Elevated Serum Alkaline Phosphatase Research Articles

Early-onset Paget's disease of bone in a Mexican family caused by a novel tandem duplication (77dup27) in TNFRSF11A that encodes RANK.

Four heterozygous in-frame tandem duplications of different lengths in TNFRSF11A, the gene that encodes receptor activator of nuclear factor κB (RANK), constitutively activate RANK and lead to high turnover skeletal disease. Each duplication elongates the signal peptide of RANK. The 18-base pair (bp) duplication at position 84 (84dup18) causes familial expansile osteolysis (FEO), the 15-bp duplication at position 84 (84dup15) causes expansile skeletal hyperphosphatasia (ESH), the 12-bp duplication at position 90 (90dup12) causes panostotic expansile bone disease (PEBD), and the 27-bp duplication causes early-onset Paget's disease of bone (PDB2). The severity of the associated skeletal disease seems inversely related to the duplication's length. Additional 15- and 18-bp duplications of TNFRSF11A fit this pattern. Herein, we delineate the skeletal disease of a middle-aged man of Mexican descent who we found to harbor a novel 27-bp tandem duplication at position 77 (77dup27) of TNFRSF11A. His disorder shares features, particularly hand involvement, with the single Japanese (75dup27) and Chinese (78dup27) kindreds with PDB2 (PDB2Jpn and PDB2Chn, respectively). However, his distinct hearing loss developed later in adulthood compared to the other 27-bp families. He reported no morbidities during childhood, but in his late 20s developed unexplained tooth loss, low-trauma fractures, post-operative hypercalcemia, and painless enlargement of his fingers. Biochemical studies showed elevated serum alkaline phosphatase (ALP), bone-specific ALP, C-telopeptide, and osteocalcin consistent with rapid bone remodeling. Radiologic imaging revealed remarkably lucent bones with vertebral compression fractures, calvarial lucencies, and thinned long bone cortices. DXA showed extremely low bone mineral density. His disorder genetically and phenotypically fits best with PDB2 and can be called PDB2Mex.

P064 Drug-Induced Liver Injury (DILI) Associated With Anti-tumor Necrosis Factor Alpha (Anti-TNFα) Agent

BACKGROUND: Anti-TNFα therapy has become the mainstay in the treatment of Crohn's disease (CD), improving the rates of response and remission in patients. Significant considerations are needed when treating patients with anti-TNFα therapy including immunogenicity, duration of treatment, and safety profile. Anti-TNFα agents have been associated with drug-induced liver injury (DILI). This case presents a highly suspected association between Renflexis and DILI. CASE REPORT: 20 year old with ileocolonic CD started on Renflexis 5 mg/kg infusions to be given at 0, 2, and 6 weeks, followed by every 8 weeks. Before receiving Renflexis, tested negative for viral hepatitis with normal liver function tests. Infusions were followed by improvement in clinical symptoms and inflammatory markers. After the fourth infusion, serum liver aminotransferases were slightly elevated and rose higher several weeks after therefore, infusions were discontinued. Extensive serological work up did not find a definite cause (viral hepatitis and autoimmune antibodies) except for a weakly positive ASMA. Liver biopsy performed that showed a pattern of chronic hepatitis, no fibrosis highly suggestive of DILI. The patient remained asymptomatic, anicteric without rash, fever, or signs of hepatic disease. She was monitored on no IBD therapy and liver aminotransferase tests started to normalized and fell to normal within 12 weeks after infusion discontinuation and budesonide 9 mgs daily. This led to a prompt clinical response and serum liver transaminases remained normal during the subsequent following weeks of treatment with budesonide taper dose. DISCUSSION: Renflexis is an anti-TNFα antagonist that is biosimilar to Remicade (infliximab) for the treatment of moderate to severe active Cronh's disease. The mechanism of action is highly similar to the originator biologic. Infliximab is a monoclonal antibody genetically engineered chimeric immunoglobulin G1 anti human tumor necrosis factor agent. It has the ability to fix complement and lyse cells expressing membrane-bound TNF-alpha and induce downregulation of the inflammatory mechanisms in the entire mucosal layer. Two liver injury issues had been associated with infliximab; reactivation of underlying chronic hepatitis B and direct hepatotoxicity with different phenotypes including acute hepatitis (hepatocellular), cholestatic, autoimmune-liked injury, and acute liver failure. The hepatocellular pattern is marked by isolated or predominant elevation of serum transaminases. Cholestatic have elevation in serum alkaline phosphatase with normal or mild elevation in serum transaminases and markedly elevated bilirubin level. An autoimmune mechanism can present with a hepatocellular pattern if the hepatocytes are involved (autoimmune hepatitis) or cholestatic or if the immune mechanism targets the biliary ducts. In this case, the pattern was hepatocellular with elevation of aminotransferase, which generally arise after 2 to 5 infusions. Elevation of transaminases are usually transient and asymptomatic. CONCLUSION: This case described an association between Renflexis and DILI. Acute liver injury caused by anti-TNFα antagonist may be a class effect since several agents in this category have been implicated. In this case, the most common presentation occurred as an autoimmune phenotype with marked hepatocellular injury. A possible dual mechanism of immune deregulation with an inflammatory response and dysfunction of liver repair may be the etiology of hepatic injury associated with infliximab use.

