A mechanism-based pain sensitivity index to characterize knee osteoarthritis patients with different disease stages and pain levels.

BACKGROUND: In a cohort of well-characterized patients with different degrees of knee osteoarthritis (OA) and pain, the aims were to utilize mechanism-based quantitative sensory testing (QST) to (1) characterize subgroups of patients; (2) analyse the associations between clinical characteristics and QST; and (3) develop and apply a QST-based knee OA composite pain sensitivity index for patient classification. METHODS: Two hundred seventeen OA pain patients and 64 controls were included. Kellgren and Lawrence (KL) grading scores were obtained, and pressure pain thresholds (PPTs), temporal summation of pain to repeated painful pressure stimulation and conditioning pain modulation (CPM) were assessed. Associations between pain score/area/duration, radiological findings and QST-related parameters were analysed. A pain sensitivity index was developed and applied based on PPT, temporal summation and CPM. z-Score, as statistical tool, was calculated for statistically comparing the pain index of a single patient with a healthy control group. RESULTS: High knee pain associated with low KL grade showed particular signs of pain sensitization. Patients showed significant associations between clinical knee pain intensity/duration and lowering of knee PPTs (p < 0.01), facilitation of temporal summation (p < 0.01), reduction of CPM function (p < 0.01) and high pain sensitivity index (p < 0.01). The index classified 27-38% of the OA patients and 3% of the controls as highly sensitive with no association to KL. The index increased for high knee pain intensities and long pain duration. CONCLUSIONS: Radiological scores, contrary to clinical pain intensity/duration, were poorly associated with QST parameters. The pain sensitivity index could classify OA patients with different degrees of OA and pain.

Identification and characterisation of osteoarthritis patients with inflammation derived tissue turnover.

OBJECTIVES: Osteoarthritis (OA) is a degenerative disease with a subset of patients experiencing joint inflammation, but C-reactive protein (CRP) has shown limited use in OA as a diagnostic marker. The aim was to identify subpopulations of patients with high or low levels of acute (high sensitive CRP (hsCRP)) and/or matrix metalloproteinase (MMP) derived inflammation (CRPM) and investigate the subpopulations' association with biomarkers of collagen degradation and Kellgren-Lawrence (KL) score. METHODS: hsCRP, CRPM and MMP-degraded type I, II and III collagen (type I collagen degraded by MMP (C1M), type II collagen degraded by MMP (C2M) and type III collagen degraded by MMP (C3M)) were quantified by enzyme linked immunosorbent assays (ELISA) in serum of 342 patients with symptomatic knee OA of which 60 underwent total knee replacement (TKR). KL was obtained. Patients were divided into quartiles by hsCRP and CRPM levels, where Q1 and Q4 were low or high in both. The biomarker levels of healthy adults provided in the ELISA kits were used as reference level. RESULTS: hsCRP was elevated in TKR (5.9(3.6-8.2 95% confidence interval (CI)) µg/mL) compared to reference level (3 µg/mL), while CRPM was highly elevated with OA independent of KL (10-14 ng/mL) compared to reference level (5 ng/mL). Q4 had higher KL than Q1 (P < 0.001), Q2 (P = 0.017) and Q3 (P < 0.001). C1M, C2M and C3M were lowest in Q1. C1M was elevated in Q3 compared to Q2 (P < 0.001), whereas C3M was lower (P = 0.019). CONCLUSION: A bigger proportion of patients were elevated in CRPM compared to hsCRP, indicating MMP-derived inflammation as a component of OA. Moreover, the levels of MMP-degraded collagens differed between the subgroups segregated by inflammation, indicating distinctively different subpopulation selected by inflammation.

Changes in 25-Hydroxyvitamin D3 to oral treatment with vitamin D3 in postmenopausal females with osteoporosis.

SUMMARY: This study reports on oral treatment with different doses of vitamin D3 ranging from 25 to 200 microg in females with 25-hydroxyvitamin D3 levels < 60 nmol/L screened for participation in an osteoporosis trial. A guidance to safely and efficiently achieve 25-hydroxyvitamin D3 levels > 60 nmol/L is presented. INTRODUCTION: The importance of vitamin D for skeletal health has been implemented in clinical trials in osteoporosis. The threshold of 25-hydroxyvitamin D for inclusion has changed from 30 to 60 nmol/L. This study reports on oral treatment with different doses of vitamin D3 in females with 25-hydroxyvitamin D3 levels < 60 nmol/L. METHODS: In 131 postmenopausal females screened for participation in an osteoporosis trial, the 25-hydroxyvitamin D3 concentration was < 60 nmol/L. They were treated with 25 (n = 22), 50 (n = 19), 75 (n = 19), 100 (n = 41) or 200 microg (n = 30) of vitamin D3 daily for at least 10 days. RESULTS: In the females treated with 25, 50, 75, 100 and 200 microg of vitamin D3 daily the 25-hydroxyvitamin D3 concentrations increased significantly from 32.4 +/- 2.7 (mean +/- SEM) to 50.8 +/- 2.9, from 46.7 +/- 2.8 to 65.8 +/- 2.6, from 41.6 +/- 2.7 to 67.4 +/- 2.9, from 46.7 +/- 1.4 to 64.4 +/- 2.2 and from 42.1 +/- 2.0 to 71.2 +/- 2.8 nmol/L, respectively (p < 0.001). S-calcium increased significantly but within the reference range (p < 0.006). CONCLUSION: Oral vitamin D3 safely increased 25-hydroxyvitamin D3 concentrations in all females above 60 nmol/L. This study demonstrates how to achieve the new recommended 25-hydroxyvitamin D concentrations within the screening period of a clinical trial.

