Clinical Issues in AIP: When to Suspect and How to Proceed CME/CE

Transcription

1 Clinical Issues in AIP: When to Suspect and How to Proceed CME/CE Supported by an independent educational grant from Recordati Rare Diseases.

2 Clinical Issues in AIP: When to Suspect and How to Proceed CME/CE This article is a CME/CE certified activity. To earn credit for this activity visit: CME/CE Released: 3/25/2016; Valid for credit through 3/25/2017 Target Audience This activity is intended for gastroenterologists, primary care physicians, emergency medicine physicians, and nurses. Goal The goal of this activity is to improve recognition, diagnosis, evaluation, and treatment of patients with acute intermittent porphyria. Learning Objectives Upon completion of this activity, participants will be able to: 1. Identify key factors used to diagnose acute intermittent porphyria (AIP) 2. Select appropriate treatment and management strategies in patients with AIP Credits Available Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s) Nurses ANCC Contact Hour(s) (1 contact hours are in the area of pharmacology) All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation. Accreditation Statements For Physicians Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Medscape, LLC designates this enduring material for a maximum of 0.50 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. For Nurses Medscape, LLC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center s Commission on Accreditation. Awarded 0.50 contact hour(s) of continuing nursing education for RNs and APNs; none of these credits is in the area of pharmacology. Medscape, LLC staff have disclosed that they have no relevant financial relationships. For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact CME@medscape.net Pg.2

3 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 the title page; 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 the title page. 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. Pg.3

4 Clinical Issues in AIP: When to Suspect and How to Proceed CME/CE Faculty and Disclosures As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines relevant financial relationships as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest. Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content. Angelika L. Erwin, MD, PhD Assistant Professor of Genetics and Pediatrics, Lerner College of Medicine; Clinical Geneticist, Cleveland Clinic, Cleveland, Ohio Disclosure: Angelika L. Erwin, MD, PhD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Alexion Pharmaceuticals, Inc. Served as a speaker or a member of a speakers bureau for: Genzyme Corporation Dr Erwin does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr Erwin does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Manisha C. Balwani, MD, MS Associate Professor, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York Disclosure: Manisha C. Balwani, MD, MS, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Alexion Pharmaceuticals, Inc.; Genzyme Corporation; Recordati Rare Diseases, Inc. Received grants for clinical research from: Alnylam Pharmaceuticals, Inc.; Genzyme Corporation; Synageva BioPharma Dr Balwani does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr Balwani does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Editor Susan L. Smith, MN, PhD Lead Scientific Director, Medscape, LLC Disclosure: Susan L. Smith, MN, PhD, 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 no relevant financial relationships. Pg.4

5 Angelika L. Erwin, MD, PhD: Hello, I am Dr Angelika Erwin. I am a clinical geneticist and an associate professor at the Lerner Collage of Medicine at the Cleveland Clinic. Welcome to this program titled, When to Suspect and How to Proceed Clinical Issues in AIP. Joining me today is Dr Manisha Balwani, an associate professor of genetics and medicine and codirector of the Porphyria Center at the Icahn School of Medicine at Mount Sinai in New York City. Manisha Balwani, MD, MS: Thank you for having me, Angelika. Dr Erwin: Acute intermittent porphyria (AIP) is 1 of 4 acute porphyrias, all of which are characterized by recurrent, acute attacks of neurovisceral symptoms. Pg.5

6 Clinical Issues in AIP: When to Suspect and How to Proceed CME/CE AIP is caused by a defect in the HMBS gene, which leads to a partial deficiency in porphobilinogen (PBG) deaminase, the third enzyme of the heme biosynthetic pathway. [1] Alcohol use, exposure to certain medications, or other factors that increase demand for heme lead to upregulation of heme biosynthesis in the liver. This results in increased production of certain heme precursors especially delta-aminolevulinic acid (ALA) and PBG. Patients who have a partial deficiency in the PBG enzyme cannot sufficiently metabolize these heme precursors. The precursors accumulate in the liver and cause the symptoms seen in patients with an AIP attack [hereafter referred to as acute attack ]. Both ALA and PBG are neurotoxic, which explains the neurologic nature of symptoms associated with AIP. AIP is an autosomal dominant disorder. Affected persons have a 50% chance of passing the genetic mutation that causes AIP to their children. Pg.6

