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Normal concentrations of serum insulinlike growth factor-1 in late polio
732
Normal Concentrations of Serum lnsulinlike Growth Factor-1 in Late Polio o
Katharina Stibrant Sunnerhagen, MD, Bengt-Ake Bengtsson, MD, Per-Arne Lundberg, MSc, Kerstin Landin, MD, Gfiran Lindstedt, MD, Prof, Gunnar Grimby, MD, Prof ABSTRACT. Stibrant Sunnerhagen K, Bengtsson B-A, Lundberg P-A, Landin K, Lindstedt G, Grimby G. Normal concentrations of serum insulinlike growth factor-1 in late polio. Arch Phys Med Rehabil 1995;76: 732-5. • A recent study of 10 men with postpolio syndrome indicated a low secretion of growth hormone (GH) as reflected by serum insulin-like growth factor-I (IGF-1). Therefore, 87 patients were studied, 17 to 71 years after acute poliomyelitis, of whom 65 % reported the occurrence of new or increased weakness (ie, during the last 2 years) in muscles previously affected by polio. Serum IGF-1 concentrations in the patients were compared with those found in a reference population comprising 392 randomly selected individuals. No differences from the reference population values were observed. No correlation was found between IGF-I concentrations and the severity of the original polio affliction, the recovery status, the need for ambulation aids, or the presence of new symptoms. The results do not indicate a need for GH substitution treatment of patients with postpolio syndrome.
© 1995 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation Today, developed countries are facing a growing problem regarding the consequences of the polio outbreaks decades ago. There is an increased prevalence of individuals with weakness in the muscular system, 1'2 but the exact number of people suffering is not known. The following definition for the postpolio syndrome (PPS) has been suggested by Halstead and Rossi2: (1) a secured case of polio; (2) a recovery that was complete or partial both neurologically and functionally; (3) a period with neurological and functional stability of at least 15 years; (4) the appearance of two or more of health problems after this stable period such as unusual tiredness, muscle and/or joint pain, new weakness in muscles that previously have or have not been affected, functional deterioration, cold intolerance, or new atrophies; and (5) no other medical explanation for these health problems. With an increasing number of people who have had polio now experiencing new muscle weakness, the awareness of the problems associated with PPS is growing, as are hopes for a cure. Shetty and colleagues 3 recently caught the interest of many polio survivors when they noted lower concentrations of insulin-like growth factor-I (IGF-1) in 10 men with PPS Compared with a control population. IGF-1 is a peptide that stimulates protein synthesis and growth in many organs. It is synthesized in many cells and tissues, eg, muscle, kidney and liver, and the secretion of IGF-1 is largely dependent on the secretion of pituitary growth hormone as well as From the Department of Rehabilitation Medicine (Drs. Stibrant Sunnerhagen, Grimby), Department of Internal Medicine, Division of Endocrinology (Drs. Bengtsson, Landin), Department of Clinical Chemistry, (Mr. Lundberg, Dr. Lindstedt) Sahlgrenska University Hospital, University of Gtiteborg, Sweden. The study was supported in part by the Swedish Medical Research Council (project 3888) and King Gustav V 80-years foundation. Submitted for publication June 28, 1994. Accepted in revised form March 21, 1995. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprint requests to Katharina Stibrant Sunnerhageo, MD, Department of Rehabilitation Medicine, Guldhedsgatan 19, Sahlgrenska Hospital, S-413 45 G~3teborg, Sweden. © 1995 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation 0003-9993/95/7608-312653.00/0
Arch Phys Med Rehabil Vol 76, August 1995
thyroid and gonadal hormones. Therefore, low concentrations of IGF-1 might reflect low-growth hormone secretion. Growth hormone has profound anabolic actions, and decreased growth hormone secretion might very well play a role in causing the reported fatigue and weakness experienced by these patients. The observations by Shetty3 imply the possible use of growth hormone in order to stop or to lessen the deterioration of function in subjects with PPS, and this has evoked hope in the population of polio survivors. The report has been cited in a patients' organization newsletter in Sweden, and people have asked whether treatment was available with growth hormone. Therefore, to further clarify this matter, IGF-1 concentrations in a larger population of polio survivors have been studied. PATIENTS AND METHODS Postpolio Population
The study included 87 patients who all had a confirmed past history of polio. The majority of the subjects were identified either from the records at the hospitals in Gtteborg from the latest polio epidemic or they were recruited through a newspaper advertisement. This subpopulation had participated in another ongoing long-term follow-up taking place in this laboratory.4 To this population persons were added who themselves had called the department of rehabilitation medicine and volunteered to participate in any polio-related research project. The population consisted of 53 women and 34 men. The average age was 53 years (ranging from 17 to 83 years). Time since the polio onset was on average 45 years (minimum time was 17 years and maximum was 71 years). Mean body height was 172cm (SD 9) for men and 162 (SD 6) for women, mean body weight was 72.8kg (SD 9.5) for men and 62.3 (SD 8.6) for women, and body mass index (BMI (weight in kg/(length in m) 2) was 24.5 (SD 2.7) for men and 23.6 (SD 3.3) for women. All patients lived at home. Of those below retirement age (72 of 87), which in Sweden is 65 years, 46% were full-time employed, 14% partially employed by their own wish. Owing to healthrelated causes, 25% were partially retired and 15% were on
