Elevated Serum Alkaline Phosphatase Levels Research Articles

Diagnosis and treatment of Paget's disease of bone: a mini-review

Paget's disease of bone (PDB) is a chronic progressive disorder of bone metabolism that may go undetected for many years, and endocrinologists should be alert to its clinical signs and promptly diagnose and treat PDB before it results in irreversible complications, such as deformity, fracture or neurological sequelae. Most commonly, PDB is suspected upon the incidental finding of elevated serum alkaline phosphatase levels or a radiographic abnormality in an otherwise healthy individual above 55 years of age. Some of these individuals may have symptoms such as bone pain or enlargement with increased warmth. In general, a basic laboratory evaluation of bone metabolism, plain radiographies of affected bones and bone scintigraphy are sufficient to corroborate the diagnosis. Antiresorptive therapy with bisphosphonates is the mainstay of treatment of symptomatic PDB, and intravenous zoledronic acid has emerged as an effective and safe treatment option, leading to sustained remission and improved quality of life. It is extremely important, though, to ensure calcium and vitamin D sufficiency before and during treatment in order to prevent hypocalcemia. The benefit of treating all asymptomatic patients is not clear, but treatment is warranted if the pagetic lesion is located in a site where progression to fracture, deformity, or compression would significantly impair the patient quality of life. This mini-review focuses on important aspects of the diagnosis and treatment of PDB.

Pregnancy complicated by focal nodular hyperplasia: a case report of one woman over two consecutive courses of pregnancy.

Key Clinical MessageWe encountered a woman with a preexisting large focal nodular hyperplasia (FNH) of the liver, persisting during two separate pregnancies. FNH size was not affected by either pregnancy. Her elevated serum γ-glutamyltransferase and alkaline phosphatase levels before pregnancy were reduced during both pregnancies, but returned to prepregnancy levels after delivery.

In vitro antioxidant activity and in vivo hepatoprotective activity of aqueous extract of Allium cepa bulb in ethanol induced liver damage in Wistar rats

The in vitro antioxidant and in vivo hepatoprotective effects of aqueous extract of Allium cepa (A. cepa) bulb were evaluated in male rats against ethanol induced liver damage in preventive and curative models. The antioxidant activity of A. cepa was assayed and activities were compared to standard antioxidant, ascorbic acid. The results revealed that the IC50 values of A. cepa bulb extract for DPPH, hydroxyl, superoxide radical scavenging activities were 195.2±0.2, 374.7±0.4 and 182.5±1.7μg/mL, respectively. Liver injury was induced by 40% ethanol administration (3.76g/kgbw, orally) for 25 days. In two different sets of experiments, the A. cepa extracts (100, 300 and 600mg/kg bw) and silymarin (100mg/kg bw) were administered orally in preventive and curative models. Ethanol administration caused severe hepatic damage in rats as evidenced by elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin levels. The A. cepa and silymarin administration prevented the toxic effect of ethanol on the above serum parameters in both preventive and curative models. The present study concludes that aqueous extract of A. cepa bulb has significant antioxidant and hepatoprotective activity against ethanol induced hepatotoxicity.

Prognostic Importance of Serum Alkaline Phosphatase in CKD Stages 3-4 in a Clinical Population

