Woman in Acute Abdominal Pain: What s the Diagnosis? CME / ABIM MOC / CE

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1 Woman in Acute Abdominal Pain: What s the Diagnosis? CME / ABIM MOC / CE Supported by an independent educational grant from Recordati Rare Diseases Pg.1

2 Woman in Acute Abdominal Pain: What s the Diagnosis? CME / ABIM MOC / CE This article is a CME / ABIM MOC / CE certified activity. To earn credit for this activity visit: CME / ABIM MOC / CE Released: 4/24/2017; Valid for credit through: 4/24/2018 Target Audience This activity is intended for physicians and nurses specializing in gastroenterology, emergency medicine, and family medicine. Goal The goal of this activity is to provide information on the differential diagnosis of acute intermittent porphyria (AIP) and its management. Learning Objectives Upon completion of this activity, participants will: have greater competence related to clinical manifestations of AIP to guide accurate diagnosis have greater competence related to appropriate diagnostic evaluations to investigate possible AIP have greater competence related to evidence-based treatments for 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. Pg.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. Pg.3

4 Woman in Acute Abdominal Pain: What s the Diagnosis? CME / ABIM MOC / CE Faculty and Disclosures FACULTY Karl E. Anderson, MD Professor of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, Texas Disclosure: Karl E. Anderson, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Alnylam Pharmaceuticals, Inc.; Mitsubishi Pharma America, Inc. Received grants for clinical research from: Alnylam Pharmaceuticals, Inc.; Recordati S.p.A. Dr Anderson 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 Anderson does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. EDITOR Laura A. DuBois Scientific Director, Medscape, LLC Disclosure: Laura A. DuBois, 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: Served as an advisor or consultant for: CRH Medical Corporation; Pfizer, Inc.; Received grants for clinical research from: Exact Medical Manufacturing, Inc.; Owns stock, stock options, or bonds from: CRH Corporation. Pg.4

5 Case 1: Patient History Jane is a 30-year-old woman who presents to the emergency department (ED) complaining of severe, poorly localized abdominal pain, nausea, and diarrhea, which started 1 week earlier and gradually worsened. Jane was hospitalized 2 times for similar episodes of severe abdominal pain with nausea and vomiting during the past year. On both occasions, physicians were unable to determine what caused her symptoms, and the pain resolved 2 weeks after she was discharged without a diagnosis. Today at her ED visit, Jane seems agitated. She claims she is upset because of the severity of her abdominal pain, which she describes as being sharp and all over and rates as a 9 or 10 on a 10-point scale. Findings from Jane s patient history and vital signs are summarized in Table 1. Table 1. Patient History and Vital Signs History Findings Medical Two hospitalizations within past year for undifferentiated abdominal pain Allergies: tested positive for sensitivities to Timothy grass and ragweed pollen No history or indications of illicit drug use No history of migraines Gynecologic Menarche: at 15 years, menses: regular 28-day cycles with 4-day menses duration. Denies use of barrier or hormonal contraception methods. Sexually active, no history of sexually transmitted diseases or unprotected sex. First day of last menstrual period was 8 days ago Surgical Appendectomy 2 years ago Social Unmarried with no children; does not smoke; drinks alcohol socially, about 1 or 2 drinks per week on average; recently completed a 5-day juice detoxification regimen for weight loss Family No known history of relapsing gastrointestinal disease or abdominal pain syndromes Current medications Over-the-counter loratadine Vital signs BP = 140/90 mm Hg, HR = 99 bpm, temperature: 99 F (37 C) (oral) BP = blood pressure; bpm = beats per minute; HR = heart rate. Question 1: What should be your first step? Acetaminophen extra strength Abdominal computed tomography with intravenous (IV) contrast media x Transvaginal ultrasound IV morphine Answer Explanation: Treating Jane s severe abdominal pain with IV morphine should be your first step. The appropriate use of opioid analgesics in patients with acute abdominal pain effectively does not interfere with diagnosis or treatment. In addition, a comfortable patient is better able to cooperate with diagnostic procedures. Pg.5

6 Woman in Acute Abdominal Pain: What s the Diagnosis? CME / ABIM MOC / CE Acute abdominal pain is the reason for 5% to 10% of ED visits, and as many as 10% of the causes of the pain are severe or life threatening. [1] The pain is the leading reason for patients to seek care in the ED setting, and pain management should be initiated as soon as medically possible. Acute undifferentiated (aka, undiagnosed) abdominal pain can present out of proportion to other clinical symptoms and often requires the use of IV opioids to reduce it to tolerable levels. [2,3] Oral analgesics are often not appropriate for a number of reasons, including the likelihood of gastrointestinal (GI) disturbances, long onset of action, and inability to adequately control high levels of pain. Studies have shown that the administration of narcotic analgesics does not obscure (in fact, it may help facilitate) the diagnosis or interfere with the treatment of the patient. [2,3] Despite this evidence, the gap between understanding and practice remains large, and abdominal pain is often undertreated, perhaps due to a hesitancy to administer opioids without a diagnosis or to a suspicion that the patients is drug seeking. Undifferentiated abdominal pain remains the diagnosis for approximately 25% of patients discharged from the ED and for 35% to 41% of patients admitted to the hospital. [1] When these patients leave care, they are often frustrated and/or fearful of relapse, because they do not know the cause of or how to prevent the excruciating pain they endured. Most abdominal pain is benign, with approximately 80% of patients discharged with undifferentiated abdominal pain that improves within 2 weeks of presentation. However, a thorough evaluation is required to distinguish nonserious causes from true emergencies. [1,4,5] At times, a diagnosis is not fully pursued when nonspecific abdominal pain is believed to be somatic (in fact, hypochondria in Late Latin means the abdomen ); however, current clinical practice dictates true medical illness must be sufficiently ruled out before discharging a patient. [6,7] When evaluating patients who present with acute abdominal pain, physicians need to consider both common and uncommon causes [8] (Table 2). Suspicion for uncommon causes of abdominal pain should be heightened in the following circumstances: patients with repeated visits to physicians or EDs for the same complaint without a definite diagnosis, an ill-appearing patient with minimal or nonspecific findings, pain out of proportion to clinical findings, and immunocompromised, HIV-infected, or elderly patients. [9] Table 2. Causes of Moderate to Severe Acute Abdominal Pain Common causes that do not Bacterial or viral gastroenteritis require surgery [3,4,8,10,11] Clostridium difficile infection Inflammatory bowel disease Herpes zoster Complications of various infections (eg, malaria, pneumonia, or HIV) Diabetic ketoacidosis Medication interactions or illicit drug use Endometriosis Hypercalcemia Muscle strain Myocardial infarction Ovarian cyst rupture Pelvic inflammatory disease Peptic ulcer disease Sickle cell crisis Toxins (eg, lead or arsenic) Urinary tract infection Pg.6

