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Biomedical subjects

I Sternlieb

Publications and source records attributed to I Sternlieb.

At least 37 records · Page 2Linked to original sources
PubMed1992

Fraternal concordance of types of abnormal hepatocellular mitochondria in Wilson's disease.

Three distinct patterns of structural abnormalities of mitochondria, indicated as types I, II and III and associated with steatosis, were identified in the hepatocytes of 40 of 42 asymptomatic and 8 of 22 symptomatic patients with documented Wilson's disease before treatment. No correlation was seen between the type of mitochondrial abnormality and the patient's age, hepatic copper concentration, degree of hepatic steatosis or serum aminotransferase level. However, comparison of the types of abnormal hepatocellular mitochondria displayed by five pairs and one trio of asymptomatic siblings revealed remarkably similar types of abnormalities in each family. The variety of mitochondrial types encountered in different families and the high degree of type identity in sibling relationships indicate that the structural changes are genetically determined.

Adolescent↗
PubMed1991

Prognosis of Wilsonian chronic active hepatitis.

Twenty of 320 patients with Wilson's disease initially presented with chemical and laboratory features of chronic active hepatitis, confirmed histologically in 17. When first seen, cirrhosis was present in all 20 and was complicated by ascites and/or jaundice in 11. Within 1 week to 8 years of the onset of over liver disease the diagnosis of Wilson's disease was established, and treatment with D-penicillamine was promptly initiated in 19 patients. One man refused treatment and died 4 months later. Treated patients received D-penicillamine or trientine for a total of 264 patient-years (median, 14 patient-years). Abnormal water retention, for which salt restriction and diuretics were added to penicillamine or trientine, disappeared in all but 1 of the patients so affected. Symptomatic improvement and virtually normal levels of serum albumin, bilirubin, aspartate aminotransferase, and alanine aminotransferase followed within 1 year in the majority of subjects. One woman died after 9 months of treatment. Two patients, who became noncompliant with the therapeutic regimen after 9 and 17 years of successful pharmacological treatment, required liver transplants. These results indicate that the prognosis of specifically treated Wilsonian chronic active hepatitis is very good in spite of the presence of cirrhosis.

Adolescent↗
PubMed1991

Copper metallothionein in patients with hepatic copper overload.

We studied the Cu-MT present in the hepatic cytosol obtained from 7 patients suffering from conditions associated with hepatic Cu overload (Wilson's disease, biliary atresia, familial cholestatic cirrhosis). Since chromatographic methods appropriate for the isolation of Zn- and Cd-MT were unsuitable for Cu-MT, we developed an indirect procedure for the estimation and resolution of the latter. This procedure involved the preparation of apo-MT and its reconstitution to holo-MT with Zn or Cd. Three predominant isoforms of MT were present in all specimens. Our results indicate that at most 36 +/- 5% of the Cu present in the 10 kDa fraction of cytosol is bound to MT in the liver of patients with hepatic copper overload.

Adolescent↗
PubMed1991

Predictive testing for Wilson's disease using tightly linked and flanking DNA markers.

We studied DNA polymorphisms for five new chromosome 13 markers in 52 Wilson's disease (WD) families from Europe, North America, and the Middle East. There was significant evidence for linkage between the Wilson's disease locus (WND) and all the marker loci. Multilocus linkage analysis, using a genetic linkage map established from reference pedigrees, suggested that WND is most likely between D13S31 and D13S59, at distances of 0.4 and 1.2 centimorgans, respectively. Our results suggest that the chromosomal location of the Wilson's disease gene is the same in all families from the populations studied. This evidence and the availability of many close, flanking, and polymorphic DNA markers make possible accurate and informative testing of potential carriers and WD homozygotes in families with at least one previously affected child. An advantage of a genetic linkage test over other laboratory methods for prediction of genotype in WD is that a reliable diagnosis can be made at a much earlier stage in life, including prenatally. In addition, DNA testing can be used in place of an invasive liver biopsy procedure to confirm a diagnosis in patients with borderline serum ceruloplasmin levels. Presymptomatic identification will also allow therapeutic intervention to prevent symptoms before irreparable liver or neurologic damage occurs. We describe the implementation of prenatal and preclinical diagnosis for two families with WD.

