Lower Alkaline Phosphatase Levels Research Articles

Prevalence of chondrocalcinosis and calcium pyrophosphate deposition disease in a cohort of adult patients with low alkaline phosphatase levels and a positive versus negative genetic ALPL study.

To estimate the prevalence of chondrocalcinosis and calcium pyrophosphate dihydrate deposition disease (CPPD) in patients with low alkaline phosphatase (ALP) levels and a positive ALPL genetic study (+GT) for hypophosphatasia (HPP) compared to those with the same biochemical abnormality and a negative genetic test (-GT). As a secondary objective, to analyze the biochemical factors associated with its presence in subjects with ALPL variants. Seventy-eight subjects with persistently low ALP levels and ALPL genetic test were included. Baseline and 24-mo knee ultrasounds were performed in 42 + GT and 36 -GT subjects, in whom the fibrocartilage, hyaline cartilage of menisci, tendons, and synovial fluid were scanned to detect calcium pyrophosphate deposits. A MyLabTwice ultrasound machine (Esaote) with a multifrequency linear array transducer (4-13MHz) was used. A higher percentage of chondrocalcinosis was observed in the +GT group [9/42 (21.4%)] compared to the -GT group [2/36 (5.6%), p=.045)]. Two patients (4.76%), both in the +GT group, had arthritis secondary to CPPD. No new cases were identified at the 24-mo control. When comparing +GT patients with and without chondrocalcinosis, ALP levels were lower, and pyridoxal-5'-phosphate (PLP) and phosphate levels were higher in the former group (p<.05). Logistic regression analysis revealed that higher PLP levels are associated with the presence of chondrocalcinosis (OR: 1.1; 95% confidence interval, CI, 1.001-1.012). Chondrocalcinosis was a frequent ultrasonographic finding in HPP. Arthritis secondary to calcium pyrophosphate deposits, however, proved less prevalent. Genetic causes, such as HPP, should be considered when evaluating patients with chondrocalcinosis in clinical practice.

7336 Decades In The Dark: The Long Road To Diagnosing And Treating Hypophosphatasia

Abstract Disclosure: V.A. Mendpara: None. G. Madrigal Loria: None. L.Z. Khan: None. Background: Hypophosphatasia (HPP) is a rare bone disorder that results from deficient activity of the tissue non-specific isoenzyme alkaline phosphatase (ALP).[1] This case highlights a patient whose diagnosis of this treatable genetic condition was significantly delayed for almost two decades, despite receiving care at a prominent academic institution. The patient's persistently low ALP levels in routine lab tests were overlooked by multiple clinicians, leading to a delay in her care and eventual treatment. Case presentation: A 61-year-old Caucasian woman presented at the endocrinology clinic with complaints of severe fatigue, generalized pain, multiple childhood fractures, and ongoing dental issues. The rheumatology clinic to which she was referred for polyarthralgia diagnosed her with Hypophosphatasia (HPP) after noting chronically low alkaline phosphatase (ALP) levels from her previous charts ranging from 15 to 24 U/L (normal range: 34 to 123 U/L) over two decades. Her serum calcium, parathyroid hormone (PTH), and 25-hydroxy vitamin D levels were within normal ranges. A DEXA scan revealed normal bone density, effectively ruling out osteoporosis. Further investigation showed elevated Vitamin B6 levels at 219.6 nmol/L (normal range: 20.0 to 125.0 nmol/L), raising suspicion for HPP. The patient's family history provided additional insight, with her mother having a history of short stature and fractures and her son experiencing premature tooth loss at the age of 2. A genetic evaluation identified a heterozygous pathogenic variant in the ALPL gene (c.881A&amp;gt;C, p.Asp294Ala), confirming the diagnosis of autosomal dominant HPP. Initiating treatment with Asfotase alfa, a medication targeting HPP, resulted in a marked improvement in the patient's symptoms. Discussion: This case shows the diagnostic complexities of HPP, stressing the significance of actively screening for this condition via ALP levels in routine laboratory testing or during osteoporosis evaluations. The diagnostic process is critical to distinguish HPP from primary osteoporosis, as treatment and potential risks differ significantly. Inadvertent use of bisphosphonates can worsen hypomineralization and lead to atypical femoral fractures in HPP patients. Asfotase alfa enzyme replacement therapy, available since 2015, offers a targeted approach by replacing the enzyme defect, thereby mitigating symptoms. Heightened awareness among healthcare providers of HPP in adults holds the potential to enhance diagnosis rates and facilitate improved treatment outcomes for this highly treatable condition.[1] Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Eighth Edition. ASBMR. Presentation: 6/2/2024