7 Common causes that may Acute appendicitis require surgery [3,10] Acute bowel obstruction Acute cholecystitis Acute diverticulitis Ectopic pregnancy Mesenteric vascular disease Uncommon causes [8,12,13] Addison disease Acute porphyrias Lead poisoning Cecal volvulus Eosinophilic gastroenteritis Epiploic appendagitis Gallstone ileus Malignancy Mesenteric adenitis or panniculitis Omental infarction Mesenteric vascular disease Acute aortic dissection Case Continues Intravenous morphine is administered to help manage Jane s pain, and an antiemetic is given to help with her nausea. Now, Jane is less agitated and you are better able to question her and review the records of previous trips to the ED. She confirms that all of the acute abdominal attacks have been similar in symptoms and severity. She also expresses frustration that she continues to have attacks after her appendectomy and continues to undergo multiple tests without a diagnosis. You ask Jane to be patient as you expand her workup to include less common causes of her abdominal attacks. You perform an physical examination and note that Jane has diffuse tenderness in the lower abdomen with no involuntary guarding. Other notable findings are summarized in Table 3. Pg.7

8 Woman in Acute Abdominal Pain: What s the Diagnosis? CME / ABIM MOC / CE Table 3. Physical Examination Area Abdomen Skin Pelvis Review of symptoms Findings Diffuse tenderness in the lower abdomen, no involuntary guarding. Negative for Murphy s, Carnett s, and closed eyes signs. Positive for bowel sounds No signs of rashes, purpura, or urticaria No inflammation or evidence of infection Lightheadedness when standing and mild leg pain, in addition to previously reported symptoms Question 2: Which of the following would be your next step in terms of diagnostics? x Pregnancy test Plain radiographs of the kidneys, ureter, and bladder Ultrasound of the abdomen Magnetic resonance imaging Answer Explanation: When evaluating a woman of childbearing age with abdominal pain, it is important to know if she is pregnant to determine whether it is safe to subject her to diagnostic approaches that involve radiation exposure. The differential diagnosis for abdominal pain is expansive. Medical history and physical examination yield the correct diagnosis for approximately half of patients with abdominal pain, although laboratory tests or imaging studies are required to confirm a diagnosis. [10] When an initial workup fails to reveal a clear diagnosis, additional blood and urine tests should be undertaken to rule out uncommon causes before contemplating diagnostic imaging or invasive procedures. [10] Women of childbearing age like Jane present a specific challenge when making decisions about diagnostic imaging. Stomach or abdominal pain is the leading reason US females 15 years and older visited the ED in [14] Gynecologic causes of abdominal pain are more common in patients of childbearing age; however, diagnostic approaches requiring radiation exposure should be avoided if pregnancy hasn t been ruled out. [4] Case Continues The laboratory tests you order include a pregnancy test and urinalysis. Blood test results confirm Jane s pregnancy test is negative, and you order abdominal and transvaginal ultrasound examinations, which show nothing remarkable. You review the blood test and urinalysis results summarized in Table 4; of note, her urine is dark red. Pg.8

9 Table 4. Laboratory Test Results Test Result Hemoglobin, g/dl 15.3 Platelet count, cells/µl 225,000 WBC count, cells/µl 6200 Neutrophils, % 50 Lymphocytes, % 36 Monocytes, % 8 Eosinophils, % 5 Basophils, % 1 AST, U/L 30 ALT, U/L 32 Amylase, U/L 63 Lipase, U/L 45 Creatinine, mg/dl 0.9 Creatinine clearance, ml/min 111 Serum sodium, meq/dl 136 Pregnancy test Negative Urinalysis Color: dark red Blood: negative ALT = alanine aminotransferase; AST, aspartate aminotransferase; WBC = white blood cell. Question 3: Dark reddish colored urine negative for blood and poorly localized abdominal pain indicate which of the following conditions is likely? x Peritonitis Acute porphyria Acute bowel obstruction Sickle cell crisis Answer Explanation: All of the conditions listed are associated with poorly localized abdominal pain; however, dark-reddish colored urine can be a tell-tale indicator of acute porphyria. Other possible causes of dark colored urine include dehydration and decreased renal blood flow. Pg.9

