Normal Alkaline Phosphatase Levels Research Articles

Saccharated ferric oxide (SFO)-induced osteomalacia: In vitro inhibition by SFO of bone formation and 1,25-dihydroxy-vitamin D production in renal tubules

A 60-year-old man with portal hypertensive gastrophathy due to type C liver cirrhosis developed severe bone pains, marked hypophosphatemia with inappropriately increased urinary excretion of phosphate (%TRP; 9.6%), and hyperalkaline phosphatasia, after intravenous administration of saccharated ferric oxide (SFO) at a dose of 80–240 mg/week over a period of more than 5 years. The total iron infused was estimated to be more than 25 g. On a diagnosis of SFO-induced osteomalacia, the infusion of iron was immediately discontinued, and phosphate and vitamin D 2 (1000 IU/day) were adminestered. Serum levels of 25-OHD 2 increased after 1 week, whereas levels of 1,25-(OH) 2D 2 did not increase until 3 months later, accompanied by improvement of renal tubular reabsorption of phosphate and gradual improvement of the bone pains. The patient has been doing well for the last 2 years, with normal serum levels of phosphate, calcium, and alkaline phosphatase, without any supplementation of phosphate, vitamin D, or iron-containing agents. In primary culture of neonatal mouse renal tubules, in which 1,25-(OH) 2D 3 was produced from 25-OHD 3 in response to PTH, SFO significantly inhibited PTH-induced production of 1,25-(OH) 2D 3 at 30 μmol/L, which is attainable in the urine of patients receiving a therapeutic intravenous dose of SFO. Furthermore, SFO decreased the calcium content and inhibited 45Ca incorporation in cultured fetal mouse parietal bones at 3 μmol/L. Such SFO concentration may be transiently observed in the plasma of patients receiving excessive intravenous doses of SFO for a prolonged period. These in vitro findings together with the clinical observations suggest that SFO, after filtration through the glomerulus and reabsorption in the proximal renal tubules, impaired proximal renal tubular function, such as tubular reabsorption of phosphate and 1α-hydroxylase activity, leading to hypophosphatemic osteomalacia. Furthermore, it is highly likely that SFO in the peripheral blood, when transferrin is saturated with iron, may impair bone formation and aggravate osteomalacia. Although SFO-induced osteomalacia is reversible simply by discontinuation of the agent, excessive and prolonged administration of SFO should be avoided.

Association of radionuclide bone scan and serum alkaline phosphatase in patients with metastatic renal cell carcinoma

We assessed the frequency of bone metastases, their association with serum alkaline phosphatase (AP), and prognostic capabilities of AP in patients with renal cell carcinoma (RCC), using bone scan as the reference standard for diagnosis. We conducted a retrospective review of patients with metastatic RCC treated with either autologous ex vivo activated T-lymphocytes and cimetidine (ALT) or cimetidine alone. Twenty-eight of 90 patients (31%) had evidence of bone metastases by bone scan. With 100 mg/ dL as the upper limit of normal, 11 of 28 (39%) patients with bone metastases had normal AP levels. Of these 11 patients, 8 had bone pain. Of the 3 asymptomatic patients with bone metastasis and normal AP levels, only 1 had bone as the only site of metastasis and would have been incorrectly staged without the scan. Patients with bone metastases had a significantly shorter median survival than those without bone metastases (13.8 versus 25.3 months; P < 0.05). Among patients without bone metastases who had elevated AP levels, those treated with ALT had significantly longer median survivals than those treated with cimetidine alone (27.6 versus 14.5 months; P < 0.05). Overall, patients treated with ALT had a significantly longer median survival than the ones treated only with cimetidine (21 versus 8.5 months; P < 0.05). Overall, the median survival for patients with elevated AP levels (10 months) was not significantly different from that of those with normal AP levels (13 months). In a high-risk group of patients with metastatic RCC, 31% had bone metastases. Elevated AP levels, the presence of bone pain, or the presence of other metastases correctly predicted bone metastasis in all but 1 patient. A bone scan may safely be omitted in patients with RCC, normal AP levels, and no bone pain. However, AP elevation itself had little prognostic capability in these patients.

