Chi nese Med i cal Jour nal (Taipei) 2001;64:735-738
Case Re port
Propylthiouracil-induced Hemolytic Anemia Chin-Sung Kuo1,3 Jeong-Shi Lin2,3 Hong-Da Lin1,3 1
Di vi sion of En do cri nol ogy and Me tab o lism, Di vi sion of Trans fu sion Med i cine, De part ment of Med i cine, Tai pei Vet erans Gen eral Hos pi tal; and 3National Yang-Ming Uni ver sity School of Med i cine, Tai pei, Tai wan,R.O.C.
2
Key Words hemolytic ane mia; hyperthyroidism; propylthiouracil
Propylthiouracil (PTU)-in duced hemolytic ane mia is ex tremely rare. We re ported a case of Graves’ dis ease with these un usual clin i cal manifestations. A 41-year-old fe male pre sented with re cur rent at tacks of severe hemolytic ane mia af ter PTU ther apy. Sugar wa ter test and ery thro cytes os motic fra gil ity test re vealed no cel lu lar mem brane de fect of red blood cells. Antinuclear antibody, direct and indirect Coombs’ tests were all neg a tive and glu cose-6-phosphate dehydrogenase ac tivity was also within nor mal lim its. PTU was not dis con tin ued promptly due to unrecognizableness of such a rare case until two months later with re cur rent at tacks of se vere hemolytic ane mia. I-131 ther apy was performed on suspicion of related hemolytic anemia. Unfortunately, chal lenge of PTU oc curred in ci den tally af ter dis con tinu a tion of PTU fol lowed by se vere hemolytic ane mia. The di ag no sis of PTU-induced hemolytic ane mia was es tab lished there af ter. A MEDLINE search revealed only one such case re ported in Eng lish lit er a ture. This is the first case re port in Tai wan. It should be kept in mind that hemolytic ane mia may be a rare com pli ca tion of PTU ther apy. [Chin Med J (Taipei) 2001;64:735-738]
P
ropylthiouracil (PTU) is com monly used in the treat ment of hyperthyroidism, and is re ported to have sev eral ad verse ef fects such as antineutrophil cyto plas mic an ti body (ANCA)-as so ci ated vasculitis,1 Wegener’s granulomatosis, 2 hepatotoxicity,3 agran ulocytosis, 4 aplastic ane mia, 5 med i ca tion-induced systemic lupus erythematosus 6 and rheu matic syn dromes with or without associated serum antinuclear antibody7,8 and splenomegaly. 9 In MEDLINE search, we found only one child re ported pre vi ously in Eng lish as PTU-induced hemolytic anemia. 10 We described a wom an with Graves’ dis ease who de vel oped hemolytic ane mia af ter PTU ther apy.
C ase Report A 41-year-old woman fol lowed at Tai pei Vet erans Gen eral Hos pi tal since Au gust 1992 when, at 33 years
of age pal pi ta tion was com plained. There was no family his tory of Graves’ dis ease. Phys i cal ex am i na tion revealed dif fuse grade II goi ter and tachy car dia with a rate of 108 beat/min. Initial laboratory studies im pressed the diagnosis of Graves’ disease: thyroxine (T4) 24.20 µg/dl (6.0 - 12.0 µg/dl), free thy rox ine (fT4) > 4.5 ng/dl (0.70 - 2.2 ng/dl), tri-iodothyronine (T3) 719 ng/dl (85-165 ng/dl), thy roid-stimulating hor mone (TSH) 0.04 µU/ml (0.4 - 3.1 µU/ml), anti- thy roglobulin antibody non-reactive and anti- micro somal an ti body 1:400. Treat ment with carbimazole was started, 30 mg daily in divided doses. Microcytic anemia was also noted at the same time: hemoglobulin 10.4 mg/dl (12 16 mg/dl), mean cor pus cu lar vol ume (MCV) 79.4 fl (81-99 fl). After 3 months of therapy, she became euthyroid clin i cally and bio chem i cally with ta per ing dos age of carbimazole. The rou tine fol low-up ex am ination done on June 23, 1993 showed nor mal hemoglobulin level (12.8 g/dl) and nor mal MCV value (84.6
Re ceived: February 15, 2001. Ac cepted: September 7, 2001. Cor re spon dence to: Hong-Da Lin, MD, Di vi sion of En do cri nol ogy and Me tab o lism, De part m ent of Med i cine, Tai pei Vet erans Gen eral Hos pi tal, 201, Sec. 2, Shih-Pai Road, Tai pei 112, Tai wan. Fax: +886-2-2874-5674; E-mail:
[email protected]
736
Chin-Sung Kuo, et al.
