High frequency of psoriasis in relatives is associated with early onset in an Italian multiple sclerosis cohort.

OBJECTIVES: An exploratory study has been carried out to assess the association of autoimmune diseases in multiple sclerosis (MS) families with clinical features and disability of MS patients. MATERIAL AND METHODS: Age at onset, symptoms and signs at onset, and disability were assessed in 177 patients with definite MS and 178 age- and sex-matched control patients with autoimmune diseases (78 with endocrine and 100 with rheumatological diseases) and correlated with the most frequent autoimmune diseases recorded in the families. RESULTS: Psoriasis was found in 30 relatives of 177 (16.9%) MS patients, thyroid disorders in 17 (9.6%) and allergies in 17 (9.6%). In the control group, psoriasis was found in 22 relatives of 178 (12%) patients, thyroid diseases in 19 (10.7%) and allergies in seven (3.9%). Of the 30 relatives with psoriasis in the MS group, 16 (53.3%) were fathers (P < 0.0001). There was a significant association of high frequency of family psoriasis with early age of MS onset (P = 0.025) but not with onset of symptoms or severe disability. CONCLUSION: In this Italian MS cohort, a subgroup of patients with a first- or second-degree relative with psoriasis had early onset of MS.

Endovascular treatment of a cavernous sinus dural arteriovenous fistula by transvenous embolisation through the superior ophthalmic vein via cannulation of a frontal vein.

We describe a new approach for transvenous embolisation of cavernous sinus dural arteriovenous fistulae through the superior ophthalmic vein (SOV), i.e., via percutaneous cannulation of a frontal vein. Modern neurointerventional angiographic materials make it possible to reach the SOV in this way without puncturing it in the orbit or a surgical exposure. Orbital phlebography should still be in the repertoire of interventional neuroradiology units in large centres.

Multiple endocrine neoplasia type 2 syndromes may be associated with renal malformations.

OBJECTIVE: The RET proto-oncogene is known to be the susceptibility gene for various disease phenotypes, including multiple endocrine neoplasia type 2 (MEN 2). Recent studies have also suggested an involvement of RET in the development of the mammalian kidney. Although kidney agenesis or dysgenesis has been observed in mice lacking functional ret, no clinically relevant kidney abnormalities have been reported in individuals with known RET mutations and familial medullary thyroid carcinoma (FMTC). We have studied a family with five members affected with isolated FMTC. DNA analysis was performed and the involved RET mutation was identified. Amongst these patients were a woman and her son. DESIGN: Case report. SETTING: University department. PATIENTS: A 32-year-old woman and her son with FMTC and unilateral renal agenesis. RESULTS: The woman's abdominal ultrasound findings demonstrated unilateral renal absence of the left kidney. Her son, when only a few months old, had undergone surgical treatment for Hirschsprung's disease. Abdominal ultrasonography was performed recently, and left-side renal absence was diagnosed. Intravenous pyelography confirmed the agenesis of his left kidney, whilst the contralateral kidney displayed compensatory hypertrophy. CONCLUSIONS: The involvement of the RET proto-oncogene in the early growth and differentiation of the human kidney is now generally accepted. We believe that at least a proportion of patients with MEN 2 may have undiagnosed renal malformations. We suggest therefore that noninvasive imaging techniques, such as ultrasonography, should be used to explore the presence of renal abnormalities in subjects with demonstrated RET mutations.

Early synthesis and correlation of serum anti-thyroid antibodies with clinical parameters in multiple sclerosis.

A high frequency of anti-thyroid antibodies has been demonstrated in multiple sclerosis (MS), but there is a lack of data on the possible association of thyroid autoimmunity with disease activity. To assess whether anti-thyroid antibodies are synthesized early in MS or are induced over the course of the disease and whether or not they are correlated with clinical findings, we assayed serum anti-peroxidase and anti-thyroglobulin antibodies in 129 relapsing-remitting MS patients at the time of diagnosis and prior to any immunosuppressive or immunomodulatory treatment. Anti-peroxidase antibodies were detected in 28/129 (21.7%) MS patients, compared to 12/130 (9.2%) neurological controls (P=0.006) and 8/152 (5.3%) normal healthy subjects (P<0.0001). High titres of anti-thyroglobulin antibodies were detected in 11/129 (8.5%) MS patients compared to 6/130 (4.6%) patients with other neurological diseases (P=0.22) and 5/152 (3.3%) normal healthy subjects (P=0.07). Anti-peroxidase antibodies were associated with initial relapse in 14 of 28 (50%) of the patients compared to 18/101 (18%) without antibodies (P=0.001). Similarly, anti-thyroglobulin antibodies were associated with first relapse in 8/11 (73%) of the patients compared to 11/118 (9.3%) of those without (P<0.0001). However, there was no correlation between anti-thyroid antibody titres and disease duration or CSF IgG index values. By contrast, a significant inverse correlation was found between anti-thyroglobulin antibody titres and EDSS score (r(s)=-0. 75; P=0.008). Our findings demonstrate that anti-peroxidase and anti-thyroglobulin antibodies are synthesized early in relapsing-remitting MS and are associated with early clinical disease activity. Furthermore, high titres of anti-thyroglobulin antibodies are associated with low disability scores, suggesting a possible protective role of these antibodies that deserves further investigation.