10 Woman in Acute Abdominal Pain: What s the Diagnosis? CME / ABIM MOC / CE Acute hepatic porphyrias are a family of 4 rare metabolic disorders characterized by the deficiency of a specific enzyme essential to heme synthesis: acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and 5-aminolevulinic acid (ALA) dehydratase porphyria (ADP). [15,16] The deficient enzymatic activity becomes a problem with exposure to factors that increase demand for hepatic heme. This demand leads to increased synthesis of aminolevulinate synthase 1 (ALAS1) -- the first and rate-limiting enzyme for this pathway in the liver. [17] Because of the increase in ALAS1 and the enzymatic deficiency of porphobilinogen deaminase (PBGD), the heme precursors, ALA and porphobilinogen (PBG), accumulate along with uroporphyrin and other porphyrins. Heme precursors are released from the liver and are often associated with an acute attack, perhaps due to the neurotoxic effects of ALA. [15,18] During an attack, the patient s urine may appear red or reddish-brown (particularly when exposed to air or ultraviolet light) because of the elevated level of porphyrins and degradation products of PBG [15,16] (Figure 1). Acute intermittent porphyria is the most common acute porphyria. ADP is the rarest acute porphyria and causes increases in urine ALA and porphyrins but not PBG. [15,19] All acute porphyrias can cause acute life-threatening neurovisceral attacks, although AIP is, on average, associated with more severe attacks than are HCP and VP. [15] However, more than 80% of people who carry a mutation for AIP, VP, or HCP never experience symptoms. [15,20] Figure 1. High levels of porphyrins and porphobilinogen degradation products cause changes in urine color. Reproduced from Chen GL, Yang DH, Wu JY, et al. Neuropathic pain in hereditary coproporphyria. Pak J Med Sci. 2013;29: [21] The symptoms of acute porphyria are variable and nonspecific (Table 5). No single sign or symptom is pathognomonic. The presenting symptoms of an acute porphyric attack are indistinguishable among the 4 types. [15,22] During an acute porphyric attack, up to 95% of patients experience gradually worsening abdominal pain. [19,23] At presentation, the abdominal pain is severe, poorly localized, and unremitting. [15,23,24] The pain is generally not associated with peritoneal signs, such as rebound tenderness or involuntary guarding. [19,24] Many of the signs and symptoms of an acute porphyria attack, including abdominal pain, are related to autonomic neuropathy. Other common manifestations include back or leg pain, constipation, diarrhea, nausea, vomiting, bladder dysfunction, tachycardia, hypertension, and postural hypotension. [15,22,25-28] Central nervous system involvement can lead to neuropsychiatric symptoms, and symptoms and signs of acute mental disturbance are common, including anxiety, depression, insomnia, agitation, paranoia, confusion, disorientation, and hallucinations. [15,20] Most mental disturbances resolve after the attack subsides. [15] More serious symptoms include sensory or peripheral motor neuropathy with muscle weakness. [22,29] Patients may experience sweating, restlessness, or tremor. [23,24,27] Pg.10

11 Table 5. Reported Incidence of Signs and Symptoms of an Acute Porphyric Attack [22,25-28] Sign or Symptom Range, % Symptoms Abdominal pain Nausea/vomiting Constipation Vital signs Tachycardia Hypertension Neuropsychiatric signs Anxiety or depression 8-55 Any mental changes Other signs Urine discoloration Hyponatremia Jane s frustration at being misdiagnosed is not uncommon; misdiagnosis of acute porphyrias is common, as are delays in diagnosis, in part because the abdominal pain is usually nonspecific and poorly localized, similar to Jane s past and current presentation. [22] An observational study of US patients with porphyria (N=108) reported that many patients underwent unnecessary appendectomy or cholecystectomy before they received the correct diagnosis. Including acute porphyria in the standard differential diagnosis for unexplained abdominal pain can reduce the risk of unnecessary tests and procedures and of a delayed or incorrect diagnosis. [25] Delayed recognition and treatment of an acute porphyria attack can lead to severe neurologic complications or adrenergic crises. [15,30] Peripheral motor neuropathy can develop, especially with a prolonged severe attack. The neuropathy is primarily a symmetrical axonal motor neuropathy but can be focal. [15] It often begins with muscle weakness proximally in the arms and then the legs and can progress to quadriplegia and respiratory weakness. [29,31] Constipation and urinary retention are common. [15,20] Cranial nerve involvement can cause difficulty swallowing and with speech. [24,29] Complications may include respiratory and urinary tract infections. Patients with acute porphyria may be misdiagnosed with Guillain-Barré syndrome (GBS). [32-37] Acute porphyria may mimic GBS and should be included in the differential diagnosis for all patients diagnosed with GBS. [29,38] Seizures also can complicate a severe attack and be the result of hyponatremia, hypomagnesemia, or acute encephalopathy due to porphyria. [20,31] Patients who experience a moderate to severe acute porphyria attack require hospitalization, with admission to the intensive care unit for individuals with neurologic or respiratory symptoms. [15] With prompt recognition and appropriate treatment, recovery is rapid and mortality is rare. [31] However, patients with severe neuromotor involvement may require weeks to months of rehabilitation to recover muscle strength; some patients may have permanent residual nerve damage with distal extremity weakness. [20,24] Pg.11

