Hyperuricosuria and increased tubular secretion of urate in sickle cell anemia

Seven young adults with uric acid overproduction due to sickle cell anemia were normouricemic with a mean serum uric acid level of 4.9 mg/100 ml. Urate clearance was greater in these patients than in normal subjects or in patients with primary hyper-uricemia due to uric acid overproduction. The increase in urate clearance was entirely accounted for by increased pyrazinamide suppressible urate clearance. Pyrarinamide administration abolished the uricosuric response to ribonucleic acid (RNA) feeding in these patients with sickle cell anemia, and maximal uricosuric response to the administration of probenecid was similar in the patients with sickle cell anemia and in normal subjects suggesting that reabsorption of both filtered and secreted urate was not impaired in sickle cell disease. Pyrazlnamide suppressible urate clearance at maximal uricosuric response to probenecid was increased in patients with sickle cell disease suggesting increased tubular secretion of urate. This increase in urate secretion permits most young adults with urate overproduction due to sickle cell anemia to remain normouricemic and may account for the low frequency of secondary gout in this disease.     

Hyperimmunoglobulinemia associated with narcotic addiction. Effects of methadone maintenance treatment

Increased serum immunoglobulins were common in narcotic addicts. Immunoglobulin M (IgM) levels were high in 75 per cent of 46 adult addicts and in 65 per cent of 63 adolescent addicts seeking methadone maintenance or detoxification. Isolated hypermacroglobulinemia was found in 56 per cent. During methadone maintenance or abstinence high IgM levels were much less frequent. History of overt hepatitis, manifest liver disease, serum glutamic oxaloacetic transaminase (SGOT) or alkaline phosphatase levels did not correlate with the presence of high serum IgM levels. Serum immunoglobulin G (IgG) was more variably and less frequently increased than IgM in the untreated addicts, but was commonly increased in the patients maintained on methadone. Prospective studies of 21 patients starting methadone maintenance showed a decrease in mean serum IgM during treatment. The incidence of normal IgM levels in these patients rose to 48 per cent after one year compared to 24 per cent before treatment. The pattern of immunoglobulin changes in narcotic addiction is significantly altered during methadone maintenance treatment, perhaps as a result in the reduction of drug abuse.     

Impaired IgM antibody responses to an influenza virus vaccine in adults with sickle cell anemia

Type-specific IgM and IgG antibody responses to a polyvalent influenza vaccine were evaluated in 16 adults with sickle cell anemia, with the use of an enzyme-linked immunosorbent assay. When compared to healthy controls, 8 out of the 16 patients had decreased or undetectable postvaccination anti-influenza IgM antibody levels. These patients were found to have significantly lower serum IgM levels and nondetectable splenic tissue (by 99Tc scans), as compared to those with normal IgM responses. Impaired IgM antibody primary immune responses may play a role in the pathogenesis of infectious complications seen in adult patients with sickle cell anemia.     

Sickel cell anemia, the nephrotic syndrome and hypoplastic crisis in a sibship

A family is presented with five siblings, three with sickle cell anemia and two with thalassemia trait. In all three children with sickle cell anemia hypoplastic crises developed after a viral infection. Two of these children were found to have the nephrotic syndrome, as did one of their siblings with thalassemia trait.Renal biopsy in the female patient with sickle cell anemia and the nephrotic syndrome revealed focal and segmental glomerulosclerosis. The biopsies of the other two patients (one with sickle cell anemia and one with thalassemia trait) revealed minimal changes. Hemosiderosis was present only in the biopsy specimens of the two patients with sickle cell anemia. All three patients were steroidresistant. Neither the other two siblings (one with sickle cell anemia and hypoplastic crisis) nor the parents have the nephrotic syndrome.The pathogenesis of nephrotic syndrome in patients with sickle cell anemia is discussed in detail. The current hypotheses relating renal disease to the sickling process are considered. The nephrotic syndrome observed in our patients appears to be familial and unrelated to sickle cell anemia, having been found in family members without, as well as with, sickle cell anemia. The findings in this family suggest that the nephrotic syndrome found in sickle cell anemia may not be causally related, but may be fortuitous, at least in some patients.     