7740 Adult-Onset Hypophosphatasia Presenting As Low Alkaline Phosphatase Level Following Denosumab Use For Osteoporosis

Abstract Disclosure: J. Ocampo Mascaro: None. P. Wax: None. M. Al Mukaddam: Grant Recipient; Self; Ipsen, Incyte Research Funding. Background: Hypophosphatasia (HPP) is a genetic disease characterized by low activity of the tissue non-specific alkaline phosphatase. It has a broad range of clinical phenotypes, with adults usually presenting with an incidental low alkaline phosphatase (ALP) finding. Differentiating this from other causes of low ALP is challenging, especially when treating osteoporosis, as antiresorptive therapy such as denosumab and bisphosphonates may cause low ALP and carry the potential of increasing risk of atypical femoral fractures in patients with undiagnosed HPP. Clinical Case: A 64-year-old woman with history of nephrolithiasis, hypercalciuria, and osteoporosis (screening DXA lowest T-score -3.3 in femoral neck (FN)) but no prior fractures or dental issues was seen in clinic. Initial bloodwork showed normal range calcium, 25-OH vitamin D, and intact PTH. Pre-treatment ALP was 42 IU/L (N 39-117). Work up for secondary causes of osteoporosis was negative. Three yearly doses of IV zoledronic acid resulted in +4.2% BMD increase in lumbar spine (LS) but no changes in FN. She had no side effects but was found to have a decrease in ALP to 33 IU/L. This normalized back to 42 IU/L during a three-year drug holiday. Follow up DXA noted significant decline in BMD, hence denosumab was initiated. ALP decreased back to the 30-35 IU/L range. Fasting Vitamin B6 level (off B6 supplements for 1 week) was 23.4 ng/ml (N 2.1-21). Urine phosphoethanolamine was mildly elevated at 5 mmol/mol creatinine (N ≤4). Genetic testing evidenced a pathogenic ALPL variant (Exon 6, c.575T&amp;gt;C (p.Met192Thr), heterozygous) compatible with HPP. She had tolerated three doses of denosumab by then with BMD improvement of 5.0% in LS but no changes in FN and no atypical femoral fracture. Denosumab was stopped. Abaloparatide was started for osteoporosis with close monitoring for worsening hypercalciuria. Conclusion: This case demonstrates that adult HPP patients may present with subtle findings and lower range of normal ALP and may tolerate short courses of antiresorptive agents. There is a need for better screening and diagnostic criteria for adult HPP patients whose ALP levels may not be initially low before initiating antiresorptive drugs for osteoporosis. The risk of adverse effects from therapy will likely vary significantly based on the clinical severity/presentation of HPP as some adults with lower ALP ranges might be more susceptible to developing atypical femur fractures (1). Balancing atypical femur fracture risk with the benefits of antiresorptive treatment in decreasing risk of osteoporotic fractures highlights the need for better risk stratification to prevent undertreatment of osteoporosis. Reference: 1. Warren AM, Ebeling PR, Grill V, Seeman E, Sztal-Mazer S. Bilateral atypical femoral fractures during denosumab therapy in a patient with adult-onset hypophosphatasia. Endocrinol Diabetes Metab Case Rep. 2021 Sep 1;2021:21-0096. Presentation: 6/2/2024

A Rare Case of Subclinical Hypophosphatasia In An Adult Patient

Background: Hypophosphatasia (HPP) is a rare genetic condition caused by a mutation in the ALPL gene. It is often misdiagnosed due to its wide range of clinical presentations and late onset of symptoms. Case Presentation: We present a case of a 48-year-old male with seemingly subclinical hypophosphatasia who initially presented with slight tooth pain. Upon further examination, chronic low alkaline phosphatase levels were identified, leading to genetic testing that confirmed HPP. The patient's elevated vitamin B6 levels and the identification of a heterozygous exon 2 deletion mutation in the ALPL gene were key diagnostic findings. Conclusion: This case highlights the spectrum of symptoms that patients with HPP can present and emphasizes the importance of considering HPP as a differential diagnosis for patients with low alkaline phosphatase levels. Recognizing this condition is crucial, as standard treatments for hypocalcemia, such as bisphosphonates, are contraindicated in HPP patients. Continued research and publication of mild and subclinical forms of HPP are vital to improve the understanding and management of this disease.

Challenges in Hypophosphatasia: Suspicion, Diagnosis, Genetics, Management, and Follow-Up.

Hypophosphatasia (HPP) is a rare genetic disorder caused by loss-of-function variants in the ALPL gene, leading to deficient tissue-nonspecific alkaline phosphatase (ALP) activity. This results in a distinctive biochemical profile marked by low serum ALP levels and elevated pyridoxal-5-phosphate (PLP). The clinical spectrum of HPP ranges from perinatal lethality to asymptomatic cases, presenting significant diagnostic and therapeutic challenges. Diagnosis of HPP relies on identifying the characteristic biochemical signature (low ALP, high PLP), concomitant with skeletal (osteomalacia, rickets, pseudofracture) or extraskeletal (muscle weakness, musculoskeletal pain, dental) manifestations. Current diagnostic frameworks lack uniformity, highlighting the imperative for a standardized diagnostic approach. Molecular genetic testing plays a pivotal role in making the diagnosis of HPP, but difficulties persist in diagnosing milder cases and correlating genotypes with phenotypes. Comprehensive multidisciplinary care is indispensable, with enzyme replacement therapy (ERT) proving efficacious in severe cases and more nuanced management approaches for milder presentations. Overcoming challenges in ERT initiation, treatment response assessment, dose titrations, and long-term surveillance necessitates further refinement of management guidelines. Mild forms of HPP and asymptomatic carriers of pathogenic ALPL variants pose substantial diagnosis and management challenges. Developing consensus-driven guidelines is crucial to enhance clinical outcomes and patient care.