Elevated total serum alkaline phosphatase (ALP) levels have been associated with mortality in the general population and in dialysis patients. Retrospective cohort study. 28,678 patients with chronic kidney disease (CKD) stages 3 and 4 (estimated glomerular filtration rate, 15-59 mL/min/1.73 m(2)) were identified using the Cleveland Clinic CKD Registry. CKD was defined as 2 estimated glomerular filtration rate values <60 mL/min/1.73 m(2) drawn more than 90 days apart using the CKD-EPI (CKD Epidemiology Collaboration) creatinine equation. ALP levels measured using the calorimetric assay were examined as quartiles (quartile [Q]1, <66 U/L; Q2, 66-81 U/L; Q3, 82-101 U/L; and Q4, ≥102 U/L) and as a continuous measure. All-cause mortality and end-stage renal disease (ESRD) were ascertained using the Social Security Death Index and US Renal Data System. After a median follow-up of 2.2 years, 588 patients progressed to ESRD and 4,755 died. There was a graded increase in risk of mortality with higher ALP quartiles (Q2, Q3, and Q4) compared to the reference quartile (Q1) after adjusting for demographics, comorbid conditions, use of relevant medications, and liver function test results. The highest ALP quartile was associated with an HR for ESRD of 1.38 (95% CI, 1.09-1.76). Each 1-SD (42.7 U/L) higher ALP level was associated with 15% (95% CI, 1.09-1.22) and 16% (95% CI, 1.14-1.18) increased risk of ESRD and mortality, respectively. Single-center observational study; lack of complete data, including parathyroid hormone level, for all study participants, and attrition bias. Higher serum ALP levels in patients with CKD stages 3-4 were associated independently with all-cause mortality and ESRD.

Factor Affecting the Vitamin D Status in South Korean Children

To establish the prevalence of vitamin D deficiency and insufficiency in healthy South Korean children aged between 1 month and 16 years and to identify factors affecting the serum vitamin D levels in South Korea. A total 969 healthy children were enrolled in this study. Serum levels of 25 hydroxyvitamin D (25(OH)D), calcium, phosphorous and alkaline phosphatase (ALP) were measured during a 1 year period. All the children were divided into four groups depending on the age. The prevalence of vitamin D deficiency (<15 ng/mL) was 20.5% and that of vitamin D insufficiency (15-20 ng/mL) was 19.5%. Overall, the mean serum 25(OH)D levels was 22.9±9.9 ng/mL. They were the highest in the preschoolers (2-5 years, 24.4 ng/mL) and the lowest in the adolescents (11-16 years,15.9 ng/mL). In addition, they were significantly higher in summer as compared with winter. There were eight cases of subclinical rickets with elevated serum ALP levels. The prevalence of vitamin D insufficiency and deficiency was relatively higher in our series of children. It is imperative that the public policies be established to provide vitamin D supplementation for South Korean children. In addition, pediatricians should consider such factors as the body mass index, sex, season and other risk factors when determining the optimal level of vitamin D.

Risk Factors of Post Endoscopic Retrograde Cholangiopancreatography Bacteremia

Background/AimsBacteremia following endoscopic retrograde cholangiopancreatography (ERCP) is a severe complication, but the risk factors for this condition have not yet been clearly determined. Thus, the aim of this study was to investigate the risk factors of post-ERCP bacteremia.MethodsAmong patients who underwent ERCP from June 2006 to May 2009, we selected patients without any signs of infection prior to the ERCP procedures. Of these patients, we further selected those who experienced bacteremia after ERCP as well as two-fold age and sex-matched controls who did not experience bacteremia after ERCP procedures. We compared clinical, laboratory and technical aspects between these two groups.ResultsThere were 70 patients (3.1%) who developed bacteremia after ERCP. In the multivariate analysis, a history of previous liver transplantation, an elevated serum alkaline phosphatase level and an endoscopic retrograde biliary drainage procedure were independent risk factors of post-ERCP bacteremia (p=0.006, p=0.001, and p=0.004, respectively). The microbiologic analysis revealed the presence of gram-negative organisms in 80% of the cases, and 11 patients had infections with bacteria expressing extended spectrum β-lactamases. Pseudomonas infection was significantly more common in patients who received liver transplantation as compared to patients without transplantation (p=0.014).ConclusionsA history of liver transplantation, elevated serum alkaline phosphatase levels and endoscopic retrograde biliary drainage procedure were independent risk factors of post-ERCP bacteremia and require additional attention in future studies.

