glycogen and Liver-Diseases

Glycogenic hepatopathy (GH) in type 1 diabetes-mellitus (T1DM) is characterized by hepatomegaly and perturbations of liver chemistries (LC) that have not been well studied. Furthermore, misdiagnosis with other hepatic complications of T1DM, such as nonalcoholic fatty liver disease, has been described. We perform a systematic review of biopsy-proven GH reports in T1DM patients to identify LC patterns.. A systematic review identified reports of biopsy-proven GH in patients with T1DM. We excluded GH with other liver diseases, Mauriac syndrome, or GH without T1DM. Two reviewers screened and extracted studies and assessed their methodological quality. LC elevation magnitude, AST-to-ALT ratio, R-ratio to designate hepatocellular, cholestatic or mixed pattern of hepatic injury, and evolution of transaminases after glycemic control were analyzed.. GH tends to have AST-predominant elevation with a median of 13 times the upper normal limit and R-ratio >2, which may distinguish it from other etiologies of AST-predominant LC elevation, and in the appropriate clinical context, may obviate invasive tests.

Topics: Adult; Diabetes Mellitus, Type 1; Female; Glycogen; Hepatomegaly; Humans; Liver Diseases; Male; Young Adult

Glycogen storage disease type I and glycogenic hepatopathy are the most common type of primary and secondary hepatic glycogenosis, with presenting common radiological features of hepatomegaly, hepatic signal, or density change. Beyond that, glycogen storage disease type I shows hepatocellular adenomas or fatty liver, while glycogenic hepatopathy does not.

Topics: Diagnosis, Differential; Glycogen; Glycogen Storage Disease Type I; Humans; Liver; Liver Diseases; Magnetic Resonance Imaging; Predictive Value of Tests; Tomography, X-Ray Computed

It is now becoming evident that the liver has an important role in the control of whole body metabolism of energy nutrients. In this review, we focus on recent findings showing that AMP-activated protein kinase (AMPK) plays a major role in the control of hepatic metabolism. AMPK integrates nutritional and hormonal signals to promote energy balance by switching on catabolic pathways and switching off ATP-consuming pathways, both by short-term effects on phosphorylation of regulatory proteins and by long-term effects on gene expression. Activation of AMPK in the liver leads to the stimulation of fatty acid oxidation and inhibition of lipogenesis, glucose production and protein synthesis. Medical interest in the AMPK system has recently increased with the demonstration that AMPK could mediate some of the effects of the fat cell-derived adiponectin and the antidiabetic drugs metformin and thiazolidinediones. These findings reinforce the idea that pharmacological activation of AMPK may provide, through signalling and metabolic and gene expression effects, a new strategy for the management of metabolic hepatic disorders linked to type 2 diabetes and obesity.

Topics: AMP-Activated Protein Kinases; Animals; Diabetes Mellitus, Type 2; Enzyme Activation; Glucose; Glycogen; Humans; Liver; Liver Diseases; Multienzyme Complexes; Obesity; Protein Serine-Threonine Kinases

Topics: Chronic Disease; Diabetes Mellitus; Diagnosis, Differential; Enzyme Inhibitors; Exercise Therapy; Glucose; Glycogen; Glycoside Hydrolase Inhibitors; Humans; Liver Diseases; Nutrition Therapy

Topics: Amino Acids; Energy Metabolism; Exercise; Exercise Therapy; Glycogen; Humans; Lipids; Liver; Liver Diseases; Physical Examination

The cerebrohepatorenal syndrome of Zellweger (CHRS) is remarkable not only for a distinctive combination of congenital anomalies, but also for an unusual variety of profound metabolic disturbances. After a discussion of the clinical diagnosis of CHRS, abnormalities in the metabolism of peroxisomes, mitochondria, iron, pipecolic acid, glycogen, bile acids, and organic acids are discussed and related to the clinical and other biochemical findings in the syndrome. Attention is also drawn to syndromes with biochemical or clinical abnormalities similar to those of CHRS. Although the biochemical findings indicate major abnormalities in oxidative metabolism, the primary defect remains obscure.

Topics: Abnormalities, Multiple; Amino Acids, Dicarboxylic; Bile Acids and Salts; Brain Diseases; Glutarates; Glycogen; Humans; Iron; Kidney Diseases; Liver Diseases; Microbodies; Mitochondria; Pipecolic Acids; Syndrome

Topics: Adenine Nucleotides; Bile; Biological Transport; Blood Circulation; Calcium; Cyclic AMP; Digestive System; Gastric Mucosa; Gastrointestinal Motility; Gluconeogenesis; Glycogen; Glycogen Storage Disease; Humans; Insulin; Intestinal Mucosa; Ions; Ketones; Lipid Metabolism; Liver; Liver Diseases; Pancreas; Potassium; Prostaglandins; Salivary Glands

Topics: Animals; Chlordan; DDT; Endoplasmic Reticulum; Ethanol; Glycogen; Lipid Metabolism; Liver; Liver Diseases; Necrosis; Nikethamide; Phenobarbital; Protein Biosynthesis; Rats; Tolbutamide

Topics: Cardiomyopathies; Glucosephosphate Dehydrogenase Deficiency; Glucosidases; Glucosyltransferases; Glycogen; Glycogen Storage Disease; Hepatomegaly; Humans; Kidney Diseases; Liver Cirrhosis; Liver Diseases; Liver Glycogen; Muscular Diseases; Pectins; Polysaccharides; Splenomegaly

Topics: Animals; Brain Chemistry; Diabetes Mellitus; Diuretics; Glycogen; Hepatolenticular Degeneration; Humans; Hypercholesterolemia; Hyperlipidemias; Liver; Liver Diseases; Poisoning; Skin Diseases; Thioctic Acid

Topics: Amylases; Biochemical Phenomena; Biochemistry; Classification; Enzymes; Glucose-6-Phosphatase; Glucosidases; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type I; Humans; Liver Diseases; Lysosomes; Metabolism; Oligosaccharides; Pentosephosphates; Phosphoglucomutase; Phosphorylase Kinase; Polysaccharides

Topics: Alanine Transaminase; Aspartate Aminotransferases; Clinical Enzyme Tests; Diabetes Mellitus; Fatty Liver; Glycogen; Glycogen Storage Disease; Hepatitis; Hepatitis A; Humans; Jaundice; Liver Cirrhosis; Liver Diseases; Liver Glycogen; Splenomegaly

The Pierre Mauriac syndrome described in the year 1930, is characterized by growth failure, cushingoid appearance, hepatomegaly and hypertransaminasemia, in a patient with chronic uncontrolled DM1. The most common age of presentation is usually in adolescence, although cases have been described in both children and adults. The hallmark of this syndrome is extreme liver enlargement from massive acucumulation of glycogen. The diagnosis of hepatopathy requires high clinical suspicion and the presence of glycogen accumulation must be corroborated with a liver biopsy. The accumulation of glycogen in hepatocytes is partly caused by long periods of hyperglycemia, in which glucose enters the hepatocyte independently of insulin and is converted to glycogen. Mauriac syndrome is currently a rare cause of liver disease, due to improvements in control and treatment of patients with DM1. However, some cases are described in people with complicated social situations or without therapeutic compliance. This is a reversible condition after improvement in glycemic control with adequate insulinization. For this reason, we believe it convenient to suspect this clinical picture in patients with poor glycemic control and symptoms of pain and abdominal distension.