GROWTH FACTOR-I IN LATE POLIO, Stibrant Sunnerhagen
full-time early retirement. In other words, 40% were considered not having full working capacity because of their prior polio illness. No more information on work capacity was available. For functional assessment, the following evaluations were performed: 1. Abilities in certain daily activities, such as rising from a chair without using arms, choice of mobility, and use of ambulatory assistive devises, orthoses. 2. Perception of difficulties in daily activities, measured by part of the Functional Status Questionnaire (FSQ), 5 which is a self-administrated questionnaire. A fourgraded scale was used for each item, and subscores for different areas were calculated (for principles of calculation see FSQS). The following areas were calculated: basal (personal) activities of daily living (ADL); instrumental ADL (ambulation, transportation, household chores); and social activities. 3. Whether or not patients fulfilled the criteria for the PPS as defined by Halstead and Rossi 2 was noted. 4. Degree of polio involvement of muscles was classified in each of the four limbs and in the trunk using a five-score method as defined by Carrington Gawne. 6 I, unaffected muscle; II, subclinical polio (no perceived muscle weakness); III, stable polio (subjective muscle weakness, but no increase during the last 2 years); IV, unstable polio (new or increased weakness); V, severe muscle atrophy. The scores for the extremities and the trunk were added to produce a total polio score, which ranged from 7 to 25. The study was approved by the Ethical Committee of the authors' university.
Reference Population Subjects from the screening procedures for the WHO MONICA project (MONICA-MONltoring of trends and determinants in CArdiovascular diseases) in G6teborg, Sweden were used as a reference population. One thousand men and 1,000 women 25 to 64 years of age were randomly selected from the population census of the city. The participation rate was 71%, ie, 1,421 individuals out of whom 50 (47 to 53) were randomly selected in each age stratum (25 to 34, 35 to 44, 45 to 54, and 55 to 64 years) for both sexes, in a total 392 individuals] The mean value of IGF-1 for each stratum was calculated and presented with one SD.
Blood Sampling and Biochemical Analyses Venous blood samples were drawn in the morning from an antecubital vein. Serum IGF-1 was determined by a hydrochloric acid-ethanol extraction radioimmunoassay using authentic IGF-I" for labeling. 7 Serum thyrotropin (TSH) was determined by an immunoradiometric assay, b Serum thyroxine (T4) was determined by a single-antibody polyethyleneglycol-assisted radioimmunoassay c and 3,5,3'-triiodothyronine (T3) by a doubleantibody polyethyleneglycol-assisted radioimmunoassay, d Serum-free T4 and free T3 were determined by ligand analog radioimmunoassays.e Serum total testosterone was determined by a nonextraction radioimmunoassay using an antiserum against a C-19
733
Table 1: Bias and Imprecision of the Biochemical Determinations Bias
Score*
Analyte
%
Imprecision
Accuracy
IGF- 1* TSH* T4* Free T4* T3** Free T3 ~
-4 5 -5 -21 - 11 -21
1 1 0 1 2
4 1 2 1 2
* Scale for score is 0 to 13, 0 being best possible value. Value in relation to results presented in Ref 7. ** Values in relation to results from an international quality assessment program (942 laboratories).
derivative of testosterone (RSL~25I testosterone, f 3.4% crossreactivity against 5a-dihydrotestosterone). Serum-free testosterone was assayed by a ligand-analog technique. ~ Tables 1 and 2 show the details of the analytical performance.
Statistics Statistics were calculated using Statview. h To establish relationships between two variables, regression analysis was applied, and for comparison between groups, the MannWhitney U test was used, with significance at p < 0.05. Analysis of variance (ANOVA) and stepwise regression were also used. RESULTS
Activities in Daily Life A total of 57 polio persons (66%) were dependent on assistive devices for ambulation; canes or crutches were used by 39 persons, wheelchairs were used by 15 persons, and 33 persons depended on orthoses. Public transportation could be used by 55% of the population, and 45% were dependent on assisted transportation (taxi or special vehicle). FSQ scores, expressed as an average percentage of maximum values, were for personal ADL 87.2 (SD 17.5), for instrumental ADL 53.5 (SD 23.4), and for social activities 71.1 (SD 30.6). This indicates major difficulties in instrumental daily activities but not in personal ADL.
Symptoms Postpolio syndrome was present in 68 out of 87 patients. New muscular weakness during the last 2 years had occurred in 63 patients in one or more muscle group, whereas the other 24 reported unchanged status in muscles clinically affected by polio. In the other 5 patients, PPS was manifest as unusual tiredness, muscle and/or joint pain, and cold intolerance. The average polio score was 12, and it varied from 7 to 21. The polio score, being a measure of the level of impairment, correlated well to the scores of FSQ (personal ADL; r = 0.524, p < 0.0001, instrumental ADL; r = 0.518, p < 0.0001, social activities; r = 0.241, p < 0.05).