12 Woman in Acute Abdominal Pain: What s the Diagnosis? CME / ABIM MOC / CE Case Continues Considering Jane s past history of abdominal pain and her urinalysis results, you tell her that you suspect she has acute porphyria but you need to confirm the diagnosis. Question 4: Which of the following is recommended as a first-line diagnostic test for acute porphyria? x Spot urine test for ALA Spot urine test for PBG 24-hour urine test for porphyrins Blood test for erythrocyte protoporphyrin Answer Explanation: Spot urine test for PBG should be performed to establish a diagnosis of acute porphyria (AIP, HCP, or VP), based on finding a substantial elevation in PBG. Urinary concentrations of ALA and porphyrins are also elevated, but ALA is usually less increased than PBG, and porphyrin elevations are also found in other medical conditions, especially hepatobiliary disease. Pg.12

13 Routine laboratory tests and imaging studies have no value in the diagnosis of acute porphyria. The fastest way to confirm a suspected attack due to AIP, HCP or VP is through biochemical testing for PBG and porphyrins. During an attack, patients excrete excessive amounts of ALA, PBG, and porphyrins in their urine. [15] In individuals having an AIP attack, urinary PBG often exceeds 10 times the upper limit of normal (normal range, 0 to 4 mg/l/d) and can remain elevated for years after the attack subsides. [15,23] Porphobilinogen may be less elevated in patients with HCP or VP and return to normal more quickly with attack resolution, whereas porphyrin elevations may persist longer. In patients with ADP, the PBG level is normal, but ALA and coproporphyrin levels are markedly elevated. The test should be performed using a fresh sample that is collected without preservative during the suspected attack and shielded from light. [16] A negative PBG screen in a symptomatic patient makes acute porphyria unlikely, whereas a positive screen justifies starting treatment. [15,23,30] Collecting a 24-hour urine sample for PBG testing delays diagnosis and is not recommended. [16,22] Measuring porphyrins is also recommended to better ensure a diagnosis of HCP and VP, as well as ADP, keeping in mind that porphyrin elevations are nonspecific. Therefore, an elevation in PBG or porphyrins always requires further evaluation with second-line testing. If a qualitative PBG test is used for screening, follow-up testing with standard quantitative tests for PBG and porphyrins should always follow, regardless of whether the PBG screening result was normal or abnormal. Second-line tests are required to confirm an acute porphyria diagnosis and to identify the specific porphyria type. [16,22] Testing for total urine porphyrins (TUPs) and fecal and plasma porphyrin levels should be conducted as soon as possible, preferably using blood, urine, or stool samples collected while symptoms were present. [16] It is best to use the same urine sample that was used for screening. Testing for TUPs is important because PBG is not elevated in patients with ADP and often is only transiently elevated in patients with VP or HCP. [22] Testing only for TUPs is insufficient because elevated porphyrin levels are common in ill patients without porphyria and therefore are not specific for acute porphyria. [15] Although urinary ALA levels are also elevated during an acute porphyria attack, measuring urinary ALA levels does not enhance what is learned from measuring urinary PBG and TUP. For example, if urinary ALA levels are elevated but urinary PBG levels are not, it might suggest ADP or lead poisoning, which presents similarly to acute porphyria. However, ADP and lead poisoning increase urinary coproporphyrin levels and can be excluded by measuring TUPs. Case Conclusion The spot urine test that you ordered shows a PBG level of 58 mg/l (normal, 0 to 4 mg/l). Now that it is confirmed that Jane has acute porphyria, a porphyria specialist is consulted. Given the high level of urinary PBG, AIP is suspected. On the specialist s advice, you order a quantitative analysis of the original urine sample for ALA, PBG, and porphyrins, along with tests for fecal and plasma porphyrins; the results confirm your suspicion: Jane has AIP. She is relieved when you let her know her AIP is treatable and there are ways to help prevent triggering future attacks. Pg.13

14 Woman in Acute Abdominal Pain: What s the Diagnosis? CME / ABIM MOC / CE Case 2: Patient History Kate, a 25-year-old woman, is admitted to the hospital under your care for severe abdominal pain that progressed to nausea, vomiting, and back pain. Kate s medical history is significant for AIP that was diagnosed 2 months ago in the ED, although she states her abdominal pain is more severe this time. Findings from the patient s history and physical examination are listed in Table 6. Initial laboratory test results are listed in Table 7. You start her on IV morphine for pain management and consider a β-blocker to help control her tachycardia and stage 1 hypertension. You order a spot urine test for PBG to confirm that her AIP is active and because this attack is worse than previous attacks. You evaluate her further to help exclude other causes of Kate s symptoms. Table 6. History and Physical Examination History Findings Medical Asthma and depression. Two months ago, admitted for abdominal pain and diagnosed with AIP. History of migraines 1 or 2 times per month Gynecologic Menarche: at 13 years; menses: regular 28-day cycles with 5-day-duration menses. Continued use of hormonal contraception method. No history of sexually transmitted diseases or unprotected sex. First day of last menstrual period was 17 days ago Social Married with no children. Does not smoke. She consumes 3 or 4 alcoholic drinks per week, on average Current medications Inhaled corticosteroid, fluoxetine, laxatives, and an oral estrogen/progestin contraceptive Physical Examination Findings Vital signs BP = 140/90 mm Hg, HR = 115 bpm, Temperature: 99 F (37 C) (oral) Body mass index 21.2 kg/m 2 Abdomen Diffuse epigastric and suprapubic tenderness without rigidity or guarding. Negative for Murphy s, Carnett s, and closed eyes signs. Positive for bowel sounds Skin No signs of rashes, purpura, or urticaria Pelvic No inflammation or evidence of infection Review of symptoms Unremarkable apart from the symptoms previously reported BMI = body mass index; bpm = beats per minute; BP = blood pressure; HR = heart rate. Pg.14

