The joint diabetic-renal clinic in clinical practice: 10 years of data from a District General Hospital.

BACKGROUND: Diabetic nephropathy is the leading cause of end-stage renal failure. Untreated, it causes continuous decline in glomerular function, worsening hypertension and a marked increase in cardiovascular risk. Joint diabetic-renal clinics were established to address these factors and prepare patients for renal replacement therapy. AIM: To determine whether our joint diabetic-renal clinic influenced progression of renal disease, and whether we were able to achieve targets from clinical trials and guidelines in routine practice. DESIGN: Retrospective review. METHODS: We collected data using clinical notes and electronic records for 130 patients attending the clinic over 10 years. RESULTS: Our patients had 62% type 2 and 38% type 1 diabetes. Mean duration of diabetes was 24 years for type 1 and 11 years for type 2 diabetes. At referral, 56% had evidence of vascular disease and 45%, proliferative retinopathy. Baseline median creatinine was 124 micromol/l. Significant improvements were made in systolic BP, diastolic BP and cholesterol (p < 0.001), compared to measurements at presentation. We analysed progression of renal disease by linear regression on 45 patients who had follow-up data for 3 years. Rate of decline of GFR was significantly reduced from 1.09 ml/min/month in the first year to 0.39 ml/min/month in the third year, (p < 0.004). DISCUSSION: Our findings suggest that the rate of deterioration of renal function can be reduced by aggressive management of risk factors. Joint diabetic-renal clinics appear to be useful in achieving targets in routine clinical practice.

Recurrent painful unilateral gynaecomastia-interactions between hyperthyroidism and hypogonadism.

We report an unusual case of recurrent, painful, unilateral gynaecomastia (GM) in an elderly male with relapsing Graves' hyperthyroidism and co-existing primary hypogonadism. This patient presented to the Breast Clinic with a 4-month history of painful, right GM. Malignancy was excluded but T3 was noted to be raised at 7.3 pmol l(-1) (normal 3.5-5.5) with a suppressed thyroid-stimulating hormone. Testosterone, luteinizing hormone and follicle-stimulating hormone were consistent with primary hypogonadism. He was later referred to physicians with night sweats and painful right GM. FT3 was 7.4 and carbimazole was commenced. Within 4 months, the night sweats and right GM had resolved but he became hypothyroid. When carbimazole was stopped, right GM recurred together with hyperthyroidism. The male breast, which is sensitive to subtle changes in T/E2 ratio, is more likely to be stimulated in an elderly male with hyperthyroidism and pre-existing hypogonadism, and hence recurrence of GM with relapsing hyperthyroidism. Recognition of this association is clinically relevant to avoid unnecessary investigations and undue patient anxiety, and to facilitate appropriate early diagnosis and treatment.

Improvements in the provision of hospital diabetes services in an English region 1988-98.

AIMS: To investigate the changes in provision of hospital-based services for patients with diabetes in an English region over a 10-year period. METHODS: Questionnaires were completed by lead clinicians in hospitals in the Northern region of England in 1988 and repeated in 1998. Information was sought on diabetes service provision including the staff and their working practices. Data are presented to demonstrate changes during the 10 years. RESULTS: During a 10-year period the number of consultants providing specialized diabetes services increased from 16 to 25 (to become one per 126 240 population). Their outpatient sessions changed from 34 to 55.5 per week, with a decrease in nonspecialists providing diabetes services. Reductions occurred in registrar numbers providing sessions from 23 to 15 and senior house officers from 16 to 14. Increases occurred in other health care professionals: diabetes specialist nurses from 19 to 30.3 whole time equivalents (WTEs); dieticians from 16 to 32.3 WTEs and chiropodists from 8 to 23 WTEs. The numbers of specialized clinics and units providing services from diabetes care centres increased. Improved facilities in clinics and access to laboratory tests were available to all units. Diabetes registers came into use in 12 of 16 units, but there have been difficulties in providing funding. 'Out-of-hours' advice has moved towards advising their patients to see their general practitioners or the accident and emergency department of the hospitals. CONCLUSIONS: The number of diabetes professional staff and the provision of specialized diabetes services have increased during a 10-year period in the Northern region of England. However, they still fall far short of recommended staffing levels and services are far from comprehensive in most districts.