Effects of two different bisphosphonates on Paget's disease of bone: ICTP assessed

Clodronate and alendronate were compared in 27 patients with active Paget's bone disease. Carboxyterminal crosslinked telopeptide of type I collagen (ICTP) was evaluated as a marker of bone turnover in Paget's bone disease. Group 1. Nineteen patients received clodronate infusions (300 mg/daily) on 5 consecutive days. After 1 year, 12 patients (63%) were still in remission; urinary hydroxyproline (64.8%) and serum alkaline phosphatase (59.4%) were significantly reduced and had returned to normal in 30%. Patients in remission had significantly higher basal values of urinary hydroxyproline. No adverse side effects were observed. Group 2. One year after clodronate, seven relapsing patients retrospectively underwent five consecutive infusions of alendronate (5 mg/daily). Within 12 months, urinary hydroxyproline fell by 74.7%, alkaline phosphatase dropped by 75.2%, osteocalcin by 47.3%, and ICTP by 56.4%. In all patients, urinary hydroxyproline and alkaline phosphatase returned to normal within 3 months and remained within the normal range during the 12-month follow-up. Most patients had mild, short course fever and arthromyalgia. Group 3. Eight newly diagnosed pagetics, received alendronate alone (5 mg/daily for 5 days). All patients responded well to alendronate within the first month. None suffered a relapse during the follow-up. At month 12, urinary hydroxyproline was down by 71.4%, alkaline phosphatase by 75.3%, osteocalcin by 58.1%, and ICTP by 67.4%. In all patients, markers of bone remodeling were in the normal range at the end of the follow-up. Moderate, transitory arthromyalgia, and fever (high and lasting for 7 days in only one case) were observed in half of the patients. Soon after alendronate infusion another patient had an acute attack of pericarditis with a moderate pericardial effusion, resolved within 7 days. ICTP (marker of Paget's disease of bone): ICTP correlated with urinary hydroxyproline but not with alkaline phosphatase; the gap was most marked 1 month after bisphosphonates, when the imbalance between bone resorption and formation was maximal. Basal ICTP levels were normal in 35% of the 27 pagetic patients, who all had abnormal basal urinary hydroxyproline and alkaline phosphatase levels. All abnormal ICTP levels were normalized by alendronate but after clodronate ICTP remained above the normal range in 6 patients (31.6%) with normal urinary hydroxyproline and alkaline phosphatase levels. Compared with a sex- and age-matched control group the sensitivity and specificity of ICTP were 0.71 and 1.38, respectively. Clodronate and alendronate are both effective in Paget's bone disease causing marked reduction in bone pain and joint stiffness. Clodronate was more active when osteoclast activity was greater. Alendronate induced a more rapid and marked inhibition of bone turnover, and is also effective in relapses after clodronate. Its antiresorptive mechanism could be different. ICTP does not appear to be a reliable marker of bone resorption in Paget's disease of bone.

Audit and its Impact in the Management of Advanced Prostatic Cancer

From a prospective database of 614 consecutive men with newly diagnosed prostatic cancer an audit of outcome was studied in 169 men who presented with bone metastases and subsequently received hormonal manipulation in the form of monotherapy. The cohort was divided into 2 groups according to serum alkaline and acid phosphatase enzyme levels. Men with normal alkaline phosphatase levels (41.5%) had a better prognosis (median survival 38 months) than those with elevated levels at presentation (58.5%) (median survival 19 months). This difference was highly significant. A similar stratification on prostatic acid phosphatase levels did not yield any prognostic significance. With regard to cause-specific survival, serum alkaline phosphatase was an even more powerful prognosticator, with a median survival of 45 and 21 months for patients with normal and elevated levels respectively. Thus monotherapy is recommended for metastatic prostate cancer patients with normal serum alkaline phosphatase, but for those with elevated alkaline phosphatase the alternative avenues of treatment must be explored.

Value of preoperative bone and liver scans and alkaline phosphatase in the evaluation of breast cancer patients

We reviewed the results of 133 bone scans and 63 liver scans (computed tomography, liver-spleen radionuclide scan, or ultrasonography) obtained for the preoperative evaluation of breast cancer patients. Information on the preoperative staging of breast cancer (TNM classification) was available in 131 of 133 patients. Bone scans had a low preoperative yield as only 4 of 133 patients (3%) had a positive bone scan that correlated with the results of plain films. Only 1 of 63 patients had a liver scan suggestive of possible metastasis. We also found that the alkaline phosphatase level was not a good predictor of bone or liver metastases in breast cancer patients. In 103 patients with normal bone scans, the majority (54%) had elevated alkaline phosphatase levels; conversely, 9 of 30 patients (30%) with abnormal scans had normal alkaline phosphatase levels. Furthermore, 51 of 63 patients (81%) with elevated alkaline phosphatase levels had normal liver scans. Approximately $74,000 was spent on these liver and bone scans.

