ISOLATED ALTERATIONS OF BIOCHEMICAL MARKERS OF LIVER DAMAGE in a seemingly healthy patient can present a challenge for the clinician. In this review we provide a guide to interpreting alterations to liver enzyme levels. The functional anatomy of the liver and pathophysiology of liver enzyme alteration are briefly reviewed. Using a schematic approach that classifies enzyme alterations as predominantly hepatocellular or predominantly cholestatic, we review abnormal enzymatic activity within the 2 subgroups, the most common causes of enzyme alteration and suggested initial investigations.

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Liver enzyme alteration: a guide for clinicians

Anti-neutrophil cytoplasmic autoantibodies have been found in patients with systemic arteritis and glomerulonephritis We studied the disease distribution and antigen specificity of these autoantibodies Anti-neutrophil cytoplasmic autoantibodies were identified by indirect immunofluorescence microscopy in 27 of 35 patients with idiopathic necrotizing and crescentic glomerulonephritis, in whom the manifestations of disease ranged from injury limited to the kidney to systemic arteritis The incidence and titers of the autoantibodies did not differ between patients with disease limited to the kidney and those with systemic disease Anti-neutrophil immunostaining was detected in 5 of 11 patients with lupus nephritis, 4 of 71 patients with other renal diseases, and none of 50 normal controls This distribution of autoantibodies was confirmed by an enzyme-linked immunosorbent assay (ELISA) using neutrophil lysate as antigen According to ELISA, anti-neutrophil cytoplasmic autoantibodies were found to be specific for constituents of primary granules Two types of autoantibodies were identified; one with reactivity with myeloperoxidase on ELISA produced an artifactual perinuclear immunostaining of alcohol-fixed neutrophils, and another with no reactivity with myeloperoxidase on ELISA produced diffuse cytoplasmic immunostaining The presence of the same serologic marker in patients with kidney-limited and arteritis-associated necrotizing and crescentic glomerulonephritis, including Wegener's granulomatosis and polyarteritis nodosa, suggests that these clinically diverse diseases may have a similar pathogenesis, initiated by autoantibody-mediated activation of neutrophils

Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis

Studies of the mode of action of the bisphosphonate alendronate showed that 1 d after the injection of 0.4 mg/kg [3H]alendronate to newborn rats, 72% of the osteoclastic surface, 2% of the bone forming, and 13% of all other surfaces were densely labeled. Silver grains were seen above the osteoclasts and no other cells. 6 d later the label was 600-1,000 microns away from the epiphyseal plate and buried inside the bone, indicating normal growth and matrix deposition on top of alendronate-containing bone. Osteoclasts from adult animals, infused with parathyroid hormone-related peptide (1-34) and treated with 0.4 mg/kg alendronate subcutaneously for 2 d, all lacked ruffled border but not clear zone. In vitro alendronate bound to bone particles with a Kd of approximately 1 mM and a capacity of 100 nmol/mg at pH 7. At pH 3.5 binding was reduced by 50%. Alendronate inhibited bone resorption by isolated chicken or rat osteoclasts when the amount on the bone surface was around 1.3 x 10(-3) fmol/microns 2, which would produce a concentration of 0.1-1 mM in the resorption space if 50% were released. At these concentrations membrane leakiness to calcium was observed. These findings suggest that alendronate binds to resorption surfaces, is locally released during acidification, the rise in concentration stops resorption and membrane ruffling, without destroying the osteoclasts.

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Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure.

Percutaneous mitral repair with the MitraClip system: safety and midterm durability in the initial EVEREST (Endovascular Valve Edge-to-Edge REpair Study) cohort.

Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ecto-nucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

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Cellular function and molecular structure of ecto-nucleotidases

Gene cloning and site-directed mutagenesis have had a profound effect on alkaline phosphatase research. Four distinct structural genes encoding placental, intestinal, and tissue-nonspecific isoenzymes have been cloned, sequenced, and mapped to human chromosomes. Differences in properties between the respective gene products are due to variations in primary structure involving only one, or a few, key amino acid residues. Recognition that alkaline phosphatase belongs to the category of molecules that are localized to cell membranes through a COOH-terminal glycan-phosphatidylinositol anchor provides a basis for understanding the generation of isoforms observed in plasma in disease. Isoforms produced by differential cleavage or preservation of the glycan-phosphatidylinositol anchor may offer new correlations with disease that are of diagnostic value. However, a more important contribution of alkaline phosphatase research to clinical chemistry may prove to be an increased understanding of disease processes at the molecular level.

Perspectives in alkaline phosphatase research.

Association of alkaline phosphatase with an autoantigen recognised by circulating anti-neutrophil antibodies in systemic vasculitis.

Inhibition of osteoclastic acid phosphatase abolishes bone resorption.

Improved electrophoretic resolution of bone and liver alkaline phosphatases resulting from partial digestion with neuraminidase.

The formation of 1,25-dihydroxycholecalciferol from 25-hydroxycholecalciferol by chick kidney homogenates is inhibited by increasing concentrations of Ca2+. The apparent Km for the hydroxylation reaction is 1×10−7m, significantly lower than that reported for isolated mitochondria. Separated cytoplasmic and particulate fractions are inactive, but on recombination activity is restored, possibly because of the presence in the soluble fraction of a factor with a high affinity for 25-hydroxycholecalciferol.

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Regulation of vitamin D metabolism: factors influencing the rate of formation of 1,25-dihydroxycholecalciferol by kidney homogenates (Short Communication)

Donald W. Moss

Papers

Perspectives in alkaline phosphatase research.

Association of alkaline phosphatase with an autoantigen recognised by circulating anti-neutrophil antibodies in systemic vasculitis.

Inhibition of osteoclastic acid phosphatase abolishes bone resorption.

Improved electrophoretic resolution of bone and liver alkaline phosphatases resulting from partial digestion with neuraminidase.

Regulation of vitamin D metabolism: factors influencing the rate of formation of 1,25-dihydroxycholecalciferol by kidney homogenates (Short Communication)