The infection by Helicobacter pylori strains expressing CagA is highly prevalent in women with autoimmune thyroid disorders.

UNLABELLED: H. pylori infection is putatively associated with extra-digestive disorders and may also play a role in the development of autoimmune thyroid diseases (ATD). It was recently found that monoclonal antibodies to an H. pylori strain with cagA-positivity reacted with follicular cells of the thyroid gland, and that an H. pylori organism possessing the cag pathogenicity island carried a gene encoding for an endogenous peroxidase. The aims of this study was (1); To ascertain whether the infection by strains endowed with an increased inflammatory potential (those expressing CagA) could further enhance the risk of developing ATD (2); To verify the possible existence of an immune cross-reactivity between autoantibodies to peroxidase and thyroglobulin and H. pylori antigens (3). To establish whether thyroid colloid antigens could cross-react with an anti-H. pylori serum. The study was partly designed retrospectively. We examined 41 consecutive women with ATD, and, as a control, 33 consecutive age- and socio-economic class-matched women without autoimmune thyroid disorders, living in the same area as patients, occurred at the same institution in the same period (six months). Both patients and controls were examined serologically for H. pylori infection and CagA status by Western blotting. Some serum samples were absorbed with H. pylori to determine whether the antibody levels decreased. Colloid proteins were resolved electrophoretically and matched with a hyperimmune serum raised in rabbits against a CagA-positive H. pylori. Thirty-two patients (78.0%) tested seropositive for H. pylori infection, vs. 16 controls (48.4%) (P = 0.008, OR = 3.78, RR = 1.61). The prevalence of anti-CagA antibodies was 71.8% in infected patients, and 50% in infected controls (P = 0.161, n.s.). The overall prevalence of infection by CagA-positive H. pylori was significantly higher in patients with ATD (23/41, or 56.0%) than that in controls (8/33, or 24.2%) (P = 0.006, OR = 3.99, RR = 2.31). The other tests gave negative or inexplicable results. IN CONCLUSION: CagA-positive H. pylori infection increases the risk of ATD development.

Thyroid carcinoma associated with familial adenomatous polyposis.

AIMS: Thyroid carcinoma is an extracolonic manifestation that is present in about 1% to 2% of patients with familial adenomatous polyposis (FAP). Less than 100 cases have been reported in detail. We have investigated the suggestion that FAP associated thyroid carcinoma is significantly different morphologically from both papillary and follicular types and can be considered as a separate entity. METHODS AND RESULTS: Specimens from three patients with FAP associated thyroid tumours, all but one having single nodules, have been analysed. All three patients belonged to an extended kindred (23 siblings in four generations) who had genetic analysis and intensive screening for thyroid nodules. Seven patients had the same APC mutation at codon 1061. Pathological examination revealed a typical papillary carcinoma, encapsulated variant, in all patients, with follicular areas in one case. All thyroid specimens, in addition to histological and immunohistological examinations, were also specifically studied for activation of the RET-PTC oncogene, that seems to be restricted to papillary thyroid carcinoma. Two of the three patients had RET-PTC activation (PTC1 isoform). CONCLUSIONS: The findings suggest that the tumours were certainly papillary, at least in the present kindred. Further studies in different families are required for a better understanding of this peculiar tumour and of its biological behaviour.

Effects of pravastatin treatment on vitamin D metabolites.

Hyperlipidemias, and notably hypercholesterolemia, represent important risk factors for atherosclerotic vascular disease. The enzymatic inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a selective and specific key enzyme involved in endogenous cholesterol synthesis, cause a significant mean reduction in low-density lipoprotein (LDL) cholesterol, both in familial and nonfamilial hypercholesterolemic forms. It has been hypothesized that these compounds might interfere with vitamin D endogenous synthesis secondarily to their effects on cholesterol. To verify this hypothesis, we studied 14 hypercholesterolemic patients treated as follows: 4 weeks of low-lipid, fiber-rich diet followed by 8 weeks of pravastatin treatment at the oral evening dose of 20 mg/d and by a 1-month washout period. No significant changes in serum calcium, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were noticed; on the contrary, significant (P < 0.01) reductions in total cholesterol and LDL cholesterol and a significant (P < 0.05) increase in high-density lipoprotein cholesterol were observed. After the final 1-month washout period, all values returned to baseline levels. In conclusion, our study confirms the clinical efficacy of pravastatin on lipid fractions and demonstrates the absence of any interference on the circulating levels of the main vitamin D metabolites.