Liver Abnormalities in Patients with Psoriatic Arthritis.

We aimed to determine the prevalence and incidence, and to identify the factors associated with liver abnormalities in patients with psoriatic arthritis (PsA). From a longitudinal cohort study, we identified PsA patients with either elevated serum transaminase or alkaline phosphatase levels or liver disease after the first visit to the PsA clinic (cases). Controls were subjects from the same cohort who never had such abnormalities or liver disease. Cases and controls were matched 1:1 by sex, age at the first clinic visit, and followup duration; variables at the onset of the first appearance of liver test abnormality associated with liver abnormalities were identified using univariate logistic and multivariate logistic regression analyses. Among 1061 patients followed in the PsA clinic, 343 had liver abnormalities. Two hundred fifty-six patients who developed liver abnormalities after the first visit were identified as cases, and 718 patients were identified as controls. The prevalence of liver abnormalities was 32% and the incidence was 39/1000 patient-years where there were 256 cases over 6533 total person-years in the PsA cohort. Liver abnormalities were detected after a mean (SD) followup duration of 8.3 ± 7.8 years. The common causes of liver abnormalities were drug-induced hepatitis and fatty liver. Independent factors associated with liver abnormalities were higher body mass index (BMI), daily alcohol intake, higher damaged joint count, elevated C-reactive protein, and use of methotrexate, leflunomide, or tumor necrosis factor inhibitors. Liver abnormalities are common among patients with PsA and are associated with higher BMI, more severe disease, and certain therapies.

Protective Effects Of Solanium Nigrum Methanolic Extract Against Isoniazid/Rifampicin Induced Hepatotoxicity In Rats

Drug-induced liver injury (DILI) is the major health problem that resulted from uses of many drugs especially from serious adverse effect of antituberculosis (ATT) drugs. forty eight rats (200-250g) were allocated into six groups (8 rats in each group), and treated as follow: group I: received normal saline orally; group II: received INH/RFP (50 mg/Kg/day of each) for 28 days orally; group III: received Silymarin (50 mg/kg/day) + INH/RFP for 28 days orally; group IV: received SNME(250 mg/Kg/day) + INH/RFP for 28 days orally; group V: received SNME (500 mg/Kg/day) + INH/RFP for 28 days orally; group VI, received SNME (1000 mg/Kg/day) + INH/RFP for 28 days orally. Co-administration of herbal plant (SNME) with INH/RFP reduced elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and (bilirubin total &direct) levels but also decreased the elevated malondialdehyde (MDA) & tumor necrosis factor-α (TNF-α) contents in liver homogenate. Moreover, co-administration of herbal plant (SNME) with INH/RFP increased glutathione peroxidase (GPX) & adiponectin activity. Solanum nigrum administration to rats, in present study, led to a remarkable alteration of histological changes observed in INH/RFP group. It is concluded that Solanum nigrum might be considered as adjuvant drug in treatment of liver disorder and/or as hepatoprotective therapy with anti-tubercular drugs.

Elevated serum alkaline phosphatase in epilepsy: effect of age and treatment

Epilepsy, a common neurological disease characterized by recurrent seizures, affects approximately 69 million people worldwide. Although incurable, seizures may be managed with antiepileptic drugs,...

Icariin Treatment Enhanced the Skeletal Response to Exercise in Estrogen-Deficient Rats.