Fractures in patients with primary idiopathic hypothyroidism.

AIM: To study fracture risk and risk factors for fractures in patients with primary idiopathic hypothyroidism (ICD 10: E03.9). DESIGN: Historical follow-up. MATERIAL AND METHODS: A self-administered questionnaire was issued to 628 patients with primary idiopathic levothyroxine-substituted hypothyroidism. A total of 412 (65.6%) responded and of these, 408 could be analyzed. The 408 respondents were age- (+/- 5 years) and gender-matched with 408 normal controls randomly selected from the background population who responded to the same questionnaire. RESULTS: Overall fracture risk was increased in patients compared to controls (relative risk: RR = 1.6, 95% CI: 1.0-2.5). However, the increase was temporary and limited to the period within the first 2 years after the diagnosis of hypothyroidism (RR = 3.1, 95% CI: 1.4-7.0). Before the diagnosis and more than 2 years after the diagnosis, the fracture risk in patients did not deviate from that of the controls. The increase in fracture risk was only significant in the age group above 50 years (RR = 1.8, 95% CI: 1-3.2), and was limited to the forearms (RR = 3.0, 95% CI: 1.4-6.3 for the entire patient population). CONCLUSIONS: There was a temporary increase in fracture risk within the first 2 years after diagnosis of primary idiopathic hypothyroidism. The fracture risk was mainly increased in the age group above 50 years, and the increased risk was limited to the forearms.

Diagnosis of growth hormone (GH) deficiency in adults with hypothalamic-pituitary disorders: comparison of test results using pyridostigmine plus GH-releasing hormone (GHRH), clonidine plus GHRH, and insulin-induced hypoglycemia as GH secretagogues.

The insulin tolerance test (ITT) is widely accepted as the method of choice to evaluate GH secretion capacity in adults with hypothalamic-pituitary disorders. However, the test is not suitable in the elderly or in patients with cardiovascular disease or seizure disorders. In recent years alternatives to the ITT have been introduced. The purpose of the present study was to investigate the diagnostic outcome with the ITT, the pyridostigmine plus GHRH (PD + GHRH) test, the clonidine plus GHRH (CLO+GHRH) test, and insulin-like growth factor I (IGF-I) in an unselected group of patients with hypothalamic-pituitary disease. An evaluation of the reproducibility of the different stimulation tests was included in the study. Based on repeated testing with the various GH stimulation tests in healthy adult males and females, the lower limits of normality for the ITT, the PD+GHRH test, and the CLO+GHRH test were 3.92, 12.8, and 19.0, microg/L, respectively. A consecutive group of 26 unselected patients with hypothalamic-pituitary disorders, 13 males and 13 females (median age, 44 ys), were tested twice with all stimulation tests, except that only 10 patients were tested once with the CLO+GHRH test due to side-effects related to clonidine. The peak GH responses between test 1 and test 2 correlated significantly in both the ITT and the PD + GHRH test (P < 0.02), and no significant difference was observed in the median peak response to repeated testing. In addition, no sex difference was observed. The coefficients of variation (CV) were 96% (ITT) and 45% (PD + GHRH), but in the majority of patients low values were repeatedly low. The peak GH response was significantly higher during the PD+GHRH test than during the ITT (P = 0.008). In the 10 patients tested with the PD+GHRH and CLO+GHRH tests there was no significant difference in the peak GH response (P = 0.398). When the test specific cut-off values were used, no significant difference in diagnostic outcome was observed between the various tests (P > 0.3). In contrast, the diagnosis obtained with IGF-I differed significantly from all GH stimulation tests (P < 0.03). Twenty (77%) and 22 (85%) patients were diagnosed to be GH deficient with the ITT and the PD+GHRH test, respectively. Of the 14 patients with multiple pituitary failure (>2 hormones affected), GH deficiency was present in more than 90% regardless of the type of stimulation test used. The IGF-I levels were only subnormal in 42% of the patients and did not correlate with the peak GH responses in any of the stimulation tests (P > 0.05). Except for 1 patient all patients with subnormal IGF-I were GH deficient in all stimulation tests. It is concluded that in patients with hypothalamic-pituitary disease and a normal IGF-I level 2 stimulation tests should be performed to establish a diagnosis of GH deficiency. In patients with a subnormal IGF-I value a single GH stimulation test should be sufficient to confirm the presence of GH deficiency.