Hormone Concentrations The values for serum IGF-1 in the postpolio population decreased within the normal reference interval, with no difference between men or women (fig 1). There was a negative Arch Phys Med Rehabil Vol 76, August 1995
734
GROWTH FACTOR-I IN LATE POLIO, Stibrant Sunnerhagen
Table 2: Imprecision of the Biochemical Determinations as Calculated From Assay of Controls Included in Each Analytical Run Coefficient of Variation (%) Analyte IGF-1
TSH
T4
Free T4
T3
Free T3
Testosterone
Free testosterone
Concentration
Within (assays)
Between (assays)
Total Variation
120/zg/L 336 #g/L 1,007 #g/L 0,08 mU/L 1.73 mU/L 28,6 rnU/L 61.3 nmol/L 94.6 nmol/L 201 nrnol/L 7.3 prnol/L 13.7 pmol/L 40.2 pmol/L 1.68 nmol/L 1.93 nmol/L 4.53 nrnol/L 3.2 prnol/L 5.5 pmol/L 14.2 pmol/L 2.0 nmol/L 11.2 nmol/L 26.8 nrnol/L 45.4 prnol/L 104 prnol/L
6.2 6.0 6.3 6.1 4.1 5.1 4.9 3.0 2.7 1,7 1,9 1.8 2.9 2.3 2.9 2.5 1.7 2.2 5.9 5.9 4.8 7.1 4.6
4.3 2.7 2.5 4.1 3.6 10 2.8 2.4 2.5 1.2 1.5 3.0 5.6 3.5 2.9 0.3 1.6 1.1 12 6,0 6,1 8.6 5.8
7.6 6.6 6.8 7.3 5.5 11 5.7 3.8 3.6 2.1 2.4 3.5 6.3 4.2 4.1 2.5 2.4 2.5 13 8.4 7.8 11 7.3
The controls were prepared from pooled patients' serum samples, and aliquots of about 1 mL were kept in sealed glass ampoules at below -20°C. A new ampoule was taken for each assay run.
However, these authors used a nonextraction radioimmunoassay in which a fixed amount of a specific antiserum reacts with free and bound analyte under specified conditions. However, there are no reasons to believe that analytical artifacts would be responsible for the divergence between their results and these results, as interference in the assay used by Shetty 3 would be expected to cause elevation rather than decrease in values. One possible cause of difference in study outcome might be the fact that the total amount of serum IGF- 1 is related to the concentration of its binding proteins, IGF BP-3 in particular. High BP-3 concentrations therefore would elevate IGF-1 values. However, BP-3 is a growthhormone dependent protein; thus low rather than high concentrations would be expected in growth-hormone deficiency. The reason for the low values observed in the 10 men reported by Shetty 3 was considered by those authors not to
IGF-1 ,00 A ~g/i
4 4-
300
4-
4-
200 4-
correlation between age at follow-up and serum concentrations of IGF-1 (r = 0.447, p < 0.0001) but not between age at onset of polio and IGF-1 concentrations or between duration since onset and IGF-1 (data not shown). No relationship was noted between serum concentrations of IGF-1 and height, weight, or BMI (data not shown). There was no difference in the correlation between concentration of IGF1 and age between patients with or without new muscular weakness (fig 2). Neither was there any correlation between concentration of IGF-1 and the degree of polio score. No differences in IGF-1 concentration were found between the groups with or without presence of postpolio syndrome or occurrence of new symptoms or not (data not shown). No difference in concentrations of IGF-1 was found when comparing patients with or without ambulatory assistive devices (data not shown). There was no correlation between activity level assessed with the questionnaire FSQ and the concentration of IGF-1 (data not shown). The concentration of serum thyrotropin and total and free thyroxine (T4) and 3,5,Y-triiodothyronine (T3) were within the normal reference intervals (data not shown). The testosterone concentrations (both total and free) were also normal (data not shown). No differences in these hormone concentrations were noted between the group with new symptoms and those with a stable condition (data not shown). DISCUSSION The present findings of serum IGF-1 concentrations in postpolio patients do not support the conclusions by Shetty 3 that such patients would be characterized by low-circulating IGF-I concentrations as in growth hormone deficiency. Arch Phys Med Rehabil Vol 76, August 1995
+
100
0
I
0
20
i
60
80 100 AGE years
WOMEN
IGF-1 400~g/I
i
40
B
300 I
4-+
4~
l**J * 4-~
200"
4-d P4÷ 1
4-+
100"
0
i
i
|
20
40
60
1
i
80 100 AGE years
Fig 1 - - R e l a t i o n s h i p between serum concentration of IGF-1 in polio patients (crosses) and age (A) men, (B) women. Mean values +_1 SD are given for each age stratum of the reference population (filled triangles and vertical line) are shown.
GROWTH FACTOR-I IN LATE POLIO, Stibrant Sunnerhagen
The only relationship observed was between age at followup and serum concentrations of IGF-1. Decreased IGF-1 concentration with age has been reported, l° and this was reaffirmed in the randomized population study. 7 There was no relationship between physical activity and the levels of IGF-1, according to results from Shetty's study 3 and the population study. 7 Neither was there any correlation with the extent of polio involvement of muscles (polio score).