7 Although AIP is the most common acute porphyria, it is nevertheless a rare disorder. Therefore, it is often misdiagnosed or undiagnosed. Due to the nonspecific presentation of AIP, healthcare providers need to have a high initial index of suspicion to recognize the classic symptoms and make the diagnosis. Manisha, how does a patient who is experiencing an acute attack typically present to the healthcare system? Dr Balwani: This is best illustrated using a case. A 24-year-old woman went to the emergency department (ED) after having a tonic-clonic seizure at home. She had a recent history of abdominal pain, nausea, and vomiting, which had worsened over the past 3 days; she also had back and chest pain. A physical examination showed her heart rate was 160 to 170 beats per minute, indicating tachycardia. She was hypertensive and had significant proximal muscle weakness. She was afebrile. This is a classic presentation of AIP, in which the patient arrives at the ED with severe symptoms. Pg.7

8 Clinical Issues in AIP: When to Suspect and How to Proceed CME/CE AIP is much more common in women than in men. In women, AIP typically presents during the reproductive years (20 to 49 years of age). More than 90% of patients with AIP present with severe, acute abdominal pain, which is a classic symptom of the disorder. The pain is usually so severe that patients will rate it as a 10 on a scale of 0 to 10. Abdominal pain is often accompanied by pain in the back, chest, or extremities, as was the case with our patient. Patients also typically have nausea and vomiting. Some patients have constipation, but diarrhea is rare. Acute onset of tachycardia and hypertension are also classic features of AIP and typically result from increased catecholamine production. The appearance of hypertension in a patient who has no history of this condition may point to AIP as a diagnosis. Patients with AIP may also experience headaches, confusion, or altered mental status. They may present with a seizure, as our patient did. Pg.8

9 Severe muscle weakness is another common feature of AIP, as was seen in our patient. Muscle weakness is typically proximal, with the upper extremities more commonly affected than the lower extremities. Dr Erwin: In my experience, patients with muscle weakness who have very severe acute attacks can develop paralysis and respiratory failure. If they are not treated appropriately, they can die. Dr Balwani: That is correct. Muscle weakness can be progressive, so it is important to carefully monitor patients who present with muscle weakness. Dr Erwin: When patients like the woman in our case present to the ED, what are the first steps in assessing them? Dr Balwani: The first thing to do, of course, is to stabilize the patient. The next step is to obtain a thorough patient history with the goal of determining what might have precipitated the attack. Did the patient recently begin taking any new drugs or increase her alcohol intake? Was anything else going on such as fasting, dieting, surgery, or an illness that could have precipitated the event? Pg.9

10 Clinical Issues in AIP: When to Suspect and How to Proceed CME/CE The physical examination is not always helpful. Patients typically have hypertension and tachycardia. Their abdominal pain is neuropathic and presents differently than abdominal pain due to other causes. It is diffuse, with no tenderness, rebound tenderness, or rigidity. Patients typically have no signs of infection. Dr Erwin: What about laboratory test results? Dr Balwani: Our patient had a normal complete blood count, which is what is usually seen during an acute attack. Although liver enzymes are typically elevated during an acute attack, the increases are usually transient. The most striking laboratory feature is hyponatremia. Our patient s critically low sodium level of 130 mg/l is probably what caused her seizure. Hyponatremia may be a clue to the diagnosis of AIP. The patient was suspected of having hematuria, probably because her urine was dark or reddish in color, but her urinalysis results were normal. Obviously, this means the patient did not have blood in her urine. The presence of porphyrins in her urine likely turned it dark or reddish in color. Porphyrins in the urine can also provide a clue to the diagnosis. Patients should undergo a complete gastrointestinal workup to rule out other causes of their symptoms. The results of our patient s gastrointestinal workup were normal. Pg.10

11 Dr Erwin: Patients first attacks of AIP are often misdiagnosed. I have seen patients who initially received a diagnosis of colitis, appendicitis, cholecystitis, or urinary tract infection. Patients are frequently given antibiotics or may even undergo surgical interventions before a correct diagnosis of AIP is made. Dr Erwin: Although common causes of AIP should first be ruled out, AIP should be part of the differential diagnosis, especially if no specific underlying cause of the symptoms is found. Are there specific laboratory tests for AIP? Dr Balwani: The diagnostic test for AIP is urinary PBG level. I want to stress that it is urinary PBG and not urinary porphyrins. Urinary PBG can be detected using a random spot urine sample. A 24-hour urine collection test can be used, but it is completely unnecessary. A random spot urine sample to test for urinary PBG will provide a definitive diagnosis. Pg.11

