Clinical significance of the human acid phosphatases: a review

During the past three decades we have witnessed significant developments in the clinical application and interpretation of both serum and tissue acid phosphatases. The human prostate is particularly rich in this enzyme, and serum enzyme levels are a useful tool in the diagnosis and management of prostatic diseases. Alterations of serum enzyme activity are not, however, unique to prostatic disorders and are seen in a wide variety of other diseases, particularly in Gaucher's disease and nonprostatic malignancies with bone involvement. It is now apparent that acid phosphatases represent a heterogeneous group of enzymes containing many isoenzymes, each specific for one type of tissue. Determination of the serum isoenzyme pattern is often a valuable aid in directing the physician's attention to one particular tissue; moreover, the isoenzyme pattern may show abnormalities in the face of normal total serum enzyme. The present trend in study of the acid phosphatases includes the combined use of biochemical, histochemical, electrophoretic, electron microscopic and immunologic technics to further our understanding of the relationship between these isoenzymes and the cellular and subcellular fractions of various tissues. Such studies will lead to a further understanding of the function of acid phosphatases and may serve to extend the clinical application of these enzymes.     

Clinical and immunologic features of transient cold agglutinin hemolytic anemia

Atypical pneumonitis, often induced by infection with Mycoplasma pneumoniae, is frequently associated with elevated cold agglutinin titers but only rarely with significant hemolytic anemia. An example and documentation of the clinical and immunologic course of such transient cold agglutinin hemolytic anemia is presented, and the immunochemical characteristics of cold agglutinins in this syndrome are assessed in regard to their biologic implications and diagnostic significance. Transient cold agglutinins, such as observed in this case, commonly appear to be of a restricted polyclonal character and as first demonstrated in this case may possess structural determinants usually considered unique for monoclonal cold agglutinins. Although the immunopathogenetic mechanisms and certain clinical manifestations of the various forms of cold agglutinin hemolytic anemia appear similar, the immunogenic basis of cold agglutinin production and the molecular structure of transient cold agglutinins are quite distinctive and provide reasonably reliable guidelines for the differential diagnosis of the cold agglutinin syndromes and for consideration of appropriate clinical management.     

Alpha 1-antitrypsin deficiency associated with PZ and MP phenotypes. Clinical and laboratory correlations

In a large kindred we have identified two siblings with the hitherto unreported PZ phenotype and eight other subjects with the MP phenotype. In subjects with the MP phenotype serum alpha₁-antitrypsin levels are near the lower limits of normal. In contrast, subjects with the PZ phenotype have severely depressed alpha₁-antitrypsin levels. One subject with the PZ phenotype at age 34 already shows evidence of obstructive lung disease. We found no convincing evidence of obstructive lung disease in family members with the MP phenotype. After purification of alpha₁-antitrypsin from the serum, isoelectric focusing and acrylamide gel electrophoresis can be used to distinguish normal protein from the products of the Pi^P and Pi^Z alleles. Subjects with the PZ phenotype have more Pi^P than Pi^Z product.     

Extraglomerular immunoglobulin deposits in human nephritis.

In order to evaluate the incidence of extraglomerular immunoglobulin deposits and to correlate their presence with histopathologic abnormalities, we performed both prospective and retrospective immunofluorescence studies of renal biopsy specimens. Of 200 diagnostic biopsy specimens examined prospectively, 21 had extraglomerular deposits, 19 in association with presumed immunologically-mediated glomerulonephritis. Nine had linear immunoglobulin deposits on tubular basement membrane (antitubular basement membrane antibodies), in one case coexisting with granular deposits, and 13 had granular deposits on tubular basement membrane, in peritubular capillaries and/or arteries, or in tubular cytoplasm (probably immune complexes). Linear deposits on tubular basement membrane were usually associated with antiglomerular basement membrane nephritis or methicillin-associated interstitial nephritis; granular extraflomerular deposits were seen primarily in systemic lupus erythematosus, cryoglobulinemia or membranoproliferative glomerulonephritis.. The incidence of immunoglobulin deposits was high in the three groups of patients examined retrospectively being present in 37 or 47 patients with antiglomerular basement membrane mephritis, 22 or 32 patients with systemic lupus erythematosus of 24 of 130 renal allograft recipients. The contribution of antitubular basement membrane antibodies to renal damage was difficult to assess, although studies in experimental animals attest to their pathogenicity. The occurrence of granular extraglomerular deposits appeared to correlate roughly with the degree of tubulointerstitial injury in the patients with systemic lupus erythematosus.     

