Case Challenges in Acute Intermittent Porphyria CME

Transcription

1 Case Challenges in Acute Intermittent Porphyria CME Supported by an independent educational grant from Recordati Rare Diseases 1

2 This article is a CME activity. To earn credit for this activity visit: CME Released: 4/24/2017; Valid for credit through: 4/24/2018 Target Audience This activity is intended for gastroenterologists, emergency medicine physicians, and primary care physicians, nurses, nurse practitioners (NPs), physician assistants (PAs), and other healthcare providers involved in the diagnosis and management of porphyrias. Goal The goal of this activity is to improve the recognition of the signs and symptoms of acute porphyria, the ability to establish a diagnosis, and appropriate tailoring of management options for patients with acute intermittent porphyria. Learning Objectives Upon completion of this activity, participants will: Recognition of clinical presentations of acute intermittent porphyria (AIP) Diagnosis of AIP Comprehensive management of patients with AIP Credits Available Physicians - maximum of 1.0 AMA PRA Category 1 Credit(s) ABIM Diplomates - maximum of 1.0 ABIM MOC points Nurses ANCC Contact Hour(s) (0.25 contact hours are in the area of pharmacology Accreditation Statements In support of improving patient care, Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. For Physicians Medscape, LLC designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. Medscape, LLC staff have disclosed that they have no relevant financial relationships. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Aggregate participant data will be shared with commercial supporters of this activity. 2

3 For Nurses Awarded 1.0 contact hour(s) of continuing nursing education for RNs and APNs; 0.25 contact hours are in the area of pharmacology. Instructions for Participation and Credit There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within the time designated on page 2; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on page 2. To receive AMA PRA Category 1 Credit, you must receive a minimum score of 75% on the post-test. Follow these steps to earn CME/CE credit*: 1. Read the target audience, learning objectives, and author disclosures. 2. Study the educational content online or printed out. 3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. We encourage you to complete the Activity Evaluation to provide feedback for future programming. You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates from the CME/CE Tracker. *The credit that you receive is based on your user profile. Hardware/Software Requirements To access activities, users will need: A computer with an Internet connection. Internet Explorer 8.x or higher, the latest versions of Firefox or Safari, or any other W3C standards compliant browser. Adobe Flash Player and/or an HTML5 capable browser may be required for video or audio playback. Occasionally other additional software may be required such as PowerPoint or Adobe Acrobat Reader. 3

4 Faculty and Disclosures FACULTY Herbert L. Bonkovsky, MD Professor Internal Medicine Director Liver Services and the Liver & Metabolic Disorders Laboratory Wake Forest University School of Medicine Winston-Salem, North Carolina Herbert L. Bonkovsky, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Alnylam Pharmaceuticals, Inc; Mitsubishi Pharma America, Inc.; Recordati Received grants for clinical research from: Alnylam Pharmaceuticals, Inc; Gilead Sciences, Inc.; Mitsubishi Pharma America, Inc. Dr Bonkovsky does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr Bonkovsky does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. EDITOR Stacey J.P. Ullman, MHS Scientific Director, Medscape, LLC Disclosure: Stacey J.P. Ullman, MHS, has disclosed no relevant financial relationships. Anne G. Le, PharmD Scientific Director, Medscape, LLC Disclosure: Anne G. Le, PharmD, has disclosed no relevant financial relationships. CME REVIEWER/NURSE PLANNER Amy Bernard, MS, BSN, RN-BC Lead Nurse Planner, Medscape, LLC Disclosure: Amy Bernard, MS, BSN, RN-BC, has disclosed no relevant financial relationships. PEER REVIEWER This activity has been peer reviewed and the reviewer has disclosed the following relevant financial relationships: Member of Data Monitoring Committee for: Alnylam 4