fl) af ter 10-month carbimazole ther apy. Un for tu nately, the followup turned ir reg u lar since June 1993. The pa tient ex pe ri enced sev eral times of hyperthyroid flare-up and re ceived carbimazole therapy off and on. The pa tient dis con tin ued anti-thyroid drug ther apy dur ing 1996 and 1997 al though she was still hyperthyroid bio chem i cally. She took PTU 150 mg daily in di vided doses for 7 days in Feb 1998, and re ceived reg u lar PTU ther apy since Au gust 21, 1998 due to ex ac er bated symp toms in clud ing pal pi ta tion and tremor of hands. On Dec 1, 1998, she was ad mit ted due to headache, dizziness, weakness and limbs numbness for about 3-4 days. The lab o ra tory data showed hemoglobulin 5.7 g/dl, MCV 86.6 fl, reticulocytes count 4.66%, hepatoglobulin < 13 mg/dl, ferritin 210 ng/ml (10-300 ng/ml), glu cose-6-phosphate dehydrogenase (G-6-PD) 12.5 U/G HB (7.3-18.4 U per gram hemoglobulin), mildly el e vated se rum uric acid, po tas sium and di rect bil i ru bin (Ta ble 1). The ANA, Coombs’ test (di rect and in di rect) and sugar wa ter test were all nega tive. Af ter packed RBC trans fu sion 500 cc, she was discharged with hemoglobulin 9.5 g/dl on Dec 5, 1998. PTU ther apy con tin ued at the Out pa tient De partment. On Dec 16, 1998, she was ad mit ted again due to the same symp toms. The lab o ra tory data showed severe hemolytic ane mia with high reticulocytes count (Ta ble 1). The anti nuclear an ti body (ANA), Coombs’ test (di rect and in di rect) and sugar wa ter test were still neg a tive. Se rum com ple ment lev els showed mildly de creased C3, 81 (90-180) mg/dl and nor mal C4, 31.8 (10-40) mg/dl. She received 1500 cc packed RBC trans fu sion and prednisolone 40 mg daily dur ing this ad mis sion. PTU in duced hemolytic ane mia was suspected. There fore, PTU was dis con tin ued. I-131 therapy was sched uled on Jan 16, 1999 with 84% up take of I-131at 24 hrs. The pa tient was dis charged on Dec 23, 1998 and readmitted on Dec 29, 1998. Severe hemolytic ane mia oc curred again (Ta ble 1). She received 1000 cc packed RBC trans fu sion and decadron ther apy. Eryth ro cytes os motic fra gil ity test re vealed 10% hemolysis at 0.43% NaCl (con trol: 0.5-0.45%); 90% hemolysis at 0.28% NaCl (con trol: 0.40-0.35%). In ci den tal chal lenge of PTU oc curred on Feb 1, 1999 while she suf fered from pal pi ta tion and tremor of hands post I-131 ther apy. She felt head ache, diz ziness and numb ness of limbs with tea-color urine soon
Chi nese Med i cal Jour nal (Taipei) Vol. 64 No. 12
af ter PTU chal lenge. She did not visit our hos pi tal until Feb 8, 1999, while the symptoms persisted. The lab o ra tory data showed hemoglobulin 6.6 g/dl, hepatoglobulin 28.5 mg/dl and reticulocytes count 6.6%. She was ad mit ted and treated with packed RBC transfu sion and decadron ther apy. Af ter dis charge, she received prednisolone ther apy. She had been away from PTU af ter the in ci den tal chal lenge of PTU. The hyperthyroidism im proved a lot as it elapsed since I-131 ther apy, and the euthyroid state came even tu ally. In May 1999, she dis con tin ued prednisolone by her self, and se vere hemolytic ane mia re ap peared. The hemoglobulin level was 8.8 g/dl on July 7, 1999. Packed RBC 2 units were trans fused and prednisolone therapy was resumed. The follow-up lab o ra tory data showed pro longed low hepatoglobulin level with mild ane mia al though head ache, diz zi ness and numbness of limbs disappeared. She required low-dose prednisolone (2.5 mg per day) to control hemolysis un til Oct 25, 2000, when she dis con tin ued prednisolone by her self again. She was well with out low-dose prednisolone ther apy un til Jan, 2001.
