Prevalence, predictors and outcomes of thyroid dysfunction in patients with acute myocardial infarction: the ThyrAMI-1 study.

PURPOSE: Thyroid dysfunction in patients with cardiac disease is associated with worse outcomes. This study aimed to evaluate the prevalence and analyse predictors and outcomes of thyroid dysfunction in patients presenting with an acute myocardial infarction (AMI). METHODS: A prospective multicentre observational study of patients recruited from six acute hospitals within the North of England. Consecutive patients without previous thyroid disease presenting with both ST-elevation AMI (STEMI) and non-ST-elevation AMI (NSTEMI) were recruited to the Thyroxine in Acute Myocardial Infarction 1 (ThyrAMI-1) cohort study between December 2014 and 2016. Thyroid profile, standard biochemistry measurements and demographic information were obtained within 12 h of admission to hospital. Multivariable logistic regression analyses were performed to assess the predictors of thyroid dysfunction and Cox proportional hazards analyses were utilised to compare all-cause mortality by categories of thyroid dysfunction up to June 2019. RESULTS: Of the 1802 participants analysed, 1440 (79.9%) were euthyroid, 312 (17.3%) had subclinical hypothyroidism (SCH), 22 (1.2%) had subclinical hyperthyroidism (SHyper) and 25 (1.3%) had low T3 syndrome (LT3S). Predictors for SCH were increasing age, female sex, higher thyroid peroxidase antibody (TPOAb) levels, higher serum creatinine levels and early morning sampling time (between 00:01-06:00 h). The predictors of SHyper were lower body mass index and afternoon sampling time (between 12:01 and 18:00 h). Predictors of LT3S were increasing age, higher creatinine levels and presence of previous ischaemic heart disease. Compared to the euthyroid group, patients with LT3S had higher all-cause mortality; adjusted hazard ratio (95% CI) of 2.02 (1.03-3.95), p = 0.04, whereas those with SCH and SHyper did not exhibit significantly increased mortality; adjusted hazard ratios (95% CI) of 1.05 (0.74-1.49), p = 0.79 and 0.27 (0.04-1.95), p = 0.19, respectively. CONCLUSIONS: Thyroid dysfunction is common in AMI patients on admission to hospital and our data provide an understanding regarding which factors might influence thyroid dysfunction in these patients. Furthermore, the negative association between LT3S and increased mortality post-AMI has once again been highlighted by this study. More research is required to assess if treatment of thyroid dysfunction improves clinical outcomes.

Treatment of hyperthyroidism with antithyroid drugs corrects mild neutropenia in Graves' disease.

CONTEXT: Neutropenia secondary to antithyroid drug (ATD) therapy in Graves' disease (GD) is well recognized. However, the effect of hyperthyroidism, prior to and after ATD therapy, on neutrophil counts in patients with GD is unclear. OBJECTIVE: To study the prevalence of neutropenia in newly diagnosed untreated GD and the effect of ATD on the neutrophil count. DESIGN: Prospective study from August 2010 to December 2014. SETTING: Endocrinology outpatient clinic in a single centre. PATIENTS: Consecutive patients (n = 206) with newly diagnosed GD. INTERVENTION: ATD therapy. MAIN OUTCOME MEASURES: Prevalence and factors predicting neutropenia (<2 × 109 /l) and change in neutrophil counts following ATD. RESULTS: At diagnosis, 29 (14·1%) of GD individuals had neutropenia. Non-Caucasians [odds ratio (95% CI) of 4·06 (1·14-14·45), P = 0·03] and patients with higher serum thyroid hormone levels [OR 1·07 (1·02-1·13), P = 0·002 for serum FT3] were the only independent predictors of neutropenia. All patients with neutropenia had normalized blood neutrophil levels after achieving euthyroidism with ATD therapy. In patients in whom data were available posteuthyroidism (n = 149), change in neutrophil count after achieving euthyroidism was independently related to reduction in thyroid hormone levels (P < 0·01). CONCLUSIONS: GD is associated with neutropenia in one in seven patients at diagnosis, especially in non-Caucasians and those with higher serum thyroid hormone levels. Neutrophil counts increase with treatment with ATD and are related to reduction in thyroid hormone concentrations. It is therefore important to check neutrophil levels in newly diagnosed patients with GD prior to commencing ATD therapy as otherwise low levels may incorrectly be attributed to ATD therapy.