5 Case 1: Patient History Cathy B is a 25-year-old woman who presents to the emergency department (ED) with severe abdominal pain after an episode of heavy alcohol consumption (approximately drinks over the course of a weekend). She has a history of abdominal pain and poor food intake, including 3 visits to the ED during the past 5 years. Question 1: Which of the following is part of the typical clinical presentation of acute porphyria? x Severe abdominal pain with nausea and vomiting Bradycardia and hypertension Increasing episode frequency after menopause Delusions of grandeur Answer Explanation: The typical clinical presentation of acute porphyria includes severe abdominal pain, nausea, vomiting, tachycardia, and hypertension. Patients may also exhibit hallucinations and seizures. Patients are usually young women with decreasing frequency of episodes after menopause. Clinical Presentation of Acute Porphyria Heme is required for the production of several critical hemoproteins, including hemoglobin, myoglobin, and the cytochrome P450 enzymes. [1] The porphyrias are a group of metabolic diseases that are characterized by deficiencies in the heme biosynthetic pathway and the accumulation of neurotoxic heme precursors, primarily as a result of mutations in genes that regulate heme production. [2,3] Accumulation of these heme precursors causes intermittent episodes of severe abdominal pain and neurologic symptoms. [3] There are 8 major porphyrias, which may be classified as either hepatic or erythropoietic depending on the primary site of overproduction and accumulation of porphyrin precursors. These include 4 acute hepatic porphyrias, hepatic cutaneous porphyria (porphyria cutanea tarda; PCT), and 3 erythropoietic cutaneous porphyrias. [1] The hepatic acute porphyrias include acute intermittent porphyria (AIP), the most common form; hereditary coproporphyria (HCP); variegate porphyria (VP); and delta-aminolevulinate dehydratase deficiency porphyria (a very rare autosomal recessive disorder). [3] The term acute signifies the life-threatening nature of these disorders, not the duration. [4] Porphyrias are rare, and it has been estimated that all forms of porphyria are clinically manifest in fewer than 200,000 people in the United States. [5] The clinical presentation of an acute hepatic porphyria typically involves neurovisceral symptoms, but can also have cutaneous symptoms. HCP and VP can have both neurovisceral and cutaneous, whereas AIP has only neurovisceral symptoms. [6,7] Acute hepatic porphyria is usually characterized by severe abdominal pain with no clear underlying causes. Abdominal pain typically begins gradually and escalates over the course of hours or days and may persist for as long as several weeks. [3] Pain often becomes very severe and is accompanied by nausea and vomiting, prompting patients to seek care at a hospital ED. [8] Other common features include tachycardia and hypertension during episodes -- returning to normal between episodes -- as well as seizures; hallucinations; and progressive polyaxonal motor neuropathy, which can progress rapidly to quadriparesis and acute respiratory insufficiency. [8-10] Other neurologic manifestations may include difficulty swallowing, other bulbar signs, confusion, and delirium. [4] In addition to the abdominal pain and neurologic symptoms associated with AIP, HCP and VP may be associated with cutaneous blistering, milia, pigmented areas, and scars on sunexposed skin. [11] 5

6 Acute porphyria is primarily a disease of young women: Approximately 80% to 90% of patients with acute porphyria are women, with episodes typically occurring between the second and fourth decade and becoming less frequent after menopause. [2,4] Attacks are often precipitated by recent heavy alcohol use, progesterone and related steroids, or by other drugs that induce hepatic 5-aminolevulinic acid (ALA) synthase or cytochrome P450 enzymes (eg, barbiturates, hydantoins, other antiepileptic drugs, and sulfonamide antibiotics), with symptoms occurring within 24 hours after exposure to a precipitating drug. [3] Recent use of a porphyrinogenic drug in a patient with abdominal pain but normal physical examination findings may provide an important clue suggesting a diagnosis of acute porphyria. Other precipitating factors include [3] Hormonal changes in women (luteal phase of the menstrual cycle, oral contraceptive use, early weeks of gestation, the immediate postpartum period) Low-calorie, low-carbohydrate diets Exposure to excess alcohol, especially with poor nutritional intake Exposure to drugs or chemicals that induce or act as suicide substrates of cytochromes P450 (increased demand for hepatic heme) Infections and other illnesses Surgery Emotional stress Case Continues Cathy B s pulse rate on presentation is 90/min to 110/min, and she is hypertensive (blood pressure [BP] 160 mm Hg-120 mm Hg). Her physical examination reveals soft abdomen with no peritoneal signs. Question 2: Which of the following, when accompanied by abdominal pain and seizures, as seen in Cathy B, strongly suggests a diagnosis of acute porphyria? x Appendicitis Markedly elevated blood urea nitrogen (BUN)/creatinine Cholecystitis Hyponatremia Answer Explanation: The triad of hyponatremia, seizures, and abdominal pain is highly suggestive of a diagnosis of acute porphyria. Physical Examination for Porphyria Physical examination of patients with porphyria usually reveals soft abdomen with no peritoneal signs and no fever. A contrast computed tomography (CT) scan is usually normal or demonstrates ileus or stool in the colon. The liver is usually normal, and there is no evidence of appendicitis or cholecystitis. [8] Many patients with acute porphyria are referred for surgery or have a history of removal of the appendix and/or gallbladder. [2] The gallbladder typically does not exhibit acute severe cholecystitis but may be recorded as showing chronic cholecystitis (few chronic inflammatory cells in wall of gallbladder) or appendicitis. Patients with acute porphyria continue to experience new pain episodes despite appendectomy/cholecystectomy. Hyponatremia is observed in approximately 25% to 60% of symptomatic patients with acute porphyria. Hyponatremia can be severe and typically resolves after recovery from the acute episode. [10,11] Causes of hyponatremia may include excessive vomiting or diarrhea, hypotonic fluid replacement, or the syndrome of inappropriate antidiuretic hormone secretion (SIADH) due to pituitary dysfunction. [3,10] Leukocytosis is usually absent or mild (eg, 11,000 to 12,000/mm3 with normal white blood cell [WBC] differential). [3,8] Apart from hyponatremia and possible mild leukocytosis, laboratory tests are usually otherwise unremarkable, including complete blood count, BUN, creatinine, glucose, and liver function tests. [12] 6