Topics: Adolescent; Adult; Biopsy; Child; Glycogen; Hepatomegaly; Humans; Liver Diseases; Obesity; Treatment Adherence and Compliance

This study examines the clinical-pathological profiles of patients with glycogenic hepatopathy in a contemporary cohort of patients at an adult acute care hospital.. Liver biopsies with glycogenic hepatopathy were retrieved from the departmental surgical pathology database, the histological findings were studied, and the clinical findings were reviewed.. Five cases of glycogenic hepatopathy were found, including cases associated with type 1 diabetes mellitus (n = 1), type 2 diabetes mellitus (n = 1), corticosteroids (n = 2), and anorexia (n = 2, including the patient with type 1 diabetes). AST and ALT were normal to mildly elevated (13-115 U/L and 7-126 U/L, respectively). Trace ascites was present in two patients. Hepatomegaly was only present in the patient with type 1 diabetes at the time of diagnosis.. Four of five cases were associated with etiologies other than type 1 diabetes, which is widely reported as the most common etiology of glycogenic hepatopathy. This study suggests that etiologies currently only rarely recognized may actually be more common causes of glycogenic hepatopathy than type 1 diabetes in a contemporary adult population. It is important not only to recognize that these rarely reported causes of glycogenic hepatopathy may be underrecognized, but that the clinical presentation may also be mild.

Topics: Adult; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycogen; Hepatomegaly; Humans; Liver Diseases

Microcystins (MC) are hepatotoxic for organisms. Liver MC accumulation and structural change are intensely studied, but the functional hepatic enzymes and energy metabolism have received little attention. This study investigated the liver and hepatocyte structures and the activity of key hepatic functional enzymes with emphasis on energetic metabolism changes after subchronic fish exposure to cyanobacterial crude extract (CE) containing MC. The Neotropical erythrinid fish, Hoplias malabaricus, were exposed intraperitoneally to CE containing 100 μg MC-LR eq kg

Topics: Acid Phosphatase; Alanine Transaminase; Alkaline Phosphatase; Ammonia; Animals; Aspartate Aminotransferases; Bilirubin; Characiformes; Complex Mixtures; Cyanobacteria; Glucose; Glycogen; Lactates; Lipids; Liver; Liver Diseases; Microcystins; Pyruvates

We report a case of severe glycogenic hepatopathy in a 17-year-old boy with poorly controlled type 1 diabetes. On presentation, major findings included unexplained pronounced hepatomegaly and increased liver enzymes, ferritin, and triglycerides. Histology and electron microscopy evaluation showed severe glycogen storage, steatosis, and signs of fibrosis, resembling the histomorphological findings of Mauriac syndrome. After information about the nature of the disease and intensification of insulin therapy with insulin pump, liver enzymes, ferritin, and triglycerides normalized within 1 month.. Glycogenic hepatopathy is a rare but important potential complication in poorly controlled juvenile diabetic patients. With improved metabolic control, it is fully reversible.

Topics: Adolescent; Diabetes Mellitus, Type 1; Glycogen; Hepatomegaly; Humans; Liver Diseases; Male

Topics: Diabetes Mellitus, Type 1; Glycogen; Humans; Liver Diseases; Liver Function Tests; Tomography, X-Ray Computed

Liver Glycogen Storage Disease IX is a rare metabolic disorder of glycogen metabolism caused by deficiency of the phosphorylase kinase enzyme (PhK). Variants in the PHKG2 gene, encoding the liver-specific catalytic γ2 subunit of PhK, are associated with a liver GSD IX subtype known as PHKG2 GSD IX or GSD IX γ2. There is emerging evidence that patients with GSD IX γ2 can develop severe and progressive liver disease, yet research regarding the disease has been minimal to date. Here we characterize the first mouse model of liver GSD IX γ2.. A Phkg2. When compared to WT controls, KO mice demonstrated significantly decreased liver PhK enzyme activity, increased liver: body weight ratio, and increased glycogen in the liver, with no glycogen accumulation observed in the brain, quadricep, kidney, and heart. KO mice demonstrated elevated liver blood markers as well as elevated urine Glc. This study provides the first evidence of a mouse model that recapitulates the liver-specific pathology of patients with GSD IX γ2. The model will provide the first platform for further study of disease progression in GSD IX γ2 as well as for the evaluation of novel therapeutics.

Topics: Animals; Disease Models, Animal; Female; Glycogen; Glycogen Storage Disease; Liver; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylase Kinase

Topics: Adolescent; Biopsy; Chronic Disease; Diabetes Mellitus, Type 1; Female; Glycogen; Humans; Hyperglycemia; Hyperlactatemia; Ketosis; Liver; Liver Diseases; Magnetic Resonance Imaging; Recurrence; Transaminases

Clear cell foci (CCF) of the liver are considered to be pre-neoplastic lesions of hepatocellular adenomas and carcinomas. They are hallmarked by glycogen overload and activation of AKT (v-akt murine thymoma viral oncogene homolog)/mTOR (mammalian target of rapamycin)-signaling. Here, we report the transcriptome and proteome of CCF extracted from human liver biopsies by laser capture microdissection. We found 14 genes and 22 proteins differentially expressed in CCF and the majority of these were expressed at lower levels in CCF. Using immunohistochemistry, the reduced expressions of STBD1 (starch-binding domain-containing protein 1), USP28 (ubiquitin-specific peptidase 28), monad/WDR92 (WD repeat domain 92), CYB5B (Cytochrome b5 type B), and HSPE1 (10 kDa heat shock protein, mitochondrial) were validated in CCF in independent specimens. Knockout of

Topics: Biomarkers, Tumor; Cell Transformation, Neoplastic; Computational Biology; Gene Expression Profiling; Glycogen; Humans; Immunohistochemistry; Liver Diseases; Liver Neoplasms; Proteomics; Transcriptome

Topics: Adult; Diabetes Complications; Diagnosis, Differential; Diffusion Magnetic Resonance Imaging; Glycogen; Glycogen Storage Disease Type I; Hepatomegaly; Humans; Liver; Liver Diseases; Liver Neoplasms; Male; Tomography, X-Ray Computed

Topics: Adolescent; Aspartate Aminotransferases; Diabetes Mellitus, Type 1; Female; Fibrosis; gamma-Glutamyltransferase; Glycogen; Hepatocytes; Hepatomegaly; Humans; Liver; Liver Diseases; Portal System; Syndrome

