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有效期間：民國 91年07月16日 至 91年07月31日 止
    Case Discussion

<Case Presentation>

A 21-yer-old girl was admitted to this hospital because of jaundice for 5 months and goiter for 3-4 month.

The patient had been in excellent health until two years ago, when she began to have palpitation, hand tremor and easy perspiration. About one year ago she began to experience loose stools, heat intolerance, frequent insomnia, and yellowish discoloration of sclera and skin. She also noticed a weight loss from 58 kg to 40 kg and a decrease in duration and frequency of menstruation in recent half a year. Insidious onset of neck swelling and proptosis developed 2 months later. She visited a local hospital, where hyperthyroidism, anemia and hyperbilirubinemia were found. Propylthiouracil, propranolol and estazolam were prescribed. Her diarrhea improved after medication, but hand tremor, heat intolerance and palpitation persisted. Besides, she felt congestion and itching of both eyes. The patient was then admitted to this hospital for further evaluation.

The temperature was 37.4℃, the pulse was 120, and the respirations were 20. The blood pressure was 130/70 mmHg. Physical examination revealed that the patient had mild icteric skin and sclera. The conjunctiva was slight pale and the eyes were bulging out. The thyroid was diffusely enlarged (grade II) with bruit. There was no cyanosis or edema of extremities. Peripheral blood smear (Fig. 1) and laboratory tests were performed (Table 1~4)

Table 1. Hematologic Laboratory Values.

WBC
K/μl

RBC
M/μL

 Hb
 g/dL

Hct
 %

MCV
 fL

PLT
 K/μL  

Reticulocyte
 %

8.35

2.59

9.4

27.5

106.2

320

17.79


Reticulocyte index: 4.26%
Haptoglobin: <5.83 mg/dL (64.81-157.48)
Stool O.B.: negative

Table 2. Blood chemical values.

BUN
 mg/dL 		Cre
 mg/dL 		Na
 mmol/L 		K
 mmol/L 		Cl
 mmol/L 		Ca
 mmol/L 		AST
 U/l

11.4

0.76

141

3.9

104

2.14

35

T-BIL
mg/dL

D-BIL
 mg/dL

LDH
 U/L

TG
 mg/dL

T-CHO
 mg/dL

Glu AC
 mg/dL 

 

3.2

1.2

1194

129

163

102

 


Table 3. Urinary Analysis.

Sp Gr

PH

Protein
 mg/dL

Glu
 g/dL

O.B.

Urobil
 EU/dL

Bil

RBC
 /HPF

WBC
 /HPF

Cast
/LPF

1.010

6.0

–

–

–

1.0

–

0-1

0-1

–


Table 4. Thyroid function and immunologic profiles.

Free T4 (CIA)
 ng/dL

HsTSH (CIA)
 μIU/mL

T3 (RIA)
 ng/dL

AMA

ATA

0.87(0.6-1.75) 0.002(0.4-4) 185 (80-200) >20480 (<1:80) >20480 (<1:80)

ANA

C3
 mg/dL

C4
 mg/dL

Coombs test

Anti-DNA
IU/mL

1:1280+
(Speckle)		 53.1(81.61-118.41) 7.1(27.45±10.72) 4+ (direct)
3+ (indirect)		 4.6 (<12)


After admission, propylthiouracil 100 mg tid and propranolol 20 mg tid were prescribed for hyperthyroidism. The marked reticulocytosis, indirect hyperbilirubinemia, the elevated lactate dehydrogenase and the decreased haptoglobin level suggests that the patient had a hemolytic anemia. The positive results of direct and indirect Coombs tests led to the diagnosis of autoimmune hemolytic anemia. Prednisolone 50 mg qd was given and her hemoglobin returned to 15 g/dL in 1 month. She was in euthyroid status during the last follow-up at out patient clinic.

病案分析

本病例為毒性彌漫性甲狀腺腫合併自體免疫性溶血性貧血的罕見病例。毒性彌漫性甲狀腺腫, 即所謂的葛雷夫茲氏病(Graves’ disease), 在診斷上相當直接。 病人的臨床表現加上生化檢查證實有甲狀腺機能亢進, 觸診可見甲狀腺腫, 外觀可見到眼球突出, 抗微粒體抗體常為陽性反應, 再加上本人或其親人有自體免疫疾病史時, 就可確定其診斷。當病人甲狀腺機能亢進, 但缺乏其他表現時, 最可靠的輔助診斷方式是核醫的甲狀腺131I 造影 (radionucleotide 131I scan) 。 甲狀腺131I造影在葛雷夫茲氏病為彌漫性的碘高量攝取, 可將之與其他引起甲狀腺機能亢進的狀況, 如甲狀腺毒性結節、破壞性的甲狀腺發炎如橋本氏甲狀腺炎、異位的甲狀腺組織、或人為製造的甲狀腺毒症, 做很好的區分。本病人臨床表現非常典型, 故而無須安排甲狀腺131I 造影即可確立診斷。在治療上, 通常使用抗甲狀腺藥物 (thionamides類如methimazole carbimazole propylthiouracil) 合併非選擇性乙型阻斷劑 (propranolol) 及抗焦慮藥物來治療病人。也可選擇131I或手術方式來減少甲狀腺的大小, 達到控制甲狀腺機能的目的。 必須注意的是, 抗甲狀腺藥物本身也有許多可能的副作用出現。如: 藥物過敏、皮膚紅疹、發燒、關節痠痛、白血球特別是嗜中性球低下、肝機能異常、血管炎, 甚至溶血性貧血等等。

