Possible role for glucagon in the control of Paget's disease of bone.

Paget's disease of bone is characterised by overactive osteoclasts that resorb bone at a higher rate than normal. Osteoblasts attempt to repair the damage by laying down new bone which in turn is resorbed leaving a chaotic pattern of lytic and dense sclerotic bone behind. Deformed bone enlarges, becomes vascularised, bends and fractures. No bone is exempt but the skull, pelvis, vertebrae and long bones are commonly affected. Pressure from pagetic bone impinges on the auditory, facial, optic, trigeminal nerves and the spinal cord, risking paraplegia or quadriplegia. Vascular complications include cardiac failure and vertebrobasilar insufficiency. Serum alkaline phosphatase and urine N-telopeptide were used to assess response to treatment with porcine, salmon and human calcitonins, glucagon and bisphonates given alone or in combination. Glucagon has few side effects and controls the disease very rapidly. It can be given alone but because remissions last a few months, repeat courses may be necessary to achieve a long-term permanent quiescent bone state. If complete disease remission is not achieved with the hormone alone, an oral or intravenous bisphosphonate is given at the end of glucagon treatment. Other options are a second-generation bisphosphonate given orally to patients who decline parenteral medication. It remains to be seen whether glucagon affects other bone disorders.

Antenatal thyroid screening and childhood cognitive function.

BACKGROUND: Children born to women with low thyroid hormone levels have been reported to have decreased cognitive function. METHODS: We conducted a randomized trial in which pregnant women at a gestation of 15 weeks 6 days or less provided blood samples for measurement of thyrotropin and free thyroxine (T(4)). Women were assigned to a screening group (in which measurements were obtained immediately) or a control group (in which serum was stored and measurements were obtained shortly after delivery). Thyrotropin levels above the 97.5th percentile, free T(4) levels below the 2.5th percentile, or both were considered a positive screening result. Women with positive findings in the screening group were assigned to 150 µg of levothyroxine per day. The primary outcome was IQ at 3 years of age in children of women with positive results, as measured by psychologists who were unaware of the group assignments. RESULTS: Of 21,846 women who provided blood samples (at a median gestational age of 12 weeks 3 days), 390 women in the screening group and 404 in the control group tested positive. The median gestational age at the start of levothyroxine treatment was 13 weeks 3 days; treatment was adjusted as needed to achieve a target thyrotropin level of 0.1 to 1.0 mIU per liter. Among the children of women with positive results, the mean IQ scores were 99.2 and 100.0 in the screening and control groups, respectively (difference, 0.8; 95% confidence interval [CI], -1.1 to 2.6; P=0.40 by intention-to-treat analysis); the proportions of children with an IQ of less than 85 were 12.1% in the screening group and 14.1% in the control group (difference, 2.1 percentage points; 95% CI, -2.6 to 6.7; P=0.39). An on-treatment analysis showed similar results. CONCLUSIONS: Antenatal screening (at a median gestational age of 12 weeks 3 days) and maternal treatment for hypothyroidism did not result in improved cognitive function in children at 3 years of age. (Funded by the Wellcome Trust UK and Compagnia di San Paulo, Turin; Current Controlled Trials number, ISRCTN46178175.).

Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer.

BACKGROUND: It is not known whether low-dose radioiodine (1.1 GBq [30 mCi]) is as effective as high-dose radioiodine (3.7 GBq [100 mCi]) for treating patients with differentiated thyroid cancer or whether the effects of radioiodine (especially at a low dose) are influenced by using either recombinant human thyrotropin (thyrotropin alfa) or thyroid hormone withdrawal. METHODS: At 29 centers in the United Kingdom, we conducted a randomized noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Patients (age range, 16 to 80 years) had tumor stage T1 to T3, with possible spread to nearby lymph nodes but without metastasis. End points were the rate of success of ablation at 6 to 9 months, adverse events, quality of life, and length of hospital stay. RESULTS: A total of 438 patients underwent randomization; data could be analyzed for 421. Ablation success rates were 85.0% in the group receiving low-dose radioiodine versus 88.9% in the group receiving the high dose and 87.1% in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid hormone withdrawal. All 95% confidence intervals for the differences were within ±10 percentage points, indicating noninferiority. Similar results were found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose radioiodine plus thyrotropin alfa (90.2%). More patients in the high-dose group than in the low-dose group were hospitalized for at least 3 days (36.3% vs. 13.0%, P<0.001). The proportions of patients with adverse events were 21% in the low-dose group versus 33% in the high-dose group (P=0.007) and 23% in the thyrotropin alfa group versus 30% in the group undergoing thyroid hormone withdrawal (P=0.11). CONCLUSIONS: Low-dose radioiodine plus thyrotropin alfa was as effective as high-dose radioiodine, with a lower rate of adverse events. (Funded by Cancer Research UK; ClinicalTrials.gov number, NCT00415233.).