Antimitochondrial antibodies in kindreds of patients with primary biliary cirrhosis: antimitochondrial antibodies are unique to clinical disease and are absent in asymptomatic family members.

The 2-oxo-acid dehydrogenase family of enzymes have been identified as the major mitochondrial autoantigens of primary biliary cirrhosis. Using immunoblotting, enzyme-linked immunosorbent assay and enzyme inhibition with both purified mitochondrial proteins and recombinant autoantigens, we have studied family members and spouses of patients with primary biliary cirrhosis for the presence of antimitochondrial antibodies. Antimitochondrial antibodies and other common autoantigens were also tested for by indirect immunofluorescence. This study included 27 index patients with primary biliary cirrhosis, 15 spouses and 48 first- and second-degree relatives. Overall, 7 relatives (11%) were positive for autoantibodies to nuclear and cytoplasmic antigens by indirect immunofluorescence against mouse liver and stomach sections. However, with immunofluorescence, the reactivity strictly paralleled that of antimitochondrial antibodies in only one of these (1:640)--a sibling with mild pruritus and a liver biopsy specimen diagnostic of primary biliary cirrhosis despite normal levels of serum alkaline phosphatase. In addition, one of the mothers, who had a history of sarcoidosis, was positive by immunoblotting for antibodies to the E2 subunit of the pyruvate dehydrogenase complex and protein X. All other relatives were negative for all of the assays. Antibodies to neither the 2-oxo-acid dehydrogenase enzymes nor the recently proposed family of naturally occurring mitochondrial antibodies were found in spouses or healthy relatives. Three other first-degree relatives suffered from liver disease: two died (one from primary biliary cirrhosis and the other from an unknown type of liver disease) and one (a sibling with primary biliary cirrhosis) was unavailable for testing. Our results are consistent with a familial predisposition to primary biliary cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Osteopenia and osteomalacia after gastrectomy: interrelations between biochemical markers of bone remodelling, vitamin D metabolites, and bone histomorphometry.

The prevalence of metabolic disease in a population of 68 postgastrectomy patients was assessed using histomorphometric evaluation of transiliac bone biopsy specimens after tetracycline double labelling. Trabecular bone volume was significantly lower in the postgastrectomy group (p less than 0.01): 62% of the patients had increased osteoid surface, 56% increased osteoid thickness, and 24% increased mineralisation lag time. Only 18%, however, fulfilled the diagnostic criteria for osteomalacia--increased osteoid thickness and increased mineralisation lag time. Postgastrectomy patients had reduced serum concentrations of calcium (p less than 0.01), phosphate (p less than 0.01), and 25-hydroxyvitamin D, while levels of alkaline phosphatase and 1,25 dihydroxyvitamin D were high (p less than 0.01). The severity of the mineralisation defect as reflected by mineralisation lag time was positively correlated to serum 25-hydroxyvitamin D, but unrelated to serum 1,25-dihydroxyvitamin D. Multiple linear regression analysis showed that serum 25-hydroxyvitamin D, age, and the duration of postoperative follow up were significant determinants of the mineralisation defect in a given patient. The limited value of serum markers in the diagnosis of osteomalacia was emphasised by the fact that six of the eight patients with osteomalacia had normal serum levels of calcium and alkaline phosphatase, and five of the eight had values for 25-hydroxyvitamin D in the normal range for healthy control subjects. The results clearly show the need for vitamin D supplementation and regular control after gastric resection.

