대 한 방 사 선 의 학 회 지 1993 ; 29 (4) : 757~ 764 Journal of Korean Radiological Society, July, 1993

Hypereosinophilic Syndrome: Clinical, Laboratory, and Imaging Manifestations in Patients with Hepatic Involvement

Gi Beom Kim, M.D., Ok Hwoa Kim, M.D.*, Jong Min Lee, M.D., Yeong Soon Sung, M.D., Duk Sik Kang, M.D.

Department 01 Radiology, Kyungpook National Universi낀I College 01 Medicine

- Abstract-

The hypereosinophilic syndrome (HES) commonly involves liver and spleen but only a few literature has reported the imaging features. In this article, we present the imaging features of the liver and spleen in HES patients together with clinical and laboratoη features. This study included 5 HES patients with hepatic involvement. Extensive laboratory tests including multiple hematologic, serolo밍 c ， parasitologic, and immunologic examinations were performed. Imaging studies includ­ ed CT, ultrasound (US) of upper abdomen and hepatosplenic scintigraphy. All patients were perio벼C 떠 lyexam­ ined by laboratory and imaging studies for 4 to 24 months. The common clinical presentations were weakness, rnild fever, and dry cough. All patients revealed leukocy­ tosis with eosinophilia of 40 to 80% and benign eosnophilic hyperplasia of the bone marrow. The percutane­ ous biopsy of the hepatic focal lesions performed in 2 patients showed numerous benign eosinophilic infIltrates and one of them revealed combined centrilobular necrosis of hepatocytes. All cases revealed hepatomegaly with m띠 tiple focallesions on at least one of CT, US, or scintigraphy. These findings completely disappeared in 2 to 6 months following medication of corticosteroid or antihistamines. The HES involved the liver and CT, US , or scintigraphic studies showed hepatic multifocal lesions with hepatomegaly. Differential diagnoses of these findings should include metastatic disease, lymphoma, leukemia, can버 diasis or other opportunistic infections.

Index Words: Hypereosinophilia Liver, CT 76 1.1 211 Liver, Neoplasm 761.31

Occasionally, despite extensive investigation, INTRODUCTION significant eosinophilia may be present without any identifiable underlying disorder, and this Eosinophilia commonly appeared in with a constitutes the term HES applied by Hardy and variety of disorders including allergic and para­ Anderson(4). sitic diseases, collagen vascular diseases, chronic The HES is a spectrum of clinical disorders granulomatous diseases, and some malignancies characterized by leukocytosis with marked eo­ (1 -3). sinophilia without identifiable cause and organ

* 울산동강병원 진단방사선과 * De.φartmeη t 01 Radiology, Doη:gkang Geη eral Hospital, Ulsan, Korea 이 논문은 1993 년 2 월 3 일 접수하여 1993 년 5 월 3 일에 채택되었음. Received February 3, Accepted May 3, 1993 …? Journa l of Korean Radio logical Society 1993; 29 (4) : 757~ 764

system dysfunction. The criteria for the diagno­ This study included five patients with manifes­ sis of HES as outlined by Chusid et al.(2) are: tation of hepatic involvement. The patients (a) a persistent eosinophilia of 1500 eosinophils ranged from 27 to 60 years of age; all were j mm3 for longer than 6 months, or death be­ male. The patients were presented with flu-like fore 6 months associated with the signs and symptoms or right upper quadrant abdorninal symptoms of hypereosinophilic disease; (b) lack dull pain and marked blood eosiniphilia. Three of evidence for parasitic, allergic, or other påtients (Cases 1, 2 and 5) with progressive known causes of eosinophilia; and (c) an evi­ organ system dysfunction were treated with dence of organ system involvement. steroid and other two patients showed stable We have encountered several HES patients laboratoη data received antihistarnine treat­ in whom CT, US, or scintigraphy of liver and ment only. spleen has demonstrated hepatic multifocal le­ Laboratory exarnination included serial sions and hepatosplenomegaly. Although there complete blood counts, urinalysis, multiple ser­ have been many reports dealing with clinical 이0멍c tests for infectious and connective tissue and laboratory findings(1 ,2, 4 - 7) of HES or diseases, bone marrow aspiration and biopsy, chest radiographic findings in patient with car­ ECG, functional tests for liver and kidney, and diopulmonary involvement(8-1 0), only a few lit­ allergic skin tests. Multiple stool samples were erature(ll), to our knowledge, have reported exarnined for ova and parasites of Clonorchis the imaging features of involved liver in HES sinensis, Entamoeba histolytica, and Para­ patient. This article presents imaging features gonimus westermani. Multiple cultures and of the liver and spleen together with clinical smears of blood and sputum for bacteria and 없ld laboratory features in our 5 HES cases. fungi and extensive immunologic evaluations (e. g., serum IgE level, T4jT8 ratio) were done. MATERIALS AND METHODS Markers for certain leukemias such as serum vi­ tarnin B 12 levels and the chromosomes were We experienced six patients who ful­ analysed. Two patients under-went US-guided filled the criteria of HES over a 2-year period. needle biopsy of the liver.

