with 1:20,000 levonordefrin was deemed safe for use because past administration was unremarkable for pathologic sequela. Even though mepivacaine is listed as one of the “unsafe” drugs, the relative effects of each individual’s hepatic microsomal system must be taken into account. During the 2-hour window of antibiotic coverage, the following occurred: (1) nonsurgical endodontia was performed on her left second maxillary premolar; (2) subgingival class V carious lesions were prepared and restored with compomer (patient was hypersensitive to mercury compounds); (3) class II carious lesions were prepared and restored with condensable composite; (4) all 4 quadrants were peridontally debrided with ultrasonic and hand scalers, and (5) topical fluoride was applied by means of carrier tray for 4 minutes. The patient tolerated these procedures well. Postoperative pain was managed with acetaminophen. Her remaining dental treatment, including the restoration of several occlusal carious lesions and the nonsurgical management of temporomandibular disorder, did not require prophylactic antibiotic administration and was completed in 3 noninvasive dental appointments. The patient is currently reappointed on a biannual basis to have a thorough periodontal prophylaxis and any other dental procedures completed using the recommended American Heart Association antibiotic prophylaxis and intravenous medication regimen.

Confirm the information obtained from the patient and briefly discuss the dental treatment plan, including proposed medications, with the physician. Discussion of medications should include local and systemic anesthetics, analgesics, antiinflammatories (including corticosteroids), antibiotics, and sedatives. If the physician has doubts concerning any of the proposed medications, discuss alternative choices (Table I). Also discuss the emergency management protocol for acute episodes with the physician. If the treating dentist is unfamiliar or uncomfortable with any of the recommended medications or management protocols, the patient should be referred to an appropriate office or medical center. 3. Management of pain and infection and the maintenance of masticatory function are of primary concern for the dentist. The high carbohydrate diets often prescribed for these patients can be detrimental to oral health. Dental practitioners should inquire about the patient’s diet and provide appropriate oral hygiene instruction. Frequent follow-up visits (every 3 to 6 months) consisting of prophylaxis, topical fluoride application, and examination are essential. 4. Chlorhexidine gluconate mouthwash may be used for caries control and the maintenance of gingival health, provided it is ethanol-free. 5. Heavy metals have been shown in animal models or tissue preparations to inhibit various enzymes of the heme synthetic pathway and are documented in the literature as having a role in the provocation of acute porphyric attacks.14,15 Accordingly, it has been recommended that these patients avoid aluminum, copper, and mercury compounds. The patient’s inability to tolerate certain types of jewelry may indicate the possibility of an existing metal intolerance. The dentist is ultimately responsible for selecting the materials used in restorations and prosthesis. His knowledge should include alloy composition and precious metal content. 6. It has been estimated that the onset of pain associated with third molar eruption approximates the time-frame of the initiation of AIP symptoms. Therefore, AIP symptoms may be expected as a consequence of dental general anesthesia or conscious sedation (short-acting barbiturates). 7. Acute porphyric disorders should be included in the differentials for patients with oral and systemic symptoms of unknown etiopathology, including orofacial pain.

DISCUSSION Management of patients with acute porphyric disorders poses a challenge to the dental practitioner. General recommendations for the dental management of patients with acute porphyric disorders follow in order to help dental practitioners render safe and effective therapy for such patients. Recommendations for dental management of patients with acute porphyric disorders 1. While obtaining the medical history from a patient with a porphyric disorder, several questions should be asked: • Which physician(s) is primarily responsible for managing the disorder? • How often do acute attacks occur? • When was the last acute attack? • What factors are known to precipitate acute attacks? • What, if any, prodromal manifestations may aid in the recognition of an acute episode? • How are acute attacks usually managed? • Has hospitalization ever been required because of an acute attack? 2. Medical consultation with the primary physician is mandatory before any invasive dental treatment.

REFERENCES 1. Rose L, Kaye D, editors. Internal medicine for dentistry. 2nd ed. St Louis: CV Mosby; 1990. p. 1102-06, 1158. 2. Mathews C, van Holde K. Biochemistry. Redwood City: (CA): Benjamin/Cummings Publishing; 1990. p. 731-4.

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3. Tietz N, Conn R, Pruden E, editors. Applied laboratory medicine. Philadelphia: WB Saunders; 1992. p. 89-97. 4. Yagiela J, Neidle E, Dowd F, editors. Pharmacology and therapeutics for dentistry. 4th ed. St Louis: Mosby-Year Book; 1998. p. 27-33. 5. Brown RS, Hays GL, Jeansonne MJ, Lusk SS. The management of a dental abscess in a patient with acute intermittent porphyria: a case report. Oral Surg Oral Med Oral Pathol 1992;73:575-8. 6. Gorchein A. Drug treatment in acute porphyria. Br J Clin Pharmacol 1997;44:427-34. 7. Witbeck E. Acute intermittent porphyria: clinical management and report of a case. Special Care in Dentistry 1985:27-9. 8. Burgoyne K, Swartz R, Ananth J. Porphyria: reexamination of psychiatric implications. Psychother Psychosom 1995;64:121-30. 9. Ravel R. Clinical laboratory medicine: clinical appreciation of laboratory data. 6th ed. St Louis: Mosby-Year Book; 1995. p. 608-12. 10. Downey D. Hereditary coproporphyria. Br J Clin Pharmacol 1994;48:97-9. 11. Gross U, Honcamp M, Daume E, Frank M, Dusterberg B, Doss

12. 13.

14. 15.

MO, et al. Hormonal oral contraceptives, rrinary porphyrin excretion and porphyrias. Horm Metab Res 1995;27:379-83. Deeg MA, Rajamani K. Normeperidine-induced seizures in hereditary coproporphyria. South Med J 1990;83):1307-08. Dajani AS, Taubert KA, Wilson W, Bolger AF, Bayer A, Ferrieri P, et al. Prevention of bacterial endocarditis: recommendations by The American Heart Association. J Am Dent Assoc 1997;128:1141-51. Downey D. Porphyria induced by palladium-copper dental prosthesis: a clinical report. J Prosthet Dent 1992;67:5-6. Hahn M, Bonkovsky HL. Multiple chemical sensitivity syndrome and porphyria. Arch Inter Med 1997;157:281-5.

Reprint requests: Arthur W. Moore, DMD University of Florida College of Dentistry, Health Science Center PO Box 100414 Gainesville, FL 32610-0414

CALL FOR REVIEW ARTICLES The January 1993 issue of Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics contained an Editorial by the Journal’s Editor in Chief, Larry J. Peterson, that called for a Review Article to appear in each issue. These Review Articles should be designed to review the current status of matters that are important to the practitioner. These articles should contain current developments, changing trends, as well as reaffirmation of current techniques and policies. Please consider submitting your article to appear as a Review Article. Information for authors appears in each issue of Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. We look forward to hearing from you.