High phosphate feeding promotes mineral and bone abnormalities in mice with chronic kidney disease

Chronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic syndrome characterized by imbalances in mineral homeostasis, renal osteodystrophy (ROD) and ectopic calcification. The mechanisms underlying this syndrome in individuals with chronic kidney disease (CKD) are not yet clear. We examined the effect of normal phosphate (NP) or high phosphate (HP) feeding in the setting of CKD on bone pathology, serum biochemistry and vascular calcification in calcification-prone dilute brown non-agouti (DBA/2) mice. In both NP and HP-fed CKD mice, elevated serum parathyroid hormone and alkaline phosphatase (ALP) levels were observed, but serum phosphorus levels were equivalent compared with sham controls. CKD mice on NP diet showed trabecular alterations in the long bone consistent with high-turnover ROD, including increased trabecular number with abundant osteoblasts and osteoclasts. Despite trabecular bone and serum biochemical changes, CKD/NP mice did not develop vascular calcification. In contrast, CKD/HP mice developed arterial medial calcification (AMC), more severe trabecular bone alterations and cortical bone abnormalities that included decreased cortical thickness and density, and increased cortical porosity. Cortical bone porosity and trabecular number strongly correlated with the degree of aortic calcification. HP feeding was required to induce the full spectrum of CKD-MBD symptoms in CKD mice.

Amelogenesis Imperfecta and Other Biomineralization Defects in Fam20a and Fam20c Null Mice

The FAM20 family of secreted proteins consists of three members (FAM20A, FAM20B, and FAM20C) recently linked to developmental disorders suggesting roles for FAM20 proteins in modulating biomineralization processes. The authors report here findings in knockout mice having null mutations affecting each of the three FAM20 proteins. Both Fam20a and Fam20c null mice survived to adulthood and showed biomineralization defects. Fam20b (-/-) embryos showed severe stunting and increased mortality at E13.5, although early lethality precluded detailed investigations. Physiologic calcification or biomineralization of extracellular matrices is a normal process in the development and functioning of various tissues (eg, bones and teeth). The lesions that developed in teeth, bones, or blood vessels after functional deletion of either Fam20a or Fam20c support a significant role for their encoded proteins in modulating biomineralization processes. Severe amelogenesis imperfecta (AI) was present in both Fam20a and Fam20c null mice. In addition, Fam20a (-/-) mice developed disseminated calcifications of muscular arteries and intrapulmonary calcifications, similar to those of fetuin-A deficient mice, although they were normocalcemic and normophosphatemic, with normal dentin and bone. Fam20a gene expression was detected in ameloblasts, odontoblasts, and the parathyroid gland, with local and systemic effects suggesting both local and/or systemic effects for FAM20A. In contrast, Fam20c (-/-) mice lacked ectopic calcifications but were severely hypophosphatemic and developed notable lesions in both dentin and bone to accompany the AI. The bone and dentin lesions, plus the marked hypophosphatemia and elevated serum alkaline phosphatase and FGF23 levels, are indicative of autosomal recessive hypophosphatemic rickets/osteomalacia in Fam20c (-/-) mice.

Prognostic factors in canine appendicular osteosarcoma – a meta-analysis

BackgroundAppendicular osteosarcoma is the most common malignant primary canine bone tumor. When treated by amputation or tumor removal alone, median survival times (MST) do not exceed 5 months, with the majority of dogs suffering from metastatic disease. This period can be extended with adequate local intervention and adjuvant chemotherapy, which has become common practice. Several prognostic factors have been reported in many different studies, e.g. age, breed, weight, sex, neuter status, location of tumor, serum alkaline phosphatase (SALP), bone alkaline phosphatase (BALP), infection, percentage of bone length affected, histological grade or histological subtype of tumor. Most of these factors are, however, only reported as confounding factors in larger studies. Insight in truly significant prognostic factors at time of diagnosis may contribute to tailoring adjuvant therapy for individual dogs suffering from osteosarcoma. The objective of this study was to systematically review the prognostic factors that are described for canine appendicular osteosarcoma and validate their scientific importance.ResultsA literature review was performed on selected studies and eligible data were extracted. Meta-analyses were done for two of the three selected possible prognostic factors (SALP and location), looking at both survival time (ST) and disease free interval (DFI). The third factor (age) was studied in a qualitative manner. Both elevated SALP level and the (proximal) humerus as location of the primary tumor are significant negative prognostic factors for both ST and DFI in dogs with appendicular osteosarcoma. Increasing age was associated with shorter ST and DFI, however, was not statistically significant because information of this factor was available in only a limited number of papers.ConclusionsElevated SALP and proximal humeral location are significant negative prognosticators for canine osteosarcoma.