本病例較為特殊的表現為其黃疸。由於黃疸的出現在用藥以前就已開始, 初步可排除為甲狀腺藥物所導致。其黃疸為非直接膽色素為主, 且不超過5 mg/dL, 加上血球容積正常的貧血、haptoglobin低下、及LDH上升, 可很快得到溶血性貧血的結論。Direct 及 indirect Coombs’ tests均呈陽性反應, 加上週邊血液檢查可見到spherocytosis及polychromasia, 證實為自體免疫性溶血性貧血(autoimmune hemolytic anemia--AIHA)。治療方式為口服prednisolone (1 mg/kg/day), 通常在1-2星期後, 即可見到病人血色素的回升。此時再逐漸將類固醇的劑量調低, 並在之後的數個月, 慢慢將類固醇停掉即可。 若病人對類固醇反應不佳, 可考慮脾臟切除手術, 或使用其他免疫抑制劑如azathioprine 或 cyclophosphamide. 靜脈注射gamma球蛋白, 對急性控制溶血現象有幫助, 但長期效果不明。

繼續教育考題
1.
(A)		 About Graves’ disease, which of the following statements is incorrect?
AHigh iodine intake is associated with a decreased prevalence of Graves’ disease. 
BGraves’ disease occurs in up to 2% of women but is one-tenth as frequent in men. 
CExtrathyroidal manifestations such as ophthalmopathy and dermopathy are due to immunologically mediated activation of fibroblasts.
DIn the elderly features of thyrotoxicosis may be subtle or masked, so-called apathetic hyperthyroidism. 
EAll of the above statements are correct.
2.
(C)		 A 28-year-old woman presented with palpitations, heat intolerance and nervousness about 3-4 weeks after delivering a baby. Her thyroid is hard but non-tender. The 24-hr radioactive 131I scan of thyroid is 1% of uptake. The most appropriate treatment for this woman is
AMethimazole.
BRadioactive iodine ablation of her thyroid gland.
CA beta-blocker.
DLithium.
EPrednisolone 50 mg/day followed by a rapid taper.
3.
(D)		 About Graves’ ophthalmopathy, which of the following statements is incorrect?
AA. The extraocular muscle most commonly involved is the inferior rectus, limiting upward gaze.
BLoss of vision from optic nerve compression is the most serious manifestation.
CUpper limits of normal proptosis measured with Hertel exophthalmomter are 18 mm in oriental, 20 mm in white and 22 mm in black.
DRadioiodine treatment for hyperthyroidism has beneficial effects on the eye diseases in most patients.
EAll of the above statements are correct.
4.
(B)		  If the woman diagnosed with Graves’ disease discovers she is pregnant, appropriate therapy includes
AA beta-blocker followed by surgical volume reduction of thyroid gland.
BPropylthiouracil therapy to maintain her thyroid function in high normal or slightly high range.
CMethimazole therapy to maintain high normal thyroid function status.
DPropylthiouracil to maintain her thyroid function in the mid-normal range.
ERadioactive iodine to ablate her thyroid gland.
5.
(E)		 If the patient treated with antithyroid drug develops adverse reactions, which of the following management is inappropriate?
AAllergic reaction such as a rash can be managed by simply administering antihistamine.
BAgranulocytosis requires immediate cessation of all antithyroid drug therapy.
CShifting to an alternative therapy such as radioactive iodine is feasible if serious adverse effects to antithyroid drugs occur.
DCholestatic jaundice and hepatocellular toxicity also require cessation of drug therapy.
EAl l of the above managements are correct.
6.
(C)		 Which of the following medication for hyperthyroidism cannot inhibit the conversion of T4 to T3?
APrednisolone.
BPropylthiouracil.
CMethimazole.
DPropranolol.
EIpodate sodium.
7.
(A)		 About the diagnosis of autoimmune hemolytic anemia, which of the following is incorrect?
AThe direct Coombs test uses antibodies specific for immunoglobulin to agglutinate RBC when these globulins are present in sera.
BIndirect Coombs test uses normal RBC to incubate with patient’s serum and IgG antibody is detected with anti-IgG.
CAntibodies that react with protein antigens are nearly always IgG and react at body temperature.
DAntibodies that react with polysaccharide antigens are usually IgM and react better at temperature lower than 37oC.
ETransient cold agglutinins occur commonly in infectious mononucleosis.
8.
(E)		 The characteristic findings of peripheral blood smear in patients with autoimmune hemolytic anemia includes all of the followings except:
ASpherocytosis.
BHypochromic macrocyte
CPolychromasia.
DNormoblast.
EAll of the above may be found in the blood films.
9.
(E)		 A 45-year-old man with a history of non-Hodgkin’s lymphoma presents with fatigue and purple discoloration of the fingertips, ears, and nose. Laboratory studies include: WBC 10,000/μl, Hct 28%, Hb 7.8 g/dl, MCV 98 fL, LDH 600 IU/L, total bilirubin 3.0 mg/dl and direct bilirubin 0.3 mg/dl. Peripheral blood smear reveals clumped RBCs and direct Coombs test is negative. Additional laboratory testing would likely reveal the following results:
APositive direct Coombs test if specimen is processed without allowing cooling.
BPositive indirect Coombs test detected with IgG antibodies.
CCirculating antibodies against mycoplasma.
DCirculating antibodies against Epstein-Barr virus.
ECirculating antibodies against fetal RBCs.
10.
(D)		 Which of the following is not a cause of immune hemolytic anemia?
AWarm-reactive (IgG) antibody.
BCold-reactive (IgM) antibody.
CDrug-dependent antibody.
DThrombotic thrombocytopenic purura.
ECold-reactive (IgG) antibody with paroxysmal cold hemoglobinuria.

