1. Z A CD Alan Chan, MD Med-peds PGY4 A case of pain… And pain…

2. Z A CD 18 yo previously healthy Caucasian female reports to local ED for abdominal pain. Had had prior visit to PCP clinic for similar situation, but had unremarkable history and exam thought was constipation and sent home with miralax. A couple months later, repeat episode of abdominal pain, more severe. Presents to the local ER with nausea, emesis. Had CT abd/pelvis scan with read demonstrating some colitis throughout colon. Stool studies not done. Labs were normal. Sent home for supportive care and antibiotics. On PCP office follow up, normal exam. Referred to GI for further evaluation – had colonoscopy with biopsy – inflammation, colitis. ?concern for IBD Chief Complaint: abd pain

3. Z A CD Several months and 5 visits later… Now in college presents again to local ED with extreme abdominal pain. Now 19 years old. Similar to prior presentations. Diffuse mild to moderate achy abdominal pain with mild guarding. Constant with “waves of increased pain” that self resolve. Has not taken any medications at home. Acute onset, shortly after exercising. Subjective fever at dorm. No chills. Moderate nausea with food anorexia. No emesis. Mild dysphagia. “Mouth feels sticky.”

4. Z A CD PMH: none PSH: none ROS: No chills, fatigue, night sweats. No trauma, vision changes No rhinorrhea, sneezing; No dyspnea on exertion, edema, no shortness of breath, wheeze No recent illness. No throat pain, no odynophagia. NO weight changes.

5. Z A CD Medications Ocella (drospirenone/ethinyl estradiol 3 mg/30 mcg) – class I monophasic OCP Allergies NKDA

6. Z A CD SH: College freshman. Never tried smoking. Tried EtOH. Patient denies other drug use or abuse. FH: remote hx of DM and HTN in 2 nd degree relatives

7. Z A CD VS in ER: Temp 100.1, Resp 18, BP 115/61, Pulse 105. 98% on RA General: Alert female appears stated age in mild distress due to pain. Thin but not anorexic. HEENT: EOMI, PERRL, no scleral changes. OP clear with intact good dentition and braces, mildly dry mucus membranes. Lips are full. Red mildly large appearing tongue. Neck: soft, supple, no LAP. Chest: CTA bilat, no wheezing.

8. Z A CD CVS: tachy regular rhythm S1, S2, no murmur Abd: BS +, TTP diffusely, non-localized. Holding abdomen at midline. Neg psoas or obturator sign. Able to walk to bathroom gingerly. Ext: no edema, 2+ pulses Neuro: CN 2-12 intact, no gross deficits. Skin: no rashes, lips red appearing.

9. Z A CD Differential Diagnosis CC: abd pain HPI: 19 year old with repeated abd pain PMH: none Exam Findings Abd exam with TTP.

10. Z A CD Laboratory Data CBC BMP Urinalysis Cardiac Enzymes Liver Function Tests Coagulation Endocrinology Serology Immunologic Studies Other Serology Body Fluid Analysis Cytology Pathology Microbiology CXR EKG Ultrasound CT Scan MRI Other Studies Other Imaging Clinical Course Differential Diagnosis Discussion

11. Z A CD Please Press to Return

12. Z A CD CBC 16.4 13.9 42.1 304 Seg Neutro 85, Lymph 3, Mono 4 MCV 84 (80-99) RDW 13.1 (<14.5)

13. Z A CD BMP 134 3.9 107 19 11 0.7 128 AG 8 (3-15) Ca 9.1 (8.8-10.5) Mg 1.9 (1.8-2.5) PO 4 xx (2.4-4.7)

14. Z A CD Urine Analysis coloryellow sp gr1.025 pH6.0 Hgbneg ketoneneg gluneg protneg LEneg nitriteneg urobilneg bilineg Microscopic 0 wbc 0 rbc

15. Z A CD UDS Negative for anything

16. Z A CD Cardiac Enzymes 1 st – actually not done

17. Z A CD Liver Function Tests AST18 (15-41) ALT25 (7-35) Alk Phos65 (32-91) Albumin3.6 (3.5-4.8) T Bilirubin1.3 (0.3-1.2) D Bilirubinxx (0.1-0.5) Protein 6.6 (6.1-7.9) Lipase < 10 (18-51)

