Chronic hepatitis C virus infection (HCV) can present with cryoglobulinemic vasculitis, which is primarily associated with type II/III cryoglobulins. Type I cryoglobulins are usually seen in lymphoproliferative disease, and large vessel involvement with this type of vasculitis is rare. A 70-year-old man with chronic HCV presented with abdominal pain, leukocytosis, and rash. Computed tomography angiography showed thickening of the abdominal aorta consistent with large-vessel vasculitis. He was found to have type I cryoglobulinemia and was treated with corticosteroids and ledipasvir/sofosbuvir with rapid resolution of his aortitis. This case emphasizes the need to recognize HCV as a potential etiology of large-vessel vasculitis

Gordon, Stuart C

Hassan, Mona

Lenhart, Adrienne

Meighani, Alireza

Henry Ford Health System Scholarly Commons

Henry Ford Health Henry Ford Health Scholarly Commons Gastroenterology Articles Gastroenterology 1-1-2017 Hepatitis C Virus-Associated Aortitis Caused by Type I Cryoglobulins Adrienne Lenhart Henry Ford Health Alireza Meighani Henry Ford Health, ameigha1@hfhs.org Mona Hassan Henry Ford Health Stuart C. Gordon Henry Ford Health, sgordon3@hfhs.org Follow this and additional works at: https://scholarlycommons.henryford.com/gastroenterology_articles Recommended Citation Lenhart A, Meighani A, Hassan M, and Gordon SC. Hepatitis C Virus-Associated Aortitis Caused by Type I Cryoglobulins. ACG Case Rep J 2017; 4:e114. This Article is brought to you for free and open access by the Gastroenterology at Henry Ford Health Scholarly Commons. It has been accepted for inclusion in Gastroenterology Articles by an authorized administrator of Henry Ford Health Scholarly Commons. Downloadedfromhttp://journals.lww.com/acgcrbyBhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws=on04/19/2022Downloadedfromhttp://journals.lww.com/acgcrbyBhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws=on04/19/2022CASE REPORT | LIVERHepatitis C Virus-Associated Aortitis Caused by Type ICryoglobulinsAdrienne Lenhart, MD1, Alireza Meighani, MD1, Mona Hassan, MD2, and Stuart Gordon,MD21Department of Internal Medicine, Henry Ford Hospital, Detroit, MI2Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, MIABSTRACTChronic hepatitis C virus infection (HCV) can present with cryoglobulinemic vasculitis, which is primarily associ-ated with type II/III cryoglobulins. Type I cryoglobulins are usually seen in lymphoproliferative disease, and largevessel involvement with this type of vasculitis is rare. A 70-year-old man with chronic HCV presented with ab-dominal pain, leukocytosis, and rash. Computed tomography angiography showed thickening of the abdominalaorta consistent with large-vessel vasculitis. He was found to have type I cryoglobulinemia and was treated withcorticosteroids and ledipasvir/sofosbuvir with rapid resolution of his aortitis. This case emphasizes the need torecognize HCV as a potential etiology of large-vessel vasculitis.INTRODUCTIONChronic hepatitis C virus (HCV) infection can present with many extrahepatic manifestations, the most common ofwhich is cryoglobulinemia. Cryoglobulinemic vasculitis is characterized by the cold precipitation of serum cryoglo-bulins on endothelial surfaces, which elicits vascular inflammation through mechanisms that are not completelyunderstood. HCV is primarily associated with type II and type III cryoglobulins, which are mixtures of monoclonalimmunoglobulins IgM and polyclonal IgG and polyclonal IgM and IgG, respectively.1,2 In rare instances, type I cryo-globulins (monoclonal IgG or IgM, less commonly IgA) have also been seen with HCV, although type I cryoglobuli-nemia is classically described in lymphoproliferative