Estrogen deficiency frequently leads to a fall in estrogen receptor-α (ERα) numbers and then reduces the skeletal response to mechanical strain. It, however, is still unclear whether phytoestrogen administration will enhance the effects of exercise on the estrogen-deficient bone loss. This study aimed to determine the effect of Icariin treatment on the response of osteogenic formation to exercise in ovariectomized (OVX) rats. Thirty-two 3-month old female Sprague–Dawley rats were randomly allocated into four groups: (1) Sham-operated (SO); (2) OVX; (3) OVX plus exercise (EX); and (4) OVX plus exercise and Icariin (EI). After 8-week interventions, the rats were killed and samples were collected for bone morphometry, reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analyses. EI interventions showed a greater improvement for the OVX-induced bone loss and the elevated serum tartrate-resistant acid phosphatase (TRAP) and alkaline phosphatase (ALP) compared with EX only. Both EX and EI interventions bettered the OVX-related reduction of BV/TV and trabecular number and thickness, and decreased the enlargement of trabecular bone separation (Tb. Sp); the improvement for BV/TV and Tb. Sp was greater in EI group. Furthermore, EX and EI treatment significantly increased the number of ALP+ cells and mineralized nodule areas compared with OVX group; the change was higher in EI group. Additionally, in comparison to OVX rats, the protein and mRNA expression of β-catenin, phosphorylated-Akt (p-Akt) or Akt, ERα, and Runt-related transcription factor 2 (Runx2) in osteoblasts were elevated in EX and EI intervention rats, with greater change observed in EI group. The upregulated β-catenin and Akt mRNA levels in EX and EI groups was depressed by ICI182780 treatment, and the difference in β-catenin and Akt mRNA levels between EX and EI groups was no longer significant. Conclusively, the combination of Icariin and exercise significantly prevent OVX-induced bone loss and increase osteoblast differentiation and the ability of mineralization compared with exercise alone; the changes might be regulated partly by ERα/Akt/β-catenin pathway.

1274 An Unusual Case of Sarcoidosis Involving the Pancreas

INTRODUCTION: Sarcoidosis is a multisystem disease primarily involving the lung. Skin, eyes, lymph nodes, spleen, liver, bones, exocrine glands, heart, kidneys, and central nervous system are the most common extrapulmonary sites involved. Clinically apparent gastrointestinal (GI) sarcoidosis is rare involving 0.1 to 0.9 percent of patients with sarcoidosis. The most commonly involved portion of the GI tract is the stomach, although sarcoidosis of the esophagus, appendix, colon, rectum, and pancreas have been reported in the literature. CASE DESCRIPTION/METHODS: A 73-year-old African American male was found to have pancreatic duct dilation on a computed tomography scan of abdomen done for investigation of mild epigastric abdominal pain that started a few months prior to presentation. He described the pain as dull, non-radiating, aggravated when hungry, subsided with food intake and associated with bloating. He had a past medical history of hypertension, hypothyroidism, and sarcoidosis involving lymph nodes and liver (not on treatment). He had no family history of GI cancer. He was a non-smoker and non-alcoholic. On presentation, his vital signs were normal; his abdomen was soft and non-tender, with normoactive bowel sounds and no masses or organomegaly. He had a normal calcium level of 9.7 mg/dL and his liver panel was significant for slightly elevated serum alkaline phosphatase, AST, ALT levels, with normal serum bilirubin. Magnetic resonance imaging showed 1.2 cm mass in the body of the pancreas obstructing the pancreatic duct and another 1.1 cm mass in the head of the pancreas concerning for malignancy. He underwent endoscopic ultrasonography with fine needle aspiration cytology of both pancreatic masses which showed numerous non-caseating granulomas consistent with sarcoidosis. Special stains for fungi and tuberculosis were negative. DISCUSSION: Less than 30 cases of biopsy-proven pancreatic sarcoidosis have been reported in the literature. Patients can have direct involvement of pancreas with sarcoidosis or 1, 25-dihydroxy vitamin D3 mediated hypercalcemia causing hypercalcemic pancreatitis. About three fourths of patients with pancreatic sarcoidosis have bilateral hilar adenopathy on chest radiography. On imaging, these patients demonstrate either a pancreatic mass (or masses) or a diffuse nodular pancreas. A biopsy is essential to distinguish between sarcoidosis, mycobacterial or fungal infection, and cancer. Treatment is usually conservative or with glucocorticoids.

