FEBRUARY,
1977
Aust. N.Z. J. Med. (1977), 7, pp. 27-32
Use of a Computer-based Postal Questionnaire for the Detection of Hypothyroidism Following Radioiodine Therapy for Thyrotoxicosis 1. C. Harrison", J. D. Buckleyt and F. I. R. Martin1 From the University of Melbourne Department of Medicine and the Endocrinology Department, Royal Melbourne Hospital
SUrnmaI'y: Use of a computer-based postal questionnaire for the detection o f hypothyroidism following radioiodine therapy for thyrotoxicosis. L. C. Harrison, D. Buckley and F. I. R. Martin, Aust. N.Z. J. Med., 1977, 7, pp. 27-32. A computer-processed postal questionnaire was devised to detect hypothyroidism in patients treated previously for th yrotoxicosis with radioiodine. I n a study of 232 patients treated with ' 311 at the Royal Melbourne Hospital between four and ten years previously, the sum of symptomatic answers in the questionnaire was a sensitive discriminator of hypothyroidism, and alto w e d 80% of euthyroid patients to be excluded from further assessment. Questions concerned with general well-being and energy, voice and skin changes, showed the highest sensitivity and specificity. The combination of these questions alone was an effective means of identifying hypoth yroidism, with a sensitivity and specificity comparable to the more sophisticated technique of discriminant function analysis. Hypothyroidism had an incidence of between 20% and 35% six t o eight years after ' " I therapy and was related to a smaller initial goitre size for a given dose of j 3 ' 1 . This postal questionnaire, in conjunction with a computer-based automatic recall system, promises to be an efficient and reliable screening tool for the detection of hypothyroidism in the increasing number of patients 'bt risk" following ' 3 1 I therapy.
It is now generally recognised that the control of thyrotoxicosis by either thyroidectomy or radioiodine is accompanied by a significant risk of hypothyroidism. The cumulative ten year 'Senior Lecturer, University of Melbourne, Department of Medicine. Royal Melbourne Hospital. Wesearch Fellow. Walter and Eliza Hall Institute, Melbourne. $Endocrinologist, Royal Melbourne Hospital; Professorial Associate, University of Melbourne, Department of Medicine Correspondence: Dr. L. C. Harrison, .. Department of Medicine, Royal Melbourne Hospital PO, Victoria 3050 Accepted for publication: 17 August, 1976
incidence of hypothyroidism ranges from 5 "(,49"" after surgery' and from 30""-70", after l3'L2 The high incidence, 7°,-220,, of hypothyroidism in the first year after I3lI therapy is followed by a steady increase of 2 ",-5 O 0 per annum without evidence of a plateau2, implying that hypothyroidism may be an inevitable outcome. Its early occurrence appears to be correlated with the dose of I 3 ' I relative to the thyroid gland size3, and is much greater after "radical" than after "conservative" thyroidectomy.' However, after low dose I 3 l I therapy or conservative surgery the speed and frequency of remission of thyrotoxicosis is lower and the later incidence of hypothyroidism, although less, is still appreciable.', It is estimated' that by 1980 there will be approximately 240,000 cases of post-treatment hypothyroidism in the United States; and according to current treatment trends most of these will have followed I3'I therapy. The results of 311treatment previously reported from the Royal Melbourne Hospitals-7 and from the Royal Prince Alfred Hospital, Sydney*, are similar to those from centres overseas. Assuming an incidence of thyrotoxicosis similar to that in the United States, there are probably close to 20,000 individuals in Australia with hypothyroidism (treated or untreated) following treatment fof thyrotoxicosis. Although the treatment of hypothyroidism with thyroxine is nearly always both simple and satisfactory, recognition of the condition is often not easy. People with mild or even moderate hypothyroidism may not consult a doctor, or may remain undiagnosed, because of the insidious and non-specific nature of their symptoms.6 The increasing number of patients who require follow-up after treatment of thyrotoxicosis has led to attempts to find sensitive and specific screening methods for the prediction and detection of hypothyroidism. As
'
28
HARRISON ET AL.
yet, no single biochemical index of thyroid function satisfies the requirements for an ideal screening test. An alternative procedure, pioneered in Great Britain, is the use of a diagnostic index based on the patient’s responses to a questionnaire designed to elicit symptoms of hypothyroidism. We describe here the use of a computer-processed postal questionnaire designed to detect hypothyroidism in patients previously treated with I 3 ’ I at the Royal Melbourne Hospital. Methods The questionnaire contained 13 questions as listed in Table 2, each question requiring a simple YES or NO answer. In 1974-75 the questionnaire was given or mailed to 250 patients previously treated with ‘311 for thyrotoxicosis at the Royal Melbourne Hospital. The patients consisted of all those treated initially in 1967 (1 10 patients), a previously well-documented group’ treated initially in 1968--69 (Y3 patients), and a miscellaneous group treated initially at other times between 1965 and 1972 (47 patients). The last group were currently attending the Thyroid Clinic for routine follow-up. The questionnaire contained a n explanatory note, a request for information on current medication and the name and address of the local doctor, and a stamped, addressed envelope for return mailing. In addition, each patient was requested to attend the hospital for a blood sample to be taken, or, in the case of country patients for this to be done locally and the sample forwarded. Blood samples were analysed for plasma thyroxine (T4) by competitive prokin binding, and for plasma triiodothyronine (T3) and plasma thyroid stimulating hormone (TSH) by radioimmunoassay. Subsequently, where possible, the survey results were sent to the local doctor. Patients were classified as euthyroid on the basis of normal T4, T3 and TSH levels and/or after clinical assessment. Those with T4 or T3 levels outside the normal ranges and those of doubtful clinical status were recalled for retesting and reassessment. Hypothyroidism was ultimately diagnosed on the basis of both biochemical and clinical
VOL.