In glycogen storage disease type III (GSD III), liver aminotransferases tend to normalize with age giving an impression that hepatic manifestations improve with age. However, despite dietary treatment, long-term liver complications emerge. We present a GSD III liver natural history study in children to better understand changes in hepatic parameters with age.. We reviewed clinical, biochemical, histological, and radiological data in pediatric patients with GSD III, and performed a literature review of GSD III hepatic findings.. Liver fibrosis can occur at an early age, and may explain the decrease in aminotransferases and Glc

Topics: Adolescent; Biomarkers; Child; Child, Preschool; Cholesterol; Female; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type I; Glycogen Storage Disease Type III; Humans; Liver; Liver Cirrhosis; Liver Diseases; Male; Oligosaccharides; Transaminases; Triglycerides; Young Adult

Topics: Diabetes Mellitus, Type 1; Gastrointestinal Diseases; Glycogen; Humans; Liver Diseases

Glycogenic hepatopathy (GH) is a rare complication of poorly controlled type 1 diabetes mellitus (T1DM), and is characterized by elevated liver enzymes, hepatomegaly, and glycogen accumulation. We herein present the case of a 23-year-old man with poorly controlled T1DM who had liver dysfunction. Imaging studies showed severe hepatomegaly and fatty liver. The examination of a liver biopsy specimen revealed fatty droplets, ballooning, inflammation, and mild fibrosis. Subsequent periodic acid-Schiff (PAS) staining after diastase digestion confirmed GH. In this case, the improvement of hyperglycemia, not HbA1c, resulted in the improvement of the patient's liver function. This is the first report on the use of continuous glucose monitoring in patients with GH to show that continuous hyperglycemia may worsen GH.

Topics: Diabetes Mellitus, Type 1; Glycogen; Hepatomegaly; Humans; Liver Diseases; Liver Function Tests; Male; Young Adult

Topics: Acidosis, Lactic; Adolescent; Blood Glucose; Diabetes Mellitus, Type 1; Female; Glycogen; Humans; Liver; Liver Diseases; Liver Function Tests; Predictive Value of Tests

Glycogenic hepatopathy is a rare and under-recognized complication in long-standing poorly controlled type 1 diabetes mellitus patients. This is a distinct entity from other causes of hepatomegaly and elevated liver enzymes in diabetics, such as nonalcoholic fatty liver disease. Glycogenic hepatopathy is characterized by the combination of poorly controlled diabetes, acute liver injury with marked elevation in serum aminotransferases, and the characteristic histological features on liver biopsy. It is important to distinguish this entity as it has the potential for resolution following improved glycemic control. In this report, we describe four cases of adult patients presenting elevated serum transaminases and hepatomegaly with a history of poorly controlled type I diabetes mellitus. One of the patients had also elevated amylase and lipase in the serum, without clinical or imagiologic evidence of acute pancreatitis (AP). Liver biopsy was performed in all patients and revealed glycogenic hepatopathy. Clinician's awareness of glycogenic hepatopathy should prevent diagnostic delay or misdiagnosis and will provide better insight and management for this condition.

Topics: Adult; Delayed Diagnosis; Diabetes Mellitus, Type 1; Diagnosis, Differential; Female; Glycogen; Humans; Liver Diseases; Male; Patient Compliance; Young Adult

In recent years, the advantages of menstrual blood-derived stem cells (MenSCs), such as minimal ethical considerations, easy access and high proliferative ability, have inspired scientists to investigate the potential of MenSCs in cell therapy of different diseases. In order to characterize the potency of these cells for future cell therapy of liver diseases, we examined the potential of MenSCs to differentiate into hepatocytes, using different protocols. First, the immunophenotyping properties and potential of MenSCs to differentiate into osteoblasts, adipocytes and chondrocytes were evaluated. Thereafter, the differentiation protocols developed by two concentrations of hepatocyte growth factor (HGF) and oncostatin M (OSM), in combination with other components in serum-supplemented or serum-free culture media, were also investigated. The sequential differentiation was monitored by real-time PCR, immunostaining and functional assays. Our primary data revealed that the isolated MenSCs exhibited mesenchymal stem cell markers in parallel to OCT-4 as an embryonic marker. Regardless of differentiation procedures, the developed cells expressed mature hepatocyte markers, such as albumin, tyrosine aminotransferase and cytokeratin-18 at the mRNA and protein levels. They also showed functional properties of hepatocytes, including albumin secretion, glycogen storage and cytochrome P450 7A1 expression. However, the degree of differentiation was dependent on the concentrations of HGF and OSM. Indeed, omission of serum during the differentiation process caused typical improvement in hepatocyte-specific functions. This study is a novel report demonstrating the differentiation potential of MenSCs into hepatocyte-like cells. We recommend a complementary serum-free differentiation protocol for enrichment of in vitro production of functional MenSC-derived hepatocyte-like cells that could lead to a major step toward applied stem cell therapy of chronic liver diseases.

Topics: Adipocytes; Adult; Albumins; Cell Differentiation; Cell Proliferation; Chondrocytes; Culture Media; Culture Media, Serum-Free; Female; Gene Expression Regulation; Glycogen; Hepatocyte Growth Factor; Hepatocytes; Humans; Immunophenotyping; Keratin-18; Liver; Liver Diseases; Menstruation; Oncostatin M; Osteoblasts; Phenotype; Real-Time Polymerase Chain Reaction; RNA, Messenger; Stem Cells

Topics: Adult; Biomarkers; Diabetes Mellitus, Type 1; Female; Glycogen; Humans; Liver Diseases; Transaminases

Adipose-derived stem cells (ADSCs) have been put forward as promising therapeutics for end-stage liver disease (ESLD). In the present study, we compared the effects of defined chemicals and liver extract on the hepatic differentiation of ADSCs. ADSCs were isolated according to the method described in our previously published study. Subsequently, the differentiation of ADSCs was induced separately by chemicals (including hepatic growth factor (HGF), fibroblast growth factor (FGF), and oncostatin M (OSM)) and liver extract (30 μg/ml) in a total period of 21 d. The efficiency of hepatic differentiation was evaluated by changes in the cell morphology, gene expression, and cellular function. The results showed that the liver extract promoted the hepatic differentiation of ADSCs to a significantly greater extent than the chemicals. In the group of ADSCs treated with liver extract, changes in the cell morphology began sooner, and the expression of alpha-FP and albumin genes was higher than that in the chemically treated group. The ADSCs in both the groups stained positive for anti-alpha trypsin (AAT) and albumin markers. The cells also exhibited glycogen storage capacity. Therefore, we concluded that the liver extract could efficiently induce the differentiation of ADSCs into hepatocyte-like cells. This study reveals the potential of mesenchymal stem cell differentiation in the liver extract, which supports further preclinical and clinical research on the application of ADSCs in ESLD treatment.

Topics: Adipose Tissue; Albumins; alpha 1-Antitrypsin; alpha-Fetoproteins; Animals; Cell Differentiation; Cell- and Tissue-Based Therapy; Cells, Cultured; Fibroblast Growth Factors; Glycogen; Hepatocyte Growth Factor; Humans; Liver Diseases; Liver Extracts; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Oncostatin M

We present the case of a 13-year-old male with poorly controlled type 1 diabetes mellitus who developed significantly deranged liver transaminases following an episode of diabetic ketoacidosis. A liver biopsy diagnosed glycogenic hepatopathy (GH). We believe the combination of GH and ischaemic hepatitis led to his presentation.