7 Urine may be red or reddish brown during an acute attack. [3,12] Freshly voided urine may be clear, whereas voided urine that is exposed to light at ambient temperature may slowly turn dark as the result of formation of uroporphyrin-like pigments (porphobilin). [12] Urinalysis may show 0 to 1 red blood cells. Case Continues Cathy B is treated with morphine for pain while waiting in the ED for results of her laboratory tests. After a wait of 12 hours, her laboratory findings are normal with the exception of hyponatremia (serum sodium concentration 125 meq/l). CT scan does not show appendicitis, cholecystitis, or gallstones. Abdominal ultrasound is also normal, and a pregnancy test is negative. The patient s severe and recurrent abdominal pain and hyponatremia remind a resident of a recent case study he came across about acute porphyria. Question 3: Which of the following, when accompanied by abdominal pain and seizures, as seen in Cathy B, strongly suggests a diagnosis of acute porphyria? x Single random urine porphyrin profile Single random urine PBG test Single random urine PBG and creatinine 24-hour urine collection, urine porphyrin profile Answer Explanation: Acute porphyria should be diagnosed using a single random urine PBG test, including creatinine to normalize the PBG concentration for dilution. A urine porphyrin screen is not specific for acute porphyria and may be elevated due to a number of other causes. Diagnostic Testing for Porphyria Due to its nonspecific presentation and normal laboratory findings, the average time to diagnosis of acute porphyria is approximately 15 years. [2] In many cases, porphyria is recognized only after several ED visits. Patients typically receive pain medications until the episode resolves, only to be discharged when laboratory and clinical findings are nondiagnostic. However, patients often return to the ED again weeks or months later with recurrence of severe pain. Urine testing for porphyrin precursors is critical for making a timely diagnosis of acute porphyria. [3,11] The acute hepatic porphyrias are caused by an inappropriately increased activity of the enzyme 5-aminolevulinic acid synthase (ALAS1), the first and rate-limiting enzyme in the heme synthesis pathway. And because the porphobilinogen deaminase (PBGD) step in the pathway normally has a low activity, the increase in ALAS1 causes the buildup of the porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) (see Figure 1). As noted previously, episodes of porphyria may be precipitated by exogenous factors such as fasting, reproductive hormones, alcohol or other drugs, or stress. These factors deplete the supply of hepatic heme, which normally suppresses the transcription and activation of ALAS1. Depletion of heme results in strong hepatic ALAS1 activation. In combination with reduced PBGD enzymatic activity, precipitating factors result in the marked accumulation and renal excretion of the metabolites ALA and PBG. [13,14] PBG is always elevated during acute porphyria attacks but not in any other medical condition. ALA alone can be elevated in lead poisoning and the genetic disorder hereditary tyrosinemia, as well as in the rare ALA dehydratase deficiency porphyria. [1,11] Guidelines for the optimal assessment and management of acute porphyria were recently developed from consensus recommendations of the physician-investigators of the National Institutes of Health-funded Porphyrias Consortium. [11] Spot urine PBG and creatinine is recommended as a sensitive and specific diagnostic test for acute porphyria; 24-hour urine collection is not necessary. Urine testing should correct for dilution by including creatinine and normalizing the PBG concentration per gram of creatinine. [3] A normal PBG concentration in a symptomatic patient excludes the 3 most common forms of acute porphyria. An exception is a very dilute urine sample, which may result in a false negative spot urine PBG test if not normalized to urine creatinine. [11] Although urine is often red or purple in color during acute attacks, it is also possible for patients to have elevated ALA and PBG even when the urine color is normal. [15] Urine PBG may return to normal after resolution of the acute episode. This is more common in patients with HCP or VP. In patients with AIP, PBG usually remains elevated for months or even years after an attack, even when the patient is asymptomatic. In anuric patients, diagnosis can be established by measuring serum PBG. [4] 7

8 It is important to note that clinicians should order urinary ALA and PBG and not a porphyrin profile or porphyrin screen. [10,15] The porphyrin screen includes fractionated urine porphyrins only; it does not include ALA or PBG. [10,12] Elevation of urine porphyrins without elevation of ALB/PBG occurs primarily in patients with cutaneous porphyria, not AIP. In addition, elevated urine porphyrin concentrations are not specific for acute porphyria and may occur in other conditions, including liver, neurologic, and hematologic diseases. [10] For patients with a positive PBG screening test, diagnosis of acute porphyria should be confirmed by measuring quantitative ALA, PBG, and total porphyrins from the same sample used for the initial test. [3,4] A 24-hour urine kept cold and protected from light should be sent for quantitative ALA, PBG, and porphyrins. In addition, a stool sample (~ g) should be collected and analyzed for total porphyrins and their distribution [the latter is generally performed by HPLC with fluorescent detection]. Currently, there are no point-of-care tests for urinary PBG. [10] ED-based rapid tests are not readily available, and very few hospital laboratories run PBG tests. As a result, there is typically a delay of 4 to 10 days between ordering the test and obtaining the results. Other recommended laboratory tests include a complete blood count, comprehensive metabolic panel with estimated glomerular filtration rate (egfr), and liver function tests. A pregnancy test should be performed in women of childbearing age whose abdominal pain might be the result of a ruptured ectopic pregnancy. [16] Case Continues Cathy B s random urine PBG test yields a value of 55 mg of PBG per gram of creatinine (reference range, 0-4), confirming the diagnosis of acute porphyria. She is referred to a porphyria Center of Excellence for further workup to determine the specific form of porphyria. Question 4: Because Cathy B has AIP, activity of which of the following markers can be expected to be decreased? x Porphobilinogen deaminase [PBGD], aka hydroxymethylbilane synthase (HMBS) Protoporphyrinogen oxidase (PPOX) Uroporphyrinogen III synthase (URO3S) Ferrochelatase (FECH) Answer Explanation: Each of the major porphyria subtypes is associated with a distinct mutation involving genes of the heme biosynthetic pathway. In patients with AIP, the most common type of acute porphyria, genetic testing reveals a disease-causing mutation of the gene encoding HMBS in greater than 90% of cases. Heme Biosynthetic Pathway A positive urine PBG test confirms that patient has some form of porphyria, but additional testing is required to identify the specific defect in heme metabolism. Heme is synthesized from glycine and succinyl-coenzyme A in an 8-step process. [11] Inherited or acquired defects of different heme synthesis pathway enzymes result in different types of porphyria (Figure 1). Pathway intermediates include the porphyrin precursors ALA and PBG, and porphyrins (present primarily in reduced forms known as porphyrinogens). [1] Inborn errors of heme biosynthesis include 3 dominantly inherited disorders: AIP, associated with deficiency of the gene encoding PBGD [HMBS] HCP, associated with deficiency of the gene encoding coproporphyrinogen oxidase (CPOX) VP, associated with deficiency of the gene encoding PPOX There is also a rare autosomal recessive form, 5-aminolevulinic acid dehydratase deficiency porphyria (ADP). [11} 8