18. Z A CD Coagulation PTT24.5 (21-33) PT11.4 (10.3-13.0) INR1.0

19. Z A CD Endocrinology TSH 2.5 (0.34-5.6) Free T4X (0.6-1.6)

20. Z A CD Serology C4 9 (14-40) C1 inhibitor antigenic protein 15 (19-37) C1 inhibitor functional level 60 (nl is >=60)

21. Z A CD Studies

22. Z A CD Cytology

23. Z A CD Other Serology Inflammatory markers – would have been elevated

24. Z A CD Body Fluid Analysis nada

25. Z A CD Microbiology UCx neg

26. Z A CD No acute cardiopulmonary process Chest X-ray

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28. nada

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30. CT abd/pelvis Findings: The appendix is poorly visualized with a small amount of thickened, enhancing appendiceal wall. There is no evidence of bowel obstruction or free air. There is a tiny amount of free fluid in the pelvis, mostly on the right. Pelvic structures are, otherwise, unremarkable. The lung bases are clear. The liver, spleen, pancreas, adrenal glands, kidneys, and gallbladder are normal. The bile ducts are not dilated. No enlarged lymph nodes are identified in the abdomen and pelvis. Impression: The appendix is visualized with changes possibly consistent with, but not confirmatory for acute appendicitis. There is small amount of free fluid in the pelvis that is thought not to be clinically significant. Clinical correlation is suggested.

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33. MRI – none nada

34. Z A CD 2-D Echocardiogram none

35. Z A CD Other Imaging HIDA - negative

36. Z A CD Clinical Course Worried about acute appendicitis. Taken to the OR the next day. Pathology back in a couple days with normal appendix without signs of appendicits. Patient is making recovery as expected on post op day 1 with some resolving pain. Still with some mild sticky swallowing. On further exam, oral exam is somewhat unchanged and pt notes this as well.

37. Z A CD Screening for hereditary angioedema positive for low complement levels. Underwent fresh frozen plasma infusion with resolution of symptoms. Diagnosed with Hereditary Angioedema type I, not started on therapy due to patient preference

38. Z A CD Discussion - Goals Complications Diagnosis and Initial Treatment Disease Background Pathophys Treatment New stuff MKSAP Q?

39. Z A CD Definition Angioedema – self limited local swelling of the skin Urticaria or hives – flushing, generalized itching, near syncope, hypotension with mast cell activation – typically < 24 hrs

40. Z A CD History First described and Autosomal Dominant inheritance pattern realized by Sir William Osler in 1888. Protein defect described in 1963 by Donaldson and Evans.

41. Z A CD Types of familial angioedema Type I – absence of one allele with resulting decreased expression of C1-inh in plasma – most cases (85%) – labs shows low antigenic protein and functional activity Type II – expression of a dysfunctional protein – normal level, but low function Suggested type III – normal levels and function, estrogen dependent

42. Z A CD Acquired type of Angioedema typically older Type I - may be from B cell malignancies, and rheumatologic disorders, autoimmune –Immune complexes that are formed more in these diseases thought to consume C1 esterase inh Type II – autoAb (IgG, IgA, or IgM) against C1 INH produced, bind and inactivate it. –Can result in inactivation of C1-INH

43. Z A CD Idiopathic Angioedema Defined as >= 3 episodes of recurrent angioedema in 1 yr period with no apparent cause Estimated to effect up to 20% of people at some point in life. Up to ½ have urticaria – not seen in other types

44. Z A CD Also seen in antibiotics, narcotics, NSAIDs, ARBs (losartan) Class effect Hapten hypothesis from allergic standpoint may explain the urticaria more than the angioedema. ACE substrate on angiotensin I and BK; excess of latter causes effect Usually onset within 1 st week, and can be a few years out from 1 st use. ACE inhibitor induced AE

45. Z A CD Background Incidence is about 1/50,000 Typically symptoms begin in childhood, although diagnosis delayed average of 10 years. As many as 20-25% are spontaneous mutation

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47. Bottom line for definition as of 2004 Clinical criteria – angioedema, abdominal pain, or largyngeal edema + Lab criteria – low C1 inh Ag level x2, low C1 inh fxn level x2, or C1 inh mutation (only tested in kids < 1 yo)

48. Z A CD Onset Typically in childhood, worsen in puberty, and unpredictable severity Attacks typically have a prodrome, like a “tingling” sensation Skin - Erythematous rash, nonpruritic Random swelling – hands, arms, feet, abdomen, face Usually no fever, or leukocytosis Shift of fluids in abdominal attacks can cause hypotension Involvement of airways – risk of asphyxiation

49. Z A CD Risks Typically attacks occur without trigger, but some may be local trauma such as dental work and stress Pregnancy seems to have decreased attack frequency – total circulating C1-INH increases. Attacks reported associated with oral contraceptive use and menstruation.