Topics: Adolescent; Biopsy; Blood Glucose; Diabetes Mellitus, Type 1; Disease Progression; Dose-Response Relationship, Drug; Fluid Therapy; Glycated Hemoglobin; Glycogen; Humans; Hypoglycemic Agents; Insulin; Liver; Liver Diseases; Male; Transaminases

Topics: Adolescent; Child; Diabetes Mellitus, Type 1; Female; Glycogen; Humans; Liver Diseases; Male; Non-alcoholic Fatty Liver Disease; Tomography, X-Ray Computed

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Glycogen; Hepatomegaly; Humans; Liver Diseases; Magnetic Resonance Imaging; Young Adult

Indications for liver biopsy in children are often specific to this age group, especially in young children for the diagnosis of cholestasis. Since liver biopsies are quite unfrequent in the children population and concern rare but various diseases, it is recommended to entrust the analysis to a specialized liver pathologist, in a laboratory where cryoconservation, specific immuno-stainings, enzymatic studies, and electron microscopy can be performed. Histology is complementary to other methods for the diagnosis, and is valuable for the evaluation of the prognosis, especially the staging of fibrosis and the grading of inflammatory diseases. In cases of co-morbidity or difficult differential diagnosis, histology can also be of great value. For metabolic disorders, the liver tissue can also be used for enzyme detection or evaluation of iron or copper overload. Biopsy is also a key element in the management after liver transplantation. The microscopic images shown here are representative of the most frequent liver diseases in childhood and illustrate the data outlined during the conference.

Topics: Biliary Tract; Biliary Tract Diseases; Biopsy; Child; Glycogen; Hamartoma; Hepatoblastoma; Hepatocytes; Humans; Hyperplasia; Liver; Liver Diseases; Metabolism, Inborn Errors

Topics: Abdominal Pain; Adult; Diabetes Mellitus, Type 1; Diagnosis, Differential; Epilepsy; Female; Glycated Hemoglobin; Glycogen; Humans; Hypoglycemic Agents; Insulin; Liver; Liver Diseases; Liver Function Tests; Ultrasonography

Topics: Adult; Glycogen; Humans; Liver Diseases; Male

Interleukin-6 (IL-6) plays an important role in liver regeneration and protection against liver damage. In addition to IL-6 classic signaling via membrane bound receptor (mIL-6R), IL-6 signaling can also be mediated by soluble IL-6R (sIL-6R) thereby activating cells that do not express membrane bound IL-6R. This process has been named trans-signaling. IL-6 trans-signaling has been demonstrated to operate during liver regeneration. We have developed methods to specifically block or mimic IL-6 trans-signaling. A soluble gp130 protein (sgp130Fc) exclusively inhibits IL-6 trans-signaling whereas an IL-6/sIL-6R fusion protein (Hyper-IL-6) mimics IL-6 trans-signaling. Using these tools we investigate the role of IL-6 trans-signaling in CCl₄ induced liver damage. Blockade of IL-6 trans-signaling during CCl₄ induced liver damage led to higher liver damage, although induction of Cyp4502E1 and thus bioactivation of CCl₄ was unchanged. Depletion of neutrophils resulted in reduced liver transaminase levels irrespective of IL-6 trans-signaling blockade. Furthermore, IL-6 trans-signaling was important for refilling of hepatocyte glycogen stores, which were depleted 24 h after CCl₄ treatment. We conclude that IL-6 trans-signaling via the soluble IL-6R is important for the physiologic response of the liver to CCl₄ induced chemical damage.

Topics: Animals; Blotting, Western; Carbon Tetrachloride; Cytochrome P-450 CYP2E1; Cytokine Receptor gp130; Enzyme-Linked Immunosorbent Assay; Glycogen; Interleukin-6; Liver; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Neutrophils; Receptors, Interleukin-6; Recombinant Fusion Proteins; Signal Transduction; Thiobarbituric Acid Reactive Substances; Up-Regulation

Human induced pluripotent stem (iPS) cells hold great promise for advancements in developmental biology, cell-based therapy, and modeling of human disease. Here, we examined the use of human iPS cells for modeling inherited metabolic disorders of the liver. Dermal fibroblasts from patients with various inherited metabolic diseases of the liver were used to generate a library of patient-specific human iPS cell lines. Each line was differentiated into hepatocytes using what we believe to be a novel 3-step differentiation protocol in chemically defined conditions. The resulting cells exhibited properties of mature hepatocytes, such as albumin secretion and cytochrome P450 metabolism. Moreover, cells generated from patients with 3 of the inherited metabolic conditions studied in further detail (alpha1-antitrypsin deficiency, familial hypercholesterolemia, and glycogen storage disease type 1a) were found to recapitulate key pathological features of the diseases affecting the patients from which they were derived, such as aggregation of misfolded alpha1-antitrypsin in the endoplasmic reticulum, deficient LDL receptor-mediated cholesterol uptake, and elevated lipid and glycogen accumulation. Therefore, we report a simple and effective platform for hepatocyte generation from patient-specific human iPS cells. These patient-derived hepatocytes demonstrate that it is possible to model diseases whose phenotypes are caused by pathological dysregulation of key processes within adult cells.

Topics: Adult; Aged; Cell Differentiation; Cell- and Tissue-Based Therapy; Cytochrome P-450 Enzyme System; Fibroblasts; Glycogen; Hepatocytes; Humans; Induced Pluripotent Stem Cells; Infant; Liver; Liver Diseases; Male; Middle Aged; Models, Biological

Autophagy is an intracellular pathway that contributes to the degradation and recycling of unfolded proteins. Based on the knowledge that autophagy affects glycogen metabolism and that alpha(1)-antitrypsin (AAT) deficiency is associated with an autophagic response in the liver, we hypothesized that the conformational abnormalities of the Z-AAT protein interfere with hepatocyte glycogen storage and/or metabolism. Compared with wild-type mice (WT), the Z-AAT mice had lower liver glycogen stores (P < 0.001) and abnormal activities of glycogen-related enzymes, including acid alpha-glucosidase (P < 0.05) and the total glycogen synthase (P < 0.05). As metabolic consequences, PiZ mice demonstrated lower blood glucose levels (P < 0.05), lower body weights (P < 0.001), and lower fat pad weights (P < 0.001) compared with WT. After the stress of fasting or partial hepatectomy, PiZ mice had further reduced liver glycogen and lower blood glucose levels (both P < 0.05 compared WT). Finally, PiZ mice exhibited decreased survival after partial hepatectomy (P < 0.01 compared with WT), but this was normalized with postoperative dextrose supplementation. In conclusion, these observations are consistent with the general concept that abnormal protein conformation and degradation affects other cellular functions, suggesting that diseases in the liver might benefit from metabolic compensation if glycogen metabolism is affected.