Cellular immune findings in Lyme disease. Correlation with serum IgM and disease activity

Cellular immune findings were studied in 48 patients with various stages of Lyme disease. At each stage, some patients, particularly those with neuritis or carditis, had elevated serum IgM levels and lymphopenia. During early disease, mononuclear cells tended to respond normally to phytohemagglutinin, and spontaneous suppressor cell activity was greater than normal. Later, during active neuritis, carditis, or arthritis, the trend was toward heightened phytohemagglutinin responsiveness and less suppression than normal. By multiple regression analysis, serum IgM levels correlated directly with disease activity (p = 0.025) and inversely with the number of T cells (p = 0.02); during acute disease only, elevated IgM levels correlated with increased phytohemagglutinin responsiveness (p = 0.004) and decreased suppressor cell activity (p = 0.03). Decreased suppression, observed later in the disease, may permit damage to host tissues because of either autoimmune phenomena or a heightened response to the Lyme spirochete.     

Serum opsonization of salmonella in sickle cell anemia.

Systemic salmonellosis occurs with increased frequency in sickle cell anemia. This predisposition to Salmonella infections is poorly understood. Since serum opsonizing activity is an important host defense mechanism, we studied the ability of serum from patients with sickle cell anemia and control subjects to promote phagocytosis and killing of Salmonella typhimurium by normal leukocytes. Heat-labile factors were required for opsonization of S. typhimurium by serum from control subjects, and this opsonizing capacity was deficient in 12 of 28 serums from patients with sickle cell anemia. In an effort to account for this decreased phagocytosis-promoting activity, we evaluated those serum factors known to serve as specific opsonins. Serum immunoglobulin and specific antibody levels were similar in the patients with sickle cell anemia and in the control subjects. In contrast, several complement system abnormalities were documented in patients with sickle cell disease. These abnormal findings included (1) defective alternative complement pathway function, (2) low levels of the third component of complement (C3) and (3) slightly reduced concentrations of the fourth component of complement (C4). Of these complement system abnormalities, only decreased function of the alternative pathway was significantly associated with deficient serum opsonizing activity (P < 0.01). The complement defects and associated opsonic deficiency may be manifestations of profound macrophage (reticuloendothelial system) dysfunction in sickle cell anemia. This reduction in complement-mediated serum opsonizing activity for Salmonella, in association with other consequences of abnormal reticuloendothelial system function, may predispose to salmonellosis in sickle cell anemia.     

Hepatobiliary diseases associated with serum antimitochondrial antibody (AMA)

In an attempt to define the clinical spectrum of hepatobiliary disease associated with antimitochondrial antibody (AMA), 41 female and four male patients with AMA were investigated. On the basis of clinical criteria, 22 patients had primary biliary cirrhosis (group I), seven had extrahepatic biliary obstruction (group II) and 16 had other liver diseases including chronic active hepatitis, cryptogenic cirrhosis and minor abnormalities of liver function (group III). Elevations of serum cholesterol, alkaline phosphatase and bile acid levels separated the patients with primary biliary cirrhosis from those with miscellaneous liver disease, whereas in those with extrahepatic biliary obstruction results were intermediate. The cholestatic syndrome of primary biliary cirrhosis was further defined by a cholic to chenodoxycholic acid ratio > 1.0 which was found in 75 per cent of the patients with primary biliary cirrhosis but in none of those with miscellaneous liver disease. No significant differences in AMA titers or immunoglobulin M (IgM) levels were found between the groups, indicating that these tests are not correlated with cholestatic liver disease. Examination of liver tissue revealed features which were compatible with the clinical impression in the majority of cases. Cholelithiasis was present in 33 per cent of the patients. Common bile duct obstruction due to stones and/or stricture was found in six cases and carcinoma in one. Since four had fully developed cirrhosis at the time of presentation, extrahepatic biliary obstruction was probably a result of gallstone disease complicating AMA positive parenchymal liver disease. AMA seems to be a marker for idiopathic parenchymal liver disease, primarily in middle-aged women, but in itself gives no. further diagnostic information and does not exclude extrahepatic biliary obstruction.     

H chain fragment and monoclonal IgA in a lymphoproliferative disorder

A patient with an indurated ulcerating lesion over the left parotid gland and left ear, and massive splehomegaly, was found to have two distinct serum immunoglobulin abnormalities. One was monoclonal immunoglobulin A (IgA) in monomeric and polymeric forms; the other was a protein fragment, immunologically related to immunoglobulin M (IgM) and devoid of light (L) chain activity. Upon Sephadex® gel filtration this fragment appeared to have a molecular weight lower than that of previously described “low molecular weight” IgM. It was concluded that of the two distinct immunoglobulin abnormalities, one was the production of an Hμ chain fragment.     

