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Original Article

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Blood Res 2022; 57(3):

Published online September 30, 2022

https://doi.org/10.5045/br.2022.2022089

© The Korean Society of Hematology

Early diagnosis of Gaucher disease in Korean patients with unexplained splenomegaly: a multicenter observational study

Young Rok Do1,#, Yunsuk Choi2,#, Mi Hwa Heo1, Jin Seok Kim3, Jae-ho Yoon4, Je-Hwan Lee5, Joon Seong Park6, Sang Kyun Sohn7, Sung Hyun Kim8, Sungnam Lim9, Joo Seop Chung10, Deog-Yeon Jo11, Hyeon Seok Eom12, Hawk Kim13, So Yeon Jeon14, Jong-Ho Won15, Hee Jeong Lee16, Jung Won Shin17, Jun-Ho Jang18, Sung-Soo Yoon19

Author Info. +

1Department of Internal Medicine, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, 2Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Division of Hematology, Department of Internal Medicine, 3Severance Hospital, Yonsei University College of Medicine, 4Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 5Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 6Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, 7Department of Oncology/Hematology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, 8Division of Hematology and Oncology, Department of Internal Medicine, Dong-A University College of Medicine, Busan, 9Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, 10Division of Hematology-Oncology, Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, 11Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, 12Department of Hematology-Oncology, Center for Hematologic Malignancy, National Cancer Center, Goyang, 13Division of Hematology, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, 14Division of Hematology/Oncology, Department of Internal Medicine, Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju, 15Division of Hematology and Oncology, Department of Internal Medicine, Soonchunhyang University Hospital, Seoul, 16Department of Internal Medicine, Hemato-Oncology, Chosun University Hospital, Gwangju, 17Division of Hematology/Oncology, Department of Medicine, 18Samsung Medical Center, 19Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

Correspondence to : Jun-Ho Jang, M.D., Ph.D.
Sung-Soo Yoon, M.D., Ph.D.
Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, 81, Irwon-ro, Gangnam-gu, Seoul 06351, Korea (J.H.J.)
Division of Hematology/Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101, Daehak-ro Jongno-gu, Seoul 03080, Korea (S.S.Y.)
E-mail: J.H.J., jh21.jang@samsung.com
S.S.Y., ssysmc@snu.ac.kr

#These authors contributed equally to this work.
*This study was supported by Sanofi.

Received: April 22, 2022; Revised: June 23, 2022; Accepted: June 27, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Background
Gaucher disease (GD) is an autosomal recessive disorder characterized by excessive accumulation of glucosylceramide in multiple organs. This study was performed to determine the detection rate of GD in a selected patient population with unexplained splenomegaly in Korea.
Methods
This was a multicenter, observational study conducted at 18 sites in Korea between December 2016 and February 2020. Adult patients with unexplained splenomegaly were enrolled and tested for β-glucosidase enzyme activity on dried blood spots (DBS) and in peripheral blood leukocytes. Mutation analysis was performed if the test was positive or indeterminate for the enzyme assay. The primary endpoint was the percentage of patients with GD in patients with unexplained splenomegaly.
Results
A total of 352 patients were enrolled in this study (male patients, 199; mean age, 48.42 yr). Amongst them, 14.77% of patients had concomitant hepatomegaly. The most common sign related to GD was splenomegaly (100%), followed by thrombocytopenia (44.32%) and, anemia (40.91%). The β-glucosidase activity assay on DBS and peripheral leukocytes showed abnormal results in sixteen and six patients, respectively. Eight patients were tested for the mutation, seven of whom were negative and one patient showed a positive mutation analysis result. One female patient who presented with splenomegaly and thrombocytopenia was diagnosed with type 1 GD. The detection rate of GD was 0.2841% (exact 95% CI, 0.0072‒1.5726).
Conclusion
The detection rate of GD in probable high-risk patients in Korea was lower than expected. However, the role of hemato-oncologists is still important in the diagnosis of GD.