Role of fibroblast growth factor-23 as an early marker of metabolic bone disease of prematurity

PurposeMetabolic bone disease of prematurity (MBDP) remains a significant cause of morbidity in extremely premature newborns. In high-risk patients, suspected diagnosis and subsequent treatment modifications, with limitations in terms of sensitivity and specificity, rely on low phosphorus levels and/or high levels of alkaline phosphatase (ALP). We investigated the potential of fibroblast growth factor-23 (FGF23) as an early marker for MBDP when measured at 3–4 weeks of life in at-risk patients.MethodsA single-center prospective observational non-interventional study including preterm newborns of both sexes, with a gestational age of less than 32 weeks and/or a birth weight of less than 1500 g. In the standard biochemical screening for MBDP performed between 3 and 4 weeks of life within a nutritional profile, the determination of FGF23 was included along with other clinical and metabolic studies. The study was conducted at Marqués de Valdecilla University Hospital in Santander, Spain, from April 2020 to March 2021. Participants provided informed consent. Biochemical analyses were conducted using various platforms, and follow-up evaluations were performed at the discretion of neonatologists. Patients at high risk for MBDP received modifications in treatment accordingly. The sample was descriptively analyzed, presenting measures of central tendency and dispersion for continuous variables, and absolute numbers/percentages for categorical ones. Tests used included t-tests, Mann‒Whitney U tests, chi-square tests, logistic regressions, Pearson correlation, and ROC curve analysis (IBM SPSS Statistics version 19). Significance level: P < 0.05.ResultsIn the study involving 25 at-risk premature newborns, it was found that 20% (n = 5) were diagnosed with MBDP. Three of these patients (60%) were identified as high-risk based on standard biochemical evaluation at 3–4 weeks of age, while the other two patients (40%) were diagnosed in subsequent weeks. However, in all 5 patients, measurement of FGF23 levels would allow for early identification and optimization of treatment before other markers become altered. Low levels of FGF23 at 3–4 weeks, even with normal phosphorus and ALP levels, indicate the need for modifications in nutritional supplementation.ConclusionsMBDP remains a significant concern in extremely premature newborns. Current diagnostic methods rely on limited biochemical markers. Early detection of low FGF23 levels enables timely interventions, potentially averting demineralization.

Hydrolyzed egg yolk peptide prevented osteoporosis by regulating Wnt/β-catenin signaling pathway in ovariectomized rats

Hydrolyzed egg yolk peptide (YPEP) was shown to increase bone mineral density in ovariectomized rats. However, the underlying mechanism of YPEP on osteoporosis has not been explored. Recent studies have shown that Wnt/β-catenin signaling pathway and gut microbiota may be involved in the regulation of bone metabolism and the progression of osteoporosis. The present study aimed to explore the preventive effect of the YPEP supplementation on osteoporosis in ovariectomized (OVX) rats and to verify whether YPEP can improve osteoporosis by regulating Wnt/β-catenin signaling pathway and gut microbiota. The experiment included five groups: sham surgery group (SHAM), ovariectomy group (OVX), 17-β estradiol group (E2: 25 µg /kg/d 17β-estradiol), OVX with low-dose YPEP group (LYPEP: 10 mg /kg/d YPEP) and OVX with high-dose YPEP group (HYPEP: 40 mg /kg/d YPEP). In this study, all the bone samples used were femurs. Micro-CT analysis revealed improvements in both bone mineral density (BMD) and microstructure by YPEP treatment. The three-point mechanical bending test indicated an enhancement in the biomechanical properties of the YPEP groups. The serum levels of bone alkaline phosphatase (BALP), bone gla protein (BGP), calcium (Ca), and phosphorus (P) were markedly higher in the YPEP groups than in the OVX group. The LYPEP group had markedly lower levels of alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) and C-terminal telopeptide of type I collagen (CTX-I) than the OVX group. The YPEP groups had significantly higher protein levels of the Wnt3a, β-catenin, LRP5, RUNX2 and OPG of the Wnt/β-catenin signaling pathway compared with the OVX group. Compared to the OVX group, the ratio of OPG/RANKL was markedly higher in the LYPEP group. At the genus level, there was a significantly increase in relative abundance of Lachnospiraceae_NK4A136_group and a decrease in Escherichia_Shigella in YPEP groups, compared with the OVX group. However, in the correlation analysis, there was no correlation between these two bacteria and bone metabolism and microstructure indexes. These findings demonstrate that YPEP has the potential to improve osteoporosis, and the mechanism may be associated with its modulating effect on Wnt/β-catenin signaling pathway.

Simple predictors for the completion of scheduled gemcitabine‑cisplatin regimens based on real‑world urothelial cancer data.