Table 1. Summary of Clinical and Laboratory Findings A α 않 pePL C pi Hematologic Data Electro­ α 찌 κ 뼈 m 따 m ” E VA Biopsy of Liver WBC, xl03/ mm3 Eosinophils, % cardiogram 1/ 27/ M Mild fever, dry 34.9 78 Numerous eosinophilic Sinus cough, weight loss (36.6-9.5) (82-39) infiltrates aπhythrnia 2/ 42/ M Fatigue, rnild fever, 25.8 50 Centrilobular necrosis Normal pruritic rash (29.5-8.1) (68-8) with eosinophilic infiltration 3/ 41 / M Cough, chest discomfort, 17.5 60 Normal weight loss, paresthesia (26.3-8.7) (65-16) 4/60/M RUQ abdorninal p떠 n ， 23 .2 75 Sinus pruritic rashes (23.2-9.6) (75-10) bradycardia 5/34/M Left lower chest and 30 .1 48 LUQ abdorninal pain (4 1.1 -13.8) (70-9) Hematologic data represent values at the time of initial exarnination; figures in parentheses represent subse­ quent extremes. 얘ω Gi Beom Kim , et al : Hypereosinophilic Syndrome

Imaging studies included CT and US scans (Table 1). of upper abdomen and hepatosplenic scintigra­ The patients presented with leukocytes be­ phy. All patients were periodic떠 ly examined by tween 10,000 and 40,000/mm3 with 40 to 80 laboratory and imaging studies for 4 to 24 % peripheral eosinophilia. Bone marrow aspira­ months. tion 뻐d biopsy revealed benign eosinophilic hyperplasia in all cases. US-guided needle biop­ RESULTS sy of hepatic focal lesions was performed in 2 patients (Cases 1, 2). Case 1 showed numerous All the 5 patients were male and the mean eosinophilic infùtrates and Case 2 showed age of onset was 41 . lnitial clinical presenta­ centrilobular necrosis of hepatocytes with eo­ tions of the patients were varied, weakness, sinophilic infiltrates (Fig. 2d). All patients had mild fever, dry cough with chest discomfort, mild liver function abnormalities with slightly and weight loss were frequent complaints. No elevated SGOT, SGPT or alkaline phosphatase remarkable allergy or drug history was presented level. Serologic and immunologic tests were un-

a b

c d Fig. 1. Case 1, A 27-year-old man with flu-like symptoms for 1 month. a. CT shows enlarged liver and spleen without focallesion. b. US of liver shows a diffuse coarse parenchym꾀 echogenicity without focal mass. c. Hepatosplenic scintigram shows marke버y enlarged liver with large photon defects in both lobes and prorni­ nent spleen. d. Follow up scintigraphy of the liver 6 months after corticosteroid treatment shows normal liver and spleen 쩌때 Journal of Korean Radiological Society 1993; 29 (4 ) : 757~ 764