9 Figure 1. Heme Biosynthetic Pathway Showing Enzymatic Defects Associated With Different Acute Hepatic Porphyrias [11] Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: Recommendations for evaluation and long-term management. Hepatology. 2017;66: by the American Association for the Study of Liver Diseases. Once acute hepatic porphyria has been identified, subsequent urinary and fecal porphyrin testing can suggest a specific acute hepatic porphyria. The enzyme deficiencies and associated biochemical markers associated with the 4 AHPs are summarized in Table 1. [1} Figure 2. Acute Hepatic Porphyrias: Major Clinical and Laboratory Features [1] AR indicates autosomal recessive; AD = autosomal dominant; NV = neurovisceral; CP = cutaneous photosensitivity; and, not applicable. *Increases that may be important for diagnosis. Republished with permission of American Society of Hematology, from The porphyrias: advances in diagnosis and treatment, Manisha Balwani and Robert J. Desnick, 120, 23, 2012; permission conveyed through Copyright Clearance Center, Inc. 9

10 Genetic testing is required to identify the specific mutation and to determine the specific type of acute porphyria. [11,17] Mutations of known causative genes are found in approximately 90% of patients AIP. [2] According to porphyria guidelines, if biochemical testing suggests a specific subtype of acute porphyria, the respective causative gene should be sequenced. If the biochemical results are incomplete or not definitive, genetic testing should include sequencing for gene mutations associated with AIP (HMBS), VP (PPOX), HCP (CPOX), or ADP (ALAD). [1,11] In patients with AIP, genetic testing reveals mutation of the gene encoding HMBS in approximately 90% of cases. [18] More than 390 distinct HMBS mutations have been identified. HMBS enzymatic activity is reduced by approximately 50% on average, with the loss of HMBS activity in an individual patient varying with the nature of the specific mutation. [10] Although AIP is linked to genetic mutation of HMBS, the penetrance of this effect is low. The mutation occurs in approximately 1 per 1700 Americans of European descent, but only about 1% of the at-risk population experiences acute attacks. [19,20] Genetic testing of family members is also important to identify those who are at risk of attacks and to address risk factors to reduce the likelihood of acute attacks and is available through the NIH Rare Diseases Consortium, which may be reached through the APF. Diagnosis and management of acute porphyrias often takes place at Centers of Excellence. Contact information for several Centers of the Excellence is available from the Porphyrias Consortium: A summary diagnostic algorithm for acute porphyrias is shown in Figure 2. [4] Figure 3. Summary Diagnostic Algorithm for Acute Porphyrias Reprinted from J Emerg Med., 49, Besur S, et al., Acute Porphyrias, , Copyright 2015, with permission from Elsevier. 10

