Ribosome orientation in Mallory bodies.
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Endoplasmic Reticulum↗
Biomedical subjects
I Sternlieb
Publications and source records attributed to I Sternlieb.
Molecular studies of ceruloplasmin deficiency in Wilson's disease.
Deficiency of serum ceruloplasmin is a characteristic biochemical abnormality of Wilson's disease, although the mechanism of this finding is unknown. Ceruloplasmin messenger RNA (mRNA) levels were therefore examined in five patients with Wilson's disease and five controls with other types of hepatic disease. Northern and dot blot hybridizations showed that detectable ceruloplasmin mRNA was present in all of the patients with Wilson's disease, including one patient with no detectable serum ceruloplasmin. However, the ceruloplasmin mRNA levels in the Wilson's disease patients were only 33% that of controls (P less than 0.001). In contrast, albumin mRNA levels in the Wilson's disease patients averaged 161% that of controls. In an attempt to better delineate the level of gene expression responsible for this decrease in ceruloplasmin mRNA, the nuclear run-on assay was used to analyze transcriptional rates. The amount of ceruloplasmin gene transcription in four Wilson's patients was decreased to 44% that of three controls. These results indicate that the diminished serum ceruloplasmin levels in patients with Wilson's disease are due at least in part to a decrease in ceruloplasmin gene transcription.
Ceruloplasmin↗
Wilson's disease and Kayser-Fleischer rings.
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Arcus Senilis↗
The effects of two new inotropic agents on microsomal liver function in patients with congestive heart failure.
The aminopyrine breath test (APBT) was used to study patients with chronic congestive heart failure before and after treatment with two chemically similar inotropic agents, amrinone (AR) and milrinone (MR), to determine their effects on hepatic microsomal function. Liver chemistries and cardiac indices were measured and correlated with the 2-hour APBT score in 11 patients with chronic congestive heart failure (5 treated with AR, 6 with MR) and five healthy control subjects. Despite normal or near-normal liver chemistries, patients with chronic congestive heart failure demonstrated overall depressed hepatic microsomal oxidative function. Patients with severe congestive heart failure had a lower mean pretreatment APBT score (AR = 3.05 +/- 1.02, MR = 5.38 +/- 3.09) when compared with healthy controls (10.02 +/- 1.02). However, the APBT score for each individual could not be predicted from the cardiac index. Although the mean cardiac index increased significantly in both the AR and the MR treated patients by 26.14% +/- 15.28 (p less than 0.01) and 40.0% +/- 42.27 (p less than 0.025), respectively, compared with pretreatment values, the mean APBT score fell by 62.02% +/- 22.5 (p less than 0.005) in the former and increased by 38.35% +/- 25.69 (p less than 0.01) in the patients receiving MR. This discordance between the effects of AR and MR suggests possible differences in the effects of the two drugs on hepatic microsomal function.
Adult↗
Canine hepatic lysosomal copper protein: identification as metallothionein.
We studied the amino acid sequence of canine hepatic lysosomal copper protein obtained from Bedlington terriers affected by inherited copper toxicosis. The primary structure was determined by manual Edman degradations and carboxypeptidase Y digestions of peptides generated by cleavage of the S-carboxyamidomethylated and S-aminoethylated protein with trypsin. Although the amino terminus was blocked and heterogeneous, the protein showed extensive sequence homology to mammalian metallothioneins. In particular, all cysteinyl residues were conserved, in agreement with their function as metal ligands. The microheterogeneity observed in the amino-terminal part of the molecule indicated the presence of two isoforms in canine liver like those found in most other mammals studied so far.
Amino Acid Sequence↗
Cytochemical detection of inherited copper toxicosis of Bedlington terriers.
Sections of paraffin-embedded specimens of liver obtained from Bedlington terriers were stained with rhodanine for copper and examined and graded by two pathologists. Their results correlated well with each other, as well as with the results of quantitative determinations of hepatic copper content. Copper toxicosis was established by cytochemistry in 20 of 21 specimens, indicating a sensitivity of 95%. The method is highly specific--none of the 19 specimens obtained from unaffected dogs displayed copper-containing granules suggestive of copper toxicosis. Copper cytochemistry appears to be a satisfactory substitute for chemical analysis of hepatic copper content.