Estudo comparativo dos valores normais das provas de função hepática em caprinos das raças Saanen, Parda Alpina, e mestiços do Estado de São Paulo

Normal levels of Alkaline phosphatase, total, direct and indirect bilirubin, and transaminases (ALT and AST) were determined in ninety milk goats reared in the State of São Paulo .The animals aged between two months and six years. The breeds evaluated were: Saanen, Alpine and cross breed animals. Age and breed were taken into account when analyzing these parameters. There was no statistic difference for none of the tests attributable to age. Concerning breeds, Saanen showed higher serum levels of direct bilirubin when compared to Alpine and cross-bred animals; and Alpine showed higher AST serum levels than cross-breed animals. Serum levels of total bilirubin and indirect bilirubin, ALT and alkaline phosphatase show no statistical difference when the breed was concerned.

Hepatic amyloidosis (Primary [AL], immunoglobulin light chain): The natural history in 80 patients

Purpose: We wished to study patients with a premortem diagnosis of primary hepatic amyloidosis to determine what clinical and laboratory features might assist in recognizing the disease and assessing prognosis. Patients and methods: A group of 80 patients with liver biopsy proven primary hepatic amyloidosis was followed from diagnosis to death. Results: At presentation, 77 percent of the group had an associated nephrotic syndrome, congestive heart failure, peripheral neuropathy, or orthostatic hypotension. Certain clues suggested the diagnosis of hepatic amyloidosis in patients with liver disease, including the following: (1) proteinuria (88 percent); (2) abnormal serum protein electrophoresis (monoclonal protein or hypogammaglobulinemia, 64 percent); (3) hyposplenism on the peripheral blood smear (62 percent), defined by the presence of Howell-Jolly bodies; and (4) hepatomegaly disproportional to the liver enzyme abnormalities. Liver function tests were not sensitive or specific. Hepatomegaly from amyloid was frequently seen, with normal levels of alkaline phosphatase, aspartate aminotransferase, and bilirubin (32 percent). Myeloma was diagnosed in 11 patients but had no effect on the clinical course. In vitro coagulation abnormalities were common, bleeding was infrequent, and liver biopsy carried a slightly increased risk. The median survival of the entire group was nine months, and projected five- and 10-year survival rates were 13 and 1 percent, respectively. Conclusion: Because survival is poor and no clinical features permit prospective recognition of those patients in whom the disease is likely to have an indolent course, a trial of therapy is warranted in all patients.

Treatment of Paget's disease of bone with intravenous 4-amino-1-hydroxybutylidene-1,1-bisphosphonate.

4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHButBP) was given intravenously (2.5-25 mg/day for 4 days) to 14 patients with Paget's disease of bone, five of whom had been treated with dichloromethylidene bisphosphonate (C12MBP) 32 months earlier. In the nine patients who had not been treated previously with bisphosphonates, the short course of AHButBP induced a suppression of serum alkaline phosphatase and urinary hydroxyproline values down to 30% of initial values. The biochemical suppression of the disease was sustained for 2-18 months and the time to relapse did correlate to the logarithm of the dose (P less than 0.001). In the five patients previously treated for Paget's disease, an apparent resistance to treatment with AHButBP was observed. However, in these patients both serum alkaline phosphatase and urinary hydroxyproline fell to or even below the nadir values which had previously been achieved with C12MBP, irrespective of the degree of relapse. Thus the degree of suppression of Paget's disease of bone, achievable after treatment with bisphosphonates, seems to be constant for each patient, such that normal levels of serum alkaline phosphatase and urinary hydroxyproline cannot usually be attained in patients with extremely active disease.

Adult hypophosphatasia with chondrocalcinosis and arthropathy: Variable penetrance of hypophosphatasemia in a large Oklahoma kindred

Three sisters, each with chondrocalcinosis/arthropathy, are described who have the clinical, laboratory and pathologic findings characteristic of the adult form of hypophosphatasia. Premature loss of adult teeth, arthralgias and pain from bilateral femoral pseudofractures were associated with subnormal circulating alkaline phosphatase levels, phosphoethanolaminuria and osteomalacia diagnosed by iliac crest biopsy. Assay of alkaline phosphatase activity in the blood of kindred members revealed hypophosphatasemia in one of two younger brothers. Several subjects in subsequent generations also had suspiciously tow alkaline phosphatase activity, but did not have histories of significant dental, bone or joint disease. Review of the medical records of the sisters' parents, aunts and uncles revealed normal alkaline phosphatase levels in their father and five of his siblings, but consistently low levels in their mother and two of her siblings. Despite hypophosphatasemia, the sisters' mother and her siblings lived to old age without clinical or radiographic evidence of bone disease. Our findings suggest that although adult hypophosphatasia can be transmitted as a dominant trait in some kindreds, there is considerable variation in the clinical expression of the biochemical defect. One person, generation or family may manifest clinical bone disease and arthropathy whereas the biochemical defect may be present but remain asymptomatic in others. Furthermore, in some cases, the adult form of hypophosphatasia may represent a developmental disorder with hypophosphatasemia appearing during adulthood.