2455 Nivolumab-Induced Immune Cholestatic Hepatitis in a Liver Transplant Recipient

INTRODUCTION: Cancer treatment has taken giant strides in recent years with the advent of immunotherapy including check-point inhibitors. We present a case of cholestatic hepatitis following treatment of recurrent HCC with Nivolumab. CASE DESCRIPTION/METHODS: A 62-year-old male with a history of alcoholic cirrhosis and hepatocellular carcinoma (HCC), was seen 5 years after liver transplantation. Approximately one year after transplant, he developed metastatic HCC in his lung and anterior abdominal wall with progression of tumor burden after several chemotherapy regimens. Two months prior to admission, he began palliative Nivolumab. He developed elevated serum alkaline phosphatase (ALP), aspartate transaminase (AST), alanine transaminase (ALT), and total bilirubin; so, he was hospitalized. Admission labs showed ALP of 813, ALT of 1265, AST of 696 and bilirubin of 8.3. Investigations were negative for viral or autoimmune hepatitis. Acute cellular rejection was unlikely given time from transplant and stable tacrolimus trough levels. Given the concern for Nivolumab-induced liver injury, high dose intravenous steroids at 2 mg/kg daily was started with temporary improvement in his liver tests. A trans-jugular liver biopsy confirmed the diagnosis of immune-induced liver injury due to Nivolumab. By hospital day 7, his liver tests continued to rise precipitously (Figure 1). Ultimately, he developed massive hematemesis and hemodynamic instability, necessitating intubation and intensive care unit (ICU) admission. An emergent upper endoscopy showed severe esophagitis with denudation of the esophageal mucosa (Figure 2) and gastric blood and clot precluding completion of the endoscopy. Steroids were increased to 4 mg/kg, for worsening hepatitis. However, his family decided to pursue comfort cares considering his rapid decline and metastatic cancer. He expired within minutes of implementing comfort care measures. DISCUSSION: We believe that Nivolumab caused a cholestatic liver injury in our patient. Nivolumab-induced liver injury has been previously reported but with paucity of data in transplants recipients or cholestatic pattern of injury. The difference in clinical, biochemical and histopathologic features may suggest subtle differences in strategies for management of Nivolumab-induced liver injury. Further prospective studies are needed to understand the pathophysiology and management of this type of liver injury as well as the benefits of PD-1 inhibitors in liver transplant recipients.

The relative expression of hepatocellular and cholestatic liver enzymes in adult patients with liver disease

Introduction and objectivesHepatocellular liver injury is characterized by elevations in serum alanine (ALT) and aspartate (AST) aminotransferases while cholestasis is associated with elevated serum alkaline phosphatase (ALP) levels. When both sets of enzymes are elevated, distinguishing between the two patterns of liver disease can be difficult. The aim of this study was to document the predicted ranges of serum ALP values in patients with hepatocellular liver injury and ALT or AST values in patients with cholestasis. Materials and methodsLiver enzyme levels were documented in adult patients with various types and degrees of hepatocellular (non-alcoholic fatty liver disease, hepatitis B and C, alcohol and autoimmune hepatitis) and cholestatic (primary biliary cholangitis and primary sclerosing cholangitis) disease. ResultsIn 5167 hepatocellular disease patients with ALT (or AST) values that were normal, 1–5×, 5–10× or >10× elevated, median (95% CI) serum ALP levels were 0.64 (0.62–0.66), 0.72 (0.71–0.73), 0.80 (0.77–0.82) and 1.15 (1.0–1.22) fold elevated respectively. In 252 cholestatic patients with ALP values that were normal, 1–5× or >5× elevated, serum ALT (or AST) values were 1.13 (0.93–1.63), 2.47 (2.13–2.70) and 4.57 (3.27–5.63) fold elevated respectively. In 56 patients with concurrent diseases, ALP levels were beyond predicted values for their hepatitis in 38 (68%) and ALT (or AST) values beyond predicted values for their cholestatic disorder in 24 (43%). ConclusionsThese data provide health care providers with predicted ranges of liver enzymes in patients with hepatocellular or cholestatic liver disease and may thereby help to identify patients with concurrent forms of liver disease.

Modulatory effects of artichoke (Cynara scolymus L.) leaf extract against oxidative stress and hepatic TNF-α gene expression in acute diazinon-induced liver injury in rats.