Topics: alpha 1-Antitrypsin; alpha-Glucosidases; Animals; Autophagy; Blood Glucose; Disease Models, Animal; Glycogen; Glycogen Storage Disease; Glycogen Synthase; Humans; Liver; Liver Diseases; Mice; Mice, Transgenic; Pulmonary Emphysema

The objective of the present study was to screen various solvent extracts of Polyalthia longifolia var. pendula (Annonaceae) leaf for anti-inflammatory activity and to evaluate the anti-inflammatory and hepatoprotective potency of the potent solvent extract. Successive extraction was performed with six different solvents, viz. petroleum ether, hexane, toluene, chloroform, acetone and methanol. Toluene, chloroform, acetone and methanol were used in acute inflammatory studies; the results revealed methanol as most potent extract. Hence three concentrations of methanolic extract (300, 600, 900 mg/kg) were used to evaluate its potential as an anti-inflammatory and hepatoprotective agent. Diclofenac sodium was used as the toxicant in hepatoprotective studies, in which various serum biochemical parameters and liver glycogen were assessed. The three concentrations of methanol showed anti-inflammatory activity comparable to that of the control (Diclofenac sodium). All the serum biochemical parameters studied revealed the hepatoprotective nature of the methanol extract, but a concentration effect was not observed. The results indicated that the methanolic extract of Polyalthia longifolia var. pendula leaf possesses significant anti-inflammatory and hepatoprotective activity. However, the appropriate effective concentration needs to be determined.

Topics: Acetone; Alanine Transaminase; Animals; Anti-Inflammatory Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Chloroform; Diclofenac; Dose-Response Relationship, Drug; Female; Glycogen; Hexanes; Liver; Liver Diseases; Male; Methanol; Plant Extracts; Plant Leaves; Polyalthia; Rats; Rats, Wistar; Toluene

Bicyclol is a synthetic antihepatitis drug with antioxidative property. The present study was performed to investigate the effect of bicyclol on liver regeneration after partial hepatectomy in rats. Bicyclol (300 mg/kg) was given to rats subjected to 70% hepatectomy three times before operation. At 6, 24, and 48 h after resection, samples were collected for the measurement of serum alanine aminotransferase (ALT), total bilirubin (TBil), hepatic glycogen, malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH). Moreover, liver regeneration rate, proliferating cell nuclear antigen (PCNA) labeling, proliferation index, and histopathological examination were evaluated at 48 h after hepatectomy. As a result, bicyclol significantly increased regeneration rate, mitotic index (MI), PCNA labeling index, and proliferation index in PH rats. Additionally, bicyclol remarkably inhibited the elevation of serum ALT and TBil levels, alleviated the formation of liver MDA, restored impaired antioxidant SOD and GSH, increased hepatic glycogen content, and also attenuated hepatic vacuolar degeneration. These results suggested that bicyclol had a beneficial effect on liver regenerative capacity of the remnant liver tissue after hepatectomy, probably due to its antioxidative property.

Topics: Alanine Transaminase; Animals; Bilirubin; Biphenyl Compounds; Cell Proliferation; Glutathione; Glycogen; Hepatectomy; Hepatocytes; Liver; Liver Diseases; Liver Regeneration; Male; Malondialdehyde; Mitotic Index; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

The aim of this study was to investigate the effect of misoprostol, silymarin or the co-administration of misoprostol + silymarin on the carbon tetrachloride (CCl(4))-induced hepatic injury in rats. Misoprostol (10, 100, 1000 microg/kg), silymarin (25 mg/kg) or misoprostol (100 microg/kg) + silymarin (25 mg/kg) was given once daily orally simultaneously with CCl(4) and for 15 days thereafter. The results showed that misoprostol (10, 100 or 1000 microg/kg) conferred significant protection against the hepatotoxic actions of CCl(4) in rats, reducing serum alanine aminotransferase (ALT) levels by 24.7%, 42.6% and 49.4%, respectively compared with controls. Misoprostol, given at 100 or 1000 microg/kg, decreased aspartate aminotransferase (AST) by 28 and 43.6% and alkaline phosphatase (ALP) by 19.3% and 53.4% respectively. Meanwhile, silymarin reduced ALT, AST and ALP levels by 62.7%, 66.1% and 65.1% respectively. The co-administration of misoprostol (100 microg/kg) and silymarin (25 mg/kg) resulted in 61.4%, 66.1% and 57.5% reduction in ALT, AST and ALP levels respectively. Histopathological alterations and depletion of hepatocyte glycogen and DNA content by CCl(4) were markedly reduced after treatment with misoprostol, silymarin or misoprostol + silymarin. Image analysis of liver specimens revealed a marked reduction in liver necrosis; area of damage: 32.4%, 24% and 10.2% after misoprostol (10, 100 or 1000 microg/kg), 7.2% after silymarin and 10.9% after treatment with misoprostol 100 microg/kg + silymarin, compared with CCl(4) control group (46.7%). These results indicate that treatment with misoprostol protects against hepatocellular necrosis induced by CCl(4). This study suggests a potential therapeutic use for misoprostol in liver injury.

Topics: Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; DNA; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glycogen; Liver Diseases; Liver Function Tests; Male; Misoprostol; Necrosis; Protective Agents; Rats; Rats, Sprague-Dawley; Silymarin

Diabetes mellitus is a major endocrine disorder and a growing health problem in most countries which can be ameliorated by numerous bio-molecules such as 1alpha,25 dihydroxyvitamin D3 [1alpha,25(OH)2VD3]. With this in mind, the current study investigated the therapeutic and preventive effects of 1alpha,25(OH)2VD3 on diabetes and its side effects: toxicity in liver, pancreas and kidneys. Our results show that administration of 1alpha,25(OH)2VD3 in diabetic rats increased the plasmatic insulin level, favored the normal blood glucose levels and normalized the hepatic glycogen concentration. In addition, 1alpha,25(OH)2VD3 enhanced superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) (by 207, 52 and 72%, respectively) compared to diabetic rats. It also reduced lipid peroxidation and the indices of toxicity in liver and kidneys by significantly decreasing alkaline phosphatases (PAL), aspartate and lactate transaminase (AST and ALT) activities, total and direct bilirubin, triglycerides (TG), cholesterol, creatinine, urea and iron levels in diabetic rats. Moreover, the plasmatic non-enzymatic antioxidant level of HDL-cholesterol, magnesium (Mg), calcium (Ca) and copper (Cu) increased after 1alpha,25(OH)2VD3 administration. The administration of 1alpha,25(OH)2VD3 in diabetic rats protects against alloxan-induced histological changes in pancreas.. from these data, it is concluded that 1alpha,25(OH)2VD3 might be useful for the therapy and prevention of diabetes and the numerous side effects especially toxicity in liver, pancreas and kidneys and this protective effect is more obvious in our preventive experiment.