12 Clinical Issues in AIP: When to Suspect and How to Proceed CME/CE Dr Erwin: How was our patient s AIP diagnosed? Dr Balwani: Her case is interesting because her mother had been told she had AIP after a urine test when she was in her early twenties. She never had any more symptoms and forgot about it until her daughter s acute attack. Because of her mother s medical history, our patient had a spot urine test for urinary PBG was done. Her urinary PBG level was more than 10 times the normal level (normal, 2 mg/l), which is diagnostic for AIP. Angelika, what are some of the factors that precipitate an acute attack? Dr Erwin: One of the most common precipitating factors is hormones. As you indicated, most patients with AIP are female and the typical age of onset is after puberty. Although the underlying causes are not fully understood, hormonal changes definitely play a role. In addition, many women who have AIP experience acute attacks during their menstrual cycle. The attacks are most common during the late luteal phase, providing further evidence of a hormonal component. Progesterone preparations are also precipitators of acute attacks. Our patient is a good example of this because she had her first acute attack after starting an oral contraceptive. Pg.12

13 Certain medications, such as sulfonamides, barbiturates, and cytochrome P450 inducers, can trigger acute attacks. Alcohol consumption and smoking can also precipitate acute attacks. I have seen quite a number of patients who experienced their first acute attack after coming back from spring break. Fasting can precipitate acute attacks. One of my patients went on a juice diet and began having acute attacks. Physiologic stress from surgery or an active infection or any cause of decreased caloric intake may lead to a catabolic state, which can also trigger an acute attack. However, in many cases, it is not possible to identify what triggered a patient s attack. Dr Balwani: That is my experience, as well. Pg.13

14 Clinical Issues in AIP: When to Suspect and How to Proceed CME/CE Dr Erwin: Once a patient is diagnosed with AIP, what is your management approach for an acute attack? Dr Balwani: The first thing to do is stabilize the patient. [2] When a patient has tachycardia and hypertension, you want to bring the patient s blood pressure and heart rate under control. The preferred drug to use is a beta-blocker, which can be given by intravenous (IV) infusion, which lowers both blood pressure and heart rate. You need to pay close attention to fluid and electrolyte levels. If a patient has hyponatremia, such as our patient, the sodium level needs to be corrected carefully. Pain is very severe during an acute attack, so it is important to provide adequate pain control. I typically use morphine, taking care to ensure that patients have good symptom relief. Patients who have nausea and vomiting during an attack may benefit from mild-to-moderate doses of a phenothiazine. Managing seizures is also important. Unfortunately, several antiseizure medications, including phenytoin, can worsen symptoms and precipitate acute attacks. You can use benzodiazepines to control seizures. It is important to review all medications the patient is receiving. You want to eliminate any medication or other factor that could precipitate an acute attack. Also, when adding a new medication, be careful to make sure it is not one that will worsen the patient s symptoms. Patients with severe symptoms, such as our patient, need to be hospitalized for further management. Pg.14

15 Dr Erwin: What about specific treatments for AIP? Dr Balwani: The specific treatment for AIP is hemin, which is reconstituted heme. Intravenous administration of hemin repletes the hepatic heme pool, thereby increasing suppression of hepatic ALAS-1 and decreasing the amount of porphyrin precursors ALA and PBG, which are neurotoxic. This helps alleviate symptoms. Hemin is available as a lyophilized powder that needs to be reconstituted. [3] It is typically given at a dose of 1 to 4 mg/kg, up to a maximum of 1 vial or 6 mg/kg/day. Hemin should be given as soon as possible, especially to patients who present with severe symptoms. Hemin is typically given for 3 to 4 days while a patient is hospitalized. While hemin is being reconstituted, patients may benefit from carbohydrate loading. [2] I administer 10% dextrose by IV infusion. Carbohydrate loading is important because it can help suppress hepatic ALAS-1. However, 10% dextrose infusions must be given cautiously, especially to patients who have hyponatremia. Dr Erwin: Dextrose will not be sufficient to abort a very severe acute attack, so hemin is the medication of choice, if possible. Dr Balwani: Yes, absolutely. Dextrose can only do so much, and hemin is the specific treatment for AIP. Pg.15