Evidence for a new Graves disease susceptibility locus at chromosome 18q21.

Graves disease (GD) is a common autoimmune thyroid disorder that is inherited as a complex multigenic trait. By using a single microsatellite marker at each locus, we screened the type 1 diabetes loci IDDM4, IDDM5, IDDM6, IDDM8, and IDDM10 and the fucosyltransferase-2 locus for linkage in sib pairs with GD. This showed a two-point nonparametric linkage (NPL) score of 1.57 (P=.06) at the IDDM6 marker D18S41, but NPL scores were <1.0 at the other five loci. Thus, the investigation of the IDDM6 locus was extended by genotyping 11 microsatellite markers spanning 48 cM across chromosome 18q12-q22 in 81 sib pairs affected with autoimmune thyroid disease (AITD). Multipoint analysis, designating all AITD sib pairs as affected, showed a peak NPL score of 3.46 (P=.0003), at the marker D18S487. Designation of only GD cases as affected (74 sib pairs) showed a peak NPL score of 3.09 (P=.001). Linkage to this region has been demonstrated in type 1 diabetes (IDDM6), rheumatoid arthritis, and systemic lupus erythematosus, which suggests that this locus may have a role in several forms of autoimmunity.

Oral health care in diabetes mellitus.

Diabetes mellitus produces many complex changes in the lives of those affected. Elevated blood glucose levels, which may occur in the absence of symptoms, lead to late complications from tissue damage. There is an increased susceptibility to infection, poor wound healing and periodontal disease. Furthermore, chronic oral infection itself may contribute to raised blood glucose levels and hence to the later complications of diabetes. Acute infection in the oral cavity needs specific and aggressive management, just as in the acutely infected diabetic foot.' The dental team may not have made a significant contribution to the shared management of the person with diabetes in the past; however, recent findings suggest that the dental team may contribute greatly to the shared care of diabetes with the diabetic team itself, and regular liaison is strongly recommended.

The cytotoxic T lymphocyte antigen-4 is a major Graves' disease locus.

Graves' disease (GD) is an autoimmune thyroid disorder that is inherited as a complex trait. We have genotyped 77 affected sib-pairs with autoimmune thyroid disease for eight polymorphic markers spanning the cytotoxic T lymphocyte antigen-4 ( CTLA-4 ) region of chromosome 2q31-q33, and for five markers spanning the major histocompatibility complex ( MHC ) region of chromosome 6p21. Non-parametric analysis showed linkage of GD to the CTLA-4 region with a peak non-parametric linkage (NPL) score of 3.43 ( P = 0.0004) at the marker D2S117. The proportion of affected full-sibs sharing zero alleles (z0) reached a minimum of 0.113 close to D2S117, giving a locus-specific lambdas for this region of 2.2. Families with brother-sister sib-pairs showed a peak NPL of 3.46 ( P = 0.0003, lambdas > 10) at D2S117, compared with 2.00 ( P = 0.02, lambdas = 1.9) in the families with only affected females, suggesting a stronger influence in families with affected males. Association between GD and the G allele of the Thr17Ala polymorphism within the CTLA-4 gene ( CTLA4A/G ) was observed using unaffected sib controls ( P = 0.005). Lesser evidence for linkage was found at the MHC locus, with a peak NPL score of 1.95 ( P = 0.026), between the markers D6S273 and TNFalpha. We demonstrate that the CTLA-4 locus (lambdas = 2.2) and the MHC locus (lambdas = 1.6) together confer approximately 50% of the inherited susceptibility to GD disease in our population.

Oral health care in diabetes mellitus.

Diabetes mellitus produces many complex changes in the lives of those affected. Elevated blood glucose levels, which may occur in the absence of symptoms, lead to late complications from tissue damage. There is an increased susceptibility to infection, poor wound healing and periodontal disease. Furthermore, chronic oral infection itself may contribute to raised blood glucose levels and hence to the later complications of diabetes. Acute infection in the oral cavity needs specific and aggressive management, just as in the acutely infected diabetic foot. The dental team may not have made a significant contribution to the shared management of the person with diabetes in the past; however, recent findings suggests that the dental team may contribute greatly to the shared care of diabetes with the diabetic team itself, and regular liaison is strongly recommended.