Differences in reproducibility and peak growth hormone responses to repeated testing with various stimulators in healthy adults.

In healthy adults, GH responses to provocative testing are variable between subjects. Information on the intra-subject variability is limited, despite the importance attached to GH stimulation tests in the diagnosis of GH deficiency. We have investigated and compared the variability of different GH stimulation tests in a group of healthy control subjects. In 16 healthy non-obese adults, two insulin tolerance tests (ITT) (0.15 IU/kg body weight i.v. and a fall in blood glucose < or = 2.2 mmol/l) two GHRH tests (1 microgram/kg body weight i.v.), and two clonidine (CLO) (300 micrograms p.o.) + GHRH (60 min later) tests were performed in the morning after an overnight fast. A pyridostigmine (PD) (120 mg p.o. 60 min before GHRH) + GHRH test was performed twice in an extended group of 31 healthy adult subjects. A wide range of GH responses was observed. Both during the ITT and the GHRH test, low values in the range generally recognized to reflect impairment of GH secretory status were encountered. The median (range) peak GH responses in tests 1 and 2 were: (a) ITT: 14.4 micrograms/l (4.1-71.1) and 14.0 micrograms/l (0.09-69.5), (b) GHRH test: 21.7 micrograms/l (0.71-56.2) and 18.4 micrograms/l (1.6-55.1); (c) CLO + GHRH test: 57.4 micrograms/l (22.9-209) and 65.8 micrograms/l (12.2-206); (d) PD + GHRH test: 36.5 micrograms/l (9.1-125) and 44.6 micrograms/l (6.3-101). The coefficients of variation (CV) were: 58% (ITT), 45% (GHRH), 46% (CLO + GHRH) and 26% (PD + GHRH). The peak GH responses were significantly different in all tests (CLO + GHRH > PD + GHRH > GHRH > ITT). In the individual subject, there was no systematic correlation between the peak GH responses in the different stimulation tests. In conclusion, we found that the stimulated GH responses were highly variable in all tests, and that the peak GH responses differed. Test results in patients should be evaluated against test-specific reference values, and caution is justified in the interpretation of low responses in a single test.

Reproducibility of growth hormone and cortisol responses to the insulin tolerance test and the short ACTH test in normal adults.

Previous studies have demonstrated poor reproducibility of growth hormone (GH) responses to insulin tolerance testing (ITT). In order to investigate whether this is a particular feature of GH secretion we studied the reproducibility of the GH and cortisol responses to ITT simultaneously and also compared the latter with the reproducibility during short ACTH testing (SAT). Eight normal men (age 26-50) and 8 normal women (age 27-45) underwent 2 ITT and 2 SAT. In the ITT no systematic differences were observed between test 1 and 2 concerning blood glucose, GH and cortisol before and after stimulation. Similar results were obtained for cortisol during SAT. During ITT reproducibility was good for the cortisol response (coefficient of variation [CV] 10%, no sex differences) but poor for the GH response (CV 41% in men, 104% in women). Reproducibility was good for the cortisol response in SAT (CV 12%, no sex differences). The peak cortisol values during ITT (mean 585, range 448-775 nmol/l) were significantly lower than in the 2 SAT (mean 723, range 486-918 nmol/l). We conclude that the GH response during testing is more variable than the cortisol response. This could account for some of the difficulties encountered in the diagnosis of GH deficiency in adults.

Test of growth hormone secretion in adults: poor reproducibility of the insulin tolerance test.

The insulin tolerance test (ITT) is regarded as the most reliable provocative test in the diagnosis of growth hormone (GH) deficiency in adults. In the present study the test was evaluated by investigating the range of GH responses in normal adult males and females and the intra-individual reproducibility of the test. Sixteen healthy non-obese adults, eight males (median age 31.5 years) and eight females (median age 31.8 years) were tested twice with the ITT, with a minimum of 72 h between each test. The females were tested between day 3 and day 10 of their menstrual cycles. Adequate hypoglycemia was achieved in all cases with a median nadir blood glucose of 1.3 mmol/l (range 0.8-2.0). Growth hormone in serum was measured by immunoradiometric assay and low values were confirmed by a different assay. Median peak GH concentration responses to the ITT were: in males 27.9 micrograms/l, range 5.0-71.1 (test 1) and 30.5 micrograms/l, range 7.9-69.5 (test 2); and in females 9.0 micrograms/l, range 4.1-17.9 (test 1) and 8.4 micrograms/l, range 0.09-42.4 (test 2). The rise in GH concentration during the ITT was higher in males than in females. In the males, all stimulated GH values were > or = 5.0 micrograms/l. In the females, four out of 16 tests gave values below 5.0 micrograms/l and in one test the GH value was around the detection limit of the assays. There was poor reproducibility during repeated testing, with no correlation between the results of the two tests. The results did not correlate to the magnitude of the hypoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone and thyroid function: is secondary thyroid failure underdiagnosed in growth hormone deficient patients?