Quantitative and qualitative studies on skin fibroblast alkaline phosphatase in fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP, also known as myositis ossificans progressiva) is a rare inherited disease, which is characterised by skeletal malformations and progressive ectopic ossification [l]. Ectopic ossification involves the connective tissue of voluntary muscles, ligaments and joints and results in serious handicap. Pathological studies have shown that the early ossifying lesions consist of an accumulation of fibroblasts [2,3]. These fibroblasts have high levels of alkaline phosphatase activity with both histochemical and biochemical assays [3-61. Subsequently these cells become morphologically indistinguishable from active osteoblasts and lay down ectopic bone [3,5]. Herrman et al. [7] were the first to measure alkaline phosphatase activity of in vitro fibroblasts from areas of uninvolved skin in FOP. They studied a single patient using a histochemical assay and found high levels of enzyme activity. This led them to propose that FOP was due to a generalised disturbance in the regulation of fibroblast behaviour. Beratis et al [8] studied one FOP patient and 10 controls and noted low normal levels of alkaline phosphatase in FOP skin fibroblasts in vitro. They used a calorimetric assay with p-nitrophenylphosphate as substrate. Miller et al [9], using the same calorimetric assay, found no detectable activity in skin fibroblasts from one FOP patient. The present study was therefore undertaken to clarify the levels of activity of alkaline phosphatase in FOP skin fibroblasts in vitro and also to study this enzyme qualitatively in FOP fibroblasts.

Preoperative evaluation of the risk of common bile duct stones.

The patient with gallstones has an unknown risk of also having choledocholithiasis. To establish this risk preoperatively, several tests were studied in 167 patients, 37 of whom had common duct stones at exploration. With no previous or current jaundice, as well as normal alkaline phosphatase levels and a duct size of less than 12 mm, there was less than a 5% risk of choledocholithiasis; elevated bilirubin and/or alkaline phosphatase levels indicated intermediate risks (33% to 66%); and a duct size of 12 mm or greater, with any combination of other factors, indicated a 90% to 100% risk of choledocholithiasis. The surgeon should be aware of these probabilities in evaluating conditions of patients with cholelithiasis.

Serum alkaline phosphatase determination. Value in the staging of advanced breast cancer.

A retrospective study of 146 patients with metastatic disease was undertaken to verify the clinical impression that radionuclide scanning rarely, if ever, discloses hepatic metastases in breast cancer patients with normal serum alkaline phosphatase (AP) levels. Only two of 39 patients with abnormal liver scans had normal AP levels, and we conclude that liver scans are not necessary as a routine screening method for liver metastases when the AP level is normal. In contrast AP levels were not predictive of bone scan results. All patients with a twofold or greater elevation of the AP level had abnormal bone, liver, or bone and liver scans. Routine AP determinations provide accurate staging information, and their proper use can decrease the cost of initial and follow-up examination of patients with breast cancer.

Serum Alkaline Phosphatase Determination

A retrospective study of 146 patients with metastatic disease was undertaken to verify the clinical impression that radionuclide scanning rarely, if ever, discloses hepatic metastases in breast cancer patients with normal serum alkaline phosphatase (AP) levels. Only two of 39 patients with abnormal liver scans had normal AP levels, and we conclude that liver scans are not necessary as a routine screening method for liver metastases when the AP level is normal. In contrast AP levels were not predictive of bone scan results. All patients with a twofold or greater elevation of the AP level had abnormal bone, liver, or bone and liver scans. Routine AP determinations provide accurate staging information, and their proper use can decrease the cost of initial and follow-up examination of patients with breast cancer. (<i>JAMA</i>242:1147-1149, 1979)

Prognostic significance of alkaline phosphatase measurements in patients with osteogenic sarcoma receiving chemotherapy

During the period January 1975 to August 1977, alkaline phosphatase levels in 30 patients with osteogenic sarcoma were closely followed in an attempt to determine if these measurements had clinical value in predicting the course of patients with this disease. Of 17 patients with elevated preoperative alkaline phosphatase levels, 12 recurred. Of 13 patients with normal preoperative alkaline phosphatase levels, only 4 recurred (p less than .05). Thus, alkaline phosphatase levels that were elevated preoperatively were correlated with poor prognosis. A similar correlation between postoperative alkaline phosphatase levels and prognosis could not be made.