Molecular assembly in the contact phase of the Hageman factor system.

Data obtained in the past few years have defined the molecular mechanisms of contact activation of the Hageman factor pathways of plasma, i.e., the kinin-forming, intrinsic clotting and fibrinolytic systems. Involved are four molecules: Hageman factor, high molecular weight (MW) kininogen, prekallikrein and factor XI. High MW kininogen serves as a surface cofactor to assemble prekallikrein or factor XI in proximity to surface-bound Hageman factor. Reciprocal proteolytic activation of Hageman factor and prekallikrein represents an essential step in the rapid activation of the contact phase. Although Hageman factor does undergo cleavage and activation in the absence of prekallikrein or high MW kininogen, the rate is approximately 50 and 100 times slower than when these molecules are present. Once Hageman factor is activated on the surface, it cleaves and activates clotting factor XI. Activated Hageman factor (HFa) exhibits two molecular forms. One of these, alpha HFa, activates prekallikrein and factor XI, and the intrinsic clotting system on the surface. alpha HFa and clotting factor XI remain surface bound. The other form of activated Hageman factor, beta HFa, leaves the surface, going into solution where it readily activates additional prekallikrein but not factor XI. Of perhaps even greater importance, kallikrein rapidly dissociates from the surface. Thus the formation of bradykinin and fibrinolysis is disseminated whereas clotting via the intrinsic system remains localized. Reviewed here is the molecular mechanism of contact activation of the Hageman factor pathways and discussed in the interaction of Hageman factor with the negatively charged surface, prekallikrein, factor XI and high MW kininogen. The multiple forms of activated Hageman factor and their potential biologic significance are also discussed.     

Competitive ligand-binding radioassays for serum proteins

This review is concerned with those competitive radioimmunoassays that are utilized for determination of the concentration of human serum proteins. Radioimmunoassays that measure the levels of the immunoglbulins, complement component C3, plasminogen, fibrinogen, hemopexin, haptoglobin, thyroxine-binding globulin, retinol-binding protein, albumin, and histocompatibility antigens are discussed. In these radioimmunoassays, which employ indirect or competitive binding, the amount of unlabeled antigen is directly proportional to the degree of inhibition it exerts on the reaction between antibody and isotope-labeled antigen. To perform the radioassay, one needs an extensively purified antigen, high affinity antibodies, and an effective means of separating the free from the bound antigen. The assays have proven to be sensitive, efficient, and economical. They are invaluable in detecting minute quantities of proteins in serum and other body fluids and are useful in evaluating structural similarities between proteins.     

Relative ventilation and perfusion of left versus right lung in mitral stenosis

We measured relative ventilation, perfusion and ventilation/perfusion ratio of the left versus the right lung using a radioactive xenon method in 15 seated patients with mitral stenosis. The relative ventilation/perfusion ratio of the left lung was significantly less in these patients than in 11 normal subjects and there was a significant negative correlation between the ventilation/perfusion ratio of the left lung and pulmonary intravascular pressure. There was little difference between relative perfusion of the two lungs, and the reduced ventilation/perfusion ratio of the left lung seems to be mainly due to relative hypoventilation, perhaps the result of compression or distortion of the left main stem bronchus. None of the patients had more than a slight reduction in the ventilation/perfusion ratio of the left lung, and it is not likely that between lungs differences in regional function significantly affect the efficiency of gas exchange.We found no significant correlation between the relative ventilation/ perfusion ratio of the left lung and pulmonary intravascular pressure in 10 patients with mitral stenosis studied in the supine position.     