Thyroid hormones and the GH/IGF-1 system show considerable mutual interference which may have physiological, pathophysiological and clinical importance. GH therapy of children and adults may induce a fall in serum T4, which seems to be due to an effect on the deiodination of T4 to T3. Animal studies suggest that the alterations in thyroid hormones in tissue may be much more prominent than the changes observed in serum. It is possible that the GH deficiency seen in the majority of patients with pituitary/hypothalamic disorders may mask secondary hypothyroidism in some patients by giving a relatively high serum T4. GH therapy may then unmask the hypothyroidism. In accordance with such a mechanism GH deficient children evaluated thoroughly to exclude secondary thyroid failure before GH administration do not develop thyroid insufficiency during GH substitution therapy. It is suggested that thyroid insufficiency should be considered in GH deficient patients with low normal serum T4.

[Abnormal flora in the small intestine. Diagnostic evaluation of the H2 breath test]. / Abnorm tyndtarmsflora. Evaluering af H2-pusteprøve ved diagnosticering.

Jejunal aspiration in order to diagnose intestinal bacterial overgrowth is more unpleasant for patients than breath testing. The object of this study was to compare the results of the glucose H2 breath test and the lactulose H2 breath test with the results of intestinal culture. On separate days, cultures of intestinal fluid collected from the Treitz region, glucose H2 breath tests (80 g glucose) and lactulose H2 breath tests (15 g lactulose) were undertaken in 20 patients with diseases predisposing to small intestinal bacterial overgrowth and in 20 controls. Twelve patients had bacterial overgrowth. Abnormal glucose H2 breath tests were observed in 11 patients, ten of whom had bacterial overgrowth. Glucose H2 breath tests were normal in seven out of eight patients without bacterial overgrowth. Only four patients had an abnormal lactulose H2 breath test. It is concluded that the glucose H2 breath test is acceptable for diagnosing bacterial overgrowth, whereas the lactulose H2 breath test in not.

Impaired growth hormone secretion in patients operated for pituitary adenomas.

The frequency of growth hormone (GH) deficiency in patients operated for pituitary neoplasms of various size and type was investigated using the insulin tolerance test. 45 patients were included in the study. 20 of the patients had a non-hormone secreting pituitary neoplasm, 9 had GH-, 6 ACTH-, 7 prolactin secreting adenomas and 3 had a craniopharyngeoma. Complete endocrinological examination was obtained in all patients after pituitary surgery. Apart from patients operated for GH secreting adenomas, GH deficiency was very common after pituitary surgery (92%), even in patients operated for small lesions. Among the 45 patients LH/FSH deficiency was found in 33%, ACTH in 33%, TSH in 18% and ADH deficiency in 9% of the patients. In this study, impaired GH secretion was found to be independent of the size of the tumors and was present in nearly all patients after pituitary surgery (with exception of GH secreting adenomas). Deficiencies of other pituitary hormones were predominantly observed after surgery for large tumors.

Hypercalcaemic crisis after excessive topical use of a vitamin D derivative.

Topical application of the vitamin D analogue calcipotriol has been found to be of clinical value in the treatment of dermatological disorders. This is considered to be safe with respect to alterations in calcium homeostasis. We report a 17-year-old female patient who developed hypercalcaemic crisis after excessive use of calcipotriol for ichthyosis. The clinical condition and serum calcium improved after cessation of calciprotiol treatment and rehydration with intravenous fluids and electrolytes. The case emphasizes the importance of limiting the topical use of calcipotriol as recommended by the manufacturer.

[Transient abnormal Q-waves]. / Forbigående patologiske Q-takker.

We present a case of transient abnormal Q-waves (TAQ) and a review of the literature. TAQ are defined as abnormal Q-waves, which disappear within ten days. They are most often seen in patients with ischemic heart disease (IHD) but are also seen in other conditions. Brief episodes of myocardial ischemia giving rise to reversible biochemical and ultrastructural myocardial changes, resulting in transient ECG changes, provide an accepted theory for the pathogenesis of TAO. Investigations have shown that the occurrence of exercise-induced TAQ may be a symptom of IHD. It is impossible to distinguish TAQ from Q-waves induced by myocardial infarction. Appearance of TAQ during exercise-testing frequently indicates IHD.