a b

c d Fig. 2. Case 2, A 42-year-old man with fatigue and pruritic rashes for 2 months. a. CT shows multiple ill-defined hypodense nodules in enlarged liver (arrows). b. US of liver shows multiple ill-defined hypoechoic nodules. c. Hepatic scintigram shows slightly enlarged liver with m버 tiple photon defects. d. Photomicrograph of liver shows centrilobular necrosis of hepatocytes and nurnerous eosinophlic infiltrates. remarkable except elevated serurn IgE level in sions were noted in four out of the 5 patients 4 patients. Other studies including and appeared as variable sized, hypodense le­ bacteriologic, parasitologic, and allergic skin sions with ill defined margins (Fig. 2a, 3a). The tests were normal. lesions of Case 4 disappeared on follow-up CT Table 2 summarized the findings of liver scan taken after 2 months. On US examination and spleen on CT, US, and scintigraphy in the the focal nodular lesions were noted in three. 5 patients. All patients showed mild to marked They were ill defined, hypoechoic (Case 2, 5) or hepatomegaly with multiple focal lesions. The hyperj isoechoic (Case 3) nodules. Our impres­ splenomegaly of mild to moderate degree with­ sion at the time of initial examination was mul­ out focal lesion was noted in four. Although tiple hemangioma due to the hyper and multiple focal lesions were visualized on at least isoechogenicity of the nodules showed in Case one of the three modalities, it was unusual that 3, but six months later these nodules were com­ these focal lesions appeared on all three pletely disappeared. Hypoechoic lesions of modalites (Case 2). On CT scans, the focal le- Cases 2 and 5 were also disappeared six and

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a b Fig. 3. Case 5, A 34-year-old man with LUQ abdominal dull pain for 1 month. a. CT shows a 3cm ill-defined hypodense lesion (arrows) in anterior aspect of the right lobe of the liver. b. US of liver shows a 3cm hypoechoic mass (large arrows) and several smaller daughter nodules in adjacent area (small arrows).

Table 2. Imaging Findings of Upper Abdomen

Case CT US SCINTIGRAM

1 Hepatosplenomegaly, Hepatosplenomegaly with Huge liver with large photon paraaortic lymph adenopathies coarse echoes, lymphadenopa- defects, splenomegaly thies in portacaval space 2 Hepatomegaly with multiple Multiple irregularly marginated Mild hepatomegaly with small hypodense lesions hypoechoic nodules in liver multiple photon defects, splenomegaly 3 Hepatomegaly with ill-defined M비 tiple hyper- and isoechoic Hepatosplenomegaly hypodense areas hepatic nodules 4 Numerous small hypodense Hepatomegaly with coarse Mild hepatomegaly with nodules in liver echoes multiple photon defects 5 Hepatomegaly with several Hepatomegaly with three hypodense masses hypoechoic lesions, prominent spleen two months after steroid therapy, respectively. The other two cases showed hepatomegaly with DISCUSSION coarse parenchym꾀 echogenicity only. Six months' follow-up US after corticosteroid ther­ Hardy and Anderson(4) introduced the apy in one (Case 1) of two showed normaliza­ term “ hypereosinophilic syndrome" to encom­ tion of size and echopattern of the liver. On pass a group of apparently interrelated diseases scintigraphy, the focal photon defects were and it included a wide spectrum of clinical noted in three of four patients. (Figs. 1c, 2c). manifestation ranging from a localized benign On the follow- up scan after 6 months, Case 1 form (Lδffler's syndrome, PIE syndrome) to a revealed normal liver and spleen without focal disseminated form (disseminated eosinophilic defect (Fig. 1d) and Case 3 showed the liver be­ collagen disease, eosinophilic leukemia) came normal in size. The HES is characterized by idiopathic pro-