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criteria. The questionnaire answers. together with accompanying data on age, sex, date and dose(s) of l 3 l I , thyroid replacement therapy, T4. T3 and TSH values were punch-coded and analysed by a Cyber 72 computer. using SPSS programmes.’ Results
The number of questionnaires returned was inversely related to the interval since treatment. A follow-up letter requesting co-operation was mailed to all “non-responders”, but added little to the final yield. 83”,, of patients in the 1968-69 treatment group responded, compared to 65 of patients in the 1967 treatment group. The majority of “non-responders” were designated by the Post Office as “address unknown”. Ultimately, by contacting the former local doctor, by scanning the telephone directory, or by searching other records in the hospital, it was possible to trace all but 5 O D of the 1968-69 group and all but 9 ” ” of the 1967 group. ilnalysis of Duta
Forty-five of the 233 “responders” had been previously diagnosed as hypothyroid and were on replacement therapy. Nine “responders” were diagnosed,for the first time, on the basis of both biochemical and clinical criteria, as being unequivocally hypothyroid (Table 1). In this group the mean number of symptomatic answers was 9 . 7 (standard deviation 1 ‘4, range 7-1 1) compared to 4 . 5 (standard deviation 3 ‘0, range 0-12) in those classified as euthyroid. The difference between the mean scores of the two groups was highly significant ( P < 0.001).
TABLE I Data on newly-diagnosed hypothyroid patients
-.
Patient
__ T4
Respor&es to questions 1 - 13t
Biochemistry* .__.~__
36 34 51 27 30 14 18 21 ‘4
.____
T3
TSH
-
19.6 26.5 61.6
0.85 0.90 1.30 0.75 0.30 0.60 0.65 0.90
17.5
22.0 19.6 81.0 45.4 31.0
I
2
3
4
5
+ + + + + + + +
+ + + + + + + +
+ + + + + +
+ + + + + + + +
+ + + +
+
-
-
-
*Normal ranges: T4 50-135 nmol/l, T3 1.4-2.8 nmol/l, TSH 0.5--5.0 yU/ml.
t(+ ) denotes a symptomatic respmse.
6
7
+ + + + + + +
+ + + + + +
8
+ + + + + - +
9 1 0 1 1 1 2 1 3
+ + + + -
+ + + + - - + + - +
+ + + + + f + -
+ - + + + +
+ + + + + + - + + + +
FEBRUARY,
1977
29
QUESTIONNAIRE DIAGNOSIS OF HYPOTHYROIDISM
TABLE 2 Most sensitive and specific questions for identifying hypothyroidism ~
Question
Hypothyroid patients with symptom ( ' I < , )
1. Do you feel as well now as you did two years ago? 2. Have you become slower (physically or mentally)? 3. Do you feel the cold more so than before? 4. Has your voice become hoarse, huskier or weaker? 5. Have your bowels become less regular, or constipated? 6. Are you getting puffy around the eyes. or any fuller in the face? 7. Has your hair become drier or thinner, or more difficult to manage? 8. Have you put on weight over the past two years? 9. Have you noticed that you prefer the warmer weather more so than before? 10. Has the skin of your arms become drier or rougher? 11. Have you been troubled by any numbness, tingling or pins-and-needles in the hands'? 1 2 Have you been troubled by muscular aches and pains or cramps more so over the past two years? 13. Do you feel less energetic now than you did two years ago?
Euthyrotd patients without symptom ( " J
I00 89
69 51
67
63
89
82
56 67 67 67 44
83
79 58
59
89
70 81
78
57
56 100
52 45
89 89 89 89
91 89 91 90
Question combinations 1f 4 If10 I + 4 + 13 1 10+ I3
+
A "cut-off' point of eight or more symptoms would have included all but one (890;) of the hypothyroid patients and 45 (20"J of the euthyroid patients. The questions, or combinations of questions, with the highest sensitivity (highest percentage of true positive answers) and specificity (highest percentage of true negative answers) for identifying hypothyroidism are shown in Table 2. Questions 1, 4 and 10 each had the required high degree of sensitivity and an acceptable degree of specificity. The combination of some questions, shown in the lower half of the table, significantly improved specificity. Answers were also examined by discriminant function analysis, a technique which gave a weighting to each symptom. This method had a sensitivity of 890; and a specificity of S O , . In other words, all but one of the hypothyroid patients were correctly classified and only eleven of the euthyroid patients were misclassified. Relationship to Biochemical Indices of Thyroid Function Analysis of the combined euthyroid and hypothyroid patient data showed that the total
number of symptoms elicited was significantly correlated with T4 ( r = -0.315, P < 0.001), T3 (r = -0.332, P < 0.005),TSH ( r = +0.393, P < 0.001) and the T4.T3 product ( v = -0.355, P < 0.005). Stepwise multiple linear regression of symptoms versus T4, T3, TSH or the T4.T3 product showed that in each case question 10 was the one accounting for most of the variance. Subsequent symptoms chosen were of little further predictive value and were different for each biochemical index. Each biochemical index was examined in relation to the presence, or otherwise, of a symptomatic answer to each question. The only question associated with a significant difference in all three biochemical indices between symptomatic and non-symptomatic responders was question 10. Late Incidence of Hypothyroidism This was determined for the 1967 and 1968-69 treatment groups, where almost complete follow-up was achieved. The 1967 group received a mean dose of 6 . 8 mCi I3'I (standard deviation 1.5) and had an eight year incidence of hypothyroidism of 35".,. The 1968-69 group, all of whom received a standard dose of 5 mCi 13'1, had a 6-7 year incidence of hypothyroidism of
30
HARRISON ET A L .