disorders.3 HCV-associated cryoglobulinemic vasculitisprimarily affects small and medium-sized vessels of the skin, kidneys, and peripheral nerves.1 Involvement of largevessels, such as the aorta, is unusual and rarely described in the literature.CASE REPORTA 70-year-old white man with a history of chronic, non-cirrhotic HCV (genotype 1a, treatment naïve) presentedwith a 1-week history of right lower quadrant abdominal pain and a new, erythematous rash on his trunk and bilat-eral lower extremities. Laboratory studies included a leukocytosis of 14 K/mL, with normal renal function, liver func-tion, and coagulation tests. Computed tomography angiography showed diffuse wall thickening of the distalabdominal aorta and common iliac vessels without evidence of an aortic aneurysm or aortic dissection (Figure 1).These findings were suspicious for focal, large-vessel vasculitis, and the patient was admitted.Additional workup revealed an elevated erythrocyte sedimentation rate of 34 mm/hr and C-reactive protein 8.7mg/dL. Human immunodeficiency virus, rapid plasma reagin, and treponemal antibody testing were negative. Thepatient had a positive antinuclear antibody test (titer>1:1,280, nucleolar pattern), but p- and c-anti-neutrophil cyto-plasmic antibody, IgG4 level, double-stranded DNA antibodies, anti-Smith antibodies, anti-ribonucleoprotein anti-bodies, and complement levels (C3/C4) were negative. HCV viral load was elevated at 183,424 IU/mL, and serumACG Case Rep J 2017;4:e114. doi:10.14309/crj.2017.114. Published online: October 25, 2017.Correspondence: Adrienne Lenhart, Department of Internal Medicine, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202 (alenhar2@hfhs.org).Copyright: © 2017 Lenhart et al. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 InternationalLicense. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0.ACG Case Reports Journal / Volume 4 acgcasereports.gi.org 1ACGCASE REPORTS JOURNALwas positive for type I cryoglobulins composed of IgG lmonoclonal proteins. Serum protein electrophoresis wasunremarkable.Punch biopsy of the patient’s rash showed papillary dermaledema and a mild superficial perivascular inflammatory infil-trate, consistent with a non-specific, superficial perivasculardermatitis (Figure 2). On hospital day 7, he was started onledipasvir/sofosbuvir 90–400 mg daily as well as prednisone40 mg daily for HCV-induced cryoglobulinemic vasculitisinvolving the small vessels of the skin and the large vessel ofthe aorta. The patient completed a 12-week course ofledipasvir/sofosbuvir and subsequently achieved a sustainedvirologic response. Repeat magnetic resonance angiography4 months later showed complete resolution of the thickeningin the abdominal aorta and common iliac arteries (Figure 3).Repeat cryoglobulin level was negative 2 months after start-ing ledipasvir/sofosbuvir, and the patient was able to betapered off steroids within 7 months.DISCUSSIONThe prevalence of cryoglobulinemia in HCV varies from 10–54% of infected individuals and is more common in women,older patients, and those with longer durations of infection.4-7Clinical symptoms include palpable purpura, arthralgias,Raynaud’s phenomenon, peripheral neuropathy, and renalimpairment.8 HCV-associated cryoglobulinemic vasculitis typ-ically affects small and medium-sized vessels, while involve-ment of larger vessels, such as the aorta, is rarely reported.Rather, aortitis is classically caused by bacterial infectionssuch as Salmonella, Staphylococcus, or syphilis, or it is sec-ondary to inflammatory conditions including giant cell arteri-tis, Takayasu arteritis, rheumatoid arthritis, and systemiclupus erythematosus.9,10 While the reasons for these differen-ces