15 Table 7. Initial Laboratory Test Results Test Result Hemoglobin, g/dl 14.2 Platelet count, cells/µl 160,000 WBC count, cells/µl 7700 Neutrophils, % 45 Lymphocytes, % 25 Monocytes, % 8 Eosinophils, % 2 Basophils, % 2 Amylase, U/L 75 Lipase, U/L 55 AST, U/L 59 ALT, U/L 72 Creatinine, mg/dl 0.7 Creatinine clearance, ml/min 101 Serum sodium, meq/dl 113 Pregnancy test Negative Urinalysis Color: dark red Blood: negative ALT = alanine aminotransferase; AST, aspartate aminotransferase; WBC = white blood cell. Question 5: How confident are you in the management of AIP? (Select ranking from 1 [Not confident] to 5 [Very confident]) 1 - Not confident Very confident Pg.15

16 Woman in Acute Abdominal Pain: What s the Diagnosis? CME / ABIM MOC / CE Question 6: After pain management, what would be your next step? x Order a urinalysis Order tests for fecal and whole blood porphyrins Administer IV saline Administer IV glucose Answer Explanation: Supportive treatments should be the next step to address the various manifestations of a suspected porphyric attack. In Kate s case, her hyponatremia levels are critical, requiring urgent saline administration to avoid a possible seizure. However, too rapid correction of hyponatremia can also be harmful. Fluids are given (with careful monitoring) to correct her electrolyte abnormalities over several days. Intravenous glucose (eg, 10% glucose in water) can contribute to hyponatremia, so it is not an appropriate treatment option for Kate at this time. In addition to pain management, initial management of a suspected AIP attack is focused on eliminating potential contributing factors, including contraindicated medications, caloric deprivation, and dehydration. Hyponatremia may be severe, requiring urgent saline administration. A protocol that minimizes the risk of brainstem damage should be followed. [30] A β-blocker is appropriate for patients with hypertension or symptomatic tachycardia. Because the tachycardia and high blood pressure are reversible in the short term with treatment of the attack, a β-blocker is usually not needed unless the tachycardia is symptomatic and blood pressure elevation is severe. It is important to monitor vital signs frequently (eg, every 4 to 6 hours) and to monitor electrolyte levels daily. Phenothiazines or triptans are effective for nausea and vomiting, and phenothiazines are also effective for anxiety and restlessness. [30] Benzodiazepines, vigabatrin, or gabapentin may be used to treat seizures; but it should be noted most antiseizure medications (eg, barbiturates and phenytoin) are contraindicated in acute porphyrias and may worsen the attack. [30] Carbohydrate loading, usually with IV glucose (at least 300 g/d), may be effective in milder acute attacks (without paresis, hyponatremia, etc). [17,39] Pg.16

17 Case Continues Despite receiving the IV fluids with saline, Kate is feeling worse and tells you she is still feeling persistent abdominal pain and reports muscle weakness in her arms. You reassess and increase her morphine dose. You also receive the results of the spot urine test, which shows a PBG level of 44 mg/d. Post-assessment Question Introduction: Kate has been admitted for abdominal pain. She is given IV fluids with saline to gradually correct hyponatremia and IV morphine for the abdominal pain. She begins to feel muscle weakness in her arms. Spot urine test shows a PBG level of 44 mg/l (normal, 0 to 4 mg/l). Question 7: Which of the following would be your approach for treating Kate s AIP attack? x Hemin injection Oral carbohydrate loading No treatment until testing excludes GBS Glucose infusion Answer Explanation: Intravenous hemin is the most effective approach for managing a moderate or severe AIP attack. Kate s attack is considered severe, because it requires opioids for relief of pain and is associated with hyponatremia. Because the clinical response is slower if IV hemin treatment is delayed, it is recommended that hemin therapy be started as soon as test results confirm a substantial elevation in the urinary PBG level. If urinary PBG test results were not immediately available (as is the case at most hospitals), hemin should be initiated given her previous AIP diagnosis and the severity of her attack. In this case, review the evidence for the prior diagnosis of AIP before starting hemin; if that is not possible, samples for PBG and second-line testing should be obtained before treatment is started. Pg.17