20 O n . There was no difference between hypothyroid and euthyroid patients with respect to mean age at the time of treatment, initial clinical state and thyroid function tests, number of I 3 l I doses administered, and, in the 1968-69 group, initial and maximum serum levels of the Long-Acting Thyroid Stimulator (LATS). However, in the 1968-69 group, given a standard I 3 ' I dose, the frequency of initial goitre size in patients becoming hypothyroid was 24 for grade 0 goitre (impalpable)and 6 ", for grade 3 goitre (large), compared with 4", and 21 0 , respectively in patients remaining euthyroid. Discussion
Thyroid disease was one of the first conditions in which statistical techniques were applied to obtain diagnostic and prognostic significances of different symptoms. Since no one symptom is specific for hypothyroidism, the development of a diagnostic index has relied on the weighting of different symptoms, or on the combination of symptoms." Recognition of hypothyroidism as the main delayed side-effect of I3'I therapy and the need to screen an ever-enlarging patient population provided the stimulus for the practical application of this technique, first pioneered by Scottish workers in Glasgow" and Aberdeen'z.'3 and now adopted by a number of other centres elsewhere in Great Britain. The questionnaire used in the present study is similar to that currently in use in Birmingham.14, l 5 The symptoms chosen were those thought to be most reliable in the clinical diagnosis of hypothyroidism ; most are common to the questionnaires in use in other centres. Some symptoms, for example loss of taste and hearing, were excluded because it was felt that they would require a more elaborate written question, and were probably better considered as signs. A screening procedure for hypothyroidism must satisfy two basic criteria. Firstly, it must have a very small probability of missing cases (high sensitivity), since treatment is so simple and effective. Preferably as well, the proportion of misclassified euthyroid patients, or false positives, who need to be recalled and reassessed should be small (high specificity). Secondly, the screening procedure should cover all "at
VOL.
7,
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1
risk" patients ; its value is negated by incomplete follow-up. We are satisfied that the present investigation fulfils both of these criteria. The number of newly-diagnosed hypothyroid patients in our study was relatively small, but the trends in the results are similar to those in other studies. The simple addition of symptoms was as sensitive a discriminator of hypothyroidism as the use of more sophisticated techniques, a finding recently made by Gardner and BarkerI5 in a comparison of statistical techniques used for analysing the Birmingham data. However, the combination of symptoms or the use of discriminant function analysis significantly improved the specificity of the questionnaire. Analysis of the Birmingham data produced similar results", but the degree of specificity achieved was less than in the present study. This may be a reflection of the small number of hypothyroid patients selected from within our more homogeneous population. A screening procedure may give better results in the hands of those who devise and first apply it, than when used generally. It remains to be seen whether the application of the diagnostic rules from the current set of data to patients followed prospectively will remain valid. In this regard it is interesting to note that skin and voice changes, the most specific symptoms in the present study, were the most specific signs in the Birmingham study.I4 On the other hand, the weighting of some symptoms is likely to differ from one community to the next, depending on social and geographical factors. For instance, cold intolerance, long considered to be an important symptom of hypothyroidism, did not rate highly in this Melbourne study, yet was the most sensitive symptom in the analysis of the Birmingham results.' The requirement for complete follow-up takes on special meaning when screening a potentially hypothyroid population. Hypothyroid individuals are less likely to respond to a postal questionnaire. The point is illustrated by the case of orle lady who failed to respond to two letters and whose telephone number was then obtained from the directory. One of US (L.H.) rang the number, and, after a very long wait, was finally rewarded by a diagnostic,
'
FEBRUARY,
1977
31
OLJESTIONNAIRE DlAGNOSlS OF HYPOTHYROIDISM
slow, croaky voice answering at the other end. The main cause of incomplete follow-up was a change in address: this will pose a continuing problem in Australia. The correlation of each biochemical index of thyroid function with the total number of symptoms provides biological support for the validity of the questionnaire, and suggests that there was a continuum between the normal euthyroid state and hypothyroidism. The question about skin changes had the greatest predictive value for each biochemical index. This question, also, was the only one associated with significant differences in all three biochemical indices between those with, and those without the symptom. A request for a thyroid function test, in conjunction with the questionnaire, has been the routine practice overseas.'2-14 Full biochemical assessment is needed on all patients if one decides not ro run the risk of a missed diagnosis. However, this then negates the value of the questionnaire. Prospective experience with the present questionnaire will enable us to assess the value of ancillary blood tests. The present study suggests that T4, T3 or TSH correlate equally well with the clinical picture. However, TSH, usually considered to be a sensitive index of hypothyroidism, may not be reliable in these circumstances, since Toft et a/.' have shown that it is elevated in a significant number of euthyroid patients 6-18 years after 1 3 1 1 therapy, but that only 2 "*-5 ",, develop overt hypothyroidism each year. The incidence of hypothyroidism in the two groups of patients followed-up almost completely was 35"" in the eight year series and 30°0 in the 6-7 year series. There were no hyperthyroid patients in the eight year series leaving 65 "" euthyroid, whilst 4 O o of the 6-7 year series were still hyperthyroid, leaving 76", euthyroid. The better results in the latter series seem unlikely to be due to the slightly shorter follow-up because, based on the reported rates of development of hypothyroidism after 1 3 1 1 2 . the difference in the cumulative incidences of hypothyroidism is greater than expected. The mean dose of l3'I in the eight year series was 6.8 mCi (standard deviation 1 - 5 ) compared to the standard 5 mCi dose in the 6-7
year series. The latter patients were routinely treated with carbimazole for one month before I 3 l ' I treatment so we cannot be sure whether the lower incidence of hypothyroidism in this group, previously noted on two year follow-up7, is due to the lower dose of 1311 used, or to carbimazole pre-treatment, or both. As noted previously by others2, the dose of 1 3 ' 1 relative to the size of the thyroid gland was related to the subsequent risk of hypothyroidism. The present study has demonstrated that a postal questionnaire can effectively identify previously unrecognised cases of hypothyroidism following 1 3 1 1 therapy. It is now being used in conjunction with a computerbased register and recall system. Patients treated with I 3 l I are entered on the register after becoming euthyroid, whether on thyroxine replacement treatment or not. They are then automatically sent a questionnaire and a request for a blood sample every year. Biochemical indices of thyroid function will be measured for the first few years of operation in order to check the reliability of the questionnaire. At present, patients with eight or more symptoms and/or abnormal blood tests are recalled for further assessment. This system promises to be an efficient, economical and reliable method of providing continuing care for the increasing pool of '"'I-treated patients "at risk" for hypothyroidism. 3 3
',
Acknowledgements
The authors thank their colleagues in the Thyroid Clinic, Drs. John Penington, Richard Larkins, Roger Melick, Peter Greenberg, John Andrews and Don Perry-Keene, for their continuing help and advice. Dr. John Mathews of the Walter and Eliza Hall Institute gave valuable assistance and advice in the initial planning stage of the project. Cheryl Newsom kindly punch-coded the data. T 3 and TSH assays were performed by Paula Heyma and Kathy Myles, and T4 measurements by the Biochemistry Department, Royal Melbourne Hospital.