Cerebrotendinous xanthomatosis: pathophysiological study on bone metabolism.

A condition of osteopenia in some cerebrotendinous xanthomatosis (CTX) patients led us to investigate bone metabolism in 8 patients belonging to 5 families. Serum calcium, phosphate and vitamin D metabolites were in the normal range; a reduction in total body density and impairment of intestinal radiocalcium absorption were found in the majority of our patients.

Long-term treatment with calcitriol in postmenopausal osteoporosis.

In order to assess the long-term effects of calcitriol treatment in postmenopausal osteoporotic patients, 1.0 micrograms/d of calcitriol was administered in two divided doses for 1 to 8 years to 270 women with symptomatic, histologically proven postmenopausal osteoporosis. No calcium supplementation was given. Clinically, the treatment resulted in substantial relief from pain, with improvement of ambulancy. Intestinal calcium absorption, which was lower than normal at baseline, increased significantly and remained higher than the baseline value as long as calcitriol was administered. Urinary calcium absorption also increased, but hypercalcemia occurred, exceptionally and transiently, in only a few patients. Urinary hydroxyproline excretion did not increase, indicating that hypercalciuria was not of resorptive origin. Total-body density, determined by dual-photon total-body absorptiometry in 56 patients, showed an increase after 18 to 24 months of therapy in most cases. The occurrence of nontraumatic, clinically relevant fractures decreased noticeably as compared with the period preceding calcitriol treatment. No change occurred in renal function, and no renal stones developed. Calcitriol was an effective and safe treatment of postmenopausal osteoporosis.

Pathophysiological aspects of calcium metabolism in spasmophilia.

In order to clarify the pathophysiological mechanisms of spasmophilia, 34 subjects (31 females and 3 males) with spasmophilia were studied. The diagnosis of spasmophilia was based on a specific clinical protocol and electromyographic criteria. In the study, markedly reduced plasma ionized calcium and serum magnesium concentrations were observed together with slightly and non-significantly reduced plasma calcium and phosphate levels. An impairment of intestinal radiocalcium absorption was also noticed. Parathyroid secretion did not show any significant disturbance, but circulating calcitonin levels were found to be significantly lower than in normal subjects. The mean value of serum 25OHD was within the normal range, while a slight reduction in bone Gla protein, an index of osteoblastic activity, was detected. No difference between patients with spasmophilia and normal subjects was observed concerning 47Ca kinetics in red blood cells. The studies indicated that an impaired intestinal calcium transport together with low levels of circulating calcitonin represent the most important pathophysiological determinants of spasmophilia.

Main endocrine modulators of vitamin D hydroxylases in human pathophysiology.

Vitamin D is considered to be devoid of direct biological activity. It must be first hydroxylated in the liver by a 25-hydroxylase (25OHase), then in the kidney by a 1 alpha-hydroxylase (1 alpha OHase) which is responsible for the synthesis of the active metabolite, 1,25-dihydroxyvitamin D (1,25(OH)2D). The activity of 1 alpha OHase is known to be under the control of a series of endocrine modulators, particularly parathyroid hormone (PTH) and estrogens. We report here our studies in humans concerning the behaviour of vitamin D hydroxylases in some pathological conditions. In chronic liver disease no severe impairment of vitamin D-25-hydroxylation has been observed, except in the latest stages: this is probably due to the great functional reserve of the liver, so that normal levels of serum 25OHD can be maintained on condition that the vitamin D supply is adequate. 1 alpha OHase is impaired in chronic renal failure due to the decrease in the number of functioning nephrons. It has been demonstrated that kidney transplantation restores normal 1,25(OH)2D levels. A decrease in 1,25(OH)2D production due to reduced PTH stimulation has been observed in hypoparathyroidism: in these patients a subcutaneous substitution therapy with synthetic human parathyroid hormone resulted in restoration of normal 1,25(OH)2D levels. A reduced activity of 1 alpha OHase due to reduced estrogen stimulation plays a key role in postmenopausal osteoporosis. In these patients estrogens increase 1,25(OH)2D levels, as it has been demonstrated directly and indirectly. In the aforementioned pathological conditions an impairment of calcium absorption has been observed; it was directly related to the reduced production of 1,25(OH)2D. Treatment with 1,25(OH)2D3 was effective in restoring normal calcium absorption. In postmenopausal osteoporosis the reduced levels of 1,25(OH)2D were accompanied by serum levels of 25-hydroxyvitamin D (25OHD) higher than in age-matched control women. In these cases long-term treatment with physiological doses of 1,25(OH)2D3 resulted in a progressive decrease in 25OHD serum levels which approached to the normal range. These findings are likely to be related one to another: the low 1,25(OH)2D levels are responsible for reduced product-inhibition of 25OHase, so that the synthesis of 25OHD increases. A similar mechanism occurs in renal failure and in hypoparathyroidism.