Serum 25-hydroxyvitamin D concentration and its determinants in the very old: the Newcastle 85+ Study.

SUMMARY: Data on vitamin D status in very old adults are lacking. The aim of this study was to assess 25-hydroxyvitamin D [25(OH)D] concentrations and its predictors in 775 adults aged 85 years old living in North-East England. Low 25(OH)D was alarmingly high during winter/spring months, but its biological significance is unknown. INTRODUCTION: Despite recent concerns about the high prevalence of vitamin D deficiency in much of the British adult and paediatric population, there is a dearth of data on vitamin D status and its predictors in very old adults. The objective of the present study was to describe vitamin D status and its associated factors in a broadly representative sample of very old men and women aged 85 years living in the North East of England (55° N). METHODS: Serum concentrations of 25-hydroxyvitamin D [25(OH)D] were analysed in 775 participants in the baseline phase of the Newcastle 85+ cohort study. Season of blood sampling, dietary, health, lifestyle and anthropometric data were collected and included as potential predictors of vitamin D status in ordinal regression models. RESULTS: Median serum 25(OH)D concentrations were 27, 45, 43 and 33 nmol/L during spring, summer, autumn and winter, respectively. The prevalence of vitamin D deficiency according to North American Institute of Medicine guidelines [serum 25(OH)D <30 nmol/L] varied significantly with season with the highest prevalence observed in spring (51%) and the lowest prevalence observed in autumn (23%; P < 0.001). Reported median (inter-quartile range) dietary intakes of vitamin D were very low at 2.9 (1.2-3.3) µg/day. In multivariate ordinal regression models, non-users of either prescribed or non-prescribed vitamin D preparations and winter and spring blood sampling were associated with lower 25(OH)D concentrations. Dietary vitamin D intake, disability score and disease count were not independently associated with vitamin D status in the cohort. CONCLUSION: There is an alarming high prevalence of vitamin D deficiency (<30 nmol/L) in 85-year-olds living in North East England at all times of the year but particularly during winter and spring. Use of vitamin D containing preparations (both supplements and medications) appeared to be the strongest predictor of 25(OH)D concentrations in these very old adults.

Changing clinical patterns and increasing prevalence in CADASIL.

OBJECTIVES: CADASIL is a monogenic small vessel vasculopathy causing recurrent stroke. Early descriptions suggested dementia and disability were common from the 5th decade but there is evidence of marked phenotypic variability. We investigated the prevalence and clinical features of CADASIL in the west of Scotland. METHODS: We undertook a retrospective review of clinical records of patients with confirmed CADASIL identified through a specialist clinic. Patients were divided to examine the effect of date of diagnosis on clinical outcomes and the characteristics at different ages. The location of pedigree members was used to estimate prevalence. RESULTS: Twenty-one different CADASIL-causing NOTCH3 mutations were identified in 49 pedigrees (61% in exon 4). Disease prevalence in Glasgow was 4.6/100,000 adults. Mutation prevalence was estimated at 10.7/100,000 population. Median age at first stroke in women (57 years) was higher than previous estimates, and stroke age in men was higher in patients diagnosed more recently (pre 2006 46 years, post 2006 56 years, P=0.034). In patients over 58 years of age, 13/34 (38%) were living independently and 17/28 (61%) were mobile without aids when last seen. CONCLUSIONS: CADASIL prevalence is at least 4.6 per 100,000 adults. Median age of first stroke may be older than previously thought. Clinicians should consider CADASIL in the differential diagnosis even in older patients with stroke.

Effect of weight loss after gastric bypass surgery on thyroid function in euthyroid people with morbid obesity.