in vessel size are not completely known, a possible expla-nation is that cryoglobulinemic vasculitis is frequentlymediated by immune complex formation, which is more likelyto precipitate in smaller vessels.11 Conversely, giant cell arteri-tis and Takayasu arteritis involve large-vessel infiltration of T-cells, macrophages, and monocytes.12Although infrequently seen, a few case series and case reportshave established an association between cryoglobulinemiaFigure 1. Computed tomography angiography of the abdomen showingdiffuse thickening of the walls of the abdominal aorta and common iliacvessels.Figure 2. (A) Blanching, erythematous macules, and papules on thepatient’s upper back. (B) Histopathology showing papillary dermal edemaand a superficial perivascular inflammatory infiltrate.Figure 3. Magnetic resonance angiography of the abdomen showing re-solution of aortitis in the distal aorta and proximal iliac vessels.Lenhart et al HCV Aortitis and Type I CryoglobulinemiaACG Case Reports Journal / Volume 4 acgcasereports.gi.org 2and aortic abnormalities in non–HCV-infected patients.13,14However, aortitis secondary toHCV-associatedcryoglobuline-mia isnotwell defined.Fukunagaetal. describedacaseofanel-derly man with known HCV-related cryoglobulinemia whopresented with an aortic dissection and histopathology thatshowed deposition of IgG within the aortic wall.15 Theman wastreatedwith steroids, underwent emergent reconstructive sur-gery, and ultimately survived. However, the authors did notcomment on definitive treatment of his underlying HCV. Ourcase is unique because our patient’s aortitis resolved with oralantiviral therapy in addition to corticosteroids.As previously mentioned, HCV-related cryoglobulinemic vas-culitis is most commonly associated with type II and III cryoglo-bulins, whereas type I cryoglobulinemia is typically seen inlymphoproliferative disorders.16,17 However, type I cryoglobu-lins have also occasionally been reported in patients withHCV.A case series by Trejo et al. reported that, out of 90 patientswith type-ablecryoglobulinemia,33patientshadtype Icryoglo-bulins, 83% of which also had concurrent HCV infection.3 Ourcase highlights a unique presentation of HCV-related cryoglo-bulinemic vasculitis associated with type I cryoglobulins.Lymphoproliferative disorders were ruled out via negative se-rum electrophoreses and the absence of lymphadenopathy oncomputed tomography imaging. HCV as the etiology of thispatient’s type I cryoglobulinemia was also supported by the re-solution of vascular inflammation and clearance of serum cryo-globulinswithantiviral therapy.In accordance with guidelines, patients with HCV-associatedcryoglobulinemic vasculitis should receive treatment for HCV,with direct-acting antivirals being the preferred agents.18,19While these guidelines were based on studies of vasculitis insmall andmedium-sizedvessels, thepresent case suggests thatthese recommendations should be extrapolated to includelarge-vessel vasculitis. Corticosteroids are often used as anadditive therapy tohelpmitigate vasculiticflares.20Ourpatientwas treated with steroids and antiviral therapy, achieving bothsustainedvirologic responseandresolutionofvasculitis.This casehighlights a rarepresentationofHCV-associatedaor-titis caused by type I cryoglobulins that ultimately resolvedwith antiviral therapy. The rapid improvement of vasculitis,cryoglobulinemia, and HCV infection following initiation ofsofosbuvir/ledipasvir emphasizes the need to search for a vi-ral etiology in similar cases and to promptly begin potentiallylife-saving therapy.DISCLOSURESAuthor contributions: A. Lenhart wrote the manuscript and isthe article guarantor. A. Meighani and M. Hassan wrote