18 Woman in Acute Abdominal Pain: What s the Diagnosis? CME / ABIM MOC / CE Although product labeling recommends an initial trial of IV glucose, hemin is the preferred first-line therapy to treat acute porphyria regardless of type. [17] Once a substantial elevation in urinary PBG level is confirmed, clinical practice experience suggests hemin dosing for an acute attack should not be less than 3 mg/kg/d and should not exceed 4 mg/kg/d. [17] The prescribing information for hemin recommends continuing treatment for 3 to 14 days, depending on clinical signs. [40] However, there is widespread agreement that the standard course of treatment hemin given once daily for 4 days, with continuation for additional days until there is substantial recovery, and discharge from the hospital when the patient no longer requires opioids and is able to maintain an adequate oral intake of food and fluids. Hemin reduces the synthesis of ALAS1, thereby reducing hepatic synthesis of ALA, PBG, and porphyrins. [40] Treatment with hemin can prevent further neuronal damage and allow recovery and repair of recent neuronal damage. [40] The degree of clinical improvement typically depends on how promptly treatment was started after symptom onset. During treatment, levels of urinary PBG and TUPs should be monitored to measure biochemical response. [40] This response is generally prompt and predictable, but when symptoms have been present for some time, the response is slow. In a survey of patients with AIP who received hemin during an acute attack, 74% said it was very effective at improving symptoms. [25] Hemin is well tolerated. [26] Adverse events include headache, infusion site phlebitis, and very rare accidental overdose. [40] To reduce phlebitis risk, hemin should be administered using a large peripheral vein or central line. [40] Reconstitution with albumin helps to prevent phlebitis, especially if peripheral veins are used. Glucose is less effective but is recommended only for mild attacks (eg, mild abdominal pain not requiring opioids and no hyponatremia, seizures, paresis, or agitation and no impairment in oral intake). Treatment in these cases is a continuous glucose infusion (at least 300 g/d) for 1 to 2 days. [25,31] During treatment, glucose levels should be monitored for hyperglycemia. [31] Glucosecontaining IV fluids may exacerbate hyponatremia, and sodium levels should be monitored. [26] If the patient does not experience clinical remission or experiences worsening of signs or symptoms in 1 to 2 days, hemin then should be administered. [31] Initial hemin treatment for mild attacks is common practice and can lead to more rapid recovery. Case Continues You consult with a porphyria specialist. Kate is started on hemin infusions and her symptoms start to resolve. The specialist reviews Kate s patient history and meets with Kate to discuss the next steps in managing her AIP. Kate wants to know what may have caused her most recent AIP attack. Post-assessment Question Introduction: Question 8: Which of Kate s current medications would most likely be a trigger of her AIP attack? x Inhaled corticosteroid Fluoxetine Over-the-counter laxatives Oral estrogen-progestin contraceptive Answer Explanation: Oral contraceptives containing a progestin are believed to increase the risk of porphyria attacks and are not recommended for women with acute porphyria. Corticosteroids, the antidepressant fluoxetine, and laxatives are medications considered safe for use in patients with acute porphyria. Selective serotonin uptake inhibitors such as fluoxetine are not considered porphyrinogenic. Pg.18

19 Any substance or event that increases demand for hepatic heme can trigger or exacerbate an porphyric attack in someone with a causative mutation (Tables 8 and 9). Most drugs cause porphyric attacks by stimulating the synthesis of cytochrome P450 enzymes, which requires the liver to make more heme; these drugs can also directly induce ALAS1, the enzyme that controls the rate of heme synthesis in the liver. [17] Many recreational drugs, alcohol, and chemicals in cigarette smoke also are cytochrome P450 enzyme inducers. [26] Heavy alcohol consumption or binge drinking may precipitate attacks, and cigarette smoking has been linked to an increased risk of recurrent attacks. [15,17] Barbiturates, phenytoin, progesterone and progestins, and sulfonamide antibiotics are among the medications known not to be safe for patients with acute porphyria. [15,17,41] The prescribing information for some medications discloses a contraindication for individuals with porphyria, but the absence of such a warning does not mean a medication is safe. [17] Databases of safe and unsafe medications are available at the websites of the American Porphyria Foundation and the European Porphyria Network. When considering a medication that might be porphyrinogenic for a patient with acute porphyria, the risks must be weighed carefully against the benefits. Consult a porphyria specialist whenever uncertainty exists about the safety of a particular medication. Table 8. Medications Contraindicated in Patients With Acute Porphyria [15,42] Barbiturates Calcium channel blockers Carbamazepine Carisoprodol Clonazepam Danazol Diclofenac Ergots Estrogen Griseofulvin Phenytoin Progesterone Pyrazinamide Rifampicin Sulfonamides Valproic acid Table 9. Potential Triggers of Acute Porphyric Attacks [42] Excessive alcohol use Fasting Infections Menstrual periods Physical or emotional stress Prescription medications or illicit drugs Smoking In some women, changes in endogenous hormone levels during the menstrual cycle, especially luteal phase increases in progesterone levels, trigger attacks. [15,17,26,41] Paradoxically, pregnancy is usually well tolerated by women with a diagnosis of acute porphyria. [15,26] However, some women experience more frequent attacks, particularly during early pregnancy. [26] Some cases of acute porphyria attacks after hormonal infertility treatment have been reported. [26] In addition, any reduction in carbohydrate or caloric intake (eg, crash dieting, illness, GI upset) can induce an attack. [15,32] Metabolic stress due to surgery or infection is another trigger. [17] Many patients say, based on experience, that emotional stress is an important contributor. Attacks often result from the combined effects of multiple triggers, some of which may not even be recognized. Other attacks have no clearly identifiable precipitant. It is important to educate patients with AIP on attack triggers and how to avoid them. [15] Pg.19