Hepatobiliary and Pancreatic: Hepatic actinomycosis

A 72-year-old man was investigated because of a 1-week history of fever, headache and myalgia. Seven years previously, he had been diagnosed with gastric adenocarcinoma and treated with a subtotal gastrectomy. On admission to hospital, his temperature was elevated (38.3°C) but no other abnormalities were detected on physical examination. Laboratory tests revealed mild anemia (hemoglobin 114 g/l), an elevated white cell count (12.6x10/l) and a mild elevation of C-reactive protein (13.6 mg/l), aspartate aminotransferase (53 u/l), alanine aminotransferase (65 u/l), alkaline phosphatase (222 u/l) and g-glutamyl transferase (264 u/l). His serum glucose was also elevated. A contrast-enhanced computed tomography (CT) scan showed several lesions of low-attenuation in both lobes of the liver (Figure 1). The differential diagnosis included liver abscesses and liver metastases. A percutaneous aspirate was obtained under ultrasound guidance and yielded thick brown turbid fluid. In wet-fixed smears, blue colonies of actinomycosis with “bales of wool” appearance were seen on a background of mixed inflammatory cells (Figure 2). In cell-block sections, there were many irregularly lobulated or scalloped basophilic granules termed “sulphur granules” that are characteristic of Actinomyces. There was no evidence of metastatic adenocarcinoma. Gram staining revealed positive filamentous bacilli (Figure 2 inset, white arrow). The patient was treated with percutaneous drainage for 2 weeks and with high-dose penicillin-G given intravenously. His fever subsided after 2 weeks and laboratory tests gradually returned to normal. The abscesses had resolved on repeat CT scan after 2 months. Hepatic actinomycosis is a rare disease. Although cases of primary hepatic actinomycosis have been described, actinomycosis appears to spread to the liver from other abdominal sites in the majority of cases. Symptoms are often non-specific with weight loss and fever. However, most patients with hepatic actinomycosis have an elevated serum alkaline phosphatase level in addition to a leucocytosis and elevated erythrocyte sedimentation rate. The typical radiological feature is that of multiple liver abscesses but multiple small lesions may be difficult to characterize. Percutaneous aspirates can be diagnostic when they contain “sulphur granules” with gram-positive bacilli. Cultures are positive in some but not all patients. Larger abscesses can be treated by percutaneous drainage but eradication of the infection usually requires prolonged courses of intravenous penicillin. The evolution of hepatic abscesses caused by actinomycosis is usually more insidious than that associated with pyogenic abscesses.

Mechanism for Release of Alkaline Phosphatase Caused by Glycosylphosphatidylinositol Deficiency in Patients with Hyperphosphatasia Mental Retardation Syndrome