Background Diazinon (DZN) causes serious liver damage in both humans and animals. In the present study, the hepatoprotective effects of Cynara scolymus L. leaf extract against DZN-induced liver injury were examined. Methods Forty male rats were divided into five groups. The control group received a normal diet. The DZN group received DZN only (25 mg/kg, po). The DZN + Syl group received DZN (25 mg/kg, po) and silymarin (Syl) (50 mg/kg, po). The DZN + Art group received DZN (25 mg/kg, po) and artichoke (Art) leaf extract (1500 mg/kg, po). The Art group received Art leaf extract only (1500 mg/kg, po). After 15 days, serum tumor necrosis factor α (TNF-α), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lipid profile, protein carbonyl content, serum and hepatic malondialdehyde (MDA), hepatic TNF-α gene expression, hepatic catalase (CAT), superoxide dismutase (SOD), and vitamin C (Vit C) were measured and histopathological examination was performed. Results DZN caused a significant elevation in serum ALP, AST, ALT, MDA, TNF-α, protein carbonyl, hepatic MDA, and TNF-α gene expression in the DZN group as opposed to the control group. Also, DZN led to the reduction of hepatic CAT, SOD, and Vit C in the DZN group relative to the control group. The administration of Art extract resulted in not only a significant reduction in serum ALP, AST, ALT, MDA, TNF-α, and protein carbonyl but also an improvement of liver histopathological changes and hepatic CAT and SOD activities as opposed to the DZN group. Conclusions This study confirmed that Art leaf extract has liver protective effects and causes downregulation of oxidative stress in acute DZN-induced liver injury in rats.

Galangin Activates Nrf2 Signaling and Attenuates Oxidative Damage, Inflammation, and Apoptosis in a Rat Model of Cyclophosphamide-Induced Hepatotoxicity.

Cyclophosphamide (CP) is a widely used chemotherapeutic agent; however, its clinical application is limited because of its multi-organ toxicity. Galangin (Gal) is a bioactive flavonoid with promising biological activities. This study investigated the hepatoprotective effect of Gal in CP-induced rats. Rats received Gal (15, 30 and 60 mg/kg/day) for 15 days followed by a single dose of CP at day 16. Cyclophosphamide triggered liver injury characterized by elevated serum transaminases, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), and histopathological manifestations. Increased hepatic reactive oxygen species, malondialdehyde, nitric oxide, and oxidative DNA damage along with declined glutathione and antioxidant enzymes were demonstrated in CP-administered rats. CP provoked hepatic nuclear factor-kappaB (NF-κB) phosphorylation and increased mRNA abundance of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) both expression and serum levels. Gal prevented CP-induced liver injury, boosted antioxidants and suppressed oxidative stress, DNA damage, NF-κB phosphorylation and pro-inflammatory mediators. Gal diminished Bax and caspase-3, and increased B-cell lymphoma-2 (Bcl-2) in liver of CP-administered rats. In addition, Gal increased peroxisome proliferator-activated receptor gamma (PPARγ) expression and activated hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) signaling showed by the increase in Nrf2, NAD(P)H: quinone acceptor oxidoreductase-1 (NQO-1) and heme oxygenase 1 (HO-1) in CP-administered rats. These findings suggest that Gal prevents CP hepatotoxicity through activation of Nrf2/HO-1 signaling and attenuation of oxidative damage, inflammation and cell death. Therefore, Gal might represent a promising adjuvant therapy to prevent hepatotoxicity in patients on CP treatment.

AMELIORATIVE EFFECT OF FRESH GARLIC AND VITAMIN E AGAINST LINEZOLID INDUCED HEPATO-RENAL OXIDATIVE DAMAGE IN RATS

The present study was conducted to compare between the protective effect of either garlic or vitamin E (Vit E) against hepatic and renal damage induced by 100mg/ kg linezolid (LNZ) administration. Thirty male albino rats were allocated into equal six groups; first three control groups; (control, tween 80 and olive oil); Group4; received 100mg LNZ / kg for 14 consecutive days. The last two groups were administered either garlic (500 mg/kg) or Vit E (100 mg/kg) prior to LNZ administration daily for 14 consecutive days. Blood samples were obtained from all rats for biochemical investigations and oxidative stress biomarkers. Specimens from liver and kidneys were excised for histopathological investigation. Linezolid induced a significant elevation in serum Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP) and urea. Alterations in antioxidant / oxidant status were noticed during LNZ administration. Administration of garlic or Vit E modulated the previous parameters and restored histological structures. In conclusion, both garlic and Vit E were able to ameliorate hepato-renal alterations induced by LNZ via their antioxidant effects.