IGF-1 400 ~g/I ra
[]
300
0 • •
nunu
an
SUMMARY
o
•
I
The hypothesis that lower concentrations of IGF-1 occur in patients with postpoliomyelitis sequelae, and new muscle weakness could not been confirmed. Today, therefore, there is no indication for using growth-hormone treatment in this patient group with the hope of diminishing postpolio symptoms.
200 ~= •m
100
o
I
I
0
20
I
40
60
I
I
80 100 AGE years
Fig 2--Relationship between serum concentration of IGF-1 and age in polio patients with (filled squares) and without (open squares) new or increased muscle weakness (r = 0.447 and p <
735
0.0001).
be physical inactivity. Whether other hormonal factors than growth hormone were involved can only be speculated. The secretion of IGF-1 may be affected also by nutritional status and other hormones such as thyroid hormones and gonadal hormones, but no such measurements were reported by Shetty. 3 The patients in this study did not show any abnormalities in thyroid or gonadal functions. Pituitary insufficiency with accompanying growth-hormone deficiency in children leads to dwarfism, but in adults more subtle changes occur, such as a feeling of weakness. Both growth hormone deficiency and increased secretion such as in acromegaly have been associated with increased risk of cardiovascular disease. 8'9 There is no known recognized hormonal imbalance such as pituitary insufficiency associated with poliomyelitis. This does not exclude the possibility that the patients observed by Shetty, 3 for reasons so far unknown, had perturbations in the central nervous regulations of factors affecting growth-hormone IGF-1 homeostasis. Average age in the two studies was comparable (54 compared with 53 years). Shetty's study 3 included only 10 men and were compared with 94 individuals recruited through advertisements, as well as 28 immobilized totally dependent bedridden men from a nursing home. Their control population had more individuals in the lowest and highest age group, but there were only 16 subjects in the 50 to 60 years age group where most of the patients were included. This should be compared with the present study of 87 postpolio patients of either gender and 392 randomized control individuals, evenly distributed for sex and age.
Acknowledgment: The authors acknowledge the valuable help from Marita Hedberg with the statistics and figures. This study would not have been possible without the help from the subjects with postpolio who are willing to give their time for research. References 1. Dalakas MC, Elder G, Hallett M, Ravits J, Baker M, Papadopoulos N, et al: A long-term follow-up study of patients with poliomyelitis neuromuscular symptoms. N Engl J Med 1986;314:959-63. 2. Halstead LS, Rossi CD: Post-polio syndrome: clinical experience with 132 consecutive outpatients. In: Halstead LS, Wiechers S, editors. Research and clinical aspects of the late effects of poliomyelitis. White Plains, NY: March of Dimes Birth Defects Foundation Orig Art Series, 1987;23:13-26. 3. Shetty KR, Mattson DE, Rudman IE, et al: Hyposomatomedinemia in men with post-poliomyelitis syndrome. J Am Ger Soc 1991;39:18591. 4. Einarsson G, Grimby G: Disability and handicap in late poliomyelitis. Scand J Rehabil Med 1990;22:113-21. 5. Jette AM, Davies AR, Cleary PD, Calkins DR, Rubenstein LV, rink A, et ah The functional status questionnaire. Reliability and validity when used in primary care. J Gen Intern Med 1986; 1:143-9. 6. Carrington Gawne A: Strategies for exercise prescription in post-polio patients. In: Halstead LS, Grimby G, editors. Post-polio syndrome. Philadelphia, Hanley & Belfus Inc, 1995:141-64. 7. Landin-Wilhelmsen K, Wilhelrnsen L, Lappas G, Rosdn T, Lindstedt G, Lundberg P-A, et al: Serum insulin growth factor I in a random population sample of men and women: relation to age, sex, smoking habits, coffee consumption and physical activity, blood pressure and concentration of plasma lipids, fibrinogen, parathyroid hormone and osteocalcin. Clin Endocrinol 1994;41:351-7. 8. Rosrn T, Bengtsson B-A: Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990;336:285-8. 9. Bengtsson B-A, Edrn S, Ernest I, Odrn A, Sj~gren B: Epidemiology and longterm survival in acromegaly. Acta Med Scand 1988;223:32735. 10. Rudman D, Kutner MH, Rogers CM, Lubin Mr, Fleming GA, Bain RP: Impaired growth hormone secretion in the adult population. Relation to age and adiposity. J Clin Invest 1981;67:1361-9.
Suppliers a. b. c. d. e. f.
IGF-I; Nichol's Institute Diagnostics, San Juan Capistrano, CA. immunoradiometric assay; Behringwerke AG, Marburg, Germany. radioimmunoassay; Farmos Diagnostica, Turku, Finland. radioimmunoassay; Diagnostic Products Corp., Los Angeles, CA. Amerlex M; Kodak Clinical Diagnostics Ltd, Amersham, UK. RSL~25I testosterone; ICN Biochemicals Inc., Diagnostics Division, Costa Mesa, CA. g. Coat-A-Count Free Testosterone, Diagnostic Products Corp., Los Angeles, CA. h. Statview; Abacus Concept, Inc., 1984 Bonita Avenue, Berkeley, CA.