Topics: Animals; Blood Glucose; Calcitriol; Catalase; Diabetes Mellitus, Experimental; Glutathione Peroxidase; Glycogen; Insulin; Kidney; Kidney Diseases; Lipid Peroxidation; Liver; Liver Diseases; Male; Organ Size; Oxidative Stress; Pancreas; Pancreatic Diseases; Rats; Rats, Wistar; Superoxide Dismutase

Topics: Biopsy; Cytoplasm; Diabetes Complications; Female; Glycogen; Hepatocytes; Humans; Liver; Liver Diseases; Transaminases; Young Adult

Cadmium is an environmental toxic metal implicated in human diseases. In the present study, the effect of diphenyl diselenide, (PhSe)(2), on sub-chronic exposure with cadmium chloride (CdCl(2)) was investigated in rats. Male adult Swiss albino rats received CdCl(2) (10 micromol/kg, orally) and (PhSe)(2) (5 micromol/kg, orally) for a period of 30 days. A number of parameters were examined as indicators of toxicity, including hepatic and renal damage, glucose and glycogen levels and markers of oxidative stress. Cadmium content, liver histology, delta-aminolevulinate dehydratase (delta-ALA-D) activity, metallothionein (MT) levels were also evaluated. Cadmium content determined in the tissue of rats exposed to CdCl(2) provides evidence that the liver is the major cadmium target where (PhSe)(2) acts. The concentration of cadmium in liver was about three fold higher than that in kidney, and (PhSe)(2) reduced about six fold the levels of this metal in liver of rats exposed. Rats exposed to CdCl(2) showed histological alterations abolished by (PhSe)(2) administration. (PhSe)(2) administration ameliorated plasma malondialdehyde (MDA) levels, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma-glutamyl transferase (GGT) activities increased by CdCl(2) exposure. Urea and bilirubin levels increased by CdCl(2) exposure were also reduced by (PhSe)(2). In conclusion, this study demonstrated that co-treatment with (PhSe)(2) ameliorated hepatotoxicity and cellular damage in rat liver after sub-chronic exposure with CdCl(2). The proposed mechanisms by which (PhSe)(2) acts in this experimental protocol are its antioxidant properties and its capacity to form a complex with cadmium.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antioxidants; Ascorbic Acid; Aspartate Aminotransferases; Benzene Derivatives; Bilirubin; Blood Glucose; Cadmium; Cadmium Chloride; Chemical and Drug Induced Liver Injury; gamma-Glutamyltransferase; Glycogen; Kidney; L-Lactate Dehydrogenase; Liver; Liver Diseases; Male; Malondialdehyde; Organoselenium Compounds; Oxidative Stress; Porphobilinogen Synthase; Rats; Rats, Wistar; Sulfhydryl Compounds

The present study has been conducted to evaluate the curative effect of propolis extract, a honey bee-hive product, against acetaminophen (APAP) induced oxidative stress and dysfunction in liver and kidney. Animals were challenged with APAP (2 g/kg, p.o.) followed by treatment of propolis extract (100 and 200 mg/kg, p.o.) once only after 24 h. Release of transaminases, alkaline phosphatase, lactate dehydrogenase, and serum bilirubin were increased, whereas hemoglobin and blood sugar were decreased after APAP administration. Antioxidant status in both the liver and kidney tissues were estimated by determining the glutathione, malondialdehyde content and activities of the CYP enzymes, which showed significant alterations after APAP intoxication. In addition, activities of adenosine triphosphatase, acid phosphatase, alkaline phosphatase, and major cell contents (total protein, glycogen and cholesterol) were also altered due to APAP poisoning. Propolis extract successfully reversed the alterations of these biochemical variables at higher dose. Improvements in hepatorenal histoarchitecture were also consistent with biochemical observations. The results indicated that ethanolic extract of propolis has ability to reverse APAP-induced hepatorenal biochemical and histopathological alterations probably by increasing the antioxidative defense activities due to various phenolic compounds present in it.

Topics: Acetaminophen; Acid Phosphatase; Adenosine Triphosphatases; Alkaline Phosphatase; Animals; Antioxidants; Bilirubin; Blood Glucose; Chemical and Drug Induced Liver Injury; Cholesterol; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Female; Glutathione; Glycogen; Hemoglobins; Kidney; Kidney Diseases; L-Lactate Dehydrogenase; Liver; Liver Diseases; Malondialdehyde; Oxidative Stress; Propolis; Rats; Rats, Sprague-Dawley; Silymarin; Transaminases

Medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) catalyzes crucial steps in mitochondrial fatty acid oxidation, a process that is of key relevance for maintenance of energy homeostasis, especially during high metabolic demand. To gain insight into the metabolic consequences of MCAD deficiency under these conditions, we compared hepatic carbohydrate metabolism in vivo in wild-type and MCAD(-/-) mice during fasting and during a lipopolysaccharide (LPS)-induced acute phase response (APR). MCAD(-/-) mice did not become more hypoglycemic on fasting or during the APR than wild-type mice did. Nevertheless, microarray analyses revealed increased hepatic peroxisome proliferator-activated receptor gamma coactivator-1alpha (Pgc-1alpha) and decreased peroxisome proliferator-activated receptor alpha (Ppar alpha) and pyruvate dehydrogenase kinase 4 (Pdk4) expression in MCAD(-/-) mice in both conditions, suggesting altered control of hepatic glucose metabolism. Quantitative flux measurements revealed that the de novo synthesis of glucose-6-phosphate (G6P) was not affected on fasting in MCAD(-/-) mice. During the APR, however, this flux was significantly decreased (-20%) in MCAD(-/-) mice compared with wild-type mice. Remarkably, newly formed G6P was preferentially directed toward glycogen in MCAD(-/-) mice under both conditions. Together with diminished de novo synthesis of G6P, this led to a decreased hepatic glucose output during the APR in MCAD(-/-) mice; de novo synthesis of G6P and hepatic glucose output were maintained in wild-type mice under both conditions. APR-associated hypoglycemia, which was observed in wild-type mice as well as MCAD(-/-) mice, was mainly due to enhanced peripheral glucose uptake.. Our data demonstrate that MCAD deficiency in mice leads to specific changes in hepatic carbohydrate management on exposure to metabolic stress. This deficiency, however, does not lead to reduced de novo synthesis of G6P during fasting alone, which may be due to the existence of compensatory mechanisms or limited rate control of MCAD in murine mitochondrial fatty acid oxidation.