Hyperphosphatasia mental retardation syndrome (HPMR), an autosomal recessive disease characterized by mental retardation and elevated serum alkaline phosphatase (ALP) levels, is caused by mutations in the coding region of the phosphatidylinositol glycan anchor biosynthesis, class V (PIGV) gene, the product of which is a mannosyltransferase essential for glycosylphosphatidylinositol (GPI) biosynthesis. Mutations found in four families caused amino acid substitutions A341E, A341V, Q256K, and H385P, which drastically decreased expression of the PIGV protein. Hyperphosphatasia resulted from secretion of ALP, a GPI-anchored protein normally expressed on the cell surface, into serum due to PIGV deficiency. In contrast, a previously reported PIGM deficiency, in which there is a defect in the transfer of the first mannose, does not result in hyperphosphatasia. To provide insights into the mechanism of ALP secretion in HPMR patients, we took advantage of CHO cell mutants that are defective in various steps of GPI biosynthesis. Secretion of ALP requires GPI transamidase, which in normal cells, cleaves the C-terminal GPI attachment signal peptide and replaces it with GPI. The GPI-anchored protein was secreted substantially into medium from PIGV-, PIGB-, and PIGF-deficient CHO cells, in which incomplete GPI bearing mannose was accumulated. In contrast, ALP was degraded in PIGL-, DPM2-, or PIGX-deficient CHO cells, in which incomplete shorter GPIs that lacked mannose were accumulated. Our results suggest that GPI transamidase recognizes incomplete GPI bearing mannose and cleaves a hydrophobic signal peptide, resulting in secretion of soluble ALP. These results explain the molecular mechanism of hyperphosphatasia in HPMR.

Associations of Serum Alkaline Phosphatase with Metabolic Syndrome and Mortality

Background Recent data suggest that elevated serum alkaline phosphatase levels are associated with increased mortality, but the mechanisms for this association are unknown. As metabolic syndrome is associated with higher serum alkaline phosphatase levels, we examined the joint association of mortality with metabolic syndrome and serum alkaline phosphatase levels in the US general population. Methods Retrospective observational study of 15,234 adult participants in the National Health and Nutrition Examination Survey III. Multivariable Cox regression analyses were used to jointly relate mortality risk to serum alkaline phosphatase and indicators of metabolic syndrome. Results Prevalence of metabolic syndrome was 14% to 41% among patients in lowest and higher quartiles, respectively, for baseline serum alkaline phosphatase. The mortality hazard ratio for each doubling of serum alkaline phosphatase was 1.52 (95% confidence interval [CI], 1.35–1.72) adjusting only for demographic factors, and 1.37 (95% CI, 1.21–1.56) adjusting for both demographic and metabolic syndrome factors in the full cohort, and was 1.83 (95% CI, 1.36–2.46) adjusting for demographic factors in the subgroup without any of the component conditions of metabolic syndrome. Conclusions In the US general population, higher levels of serum alkaline phosphatase is a predictor of mortality independent of the baseline prevalence of metabolic syndrome. Further studies are warranted to unravel the mechanisms of this association.

Clinical significance of serum alkaline phosphatase level in advanced pancreatic cancer.

183 Background: Alkaline phosphatase (ALP) is an enzyme that is elevated by various hepatobiliary diseases. Generally its elevation is thought to indicate bile stasis. There are some reports that show ALP is an important prognostic factor for several cancers such as colon, lung, and gastric cancer. Often it is speculated that ALP elevation indicates bile stasis caused by liver metastasis. However, the significance of ALP elevation in advanced pancreatic cancer (APC) patients is not well evaluated. The aim of this study was to determine the significance of elevated serum ALP as a prognostic factor in patients with APC even without jaundice and liver metastasis. Methods: Serum ALP levels were measured in 393 patients with APC receiving gemcitabine monotherapy before treatment, and according to those levels, patients were subgrouped (ALP&lt;upper normal limit (UNL), UNL-500 U/L, 501-700 U/L, 701-1000 U/L, 1000U/L &lt; ALP). The clinical data of each group were analyzed to see characteristics of elevated ALP patients. The relationship between ALP level and survival, response were also examined. Results: The elevated ALP group included poor performance status (PS&gt;1) patients (41.3%, p=0.001), and associated with low serum albumin (3.31±0.38, p&lt;0.01). The elevated ALP group (median survival time (MST) 112 days) showed significantly worse prognosis and lower disease control rate compared to the normal ALP group (MST 217days) (p&lt;0.001, p&lt;0.001). Multivariate analysis revealed ALP (p&lt;0.001), CRP (p&lt;0.001), ascites (p&lt;0.001), distant metastasis (p=0.003), white blood cell count (p=0.005), PS (p=0.020), AST (p=0.020), and ALT (p=0.020) were independent prognostic factors. Similar results were seen in liver metastasis free patients without jaundice. Conclusions: Elevated serum ALP level correlated with poor performance status and low serum albumin. ALP was also the independent prognostic factor in liver metastasis free APC patients without jaundice. No significant financial relationships to disclose.