Keywords Acid β-glucosidase, Dried blood spot, Gaucher disease, Lysosomal storage disorder, Splenomegaly, Thrombocytopenia

Article

Original Article

Blood Res 2022; 57(3): 207-215

Published online September 30, 2022 https://doi.org/10.5045/br.2022.2022089

Copyright © The Korean Society of Hematology.

Early diagnosis of Gaucher disease in Korean patients with unexplained splenomegaly: a multicenter observational study

Young Rok Do1,#, Yunsuk Choi2,#, Mi Hwa Heo1, Jin Seok Kim3, Jae-ho Yoon4, Je-Hwan Lee5, Joon Seong Park6, Sang Kyun Sohn7, Sung Hyun Kim8, Sungnam Lim9, Joo Seop Chung10, Deog-Yeon Jo11, Hyeon Seok Eom12, Hawk Kim13, So Yeon Jeon14, Jong-Ho Won15, Hee Jeong Lee16, Jung Won Shin17, Jun-Ho Jang18, Sung-Soo Yoon19

1Department of Internal Medicine, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, 2Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Division of Hematology, Department of Internal Medicine, 3Severance Hospital, Yonsei University College of Medicine, 4Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 5Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 6Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, 7Department of Oncology/Hematology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, 8Division of Hematology and Oncology, Department of Internal Medicine, Dong-A University College of Medicine, Busan, 9Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, 10Division of Hematology-Oncology, Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, 11Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, 12Department of Hematology-Oncology, Center for Hematologic Malignancy, National Cancer Center, Goyang, 13Division of Hematology, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, 14Division of Hematology/Oncology, Department of Internal Medicine, Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju, 15Division of Hematology and Oncology, Department of Internal Medicine, Soonchunhyang University Hospital, Seoul, 16Department of Internal Medicine, Hemato-Oncology, Chosun University Hospital, Gwangju, 17Division of Hematology/Oncology, Department of Medicine, 18Samsung Medical Center, 19Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

Correspondence to:Jun-Ho Jang, M.D., Ph.D.
Sung-Soo Yoon, M.D., Ph.D.
Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, 81, Irwon-ro, Gangnam-gu, Seoul 06351, Korea (J.H.J.)
Division of Hematology/Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101, Daehak-ro Jongno-gu, Seoul 03080, Korea (S.S.Y.)
E-mail: J.H.J., jh21.jang@samsung.com
S.S.Y., ssysmc@snu.ac.kr

#These authors contributed equally to this work.
*This study was supported by Sanofi.

Received: April 22, 2022; Revised: June 23, 2022; Accepted: June 27, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background
Gaucher disease (GD) is an autosomal recessive disorder characterized by excessive accumulation of glucosylceramide in multiple organs. This study was performed to determine the detection rate of GD in a selected patient population with unexplained splenomegaly in Korea.
Methods
This was a multicenter, observational study conducted at 18 sites in Korea between December 2016 and February 2020. Adult patients with unexplained splenomegaly were enrolled and tested for β-glucosidase enzyme activity on dried blood spots (DBS) and in peripheral blood leukocytes. Mutation analysis was performed if the test was positive or indeterminate for the enzyme assay. The primary endpoint was the percentage of patients with GD in patients with unexplained splenomegaly.
Results
A total of 352 patients were enrolled in this study (male patients, 199; mean age, 48.42 yr). Amongst them, 14.77% of patients had concomitant hepatomegaly. The most common sign related to GD was splenomegaly (100%), followed by thrombocytopenia (44.32%) and, anemia (40.91%). The β-glucosidase activity assay on DBS and peripheral leukocytes showed abnormal results in sixteen and six patients, respectively. Eight patients were tested for the mutation, seven of whom were negative and one patient showed a positive mutation analysis result. One female patient who presented with splenomegaly and thrombocytopenia was diagnosed with type 1 GD. The detection rate of GD was 0.2841% (exact 95% CI, 0.0072‒1.5726).
Conclusion
The detection rate of GD in probable high-risk patients in Korea was lower than expected. However, the role of hemato-oncologists is still important in the diagnosis of GD.

Keywords: Acid β-glucosidase, Dried blood spot, Gaucher disease, Lysosomal storage disorder, Splenomegaly, Thrombocytopenia

Fig 1.