Blisters, ulceration and autonomic neuropathy in carpal tunnel syndrome.

We describe three patients with trophic ulceration and blistering of the fingertips associated with carpal tunnel syndrome. One of the patients also had non-insulin-dependent diabetes mellitus. Autonomic neuropathy distal to the carpal tunnel was probably present in all subjects at the time of presentation; in the patient with recent symptoms the skin was warm, and sweating was virtually absent, whilst the other two patients described cold skin, consistent with prolonged autonomic neuropathy.

Intravenous gammaglobulin therapy in the thrombocytopenia of haemorrhagic varicella.

We report the case of a teenage boy with thrombocytopenia complicating varicella infection, which responded promptly to treatment with intravenous immunoglobulin therapy. Such treatment is well recognized in the management of immune thrombocytopenia, particularly where steroids are contra-indicated, but we have not found any previous case reports of the use of immunoglobulin in this condition.

Unilateral thyroid swelling due to actinomycosis.

A case of unilateral thyroid swelling due to actinomycosis in a 27 year old farm worker is described. Diagnosis was made by fine needle biopsy under ultrasound control.

Short-term effects of beta-adrenoceptor blocking drugs with and without cardioselectivity and intrinsic sympathomimetic activity on lipoprotein metabolism in hypertriglyceridaemic patients and in normal men.

In six patients with hypertriglyceridaemia presenting whilst receiving treatment with beta-adrenoreceptor blocking drugs (mean serum triglycerides 31.2 mmol/l) the half-life (t1/2) of an intravenously administered triglyceride emulsion was 32.8 +/- 7.9 min (mean +/- SEM) on beta-blocker and 22.8 +/- 4.8 min after stopping beta-blocker treatment. In three of these patients subsequent administration of a beta-blocker with intrinsic sympathomimetic activity had no effect on t1/2. In a cross-over trial of placebo, atenolol (beta 1-blocker), propranolol (beta 1- and beta 2-blocker) and pindolol (beta 1- and beta 2-blocker with intrinsic sympathomimetic activity) in 11 normal men t1/2 was 11.8 +/- 0.9, 12.6 +/- 1.1, 14.3 +/- 1.7 and 12.4 +/- 1.1 min respectively. None of the apparent differences achieved statistical significance, but in two men marked increases in t1/2 occurred on propranolol. The concentrations of serum triglycerides and very low density lipoprotein cholesterol in the normal men were, however, increased by beta-blockade, most markedly by pindolol. Serum high density lipoprotein (HDL) cholesterol concentration decreased in normal men on beta-blockers, most clearly on atenolol and propranolol. This decrease was due to a reduction in cholesterol in the HDL2 subfraction. No statistically significant effects on serum low density lipoprotein cholesterol or apolipoprotein B concentrations occurred in the normal men. The doses of atenolol and propranolol used in this study were equipotent as judged by the heart rate response to exercise.

Evidence that adrenal oestrogens are not involved in benign breast disease.

We have studied 30 women with symptomatic benign breast disease in order to test the hypothesis that in some it might be caused by an enzyme variant leading to excessive adrenal production of oestrone. Synthetic 1-24 ACTH (Synacthen) was given intramuscularly after overnight suppression with dexamethasone, during the early follicular phase of the menstrual cycle. In no subjects did plasma oestrone levels show a consistent and significant response to ACTH despite the expected consistent rises in androstenedione and cortisol. We conclude that it is unlikely that adrenal oestrogens play a significant role in the pathophysiology of even a minority of patients with benign breast disease.

High dose androgen therapy in male pseudohermaphroditism due to 5 alpha-reductase deficiency and disorders of the androgen receptor.