Serum alkaline phosphatase and γ-glutamyl transferase in acute pyelonephritis.

BackgroundElevated serum alkaline phosphatase (AP) and γ-glutamyl transferase (γ-GT) are commonly observed in patients with acute pyelonephritis. The goal of this study was to examine the clinical significance of elevated serum AP and γ-GT levels and to explore the mechanisms underlying these changes.MethodsWe examined serum AP and γ-GT levels in 438 patients with acute pyelonephritis. Urine AP/creatinine (Cr), urine γ-GT/Cr, fractional excretion of AP, and fractional excretion of γ-GT (FEγ-GT) were evaluated in patients with elevated and normal serum levels. AP isoenzymes were also examined.ResultsWe identified 77 patients (17.6%) with elevated serum AP and 134 patients (30.6%) with elevated serum γ-GT. Among them, both enzymes were elevated in 64 patients (14.6%). Older age, longer hospital stay, elevated baseline serum Cr, and complicated pyelonephritis were associated with increases in serum AP and γ-GT. Multivariate analysis showed that high serum AP levels were significantly correlated with renal impairment (odds ratio, 2.13; 95% confidence interval, 1.08–4.19; P = 0.029). FEγ-GT was significantly lower in patients with elevated serum enzyme levels. The liver fraction for AP isoenzyme profile did not increase in patients with elevated serum AP.ConclusionOur results demonstrated that elevated serum AP and γ-GT levels are associated with complicated pyelonephritis and renal impairment. Lower FEγ-GT levels in patients with elevated serum enzymes may be the result of decreased urinary excretion of these enzymes.

Study of mineral status & alkaline phosphatase activity in rheumatoid arthritis patients in Shivamogga district

Introduction: Rheumatoid arthritis (RA) is a prototypical inflammatory joint disease of unknown etiology affecting various joints of the body leading to stiffness, swelling, pain, and finally functional inability. Elevated serum alkaline phosphatase (ALP) is a common feature in rheumatoid arthritis (RA) and its origin remains unclear. Inflammatory conditions are more likely to alter mineral status. Aim of the Study: The aim of this study was to investigate the level of serum ALP, Calcium, Phosphorus & Magnesium levels in Rheumatoid arthritis patients and compare it with healthy subjects. Materials and Methods: Fifty four RA patients and fifty four age matched healthy controls between 35-65 years were included in the study. Serum Calcium, Phosphorus, Magnesium & ALP activity were measured in all the subjects and correlated. Results: Serum ALP (145.17±15.87 versus 83.19±17.55 U/L) and phosphorus levels (4.84±0.24 versus 3.84±0.44 mg/dl) were found significantly higher; serum Calcium (7.66±0.34 versus 9.27±0.49) and serum Magnesium levels (1.72±0.24 versus 1.95±0.29 were found to be lower in RA cases as compared to controls and were statistically significant (p Conclusion: Increase in ALP in RA patients when compared to healthy controls suggests the role of serum ALP as a marker of disease activity in RA. The altered mineral status in rheumatoid arthritis, observed in this study reflects on the pathogenesis of RA. Therefore we conclude that serum ALP & mineral estimation can also be used as markers of disease activity in rheumatoid Arthritis. Keywords: Alkaline phosphatase, Serum calcium, Phosphorus, Magnesium, Rheumatoid arthritis.

Novel biomarkers for primary biliary cholangitis to improve diagnosis and understand underlying regulatory mechanisms.

Primary biliary cholangitis is an autoimmune biliary disease characterized by injury of bile ducts, eventually leading to cirrhosis and death. In most cases, anti-mitochondrial antibodies and persistently elevated serum alkaline phosphatase are the basis for the serological diagnosis.Anti-nuclear antibodies are also useful and may indicate a more aggressive diseases course. In patients in which anti-mitochondrial antibodies are not detected, an accurate diagnosis requires liver histology. This study aims at identifying specific biomarkers for the serological diagnosis of primary biliary cholangitis. Sera from patients affected by primary biliary cholangitis, primary sclerosing cholangitis, hepatitis C virus (with and without cryoglobulinemia), hepatocarcinoma and healthy donors were tested on a protein array representing 1658 human proteins. The most reactive autoantigens were confirmed by DELFIA analysis on expanded cohorts of the same mentioned serum classes, and on autoimmune hepatitis sera, using anti-PDC-E2 as reference biomarker. Two autoantigens, SPATA31A3 and GARP, showed high reactivity with primary biliary cholangitis sera, containing or not anti-mitochondrial antibodies. Their combination with PDC-E2 allowed to discriminate primary biliary cholangitis from all tested control classes with high sensitivity and specificity. We found that GARP expression is upregulated upon exposure to biliary salts in human cholangiocytes, an event involving EGFR and insulin pathways. GARP expression was also detected in biliary duct cells of PBC patients. This study highlighted SPATA31A3 and GARP as new biomarkers for primary biliary cholangitis and unravelled molecular stimuli underlying GARP expression in human cholangiocytes.