Oral and maxillofacial desmoid-type fibromatoses in an eastern Chinese population: a report of 20 cases

Primary desmoid-type fibromatoses arising from the oral and maxillofacial region are uncommon and hold the character of local invasion and regional recurrence. The purpose of this study was to analyze the clinicoepidemiologic characteristics of this rare disease in an eastern Chinese population. Epidemiological and clinicopathological data on 20 patients were reviewed from the hospital records and analyzed accordingly. Twelve males and 8 females with a ratio of 3:2 were involved. The mandible was the most common site of presentation. Suspected malignant change was found in 6 cases and an extremely high recurrence rate was also found in up to 53%. Abnormally high blood levels of alkaline phosphatase were found in 65% of patients, which had a close relation with tumor malignant change. Chinese people are more susceptible to desmoid-type fibromatoses and are at an extremely high risk of regional malignant change. Elevated serum alkaline phosphatase levels may be taken as an indicator for malignant transformation.

Successful Treatment of Immunoglobulin D Myeloma by Bortezomib and Dexamethasone Therapy

Immunoglobulin D (IgD) myeloma is a rare subtype and it is widely accepted as an aggressive disease. Here, we report a 66-year-old woman with IgD myeloma who had anemia, lumbago, multiple osteolytic lesions and hypercalcemia. The patient refused a blood transfusion because of her beliefs, so we administered bortezomib and dexamethasone (BD) after high-dose dexamethasone therapy. Marked improvement of anemia and elevated serum alkaline phosphatase levels was recognized. After 5 cycles of BD therapy, the patient achieved a stringent complete response according to International Myeloma Working Group Response Criteria. BD therapy might be a feasible and useful treatment option for IgD myeloma.

Release of Alkaline Phosphatase Caused by PIGV Mutations In Patients with Hyperphosphatasia-Mental Retardation Syndrome (HPMR), a Recently Found Second Inherited GPI Anchor Deficiency.

AbstractAbstract 2031Recent whole exome sequencing of three sibs of non-consanguineous parents demonstrated PIGV mutations in Hyperphosphatasia-Mental Retardation syndrome (HPMR), an autosomal recessive disease characterized by mental retardation and elevated serum alkaline phosphatase (ALP) levels (Eur J Med Genet, vol.53, issue2, p85, 2010). PIGV is the second mannosyltransferase essential for glycosylphosphatidylinositol (GPI) biosynthesis. Mutations found in four families caused amino acid substitutions A341E, A341V, Q256K and H385P. We have shown that these mutant PIGV proteins are unstable and the mutant cDNAs restored only subnormal GPI biosynthetic activity after transfection into PIGV deficient CHO cells. The backbone of GPI-anchor is synthesized in the endoplasmic reticulum (ER) and is transferred to the proteins which have GPI attachment signal at the C-terminal. It is known that GPI-anchored proteins are not expressed on the surface of GPI deficient cells due to degradation within the cells or secretion. ALP, a GPI anchored protein, was efficiently secreted into medium from PIGV deficient CHO cells, in which incomplete GPI bearing one mannose was accumulated. In contrast, ALP was degraded in PIGL, DPM2 or PIGX deficient CHO cells, in which GPIs lacking mannose were accumulated. Secretion of ALP required GPI transamidase that cleaves the C-terminal GPI attachment signal peptide and replaces it with GPI. It seems that GPI transamidase is activated by GPI bearing at least one mannose, cleaving the hydrophobic signal peptide and resulting in secretion of soluble ALP. It is well known that hypophosphatasia is caused by a deficiency of liver-, bone-, kidney-type alkaline phosphatase due to mutations in the tissue-nonspecific alkaline phosphatase (ALPL) gene. This inherited disorder is characterized by defective bone mineralization and some patients develop epilepsy caused by the disturbance of pyridoxal-5-phosphate (PLP) dependent metabolism of neurotransmitters due to the defect in ALPL which converts PLP to pyridoxal (PL) thereby facilitating passive uptake of this freely diffusible form at the cell surface. Some of the HPMR patients have seizures and the patients with previously reported inherited GPI deficiency caused by defective PIGM encoding the first mannosyltransferase (Nature Med. 12, p846 2006) also have seizures. This common symptom may be caused by the loss of membrane bound ALPL. On the other hand, patients with HPMR do not have the portal vein thrombosis seen in the patients with PIGM deficiency. The affected cell types and the degree of deficiencies in various GPI-anchored proteins might be the cause of the variability of the clinical features among GPI deficiencies. Disclosures:No relevant conflicts of interest to declare.