Do high risk patients alter their lifestyle to reduce risk of colorectal cancer?

BACKGROUND: Colorectal cancer (CRC) may be reduced by healthy lifestyle behaviours. We determined the extent of self-reported lifestyle changes in people at increased risk of CRC, and the association of these reports with anxiety, risk and knowledge-based variables. METHODS: We randomly selected 250 participants who had undergone surveillance colonoscopy for family history of CRC. A telephone interview was conducted, recording demographics and family history. Self-reported lifestyle change due to thoughts about CRC across a range of dietary and lifestyle variables was assessed on a four-point scale. Participants' perceptions of the following were recorded: risk factor knowledge, personal risk, and worry due to family history. General anxiety was assessed using the GAD-7 scale. Ordinal logistic regression was used to calculate adjusted results. RESULTS: There were 148 participants (69% response). 79.7% reported at least one healthy change. Change in diet and physical activity were most frequently reported (fiber, 63%; fruit and vegetables, 54%; red meat, 47%; physical activity, 45%), with consumption of tobacco, alcohol, and body weight less likely (tobacco, 25%; alcohol, 26%; weight 31%). People were more likely to report healthy change with lower levels of generalized anxiety, higher worry due to family history, or greater perceived knowledge of CRC risk factors. Risk perception and risk due to family history were not associated with healthy changes. CONCLUSIONS: Self-reported lifestyle changes due to thoughts about CRC were common. Lower general anxiety levels, worries due to family history, and perceived knowledge of risk factors may stimulate healthy changes.

Improving early detection of colorectal cancer in Aotearoa New Zealand; how do the direct access criteria perform?

AIM: Colorectal cancer (CRC) is a common malignancy in New Zealand, and there is increasing pressure on investigative resources for diagnosis. The national direct access referral guidelines from the Ministry of Health (MoH) guide who should be referred for investigation, but their performance in detecting CRC and other significant diseases has not been reported previously. This paper describes the yield, by direct access criterion, of all referrals through the direct access pathway to the Canterbury District Health Board (CDHB) during 2018. METHODS: First referrals received through the direct access colonoscopy/computed tomography colonography (CTC) pathway for 2018 were audited. Patients were assigned to symptom groups corresponding to the MoH direct access criteria, and demographic data were captured. Diagnostic outcomes were collected through analysis of all endoscopy, CT colonography and histology reports in the 18 months following referral for primary analysis, with further follow-up through to May 2021 to detect missed pathology. RESULTS: Three thousand two hundred referrals were analysed, and 88.5% underwent colorectal investigation. 128 CRC were diagnosed, 176 advanced polyps, 49 cases of inflammatory bowel disease (IBD) and there were 56 other significant findings. The yield by category for the direct access criteria varied between 0-15.0%, and one urgent criterion had a CRC yield lower than two semi-urgent categories. For patients whose symptoms met at least one of the criteria, excluding those referred with suspected IBD, the combined CRC yield was 4.9%, compared with 1.8% in those who did not meet criteria. The sensitivity and specificity of the criteria for CRC (excluding IBD) was 90% and 23% respectively. There were no CRC detected during the extended follow-up period. CONCLUSION: In this referred population, the MoH direct access colonoscopy/CTC criteria varied significantly in their CRC yield, with an arbitrary distinction between urgent and semi-urgent categories. The low specificity of the criteria means the number needed to investigate to detect one CRC was one in 22. Improved diagnostic algorithms are urgently required to improve both the sensitivity and specificity, thereby more appropriately allocating finite resources to those patients who are most in need of investigation.

Measurement of urinary free cortisol by tandem mass spectrometry and comparison with results obtained by gas chromatography-mass spectrometry and two commercial immunoassays.