Gout with purine overproduction due to increased phosphoribosylpyrophosphate synthetase activity

Two brothers with marked purine overproduction and clinical gout showed activity of the enzyme phosphoribosylpyrophosphate (PP-ribose-P) synthetase in erythrocyte lysates 2.5 to 3.0-fold greater than that found in normal subjects or in other patients with gout. Associated with the increased activity of this enzyme, which catalyzes the synthesis of the regulatory substrate PP-ribose-P from adenosine triphosphate (ATP) and ribose-5-phosphate, was an increased intracellular PP-ribose-P concentration and an increased ability of intact erythrocytes to generate PP-ribose-P. In fibroblasts cultured from one of the affected brothers, these findings were confirmed, and an increased rate of the de novo purine biosynthetic pathway was demonstrated both in fibroblasts and in the affected brothers in vivo. The association of altered PP-ribose-P synthetase activity with increased intracellular PP-ribose-P generation and increased purine synthesis suggested that the proximal cause of the patients' gout was the increased enzyme activity.Hemolysates from a daughter of one of the affected brothers contained increased enzyme activity suggesting dominant hereditary transmission of the abnormality.The increased enzyme activity appeared to reside in the enzyme protein, although no evidence for a structural alteration in the patients' enzyme has thus far been found. Increased PP-ribose-P synthetase activity was apparent over a wide range of inorganic phosphate concentrations distinguishing the present abnormality from one previously described.Increased PP-ribose-P synthetase activity represents another hereditary enzyme aberration resulting in purine overproduction and clinical gout and demonstrates that human disease states can result from overabundance of enzyme activity as well as from deficiency.     

Diuretic potency of combined hydrochlorothiazide and furosemide therapy in patients with azotemia

The effect of combined hydrochlorothiazide and furosemide therapy was studied in eight hypertensive patients with renal insufficiency who had a poor response to either furosemide or hydrochlorothiazide alone. The study was divided into two parts. In part A, five patients who had an inadequate response to furosemide in doses of 160 to 240 mg/day followed a strict protocol in order to compare the effect of increased doses of furosemide with combined hydrochlorothiazide-furosemide administration. All had azotemia, presumably from nephrosclerosis, and had serum creatinine concentrations ranging from 2.3 to 4.9 mg/dl. Four of the five patients had inadequate arterial pressure control, and the remaining patient had fluid retention from the administration of minoxidil. In all five patients, plasma volume was either increased or normal, despite long-term treatment with furosemide. Increasing the dose of furosemide to between 320 and 480 mg/day had only a modest additional diuretic effect, and plasma volume and arterial pressure were not significantly changed. Adding hydrochlorothiazide, 25 to 50 mg twice a day, produced a marked diuresis, and a significant reduction in weight, plasma volume and mean arterial pressure (p < 0.025 for all three patients). In part B, combined hydrochlorothiazide-furosemide therapy was used to treat three additional patients who had an inadequate response to either diuretic alone. The results indicate that combined hydrochlorothiazide-furosemide is a potent diuretic regimen and is effective in many patients with chronic renal failure who have a poor response to furosemide alone.     

Campylobacter enteritis associated with unpasteurized milk

Campylobacter fetus ss. jejuni has recently been recognized as a human enteric pathogen. Laboratory isolation has been hindered by its fastidious nature. Methods for recovery of this organism from stool culture and a specific serologic test are described. An outbreak is reported in which three members of the same family became simultaneously ill with fever, severe abdominal cramps and diarrhea. C. fetus ss. jejuni was recovered from stool specimens from all three. A fourfold increase in serum immunoglobulin G (IgG) titer to this organism was demonstrated in each patient. All three patients had been consuming unpasteurized milk from a cow whose feces were infected with C. fetus ss. jejuni.     

Activation of Hageman factor in the nephrotic syndrome

The patient described had the nephrotic syndrome associated with decreased levels of plasma coagulation factors XI (35 per cent) and XII (15 per cent). The patient also had a decrease in concentration of prekallikrein and kallikrein inhibitor, suggesting that the kallikrein system was activated. Addition of purified factor XII did not correct this defect. The fibrinolytic system was activated as indicated by an increase in fibrinogen split products. Thus, it seems that three Hageman-dependent proteolytic pathways (coagulation, fibrinolysis and kallikrein) were activated in this patient with the nephrotic syndrome.Another possible cause of decreased factors XI and XII is urinary loss of these proteins. The urine did contain apparent activities of factors XI and XII. The finding of factor VIII in the urine in higher concentrations than XI or XII, however, as well as the inability to adsorb the activity with Celite®, suggested that the activity was due to a nonspecific urinary procoagulant. This hypothesis was confirmed by removal of the activity via adsorbtion of the urine with barium citrate.     