Obesity is positively associated with serum thyrotropin (TSH) concentrations at the high end of the normal range. The relationship between weight loss and thyroid function is less clear and studies to date have yielded inconsistent results. Our aim was to describe changes in thyroid function in obese people in relation to durable and significant weight loss after Roux-en-Y gastric bypass (RYGB) surgery. We recorded percentage of excess weight loss (% EWL), serum TSH and free thyroxine (fT4) before and median 4.5, 15 and 24 months after RYGB in 55 euthyroid patients with morbid obesity ranging in age from 18 to 64 years in a retrospective cohort analysis in a university hospital in Greater Manchester. Mean ± standard error preoperative weight was 135.13 ± 4.23 kg and BMI 48.08 ± 1.58 kg m(-2) . Patients attained nadir %EWL of 68% by median 15 months after RYGB. TSH was 2.00 ± 0.14 mU L(-1) at baseline and 2.02 ± 0.22 mU L(-1) at 24 months after RYGB (non-significant). Baseline fT4 was 13.46 ± 0.28 pmol L(-1) , and increased significantly to 15.14 ± 0.55 pmol L(-1) at 24 months (P < 0.004). In conclusion, we report that weight loss after RYGB was accompanied by significant increase in serum fT4 but no change in TSH concentrations. Further study to elucidate the effect of significant weight loss on the thyroid axis is required.

Severe statin-induced rhabdomyolysis mimicking Guillain-Barré syndrome in four patients with diabetes mellitus treated with fusidic acid.

BACKGROUND: An interaction between fusidic acid and HMG coenzyme A reductase inhibitors (statins), resulting in rhabdomyolysis, has been described. Pain and mild weakness are common presenting symptoms. CASE REPORT: We report four patients with Type 2 diabetes prescribed long-term statin treatment who, following treatment with fusidic acid, presented atypically with painless, severe flaccid paralysis suggestive of Guillain-Barré syndrome. This, together with nerve conduction studies consistent with Guillain-Barré syndrome, resulted in the delayed recognition of rhabdomyolysis in these cases. CONCLUSIONS: The addition of fusidic acid can precipitate rhabdomyolysis in patients with diabetes already taking a statin. This can present with rapidly progressive weakness resembling Guillain-Barré syndrome. We recommend that creatine kinase is checked in patients with diabetes on statin therapy who present with profound weakness and routinely in those commenced on prolonged courses of fusidic acid.

Circulating endothelial progenitor cells, endothelial function, carotid intima-media thickness and circulating markers of endothelial dysfunction in people with type 1 diabetes without macrovascular disease or microalbuminuria.

AIMS/HYPOTHESIS: Type 1 diabetes is associated with premature arterial disease. Bone-marrow derived, circulating endothelial progenitor cells (EPCs) are believed to contribute to endothelial repair. The hypothesis tested was that circulating EPCs are reduced in young people with type 1 diabetes without vascular injury and that this is associated with impaired endothelial function and increased carotid intima-media thickness (CIMT). METHODS: We compared 74 people with type 1 diabetes with 80 healthy controls. CD34, CD133, vascular endothelial (VE) growth factor receptor-2 (VEGFR-2) and VE-cadherin antibodies were used to quantify EPCs and progenitor cell subtypes using flow-cytometry. Ultrasound assessment of endothelial function by brachial artery flow-mediated dilatation (FMD) and CIMT was made. Circulating endothelial markers, inflammatory markers and plasma plasminogen activator inhibitor-1 (PAI-1) levels were measured. RESULTS: CD34+VE-cadherin+, CD133+VE-cadherin+ and CD133+VEGFR-2+ EPC counts were significantly lower in people with diabetes (46-69%; p = 0.004-0.043). In people with type 1 diabetes, FMD was reduced by 45% (p < 0.001) and CIMT increased by 25% (p < 0.001), these being correlated (r = -0.25, p = 0.033). There was a significant relationship between FMD and CD34+VE-cadherin+ (r = 0.39, p = 0.001), CD133+VEGFR-2+ (r = 0.25, p = 0.037) and CD34+ (r = 0.34, p = 0.003) counts. Circulating high-sensitivity C-reactive protein, PAI-1, interleukin-6 and E-selectin were significantly higher in the diabetes group (p < 0.001 to p = 0.049), the last two of these correlating with FMD (r = -0.27, p = 0.028 and r = -0.24, p = 0.048, respectively). CONCLUSIONS/INTERPRETATION: These findings suggest that abnormalities of endothelial function in addition to pro-inflammatory and pro-thrombotic states are already common in people with type 1 diabetes before development of clinically evident arterial damage. Low EPC counts confirm risk of macrovascular complications and may account for impaired endothelial function and predict future cardiovascular events.

Asymptomatic pontine myelinolysis.