A Case of Osteomalacia Related to Adefovir in a Patient with Chronic Hepatitis B

Adefovir dipivoxil, an acyclic nucleoside analogue, has been approved for the treatment of patients with chronic hepatitis B. This agent is efficacious particularly in those who have developed lamivudine resistance. The report according to hypophosphatemia induced by low dose adefovir therapy is very rare. We report one case in which osteomalacia with hypophosphatemia developed in a patient with chronic hepatitis B on adefovir dipivoxil at a low dose, 10 mg daily. A 66-year-old man, who had been taking adefovir for more than 4 years due to lamivudine resistance, presented with muscle weakness and bone pain in both thighs. After 3 years of adefovir therapy, hypophosphatemia and elevated serum alkaline phosphatase levels had been noted. A bone scan showed multiple hot uptakes. All the image findings and clinical symptoms, such as bone pain and muscle weakness were improved after correcting the hypophosphatemia with oral phosphorous supplementation.

Camurati–Engelmann disease: imaging, clinical features and differential diagnosis

We report four sporadic and three familial patients with Camurati-Engelmann disease. One patient had follow-up examinations over 8 years. Pain in the extremities and muscle weakness were common clinical symptoms. Most patients also had cranial nerve impairment, hepatosplenomegaly, a waddling gait, and elevated serum alkaline phosphatase levels. Long bones were affected in all. We discuss the differential diagnosis for this interesting bone entity.

Markedly elevated serum alkaline phosphatase level in an uncomplicated pregnancy

In normal pregnancy, although maternal serum alkaline phosphatase increases and reaches the two-fold of non-pregnant serum level, above this level, hepatic, renal, osteal diseases and malignancies should be kept in mind. We report a case of 28-year-old pregnant woman with increased maternal serum level of alkaline phosphatase activity (17-fold) due to an increased level of placental isozyme. She delivered vaginally a healthy female baby. After delivery, maternal serum alkaline phosphatase activity returned to normal reference range. The aim of this case report is to show this exaggerated isozyme activity of alkaline phosphatase in pregnancy, and to differentiate it from other causes of elevated level of alkaline phosphatase.

Prognostically Relevant Breakdown of 138 Patients with Systemic Mastocytosis Associated with Another Hematological Malignancy