11 Question 5: The Porphyria Center of Excellence is most likely to treat Cathy B s acute attack with x Oral glucose Intravenous (IV) glucose Hemin for 24 hours Hemin for 4 days Answer Explanation: The most effective therapy for an attack of acute porphyria is hemin, which is usually administered IV for 4 days. Managing Acute Attacks Management of an acute attack is identical for all of the acute porphyrias, and focuses primarily on the rapid treatment of symptoms and prevention of additional complications. [3,4] Unless the attack is mild, patients are hospitalized in a darkened private room. Hemin is the only specific treatment for acute porphyria, [3,12] and management guidelines recommend that most acute attacks should be treated with hemin infusions. [11] By downregulating hepatic ALAS1, hemin injection limits the body s production of ALA, PBG, and porphyrins. Glucose loading also downregulates ALAS1 activity and relieves symptoms but is less potent than hemin. [3,8] One hematin formulation (Panhematin ) is approved for use in the United States. The recommended hemin dose is 3 mg/ kg to 4 mg/kg body weight/d for 4 days, usually administered while the patient is hospitalized. If the diagnosis is confirmed, the first dose may be administered in the ED. [8] Pain usually improves after the third day. If initiation of hemin treatment is delayed, nerve damage may be more severe and recovery may be delayed or incomplete. [3] In an open-label study of 111 patients with acute porphyria who were treated for a total 305 acute attacks, hemin was regarded as effective for all attacks in 73% of patients. [21] In a retrospective study of 108 patients who had previously been treated for acute porphyrias, hemin infusions were reported by patients to be the most effective treatment option for acute attacks. Hemin was rated as effective for improving abdominal pain and other manifestations of acute attacks by 74% of patients, whereas opiate pain medications were described as effective by 44% of patients. [2] Hemin treatment may be continued if recovery is not evident within 4 days. [8] The most common adverse reactions in patients receiving hemin infusions were headache, pyrexia, infusion site reactions, and phlebitis. [22] Hemin is available in the United States as a sterile, lyophilized powder that is reconstituted in a glass vial with sterile water. [3] It may also be reconstituted using human albumin. Reconstitution with albumin rather than sterile water may reduce the risk of infusion-site phlebitis, which can compromise venous access. [8] For example, it has been recommended that a 313-mg vial of hemin should be reconstituted with 132 ml of 25% human serum albumin, swirling the solution 15 to 20 times to mix. [8,23] A sterile 0.45 micron or smaller filter should be used to remove any undissolved particulate matter. [22] The dose may be administered directly from the vial over a period of at least 30 minutes. After the infusion, the vein should be flushed with 100 ml of 0.9% sodium chloride. [22] The solution contains no bacteriostatic agents and should be used within 1 hour of preparation. [8] Other medications that may be used to relieve symptoms during an acute attack include narcotic analgesics for abdominal pain; phenothiazines for nausea, vomiting, anxiety, and restlessness; and chloral hydrate or some short-acting benzodiazepines for insomnia. [1] Intravenous glucose loading (at least 3 L of 10% glucose daily) may be used for mild attacks (ie, pain controlled with little or no narcotic pain medication, with no hyponatremia or motor weakness) or while waiting for hematin to become available. [3,8] Patients should be carefully monitored for pain and other symptoms, and for potential complications of acute porphyria or hematin treatment (eg, respiratory impairment, hyponatremia and neuropsychiatric manifestations).electrolyte imbalances (eg, hyponatremia, hypomagnesemia) should be corrected and monitored. [8] Ongoing follow-up evaluation is needed to monitor patients for complications and should include heart rate, BP, fluid and electrolyte balance, neurologic status, bladder function, muscle and tendon function, respiratory function, and oxygen saturation. [3] Patients with porphyria should also maintain a well-balanced diet with at last 300 g of carbohydrates per day. Patients with severe recurrent symptoms should avoid alcohol and smoking. [11] 11

12 Due to the rarity of porphyria, few physicians have extensive experience diagnosing and treating it. The American Porphyria Foundation ( provides additional support and advice for the diagnosis and management of porphyria. It also maintains a list of porphyria specialists, which is available at: porphyriafoundation.com/testing-and-treatment/finding-a-doctor. Case Conclusion After the fourth day of daily IV heme, Cathy reported no further pain; her pulse rate and BP returned to normal. She was discharged on the fifth hospital day. She was strongly advised not to drink more than 1 drink of alcohol per day, not to smoke, not to take in any known or risky porphyrogenic drugs. Cathy did not experience any further acute attacks in the ensuing 2 years. 12

13 Case 2: Patient History Julia is a 34-year-old woman who was referred to a psychiatrist by her primary care physician. She has a history of multiple somatic complaints including abdominal pain and constipation, nausea, and vomiting. She also has difficulty concentrating. Physical examination and routine laboratory workups have been nondiagnostic, with the exception of hyponatremia (serum sodium, 120 meq/l), which her primary care physician attributes to vomiting. Julia is initially diagnosed with somatoform disorder by her psychiatrist, and she begins treatment with a serotonin-norepinephrine reuptake inhibitor (SNRI). However, she reports no significant improvement in her somatic symptoms at a follow-up visit with her psychiatrist 6 months after beginning treatment. Two weeks later, she experiences a tonic-clonic seizure. Question 6: Which of the following anticonvulsants would be most appropriate for Julie, who has acute porphyria? x Levetiracetam Valproate Phenytoin Carbamazepine Answer Explanation: Most antiepileptic drugs (AEDs) are associated with increased risk of acute porphyria attacks and are strongly contraindicated in patients with AIP. Anticonvulsants that are probably safe include levetiracetam, topiramate, and vigabatrin. Anticonvulsants and Acute Porphyria AIP and the other acute hepatic porphyrias are associated with a number of neuropsychiatric complications, including psychiatric comorbidities, seizures, and neuropathic pain. [2] In particular, anxiety and/or depression is reported by more than half of patients during acute attacks, and more than 30% of patients with AIP have comorbid psychiatric conditions (compared with a reported incidence of 16% of the US generation population). [2] Other psychiatric symptoms include sleep disorders, psychotic symptoms, bipolar disorder, cognitive impairment/altered mental status, and chronic fatigue. [6] Patients with acute porphyria are often seen by psychiatrists due to their history of frequent somatic symptoms with no clear physical cause. In many cases, porphyria is misdiagnosed as somatoform disorder or another psychiatric condition, exposing the patient to ineffective treatments or treatments that worsen their symptoms. [2,6] Porphyria should be considered as a potential diagnosis for patients with nonspecific clinical presentations, poor response to treatment, and somatic symptoms. [6] Seizures are also common among people with acute porphyria. In an observational study of 108 patients with acute porphyria, 9% reported a history of seizures (occurring primarily during acute attacks), compared with a reported incidence among the US general population of approximately 0.6%. [2] Treatment of seizures is complicated in patients with porphyria because exposure to most AEDs (eg, phenytoin, valproate, carbamazepine) may precipitate acute attacks and are strongly contraindicated in patients with AIP. [12,24] These agents may cause severe weakness and the need for respiratory support. Anticonvulsants that are probably safe for patients with acute porphyria include levetiracetam, topiramate, and vigabatrin. [3] Neuropathic pain in acute porphyria is thought to reflect the neurotoxicity and oxidative damage from overproduction of ALA. [25] Pregabalin or neurontin may be of some benefit for pain in these patients. [26] 13