16 Clinical Issues in AIP: When to Suspect and How to Proceed CME/CE There is significant clinical variability and presentation of AIP. Angelika, what is your experience? Dr Erwin: Yes, there is extreme variability in how AIP presents. Most patients who carry AIP-causing gene mutations never have symptoms. Patients who do experience symptoms are classified into 2 groups. One group experiences only 1 or maybe a few acute attacks, but then the disorder becomes latent and they have no further attacks. The other group has frequent and severe recurrent attacks that are often refractory to treatment. These patients have very debilitating disease that significantly affects their quality of life. That is very nicely illustrated by the case we have been discussing. The patient and her mother have the same genetic mutation. However, the mother never had any symptoms, whereas the daughter was severely affected and had several attacks after her initial visit to the ED. Pg.16

17 Dr Balwani: What are some of the consequences of the metabolic alterations that occur during an acute attack? Dr Erwin: As observed in our patient, hyponatremia is often part of an acute attack and puts patients at a high risk for seizures. Patients with hyponatremia may also present with psychiatric symptoms, such as hallucinations, confusion, and even psychosis. Many have anxiety or insomnia. What are the long-term implications of AIP for patients? Dr Balwani: Many patients, particularly those who have had recurrent, acute attacks or have been undertreated, develop chronic neuropathy, which can be very debilitating. Patients can have chronic pain, which greatly affects their quality of life. Patients with AIP or any of the acute hepatic porphyrias have an increased risk of developing renal dysfunction. A case series found that up to 60% of symptomatic patients develop chronic kidney disease (CKD). [4] That is quite significant. Chronic hypertension can contribute to CKD, but it is not the only cause. It is very important to remain vigilant about monitoring renal function in patients with AIP. Patients with AIP also have a higher risk of hepatocellular carcinoma (HCC) than the general population. [4] This risk is well documented, and all patients with AIP should be monitored and screened for HCC. I typically recommend screening patients older than 50 years, using liver ultrasound and serum alpha-fetoprotein level. Dr Erwin: What is really interesting is that patients have an increased risk of HCC even if they have no predisposing factors, such as hepatitis C virus infection. Porphyria alone increases their risk of developing HCC. Pg.17

18 Clinical Issues in AIP: When to Suspect and How to Proceed CME/CE Dr Balwani: What are your thoughts about the best approach for long-term care of patients with AIP? Dr Erwin: Because AIP is a complex disorder with multisystemic involvement, I recommend a multidisciplinary approach. Most patients who experience recurrent, acute attacks have chronic pain and benefit greatly from a consultation with a pain management specialist. Patients who experience peripheral neuropathy should be referred to a neurologist, who can better classify their neuropathy so it can be treated appropriately. This may require electromyography or a nerve conduction velocity study. Patients who have psychiatric symptoms during acute attacks or during asymptomatic phases between attacks may need to see a psychiatrist. I usually involve a nephrologist if a patient has a long-term complication, such as CKD. Patients who develop HCC need to be referred to a hepatologist. Pregnant women with AIP need to be followed by a high-risk obstetrician. I would like to point out that there is no contraindication to giving hemin to pregnant women during an acute attack. Hemin has not been reported to have adverse effects on pregnancy. Because AIP is an autosomal dominant disorder, I recommend referring patients and their family members to a geneticist or genetic counselor to assess their risk of developing AIP. That would be done by establishing a molecular diagnosis, meaning genetic diagnosis, which we can use to test family members. Finally, I recommend that patients with AIP see a porphyria specialist regularly, if one is available, to make sure they are receiving adequate treatment. Pg.18