Fibrogenesis Imperfecta Ossium.

Fibrogenesis imperfecta ossium (FIO) is an extremely uncommon fatal bone disorder of poorly understood etiology. The pathogenesis of FIO is not well known. The fundamental skeletal defect appears to be an abnormality in organic matrix of bone characterized by defective mineralization of the abnormal collagen. FIO clinically manifests in middle-aged adults presenting with fracture and bone pain. Elevated serum alkaline phosphatase is the only and the most consistent biochemical abnormality. Although paraproteinemia is observed in one-third of cases, the pathogenic link to the disease process is unclear. Limited information on FIO and its close resemblance to many metabolic bone disorders leads to delayed or missed diagnoses and management. Prednisolone, bisphosphonates, melphalan and steroids have been tried previously with variable success. Recently, a trial of recombinant growth hormone therapy was found to be effective. Further research focused on the pathogenetic mechanisms of FIO is needed to identify and develop targeted therapeutic options.

Serum Alkaline Phosphatase Level is Associated with Angiographic Vasospasm, Delayed Cerebral Ischemia-Caused Clinical Deterioration, and Functional Outcome After Aneurysmal Subarachnoid Hemorrhage.

Alkaline phosphatase (ALP) has been implicated to be associated with poor outcome in ischemic stroke patients, yet its role in aneurysmal subarachnoid hemorrhage (aSAH) patients is unknown. The current study aimed to investigate the on-admission and short-term variation trend of ALP levels in aSAH patients as well as its associations with vasospasm, delayed cerebral ischemia (DCI), and outcome after aSAH. Between January 2014 and May 2018, all consecutive aSAH patients were prospectively enrolled. Blood samples from patients and 78 healthy individuals were obtained. Baseline information, clinical data, and radiologic data were collected, and serum ALP levels during hospitalization were measured. Patients were followed up for 6months. One hundred and ninety-six aSAH patients were included. The serum ALP levels in aSAH patients were significantly higher compared to controls (71 vs. 61U/L, p = 0.0002), yet did not differ significantly between patients with severe (WFNS 4-5) and mild clinical condition (72 vs. 63U/L, p = 0.3362). However, ALP was significantly higher in patients with severe radiologic status (modified Fisher 3-4) compared to those with mild radiologic status (77 vs. 61.5U/L, p = 0.0005). A significant correlation emerged between modified Fisher score and ALP level (r = 0.246, p = 0.001). Multivariable analysis found that higher ALP level was associated with angiographic vasospasm (OR 1.019, 95%CI 1.002-1.036, p = 0.026) and DCI-caused clinical deterioration (OR 1.019, 95%CI 1.001-1.037, p = 0.037), while higher WFNS score, modified Fisher score, and ALP level were independently associated with unfavorable outcome (serum ALP level, OR 1.083, 95%CI 1.041-1.127, p < 0.001). Trend analysis of ALP level based on 103 patients' data revealed a significant decrease in ALP level on post-admission day 7-9 (median; on-admission day vs. post-admission day 7-9, 72 vs. 60U/L, p = 0.0012; post-admission day 3-5 vs. day 7-9, 70 vs. 60U/L, p = 0.0052) and subsequent increase in ALP level on post-admission day 12-14 (median, 84U/L, p < 0.0001). Higher ALP levels were observed in patients with unfavorable outcome on on-admission day, post-admission day 3-5, and 12-14 (median; unfavorable vs. favorable; on-admission day, 86 vs. 67U/L, p = 0.0122; post-admission day 3-5, 80 vs. 64U/L, p = 0.0044; post-admission day 7-9, 75 vs. 53.5U/L, p < 0.0001) but not on post-admission day 12-14. Elevated serum ALP level is associated with vasospasm, DCI-caused clinical deterioration, and functional outcome after aSAH. Further studies are required to examine the potential role of serum ALP as an outcome predictor for aSAH patients.