14 Case Continues After Julia experiences a seizure, the psychiatrist suspects AIP based on her history of abdominal pain and hyponatremia. However, the diagnosis is missed because the psychiatrist orders a porphyrin test instead of PBG. The patient continues to experience episodes of difficulty concentrating and abdominal pain, which is not relieved by treatment for her somatoform disorder. She switches to a second psychiatrist, who orders a PBG test and makes the correct diagnosis. The psychiatrist reviews with Julia drugs that should be avoided, and refers Julia to a gastroenterologist for additional treatment and follow-up. Question 7: Which of the following is considered unsafe in a patient like Julia with AIP? x Oral contraceptives Opioids Ibuprofen Aminoglycoside antibiotics Answer Explanation: Oral contraceptives are one of several types of medication that can trigger acute attacks in patients with AIP. Medications and Acute Porphyria Several organizations and societies have developed lists of drugs that should be avoided in patients with AIP. Although they vary somewhat in specific recommendations, they do agree on the most important medications that should be avoided (eg, barbiturates, hydantoins, sulfa drugs, valproate, rifampin). A list of potentially unsafe, possibly unsafe, and probably safe drugs is shown in table 2. [12] Rapid progression of generalized weakness to quadriparesis and acute respiratory insufficiency is especially common in patients who were misdiagnosed and treated with barbiturates or hydantoins (eg, for seizures). [4] Hepatic ALAS1 can be induced by many of the same substances that induce cytochrome P450 enzymes. [1] In general, any drug that is a strong inducer of cytochrome P450 and that undergoes extensive phase 1 metabolism by the liver should be avoided in patients with AIP. Medication Safety Medication Safety Anticonvulsants Anticonvulsants Lorazepam Probably Safe Ketamine Probably Unsafe Gabapentin Probably Safe Phenytoin Unsafe Megnesium Sulfate Probably Safe Barbituates (all types) Unsafe Propofol Probably Safe Valproic Acid Unsafe Bromides Probably Safe Carbamazepine Unsafe Clonazepam Probably Unsafe Primidone Unsafe 14

15 Medication Safety Medication Safety Other Medications Other Medications Furosemide Probably Safe Sulfa Antibiotics Probably Unsafe Chlorpromazine Probably Safe Erythromycin Probably Unsafe Ibuprofen Probably Safe Fluconazole Probably Unsafe Opioids Probably Safe Nitrofurantoin Probably Unsafe Diphenhydramine Probably Safe Rifampicin Probably Unsafe Lithium Probably Safe Oral Contraceptives Unsafe Meclizine Probably Safe Progestins Unsafe Penicillins Probably Safe Carisoprodol Unsafe Warfarin Probably Safe Spironolactone Unsafe Imipramine Probably Unsafe *Agents that are listed as being unsafe should be considered only if a less risky alternative is not available, the indication is urgent, and the use will be short-term. Those that are listed as being possibly unsafe should be used with caution, and those that are listed as being probably safe have been deemed so on the basis of use in patients with acute porphyria. More detailed information is provided at and From N Engl J Med.,Bissell DM, et al., Porphyria, 377, Copyright 2017 Massachusetts Medical Society. Reprinted with permission from MassachusettsMedical Society. Case Continues Julia s symptoms improve somewhat after her diagnosis of porphyria and attention to reducing and eliminating attack triggers. However, she continues to experience monthly episodes of severe abdominal pain and nausea coinciding with her menstrual cycle. Six months later, she has a severe attack of AIP after contracting influenza and experiencing significant nausea, vomiting, and an accompanying reduction in food intake. This episode results in hospital admission for hemin treatment and stabilization. Over the next 11 months, she experiences 3 more episodes requiring hospitalization and hemin treatment that coincide with her menstrual cycle. Her physician recommends prophylactic treatment with IV Panhematin to reduce the frequency of recurrent attacks. Question 8: How confident are you in managing patients with AIP? (Select ranking from 1 [Not confident] to 5 [Very confident]) 1 Not confident Very Confident 15