Immunospecific immunoglobulins and IL-10 as markers for Trypanosoma brucei rhodesiense late stage disease in experimentally infected vervet monkeys

Objective  To determine the usefulness of IL-10 and immunoglobulin M (IgM) as biomarkers for staging HAT in vervet monkeys, a useful pathogenesis model for humans.
Methods  Vervet monkeys were infected with Trypanosoma brucei rhodesiense and subsequently given sub-curative and curative treatment 28 and 140 days post-infection (dpi) respectively. Matched serum and CSF samples were obtained at regular intervals and immunospecific IgM, immunoglobulin G (IgG) and IL-10 were quantified by ELISA.
Results  There was no detectable immunospecific IgM and IgG in the CSF before 49 dpi. CSF IgM and IgG and serum IgM were significantly elevated with peak levels coinciding with meningoencephalitis 98 dpi. The serum IL-10 was upregulated in both early and late disease stage, coinciding with primary and relapse parasitaemia respectively. CSF white cell counts (CSF WCC) were elevated progressively till curative treatment was given. After curative treatment, there was rapid and significant drop in serum IgM and IL-10 concentration as well as CSF WCC. However, the CSF IgM and IgG remained detectable to the end of the study.
Conclusions  Serum and CSF concentrations of immunospecific IgM and CSF IgG changes followed a pattern that mimics the progression of the disease and may present reliable and useful biomarkers of the disease stage. Due to rapid decline, serum IgM and IL-10 are, additionally, potential biomarkers of the success of chemotherapy.     

Liver function and the diagnostic significance of conjugated cholic acid and chenodeoxycholic acid in serum of African patients with sickle cell disease

Concentrations of two primary bile acids (cholic acid and chenodeoxycholic acid) were determined by radioimmunoassay in the serum of 15 African homozygous sickle cell patients, ages ranging from 4 to 22 years. The mean serum levels of the two primary bile acids studied were significantly elevated when compared with the normal mean values. About 67% of the patients had pathological elevation of both primary bile acids, thereby indicating some hepatobiliary damage. Serum conjugated cholic acid correlated significantly with serum chenodeoxycholic acid in the sickle cell disease (r = 0.91, p less than 0.001). The results suggest that radioimmunoassays of serum conjugated cholic acid and chenodeoxycholic acid in sickle cell disease may also serve as useful biochemical assays in predicting liver dysfunction in sickle cell disease.     

Waldenström's macroglobulinemia in a patient with a chronic biologic false-positive serologic test for syphilis

Acute and chronic biologic false-positive serologie reactions for syphilis (VDRL) have been associated with a variety of diseases. Several investigators emphasize that false-positive VDRL titers are usually very low. This report describes a 73 year old man with Waldenström's macroglobulinemia. The biologic false-positive serologic test for syphilis was recognized 33 years before the diagnosis of Waldenström's macroglobulinemia was made. VDRL titers were as high as 1:8192 and 1:32,000 during exacerbations of the macroglobulinemia. A biologic false-positive serologic test for syphilis is frequently associated with an elevated immunoglobulin M (IgM) level. It would be interesting to search for a relation between biologic false-positive serologic tests for syphilis and diseases characterized by monoclonal gammopathies.     

Circulating thymic hormone activity in patients with primary and secondary immunodeficiency diseases

Levels of circulating thymic hormone, facteur thymique serique (FTS), were quantitated in the serum of normal subjects ranging in age from three days to 85 years and in a wide variety of patients with primary and secondary immunodeficiency diseases. FTS levels were low in the serum of a high proportion of patients with common variable immunodeficiency and selective absence or deficiency of IgA. Patients with DiGeorge syndrome always had low levels. In infants with severe combined immunodeficiency (SCID) FTS levels were low in 21 of 23 instances and normal in only two. In patients classified as having primary T-cell deficiency FTS levels were regularly lower than normal as in those with osteopetrosis and ataxia telangiectasia. In patients with Wiskott-Aldrich syndrome and chronic mucocutaneous candidiasis FTS levels were frequently lower than normal. In patients with systemic lupus erythematosus (SLE) FTS levels were below the normal range in the majority of instances, whereas FTS levels within the normal range were characteristic of patients with the X-linked infantile form of agammaglobulinemia (Bruton's disease) and patients with progeria. Serums from seven patients were shown to inhibit FTS activity. Of these, serum from six patients with common variable immunodeficiency was studied for its capacity to inhibit synthetic FTS and FTS activity in normal serum. In two of these, FTS activity was inhibited in normal serum, and in five synthetic FTS activity was inhibited. Another patient with immunodeficiency, who had increased IgM levels and neutropenia, also had a serum inhibitor that was active against FTS. Search for an inhibitor of FTS in the serum of individual patients with SCID, chronic mucocutaneous candidiasis and a thymectomized infant revealed no such inhibition. Twenty-seven patients with common variable immunodeficiency were studied for both FTS activity and lymphocytic proliferative responses to phytomitogens and antigens. In 10 of these patients, FTS levels were low and in three of these 10 the responses to both mitogens and antigens were deficient; in four, responses were normal for both, and in three, the responses to antigen were low but the responses to mitogen were normal. In four of 27 patients with low FTS titers, however, an inhibitor against FTS activity was present in their serum, but their proliferative response to mitogens was normal and in two responses to antigens were reduced as well. This finding may explain the frequent dissociation of FTS activity and lymphocyte functions.     