Age Factors↗
Chronic active hepatitis in Doberman pinschers.
Eleven Doberman Pinschers were affected with a disease that had clinical signs, serum biochemical abnormalities, and histologic features of chronic active hepatitis. Intrahepatic cholestasis and accumulations excess hepatic copper were prominent features. Most of the dogs deteriorated within weeks to months, and 6 died within 9 months after the 1st signs of disease were noticed.
Animals↗
The cardiomyopathy of Wilson's disease. Myocardial alterations in nine cases.
Though myocardial alterations are well recognized in haemochromatosis, little attention has been paid to the cardiac changes in Wilson's disease. To define the extent of myocardial degeneration in newly diagnosed or chronically treated Wilson's disease, we reviewed the autopsy findings in 9 cases with this condition. We compared our observations with those in 3 control cases, selected for comparable age and with liver disease having no known association with cardiac degeneration. Our results revealed cardiac hypertrophy in 5 out of 9 cases of Wilson's disease. There was evidence of interstitial and replacement fibrosis, intramyocardial small vessel sclerosis and focal inflammatory cell inflammation to a variable degree in all cases. One case had AV nodal degeneration, and a 15 year old boy had severe atherosclerosis of the left main coronary artery. Two patients died suddenly, presumably secondary to an arrhythmia; one of these patients had the most marked myocardial alterations. We could not correlate these changes specifically with the tissue levels of copper, treatment with D-penicillamine, or the presence of cirrhosis. We conclude that there are definite morphological abnormalities in the hearts of patients with Wilson's disease consistent with a cardiomyopathy. Though the myocardial changes were non-specific, the fact that 2 patients died suddenly, suggests the need for a prospective study of cardiac function in these patients in the future.
Adolescent↗
IgA interaction with the asialoglycoprotein receptor.
IgA present in normal human serum reacts with the hepatic receptor specific for asialoglycoproteins as demonstrated by inhibition of receptor-mediated erythroagglutination. Inhibition is reversibly abolished by the oxidation of the galactose or N-acetylgalactosamine residues of IgA with galactose oxidase. The site of receptor recognition appears to be the O-glycosidically linked oligosaccharides present on the hinge region of the IgAI subtype of IgA. The demonstration of a specific binding, in vitro, of IgA by the hepatic receptor suggests that the uptake of polymeric IgA by the liver in vivo may be mediated by this reaction.
Animals↗
[Diagnosis of Wilson's disease in 1981].
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Ceruloplasmin↗
[Clinical range of copper toxicity].
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Adult↗
Endocytosis of asialoglycoprotein-enzyme conjugates by hepatocytes.
Desialylated glycoproteins were covalently linked to two cytochemically detectable enzymes, horseradish peroxidase or tyrosinase, and injected intravenously in amounts of approximately 0.5 per cent of total plasma glycoproteins into rats. Comparative studies of the rates of disappearance and distribution of free enzyme and conjugates established that recognition of the conjugates by the plasma membranes of hepatocytes was due to the exposure of the terminal galactose residue of the desialylated glycoproteins. At 1 minute after injection, reaction products of the enzyme markers were seen in coated pits and vesicles, elongated pinocytic channels and pleomorphic vesicles, at or close to the sinusoidal surface of hepatocytes. Vesicles containing reaction products were also observed along the lateral surfaces of hepatocytes. By 10 minutes, reaction products were seen in residual bodies near the biliary poles of hepatocytes. These studies confirm the existence of hepatocellular channels previously seen only with large excess of hemoglobin or following partial hepatectomy. They also indicate that the specific receptor for asialoglycoproteins is not restricted to the sinusoidal surfaces of hepatocytes and that transport to the catabolic sites proceeds via cytoplasmic channels and vesicles.
Animals↗
Inheritance of copper toxicosis in Bedlington terriers.