16 Post-assessment Question Introduction: Julia is a 34-year-old woman who was referred to a psychiatrist by her primary care physician. She has a history of multiple somatic complaints including abdominal pain and constipation, nausea, and vomiting. She also has difficulty concentrating. After Julia experiences a seizure, the psychiatrist suspects AIP based on her history of abdominal pain and hyponatremia. Six months later, she has a severe attack of AIP after contracting influenza and experiencing significant nausea, vomiting, and an accompanying reduction in food intake. This episode results in hospital admission for hemin treatment and stabilization. Over the next 11 months, she experiences 3 more episodes requiring hospitalization and hemin treatment that coincide with her menstrual cycle. Her physician recommends porphyria prophylaxis to reduce the risk of recurrent attacks. Question 9: Which of the following prophylactic regimens would be the best option for Julia? x Hemin infusions Daily oral glucose loading Weekly IV glucose infusion Liver transplantation Answer Explanation: In patients with AIP, hemin infusions are recommended for long-term prophylaxis to reduce the risk of new attacks. Managing Recurrent Attacks With Porphyria Many patients with porphyria experience persistent recurrent attacks, which are associated with decreased quality of life. [27] In addition to their acute abdominal symptoms, patients with acute porphyria often experience debilitating prodromal symptoms that may begin several days before the onset of severe pain, such as difficulty concentrating, irritability, and fatigue. Patients also report that acute attacks negatively affect their interpersonal relationships and contribute to feelings of isolation. Fear of recurrence and the potential need for hospitalization makes it difficult for patients to travel or engage in other day to day activities, such as school or work. [27] As noted previously, the standard treatment for acute attacks is IV hemin infusion, which is usually administered for 4 days. [22] In addition, some patients with severe recurrent attacks (eg, patients with monthly attacks during the luteal phase of the menstrual cycle, at least 4 attacks within the past 12 months) receive prophylactic hemin infusions to prevent recurrence after identifiable triggers have been removed. [11,28] In an observational study of 31 patients who received prophylactic hemin infusions for up to 8 months, 68% reported no new acute porphyria attacks. [21] In a second observational study that included patients with acute porphyria who had received hemin infusions, glucose infusions, or pain medications for prophylaxis, hemin infusions were rated by patients as more effective by a wide margin. [2] The mean patient rating of effectiveness of heme infusion was 7.9 (on a scale of 0 [least effective] to 10 [highly effective]). Glucose infusions, high-carbohydrate diets, and pain medications received average ratings of 4.4, 4.7, and 4.2, respectively. Heme is metabolized rapidly by heme oxygenase and its effects on ALAS1 may not persist for more than 1 week, though some patients benefit from biweekly or monthly infusions. [11] The need for continued prophylaxis should be reassessed after 6 to 12 months of repeated prophylactic therapy. Guidelines suggest that interrupting and restarting prophylaxis (if necessary) may be more effective than gradual tapering of the dose or frequency of injection when assessing the need for continued prophylaxis. [11] In addition to hemin infusion, acute attacks related to menstrual cycle may be prevented by administration of a gonadotropin-releasing hormone (GnRH) agonist plus low-dose estrogen. Low-dose hormonal contraceptives may also reduce premenstrual attacks, though the progestin component may exacerbate porphyria. [3] Oophorectomy and hysterectomy are not usually considered unless there is another indication. Measuring serum progesterone at the onset of symptoms can help to identify luteal-phase attacks. [11] Carbohydrate loading with glucose tablets or concentrated dextrose solutions has not been clearly shown to provide benefit for prevention of acute attacks. [11] Although some patients may be able to forestall severe symptoms by oral glucose loading at the first sign of an acute attack, this approach may also increase the risk of weight gain and dental caries. [3] 16

17 Hemin contains 9% iron by weight, and may contribute to iron overload in patients who receive repeated long-term injections. Guidelines recommend assessing serum ferritin at intervals of 3 to 6 months, or after approximately every 12 doses. [11] To avoid acute effects of heme infusion on iron concentration, serum ferritin should be measured between attacks and before the next infusion of hemin. Therapeutic phlebotomy is recommended when ferritin levels reach 1000 ng/ml (or earlier), with a target level of approximately 150 ng/ml. [11] Patients who experience prodromal symptoms may receive on-demand hemin infusions at an outpatient center to control symptoms and prevent hospitalization. [11] Patients who have not yet progressed to severe abdominal pain, vomiting, and hypertension may receive a single outpatient infusion or repeated outpatient doses on consecutive days. Those who have already progressed to severe abdominal pain, vomiting, and hypertension are at high risk for rapid deterioration, and should be managed as inpatients. [11] Liver transplantation has been shown to eliminate AIP attacks and to restore urinary ALA and PBG levels in patients with recurrent attacks. [29,30] Liver transplantation is an option for patients with severe, disabling, recurrent attacks who are at risk of renal damage or permanent neurologic damage. [3] Due to the potential for morbidity or mortality, this is considered a treatment of last resort. Patients with acute porphyrias should not serve as liver donors because recipients of donor livers from people with acute porphyrias have developed acute porphyric syndromes. Kidney transplantation, with or without simultaneous liver exchange, should be considered for patients with active disease and terminal renal failure due to increased risk of nerve damage with initiation of dialysis. [3] Long-term follow-up is recommended to prevent attacks, hospitalizations, and long-term complications. The followup approach is individualized based on the patient s age, clinical features, and ongoing treatment. Patients with acute porphyria can be classified into 4 subgroups [11] : Latent carriers of porphyria-associated gene mutations who are asymptomatic and biochemically inactive (normal levels of ALA and PBG) Asymptomatic high excretors (ASHE) who have increased urinary ALA and PBG ( 4 times the upper limit of normal) but who do not currently have acute attacks Patients with sporadic, infrequent acute attacks (<4/y) Patients with frequent recurrent attacks ( 4/y) Recommended follow-up assessments for these 4 subgroups are summarized in Figure 5. [11] Patients with porphyria are at increased risk for systemic arterial hypertension, renal disease, liver disease, and hepatocellular carcinoma (HCC). For patients older than 50 years or with sporadic or recurring attacks, recommended monitoring for HCC includes alphafetoprotein testing and liver ultrasound every 6 months. [11] 17