때 Journal of Korean Radiological Society 1993; 29 (4) : 757~764 longed blood eosinophilia and organ system lesions appeared in all modalities (Case 2) foì• dysfunction, presumably caused by invasion of each case. The nature of imaging findings of tissue by eosinophilic leukocytes (1 , 2, 12). This focal lesions on CT, US, and scintigraphy was syndrome shows marked male predominance varied according to the patient. On CT scan, all and is primarily a disease of middle age. Initial focal lesions identified in 4 patients appeared clinical presentation of the disease is varied, as hypodense foci with variable size. These foci but weakness, drγ cough, and weight loss of in­ on US examination appeared as hypoechoic in sidious onset are known as frequent complaints. 2 cases and mixture of isoechoic and 깐le m맹 ority of patients usually presented with hyperechoic in 1 case. On scintigraphy, all the elevated leukocyte ranged from 10,000 to 100, foci appeared as photon deficient areas. 000 j mm3 in peripher때 blood smear and with All our patients had only mild elevation of 30 to 70% eosinophilia. Some patients reveal biochemical tests for liver function. The com­ abnormal serum B12 levels or abnormalities of mon pathologic finding of the liver is infiltra­ chromosomal configuration(1 ,2,4,6, 1 0). tion of mature eosinophils in the periportal re­ The commonly involved organs with HES gions, with over꾀 1 normal hepatic architecture are hematopoietic, cardiovascular, hepato­ (1, 2,14,15). However, one patient (Case 2) splenic and pulmonaη system. The involvement showed extensive centrilobular necrosis of of nervous, lymphatic, gastrointestinal, and hepatocytes with numerous eosinophilic infil­ renal systems and skin is less frequently encoun­ trates. A few experimental studies documented tered(1, 2,6,13). Bone marrow was involved in the tissue damage effect of eosinophils by local all subjects, and more serious consequences are deposition of toxic eosinophilic proteins such from the involvement of the heart and the cen­ as cationic protein and major basic protein(l 6, tral nervous system. Although two of our cases 17). We considered the localized eosinophilic showed sinus arrhythmia on EKG, none had infiltrates with or without hepatocellular necro­ symptoms referable to the cardiovascular sis were responsible for the multifocal lesions system. The involvement of nervous system in­ identified on imaging studies. cludes both central and peripheral nervous The prognosis of HES, while generally systens. However, only one of our patients pre­ poor, is variable. Our patients were followed sented paresthesia on extremities. for 4 to 22 months. All patients are still surviv­ This study included 5 HES patients with ing and showing gradual or dramatic response findings of hepatic involvement on at least one to therapy with corticosteroid or antihistamines. of CT, US, or scintigraphy. Many reports de­ In summarγ ， the HES is characterized by id­ scribed hepatic involvement in HES patients, iopathic persistent eosinophilia and multisystem with high incidence of 50 to 90% and typified organ involvement caused by eosinophilic by hepatosplenomegaly on physical examination infiltration. This study included the 5 HES pa­ or autopsy and minor abnormalities of liver tients with hepatiç involvement, and imaging function tests(1 ,4,6,10). To our knowledge, studies of these patients showed intrahepatic however, only a few literature has reported multifocal lesions as well as hepatomegaly. Diε imaging features of HES involved liver(ll). All ferential diagnosis of these imaging findings our cases revealed hepatomegaly with multiple should include metastatic disease, lymphoma, focal lesions on at least one of CT, US, and leukemia, candidiasis or other opportunistic in­ scintigraphy. Although multiple intr하lepatic fections. focal lesions were identified on at least one of three modalities, it was unusual that these focal