A 43-year-old lady presented with bilateral foot drop due to alcohol-related peripheral neuropathy. There was no history of electrolyte disturbance or altered consciousness. Cranial nerve, bulbar and pyramidal symptoms and signs were absent. Nerve conduction studies confirmed the neuropathy. Inadvertently requested neuroimaging of brain demonstrated signal change typical of central pontine myelinolysis. Asymptomatic pontine myelinolysis occurs rarely in alcoholics in the absence of bulbar dysfunction. It is important for physicians to be aware of the clinical entity of asymptomatic pontine myelinolysis to avoid misinterpretation of abnormalities detected on cerebral imaging in alcoholic individuals.

Is inadequate family history a barrier to diagnosis in CADASIL?

OBJECTIVES: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) has typical clinical features that include stroke, migraine, mood disturbances and cognitive decline. However, misdiagnosis is common. We hypothesized that family history is poorly elicited in individuals presenting with features of CADASIL and that enquiry into family history of all four cardinal manifestations of CADASIL is superior to elicitation of family history of premature stroke alone in raising the diagnostic possibility of CADASIL. MATERIALS AND METHODS: Retrospective review of family histories at presentation in 40 individuals with confirmed CADASIL was performed through structured interview in a Neurovascular Genetics clinic (182 first-degree and 242 second-degree relatives identified). Family history obtained from structured interview was compared to family history initially documented at presentation. RESULTS: At initial presentation, 30% of individuals were inaccurately documented to have no family history of significant neurological illness. Thirty-five per cent of patients had an initial alternative diagnosis. Initial inaccurate documentation of negative family history was more frequent in individuals with an initial alternative diagnosis. After structured interviews, 34% of 182 first-degree and 35% of 242 second-degree relatives of CADASIL patients had history of stroke (16% of first-degree relatives had stroke before the age of 50 years). Forty-three per cent of first-degree and 28% of second-degree relatives had migraine, mood disturbance or cognitive decline. CONCLUSIONS: A false-negative family history was commonly documented in individuals presenting with features of CADASIL and was associated with initial misdiagnosis. Restriction of family history to premature stroke alone is probably inadequate to identify affected CADASIL pedigrees.

The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is caused by mutations of the Notch3 gene on 19p13. Varying phenotypic expression leads to under recognition and misdiagnosis. Prevalence therefore remains uncertain. We sought to estimate the prevalence of CADASIL in the west of Scotland. METHODS: A register for CADASIL was established at a regional neurosciences centre in 2002. All patients with genetically (exons 3, 4, 5, and 6) or histologically confirmed CADASIL residing in two defined administrative health areas were identified. Pedigree members at varying risk of carrying the mutation were also identified and the number of probable Notch3 mutation carriers in the defined population was predicted. Prevalence was calculated for definite CADASIL cases, with and without probable carrier numbers, based upon adult population figures from the 2002 national census. RESULTS: Twenty two individuals from seven pedigrees with confirmed CADASIL and resident in the defined geographical area were identified, yielding a prevalence of 1.98 (95% confidence interval 1.24-3.00) per 100 000 adults. An additional 37 individuals were predicted to be carriers of the Notch3 mutation, yielding a probable mutation prevalence of 4.14 (3.04-5.53) per 100,000 adults. CONCLUSIONS: The prevalence of genetically proven CADASIL was 1.98 per 100,000 adults in the defined population. This figure underestimates disease burden.

Design of new questionnaires to measure quality of life and treatment satisfaction in hypothyroidism.

INTRODUCTION: This paper reports work undertaken to design two new condition-specific questionnaires for use in hypothyroidism: the Underactive Thyroid-Dependent Quality of Life Questionnaire (ThyDQoL) and the Underactive Thyroid Treatment Satisfaction Questionnaire (ThyTSQ). METHODS: Semistructured interviews exploring quality of life (QoL) and experiences of treatment were conducted with 30 women and 8 men with hypothyroidism, (mean age, 51.9; range, 29-79 years), 37 of 38 treated with thyroxine, recruited from hospital clinics and primary care. RESULTS: Despite thyroxine treatment, most interviewees reported negative impact of hypothyroidism on QoL, particularly on energy, physical capabilities, motivation, physical appearance, and weight. The newly designed ThyDQoL has 18 domains covering these and other aspects of life affected by hypothyroidism. It is an individualized measure of patients' perceived impact of hypothyroidism on their QOL, which takes into account the importance of personally applicable life domains to the patient. A 7-item measure of satisfaction with current treatment was designed (ThyTSQ-Present) but interviews also indicated the need for a separate 4-item section measuring satisfaction with past treatment around the time of diagnosis (ThyTSQPast). CONCLUSIONS: The ThyDQoL and ThyTSQ questionnaires have good face validity and content validity for adults with hypothyroidism. They are now ready for use in clinical research and psychometric evaluation.