andedited themanuscript. S.Gordonedited themanuscript.Financial disclosure: None to report.Informed consent was obtained for this case report.ReceivedApril 13, 2017;AcceptedSeptember 13,2017REFERENCES1. Charles ED, Dustin LB. Hepatitis C virus-induced cryoglobulinemia.Kidney Int. 2009;76(8):818–24.2. Brouet JC, Clauvel JP, Danon F, et al. Biologic and clinical significanceof cryoglobulins: A report of 86 cases.Am JMed. 1974;57:775–88.3. Trejo O, Ramos-Casals M, García-Carrasco M, et al. Cryoglobulinemia:Study of etiologic factors and clinical and immunologic features in 443patients from a single center.Medicine. 2001;80(4):252–62.4. Lunel F, Musset L, Cacoub P, et al. Cryoglobulinemia in chronic liver dis-eases: Role of hepatitis C virus and liver damage. Gastroenterology.1994;106(5):1291–300.5. Adinolfi LE, Utili R, Attanasio V, et al. Epidemiology, clinical spectrumand prognostic value of mixed cryoglobulinaemia in hepatitis C viruspatients: A prospective study. Ital J Gastroenterol. 1996;28(1):1–9.6. Wong VS, Egner W, Elsey T, Brown D, Alexander GJ. Incidence, charac-ter and clinical relevance of mixed cryoglobulinaemia in patients withchronic hepatitis C virus infection.Clin Exp Immunol. 1996;104(1):25–31.7. Cicardi M, Cesana B, Del Ninno E, et al. Prevalence and risk factors forthe presence of serum cryoglobulins in patients with chronic hepatitis C.J Viral Hepat. 2000;7(2):138–43.8. Dammacco F, Racanelli V, Russi S, Sansonno D. The expanding spectrumof HCV-related cryoglobulinemic vasculitis: A narrative review.Clin ExpMed. 2016;16:233–42.9. Rojo-Leyva F, Ratliff NB, Cosgrove DM 3rd, Hoffman GS. Study of 52patients with idopathic aortitis from a cohort of 1,204 surgical cases.Arthritis Rheum. 2000;43:901–7.10. Pacini D, Leone O, Turci S, et al. Incidence, etiology, histologic findings,and course of thoracic inflammatory aortopathies. Ann Thorac Surg.2008;86(5):1518–23.11. Cacoub P, Comarmond C, Domont F, Savey L, Saadoun D. Cryoglobulinemiavasculitis.AmJMed. 2015;128(9):950–5.12. Weyand CM, Goronzy JJ. Medium- and large vessel vasculitis. N Engl JMed. 2003;349(2):160–9.13. Au WY, Kwok JS, Chu KM, Ma ES. Life-threatening cryoglobulinemia inHCV-negative Southern Chinese and a novel association with structuralaortic abnormalities.Ann Hematol. 2005;84(2):95–8.14. Dabala A, Musso L, Oreste PL, et al. Antiapolipoprotein B cryoglobuline-mia associated with normal plasma lipids and severe atherosclerosis.Appl Pathol. 1986;4(4):260–9.15. Fukunaga N, Fujiwara H, Nasu M, Okada Y. Aortic dissection caused byaortitis associated with hepatitis C virus-related cryoglobulinemia. JThorac Cardiovasc Surg. 2010;140(5):e81–2.16. Néel A, Perrin F, Decaux O, et al. Long-term outcome of monoclonal(type 1) cryoglobulinemia.Am J Hematol. 2014;89(2):156–61.17. Terrier B, Karras A, Kahn JE, et al. The spectrum of type I cryoglobuline-mia vasculitis: New insights based on 64 cases.Medicine. 2013;92(2):61–8.18. AASLD/IDSA HCVGuidance Panel. Hepatitis C guidance: AASLD-IDSArecommendations for testing, managing, and treating adults infectedwith hepatitis C virus.Hepatology. 2015;62(3):932–54.19. European Association for Study of Liver. EASL recommendations ontreatment of hepatitic C 2015. J Hepatol. 2015;63(1):199–236.20. Dammacco F, Sansonno D, Han JH, et al. Natural interferon-alpha versusits combination with 6-methyl-prednisolone in the therapy of type IImixed cryoglobulinemia: A long-term, randomized, controlled study.Blood. 1994;84(10):3336–43.Lenhart et al HCV Aortitis and Type I CryoglobulinemiaACG Case Reports Journal / Volume 4 acgcasereports.gi.org 3

Hepatitis C Virus-Associated Aortitis Caused by Type I Cryoglobulins

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