References I
2 3. 4
5. 6.
BWKFR.11. V. and HIJKLEY,J . R (1972): The impact of technology on clinical practice i n Grave5' disease. M q u Clm. ProNL. E J 11960): Clinical and metabolic studies in thyroid disease, Brrr. mrd. J I, 78.
VOL.
7,
NO.
1
R , DUTHIL, M. B. and CRO~IKS, J (1968): A follow-up scheme for detecting hypothyroidism in thyrotoxic paIients treated with rddioiodine. Lancer 2, 1336. HFDLFY,A. J., S c O i 7 , A. M., WEIR, K.D. a n d C m o ~ sJ., (1970). Computerassisted follow-up register for the north-east ofscotland, Brri mcd. J . 1, 556. B A R K t K , D J P. and BISHOP.J M .(1969):Computer-based screening system for patients at risk of hypothyroidism, Lancer 2, 835 GARDNBR, M. I. and BARKER, D. J . P. (1975): Diagnosis of hypothyroidism: A comparison of statistical techniques Brit. med 1.2, 260. TOFT, A. D.. IRWNE, W. I., SETH,J., HuNTtR, W. M and CAMERON. E. H.D. (1975):Thyroid function in the long-term follow-up of patients treated with iodine-131 for thyrotoxicosis, Lancer 2, 576.
12. PHILP, J .
13. 14. 15. 16.
Aust. N.Z. J. Med. (1977). 7. DD. 31-35
Bacteraemia Following Oesophageal Dilatation and Oesophago-Gastroscopy P. M. Stephenson*, L. Dorringtont, 0. D. Harris1 and A. Rao"" F r o m t h e D e p a r t m e n t s of G a s t r o e n t e r o l o g y a n d B a c t e r i o l o g y Princess A l e x a n d r a Hospital, B r i s b a n e
Summary: dilatation
Bacteraemia following oesophageal and oesophago-gastroscopy. P. M.
Stephenson, L. D o r r i n g t o n , 0. D . Harris a n d A. Rao, Aust. N.Z. J. Med., 1977, 7, p p . 32-35.
Significant, but asymptomatic, bacteraemia after oesophageal dilatation w i t h Hurst's bougies for oesophageal stricture or spasm was detected in six of 1 1 patients. No bacteraemia was identified in ten volunteers without oesophageal pathology, w h o underwent passage of the same dilators. After oesophago-gastroscopy significant bacteraemia was identified in one of ten patients examined. The predominant bacterial isolates were streptococci ( St rept o coccus viridans" and non-haemolytic Streptococcus sp.). All the strains were sensitive in vitro to penicillin, ampicillin and cephalosporins. Any of these antibiotics are considered suitable for prophylactic use prior to performing oesophageal dilatation and upper gastrointestinal endoscopy in 'bt risk" patients. The risk of bacteraemia is much lower after endoscopy than oesophageal dilatation for stricture or oesophageal "
*Gastroenterology Registrar. tGastroenterology Senior Resident Medical Officer. :Co-ordinator of Gastroenterology. *Medical Bacteriologist. Correspondence: Dr. 0. D. Harris. Gastroenterology Department, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 41 02 Accepted for publication: 18 October, 1976
spasm. Mucosal trauma is concIuGYd as the site of entry of pharyngeal commensals leading to bacteraemia; and the incidence of bacteraemia appears related to the degree of trauma to the oesophagus.