Screening for diabetic retinopathy: a cause for concern in people who drive.

AIMS: To report a case of a road traffic accident in a lady driving home from a diabetes clinic after pupillary dilatation. We also present the findings of a questionnaire survey of health professionals to elicit their practice in dealing with such patients. METHODS: We present the case report of a lady having a road traffic accident on her way back from a retinal screening appointment after having had pupillary dilatation. A subsequent postal questionnaire survey was undertaken to find out current practice in screening patients who drive on the day of their retinal screening. RESULTS: A lady was involved in a road traffic accident whilst returning home after retinal screening. Her motor insurance company refused to cover subsequent claims for damage because her pupils had been dilated. She was also prosecuted by the police for driving without valid motor insurance. We conducted a postal survey of 500 health care workers including ophthalmologists, optometrists, diabetologists and general practitioners regarding the use of dilating drops in people with diabetes who intend to drive. Analysis of 320 valid responses confirmed that there is no consistent practice with regard to either the use of dilating drops in drivers or in ensuring that arrangements are made for subsequent adequate visual inspection in those whom dilatory drops are not instilled. CONCLUSIONS: Guidelines, for use by health care professionals and people with diabetes, are clearly required regarding the use of pupillary dilating drops in drivers.

Tilt table testing in patients referred from an epilepsy clinic.

OBJECTIVE: To assess the role of head up tilt testing (HUT) in diagnosing probable or possible vasovagal syncope (VVS) in patients referred from an epilepsy clinic. METHODS: One hundred thirty two patients underwent HUT over 36 months. Complete data were available on 128 patients (52 male) aged 14-80 (mean 36.7) years. The main indication for HUT (head up tilt at 70 degrees for 45 minutes) was recurrent undiagnosed blackouts, likely to be VVS. Patients were divided, prior to knowledge of the HUT results, into probable VVS, possible VVS, or probable/possible VVS associated with definite epilepsy. RESULTS: HUT was positive in 72 patients (56%), and led to an alternative definite diagnosis in 31 (24%). Diagnostic change was more likely in those provisionally labelled either as possible VVS (15 of 34; 44%) or as a combination of epilepsy with possible or probable VVS (12 of 19; 63%) compared to those with probable VVS (4 of 75; 5%; P<0.01).Of the 45 patients previously treated with antiepileptic medications 27 did not have epilepsy. CONCLUSION: HUT has an important role in confirming or refuting the diagnosis of VVS in patients presenting with undiagnosed blackouts to an epilepsy clinic, and particularly so in patients with possible rather than probable VVS, and in those thought to have a combination of epilepsy and possible or probable VVS.

Outcome of intravenous immunoglobulin-transmitted hepatitis C virus infection in primary immunodeficiency.

Physicians in the United States who treat patients with primary immunodeficiency were contacted to identify subjects who had been infected with hepatitis C due to exposure to contaminated intravenous immunoglobulin (IVIg) in 1993-1994. From this survey we gathered information on 58 PCR-positive hepatitis C-infected patients; 37 had CVID, 9 had XLA, 5 were IgG subclass deficient, 4 were antibody deficient with normal immunoglobulin levels, 2 had SCID after BMT, and 1 had B cell linker deficiency. Of the 58 subjects, 30 had been treated with IFN-alpha in combination with ribavirin in 5 cases, and 26 other subjects were not treated. Of those who were treated, 11 (37%) resolved the infection and became PCR-negative; of the 26 who were not treated, 5 (19%) have resolved the infection, outcomes not significantly different. Patients 20 years of age or younger had a significantly better outcome compared to those older than age 20 (P = 0.02). Five subjects of the 58 have had a liver transplantation, a sixth has had two transplants, and 10 (17%) of the group have died. This survey demonstrates the heterogeneity of the clinical outcome in subjects with primary immunodeficiency who contracted hepatitis C due to viral contamination of IVIg.