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9. Citro LA, Gordon ME, Miller WT. Eosinophilic lung disease. A]R 1973; 117:787-798 REFERENCES 10. Epstein DM, Taorrnina V, Gefter WB , Miller WT. The hypereosinophilic syndrome. Radiology 1. Fauci AS, Harley ]B, Robert WC, Ferrans V], 1981; 140:59-62 Gr허nick HR, Bijornson BH. The idiopathic 11. Shiorni S, Kuroki T, Ueda T, Ikeoka N, hypereosinophilic syndrome: clinical, Kobayashi K, Ochi H. Hypereosinophilic pathophysiologic, and therapeutic considera­ syndrome as a focal defect on liver scan. Ann tions. Ann Intem Med 1982; 97:78-92 Nucl Med 1991; 5:171-173 2. Chusid M] , Dale DC, West BC, Wolff SM. The 12. Roberts WC, Liegler DG, Carbone PP. hypereosinophilic syndrome: an꾀ysis of fourteen Endomyocardial disease and eosinophilia. Am ] cases with review of the literature. Medicine Med 1969; 46:28-42 1975; 54:1-27 13. Parrillo ]E, Fausi AS, Wolff SE. πlerapy of the 3. Liao KT, Rosai], Dameshek K, et al. Malignant hypereosinophilic syndrome. Ann Intern Med histiocytosis with cutaneous involvement and eo­ 1978; 89:167-172 sinophilia. Am] Clin Path 1972; 57:438-448 14. Foong A, Scholes ]V, Gleich G], Kephart GM, 4. Hardy WR, Anderson RE. The hypereosinophilic Holt PR. Eosinophil-induced chronic active hep­ syndrome. Ann Intern Med 1968; 68:1220- atitis in the idiopathic hypereosinophilic 1229 syndrome. Hepatology. 1991; 13: 1 090-1 094 5. Flaum MA, Schooley RT, Fauci AS, Gralink H R. 15. Croffy BC, Kopelman RK, Kaplan M. A clinicopathologic correlation of the idiopathic Hypereosinophilic syndrome: association with hypereosinophilic syndrome: hematologic mani­ chronic active hapatitis. Dig Sci 1988; 33:233- festations. Blood 1981; 58:1012-1020 239 6. Benvenistic DS , Ultmann]E. Eosinophilic leuke­ 16. Gleich G], Schroeter AL, Marcoux ]P, Sachs rnia: report of five cases and review of literature. MI, 0 ’Connell E], Kojler PF. Episodic Ann Intern 1\‘ed 1969; 71: 731-745 angioedema associated with eosinophilia. N Engl 7. Brink A], Weber HW. Fibroplastic parietal endo­ ] Med 1984; 310:1621-1626 carditis with eosinophilia (Löffler’s endocardi­ 17. Keshavarzian A, Saverymuttu SH, Tai PC, et al. tis). Am] Med 1963; 34:52-76 Active eosinophils in farnilial eosinophilic 8. Carrington CB, Addington WW, Goff AM, et al. gastroenteritis. Gastroenterology 1985; 88: Chronic eosinophilic pneumonia. N Engl] Med 1041-1049 1969; 280:787-798

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〈 국문 요약 〉

과호산구 증후군 : 간장을 침범한 환자들의 임상적， 검사실 및 영상소견

경북대학교 의 과대학 진 단 방사선과학 교실， 울산 동강병원 진단방사선과*

김기범 • 김옥화 * • 이종민 • 성영순 • 강덕식

과호산구 증후군은 간장과 비장을 흔히 침범하나 그들의 영상소견에 대해서는 별로 보고된바 없었 다. 본 연구는 간장을 침범한 5 예의 과호산구 증후군 환자들을 대 상으로 임상소견 및 검사실 소견과 함께 복부 CT, 초음파 및 간 비 신티그램 소견을 조사하였다. 환자들은 전신쇄약， 미 열 및 마른기침과 같은 전신 증상을 주소로 하였다. 모든 환자들은 말초 혈액에 호산구 증다 증을 나타냈으며， 골수에는 양성 호산구의 과증식을 보였다. 2 예에서 실시한 국소병변의 미세침 경피생검 소견은 수 많은 호산구의 간내 침윤을 보였고， 이중 l 예에서는 간소엽 중심간세포의 통반된 괴사를 보였다. 모든 환자틀은 CT, 초음파 또는 신티그라피중 적어도 하나 이 상에서 간종대 및 간내 다수의 국소병변을 보였다 . 이러한 소견들은 스테로이드 또는 항히스타민제 투여후 2-6개월에 모두 사라졌다. 요약하면 과호산구 증후군은 CT , 초음파 또는 신티그라피에서 간내 다수의 국소병변을 나타낼 수 있으며 이러한 국소병변은 호산구의 침윤과 인접한 간세포의 괴사 때문 이 라고 추측된다. 영상소견상 이와같은 소견은 전이암， 임파 종 또는 캔 디 다증 등을 감별해야 할것으로 생각된다.

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