Gemcitabine plus cisplatin (GC) is the standard first line of chemotherapy for urothelial carcinoma. However, it is often difficult to complete scheduled GC therapy because of real-world adverse events. Therefore, the reasons behind delays, scheduled cancelations and determined predictive factors for completing scheduled GC therapy were retrospectively analyzed. Patients diagnosed with locally advanced or metastatic urothelial carcinoma from 2009 to 2020 received a 4-week GC therapy schedule in Oita University Hospital. Information was retrospectively extracted from medical records and all cycles were divided into two groups: One wherein all treatments were administered and completed on schedule and the other wherein treatment was either delayed or canceled in during the treatment schedule. Predictive factors were then statistically extracted between the two groups. In total, 70 patients received 201 cycles of a 4-week scheduled GC therapy. Of the 201 cycles, a total of 68 (33.8%) completed all scheduled treatments, while 133 (66.1%) did not complete the treatment as scheduled. In the group where administration was not completed on schedule, the factors of male, ureteral cancer, lower stage, <90% of gemcitabine and cisplatin dosage, solitary kidney, high creatinine level, low estimated glomerular filtration rate level, low platelet count and high alkaline phosphatase level at the initiation of each cycle were more significant. Additionally, the lowest anticancer drug percentage administration was on day 15. From these results, predictive factors for patients with various backgrounds who completed the scheduled 4-week GC therapy based on real-world data were identified. This information can be useful for clinical physicians when deciding the course of treatment.

Risk Factors for Immune Checkpoint Inhibitor-Induced Liver Injury and the Significance of Liver Biopsy.

Immune checkpoint inhibitor (ICI)-induced liver injury (LI) is a common adverse event, but the clinical characteristics based on the classification of hepatocellular injury and cholestatic types are not fully evaluated. This study aims to analyze risk factors and histological findings in relation to the classification of ICI-induced LI. In total, 254 ICI-induced LI patients among 1086 treated with ICIs between September 2014 and March 2022 were classified according to the diagnostic criteria for drug-induced LI (DILI), and their risk factors and outcomes were evaluated. Kaplan-Meier analyses showed that overall survival in patients with hepatocellular-injury-type LI was significantly longer than others (p < 0.05). Regarding pre-treatment factors, the lymphocyte count was significantly higher in patients with ICI-induced LI, especially in hepatocellular-injury-type LI. Gamma glutamyl transferase (γGTP) and alkaline phosphatase (ALP) were also significantly lower in patients with ICI-induced LI (p < 0.05). Multivariate analyses revealed that malignant melanoma, high lymphocyte count, and low ALP levels were extracted as factors contributing to hepatocellular-injury-type LI. The histological findings among 37 patients diagnosed as ICI-induced LI via liver biopsy also revealed that the spotty/focal necrosis was significantly frequent in hepatocellular-injury-type LI, whereas ductular reactions were frequently observed in cholestatic-type LI. It is suggested that the histological inflammation pattern in patients with LI is closely correlated with the type of DILI.

Hypophosphatasia Presenting as a Chronic Diffuse Pain Syndrome with Extra-Articular Calcifications.

Hypophosphatasia is a rare genetic disease characterized by abnormal alkaline phosphatase activity and deficiency of bone and teeth mineralization. Hypophosphatasia is well known in pediatrics with typical presentations in children, but mild forms can also be present in adults and are difficult to detect. We present the case of a 50-year-old woman referred for pain management, with a previous diagnosis of fibromyalgia. The association of clinical features (diffuse pain syndrome, early dental loosening, personal history of two fractures with osteoporosis, and family history of osteoporosis) with radiographic (heterotopic calcifications of the yellow and interspinous lumbar ligaments) and biological (low levels of total alkaline phosphatase) indices was suggestive of hypophosphatasia, which was confirmed by genetic analysis. We review and discuss the association between hypophosphatasia, musculoskeletal pain, and calcium pyrophosphate deposition and the importance of raising the diagnosis of adult-onset hypophosphatasia when facing these two rheumatologic entities.

Exploratory Study on the Relationship Between Age, Reproductive Stage, Body Condition Score, and Liver Biochemical Profiles in Rembi Breed Ewes

Background: The Rembi sheep breed is renowned for its exceptional meat quality and significant economic profit. Nevertheless, there is a gap in research on the hepatic parameters of this breed in Algeria despite the considerable value of the liver in the Algerian population’s diet. Objectives: The research aimed to determine the impact of physiological factors (age, physiological stage, and body condition score) on biochemical sheep liver parameters. Methods: Sixty clinically healthy female Rembi breed sheep, aged between 3 months and 7 years, raised at the Technical Institute of Livestock (ITELV) Ksar Chellala Farm in Tiaret Province, Algeria, were selected for biochemical analysis and assessing aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), total bilirubin (TBIL), direct bilirubin (DBIL), albumin (ALB), and total protein (TP). Results: The concentrations of AST, ALP, and GGT increased significantly (P≤0.001) in young sheep, while ALT and TP levels decreased (P≤0.05). However, a high level of GGT (P&lt;0.001) was also observed in lactating ewes, and during pregnancy, females have a low level of ALP (P&lt;0.001). Furthermore, the body condition score does not affect any of the measurements. Conclusion: Considering the animal’s age and physiological stage is critical before interpreting the results.