Chromosome Mapping↗
PubMed1991

Light- and electron-microscopical study of a case of gold salt-induced hepatotoxicity.

A 56-yr-old woman with long-standing rheumatoid arthritis exhibited jaundice, pruritus and abdominal discomfort after 8 yr of periodic gold sodium thiomalate injections amounting to a cumulative dose in excess of 2.5 gm. Histopathological examination of the liver biopsy specimen showed submassive loss of parenchyma, collapse of reticulin and mixed cellular inflammatory infiltrates. Macrophages contained dark granules, which displayed the characteristics of aurosomes when examined by transmission electron microscopy and electron microprobe analysis. It is likely that hepatocellular injury occurred when the lysosomal storage capacity for gold was exceeded.

Arthritis, Rheumatoid↗
PubMed1990

Detection of multiple forms of human ceruloplasmin. A novel Mr 200,000 form.

Three polypeptides with apparent Mr = 200,000, 135,000, and 115,000, reacting with antibody to human ceruloplasmin (Cp), were consistently found in sera of normal adult and newborn subjects, patients with Wilson's disease, as well as in the oxidase-active fraction of purified human Cp, resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The concentrations of the three Cp polypeptides were proportional to the total Cp oxidase activity measured in whole serum. Peptide mapping revealed that the three Cp polypeptides were closely related. Cross-linking of Cp135 resulted in dimers with electrophoretic mobility similar to that of Cp200. A common shift in electrophoretic mobility following N-glycanase treatment indicated that all three polypeptides were N-glycosylated, and that the apparent differences in molecular mass could not be related to the carbohydrate moiety. Immunoprecipitates of cell lysates of [35S]cysteine labeled HepG2 cells revealed the presence of two species of newly synthesized Cp polypeptides, Mr 200,000 and 135,000, which were secreted into the media. Secretion of Cp200 by the human liver appears to be physiologic and may be the result of posttranslational modification of Cp135.

Carcinoma, Hepatocellular↗
PubMed1990

The cytopathology of metal overload.

Researchers have been able to demonstrate the cytotoxicity of copper overload in animal models. This has allowed them to not only localize the intracellular distribution of copper but also to study directly the subsequent organelle injury at the ultrastructural level. The lesions seen in copper overload appear to vary from species to species. In humans, marked mitochondrial abnormalities are seen in Wilson's disease while diet overloaded rats show nuclear destruction and various membranous abnormalities. Sequestration of copper within lysosomes appears to protect hepatocytes from its toxicity. However, the mechanism by which the metal is incorporated into lysosomes is not known.

Animals↗
PubMed1989

Hepatic peroxisomal abnormalities in abetalipoproteinemia.

Spinocerebellar degeneration in a 17-yr-old boy with abetalipoproteinemia was associated with vitamin E deficiency and hepatic steatosis. In liver biopsy samples before and after 15 mo of vitamin E treatment, hepatocellular peroxisomes were morphologically abnormal; pleomorphic, with a broadened range of sizes; often larger than normal; and with marginal bars in some. In the first sample, peroxisomes exhibited matrical heterogeneity and dense nucleoids. Peroxisomes in the second biopsy sample lacked nucleoids and contained more homogeneous matrices. The mean peroxisomal diameter increased from 0.77 +/- 0.33 to 0.86 +/- 0.32 microM (normal, 0.62 +/- 0.14). These observations raise the possibility that peroxisomes may be involved in the metabolism of apolipoprotein B or may be affected by the disturbances of hepatocellular lipid metabolism caused by this disease.

Abetalipoproteinemia↗
PubMed1989

Hepatocellular copper toxicity and its attenuation by zinc.

We studied the mechanisms by which excess copper exerts, and zinc mitigates, toxic effects on HepG2 cells. Survival and cell growth were reduced in media containing greater than 500 microM copper chloride for 48 h; LD50 was 750 microM. At 1,000 microM copper for 1 h, there was a general reduction of protein synthesis, and no recognizable changes in cellular ultrastructure. Incubation of cells with 200 microM zinc acetate before exposure to copper, raised the LD50 for confluent cells to 1,250 microM copper chloride, improved protein synthesis, and increased synthesis of a 10-kD protein, apparently metallothionein. The mitigation, by zinc, of copper's toxicity may in part be mediated through induction of this protein in the hepatocyte.