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Figure 1.Flow diagram of the disposition of patients.
Blood Research 2022; 57: 207-215https://doi.org/10.5045/br.2022.2022089

Fig 2.

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Figure 2.Acid β-glucosidase assay and GBA gene mutation analysis results.
Blood Research 2022; 57: 207-215https://doi.org/10.5045/br.2022.2022089

Fig 3.

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Figure 3.Abdominal CT showing huge splenomegaly before enzyme replacement therapy (2017).
Blood Research 2022; 57: 207-215https://doi.org/10.5045/br.2022.2022089

Fig 4.

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Figure 4.Abdominal CT showing reduced size of the spleen after ERT (2021).
Blood Research 2022; 57: 207-215https://doi.org/10.5045/br.2022.2022089

Table 1 . Demographic and clinical characteristics..

ParameterN=352
Age (yr)48.42±15.81 SD
Gender, N (%)
Male199 (56.53)
Female153 (43.47)
Weight (kg)66.95±13.51 SD
Height (cm)166.38±9.35 SD
Nationality, N (%)
Korean351 (99.72)
Non-Korean1 (0.28)
Method of diagnosis of splenomegaly*, N (%)
Magnetic resonance imaging250 (71.02)
Abdominal ultrasound81 (23.01)
Physical examination23 (6.53)
Computed tomography2 (0.57)
Others6 (1.70)
Duration of splenomegaly (days), median (range)90 (1–15629)
Size of splenomegaly, cm (N=223)14.57±3.40 SD
Hepatomegaly, N (%)52 (14.77)
Bone marrow biopsy result, N (%) [N=161]
No specific abnormality88 (25.00)
Specific abnormality73 (20.74)
Confirmed1 (0.28)
Unconfirmed160 (45.45)
Signs and symptoms related to Gaucher, N (%)
Splenomegaly352 (100.00)
Thrombocytopenia156 (44.32)
Anemia144 (40.91)
Hepatomegaly52 (14.77)
Bone pain14 (3.98)
Pathologic fracture1 (0.28)
Osteonecrosis1 (0.28)
Others41 (11.65)
Duration of signs and symptoms (days), median (range)338 (1–15629)

a)The data are presented as mean (standard deviation) unless otherwise specified. b)Duration of splenomegaly (days)=(date of informed consent-date of diagnosis of splenomegaly+1). c)Duration of signs and symptoms (days)=(date of informed consent-date of first onset+1)..

*Method of diagnosis and signs and symptoms were collected in duplicate for the same patient. If the symptoms of one patient were collected more than once, the duration of signs and symptoms used the maximum result..

Table 2 . Summary of laboratory parameters..

ParameterMean SDAbnormal laboratory values, N (%)
Hemoglobin, g/dL (N=348)12.21±2.73 SD181 (52.01)
WBC, ×103/L (N=349)8.19±21.88 SD147 (42.12)
RBC, ×106/L (N=349)4.07±0.92 SD181 (51.86)
Platelet, ×103/L (N=349)163.87±143.11 SD190 (54.44)
Serum iron, µg/dL (N=103)85.89±62.24 SD40 (38.83)
Serum ferritin, µg/dL (N=136)541.61±1099.10 SD56 (41.18)
Transferrin, mg/dL (N=15)144.94±123.09 SD7 (46.67)
BUN, mg/dL (N=296)15.54±8.70 SD57 (19.26)
Creatinine, mg/dL (N=329)0.97±1.15 SD93 (28.27)
SGPT, U/L (N=333)28.32±31.48 SD52 (15.62)
SGOT, U/L (N=333)31.16±43.33 SD64 (19.22)
Total bilirubin, mg/dL (N=331)1.10±1.20 SD77 (23.26)
Total protein, mg/dL (N=334)6.95±0.83 SD78 (23.35)
Albumin, g/dL (N=334)4.11±0.67 SD49 (14.67)

Abbreviations: BUN, blood urea nitrogen; RBC, red blood cells; SD, standard deviation; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase; WBC, white blood cells..
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