Effect of Mongolian medicine alcohol spray therapy on fracture healing in rabbits

Purpose: To evaluate the healing effect and mechanism of Mongolian medicine alcohol spray therapy on fracture healing process in rabbits.&#x0D; Methods: Thirty New Zealand white rabbits were randomly divided into normal, fracture, and treatment groups, with 10 rabbits in each group. Fracture and treatment groups underwent bone-fracture modeling, with the latter receiving daily alcohol spraying and stroking for six weeks. Serum calcium and phosphorus were measured using an automatic biochemical analyzer. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of BMP-2, ALP, and TGF-β. Biomechanical testing was performed to assess callus properties, and real-time polymerase chain reaction (PCR) and western blot were performed to assess BMP-2, Runx2, and p-Smad1/5 expressions in callus.&#x0D; Results: There were low serum calcium, phosphorus, BMP-2, ALP, and TGF-β levels in fracture and treatment groups, compared to normal group. Similarly, treatment group showed significantly increased levels of serum calcium, phosphorus, bone morphogenetic protein 2 (BMP-2), alkaline phosphatase (ALP), and transforming growth factor-β (TGF-β) (p &lt; 0.05) compared to fracture group. Biomechanical testing revealed that maximum load, stiffness, and deflection of callus in the fracture and treatment groups were significantly lower compared to normal group (p &lt; 0.05). expressions of BMP-2, Runx2, and p-Smad1/5 mRNA in the callus significantly decreased in both fracture and treatment groups compared to normal group (p &lt; 0.05). However, treatment group showed significantly increased expression levels compared to fracture group (p &lt; 0.05).&#x0D; Conclusion: Mongolian medicine alcohol spray therapy promotes fracture healing in rabbits and increases maximum load of the callus, possibly through upregulation of the BMP-2 signaling pathway. Further research is necessary to confirm the exact mechanism by which alcohol spray therapy regulates BMP-2 signaling pathway.

THE INDEPENDENT EFFECTS OF TYPE 2 DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE ON BONE TURNOVER MARKERS.

Chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) are associated with disturbed mineral homeostasis and serum bone biomarkers. The interplay between T2DM and CKD on serum bone turnover markers (BTM) is unclear. Our aim was to describe the BTM in patients with T2DM, CKD or both. In this observational, single-centre, prospective study, we included 320 patients over 40 years, divided into four groups: T2DM and normal kidney function (n=142), T2DM and CKD (n=36), CKD and normal glucose metabolism (n=29) and healthy controls (n=113). We excluded patients treated for osteoporosis and with secondary osteoporosis. Patients were compared by age, levels of glycated hemoglobin, PTH, alkaline phosphatase, osteocalcin (OC), CTx and 25 OH vitamin D. Univariate analysis showed that GFR correlated significantly with PTH (r=0.37), OC (r=0.43) and CTX (r=0.45) in the diabetes group but only with PTH (r=0.34) in the non-T2DM group. Multivariate analysis showed that GFR remained significantly correlated with the same bone markers even after adjustment for age, sex or 25(OH)D levels. Diabetics seem to have lower levels of alkaline phosphatase (68±22.1 U/L) and CTX (0.37±0.24 ng/mL) than those without diabetes (76.7±29.6. U/L and 0.5±0.19 ng/mL, respectively). There was no correlation between BTM and glycated hemoglobin. Bone turnover markers correlate with GFR, particularly in patients with T2DM. However, alkaline phosphatase is lower in T2DM than in non-T2DM.

Гормональные, биохимические показатели и уровни микроэлементов крови у молодых женщин с субклиническим гипотиреозом в сочетании с носительством антител к тиреопероксидазе

Many studies have been devoted to investigating the relationship between subclinical hypothyroidism (SH), thyroid gland (TG) autoimmunity, and blood trace elements; however, the data presented in these studies are often contradictory. Aim of study. To identify the factors associated with SH in combination with the presence of Anti-thyroid peroxidase antibody (TPO-Ab). Design. Single-center, observational, single-cohort, cross-sectional, and uncontrolled study. Materials and Methods. This study analyzed 859 women aged 18–45 with SH and without TG dysfunction. Based on thyroid function and TPO-Ab status (presence (+) or absence (–)), four study groups were formed: Group 1 — Euthyroidism and TPO-Ab(–) (n = 503); Group 2 — Euthyroidism and TPO-Ab(+) (n = 164); Group 3 — SH and TPO-Ab(–) (n = 128); Group 4 — SH and TPO-Ab(+) (n = 64). Determination of thyroid-stimulating hormone (TSH), free thyroxine (FT4), and TPO-Ab levels in serum was provided by enzyme immunoassay on the Evolis Robotized System using the test systems "Thyroid-ELISA-TSH, 0.23–3.4 µIU/ml", "Thyroid-ELISA FT4, 10–23.2 pmol/l", and "Thyroid ELISA-TPO-Ab &lt; 30 U/ml". The reference values were taken from the instructions of the manufacturer Alkor Bio Group (Russia). Measurement of element concentrations was conducted on the atomic absorption spectrometer "МГА-915МД" from Lumex (Russia). Logistic regression analysis with a series of univariate and multivariate models was performed to determine independent predictors of the likelihood of SH and TPO-Ab positive status (relative to euthyroid and TPO-Ab negative individuals). Results. In young women, a decrease in FT4 is associated with increasing age, elevated levels of TSH, TPO-Ab, mercury, decreased heart rate, and reduced levels of thyroglobulin, alkaline phosphatase (ALP), manganese, nickel, selenium, lead, and the triglyceride/glucose index. An increase in TSH is associated with lower levels of ALP, manganese, and nickel, and higher mercury levels. The likelihood of having SH combined with the presence of TPO-Ab, compared to the group without thyroid dysfunction and elevated antibodies, increases with reduced concentrations of iodine (odds ratio (OR) = 0.739; 95% confidence interval (CI): 0.618–0.884, p = 0.001), selenium (OR = 0.987; 95% CI: 0.976–0.998, p = 0.018), and zinc (OR = 0.998; 95% CI: 0.997–0.999, p = 0.023), and with elevated lead levels (OR = 1.106; 95% CI: 1.006–1.217, p = 0.038). In a multivariate regression model, the probability also increases with decreased iodine and cadmium levels, and elevated lead levels. Conclusion. Reduced concentrations of iodine, selenium, and zinc, along with elevated blood lead levels, are factors associated with the activation of thyroid autoimmunity and the presence of SH in combination with elevated TPO-Ab levels. Keywords: thyroid gland, thyroid function hormones, microelements, thyroid peroxidase antibodies, young age, women.