Topics: Acyl-CoA Dehydrogenase; Animals; Blood Glucose; Carbohydrate Metabolism; Disease Models, Animal; Energy Metabolism; Fatty Acids; Gene Expression Regulation, Enzymologic; Glucose-6-Phosphate; Glycogen; Hypoglycemia; Lipopolysaccharides; Liver; Liver Diseases; Male; Mice; Mice, Knockout; Mitochondria, Liver

High-fat diets and oxidative damage may contribute to the development of type 2 diabetes. Hypolipidaemic drugs and antioxidants were supposed to prevent the development of the disease. In this study, we investigated preventive effects of fenofibrate (200 mg kg(-1)), vitamin C (30 mg kg(-1)), combination of both in mice induced by streptozotocin (35 mg kg(-1)) and soluble lard (15 ml kg(-1)). The results showed the mice demonstrated hyperglycaemia and hypercholesterolaemia, visceral fat accumulation, and a slight increase in liver glycogen/triglyceride and oxidative stress within 60 days of treatment. Fenofibrate enhanced insulin sensitivity, improved glycaemic control, lowered serum triglycerides, reduced body and visceral fat weights, and decreased liver glycogen/lipid levels but showed hepatotoxicity in the mice. Vitamin C neither itself prevented nor enhanced preventive effects of fenofibrate on glucose and lipid metabolism but partly attenuated the hepatotoxicity of fenofibrate. These results suggest that fenofibrate inhibit development of type 2 diabetes induced by high-fat diets and oxidative stress. However, here, vitamin C just can serve as an adjunct to fenofibrate therapy against its hepatotoxicity. In the future study, we should investigate if higher dosage of vitamin C or other antioxidants would enhance preventive effects of fenofibrate in type 2 diabetes.

Topics: Animals; Antioxidants; Ascorbic Acid; Blood Glucose; Chemical and Drug Induced Liver Injury; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Fats; Drug Therapy, Combination; Fenofibrate; Glycogen; Hypercholesterolemia; Hyperglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Intra-Abdominal Fat; Liver; Liver Diseases; Male; Matrix Metalloproteinase 9; Mice; Oxidative Stress; Streptozocin; Triglycerides

An elevated serum biotinidase activity in patients with glycogen storage disease (GSD) type Ia has been reported previously. The aim of this work was to investigate the specificity of the phenomenon and thus we expanded the study to other types of hepatic GSDs. Serum biotinidase activity was measured in a total of 68 GSD patients and was compared with that of healthy controls (8.7 +/- 1.0; range 7.0-10.6 mU/ml; n = 26). We found an increased biotinidase activity in patients with GSD Ia (17.7 +/- 3.9; range: 11.4-24.8; n = 21), GSD I non-a (20.9 +/- 5.6; range 14.6-26.0; n = 4), GSD III (12.5 +/- 3.6; range 7.8-19.1; n = 13), GSD VI (15.4 +/- 2.0; range 14.1-17.7; n = 3) and GSD IX (14.0 +/- 3.8; range: 7.5-21.6; n = 22). The sensitivity of this test was 100% for patients with GSD Ia, GSD I non-a and GSD VI, 62% for GSD III, and 77% for GSD IX, indicating reduced sensitivity for GSD III and GSD IX, respectively. In addition, we found elevated biotinidase activity in all sera from 5 patients with Fanconi-Bickel Syndrome (15.3 +/- 3.7; range 11.0-19.4). Taken together, we propose serum biotinidase as a diagnostic biomarker for hepatic glycogen storage disorders.

Topics: Biomarkers; Biotinidase; DNA Mutational Analysis; Glycogen; Glycogen Storage Disease Type I; Glycogen Storage Disease Type II; Glycogen Storage Disease Type III; Glycogen Storage Disease Type VI; Humans; Liver; Liver Diseases; Sensitivity and Specificity; Specimen Handling

Phosphatidylinositol transfer proteins (PITPs) regulate the interface between lipid metabolism and cellular functions. We now report that ablation of PITP alpha function leads to aponecrotic spinocerebellar disease, hypoglycemia, and intestinal and hepatic steatosis in mice. The data indicate that hypoglycemia is in part associated with reduced proglucagon gene expression and glycogenolysis that result from pancreatic islet cell defects. The intestinal and hepatic steatosis results from the intracellular accumulation of neutral lipid and free fatty acid mass in these organs and suggests defective trafficking of triglycerides and diacylglycerols from the endoplasmic reticulum. We propose that deranged intestinal and hepatic lipid metabolism and defective proglucagon gene expression contribute to hypoglycemia in PITP alpha-/- mice, and that hypoglycemia is a significant contributing factor in the onset of spinocerebellar disease. Taken together, the data suggest an unanticipated role for PITP alpha in with glucose homeostasis and in mammalian endoplasmic reticulum functions that interface with transport of specific luminal lipid cargoes.

Topics: Adenosine Triphosphate; Animals; Brain; Carrier Proteins; Cerebellum; Dose-Response Relationship, Drug; Endoplasmic Reticulum; Fatty Acids; Genetic Vectors; Genotype; Glucagon; Glycogen; Hypoglycemia; In Situ Nick-End Labeling; Intestinal Diseases; Lipid Metabolism; Liver; Liver Diseases; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron; Models, Genetic; Phenotype; Phospholipid Transfer Proteins; Proglucagon; Protein Precursors; Saccharomyces cerevisiae Proteins; Spinocerebellar Degenerations; Time Factors

Hepatocyte transplantation is a potential therapy for both acute and chronic hepatic insufficiency and also for treatment of inborn errors of metabolism affecting the liver. The peritoneum is one site for implantation and has several advantages: cells implanted there can be easily identified and observed, and it has a relatively large capacity. Long-term survival using "pure" hepatocytes in the peritoneum have been disappointing. We hypothesized that cotransplantation of hepatocytes with nonparenchymal cells would help maintain differentiated hepatocyte function. Rat liver cells transplanted intraperitoneally into August rats were sacrificed at 7 days, 1, 3, 6, 9, and 12 months and analyzed for presence, basal proliferation, and functionality of hepatocytes. To demonstrate that ectopic hepatocytes remained susceptible to exogenous growth factors affecting cell proliferation, rats 9 and 12 months after transplantation were stimulated with tri-iodothyronine and KGF. Hepatocytes were identified 7 days to >12 months, by H&E and immunohistochemically, as ectopic islands in the omental fat. Functionality was confirmed by glycogen deposition. Basal proliferation in 7-day rats was 28.0 +/- 10/1000 hepatocytes in ectopic islands (cf. 5.70 +/- 2.7/1000 in recipient liver). Proliferation in ectopic islands was greater than host liver. Growth factor-stimulated proliferation in ectopic islands induced a 70-fold increase in DNA synthesis. In conclusion, hepatocytes transplanted with nonparenchymal cells survive, proliferate, and function in the peritoneum of normal rats, and respond to exogenous growth stimuli. Their survival and proliferation in the presence of a normal functioning liver has implications for the potential use of the peritoneal site clinically for supplementation of liver function in metabolic disorders.