Arch Phys Med Rehabil Vol 76, August 1995
Normal Concentrations of Serum lnsulinlike Growth Factor-1 in Late Polio o
Katharina Stibrant Sunnerhagen, MD, Bengt-Ake Bengtsson, MD, Per-Arne Lundberg, MSc, Kerstin Landin, MD, Gfiran Lindstedt, MD, Prof, Gunnar Grimby, MD, Prof ABSTRACT. Stibrant Sunnerhagen K, Bengtsson B-A, Lundberg P-A, Landin K, Lindstedt G, Grimby G. Normal concentrations of serum insulinlike growth factor-1 in late polio. Arch Phys Med Rehabil 1995;76: 732-5. • A recent study of 10 men with postpolio syndrome indicated a low secretion of growth hormone (GH) as reflected by serum insulin-like growth factor-I (IGF-1). Therefore, 87 patients were studied, 17 to 71 years after acute poliomyelitis, of whom 65 % reported the occurrence of new or increased weakness (ie, during the last 2 years) in muscles previously affected by polio. Serum IGF-1 concentrations in the patients were compared with those found in a reference population comprising 392 randomly selected individuals. No differences from the reference population values were observed. No correlation was found between IGF-I concentrations and the severity of the original polio affliction, the recovery status, the need for ambulation aids, or the presence of new symptoms. The results do not indicate a need for GH substitution treatment of patients with postpolio syndrome.
© 1995 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation Today, developed countries are facing a growing problem regarding the consequences of the polio outbreaks decades ago. There is an increased prevalence of individuals with weakness in the muscular system, 1'2 but the exact number of people suffering is not known. The following definition for the postpolio syndrome (PPS) has been suggested by Halstead and Rossi2: (1) a secured case of polio; (2) a recovery that was complete or partial both neurologically and functionally; (3) a period with neurological and functional stability of at least 15 years; (4) the appearance of two or more of health problems after this stable period such as unusual tiredness, muscle and/or joint pain, new weakness in muscles that previously have or have not been affected, functional deterioration, cold intolerance, or new atrophies; and (5) no other medical explanation for these health problems. With an increasing number of people who have had polio now experiencing new muscle weakness, the awareness of the problems associated with PPS is growing, as are hopes for a cure. Shetty and colleagues 3 recently caught the interest of many polio survivors when they noted lower concentrations of insulin-like growth factor-I (IGF-1) in 10 men with PPS Compared with a control population. IGF-1 is a peptide that stimulates protein synthesis and growth in many organs. It is synthesized in many cells and tissues, eg, muscle, kidney and liver, and the secretion of IGF-1 is largely dependent on the secretion of pituitary growth hormone as well as From the Department of Rehabilitation Medicine (Drs. Stibrant Sunnerhagen, Grimby), Department of Internal Medicine, Division of Endocrinology (Drs. Bengtsson, Landin), Department of Clinical Chemistry, (Mr. Lundberg, Dr. Lindstedt) Sahlgrenska University Hospital, University of Gtiteborg, Sweden. The study was supported in part by the Swedish Medical Research Council (project 3888) and King Gustav V 80-years foundation. Submitted for publication June 28, 1994. Accepted in revised form March 21, 1995. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprint requests to Katharina Stibrant Sunnerhageo, MD, Department of Rehabilitation Medicine, Guldhedsgatan 19, Sahlgrenska Hospital, S-413 45 G~3teborg, Sweden. © 1995 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation 0003-9993/95/7608-312653.00/0
Arch Phys Med Rehabil Vol 76, August 1995
thyroid and gonadal hormones. Therefore, low concentrations of IGF-1 might reflect low-growth hormone secretion. Growth hormone has profound anabolic actions, and decreased growth hormone secretion might very well play a role in causing the reported fatigue and weakness experienced by these patients. The observations by Shetty3 imply the possible use of growth hormone in order to stop or to lessen the deterioration of function in subjects with PPS, and this has evoked hope in the population of polio survivors. The report has been cited in a patients' organization newsletter in Sweden, and people have asked whether treatment was available with growth hormone. Therefore, to further clarify this matter, IGF-1 concentrations in a larger population of polio survivors have been studied. PATIENTS AND METHODS Postpolio Population
The study included 87 patients who all had a confirmed past history of polio. The majority of the subjects were identified either from the records at the hospitals in Gtteborg from the latest polio epidemic or they were recruited through a newspaper advertisement. This subpopulation had participated in another ongoing long-term follow-up taking place in this laboratory.4 To this population persons were added who themselves had called the department of rehabilitation medicine and volunteered to participate in any polio-related research project. The population consisted of 53 women and 34 men. The average age was 53 years (ranging from 17 to 83 years). Time since the polio onset was on average 45 years (minimum time was 17 years and maximum was 71 years). Mean body height was 172cm (SD 9) for men and 162 (SD 6) for women, mean body weight was 72.8kg (SD 9.5) for men and 62.3 (SD 8.6) for women, and body mass index (BMI (weight in kg/(length in m) 2) was 24.5 (SD 2.7) for men and 23.6 (SD 3.3) for women. All patients lived at home. Of those below retirement age (72 of 87), which in Sweden is 65 years, 46% were full-time employed, 14% partially employed by their own wish. Owing to healthrelated causes, 25% were partially retired and 15% were on
GROWTH FACTOR-I IN LATE POLIO, Stibrant Sunnerhagen
full-time early retirement. In other words, 40% were considered not having full working capacity because of their prior polio illness. No more information on work capacity was available. For functional assessment, the following evaluations were performed: 1. Abilities in certain daily activities, such as rising from a chair without using arms, choice of mobility, and use of ambulatory assistive devises, orthoses. 2. Perception of difficulties in daily activities, measured by part of the Functional Status Questionnaire (FSQ), 5 which is a self-administrated questionnaire. A fourgraded scale was used for each item, and subscores for different areas were calculated (for principles of calculation see FSQS). The following areas were calculated: basal (personal) activities of daily living (ADL); instrumental ADL (ambulation, transportation, household chores); and social activities. 3. Whether or not patients fulfilled the criteria for the PPS as defined by Halstead and Rossi 2 was noted. 4. Degree of polio involvement of muscles was classified in each of the four limbs and in the trunk using a five-score method as defined by Carrington Gawne. 6 I, unaffected muscle; II, subclinical polio (no perceived muscle weakness); III, stable polio (subjective muscle weakness, but no increase during the last 2 years); IV, unstable polio (new or increased weakness); V, severe muscle atrophy. The scores for the extremities and the trunk were added to produce a total polio score, which ranged from 7 to 25. The study was approved by the Ethical Committee of the authors' university.