Laparoscopic pancreaticoduodenectomy versus open pancreaticoduodenectomy for carcinoma of the ampulla of Vater in a medium-volume center: a propensity score matching analysis.

To compare the efficacy of laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD) in a medium-volume medical center. Data for patients who underwent OPD or LPD for carcinoma of the ampulla of Vater (VPC) between January 2017 and June 2022 were acquired retrospectively. Propensity score-matching (PSM) analysis was performed to balance the baseline characteristics between the groups. The primary outcome was disease-free survival (DFS). Cox regression analysis was used to explore the independent risk factors for DFS. A total of 124 patients with pathologically diagnosed VPC were included. After 1:1 matching, there were 23 cases each in the OPD and LPD groups. Kaplan-Meier survival analyses showed that the median DFS in the OPD and LPD groups was identical (16.0 months vs 16.0 months, respectively). Multivariate Cox regression analysis showed that low levels of alkaline phosphatase and γ-glutamyl transpeptidase, positive surgical margin, and lymph node enlargement were independent risk factors for DFS. LPD in medium-volume centers with acceptable technical conditions may approach or even achieve the efficacy of LPD in large-volume centers.

Compromised Muscle Properties in a Severe Hypophosphatasia Murine Model.

Hypophosphatasia (HPP) is a rare metabolic bone disorder characterized by low levels of tissue non-specific alkaline phosphatase (TNAP) that causes under-mineralization of the bone, leading to bone deformity and fractures. In addition, patients often present with chronic muscle pain, reduced muscle strength, and an altered gait. In this work, we explored dynamic muscle function in a homozygous TNAP knockout mouse model of severe juvenile onset HPP. We found a reduction in skeletal muscle size and impairment in a range of isolated muscle contractile properties. Using histological methods, we found that the structure of HPP muscles was similar to healthy muscles in fiber size, actin and myosin structures, as well as the α-tubulin and mitochondria networks. However, HPP mice had significantly fewer embryonic and type I fibers than wild type mice, and fewer metabolically active NADH+ muscle fibers. We then used oxygen respirometry to evaluate mitochondrial function and found that complex I and complex II leak respiration were reduced in HPP mice, but that there was no disruption in efficiency of electron transport in complex I or complex II. In summary, the severe HPP mouse model recapitulates the muscle strength impairment phenotypes observed in human patients. Further exploration of the role of alkaline phosphatase in skeletal muscle could provide insight into mechanisms of muscle weakness in HPP.

THU457 Variable Presentations Of Hypophosphatasia In Two Patients In The Outpatient Setting

Abstract Disclosure: A. Elmaaz: None. S. Batool: None. P. Dandona: None. Introduction: Hypophosphatasia is a rare disorder characterized by defective mineralization of bone and teeth which is caused by an autosomal inherited mutation in the tissue nonspecific alkaline phosphatase (ALP) encoding genes. Here we present two cases of multiple dental and bony defects secondary to low ALP enzyme activity due to hypophosphatasia. Case 1: A 27-year-old female with history of mitochondrial disease, gastroparesis, malabsorption syndrome, and autonomic dysfunction was referred to Endocrinology clinic because of persistently low serum ALP levels associated with recurrent muscle, joint, and bone pain since the age of 13. She had history of multiple tooth extractions because of dental developmental abnormalities and fractures. She also reported history of fractures of three of her fingers in both hands during her childhood and teenage years. The patient was adopted and was unaware of any biological family history. Physical examination was remarkable for short-statured female, 4'8". Notably, the middle phalanges in little fingers bilaterally were shorter than the other fingers. Workup showed vitamin D level of 21 (30-80) ng/ml, despite being on 50,000 IU twice a week for 6 months with normal PTH and ionized calcium levels. The repeated serum level of ALP was 24 (31-125) U/L with bone and liver isoenzymes levels of 42% and 58 % respectively. Vitamin B6 level was 13.2 (2.1-21.7) ng/ml. Bone mineral density was unremarkable. Case 2: A 53-year-old female with history of congenital left hip dysplasia, hypertension, and dyslipidemia was seen by Endocrinology service for evaluation of decreased ALP levels. She denied any history of falls or fractures. However, she reported chronic bone pain, especially in bilateral hip joints with history of multiple surgeries in her left hip joint. She had required teeth braces and multiple dental surgeries during her childhood due to dental maldevelopment. Her height was 4'8". Laboratory workup was remarkable for low serum ALP level of 30 U/L with bone isoenzyme of 24 %. Vitamin B6 level was 206.7 (2.1-21.7) ng/ml. She had elevated serum phosphorus levels with normal calcium, PTH, and vitamin D levels. Pyridoxal-5- Phosphate level was high. Bone mineral density revealed osteopenia. Conclusion: Hypophosphatasia is a rare disease, hence it could be easily missed due to high variability in clinical presentations and severity of symptoms. Low serum levels of ALP with history of bone pain, recurrent fractures, premature loss of deciduous teeth, or loss of adult dentition should raise the suspicion of hypophosphatasia. Resistance to vitamin D supplementation is another clue to the diagnosis. A multidisciplinary approach is required for appropriate management. Presentation: Thursday, June 15, 2023