20 Woman in Acute Abdominal Pain: What s the Diagnosis? CME / ABIM MOC / CE Case Continues After 4 days of hemin treatment, Kate s symptoms resolved. After her discharge, Kate was highly motivated to prevent another attack. Kate met with a porphyria expert and received counseling on how to recognize the early onset of symptoms and avoid attack triggers, which included discontinuing her oral contraceptive and refraining from drinking alcohol. She also met with a nutritionist and was careful to maintain a diet with the appropriate levels of calories and carbohydrates. She did well for several months, but then had 4 attacks that required trips to the ED during a 4-month period. On 1 occasion, she recognized mild symptoms as indicative of an AIP attack early and was treated with IV glucose. On the other 3 occasions, her symptoms progressed quickly and she received hemin. Concerned with the frequency and the severity of most of her attacks, you consult Kate s porphyria specialist about other options for preventing her attacks. He notices that since Kate stopped taking the oral contraceptive, her attacks appeared to coincide with the luteal phase of her menstrual cycle, which is frequently observed in young women with AIP. Moreover, early in the most recent attack, serum progesterone test results documented a luteal-phase level. Question 9: Which of the following treatments would be the most appropriate to help reduce repeated premenstrual attacks for Kate? x A gonadotropin-releasing hormone (GnRH) analogue Hysterectomy with oophorectomy Prophylactic hemin Liver transplantation Answer Explanation: Data suggest that GnRH analogues, which are not porphyrinogenic, may prevent acute porphyria attacks during the luteal phase of a woman s menstrual cycle when progesterone levels are elevated. This reversible, nonsurgical option is preferred over oophorectomy, which is irreversible. If a GnRH analogue is not effective in preventing attacks, an oophorectomy will also not be effective. Pg.20

21 There is no clear definition of what constitutes a recurrent AIP attack. [15] Patients who have minor symptoms suggestive of an attack may be able to manage them at home through carbohydrate supplementation and analgesics. [26] However, approximately 3% to 5% of patients with newly diagnosed AIP have severe recurrent attacks, defined as 4 or more attacks per year that require hospitalization. [15,24] Women are more likely to have recurrent attacks than men, with many women experiencing premenstrual recurrent attacks, which characteristically resolve with the onset of menses. [26] Signs and symptoms of recurrent severe attacks demonstrate a high degree of interindividual variability but less intraindividual variability. Patients who have recurrent severe AIP attacks should consult with a porphyria specialist. [15] Preventive measures are typically considered when the patient has had no improvement in the frequency or severity of attacks after 6 to 12 months. [15] Most patients with AIP who have recurrent attacks are young women, and if attacks coincide with the luteal phase of the menstrual cycle, as they did for Kate, treatment with a GnRH analogue may be considered. [26,30,43-45] Although hemin is not approved for prophylaxis, it is widely used. [15,40,46] Prophylactic hemin is given as a single weekly dose in an outpatient setting to prevent cyclic attacks. Liver transplantation is a last resort for patients with AIP who experience severe intractable neurovisceral symptoms. [26,47] Replacing the liver corrects the deficiency of hepatic hydroxymethylbilane synthase (HMBS) and restores normal levels of PBG and ALA. [47] Case Continues The porphyria specialist suggested that Kate receive a GnRH analogue, which was started in consultation with a gynecologist. She did not experience an attack for the next 3 months, at which time the gynecologist prescribed a low-dose estrogen patch to prevent hot flashes and bone density loss. The plan was to stop the GnRH analogue and estrogen patch in 6 to 12 months to see if they were still needed. The specialist also recommends DNA sequencing of HMBS. Question 10: Which of the following is the primary reason to conduct DNA sequencing of the HMBS gene in a patient who has already received a biochemical diagnosis of AIP? x To determine whether the patient also has HCP or VP To evaluate the patient s prognosis based on the severity of the mutation To identify a pathogenic mutation for testing of the patient s family To determine whether the patient is eligible for gene therapy Answer Explanation: The primary reason to perform DNA sequencing in a patient who received a biochemical diagnosis of AIP is to identify an HMBS variant that can be used for cascade screening of the patient s family for potential carriers. HCP and VP are associated with mutations of CPOX and PPOX, respectively, and a gene test for an HMBS mutation would not identify these forms of porphyria. Also, the rarity of the acute porphyrias makes it exceedingly unlikely someone would have HCP or VP in addition to AIP. Pg.21

22 Woman in Acute Abdominal Pain: What s the Diagnosis? CME / ABIM MOC / CE There are more than 400 HMBS mutations causative for AIP. [15] HMBS (also known as PBG deaminase) is the third enzyme in the pathway for heme synthesis (Figure 2). The HMBS defect that causes AIP is heterozygous, so approximately 50% of the enzyme activity is retained, which is adequate for maintaining cellular heme homeostasis. [15,26] Once biochemical testing has established a diagnosis of AIP in a patient who is having an attack, direct DNA sequencing of the HMBS gene can identify the causative mutation in more than 95% of cases. [31] DNA sequencing of the index patient serves 2 important functions: it establishes the diagnosis of AIP, HCP, or VP more definitively because biochemical findings are variable, and it identifies the causative HMBS, CPOX, or PPOX mutation, which makes screening of the patient s relatives much more reliable. [14] Biochemical testing lacks the specificity and sensitivity to diagnose AIP in relatives with latent AIP, who are likely to have normal levels of PBG. [15,24] Figure 2. The role of PBG deaminase in the heme biosynthetic pathway. Reproduced from Bovenschen HJ, Vissers WH. Primary hemochromatosis presented by porphyria cutanea tarda: a case report. Cases J. 2009; 2:7246. The estimated prevalence of AIP is 5 per 100,000 in the United States. [19] Most carriers of an AIP-causing mutation never develop symptoms and are considered to have latent AIP. [24] Even though individuals with latent AIP are less susceptible to a porphyria attack, all relatives who carry the familial mutation should be counseled on how to avoid attack triggers. Carriers should also undergo testing for ALA and PBG to establish baseline values. [26] It is rare for someone with AIP to have an attack before puberty. [24] Individuals of reproductive age should be informed that their offspring have a 50% chance of inheriting the familial mutation. [26] Parents who carry a pathogenic mutation should be counseled to help them decide whether or when to have their children screened. [26] Case Conclusion During the next year, Kate had one attack, which was not associated with an elevation in progesterone levels and therefore was due to an unknown triggering factor. Kate underwent genetic counseling and testing, and DNA studies established the HMBS mutation causing Kate s AIP. She informed her 2 sisters, who were tested for the same mutation. One sister tested positive for the same mutation, and Kate put her in touch with her porphyria specialist. Kate s treatment with the GnRH analogue was stopped after 1 year to see if it was still needed, and follow-up is ongoing. Pg.22