Mechanism of spontaneous supine blood pressure variations in chronic autonomic insufficiency

Of 20 patients with idiopathic orthostatic hypotension (IOH), four manifested marked spontaneous fluctuations in arterial pressure when in the supine position (supine blood pressure). Blood pressure (intra-arterial recording) varied from 20 to 80 per cent between hemodynamic studies. The only significant difference between the lowest and highest pressure was in total peripheral resistance, which was 32 and 49 U · m² respectively (P < 0.01). In these patients, changes in blood pressure did not correlate with changes in blood volume, plasma renin activity, urinary sodium excretion or the aldosterone excretion rate. It is concluded that spontaneous changes in total peripheral resistance account for the marked variations in supine blood pressure in some patients with idiopathic orthostatic hypotension. The spontaneous vasoconstriction in the supine position is contrasted to the lack of vasoconstriction with upright tilt or standing in the same patients. The possible mechanism and clinical implications of the spontaneous alterations in total peripheral resistance in some patients with idiopathic orthostatic hypotension are briefly discussed.     

Blood in the lymph (hemochylia) and intestinal lymphangiectasia associated with Lutembacher's syndrome

A 31 year old man presenting with Lutembacher's syndrome and protein-losing enteropathy is described. Reversal of the protein-losing enteropathy 7 months after cardiac surgery suggested that it was secondary to the cardiac disorder. Spontaneous rupture of a congenital aneurysm of the splenic artery created a spleno-portal arteriovenous fistula which caused a massive sequestration of blood into the dilated abdominal lymphatic system, severe hypovolemic shock and death.The pathogenesis and relation of two rare disorders of the lymphatic system, contamination of the lymph with blood (hemochylia) and intestinal lymphangiectasia are discussed.     

Hypertension associated with early stage kidney disease: Complementary roles of circulating renin,the body sodium/volume state and duration of hypertension

Interrelations among blood pressure, exchangeable sodium, blood volume and plasma renin activity were studied in 40 normal subjects and in 40 patients with early stage kidney disease (mean plasma creatinine, 2 mg/100 ml). Findings in eight normotensive patients did not differ significantly from those in normal subjects. However, 32 hypertensive patients showed increases (p < 0.05) in mean exchangeable sodium and in the products of the logarithm of plasma renin activity and exchangeable sodium or blood volume. In normal subjects, blood pressure did not correlate with any of the parameters measured. In the patients, it correlated significantly (p < 0.05) with duration of hypertension (r = 0.70), exchangeable sodium (r = 0.34) and with sodium-renin (r = 0.38) or volume-renin (r = 0.30) products, but not with blood volume or circulating renin individually. Multiple regression analysis with blood pressure as a dependent variable, and duration of hypertension and the sodium-renin or volume-renin products as independent variables, revealed correlation coefficients of 0.77 and 0.76, respectively. These findings suggest that hypertension accompanying early stage kidney disease may depend at least partly on subtle abnormalities in the sodium/ volume-renin feedback mechanism as well as on a factor related to the duration of preexisting hypertension.     

Lead poisoning from a gunshot wound. Report of a case and review of the literature.

A man was hospitalized on three occasions for symptoms of lead intoxication 20 to 25 years after a gunshot wound that resulted in retention of a lead bullet in his hip joint. The potential for lead toxicity as a complication of a lead missile injury appears to be related to (1) the surface area of lead exposed for dissolution, (2) the location of the lead projectile, and (3) the length of time during which body tissues are exposed to absorbable lead. Cases of lead poisoning of immediate onset resulting from lead shot have been reported in Europe, but all documented cases of ammunition-related plumbism reported in the United States have involved synovial fluid dissolution of a single lead bullet over many years. The solvent characteristics of synovial fluid and associated local arthritis are apparently important factors in the dissolution and absorption of lead from projectiles located in joints. Awareness that lead intoxication can be a complication of retained lead projectiles should allow rapid institution of appropriate diagnostic and therapeutic modalities when such a clinical situation arises.