Reference Population Subjects from the screening procedures for the WHO MONICA project (MONICA-MONltoring of trends and determinants in CArdiovascular diseases) in G6teborg, Sweden were used as a reference population. One thousand men and 1,000 women 25 to 64 years of age were randomly selected from the population census of the city. The participation rate was 71%, ie, 1,421 individuals out of whom 50 (47 to 53) were randomly selected in each age stratum (25 to 34, 35 to 44, 45 to 54, and 55 to 64 years) for both sexes, in a total 392 individuals] The mean value of IGF-1 for each stratum was calculated and presented with one SD.
Blood Sampling and Biochemical Analyses Venous blood samples were drawn in the morning from an antecubital vein. Serum IGF-1 was determined by a hydrochloric acid-ethanol extraction radioimmunoassay using authentic IGF-I" for labeling. 7 Serum thyrotropin (TSH) was determined by an immunoradiometric assay, b Serum thyroxine (T4) was determined by a single-antibody polyethyleneglycol-assisted radioimmunoassay c and 3,5,3'-triiodothyronine (T3) by a doubleantibody polyethyleneglycol-assisted radioimmunoassay, d Serum-free T4 and free T3 were determined by ligand analog radioimmunoassays.e Serum total testosterone was determined by a nonextraction radioimmunoassay using an antiserum against a C-19
733
Table 1: Bias and Imprecision of the Biochemical Determinations Bias
Score*
Analyte
%
Imprecision
Accuracy
IGF- 1* TSH* T4* Free T4* T3** Free T3 ~
-4 5 -5 -21 - 11 -21
1 1 0 1 2
4 1 2 1 2
* Scale for score is 0 to 13, 0 being best possible value. Value in relation to results presented in Ref 7. ** Values in relation to results from an international quality assessment program (942 laboratories).
derivative of testosterone (RSL~25I testosterone, f 3.4% crossreactivity against 5a-dihydrotestosterone). Serum-free testosterone was assayed by a ligand-analog technique. ~ Tables 1 and 2 show the details of the analytical performance.
Statistics Statistics were calculated using Statview. h To establish relationships between two variables, regression analysis was applied, and for comparison between groups, the MannWhitney U test was used, with significance at p < 0.05. Analysis of variance (ANOVA) and stepwise regression were also used. RESULTS
Activities in Daily Life A total of 57 polio persons (66%) were dependent on assistive devices for ambulation; canes or crutches were used by 39 persons, wheelchairs were used by 15 persons, and 33 persons depended on orthoses. Public transportation could be used by 55% of the population, and 45% were dependent on assisted transportation (taxi or special vehicle). FSQ scores, expressed as an average percentage of maximum values, were for personal ADL 87.2 (SD 17.5), for instrumental ADL 53.5 (SD 23.4), and for social activities 71.1 (SD 30.6). This indicates major difficulties in instrumental daily activities but not in personal ADL.
Symptoms Postpolio syndrome was present in 68 out of 87 patients. New muscular weakness during the last 2 years had occurred in 63 patients in one or more muscle group, whereas the other 24 reported unchanged status in muscles clinically affected by polio. In the other 5 patients, PPS was manifest as unusual tiredness, muscle and/or joint pain, and cold intolerance. The average polio score was 12, and it varied from 7 to 21. The polio score, being a measure of the level of impairment, correlated well to the scores of FSQ (personal ADL; r = 0.524, p < 0.0001, instrumental ADL; r = 0.518, p < 0.0001, social activities; r = 0.241, p < 0.05).