Scintigraphic quantitation of splenic function in SLE: correlation with IgM levels in serum

The relationship between quantitative splenic uptake of sulfur colloid and immunoglobulin M level in serum was studied in 15 patients with systemic lupus erythematosus (SLE). Splenic function correlated positively with IgM level (r = 0.58, p = 0.02) and inversely with antibody titre to n-DNA (r = -0.74, p = 0.003), and was reduced (p greater than 0.001) in patients with depressed IgM levels. IgM level in serum may be a useful correlate of splenic phagocytic function in SLE patients.     

Echocardiographic findings in patients with sickle cell disease

Pulmonary hypertension is a complication of sickle cell disease that is associated with increased mortality. Whether this complication is associated with hemolysis has been questioned. Systolic pulmonary artery blood pressure can be estimated from echocardiography-determined tricuspid regurgitation velocity (TRV). A velocity of 2.5 m/s or higher suggests possible pulmonary hypertension. A retrospective review of hospital records from adult patients with sickle cell disease undergoing echocardiography in 2006 and 2007 was performed at a tertiary level hospital. Echocardiographic, demographic, and clinical laboratory data were collected. Echocardiographic results were available for 105 adult sickle cell patients. Of these, 62 (59%) had a TRV ≥2.5 m/s and 24 (22.8%) had a TRV ≥3.0 m/s. Mitral valve regurgitation was observed in 44% and left ventricular abnormalities (defined by either hypertrophy or dilation) in 28% of cases. Elevated TRV had independent and significant associations with greater age, higher serum lactate dehydrogenase (LDH) concentration, and lower hemoglobin concentration. We confirmed that elevated TRV is common among hospital-based adults with sickle cell disease. Significant, independent associations were found with both elevated LDH concentration and degree of anemia, suggesting that hemolytic and other mechanisms contribute to pulmonary hypertension in patients with sickle cell disease.     

A case of hemoglobin SC disease with cold agglutinin-induced hemolysis

Children with sickle cell disease commonly require red blood cell (RBC) transfusion. We report the first case of hemoglobin (Hb) SC disease with development of severe anemia induced by cold agglutinin hemolysis after Mycoplasma infection. Complete blood count (CBC) showed falsely decreased RBC count and hematocrit and falsely elevated MCV and MCHC. Peripheral blood smear showed RBC clumping at room temperature; this disappeared after warming to 37 degrees C. Anti C3b-C3d was present on red cells, and indirect antiglobulin test revealed a circulating cold agglutinin. Furthermore, anti-Mycoplasma pneumoniae IgM antibody was detected in serum. Careful evaluation of CBCs and peripheral blood smears is required in cases of worsening anemia among sickle cell patients and consideration should be given to cold hemagglutinin disease as an etiology.     

Immunoglobulin and autoantibody response in acute and chronic liver disease

Serum immunoglobulin and nonorgan-specific autoimmune responses (autoantibody response) were studied in 269 patients with a variety of acute and chronic liver disease. A majority of patients with hepatitis B antigen (HB Ag)-positive and HB Agnegative acute viral hepatitis showed a mild elevation in total globulin, gamma globulin, immunoglobulin G (IgG) levels and a moderate elevation in immunoglobulin M (IgM) levels during the first 2 weeks of illness; these levels began to subside by the 8th week of illness and were completely normal by the 12th week, concomitant with the return of normal transaminase values. Serum complement (C₃) levels were low in 20 per cent of the patients with acute viral hepatitis, during the first 2 weeks of illness and returned to normal thereafter. Of the 80 patients with acute viral hepatitis, 42.5 per cent had smooth muscle antibody (SMA), 20.5 per cent had mitochondrial antibody (MA), 10 per cent had rheumatoid factor (RA), and none had antinuclear antibody (ANA); these nonorgan-specific autoimmune markers were only transiently present (mean, 2 weeks) and became undetectable as the patient's condition improved. There was no difference in these immunologic responses between patients with HB Ag-positive and HB Ag-negative acute viral hepatitis. High levels of gamma globulin and IgG were seen in chronic active liver disease, either of viral or alcoholic etiology. Serum immunoglobulin A (IgA) levels were elevated only in those with alcoholic liver disease, whereas IgM levels were high in those with liver disease associated with an active hepatocellular damage either of alcoholic or viral etiology. HB Ag-positive blood donors with asymptomatic mild liver disease had normal immunochemistry values.     