Effect of a long-term treatment with 1,25-dihydroxyvitamin D3 on osteocalcin in postmenopausal osteoporosis.

Serum bone Gla-protein (BGP or osteocalcin) was measured in 25 women with histologically confirmed postmenopausal osteoporosis before and during long-term treatment with 1 microgram/day of 1,25-dihydroxyvitamin D3(1,25(OH)2D3). Basal serum BGP was significantly lower in osteoporotic women (3.8 +/- 1.4 ng/ml) than in age-matched controls (6.8 +/- 2.0 ng/ml). During 1,25(OH)2D3 therapy serum BGP increased so that the mean of the values observed on treatment (4.8 +/- 1.5) was significantly higher than the mean basal value. It is known that BGP synthesis is stimulated by 1,25(OH)2D3 and that serum BGP is a specific marker of bone formation; therefore, it is possible that the low basal levels of osteocalcin we observed were related to the low serum 1,25(OH)2D concentrations reported in osteoporotic women and that the increase in BGP levels observed under 1,25(OH)2D3 treatment was a consequence of osteoblast stimulation.

Vitamin D status in the extreme age of life.

The aim of the present study was to investigate vitamin D status in the extreme age of life and to assess the ability of elderly people to synthesize vitamin D in skin, in response to artificial ultraviolet irradiation, and to hydroxylate the newly synthesized vitamin in the liver. The authors have determined the serum 25-hydroxyvitamin D concentrations in 43 healthy subjects (17 males and 26 females) aged 84 years or more. The changes induced in 25-OHD serum levels by whole-body artificial ultraviolet irradiation have also been studied in 10 healthy volunteers aged 41-90 years and, as a control, in 8 normal subjects aged 24-40 years. Serum 25-OHD has been determined, after lipid extraction of samples and column chromatography, by competitive protein binding assay using rat serum as the source of binding protein. The mean 25-OHD serum level in the group studied was 5.7 +/- 4.3 ng/ml, much lower than the mean observed in normal subjects aged 20-40 years (21.3 +/- 8.2 ng/ml). Men had higher levels than women. In the age group 84-89 years 25-OHD levels were higher than in subjects aged 90-96. Serum 25-OHD increased remarkably in all our normal subjects in response to artificial ultraviolet irradiation. Age-related differences in 25-OHD response to irradiation were not significant. The results of the present study indicate that vitamin D deficiency is common in the extreme age of life. It is probably a consequence of poor diet and lack of exposure to sunshine rather than of an impairment of cutaneous synthesis or liver hydroxylation of vitamin D.

Studies on the hydroxylation of vitamin D in man.

The authors have studied some of the factors influencing vitamin D hydroxylases in man, using two indirect experimental approaches. In the first study they have considered the effect of a long-term treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the serum levels of 25-hydroxyvitamin D (25-OHD) in postmenopausal osteoporosis, a condition in which high serum levels of 25-OHD and low mean levels of 1,25(OH)2D have been observed. In the second study the effects of the infusion of physiological doses of human parathyroid hormone (PTH) on the serum levels of 1,25(OH)2D and 24,25(OH)2D have been investigated. In the first study a decrease in the circulating levels of 25-OHD was observed during 1,25(OH)2D3 treatment. This could be considered as an indirect evidence of an inhibitory action of 1,25(OH)2D3 on 25-hydroxylase: in this view 1,25(OH)2D3 treatment decreases 25-hydroxylase activity, which is higher than normal in postmenopausal osteoporosis due to the low levels of 1,25(OH)2D. In the second study PTH infusion was followed by a remarkable increase in 1,25(OH)2D serum levels as a result of 1 alpha-hydroxylase stimulation, which was much higher in patients with hypoparathyroidism. The determination of 24,25(OH)2D levels during PTH infusion indicated an inhibitory effect on 24-hydroxylase.