Hormone Concentrations The values for serum IGF-1 in the postpolio population decreased within the normal reference interval, with no difference between men or women (fig 1). There was a negative Arch Phys Med Rehabil Vol 76, August 1995
734
GROWTH FACTOR-I IN LATE POLIO, Stibrant Sunnerhagen
Table 2: Imprecision of the Biochemical Determinations as Calculated From Assay of Controls Included in Each Analytical Run Coefficient of Variation (%) Analyte IGF-1
TSH
T4
Free T4
T3
Free T3
Testosterone
Free testosterone
Concentration
Within (assays)
Between (assays)
Total Variation
120/zg/L 336 #g/L 1,007 #g/L 0,08 mU/L 1.73 mU/L 28,6 rnU/L 61.3 nmol/L 94.6 nmol/L 201 nrnol/L 7.3 prnol/L 13.7 pmol/L 40.2 pmol/L 1.68 nmol/L 1.93 nmol/L 4.53 nrnol/L 3.2 prnol/L 5.5 pmol/L 14.2 pmol/L 2.0 nmol/L 11.2 nmol/L 26.8 nrnol/L 45.4 prnol/L 104 prnol/L
6.2 6.0 6.3 6.1 4.1 5.1 4.9 3.0 2.7 1,7 1,9 1.8 2.9 2.3 2.9 2.5 1.7 2.2 5.9 5.9 4.8 7.1 4.6
4.3 2.7 2.5 4.1 3.6 10 2.8 2.4 2.5 1.2 1.5 3.0 5.6 3.5 2.9 0.3 1.6 1.1 12 6,0 6,1 8.6 5.8
7.6 6.6 6.8 7.3 5.5 11 5.7 3.8 3.6 2.1 2.4 3.5 6.3 4.2 4.1 2.5 2.4 2.5 13 8.4 7.8 11 7.3
The controls were prepared from pooled patients' serum samples, and aliquots of about 1 mL were kept in sealed glass ampoules at below -20°C. A new ampoule was taken for each assay run.
However, these authors used a nonextraction radioimmunoassay in which a fixed amount of a specific antiserum reacts with free and bound analyte under specified conditions. However, there are no reasons to believe that analytical artifacts would be responsible for the divergence between their results and these results, as interference in the assay used by Shetty 3 would be expected to cause elevation rather than decrease in values. One possible cause of difference in study outcome might be the fact that the total amount of serum IGF- 1 is related to the concentration of its binding proteins, IGF BP-3 in particular. High BP-3 concentrations therefore would elevate IGF-1 values. However, BP-3 is a growthhormone dependent protein; thus low rather than high concentrations would be expected in growth-hormone deficiency. The reason for the low values observed in the 10 men reported by Shetty 3 was considered by those authors not to
IGF-1 ,00 A ~g/i
4 4-
300
4-
4-
200 4-
correlation between age at follow-up and serum concentrations of IGF-1 (r = 0.447, p < 0.0001) but not between age at onset of polio and IGF-1 concentrations or between duration since onset and IGF-1 (data not shown). No relationship was noted between serum concentrations of IGF-1 and height, weight, or BMI (data not shown). There was no difference in the correlation between concentration of IGF1 and age between patients with or without new muscular weakness (fig 2). Neither was there any correlation between concentration of IGF-1 and the degree of polio score. No differences in IGF-1 concentration were found between the groups with or without presence of postpolio syndrome or occurrence of new symptoms or not (data not shown). No difference in concentrations of IGF-1 was found when comparing patients with or without ambulatory assistive devices (data not shown). There was no correlation between activity level assessed with the questionnaire FSQ and the concentration of IGF-1 (data not shown). The concentration of serum thyrotropin and total and free thyroxine (T4) and 3,5,Y-triiodothyronine (T3) were within the normal reference intervals (data not shown). The testosterone concentrations (both total and free) were also normal (data not shown). No differences in these hormone concentrations were noted between the group with new symptoms and those with a stable condition (data not shown). DISCUSSION The present findings of serum IGF-1 concentrations in postpolio patients do not support the conclusions by Shetty 3 that such patients would be characterized by low-circulating IGF-I concentrations as in growth hormone deficiency. Arch Phys Med Rehabil Vol 76, August 1995
+
100
0
I
0
20
i
60
80 100 AGE years
WOMEN
IGF-1 400~g/I
i
40
B
300 I
4-+
4~
l**J * 4-~
200"
4-d P4÷ 1
4-+
100"
0
i
i
|
20
40
60
1
i
80 100 AGE years
Fig 1 - - R e l a t i o n s h i p between serum concentration of IGF-1 in polio patients (crosses) and age (A) men, (B) women. Mean values +_1 SD are given for each age stratum of the reference population (filled triangles and vertical line) are shown.
GROWTH FACTOR-I IN LATE POLIO, Stibrant Sunnerhagen
The only relationship observed was between age at followup and serum concentrations of IGF-1. Decreased IGF-1 concentration with age has been reported, l° and this was reaffirmed in the randomized population study. 7 There was no relationship between physical activity and the levels of IGF-1, according to results from Shetty's study 3 and the population study. 7 Neither was there any correlation with the extent of polio involvement of muscles (polio score).