50. Z A CD C1 Inhibitor function, a serine protease (like a1 antitrypsin, antithrombin) Inactivation of Factors XIIa (Hageman), XIIf, and XIa Direct ininhibition of activated kallikrein Prevention of C1 complement autoactivation in classical cascade

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52. Contact system C1 inhibitor suggested to inactivated 90% of factor XIIa and its metabolite XIIf, and almost half of kallikrein Kallikrein cleaves HMW kininogens and bradykinin release Also cleaves plasminogen to active plasmin, which cleaves factor XII Factor XII undergoes some autoactivation

53. Z A CD Short term treatment use C1 inh replacement, FFP. Latter is controversial because it has contact proteins that could promote bradykinin release Prophylaxis (prior to dental work) – C1 inh, or androgen (takes days), or FFP 1-12 hr before C1 inh replacement (Cinryze and Berinert P) – very expensive! Antifibrinolytics (EACA, TA) – thought to inhibit plasmin activation – sparing effect. Not FDA approved.

54. Z A CD Long term Tx Avoid triggers including drugs, estrogen meds, tamoxifen, ACEI 17a – androgens (danazol and stanozolol), to increase C1 INH, C4, and C2 levels – thought to increase aminopeptidase P (inactivates kinins), increase hepatic production of C1 INH. Doses can be adjusted to as low as danazol 200 mg 3 days a week.

55. Z A CD Androgens These attenuated androgens contraindicated in pregnancy, childhood. Risk of hepatic involvement – cases of hepatocellular carcinoma in patients taking over 10 years. Also abnormal liver enzymes, lipid abnormalities. Common – weight gain, virilization, acne, muscle pains, constipation, HTN

56. Z A CD Antifibrinolytic agents Used in pediatrics (before Tanner V puberty), but not as affective. Only EACA (E-aminocaprioic acid) available in US. Also used in acquired angioedema. Common side effects - muscle cramps, myalgia, elevated CK New agents – Bradykinin receptor blocker

57. Z A CD 25 yo man wants a 2 nd opinion for evaluation of episodes of large, raised red welts and intense itching all over his body. The lesions usually last 24 h + and then disappear. He has >= 2-3 episodes / wk, and he cannot identify any specific trigger for the attacks. He was told his condition was hives and was given hydroxyzine and then fexofenadine, neither of which significantly controlled his symptoms. He reports no mouth or lip swelling, no difficulty breathing, and no GI symptoms. His weight has been stable. Temp 38.1 °C. Discrete dark wheal and flare lesions consistent with urticaria on both arms and legs and the trunk and back. Some lesions look like purpura. UA shows rbc and rbc casts Which of the following is most likely to help establish the diagnosis? A C1 esterase inhibitor measurement B Urine eosinophil count C Skin biopsy D Antigenic skin testing E Thyroid-stimulating hormone measurement

58. Z A CD Urticaria that does not respond to usual treatment should prompt a workup for urticarial vasculitis, including esr, cbc, skin biopsy from the edge of the wheal. Histopathologic evidence of vascular damage, nuclear debris, or erythrocyte extravasation is diagnostic. This form of leukocytoclastic vasculitis is often limited to the skin, but, occasionally, there is organ involvement or systemic signs, such as fever, abdominal pain, or nephritis. Most cases are idiopathic, but they can also be drug-induced (ACE inhibitors, penicillin, and sulfonamide), related to rheumatic diseases such as lupus, or caused by viral disease, including hepatitis B and C infection, and infectious mono. Treatment is dictated by the underlying cause, if one is found. If not, a trial of anti-inflammatory or immunomodulating medications is indicated. Often, more than one agent must be tried before there is long-term relief.

59. Z A CD Key point Urticaria that does not respond to usual treatment should prompt a workup for urticarial vasculitis, including erythrocyte sedimentation rate, complete blood count, and skin biopsy from the edge of the wheal.

60. Z A CD References MKSAP 14 Weis M. Clinical Review of HAE: Diagnosis and Management. Postgraduate Medicine 2009; 121(6): 113-120. Nzeako UC, Frigas E, Tremaine WJ. Hereditary Angioedema. Arch Intern Med. 2001; 161: 2417-2429. Zuraw B. Hereditary Angioedema. NEJM. 2008; 359: 1027-36. Bowen T, Cicardi M, Frank M. Hereditary angiodema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann Allergy Asthma Immunol. 2008; 100(Suppl 2): S30-40. Frank MM, Jiang H. New therapies for hereditary angioedema: Disease outlook changes dramatically. J Allergy Clin Immunol. 2008; 121(1); 272-80. Uptodate articles accessed 10/2/2010. Diagnosis of hereditary and acquired angioedema (C1 inhibitor disorders)

61. Z A CD "Worst case of pedal edema I've ever seen."