The mode of transmission of copper toxicosis, previously reported to be associated with progressive hepatic disease in certain Bedlington Terriers, has been studied by means of 5 matings involving affected and unaffected Bedlington Terriers and dogs of different breeds. The abnormally large concentration of hepatic copper underlying the disorder was found to follow an autosomal recessive pattern of inheritance.
Animals↗
Familial cholestatic cirrhosis associated with Kayser-Fleischer rings.
A brother and sister who suffered from pruritus since infancy developed hepatic cirrhosis early in life. Although this clinical picture has never been seen in Wilson's disease, Kayser-Fleischer rings in the boy made further studies necessary. Oral radiocopper loading tests administered to both children and to their parents served to exclude Wilson's disease conclusively. Determinations of the concentrations and patterns of bile acids in the serum indicated that the abnormalities observed in these children are not related to errors in bile acid synthesis. Although a defect in bile acid transport is present, it appears to have occurred as a consequence of the liver disease.
Child↗
The significance of variations in the distribution of copper in liver disease.
Biopsy and autopsy specimens of liver from patients with Wilson's disease in various stages, chronic cholestatic conditions (including primary biliary cirrhosis, extrahepatic biliary obstruction, sclerosing cholangitis, and biliary atresia), chronic active hepatitis, and Indian childhood cirrhosis, as well as normal neonates, were examined by means of histochemical techniques for copper and copper-associated protein. The intracellular localization of copper and the lobular distribution of the metal and its associated protein differed in these conditions. Periportal hepatocytes containing granules (lysosomes) that were reactive for copper and for copper-associated protein were characteristic of cholestasis and neonatal liver. However, in cholestasis extralysosomal copper was often present in the hepatocellular cytoplasm. In contrast, in Wilson's disease, despite very high concentrations of copper in the early stages, the metal was diffuse in the cytoplasm, and the histochemical reactions for granular copper and its associated protein were usually negative. Therefore, a failure to stain for copper does not exclude the diagnosis of Wilson's disease. In the late stages of Wilson's disease staining varied in different nodules. In Indian childhood cirrhosis copper was present throughout the parenchyma, with periportal predominance. Differences in the distribution of copper and the cellular changes associated with its deposition suggest that different pathogenetic mechanisms and possibly different intracellular targets are susceptible to the toxic effects of the metal. For diagnosis, staining for copper and for copper-associated protein may assist in the differentiation of primary biliary cirrhosis from chronic active hepatitis.
Adolescent↗
Clinical, morphologic, and chemical studies on copper toxicosis of Bedlington Terriers.
In a study of 90 Bedlington Terriers, 68 had a defect that resulted in the accumulation of toxic excesses of copper in the liver. Concentrations of copper were 5 to 50 times that of clinically normal mongrel dogs. The bulk of this excess copper was sequestered in lysosomes. When copper concentrations exceeded 2,000 micrograms/g dry liver, progressive signs of functional and morphologic disturbance appeared as focal hepatitis, chronic active hepatitis, and ultimately cirrhosis. The disorder, which appears to be inherited, could only be diagnosed by liver biopsy. It was latent for many years in some dogs but led early in life to acute or chronic hepatic disease and death in others.
Animals↗
Cytoplasmic copper and its toxic effects. Studies in Indian childhood cirrhosis.
Morphological, histochemical, and chemical study of three necropsy specimens of liver in the terminal stage of Indian Childhood Cirrhosis revealed a strikingly high copper content. it is proposed that excess accumulation of copper in the cytoplasm of hepatocytes disturbs the microtubular system, causing hydropic swelling and the formation of Mallory's hyalin. Copper and copper-binding protein showed topographical association with Mallory's hyalin. Diffuse cytoplasmic staining and the lysosomal copper distribution also suggested that copper had a cytotoxic effect. The pattern of copper distribution in Indian Childhood Cirrhosis differs from that in Wilson's disease and in prolonged cholestasis with excessive hepatic copper deposition, indicating a different mechanism of the copper accumulation.
Child, Preschool↗