BACKGROUND: Determination of urinary free cortisol (UFC) is an important adjunct for the assessment of adrenal function. In this study, we have analysed cortisol concentrations in urine samples by gas chromatography-mass spectrometry (GC-MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and two immunoassays. The results were compared with GC-MS. The interference of cortisol ring-A metabolites in immunoassays was also assessed. METHODS: The GC-MS technique involved solvent extraction, LH-20 clean-up and derivatization. Only solid-phase extraction procedure was used for LC-MS/MS. The samples were analysed in positive electro-spray ionization mode, monitoring the transitions for cortisol and deuterated-cortisol at m/z 363.3 > 121.2 and m/z 365.3 > 122.2, respectively. Immunoassays were performed according to the manufacturer's instructions. RESULTS: When compared with GC-MS results both immunoassays (Coat-A-Count; approximately 1.9-fold, Centaur; approximately 1.6-fold) overestimated UFC concentrations. Cortisol ring-A dihydro- and tetrahydrometabolites contribute significantly to this overestimation. There was no interference by these metabolites in either GC-MS or LC-MS/MS methods. The sensitivity of the LC-MS/MS procedure was 2 nmol/L and the intra- and inter-assay variations were <5% in each quality-control sample. The comparison of the UFC results achieved by assaying the study samples with GC-MS and LC-MS/MS indicated that the agreement between the two methods was excellent (LC-MS/MS = 1.0036GC-MS - 0.0841; r2 = 0.9937). CONCLUSIONS: The interference of cortisol ring-A metabolites in immunoassays contribute to overestimation of UFC concentrations. The LC-MS/MS procedure had the sensitivity, specificity, linearity, precision and accuracy for the determination of UFC concentrations. The method is suitable for routine use provided that method-dependant reference values are established.

Inhibition of cancer cell mitosis by reducing the availability of phosphate.

The addition of phosphate groups is an essential requirement for the proper functioning of cyclin and cyclin dependent kinase which control various stages in the mitotic division of cancer cells. Thus limiting the availability of phosphate is likely to interfere with the metabolism of rapidly growing malignant cells. The human hormone glucagon and the anti metabolite mithramycin reduce serum phosphate by increasing phosphaturia and are both very effective in treating Paget's disease of bone, a precancerous condition. In this disorder large doses of glucagon given intravenously relieve bone pain and cause serum phosphate and alkaline phosphatase as well as urine hydroxyproline to fall, indicating a marked reduction in bone turnover. A constant iv infusion of glucagon was given to each of three patients all of whom had secondary malignant bone deposits. Two of the patients had primary prostate cancer and one had a squamous cell lung tumour. All three patients had relief of bone pain and a fall in serum alkaline phosphatase. Serum acid phosphatase also fell in the two patients with prostate cancer. It is proposed that the marked drop in serum phosphate due to glucagon causes intracellular phosphate to fall. This in turn disrupts the addition and removal of phosphate groups essential for the proper functioning of cyclin and cyclin dependent kinase. These two proteins control the transition from G1 to S (DNA synthesis phase) and G2 to M (mitotic phase) in the dividing cycle of malignant cells. Depriving a tumour of an essential ingredient used in phosphorylation reactions will disrupt its growth. It is also proposed that, by the same mechanism, glucagon induced hypophosphataemia renders malignant cells more sensitive to established chemotherapeutic agents and radiation waves. If this hypothesis proves to be correct, lowering intracellular phosphate may become an useful tool in cancer therapy. However extensive studies are necessary to determine whether mitosis in cancer cells can be advantageously disrupted by glucagon induced hypophosphataemia.

A cross-sectional and a prospective study of thyroid disorders in lithium-treated patients.

BACKGROUND: The effects of lithium treatment on the thyroid gland have been demonstrated in a number of studies. Most of this research is based on cross-sectional studies and prospective studies are required to confirm these observations. METHOD: During our genetic association studies, we recruited 115 males and 159 females suffering with affective disorders who had received lithium treatment. We observed longitudinally 57 of these patients, who attended our clinic for between 1 and 7 years and had no thyroid abnormalities at baseline. We performed regular checks of thyroid antibodies, thyroid function tests and lithium levels. RESULTS: Hypo- and hyperthyroidism, including cases that developed prior to lithium treatment, were more common in women (25.8%) than in men (8.7%) and increased with age. By the age of 65, the risk in women increased to 50%. Hypothyroidism was induced by lithium in 17% women. In the prospective study, 4 out of 33 women developed hypothyroidism (an incidence of 27.4 cases per 1000 years). One woman developed thyrotoxicosis. CONCLUSIONS: The risk for hypothyroidism induced by lithium is especially increased in women over the age of 50. Women should be warned of the risks involved when offered lithium treatment. The frequency of lithium-induced thyrotoxicosis is very low.