D iscussion PTU-induced hemolytic ane mia is ex tremely rare. To our knowl edge, only one case has been re ported:10 a 5 1/2 year-old girl with hyperthyroidism who received PTU 200 mg daily in divided doses. Af ter 18-month ther apy, the pa tient suf fered from hemolytic ane mia (the low est Hgb 10.2 g/dl) and granulocytopenia (2500/mm3, 2% polymorpho nu clear neu tro phils). The di ag no sis was con firmed by chal lenge of low dose (25-50 mg daily) of PTU 2 months later when both hemolytic ane mia and granulocytopenia followed. After 1-year followup, hemolytic ane mia and granulocytopenia did not re cur after PTU dis con tinu a tion. In our case, the pos si bil ity of cel lu lar mem brane de fect of red blood cells was ex cluded by sugar wa ter tests and erythrocytes osmotic fragility test. ANA, Coombs’ tests and cryoglobulin were all neg a tive. Inci den tal chal lenge of PTU es tab lished the di ag no sis. How ever, it was some what dif fer ent from the pre viously re ported case in which pro longed low se rum hepatoglobulin level with sus pected mild hemolytic ane mia per sisted for 19 months af ter PTU dis con tinu-
December 2001
Propylthiouracil-induced Hemolytic Ane mia
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Table 1. Clinical course of propylthiouracil-induced hemolytic anemia Date
Hgb (12-16 g/dl)
Aug/26/92 Jun/15/93 Jan/95 Jan/6/98 Aug/24/98 Dec/2/98 Dec/5/98 Dec/16/98 Dec/21/98 Dec/29/98 Feb/1/99 Feb/8/99 Apr/24/99 Jun/7/99 Nov/17/99 May/18/00 Sep/16/00 Oct/18/00 Oct/25/00 Nov/15/00
11.2 12.8 12.0 12.2 11.4 6.2 9.5 6.2 9.5 5.9 9.4 6.6 11.5 8.8 12.2 12.2 11.6 12.0 11.9 11.4
MCV Reticulocytes Hepatoglobulin Total/direct (81-99 count (%) (70.3-379 bilirubin (mg/dl) fl) mg/dl) (0.2-1.6)/(0-0.3) 79.4 84.6 82.6 80.1 81.8 81.9 85.7
91.5 95 96.7 97.8 93.4 91.7 93.3 90.8 93.0 91.5
Uric acid (1.8-6.2 mg/dl)
TSH (0.4-3.1 µU/ml)
Free T4 Propylthiouracil Carbimazole (0.70-2.2 50 mg tid 10mg tid ng/dl)
4.69
< 13
1.3/0.4
7.0 7.8
0.04 0.12 1.89 0.13 0.062 0.019
4.59
< 13
2.2/0.5
9.6
0.015
2.33
4.52 3.09 8.71 3.69
< 13
2.4/0.7
8.7 < 0.006
2.46
0.09
0.71
0.65
1.21
6.4
28.5 13
2.14 1.82 2.79 2.08
27.4 < 13 20.3 24.2
2.64
33.9
0.5/0.1
12.2
1.9/0.6 1.0/0.2 1.3/0.3 1.2/0.2
10.9
> 4.5 3.72 1.13 > 4.5 > 4.5 1.28
Discontinued
Hgb = hemoglobulin; MCV = mean corpuscular volume; TSH = thyroid-stimulating hormone; T4 = thyroxine; arrow line = therapy period; dashed arrow line = irregular therapy period.
ation. Granulocytopenia did not occur in our case (data not shown). There were two pos si ble ex pla nations for the clin i cal course. First, the de lay in re covery of mild hemolytic ane mia af ter PTU ther apy was due to the prolonged effect of PTU itself. The hemolytic ane mia was fi nally re solved with out any med i ca tion af ter dis con tinu ance of PTU. Such course has not been re ported in the lit er a ture. Sec ond, the patient might suf fer from subclinical id io pathic hemolytic ane mia with acute ex ac er ba tion by PTU ther apy. No matter which possible explanation was, it was wor thy to re port the rare case. The pathophysiology of PTU-induced hemolytic ane mia is un known. The hemolytic ane mia would be trig gered by PTU-induced autoantibody due to mildly de creased C3 on Dec 17, 1998. The man age ments of PTU-induced hemolytic ane mia in clude prompt discon tinu a tion of PTU. In this case, ste roid is use ful for the con trol of the hemolysis. We re port this case to show that hemolytic ane mia may be one of the compli ca tions of PTU ther apy.
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