Prognostic value of serum alkaline phosphatase in spinal metastatic disease

BackgroundDetermination of the appropriateness of invasive management in patients with spinal metastatic disease requires accurate pre-operative estimation of survival. The purpose of this study was to examine serum alkaline phosphatase as a prognostic marker in spinal metastatic disease.MethodsChart reviews from two tertiary care centres were used to identify spinal metastatic disease patients. Bivariate and multivariate analyses were used to determine if serum alkaline phosphatase was an independent prognostic marker for survival.ResultsOverall, 732 patients were included with 90-day and 1-year survival of n = 539 (74.9%) and n = 324 (45.7%), respectively. The 1-year survival of patients in the first quartile of alkaline phosphatase (≤73 IU/L) was 78 (57.8%) compared to 31 (24.0%) for patients in the fourth quartile (>140 IU/L). Preoperative serum alkaline phosphatase levels were significantly elevated in patients with multiple spine metastases, non-spine bone metastasis, and visceral metastasis but not in patients with brain metastasis. On multivariate analysis, elevated serum alkaline phosphatase was identified as an independent prognostic factor for survival in spinal metastatic disease.ConclusionSerum alkaline phosphatase is associated with preoperative metastatic tumour burden and is a biomarker for overall survival in spinal metastatic disease.

Liver disorders related to exposure to gasoline fumes in male rats and role of fenugreek seed supplementation.

Progressive effects of inhalation of gasoline fumes on the liver and the protective potential with fenugreek seed supplementation were evaluated in adult male rats. Twenty-four rats were divided into four groups, unexposed control and fenugreek groups, as well as exposed groups to gasoline fumes for 6h/6days/week for 10weeks, with and without supplementation of fenugreek seed powder in food (5%w/w). Exposure to gasoline fumes resulted in a significant elevation in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, total bilirubin, total cholesterol, total triglycerides, and low-density lipoprotein, along with a significant decrease in high-density lipoprotein, total protein, and albumin contents compared to the control. Meanwhile, liver oxidative stress markers, malondialdehyde, hydrogen peroxide, and nitric oxide, were highly detected with decreased antioxidants, superoxide dismutase and catalase. Also, levels of inflammatory markers, interleukin(IL)-1β and IL-6, were significantly elevated with fibrotic markers, transforming growth factor (TGFβ1), fibroblast growth factor (FGF1), and collagen I. Histopathological studies illustrated that rats exposed to gasoline fumes have degenerated hepatocytes with cellular infiltration and necrotic areas, along with remarkable deposition of collagen fibers, suggesting an incidence of liver fibrosis. Administration of fenugreek seeds, rich with antioxidant and anti-inflammatory components, during gasoline exposure showed significant amelioration through suppressing oxidative stress and inflammation.

Alkaline phosphatase is a predictor of Bone Mineral Density in postmenopausal females.

Objectives:The study was planned to determine whether serum calcium, phosphate and alkaline phosphatase (ALP) are predictors of bone mineral density (BMD) in postmenopausal non-osteoporotic, osteopenic, and osteoporotic females.Methods:In this cross sectional study, conducted at Shaikh Zayed Hospital, Lahore in the year 2014-2015, postmenopausal females between 50-70 years of age were taken and divided into three groups non-osteoporotic (n=52), osteopenic (n=69) and osteoporotic (n=47). Serum ALP, phosphate and calcium were used in a stepwise multiple regression analysis to predict T-score in these groups.Results:In normal postmenopausal females, the prediction model was statistically significant, F(2, 41) = 6.041, p < 0.05 and showed a T-score variance of 22%. T-score was primarily predicted by higher levels of phosphate and calcium. In postmenopausal osteopenic females, T-score was only predicted by lower levels of ALP. The model was statistically significant, F(1, 59) = 4.995, p < 0.05, and accounted for approximately 7% of the variance of T-score. In postmenopausal osteoporotic females, the prediction model contained no predictors.Conclusion:Our study suggested that calcium and phosphate are the strongest predictors of T-score in postmenopausal normal females, while in postmenopausal osteopenic females ALP was the strongest predictor of T-score. Elevated serum ALP levels may help in determining loss of BMD in postmenopausal females.