19 What do you do to help patients prevent acute attacks? Dr Balwani: One of the first things I do is spend a lot of time counseling patients about precipitating factors. Patients should be aware that certain drugs can precipitate an acute attack. [2] I educate the patient and the patient s physician on how to check whether a prescription or over-the-counter drug increases the risk of an attack. Crosschecking can be done using a free online drug database. Symptomatic patients should avoid alcohol use and smoking, which are precipitating factors. I also tell patients to avoid fasting or dieting and to maintain a well-balanced diet. Sometimes I recommend they see a nutritionist to ensure they are getting adequate nutrition. I also tell patients to learn to recognize their symptoms. Patients can often recognize the onset of symptoms a few days before an acute attack. For instance, some patients may experience insomnia a week before the onset of acute abdominal pain or other symptoms that suggest they are about to have an acute attack. Intervening with outpatient hemin therapy during this critical window can prevent a visit to the ED and subsequent hospitalization. For women who have recurrent, menstrual-related acute attacks, using gonadotropin hormone-releasing analogues to suppress the menstrual cycle may help prevent the attacks. For women whose AIP attacks are not related to the menstrual cycle, prophylactic hemin administered on an outpatient basis, weekly or biweekly, may prevent them. Pg.19

20 Clinical Issues in AIP: When to Suspect and How to Proceed CME/CE Angelika, I know you have been involved in liver transplantation for patients with AIP. Can you discuss your experience? Dr Erwin: I know of 2 AIP patients in the United States who have received a liver transplant for AIP. Both patients had frequent, treatment-refractory, acute AIP that required prolonged hospitalization. [5] After the liver transplants, both patients ALA and PBG levels completely normalized, and they have not experienced any recurrent, acute attacks. Dr Balwani: Does the liver transplant reverse any of the chronic neuropathic symptoms? Dr Erwin: So far, experience shows the liver transplant can decrease neuropathic symptoms to a certain degree, but it does not resolve them. Dr Balwani: What about kidney transplantation in these patients? Dr Erwin: A combined liver-kidney transplant may be recommended for patients who require a liver transplant and have CKD or end-stage renal disease. There are reports from Europe of patients who have really benefited from this approach. [6] Pg.20

21 Dr Balwani: What about emerging therapies for AIP? Dr Erwin: New treatment approaches, such as the use of small interfering RNAs (sirnas), are being studied in early-phase clinical trials. [7,8] It will be interesting to see whether new therapeutic options will help patients with AIP. Thank you, Manisha, for joining me in this interesting discussion. Dr Balwani: It has been a pleasure. Dr Erwin: Thank you for participating in this activity. Click on the Earn CME/CE Credit link to take the CME/CE posttest and evaluation. This transcript has been edited for style and clarity. Pg.21

22 Clinical Issues in AIP: When to Suspect and How to Proceed CME/CE Abbreviations AIP = acute intermittent porphyria ALA = delta-aminolevulinic acid dehydratase ALAS-1 = delta-aminolevulinate synthase 1 ALT = alanine aminotransferase AST = aspartate aminotransferase CKD = chronic kidney disease ED = emergency department EMG = electromyography GI = gastrointestinal HCC = hepatocellular carcinoma HMBS = porphobilinogen deaminase IV = intravenous OLT = orthotopic liver transplant PBG = porphobilinogen PBGD = porphobilinogen deaminase raav = recombinant adeno-associated viral sirna = small interfering RNA UTI = urinary tract infection References 1. Kauppinen R. Porphyrias. Lancet. 2005;365: Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Hematology. 2012:120: Panhematin. Recordati Rare Diseases Inc. Lebaon, NJ.4. Pischik E, Kauppinen R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015;8: Pischik E, Kauppinen R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015;8: Soonawalla ZF, Orug T, Badminton MN, et al. Liver transplantation as a cure for acute intermittent porphyria. Lancet. 2004;363: Wahlin S, Harper P, Sardh E, et al. Combined liver and kidney transplantation in acute intermittent porphyria. Transpl Int. 2010;23:e Harper P, Sardh E. Management of acute intermittent porphyria. Expert Opinion on Orphan Drugs. 2014;2: Yasuda M, Gan L, Chen B, et al. RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice. Proc Natl Acad Sci. 2014;111: Disclaimer The educational activity presented above may involve simulated case-based scenarios. The patients depicted in these scenarios are fictitious and no association with any actual patient is intended or should be inferred. The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on medscape.org. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity. Medscape Education 2016 Medscape, LLC This article is a CME/CE certified activity. To earn credit for this activity visit: Pg.22