Alkaline phosphatase isoenzyme patterns in hyperthyroidism.

Fifteen of 36 hyperthyroid patients had elevation in serum alkaline phosphatase activity. There was no difference in mean thyroxine (T4), triiodothyronine (T3), age, or duration of illness between the groups with high alkaline phosphatase and normal alkaline phosphatase levels. After treatment, serum alkaline phosphatase levels rose as T4 levels declined; at 3 months, the mean serum alkaline phosphatase value rose from 7.1 Bodansky units to 10.3 Bodansky units (P less than 0.005), while the mean T4 value fell from 18 microgram/dl to 7.2 microgram/dl (P less than 0.005). In some patients, serum alkaline phosphatase values have remained elevated for more than 1 year, despite continued normality in thyroid variables. Before therapy, isoenzyme patterns analyzed by polyacrylamide gel electrophoresis were qualitatively normal. As therapy was instituted, the isoenzyme patterns changed markedly, with increased amounts of bone alkaline phosphatase appearing in the serum as T4 levels were declining and total alkaline phosphatase was rising. Thyroid tissue homogenates from patients with Graves' disease were found to have very low levels of alkaline phosphatase activity and an isoenzyme pattern quite distinct from that found in the serum.

Comparison of Enzyme, Clinical, Radiographic, and Radionuclide Methods of Detecting Bone Metastases from Carcinoma of the Prostate

Patients (219) with prostatic adenocarcinoma were classified on the basis of whether or not their bone scans were positive for metastasis. Acid and alkaline phosphatase determinations and clinical evaluations for bone metastases were reviewed. Of those with proved metastases, 43% had no bone pain, 39% had normal acid phosphatase levels, 23% normal alkaline phosphatase levels, 19% normal levels of both enzymes, and 15% normal enzyme levels without bone pain. Twenty-four per cent of the patients with normal enzyme levels and clinically unsuspected bone metastases had bone scans which proved positive for metastasis; 62% of these had normal radiographs.

Jaundice following open-heart surgery.

Singh, H. M., and Baker, J. T. (1974). Thorax, 29, 68-74. Jaundice following open-heart surgery. A study was made into the factors influencing the onset of jaundice in 102 patients undergoing valve replacement during cardiopulmonary bypass. Postoperative jaundice appeared to be correlated with double valve replacement, the co-existence of an uncorrected valvular lesion, length of perfusion and myocardial ischaemia times, and also the age of the patient. Factors appearing not to be correlated with the onset of jaundice included preoperative pulmonary artery pressure, cardiac index, parameters of preoperative renal and hepatic function, and the amount of blood used during bypass. The biochemical features of the jaundice seemed to follow a pattern not previously recognized in this context, with sometimes considerably raised bilirubin levels in association with virtually normal levels of transaminases and alkaline phosphatase.

Needle Bone Biopsy in

Results of diagnostic needle bone biopsies in 25 patients subsequently undergoing neck exploration for parathyroid disease are reported. Histologic changes believed to represent hyperparathyroidism in bone biopsy specimens included evidence of (1) increased osteoblastic activity; (2) increased osteoid formation; and (3) excessive osteoclastic activity. Such changes were seen in 23 of 25 biopsies. The results of two biopsies were negative. A positive correlation between pathologic findings in bone and surgically proven primary hyperparathyroidism was noted in 20 of 25 patients. Nine of the patients with abnormal biopsies had hyperparathyroidism, despite normal roentgenograms and alkaline phosphatase levels. Explanations accounting for abnormal biopsies in three patients with negative results for neck exploration were available. Two patients with proven parathyroid adenoma had negative results for bone biopsies. With proper interpretation, needle bone biopsy is a useful tool for evaluation of primary hyperparathyroidism.