Thyroid stimulating hormone and free thyroxine in pregnancy: expressing concentrations as multiples of the median (MoMs).

BACKGROUND: Thyroid stimulating hormone (TSH) and free thyroxine (FT4) concentrations vary during pregnancy and conventional units can vary between laboratories. Reference ranges are widely quoted but are arbitrary and do not allow for inter-laboratory differences or gestational age. We therefore explored using multiple of the median (MoM) values to overcome these limitations. METHODS: TSH and FT4 concentrations from 16,346 UK and 5500 Italian women less than 16 weeks of gestation collected as part of the CATS study were converted into MoMs. Effects of maternal age, gestational age, maternal weight, smoking, parity and season of blood sampling were analysed and values adjusted for influencing factors. Distributions of adjusted MoMs were determined. RESULTS: TSH and FT4 (MoMs) significantly reduced the difference between UK and Italian samples (FT4>TSH) compared with conventional units. TSH and FT4 MoMs were statistically significantly influenced by weight, smoking and parity; season also influenced TSH and age influenced FT4. The first and 99th centile MoMs were TSH 0.2 and 4.01, and FT4 0.75 and 1.39. CONCLUSION: Use of TSH and FT4 MoMs in early pregnancy allows for systematic differences between laboratories and other factors. Their use indicates high or low levels in a quantitative manner independent of reference ranges.

Perceived risks and benefits of surveillance colonoscopy in people undergoing surveillance for family history of colorectal cancer.

AIM: To determine perceived risks and benefits of colonoscopy surveillance among patients undergoing surveillance colonoscopy due to family history of colorectal cancer (CRC). METHOD: We conducted a standardised phone interview of 250 randomly selected people who had undergone surveillance colonoscopy at Dunedin Hospital. We assessed perceptions of colonoscopy effectiveness, complication rates, and CRC risk. RESULTS: We included 148 (69%) participants. Most felt well informed about surveillance (66.7%), but many wanted further information (63.2%). Most accurately estimated complication rates (discomfort: Common/Uncommon 70.3%; pain: Rare/Uncommon 58.8%; bleeding: Rare/Uncommon 72.3%; perforation: Very rare 62.8%), and benefits (mean reduction in risk of CRC 72.6% and death 76.2%). Most (55.1%) over-estimated their CRC risk. 13.5% thought perforation never occurred, and 12.8% thought colonoscopy either completely prevented, or had no effect on risk of developing or dying from CRC. Patients giving unrealistic estimates had similar demographics and clinical variables to the wider cohort. CONCLUSION: Our results suggest current surveillance education adequately communicates risks and benefits to most patients. A minority have unrealistic views and further education may be indicated.

Transient congenital hypothyroidism due to thyroid-stimulating hormone receptor blocking antibodies: a case series.

We describe seven infants with transient congenital hypothyroidism (CH) due to maternal thyroid-stimulating hormone receptor (TSH-R) blocking antibodies (TRAb) identified over three decades of newborn screening for CH in Wales, UK that represents a minimum incidence of 1.6% of CH cases. Infants with transient CH due to maternal TRAb presented with a spectrum of clinical and biochemical hypothyroidism. Blood spot TSH concentrations ranged 60.5-332 mIU/L. CH was confirmed by plasma thyroid function tests in all cases (plasma TSH ranged 21-752 mIU/L). The seven infants belonged to five different families. On examination, four infants were clinically hypothyroid. Five infants had a thyroid ultrasound, of which three were abnormal. All infants were treated with thyroxine, which was subsequently withdrawn from three. Following thyroxine withdrawal, one infant resumed normal thyroid function and two developed compensated hypothyroidism. Of the five mothers, two had undiagnosed hypothyroidism and three were receiving thyroxine for longstanding hypothyroidism. Thyroid peroxidase antibody (aTPO) was measured in four and was negative in two, borderline positive in one and strongly positive in another. TRAb was measured in all five women and was strongly positive in all of them. This case series highlights the importance of identifying CH due to TRAb by investigating both the infant and the mother following a raised TSH found on newborn screening. The identification of those infants with transient CH caused by maternal transfer of TRAb is essential for optimizing management during childhood (including potential withdrawal of thyroxine replacement in the longer term) and in any subsequent pregnancy.