IGF-1 400 ~g/I ra
[]
300
0 • •
nunu
an
SUMMARY
o
•
I
The hypothesis that lower concentrations of IGF-1 occur in patients with postpoliomyelitis sequelae, and new muscle weakness could not been confirmed. Today, therefore, there is no indication for using growth-hormone treatment in this patient group with the hope of diminishing postpolio symptoms.
200 ~= •m
100
o
I
I
0
20
I
40
60
I
I
80 100 AGE years
Fig 2--Relationship between serum concentration of IGF-1 and age in polio patients with (filled squares) and without (open squares) new or increased muscle weakness (r = 0.447 and p <
735
0.0001).
be physical inactivity. Whether other hormonal factors than growth hormone were involved can only be speculated. The secretion of IGF-1 may be affected also by nutritional status and other hormones such as thyroid hormones and gonadal hormones, but no such measurements were reported by Shetty. 3 The patients in this study did not show any abnormalities in thyroid or gonadal functions. Pituitary insufficiency with accompanying growth-hormone deficiency in children leads to dwarfism, but in adults more subtle changes occur, such as a feeling of weakness. Both growth hormone deficiency and increased secretion such as in acromegaly have been associated with increased risk of cardiovascular disease. 8'9 There is no known recognized hormonal imbalance such as pituitary insufficiency associated with poliomyelitis. This does not exclude the possibility that the patients observed by Shetty, 3 for reasons so far unknown, had perturbations in the central nervous regulations of factors affecting growth-hormone IGF-1 homeostasis. Average age in the two studies was comparable (54 compared with 53 years). Shetty's study 3 included only 10 men and were compared with 94 individuals recruited through advertisements, as well as 28 immobilized totally dependent bedridden men from a nursing home. Their control population had more individuals in the lowest and highest age group, but there were only 16 subjects in the 50 to 60 years age group where most of the patients were included. This should be compared with the present study of 87 postpolio patients of either gender and 392 randomized control individuals, evenly distributed for sex and age.
Acknowledgment: The authors acknowledge the valuable help from Marita Hedberg with the statistics and figures. This study would not have been possible without the help from the subjects with postpolio who are willing to give their time for research. References 1. Dalakas MC, Elder G, Hallett M, Ravits J, Baker M, Papadopoulos N, et al: A long-term follow-up study of patients with poliomyelitis neuromuscular symptoms. N Engl J Med 1986;314:959-63. 2. Halstead LS, Rossi CD: Post-polio syndrome: clinical experience with 132 consecutive outpatients. In: Halstead LS, Wiechers S, editors. Research and clinical aspects of the late effects of poliomyelitis. White Plains, NY: March of Dimes Birth Defects Foundation Orig Art Series, 1987;23:13-26. 3. Shetty KR, Mattson DE, Rudman IE, et al: Hyposomatomedinemia in men with post-poliomyelitis syndrome. J Am Ger Soc 1991;39:18591. 4. Einarsson G, Grimby G: Disability and handicap in late poliomyelitis. Scand J Rehabil Med 1990;22:113-21. 5. Jette AM, Davies AR, Cleary PD, Calkins DR, Rubenstein LV, rink A, et ah The functional status questionnaire. Reliability and validity when used in primary care. J Gen Intern Med 1986; 1:143-9. 6. Carrington Gawne A: Strategies for exercise prescription in post-polio patients. In: Halstead LS, Grimby G, editors. Post-polio syndrome. Philadelphia, Hanley & Belfus Inc, 1995:141-64. 7. Landin-Wilhelmsen K, Wilhelrnsen L, Lappas G, Rosdn T, Lindstedt G, Lundberg P-A, et al: Serum insulin growth factor I in a random population sample of men and women: relation to age, sex, smoking habits, coffee consumption and physical activity, blood pressure and concentration of plasma lipids, fibrinogen, parathyroid hormone and osteocalcin. Clin Endocrinol 1994;41:351-7. 8. Rosrn T, Bengtsson B-A: Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990;336:285-8. 9. Bengtsson B-A, Edrn S, Ernest I, Odrn A, Sj~gren B: Epidemiology and longterm survival in acromegaly. Acta Med Scand 1988;223:32735. 10. Rudman D, Kutner MH, Rogers CM, Lubin Mr, Fleming GA, Bain RP: Impaired growth hormone secretion in the adult population. Relation to age and adiposity. J Clin Invest 1981;67:1361-9.
Suppliers a. b. c. d. e. f.
IGF-I; Nichol's Institute Diagnostics, San Juan Capistrano, CA. immunoradiometric assay; Behringwerke AG, Marburg, Germany. radioimmunoassay; Farmos Diagnostica, Turku, Finland. radioimmunoassay; Diagnostic Products Corp., Los Angeles, CA. Amerlex M; Kodak Clinical Diagnostics Ltd, Amersham, UK. RSL~25I testosterone; ICN Biochemicals Inc., Diagnostics Division, Costa Mesa, CA. g. Coat-A-Count Free Testosterone, Diagnostic Products Corp., Los Angeles, CA. h. Statview; Abacus Concept, Inc., 1984 Bonita Avenue, Berkeley, CA.
Arch Phys Med Rehabil Vol 76, August 1995