An apparent portal of entry for bacteria preceding bacterial endocarditis can be frequently demonstrated and has varied in reported series from 24 to 62 2 , 3 ., a dental or surgical procedure was implicated as the precipitating event in the development of bacterial endocarditis in many cases. Hooke and Kay4 have shown that antibiotic prophylaxis decreases but does not eliminate bacteraemia. No definitive study has been undertaken to show how effective prophylactic antibiotics are in the prevention of bacttrial endocarditi~.~.However in our present state of knowledge, it seems obligatory to use prophylactic antibiotics in those at risk patients undergoing procedures leading to ba~teraernia.~. Okell and Elliott6 in 1935 investigated bacteraemia following teeth extraction and were able to show that the frequency of bacteraemia was related to the degree of disease of the gums, and also to the degree of trauma inflicted during the procedure. However, obvious infection is not always present and trauma or massage of mucosal surface with its normal
1977
Aust. N.Z. J. Med. (1977), 7, pp. 27-32
Use of a Computer-based Postal Questionnaire for the Detection of Hypothyroidism Following Radioiodine Therapy for Thyrotoxicosis 1. C. Harrison", J. D. Buckleyt and F. I. R. Martin1 From the University of Melbourne Department of Medicine and the Endocrinology Department, Royal Melbourne Hospital
SUrnmaI'y: Use of a computer-based postal questionnaire for the detection o f hypothyroidism following radioiodine therapy for thyrotoxicosis. L. C. Harrison, D. Buckley and F. I. R. Martin, Aust. N.Z. J. Med., 1977, 7, pp. 27-32. A computer-processed postal questionnaire was devised to detect hypothyroidism in patients treated previously for th yrotoxicosis with radioiodine. I n a study of 232 patients treated with ' 311 at the Royal Melbourne Hospital between four and ten years previously, the sum of symptomatic answers in the questionnaire was a sensitive discriminator of hypothyroidism, and alto w e d 80% of euthyroid patients to be excluded from further assessment. Questions concerned with general well-being and energy, voice and skin changes, showed the highest sensitivity and specificity. The combination of these questions alone was an effective means of identifying hypoth yroidism, with a sensitivity and specificity comparable to the more sophisticated technique of discriminant function analysis. Hypothyroidism had an incidence of between 20% and 35% six t o eight years after ' " I therapy and was related to a smaller initial goitre size for a given dose of j 3 ' 1 . This postal questionnaire, in conjunction with a computer-based automatic recall system, promises to be an efficient and reliable screening tool for the detection of hypothyroidism in the increasing number of patients 'bt risk" following ' 3 1 I therapy.
It is now generally recognised that the control of thyrotoxicosis by either thyroidectomy or radioiodine is accompanied by a significant risk of hypothyroidism. The cumulative ten year 'Senior Lecturer, University of Melbourne, Department of Medicine. Royal Melbourne Hospital. Wesearch Fellow. Walter and Eliza Hall Institute, Melbourne. $Endocrinologist, Royal Melbourne Hospital; Professorial Associate, University of Melbourne, Department of Medicine Correspondence: Dr. L. C. Harrison, .. Department of Medicine, Royal Melbourne Hospital PO, Victoria 3050 Accepted for publication: 17 August, 1976
incidence of hypothyroidism ranges from 5 "(,49"" after surgery' and from 30""-70", after l3'L2 The high incidence, 7°,-220,, of hypothyroidism in the first year after I3lI therapy is followed by a steady increase of 2 ",-5 O 0 per annum without evidence of a plateau2, implying that hypothyroidism may be an inevitable outcome. Its early occurrence appears to be correlated with the dose of I 3 ' I relative to the thyroid gland size3, and is much greater after "radical" than after "conservative" thyroidectomy.' However, after low dose I 3 l I therapy or conservative surgery the speed and frequency of remission of thyrotoxicosis is lower and the later incidence of hypothyroidism, although less, is still appreciable.', It is estimated' that by 1980 there will be approximately 240,000 cases of post-treatment hypothyroidism in the United States; and according to current treatment trends most of these will have followed I3'I therapy. The results of 311treatment previously reported from the Royal Melbourne Hospitals-7 and from the Royal Prince Alfred Hospital, Sydney*, are similar to those from centres overseas. Assuming an incidence of thyrotoxicosis similar to that in the United States, there are probably close to 20,000 individuals in Australia with hypothyroidism (treated or untreated) following treatment fof thyrotoxicosis. Although the treatment of hypothyroidism with thyroxine is nearly always both simple and satisfactory, recognition of the condition is often not easy. People with mild or even moderate hypothyroidism may not consult a doctor, or may remain undiagnosed, because of the insidious and non-specific nature of their symptoms.6 The increasing number of patients who require follow-up after treatment of thyrotoxicosis has led to attempts to find sensitive and specific screening methods for the prediction and detection of hypothyroidism. As
'
28
HARRISON ET AL.
yet, no single biochemical index of thyroid function satisfies the requirements for an ideal screening test. An alternative procedure, pioneered in Great Britain, is the use of a diagnostic index based on the patient’s responses to a questionnaire designed to elicit symptoms of hypothyroidism. We describe here the use of a computer-processed postal questionnaire designed to detect hypothyroidism in patients previously treated with I 3 ’ I at the Royal Melbourne Hospital. Methods The questionnaire contained 13 questions as listed in Table 2, each question requiring a simple YES or NO answer. In 1974-75 the questionnaire was given or mailed to 250 patients previously treated with ‘311 for thyrotoxicosis at the Royal Melbourne Hospital. The patients consisted of all those treated initially in 1967 (1 10 patients), a previously well-documented group’ treated initially in 1968--69 (Y3 patients), and a miscellaneous group treated initially at other times between 1965 and 1972 (47 patients). The last group were currently attending the Thyroid Clinic for routine follow-up. The questionnaire contained a n explanatory note, a request for information on current medication and the name and address of the local doctor, and a stamped, addressed envelope for return mailing. In addition, each patient was requested to attend the hospital for a blood sample to be taken, or, in the case of country patients for this to be done locally and the sample forwarded. Blood samples were analysed for plasma thyroxine (T4) by competitive prokin binding, and for plasma triiodothyronine (T3) and plasma thyroid stimulating hormone (TSH) by radioimmunoassay. Subsequently, where possible, the survey results were sent to the local doctor. Patients were classified as euthyroid on the basis of normal T4, T3 and TSH levels and/or after clinical assessment. Those with T4 or T3 levels outside the normal ranges and those of doubtful clinical status were recalled for retesting and reassessment. Hypothyroidism was ultimately diagnosed on the basis of both biochemical and clinical
VOL.