Background: Systemic mastocytosis (SM) sometimes coexists with an associated clonal hematological non mast cell lineage disease and such an occurrence is recognized by the 2001 World Health organization (WHO) classification system as SM-AHNMD (Leuk Res. 2001 25:603). However, SM-AHNMD has not been further stratified into prognostically relevant subgroups. This was the major objective of the current study, which also provides information on prevalence and relevance of detecting KITD816V and JAK2V617F mutations.Methods: Patient records in the institutional electronic database from January 1976 to October 2007 were reviewed and SM patients 18 years of age or older identified; the date of diagnosis ranged from July 1964 to October 2007. Only those cases where diagnosis was confirmed by bone marrow (BM) histology were included in the analysis. SM- and AHNMD-components were classified according to WHO criteria.Results:AHNMD sub-classification: Of 342 consecutive cases of SM that were screened, 138 (40%) were identified as having SM-AHNMD (median age 65 years, range 20–87). The most frequent AHNMD was chronic myelomonocytic leukemia (SM-CMML) seen in 38 (28%) patients. 23 (17%) patients had SM associated with myelodysplastic syndrome (SM-MDS), 22 (16%) with hypereosinophilic syndrome/chronic eosinophilic leukemia (SM-HES/CEL) and 33 (24%) with another myeloproliferative neoplasm (SM-MPN). The number of cases with other SM-AHNMD was much lower and included lymphoma 8 (6%), acute leukemia 3 (2%), MDS/MPN 3 (2%), and 8 (6%) cases of multiple myeloma, primary amyloidosis or chronic lymphocytic leukemia. Of the 33 SM-MPN patients, 2 had polycythemia vera, 6 essential thrombocythemia, and 2 myelofibrosis; the remaining 23 patients had an unclassified MPN in association with SM.Clinical characteristics at presentation: The combined incidence of urticaria pigmentosa (UP) was 18%, mast cell mediator release symptoms 28% and constitutional symptoms 62%. 76 patients (57%) had palpable splenomegaly. 99 patients (72%) had anemia, 18 (13%) leukopenia (43% with SM-MDS; p<0.0001) and 76 (55%) thrombocytopenia. 70 (51%) patients had leukocytosis and 63 (55%) displayed circulating immature myeloid cells (78% with CMML; p=0.001). 59 (54%) patients had elevated serum alkaline phosphatase level: SM-CMML 70%, SM-MPN 60%, SM-HES/CEL 40%, and SM-MDS 30% (p=0.01). Where evaluated, serum tryptase was elevated in 92% of the patients (median=75 ng/mL; range=4–1360). BM blasts were ≥5% in 25 patients (22%), including 48% with SM-MDS (p=0.004). 12 of 35 patients tested carried the FIP1L1-PDGFRA mutation (all had SM-HES/CEL; p<0.0001).Disease course and prognostic factors At a median follow up of 15 months (range 0–182), 99 deaths were recorded and the combined median survival was 24 months: SM-CMML 15 months; SM-MDS 15 months, SM-MPN 30 months; and SM-HES/CEL 87 months (p=0.003). Fifteen patients (11%) transformed to acute leukemia or mast cell leukemia. Multivariate analysis of parameters at the time of diagnosis showed a significant and independent association between inferior survival and SM-AHNMD sub-type (p=0.007), presence of constitutional symptoms (p=0.04), thrombocytopenia (p=0.01), presence of circulating immature myeloid cells (p=0.006), and hypoalbuminemia (p<0.0001). In SM-CMML, hypoalbuminemia was associated with inferior survival (p=0.03).KITD816V andJAK2V617F analysis: Archived BM was available in 88 patients for KITD816V and JAK2V617F analysis. By DNA sequencing, overall KITD816V detection rate was 33%: SM-CMML 48%, SM-MDS 21%, SM-HES 8%, and SM-MPN 45% (p=0.03). In patients with SM-HES/CEL (p=0.0009) and SM-MPN (p=0.04), detection of KITD816V was associated with inferior survival. Greater than 1% (range 5–57) JAK2V617F allele burden was detected in 6 patients (9%): 4 in SM-MPN, 1 in SM-CMML and 1 in SM-MDS.Conclusions: The WHO-defined SM-AHNMD comprises prognostically diverse subcategories among which SM-CMML is the most frequent. Survival is favorable in SM-HES/CEL and significantly worse in SM-CMML and SM-MDS. Additional independent predictors of inferior survival include constitutional symptoms, thrombocytopenia, circulating immature myeloid cells, and hypoalbuminemia. In SM-HES/CEL and SM-MPN, BM KITD816V allele burden may influence survival. JAK2V617F occurs infrequently in SM-AHNMD and when it does, it clusters with SM-MPN.