Adenosine Triphosphate↗
PubMed1988

Morphologic and chemical studies on a murine mutation (toxic milk mice) resulting in hepatic copper toxicosis.

The accumulation of excessive amounts of copper in the livers of toxic milk mice results in gross morphologic, histologic, and ultrastructural changes that are progressive with age even though the concentrations of copper tend to decrease in mice older than 6 months. Striking differences in morphologic integrity between regenerative nodules and the intervening parenchyma were observed. Profound changes in mitochondria, endoplasmic reticulum, and nuclei as well as accumulation of microvesicular lipid droplets were observed in injured hepatocytes. By contrast, the hepatocytes of regenerative nodules appeared well preserved. Comparisons with other inherited mammalian disorders associated with hepatic copper toxicosis indicate that copper causes species specific organelle injury.

Animals↗
PubMed1988

Eight closely linked loci place the Wilson disease locus within 13q14-q21.

Wilson disease (WD) is an autosomal recessive disorder resulting in an accumulation of copper in the liver, brain, and other organs. The WD locus (WND) has previously been linked to esterase D (ESD) and localized to 13q14-22. With the large Centre d'Etude Polymorphisme Humain cohort, a refined map of DNA markers from this region was constructed, with the following locus order: D13S1-D13S21-D13S22-D13S10-ESD-RB-WND-D 13S26-D13S12-D13S2. A significant excess of male recombination was observed between D13S21 and D13S22. Intervals distal to D13S22 showed an excess of female recombination. When these markers were tested on 19 WD families from a variety of ethnic backgrounds, the two closest loci were shown to be RB and D13S26. The retinoblastoma gene locus (RB) was shown to be proximal to WND at a distance of 4.4 centimorgans (cM), and D13S26 was placed distal to WND at a distance of 4.0 cM. ESD was assigned proximally at a distance of 9.4 cM. In all families studied WND was linked to one or more of the loci ESD, RB, or D13S26.

Chromosome Mapping↗
PubMed1987

The use of trientine in preventing the effects of interrupting penicillamine therapy in Wilson's disease.

Penicillamine is known to be effective therapy for Wilson's disease. However, the clinical consequences of the abrupt and permanent withdrawal of penicillamine have not been investigated. We studied 11 patients who stopped their own treatment after having been treated successfully with penicillamine (1 to 2 g per day) for periods of 3 to 19 years. Eight died of hepatic decompensation or fulminant hepatitis after an average survival of only 2.6 years. In another 13 patients, penicillamine was discontinued by the physician because of serious adverse reactions. In these patients, penicillamine was replaced with trientine (1 to 1.5 g per day), a newer chelating agent. All but one of these patients (who was killed accidentally) are alive at this writing, from 2 to 15 years later. Our observations suggest that discontinuation of penicillamine in patients with Wilson's disease results in rapid clinical deterioration, which is often fatal. The replacement of penicillamine with trientine appears to prevent this adverse clinical course.

Ethylenediamines↗
PubMed1987

Hepatic lysosomal copper-thionein.

In certain pathological and experimental conditions associated with hepatic copper overload, an important portion of the excess metal is bound to a copper-thionein and sequestered in hepatocellular lysosomes. The localization can be demonstrated visually by using histochemical and immunocytochemical stains and by extraction of the Cu-protein from particulate fractions of liver homogenates. The livers of Bedlington terriers affected by an inherited defect resulting in the accumulation of large quantities of copper display hepatocellular lysosomes which appear as dense, insoluble, copper-rich granules. Purification and solubilization of the fraction containing these granules yields a copper-thionein with little zinc, which displays homology with other known metallothioneins. Although the primary genetic defect which underlies the pathogenesis of this form of hepatic copper overload is still unknown, circumstantial evidence suggests that sequestration of the protein by lysosomes may be temporarily cytoprotective.

Aging↗