Splenic function in children with sickle cell disease: two different patterns in Saudi Arabia

Splenic function in 35 Saudi children homozygous for sickle cell disease (age range 3-9 years) was studied using radioactive colloid scans. Two different patterns emerged. Splenic dysfunction was demonstrated in more than 80% of children who were originally from the south-western part of the country. They were found to have low HbF levels. In contrast normal or nearly normal splenic function was found in all patients from the Eastern Province in whom HbF levels were high. These different patterns of splenic function may contribute to the severe and mild forms of sickle cell disease seen in Saudi Arabia.     

Transient functional asplenism in sickle cell-C disease

During a painful crisis, the spleen of a patient with sickle cell-C disease failed to visualize with 99^m Tc-sulfur colloid although it was significantly enlarged by palpation. At that time, the peripheral blood smear showed numerous sickle cells, normoblasts and erythrocytes containing Howell-Jolly bodies. After therapy with hypotonic saline solution and with clinical improvement, the enlarged spleen was completely visualized on repeat scanning. The normoblasts and erythrocytes containing Howell-Jolly bodies also decreased in number. This case of transient asplenism is similar to the cases previously reported only in children with homozygous sickle cell disease. The significance of this phenomenon with respect to increased susceptibility to infection is discussed.     

Nephropathy associated with sickle cell anemia: an autologous immune complex nephritis. I. Studies on nature of glomerular-bound antibody and antigen identification in a patient with sickle cell disease and immune deposit glomerulonephritis.

The nature of the glomerular-bound antibody and the putative antigen was investigated in one of the patients with sickle cell disease and immune deposit membranoproliferative glomerulonephritis by immunohistologic and glomerular antibody elution. Renal proximal tubular epithelial antigen was localized in association with immunoglobulins G (IgG), M (IgM), Clq fraction of the first component of complement (Clq) and the third component of complement (C3) in a granular pattern along the glomerular basement membrane of the patient's kidney. IgG and IgM were eluted from glomeruli. These immunoglobulins fixed to the proximal tubules of normal human kidney by direct immunofluorescence. This localization was abolished by absorption of the eluted immunoglobulins with renal tubular epithelial (RTE) antigen. The IgG eluted from the glomeruli blocked the fixation of rabbit anti-RTE antigen to normal proximal tubular brush border. These studies suggest that the nephritis in this patient was due to deposition of complexes or RTE antigen and specific antibody. An autologous immune complex nephritis may develop in some patients with sickle cell anemia secondary to RTE antigen released possibly after renal ischemia or some other phenomenon causing renal tubular damage.     

Cell-surface immunoglobulins in chronic lymphocytic leukemia and allied disorders

Immunoglobulin on the surface of peripheral blood lymphocytes from 57 patients with chronic lymphocytic leukemia (CLL) and allied disorders was investigated by fluorescence microscopy and correlated with circulating immunoglobulin. In 38 of 48 patients with CLL, the predominant surface immunoglobulin identified on peripheral blood lymphocytes was M (IgM) of either kappa or lambda light chain type. In five patients, the predominant surface protein was immunoglobulin G (IgG) of either kappa or lambda type. In three others, the lymphocyte surface immunoglobulin could not be definitely identified and in two, no surface immunoglobulin was detected. Circulating immunoglobulin levels, particularly IgM, were depressed in the majority of patients with CLL. In three subjects with IgM-bearing lymphocytes, the serum contained a circulating IgM M component and three of the five subjects with IgG-bearing cells, had a circulating IgG M component. In three patients with CLL, immunoglobulin disappeared from the cell surface with progression of the disorder, although neoplastic cells remained in the circulation. The amount of immunoglobulin on the surface of cells from patients with chronic lymphosarcoma cell leukemia was much greater than that on cells from patients with CLL, and the surface immunoglobulin pattern in hairy cell leukemia also appeared distinctive. Study of immunoglobulin on the surface of lymphocytes has helped to define the cellular origin and monoclonal nature of CLL, the source of circulating M components in this disease, and the relationship of CLL to other lymphoproliferative disorders. Although technically demanding, the study of surface immunoglobulin should prove useful in clinical medicine.