Rafik Karmali

Vitamin D-dependent rickets type II: extreme end organ resistance to 1,25-dihydroxy vitamin D3 in a patient without alopecia.

Vitamin D-dependent rickets type II (VDDR II) is a rare syndrome resulting in severe rickets and is resistant to treatment with vitamin D and its derivatives. Patient with this disease, who are frequently the children of consanguinous marriages, present with elevated circulating concentrations of 1,25-dihydroxy vitamin D, the active metabolite of vitamin D, and in vitro studies have indicated a failure of intracellular binding of the hormone. Alopecia has been noted in many of these patients and it has been suggested that this feature may indicate a more marked resistance to treatment. However we describe a 3-year-old boy with this disease who, although having normal hair growth, displayed extreme resistance to treatment with active vitamin D metabolites. In vitro studies of skin fibroblasts disclosed not only an absence of hormone binding or 1,25(OH)2D3-induced 24-hydroxylase activity but reduced metabolism of 1,25(OH)2D3 itself. In this child, treatment with exogenous 1,25-dihydroxy vitamin D3 at doses of up to 24μg/day, which increased the circulating concentration of the metabolite to greater than 100 times the normal adult mean, failed to alleviate his condition and he died at the age of 39 months. This would therefore suggest that absence of alopecia, in this condition, cannot be regarded as a constant predictive sign of a lesser resistance and of responsivenes to Vitamin D treatment.

Calcium and vitamin D metabolism in granulomatous diseases

SummaryOverproduction of the active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) has been described in sarcoidosis and other granulomatous diseases. High circulating concentrations of 1,25(OH)2D lead to increased intestinal absorption of calcium, possibly to enhanced bone resorption, and may result in hypercalcaemia and/or hypercalciuria. Data obtained in vivo and in vitro demonstrated that the unregulated production of 1,25(OH)2D lies within the granulomatous tissue and is controlled by glucocorticoids. This abnormal production of 1,25(OH)2D seems to be a general phenomenon of granulomatous processes, which is not exceptional in sarcoidosis, but appears seldom in tuberculosis. These abnormalities, however, are not pathognomonic of granulomatous processes, since they have been described in other diseases such as lymphomas.

Fibroblast growth factor 23 and its role in phosphate homeostasis

Phosphate homeostasis is complex and incompletely understood. The identification of different factors involved in the regulation of phosphate balance, also called phosphatonins, has largely changed our view on the regulation of phosphate homeostasis. The active role of bone has been demonstrated clearly. Currently, maintaining phosphate homeostasis is considered the result of a complex network of endocrine feedback loops between parathyroid gland, kidney, and bone. This review describes current knowledge on fibroblast growth factor 23, which is one of the best studied phosphatonins.

Expression of mRNA of parathyroid hormone-related peptide in fetal bones of the rat

SummaryPrevious studies have indicated that 19-dayold fetal long bones of the rat contain an adenylyl cyclase-stimulating activity antigenically related to parathyroid hormone-related peptide. To ascertain its origin, Northern blotting and in situ hybridization histochemistry were performed. Results demonstrate that mRNA of parathyroid hormone-related peptide is present in RNA extracted from fetal long bones of the rat and that cells responsible for its production are localized in the periosteum. These cells are not mature osteoblasts because they do not synthesize mRNA of osteocalcin. Thus the present study shows that parathyroid hormone-related peptide could be produced locally, at least in part, in the skeleton of fetal rats.

Primary Adrenal Insufficiency Due to Bilateral Adrenal Hemorrhage-Adrenal Infarction in the Antiphospholipid Syndrome: Long-Term Outcome of 16 Patients

CONTEXT Primary adrenal insufficiency due to bilateral adrenal hemorrhage-adrenal infarction is a rare and life-threatening manifestation of the antiphospholipid syndrome (APLS). Data on the long-term outcome are scarce. OBJECTIVE The aims of the present study were to analyze the long-term outcome related to APLS per se and to characterize the course of adrenal involvement. DESIGN We conducted a retrospective study of patients with bilateral adrenal hemorrhage-adrenal infarction secondary to APLS seen in the Department of Internal Medicine of Pitié-Salpêtrière Hospital in Paris (France) between January 1990 and July 2010. RESULTS Three patients died during the acute phase related to APLS manifestations. Sixteen patients (7 males; 9 females) were followed up during a median period of 3.5 years (range 0.3-28.1 years). Three episodes of recurrent thrombosis were noted. One patient died from cerebral hemorrhage 3 months after the onset of adrenal insufficiency. Repeated Synacthen tests showed complete absence of response in 8 of the 10 patients assessed; cortisol and aldosterone increased appropriately in one patient and to some extent in another one. Dehydroepiandrosterone levels and 24-hour urinary epinephrine levels remained abnormally low in all evaluated patients. Adrenal imaging performed more than 1 year after the initial event revealed completely atrophic glands in 9 of 11 patients. CONCLUSIONS This particular subset of APLS patients who survive the acute phase has a rather favorable long-term outcome. Although adrenal dysfunction is generally irreversible, adrenocortical function may, at least partially, recover in rare cases. In this view, measurement of early morning cortisol during follow-up is indicated to detect these patients.

Intermittent hypercalcaemia and vitamin D sensitivity in Hodgkin's disease.