7,
NO.
1
criteria. The questionnaire answers. together with accompanying data on age, sex, date and dose(s) of l 3 l I , thyroid replacement therapy, T4. T3 and TSH values were punch-coded and analysed by a Cyber 72 computer. using SPSS programmes.’ Results
The number of questionnaires returned was inversely related to the interval since treatment. A follow-up letter requesting co-operation was mailed to all “non-responders”, but added little to the final yield. 83”,, of patients in the 1968-69 treatment group responded, compared to 65 of patients in the 1967 treatment group. The majority of “non-responders” were designated by the Post Office as “address unknown”. Ultimately, by contacting the former local doctor, by scanning the telephone directory, or by searching other records in the hospital, it was possible to trace all but 5 O D of the 1968-69 group and all but 9 ” ” of the 1967 group. ilnalysis of Duta
Forty-five of the 233 “responders” had been previously diagnosed as hypothyroid and were on replacement therapy. Nine “responders” were diagnosed,for the first time, on the basis of both biochemical and clinical criteria, as being unequivocally hypothyroid (Table 1). In this group the mean number of symptomatic answers was 9 . 7 (standard deviation 1 ‘4, range 7-1 1) compared to 4 . 5 (standard deviation 3 ‘0, range 0-12) in those classified as euthyroid. The difference between the mean scores of the two groups was highly significant ( P < 0.001).
TABLE I Data on newly-diagnosed hypothyroid patients
-.
Patient
__ T4
Respor&es to questions 1 - 13t
Biochemistry* .__.~__
36 34 51 27 30 14 18 21 ‘4
.____
T3
TSH
-
19.6 26.5 61.6
0.85 0.90 1.30 0.75 0.30 0.60 0.65 0.90
17.5
22.0 19.6 81.0 45.4 31.0
I
2
3
4
5
+ + + + + + + +
+ + + + + + + +
+ + + + + +
+ + + + + + + +
+ + + +
+
-
-
-
*Normal ranges: T4 50-135 nmol/l, T3 1.4-2.8 nmol/l, TSH 0.5--5.0 yU/ml.
t(+ ) denotes a symptomatic respmse.
6
7
+ + + + + + +
+ + + + + +
8
+ + + + + - +
9 1 0 1 1 1 2 1 3
+ + + + -
+ + + + - - + + - +
+ + + + + f + -
+ - + + + +
+ + + + + + - + + + +
FEBRUARY,
1977
29
QUESTIONNAIRE DIAGNOSIS OF HYPOTHYROIDISM
TABLE 2 Most sensitive and specific questions for identifying hypothyroidism ~
Question
Hypothyroid patients with symptom ( ' I < , )
1. Do you feel as well now as you did two years ago? 2. Have you become slower (physically or mentally)? 3. Do you feel the cold more so than before? 4. Has your voice become hoarse, huskier or weaker? 5. Have your bowels become less regular, or constipated? 6. Are you getting puffy around the eyes. or any fuller in the face? 7. Has your hair become drier or thinner, or more difficult to manage? 8. Have you put on weight over the past two years? 9. Have you noticed that you prefer the warmer weather more so than before? 10. Has the skin of your arms become drier or rougher? 11. Have you been troubled by any numbness, tingling or pins-and-needles in the hands'? 1 2 Have you been troubled by muscular aches and pains or cramps more so over the past two years? 13. Do you feel less energetic now than you did two years ago?
Euthyrotd patients without symptom ( " J
I00 89
69 51
67
63
89
82
56 67 67 67 44
83
79 58
59
89
70 81
78
57
56 100
52 45
89 89 89 89
91 89 91 90
Question combinations 1f 4 If10 I + 4 + 13 1 10+ I3
+
A "cut-off' point of eight or more symptoms would have included all but one (890;) of the hypothyroid patients and 45 (20"J of the euthyroid patients. The questions, or combinations of questions, with the highest sensitivity (highest percentage of true positive answers) and specificity (highest percentage of true negative answers) for identifying hypothyroidism are shown in Table 2. Questions 1, 4 and 10 each had the required high degree of sensitivity and an acceptable degree of specificity. The combination of some questions, shown in the lower half of the table, significantly improved specificity. Answers were also examined by discriminant function analysis, a technique which gave a weighting to each symptom. This method had a sensitivity of 890; and a specificity of S O , . In other words, all but one of the hypothyroid patients were correctly classified and only eleven of the euthyroid patients were misclassified. Relationship to Biochemical Indices of Thyroid Function Analysis of the combined euthyroid and hypothyroid patient data showed that the total
number of symptoms elicited was significantly correlated with T4 ( r = -0.315, P < 0.001), T3 (r = -0.332, P < 0.005),TSH ( r = +0.393, P < 0.001) and the T4.T3 product ( v = -0.355, P < 0.005). Stepwise multiple linear regression of symptoms versus T4, T3, TSH or the T4.T3 product showed that in each case question 10 was the one accounting for most of the variance. Subsequent symptoms chosen were of little further predictive value and were different for each biochemical index. Each biochemical index was examined in relation to the presence, or otherwise, of a symptomatic answer to each question. The only question associated with a significant difference in all three biochemical indices between symptomatic and non-symptomatic responders was question 10. Late Incidence of Hypothyroidism This was determined for the 1967 and 1968-69 treatment groups, where almost complete follow-up was achieved. The 1967 group received a mean dose of 6 . 8 mCi I3'I (standard deviation 1.5) and had an eight year incidence of hypothyroidism of 35".,. The 1968-69 group, all of whom received a standard dose of 5 mCi 13'1, had a 6-7 year incidence of hypothyroidism of
30
HARRISON ET A L .