THU459 Hypophosphatasia With Normal ALPL Gene Test; A Case Report

Abstract Disclosure: K. Alkwatli: None. L.Z. Khan: None. Introduction: Hypophosphatasia is a rare hereditary disorder caused by loss of tissue nonspecific alkaline phosphatase activity, an essential enzyme in phosphate metabolism. Severe cases present perinatally and in early childhood. Mild cases can present in adulthood and can be misdiagnosed. We present an interesting patient who was clinically diagnosed with hypophosphatasia despite negative molecular genetic testing. Case presentation: 40 years-old female with a history of fibromyalgia and multiple bone fractures presented to the clinic with a long-standing history of multiple cavities, severe fatigue, headaches, muscle cramps, and arthralgia. The patient had numerous fractures throughout her life that started at age five without significant trauma, including wrist, forearm, and metatarsal bones. Her family history was negative. Laboratory testing showed low alkaline phosphatase levels on multiple occasions, 28,29,30 U/L (reference range 34-123). Her vitamin B6 was elevated at 309 nmol/L (20-125). Her zinc, calcium, vitamin D, and liver function tests were all within normal limits. Bone density scan showed a Z score of -1.0 at the lumbar spine and a Z score of -0.3 at the left femoral neck. Molecular genetic testing of the ALPL gene was negative. Hypophosphatasia was diagnosed based on her clinical and lab assessments, and she is being treated with Asfotase alfa. Her clinical course is yet to be determined. Discussion: ALPL gene is responsible for encoding the tissue nonspecific alkaline phosphatase (TNALP), the main enzyme affected in patients with hypophosphatasia. TNALP degrades inorganic pyrophosphate (PPi) to inorganic phosphate (Pi), an essential element for bone mineralization. It also facilitates vitamin B6 to cross the cell membranes. Therefore, loss of function mutations of the ALPL gene cause accumulation of PPi, which impairs the calcium-phosphate hemostasis and causes damage to multiple organs. In addition, the accumulation of the active form of vitamin B6 extracellularly can result in neurological damage.Patients present with a broad spectrum of musculoskeletal, renal, dental, and neurological symptoms. The variability of the phenotypic magnitudes is thought to be due to heterogeneity in the ALPL gene mutations. Over 400s of ALPL gene mutations have been identified in patients with hypophosphatasia. Novel variants are increasingly being reported.Negative genetic testing of the ALPL gene can still be seen in patients with hypophosphatasia due to either a variant that is undetectable by current testing methodology or if the causative gene/s are not on the ALPL gene panel. Conclusion: Genetic testing is helpful in confirming the disease and providing genetic counseling; however, treatment should still be considered if patients have sufficient clinical and laboratory findings. Presentation: Thursday, June 15, 2023

P06 Think of hypophosphatasia if atypical fracture with persistent low ALP levels