 

答案解說
  1. (A ) Graves’ disease accounts for 60-80% of thyrotoxicosis, the prevalence depends mainly on iodine intake, and high iodine intake is associated with an increased prevalence of Graves’ disease.
  2. (C) The patient has a destructive thyroiditis—postpartum thyroiditis that occurs in 5-9% of postpartum women. Since the thyrotoxicosis is transient and caused by the release of preformed thyroid hormone from a damaged thyroid gland, therapy is symptomatic with a beta-blocker with or without an anxiolytic agent. The thyrotoxicosis usually resolves spontaneously and steroid is unnecessary.
  3. (D ) Some studies suggest that Radioiodine treatment for hyperthyroidism worsens the eye disease in a small portion of patients especially smokers. A course of prednisolone immediately following radioactive iodine therapy will prevent the worsening of thyroid eye disease.
  4. (B) Radioiodine should never be given to a pregnant woman due to its potential teratogenicity. Beta-blockers may lead to neonatal hypoglycemia and is not suitable in pregnant woman. Methimazole increases the incidence of aplasia cutis, a fetal scalp defect, and should be avoided in pregnant woman. When a pregnant woman is in mid-euthyroid status, her fetus is hypothyroid. The treatment of choice in pregnant woman with Graves’ disease is propylthiouracil, which crosses placenta in minimal amount, and maintains a mild maternal hyperthyroidism.
  5. (E) Mild skin rash can be managed by simply administering antihistamines and it is not an indication for discontinuing drug therapy. Agranulocytosis is heralded by sore throat and fever, all patients receiving antithyroid drugs are instructed that if sore throat or fever develops, they should stop the drug and obtain a white blood cell and differential count, and see their physician. Besides, cholestatic jaundice, hepatocellular toxicity, and hemoptysis (indicating a vasculitis) are serious but rare side effects that also require cessation of drug therapy.
  6. (C) Propylthiouracil has one advantage over methimazole in that it partially inhibits the conversion of T4 to T3, quickly brining down the levels of activated thyroid hormone, and is more suitable in the initial treatment of thyrotoxic crisis.
  7. (A) Direct Coombs test (DAT) relies on the ability of antibodies specific for immunoglobulins to agglutinate RBC when these proteins are present on the RBC. The DAT measures the ability of anti-IgG antisera to agglutinate the patient’s RBC that is already coated with IgG. The indirect Coombs test, in which the serum of the patient is incubated with normal RBC and antibody is detected with anti-IgG, measures the ability of anti-IgG antisera to agglutinate the RBC when the IgG is presented in patient’s serum.
  8. (E) New RBCs released early from the bone marrow may be found in the blood films of patients with AIHA. The spherocytosis seen in autoimmune hemolytic anemia may be indistinguishable form those in hereditary spherocytosis. Because hemolysis is often more severe,there may be a prominent populatino of hypochromic and normochromic macrocypes.
  9. (E) The patient suffers from so-called cold-reactive hemolysis that is most likely related to his lymphomatous neoplasm. The specificity of the cold agglutinin antibody may be helpful in that a reaction with adult RBCs compared with fetal (cord) RBCs is more common in benign lymphoproliferative disorders. Antibodies that react more strongly with fetal RBCs compared with adult RBCs are generally seen in lymphomas.
  10. (D ) Thrombotic thrombocytopenic purura is a disease resulting from agglutination of platelets, which is mediated by unusually large multimers of von-Willebrand factor. The localized platelet thrombus caused microangiopathic hemolytic anemia and is a kind of traumatic hemolytic anemia.
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