We describe the clinical and biochemical features of six men with male pseudohermaphroditism due to androgen resistance. Each of the subjects had male-gender behavior but incomplete virilization. The underlying defects in androgen metabolism were defined by studies of the 5 alpha-reductase enzyme and the androgen receptor in fibroblasts cultured from biopsies of genital skin. Four of the six have 5 alpha-reductase deficiency, and two have defects of the androgen receptor (the Reifenstein syndrome). The responses of these men to androgen treatment were assessed by monitoring nitrogen balance, plasma luteinizing hormone (LH) values, and clinical parameters of virilization including penile growth, potency and ejaculatory volume, muscle bulk, and growth of body and facial hair. In all of the subjects with 5 alpha-reductase deficiency and one man with the Reifenstein syndrome significant response occurred, as evidence by nitrogen retention, lowered plasma LH levels, and improved virilization, with doses of parenteral testosterone esters that raised plasma testosterone levels above the normal male range and brought plasma dihydrotestosterone levels into the normal male range. The subject who did not respond with clinical virilization nevertheless showed nitrogen retention in response to acute testosterone administration. This patient had a profound deficiency of the androgen receptor, whereas the man with a receptor defect who did respond clinically to therapy had normal amounts of a qualitatively abnormal receptor. We conclude that high dose androgen therapy may be of benefit in improving virilization, self-image, and sexual performance in subjects with 5 alpha-reductase deficiency who have male-gender behavior and in some subjects with defects of the androgen receptor.

Which testosterone replacement therapy?

Three different forms of testosterone (T) replacement therapy were compared; they were the intramuscular injection of mixed testosterone esters 250 mg; the subcutaneous implantation of 6 X 100 mg pellets of fused testosterone; and the oral administration of testosterone undecanoate (TU) 80 mg twice daily. Six hypogonadal males were treated with oral TU for an eight week period, during which time serial serum hormonal estimations were performed over 10 h at the initiation and after four and eight weeks of therapy. Serum T levels showed marked variability both between subjects and within the same subject on different occasions. We attribute this to variability in absorption of TU, which is formulated in oleic acid. The overall mean T level calculated from the areas under the profiles of TU was 12.0 nmol/l. Hormone responses to injected T esters were studied in nine hypogonadal males. Serum T rose to supraphysiological peak concentrations (mean 71 nmol/l) 24-48 h after an injection, followed by an exponential decay to reach baseline concentrations after 2-3 weeks. The overall calculated mean T level in subjects receiving testosterone esters 250 mg every three weeks was 27.7 nmol/l. Subcutaneous implantation of testosterone in six hypogonadal men produced a gradual rise in serum T followed by a slow decline, with T levels remaining within the normal range for 4-5 months. The calculated overall mean T level over 21 weeks after implantation was 17.0 nmol/l. Serum oestradiol (E2) levels remained within the normal male range throughout the study periods on both TU and T implant therapy but showed a supraphysiological peak (mean 347 pmol/l) 24-48 h after a T injection. 5 alpha-dihydrotestosterone (DHT) levels appeared to parallel those of T on the three forms of therapy, with DHT:T ratios being highest for TU therapy. This was also true for the target organ metabolite 5 alpha-androstane-3 alpha,17 beta-diol. At the doses studied drug costs were similar for T implantation (every 5 months) and T ester injections (every 3 weeks), but were 7-8 times higher for TU (80 mg twice a day). We conclude that T implantation remains overall the most physiological form of androgen replacement therapy, is generally well accepted and attended by few side effects; TU may have a useful role in the initial phases of therapy.

A simple test for the hormonal assessment of early puberty in boys.

The initial hormonal changes in male puberty occur at nighttime, with episodic rises of LH and testosterone (T). Only much later do the daytime levels of these hormones rise. Nocturnal sampling is impractical for routine clinical assessment, so we have examined the relationship between peak nocturnal T levels and those produced in the same subject by a single intravenous injection of gonadotrophin releasing hormone (GnRH, 100 micrograms) in the morning. Nocturnal T profiles and daytime GnRH tests have been conducted in eight boys in early (delayed) puberty, three with pubertal gynaecomastia in later puberty, two normal men, and one man with gynaecomastia. Excellent agreement was obtained between peak nocturnal and post-GnRH T levels. The serum testosterone level 3 hours after 100 micrograms IV GnRH is a simple and useful hormonal marker of pituitary-Leydig cell activity during puberty.

Pulmonary sarcoidosis presenting with large haemoptysis.

We describe a previously healthy young male Caucasian with pulmonary sarcoidosis whose presenting symptoms were two copious haemoptyses.