Abstract Introduction Hypophosphatasia (HPP), a rare, underdiagnosed metabolic genetic bone disease caused by diminished or absent expression of the tissue non-specific alkaline phosphatase (TNSALP) enzyme. The mutation of alkaline phosphatase (ALPL) gene leads to wide-ranging clinical manifestations, broadly classified into six different types based on age of onset and severity of the disease. Fragility fractures are predominant characteristics of adult onset HPP and are often misdiagnosed as osteoporosis, stipulating antiresorptive treatment. However, bisphosphonates (BP) make HPP more susceptible to atypical fractures and thus are contraindicated. A recent study shows 1:4 atypical femoral fracture cases are linked with monogenic bone diseases including HPP. Case description A 63-year-old Caucasian female was referred to our osteoporosis clinic, at the age of 57 following an atypical right femur fracture while on bisphosphonate and steroids. Her past medical history includes multiple right thigh sarcoma at the age of 39, 45 and 49 years requiring multiple surgeries and localised radiotherapy. She was also diagnosed with ocular myasthenia gravis two years before the atypical fracture, requiring long term high dose steroids. Her other co-morbidities include type 2 diabetes and hypertension. Due to long term steroids, her primary care physician initiated weekly 70 mg oral alendronic acid. However, three months later she had a spontaneous right mid shaft femur fracture. The patient experienced one year of right thigh pain prior to fracture which was not brought to medical attention. She underwent intramedullary nailing and successful rehabilitation. A thorough assessment in fracture liaison service spotted the history of primary tooth loss with roots intact in childhood, and chronic dental problems crowning in adult life requiring many caps and crowns. Her mother has a history of “childhood onset rickets”, bowing of legs and complete loss of all her permanent teeth at the age of 30 years. A review of blood tests revealed normal calcium, vitamin D and parathyroid levels, multiple low alkaline phosphatase levels between 16 – 23 U/L(normal range 30-130 U/L) prior to bisphosphonates, vitamin B6 fasting blood test had shown raised result at 140 (normal range 40-100). Xray of the left femur was normal. The dual energy X-ray absorptiometry (DEXA) scan yielded normal T score. The genetic test confirmed heterozygous gene mutation in ALPL gene, confirming a diagnosis of hypophosphatasia. She recovered well from her fracture and manages to walk more than one mile unaided. She is currently under regular follow-up in our hypophosphatasia clinic and has stopped bisphosphonates indefinitely. Discussion The underlying cause for atypical femoral fracture (AFF) in this case is multifactorial; long-term steroids, radiotherapy, HPP and bisphosphonate usage. Regardless, there is a relationship between hypophosphatasia and AFF. Some studies have proved that more than 90% of the patients with AFF used long term BPs. The defective ALPL gene in HPP affects bone mineralisation, resulting in accumulation of inorganic pyrophosphate (PPi), which impairs hydroxyapatite crystal formation causing recurrent fractures, osteopenia, delayed wound healing, dental problems, atypical and pseudo fractures. Bisphosphonates are chemical derivates of PPi, and thus inversely affect bone mineralisation especially in cases of TNSALP mutations and thus are contraindicated in HPP. The atypical fractures often may remain undiagnosed for a long time despite often prolonged prodromal pain occurring before the actual fracture. Careful clinical evaluation and plain X-ray will help to make the diagnosis. Hypophosphatasia related fractures mostly occur laterally in the subtrochanteric diaphysis. AFF cases often require surgical repair with intramedullary nailing. If an imminent atypical fracture is diagnosed early, prophylactic surgery is sometimes recommended. After three months of alendronic acid, bone turnover markers are usually suppressed, therefore despite the short time of alendronate exposure, this is likely to have contributed to the atypical femur fracture. Also, genetic test revealed inherited autosomal dominant trait of HPP in this case, enabled family screening and prevention of potential use of future bisphosphonates in affected family members. Key learning points HPP presenting in adulthood may be more common than previously though with a recent study estimating prevalence of the mild HPP genotype to be 1:508, although not all cases will be symptomatic. A persistent low alkaline phosphatase together with a fragility or atypical fracture raises suspicion of hypophosphatasia. A thorough clinical evaluation, fasting vitamin B6 levels, urine phosphoethanol amine levels and ALPL genetic test will aid the diagnosis. Severe cases of hypophosphatasia are treated with asfotase alfa, enzyme replacement therapy, to prevent debilitating complications, while most mild and moderate cases are offered supportive management. Bisphosphonate treatment is contraindicated in hypophosphatasia. It is worth reviewing ALP levels prior to antiresorptive therapy in suspected cases, as bisphosphonates often reduce ALP levels, masking the diagnosis. High risk Osteoporosis cases should be discussed in a multidisciplinary setting with careful risk-benefit evaluation. Cases like this highlight the importance of early HPP diagnosis to avoid contraindicating treatments and their consequences.

Could Some Patients With Fibromyalgia Potentially Have Hypophosphatasia? A Retrospective Single-Center Study.

Hypophosphatasia (HPP) is a rare disease characterized by incomplete or defective bone mineralization due to a mutation in the alkaline phosphatase (ALP) gene causing low levels of ALP. Disease presentation is heterogeneous and can present as a chronic pain syndrome like fibromyalgia (FM). Our objective was to determine if there are any potential patients with HPP in the group of patients who were diagnosed with FM. Antiresorptive therapy use can trigger atypical femur fractures in patients with HPP. We performed a retrospective chart review of all patients 18 years or older at a single academic center who were diagnosed with FM and had either a low or a normal ALP level. The following characteristics were reviewed: biological sex; age; history of fractures; diagnosis of osteoporosis, osteopenia, osteoarthritis, and chondrocalcinosis; genetic testing; vitamin B6 level testing; and medications. Six hundred eleven patients with FM were identified. Two hundred had at least one low ALP level, and 57 had at least three consecutively low measurements of ALP, 44% of which had a history of fractures. No patients had vitamin B6 levels checked. None of the patients had previous genetic testing for HPP or underwent testing for zinc or magnesium levels. The percentage of patients with FM who were found to have consistently low ALP levels was 9.3%. None had vitamin B6 level or genetic testing, suggesting that the diagnosis was not suspected. It is important to diagnose HPP given the availability of enzyme replacement therapy to prevent complications from HPP such as fractures. Our data support screening for this condition as a part of the initial workup of FM.