20 O n . There was no difference between hypothyroid and euthyroid patients with respect to mean age at the time of treatment, initial clinical state and thyroid function tests, number of I 3 l I doses administered, and, in the 1968-69 group, initial and maximum serum levels of the Long-Acting Thyroid Stimulator (LATS). However, in the 1968-69 group, given a standard I 3 ' I dose, the frequency of initial goitre size in patients becoming hypothyroid was 24 for grade 0 goitre (impalpable)and 6 ", for grade 3 goitre (large), compared with 4", and 21 0 , respectively in patients remaining euthyroid. Discussion
Thyroid disease was one of the first conditions in which statistical techniques were applied to obtain diagnostic and prognostic significances of different symptoms. Since no one symptom is specific for hypothyroidism, the development of a diagnostic index has relied on the weighting of different symptoms, or on the combination of symptoms." Recognition of hypothyroidism as the main delayed side-effect of I3'I therapy and the need to screen an ever-enlarging patient population provided the stimulus for the practical application of this technique, first pioneered by Scottish workers in Glasgow" and Aberdeen'z.'3 and now adopted by a number of other centres elsewhere in Great Britain. The questionnaire used in the present study is similar to that currently in use in Birmingham.14, l 5 The symptoms chosen were those thought to be most reliable in the clinical diagnosis of hypothyroidism ; most are common to the questionnaires in use in other centres. Some symptoms, for example loss of taste and hearing, were excluded because it was felt that they would require a more elaborate written question, and were probably better considered as signs. A screening procedure for hypothyroidism must satisfy two basic criteria. Firstly, it must have a very small probability of missing cases (high sensitivity), since treatment is so simple and effective. Preferably as well, the proportion of misclassified euthyroid patients, or false positives, who need to be recalled and reassessed should be small (high specificity). Secondly, the screening procedure should cover all "at
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risk" patients ; its value is negated by incomplete follow-up. We are satisfied that the present investigation fulfils both of these criteria. The number of newly-diagnosed hypothyroid patients in our study was relatively small, but the trends in the results are similar to those in other studies. The simple addition of symptoms was as sensitive a discriminator of hypothyroidism as the use of more sophisticated techniques, a finding recently made by Gardner and BarkerI5 in a comparison of statistical techniques used for analysing the Birmingham data. However, the combination of symptoms or the use of discriminant function analysis significantly improved the specificity of the questionnaire. Analysis of the Birmingham data produced similar results", but the degree of specificity achieved was less than in the present study. This may be a reflection of the small number of hypothyroid patients selected from within our more homogeneous population. A screening procedure may give better results in the hands of those who devise and first apply it, than when used generally. It remains to be seen whether the application of the diagnostic rules from the current set of data to patients followed prospectively will remain valid. In this regard it is interesting to note that skin and voice changes, the most specific symptoms in the present study, were the most specific signs in the Birmingham study.I4 On the other hand, the weighting of some symptoms is likely to differ from one community to the next, depending on social and geographical factors. For instance, cold intolerance, long considered to be an important symptom of hypothyroidism, did not rate highly in this Melbourne study, yet was the most sensitive symptom in the analysis of the Birmingham results.' The requirement for complete follow-up takes on special meaning when screening a potentially hypothyroid population. Hypothyroid individuals are less likely to respond to a postal questionnaire. The point is illustrated by the case of orle lady who failed to respond to two letters and whose telephone number was then obtained from the directory. One of US (L.H.) rang the number, and, after a very long wait, was finally rewarded by a diagnostic,
'
FEBRUARY,
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31
OLJESTIONNAIRE DlAGNOSlS OF HYPOTHYROIDISM
slow, croaky voice answering at the other end. The main cause of incomplete follow-up was a change in address: this will pose a continuing problem in Australia. The correlation of each biochemical index of thyroid function with the total number of symptoms provides biological support for the validity of the questionnaire, and suggests that there was a continuum between the normal euthyroid state and hypothyroidism. The question about skin changes had the greatest predictive value for each biochemical index. This question, also, was the only one associated with significant differences in all three biochemical indices between those with, and those without the symptom. A request for a thyroid function test, in conjunction with the questionnaire, has been the routine practice overseas.'2-14 Full biochemical assessment is needed on all patients if one decides not ro run the risk of a missed diagnosis. However, this then negates the value of the questionnaire. Prospective experience with the present questionnaire will enable us to assess the value of ancillary blood tests. The present study suggests that T4, T3 or TSH correlate equally well with the clinical picture. However, TSH, usually considered to be a sensitive index of hypothyroidism, may not be reliable in these circumstances, since Toft et a/.' have shown that it is elevated in a significant number of euthyroid patients 6-18 years after 1 3 1 1 therapy, but that only 2 "*-5 ",, develop overt hypothyroidism each year. The incidence of hypothyroidism in the two groups of patients followed-up almost completely was 35"" in the eight year series and 30°0 in the 6-7 year series. There were no hyperthyroid patients in the eight year series leaving 65 "" euthyroid, whilst 4 O o of the 6-7 year series were still hyperthyroid, leaving 76", euthyroid. The better results in the latter series seem unlikely to be due to the slightly shorter follow-up because, based on the reported rates of development of hypothyroidism after 1 3 1 1 2 . the difference in the cumulative incidences of hypothyroidism is greater than expected. The mean dose of l3'I in the eight year series was 6.8 mCi (standard deviation 1 - 5 ) compared to the standard 5 mCi dose in the 6-7
year series. The latter patients were routinely treated with carbimazole for one month before I 3 l ' I treatment so we cannot be sure whether the lower incidence of hypothyroidism in this group, previously noted on two year follow-up7, is due to the lower dose of 1311 used, or to carbimazole pre-treatment, or both. As noted previously by others2, the dose of 1 3 ' 1 relative to the size of the thyroid gland was related to the subsequent risk of hypothyroidism. The present study has demonstrated that a postal questionnaire can effectively identify previously unrecognised cases of hypothyroidism following 1 3 1 1 therapy. It is now being used in conjunction with a computerbased register and recall system. Patients treated with I 3 l I are entered on the register after becoming euthyroid, whether on thyroxine replacement treatment or not. They are then automatically sent a questionnaire and a request for a blood sample every year. Biochemical indices of thyroid function will be measured for the first few years of operation in order to check the reliability of the questionnaire. At present, patients with eight or more symptoms and/or abnormal blood tests are recalled for further assessment. This system promises to be an efficient, economical and reliable method of providing continuing care for the increasing pool of '"'I-treated patients "at risk" for hypothyroidism. 3 3
',
Acknowledgements
The authors thank their colleagues in the Thyroid Clinic, Drs. John Penington, Richard Larkins, Roger Melick, Peter Greenberg, John Andrews and Don Perry-Keene, for their continuing help and advice. Dr. John Mathews of the Walter and Eliza Hall Institute gave valuable assistance and advice in the initial planning stage of the project. Cheryl Newsom kindly punch-coded the data. T 3 and TSH assays were performed by Paula Heyma and Kathy Myles, and T4 measurements by the Biochemistry Department, Royal Melbourne Hospital.