18 Figure 4. Follow-Up Assessment for Patients With Acute Porphyria Abbreviations AFP, alpha-fetoprotein; CBC, complete blood count; CMP, comprehensive metabolic panel; DXA, dual-energy X-ray absorptiometry, egfr, estimated glomerular filtration rate; Gyn, gynecological; US, ultrasound Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: Recommendations for evaluation and long-term management. Hepatology. 2017;66: by the American Association for the Study of Liver Diseases. 18

19 Julia tells her gastroenterologist that she is considering conceiving a child and that she is concerned about how conception and pregnancy might be affected by AIP or its treatment. Question 10: Which of the following is TRUE regarding pregnancy in patients with AIP, such as Julia? x Fertility is usually markedly impaired in women with AIP Fertility-inducing drugs may precipitate acute attacks and should be used with caution Pregnancy is a contraindication to hemin therapy The risk of acute attacks is greatest during the third trimester Answer Explanation: Fertility is not usually impaired in women with AIP, and hemin infusion is not contraindicated during pregnancy. Fertility-inducing drugs may precipitate acute attacks and should be used with caution. [11,12,31,32] Acute Porphyria and Fertility Fertility is not usually impaired in women with AIP, except in cases where the patient is debilitated and anovulatory due to repeated attacks. [11] Fertility-inducing drugs have been associated with new attacks and should be used with caution. Pregnancy is usually uncomplicated, although a minority of women with AIP experience more attacks during pregnancy. [31] Nausea during pregnancy may contribute to decreased caloric intake, resulting in increased risk of attacks. Attacks are especially likely during early pregnancy and the postpartum period. [3,32] Women with AIP may also be at increased risk of miscarriage. Women who are considering pregnancy should undergo a preconception evaluation to discuss potential risks. Pregnant women with AIP should be followed by a high-risk obstetrician during and after pregnancy. [11] Although there is a 50% chance of gene mutation transmission to a child, the low penetrance rate makes it unnecessary to recommend a patient not have children. Pregnancy is not a contraindication to hemin infusion. Acute flare-ups that occur during pregnancy may be treated with hemin infusion without risk to the fetus. [12,31,32] Case Conclusion Julia has a portacath inserted into her right subclavian vein, and she begins weekly IV heme infusions at a dose of 3 mg/ kg of body weight/wk. During the ensuing 2 years, she does not experience any further acute attack that requires hospital admission. Educational Impact Challenge What did you learn from this activity? Please click on the Next button to proceed to a brief survey to see how your knowledge improved after the education. You can also see how your answers compare with those of your peers. 19

20 Abbreviations AD = autosomal dominant ADP = acid dehydratase deficiency porphyria AED = antiepileptic drug AIP = acute intermittent porphyria ALA = 5-aminolevulinic acid ALAS1 = 5-aminolevulinate synthase AR = autosomal recessive ASHE = asymptomatic high excretor BP = blood pressure BUN = blood urea nitrogen CP = cutaneous photosensitivity CPOX = coproporphyrinogen oxidase CT = computed tomography ED = emergency department egfr = estimated glomerular filtration rate FECH = ferrochelatase GnRH = gonadotropin-releasing hormone HCC = hepatocellular carcinoma HCP = hereditary coproporphyria HMBS = hydroxymethylbilane synthase IV = intravenous NP = nurse practitioner NV = neurovisceral PA = physician assistant PBG = porphobilinogen PBGD = porphobilinogen deaminase PCT = porphyria cutanea tarda PPOX = protoporphyrinogen oxidase SIADH = syndrome of inappropriate antidiuretic hormone secretion SNRI = serotonin-norepinephrine reuptake inhibitor URO3S = uroporphyrinogen III synthase VP = variegate porphyria WBC = white blood cell Related Links Children With Vomiting and Muscular Weakness: What s the Diagnosis? Woman in Acute Abdominal Pain: What s the Diagnosis? Hyperammonemia: Best Practices for Diagnosis and Treatment 20

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