A patient with Hodgkins disease spontaneously developed steroid-responsive hypercalcaemia during two consecutive summers. Administration of 3000 U/day of vitamin D, while he was normocalcaemic, caused a sharp increase in serum 1,25(OH)2D3 (from 59 pg/ml to 142 pg/ml) and subsequently hypercalcaemia while serum 25(OH)D3 rose moderately within the normal range (from 2.8 ng/ml to 10 ng/ml). During a spontaneous episode of hypercalcaemia which was accompanied by increased circulating 1,25(OH)2D3 concentrations, administration of hydrocortisone decreased serum 1,25(OH)2D3 rapidly (from 115 pg/ml to 62 pg/ml) and eventually led to normocalcaemia while serum 25(OH)D3 remained unchanged. Thus the disturbances of mineral metabolism found in this patient with Hodgkins disease are very similar to those previously described in sarcoidosis.

Anti DNA antibodies are not restricted to a specific pattern of fluorescence on HEp2 cells

Abstract Background: Antinuclear autoantibody determination relies on an initial screening step using immunofluorescence on HEp2 cells. This may be followed by anti-deoxyribonucleic acid (DNA) determination, if the fluorescence of nuclei is homogeneous. We assessed the validity of a restricted algorithm and compared this to a more comprehensive algorithm that accepted any nuclear pattern as a positive indicator. Methods: Our retrospective study analyzed routine results for antinuclear antibodies (ANA) and their anti-DNA identification [double stranded nuclear DNA (ds-DNA), membrane associated DNA (mDNA), nucleosomes] for 58 systemic lupus erythematosus (SLE) patients (690 sera). We included 158 patients with systemic or organ-specific autoimmune diseases (888 sera), 44 with viral disease (88 sera), 34 cancer patients (89 sera) and 111 patients with inflammation that served as controls (122 sera) for a total of 1187 samples. Results: 1) Anti DNA antibodies are not associated only with a homogeneous pattern, but can also be seen with a speckled or nucleolar pattern. 2) The observed pattern is typical for a particular patient rather than for a specific pathology. 3) A homogeneous pattern does not necessarily indicate SLE, nor does the presence of circulating anti DNA antibodies. 4) Determination of various specificities of anti DNA antibodies, whatever the immunofluorescent pattern, increases the sensitivity and specificity for SLE. Conclusions: If diagnosis is based exclusively on a homogenous pattern, preselection would have missed identification of SLE as high levels of anti DNA antibodies were also associated with speckled or nucleolar pattern. Clin Chem Lab Med 2009;47:543–9.

Safety of furosemide administration in an elderly woman recovered from thiazide-induced hyponatremia

BACKGROUND Elderly women are at risk to develop severe hyponatremia after thiazide but not loop diuretic administration. In patients with previous thiazide-induced hyponatremia, the risk for recurrent hyponatremia after furosemide has not been established. METHODS In order to determine how both diuretics affect water metabolism, we here compare the effects of a rechallenge with either amiloride-hydrochlorothiazide fixed association (AmHTZ; amiloride chlorhydrate 5 mg+hydrochlorothiazide 50 mg; Moduretic) or furosemide (F; 40 mg; Lasix) on water excretion in a 79 year old woman who was previously admitted for severe symptomatic hyponatremia secondary to a 5 days course of AmHTZ for systolic hypertension. After correction of initial hydromineral disturbances, a standard oral water load (WL; 20 mL per kg body weight) was administered before, during and after AmHTZ or F challenges. RESULTS Hyponatremia developed after AmHTZ but not after F challenge. A negative free water clearance (CH(2)O) was only observed during AmHTZ (-0.39 mL/min), while maximal CH(2)O during F was 3.17 mL/min. Based on the results obtained during WL, the calculated maximal daily electrolyte free water clearance ability was only 888 mL after AmHTZ but 10,166 mL after F therapy. Taking into account a measured mean daily water intake of 1830 mL, severe hyponatremia could be predicted to occur after a few days treatment with AmHTZ. In comparison, F appears to be safer, without risk of hyponatremia, during an equivalent period of time. CONCLUSIONS We here showed that F may be administered to a patient with previous AmHTZ induced hyponatremia without risk for recurrent hyponatremia.

Toxoplasma encephalitis in a HIV patient: unusual involvement of the corpus callosum

In patients with acquired immuno-deficiency syndrome, the differential diagnosis between primary brain lymphoma and toxoplasma encephalitis is not radiologically always straightforward, especially in the presence of a solitary cerebral lesion. In this context, involvement of the corpus callosum is almost exclusively associated with primary brain lymphoma. We describe here an HIV-infected patient who presented with a single and large cerebral lesion affecting the corpus callosum, suggestive of primary brain lymphoma on MRI-scan but who nonetheless responded clinically and radiologically to an anti-toxoplasma drug trial confirming the diagnosis of toxoplasma encephalitis.

Hyperuricemia and renal handling of urate in primary hyperparathyroidism.

Serum urate and the renal handling of urate were measured in 37 patients with primary hyperparathyroidism and in normal sex- and age-matched subjects. Serum urate was increased in the hyperparathyroid group compared to the control group (6.23 +/- 1.46 versus 4.64 +/- 1.24 mg/100 ml; p less than 0.005), whereas the fractional excretion of urate was decreased in hyperparathyroid patients compared to the controls (6.80 +/- 2.69 versus 8.73 +/- 3.47%; p less than 0.005). Twenty-four of these hyperparathyroid patients were studied 6 months after surgical correction of their disease. Serum urate decreased after surgery (5.14 +/- 1.65 mg/100 ml) compared to the preoperative state (5.92 +/- 1.46 mg/100 ml) and was no longer different from the normal values. The possible mechanisms of hyperuricemia associated with the hyperparathyroid state are discussed.