23 References 1. Kendall JL, Moreira ME. Evaluation of the adult with abdominal pain in the emergency department. UpToDate. Accessed March 3, Brownfield E. Pain management. Use of analgesics in the acute abdomen. In: Making health care safer: a critical analysis of patient safety practices. Accessed March 14, Macaluso CR, McNamara RM. Evaluation and management of acute abdominal pain in the emergency department. Int J Gen Med. 2012;5: Cartwright SL, Knudson MP. Evaluation of acute abdominal pain in adults. Am Fam Physician. 2008;77: Bhuiya FA, Pitts SR, McCaig LF. Emergency department visits for chest pain and abdominal pain: United States, NCHS Data Brief. 2010; Kennedy JC, Huffman JC, Stern TA. Fear of medical illness: differential diagnosis, workup, and treatment. Prim Care Companion J Clin Psychiatry. 2008;10: Online etymology dictionary. Hypochondria (n.). Accessed March 17, Fishman MB, Aronson MD. Differential diagnosis of abdominal pain in adults. UpToDate. Residents%20Core%20Reading/ACUTE%20&%20CHRONIC%20ABDO%20PAIN/Diff%20Diagnosis%20Abdo%20Pain.htm. Accessed March 19, Pearigen P. Unusual causes of abdominal pain. Emerg Med Clin North Am. 1996;14: Gans SL, Pols MA, Stoker J, et al; Expert Steering Group. Guideline for the diagnostic pathway in patients with acute abdominal pain. Dig Surg. 2015;32: Mueller PD, Benowitz NL. Toxicologic causes of acute abdominal disorders. Emerg Med Clin North Am. 1989;7: Purysko AS, Remer EM, Filho HM, et al. Beyond appendicitis: common and uncommon gastrointestinal causes of right lower quadrant abdominal pain at multidetector CT. Radiographics. 2011;31: Hariharan M, Balasubramaniam R, Shetty S, et al. Uncommon causes of acute abdominal pain: a pictorial essay. J Clin Imaging Sci. 2016;6: Rui P, Kang K, Albert M. National Hospital Ambulatory Medical Care Survey: 2013 emergency department summary tables. Published Accessed March 17, Stein PE, Badminton MN, Rees DC. Update review of the acute porphyrias. Br J Haematol. 2017;176: Woolf J, Marsden JT, Degg T, et al. Best practice guidelines on first-line laboratory testing for porphyria. Ann Clin Biochem. 2017;54: Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005;142: Bustad HJ, Vorland M, Ronneseth E, et al. Conformational stability and activity analysis of two hydroxymethylbilane synthase mutants, K132N and V215E, with different phenotypic association with acute intermittent porphyria. Biosci Rep. 2013;33: Ramanujam VM, Anderson KE. Porphyria diagnostics, part 1: a brief overview of the porphyrias. Curr Protoc Hum Genet. 2015;86: Puy H, Gouya L, Deybach JC. Porphyrias. Lancet. 2010;375: Chen GL, Yang DH, Wu JY, et al. Neuropathic pain in hereditary coproporphyria. Pak J Med Sci. 2013;29: Ventura P, Cappellini MD, Biolcati G, et al. A challenging diagnosis for potential fatal diseases: recommendations for diagnosing acute porphyrias. Eur J Intern Med. 2014;25: Besur S, Schmeltzer P, Bonkovsky HL. Acute porphyrias. J Emerg Med. 2015;49: Whatley SD, Badminton MN. Acute intermittent porphyria. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews. Seattle, WA: University of Washington, Seattle; Bonkovsky HL, Maddukuri VC, Yazici C, et al. Acute porphyrias in the USA: features of 108 subjects from Porphyria Consortium. Am J Med. 2014;127: Harper P, Sardh E. Management of acute intermittent porphyria. Expert Opin Orphan Drugs. 2014;2: Suarez JI, Cohen ML, Larkin J, et al. Acute intermittent porphyria: clinicopathologic correlation. Report of a case and review of the literature. Neurology. 1997;48: Szlendak U, Bykowska K, Lipniacka A. Clinical, biochemical and molecular characteristics of the main types of porphyria. Adv Clin Exp Med. 2016;25: Simon NG, Herkes GK. The neurologic manifestations of the acute porphyrias. J Clin Neurosci. 2011;18: Bonkovsky HL Caballes FR. Acute porphyrias. Clinical Advisor. Published Accessed February 1, Pischik E, Kauppinen R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015;8: Schutte CM, van der Meyden CH, van Niekerk L, et al. Severe porphyric neuropathy -- importance of screening for porphyria in Guillain-Barré syndrome. S Afr Med J. 2015;106: Sharma Y, Padhy BP, Khadilkar S. Rare Guillian-Barre syndrome mimicker: acute intermittent porphyria. Bombay Hosp J. 2012;54: Cuquemelle E, Ehrmann S, Razazi K, et al. An atypical case of Guillain-Barré syndrome: acute intermittent porphyria. Intens Care Med. 2012;38: Pg.23