References I
2 3. 4
5. 6.
BWKFR.11. V. and HIJKLEY,J . R (1972): The impact of technology on clinical practice i n Grave5' disease. M q u Clm. ProNL. E J 11960): Clinical and metabolic studies in thyroid disease, Brrr. mrd. J I, 78.
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R , DUTHIL, M. B. and CRO~IKS, J (1968): A follow-up scheme for detecting hypothyroidism in thyrotoxic paIients treated with rddioiodine. Lancer 2, 1336. HFDLFY,A. J., S c O i 7 , A. M., WEIR, K.D. a n d C m o ~ sJ., (1970). Computerassisted follow-up register for the north-east ofscotland, Brri mcd. J . 1, 556. B A R K t K , D J P. and BISHOP.J M .(1969):Computer-based screening system for patients at risk of hypothyroidism, Lancer 2, 835 GARDNBR, M. I. and BARKER, D. J . P. (1975): Diagnosis of hypothyroidism: A comparison of statistical techniques Brit. med 1.2, 260. TOFT, A. D.. IRWNE, W. I., SETH,J., HuNTtR, W. M and CAMERON. E. H.D. (1975):Thyroid function in the long-term follow-up of patients treated with iodine-131 for thyrotoxicosis, Lancer 2, 576.
12. PHILP, J .
13. 14. 15. 16.
Aust. N.Z. J. Med. (1977). 7. DD. 31-35
Bacteraemia Following Oesophageal Dilatation and Oesophago-Gastroscopy P. M. Stephenson*, L. Dorringtont, 0. D. Harris1 and A. Rao"" F r o m t h e D e p a r t m e n t s of G a s t r o e n t e r o l o g y a n d B a c t e r i o l o g y Princess A l e x a n d r a Hospital, B r i s b a n e
Summary: dilatation
Bacteraemia following oesophageal and oesophago-gastroscopy. P. M.
Stephenson, L. D o r r i n g t o n , 0. D . Harris a n d A. Rao, Aust. N.Z. J. Med., 1977, 7, p p . 32-35.
Significant, but asymptomatic, bacteraemia after oesophageal dilatation w i t h Hurst's bougies for oesophageal stricture or spasm was detected in six of 1 1 patients. No bacteraemia was identified in ten volunteers without oesophageal pathology, w h o underwent passage of the same dilators. After oesophago-gastroscopy significant bacteraemia was identified in one of ten patients examined. The predominant bacterial isolates were streptococci ( St rept o coccus viridans" and non-haemolytic Streptococcus sp.). All the strains were sensitive in vitro to penicillin, ampicillin and cephalosporins. Any of these antibiotics are considered suitable for prophylactic use prior to performing oesophageal dilatation and upper gastrointestinal endoscopy in 'bt risk" patients. The risk of bacteraemia is much lower after endoscopy than oesophageal dilatation for stricture or oesophageal "
*Gastroenterology Registrar. tGastroenterology Senior Resident Medical Officer. :Co-ordinator of Gastroenterology. *Medical Bacteriologist. Correspondence: Dr. 0. D. Harris. Gastroenterology Department, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 41 02 Accepted for publication: 18 October, 1976
spasm. Mucosal trauma is concIuGYd as the site of entry of pharyngeal commensals leading to bacteraemia; and the incidence of bacteraemia appears related to the degree of trauma to the oesophagus.
An apparent portal of entry for bacteria preceding bacterial endocarditis can be frequently demonstrated and has varied in reported series from 24 to 62 2 , 3 ., a dental or surgical procedure was implicated as the precipitating event in the development of bacterial endocarditis in many cases. Hooke and Kay4 have shown that antibiotic prophylaxis decreases but does not eliminate bacteraemia. No definitive study has been undertaken to show how effective prophylactic antibiotics are in the prevention of bacttrial endocarditi~.~.However in our present state of knowledge, it seems obligatory to use prophylactic antibiotics in those at risk patients undergoing procedures leading to ba~teraernia.~. Okell and Elliott6 in 1935 investigated bacteraemia following teeth extraction and were able to show that the frequency of bacteraemia was related to the degree of disease of the gums, and also to the degree of trauma inflicted during the procedure. However, obvious infection is not always present and trauma or massage of mucosal surface with its normal