Topics: Animals; Cell Differentiation; Cell Division; Cell Survival; Cell Transplantation; Cells, Cultured; DNA; Female; Glycogen; Graft Survival; Growth Substances; Hepatocytes; Liver Diseases; Liver Failure; Male; Peritoneum; Rats; Rats, Inbred Strains; Rats, Wistar; Stromal Cells; Up-Regulation

Principal component analysis (PCA) has been applied to three nuclear magnetic resonance (NMR) spectral editing methods, namely, the Carr-Purcell-Meiboom-Gill spin-echo, diffusion editing, and skyline projection of a two-dimensional J-resolved spectrum, obtained from high-resolution magic-angle spinning NMR spectroscopy of liver tissues, to distinguish between control and hydrazine-treated rats. The effects of the toxin on rat liver biochemistry were directly observed and characterized by depleted levels of liver glycogen, choline, taurine, trimethylamine N-oxide, and glucose and by elevated levels of lipids and alanine. The highly unsaturated omega-3-type fatty acid was observed for the first time in hydrazine-treated rat liver. The contributions of the metabolites to the separation of control from dosed liver tissues varied depending on the type of spectral editing method used. We have shown that subtle changes in the metabolic profiles can be selectively amplified using a metabonomics approach based on the different NMR spectral editing techniques in conjunction with PCA.

Topics: Alanine; Animals; Chemical and Drug Induced Liver Injury; Choline; Glucose; Glycogen; Hydrazines; Lipids; Liver; Liver Diseases; Magnetic Resonance Spectroscopy; Male; Methylamines; Rats; Rats, Sprague-Dawley; Taurine; Toxins, Biological

To evaluate the effect of glycogen on calcium concentration of rabbit donor liver during ischemia-reperfusion period.. Donor group (n=21) was divided into 3 subgroups randomly: Group A (n=7): fasting for 24 hours before harvesting; Group B (n=7): normal laboratory chew; Group C (n=7): normal laboratory chew plus glucose supplement intravenously. Based on the self-created animal model for ischemia-reperfusion, the levels of glycogen content, ATP level, viability of Ca(2+)ATPase and plasmic free Ca(2+) concentration ([Ca(2+)]i) of liver tissue were measured.. Before cold preservation, there was a significant difference of glycogen content among the three groups at all time points except at the end of rewarming period. ATP level and Ca(2+)ATPase viability were significantly higher in group C than in other two groups. But the plasmic free Ca(2+) concentration was lower in groups with higher glycogen content.. Donor liver with high glycogen content can provide relatively sufficient ATP, maintain better Ca(2+)ATPase viability and prevent plasmic free Ca(2+) concentration overloading. This maybe an important mechanism for glycogen to ameliorate ischemia-reperfusion injury to the donor livers.

Topics: Adenosine Triphosphate; Animals; Calcium; Calcium-Transporting ATPases; Cytosol; Female; Glycogen; Liver Diseases; Liver Transplantation; Male; Models, Animal; Rabbits; Reperfusion Injury

Activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element-binding protein family of transcription factors, is a transcriptional repressor, and the expression of its corresponding gene, ATF3, is induced by many stress signals. In this report, we demonstrate that transgenic mice expressing ATF3 in the liver had symptoms of liver dysfunction such as high levels of serum bilirubin, alkaline phosphatase, alanine transaminase, aspartate transaminase, and bile acids. In addition, these mice had physiological responses consistent with hypoglycemia including a low insulin:glucagon ratio in the serum and reduced adipose tissue mass. Electrophoretic mobility shift assays indicated that ATF3 bound to the ATF/cAMP-responsvie element site derived from the promoter of the gene encoding the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). Furthermore, transient transfection assays indicated that ATF3 repressed the activity of the PEPCK promoter. Taken together, our results are consistent with the model that the expression of ATF3 in the liver results in defects in glucose homeostasis by repressing gluconeogenesis. Because ATF3 is a stress-inducible gene, these mice may provide a model to investigate the molecular mechanisms of some stress-associated liver diseases.

Topics: Activating Transcription Factor 3; Animals; Animals, Newborn; Bilirubin; Chloramphenicol O-Acetyltransferase; Gene Expression Regulation, Enzymologic; Glycogen; Liver Diseases; Mice; Mice, Knockout; Phosphoenolpyruvate Carboxykinase (ATP); Promoter Regions, Genetic; Protein Binding; Time Factors; Transcription Factors; Transfection

Harvesting trauma to the graft dramatically decreases survival after liver transplantation. Since activated Kupffer cells play a role in primary nonfunction, the purpose of this study was to test the hypothesis that organ manipulation activates Kupffer cells. To mimic what occurs with donor hepatectomy, livers from Sprague-Dawley rats underwent dissection with or without gentle organ manipulation in a standardized manner in situ. Perfused livers exhibited normal values for O(2) uptake (105 +/- 5 micromol. g(-1). h(-1)) measured polarigraphically; however, 2 h after organ manipulation, values increased significantly to 160 +/- 8 micromol. g(-1). h(-1) and binding of pimonidazole, a hypoxia marker, increased about threefold (P < 0.05). Moreover, Kupffer cells from manipulated livers produced three- to fourfold more tumor necrosis factor-alpha and PGE(2), whereas intracellular calcium concentration increased twofold after lipopolysaccharide compared with unmanipulated controls (P < 0.05). Gadolinium chloride and glycine prevented both activation of Kupffer cells and effects of organ manipulation. Furthermore, indomethacin given 1 h before manipulation prevented the hypermetabolic state, hypoxia, depletion of glycogen, and release of PGE(2) from Kupffer cells. These data indicate that gentle organ manipulation during surgery activates Kupffer cells, leading to metabolic changes dependent on PGE(2) from Kupffer cells, which most likely impairs liver function. Thus modulation of Kupffer cell function before organ harvest could be beneficial in human liver transplantation and surgery.

Topics: Animals; Cells, Cultured; Dinoprostone; Female; Glycogen; Hypoxia; Kupffer Cells; Liver; Liver Diseases; Physical Stimulation; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Three procedures were used to stimulate hepatocyte proliferation in the rat without reducing liver mass, resulting in a supplementary growth which differs from the regenerative growth observed after loss of liver mass by hepatectomy or toxic necrosis. They were: (a) the ingestion of cyproterone, a cytochrome P450 inducing drug (b) the injection of an irritant which provokes glycogenesis and synthesis of acute-phase proteins (c) the injection of albumin-bound bilirubin leading to elimination of glucuronated bilirubin in bile. This ensuing supplementary growth was studied in the rat under several conditions of hepatic proliferation: 1. In normal adult rats, in which hepatocyte proliferation is very low, the effect on proliferation was either weak or undetectable. 2. In suckling rats, with a rapid body and liver growth, all the stimulants provoked a synchronized wave of proliferation with a steep increase of the percentage of S-phase hepatocytes from 4.5% in controls to 15-30% in treated rats. This increase was followed by a compensatory period of low proliferation during which a treatment with a second stimulant was much less effective. 3. In 2/3 hepatectomized adult rats, the proliferation induced by cyproterone was higher than the spontaneous regenerative proliferation alone and additional to it during all of the regenerative process. The proliferation induced by acute inflammation was competitive with the synchronous spontaneous proliferation during the early period of synchronized proliferation following surgery, suggesting that both are similar acute responses. Differently, during the late period of lower and unsynchronized regenerative proliferation, the proliferation provoked by acute inflammation was additional to the spontaneous one. A stimulation of proliferation by injection of the albumin-bilirubin complex was observed during the late period after 2/3 hepatectomy. The highest level of stimulation occurred when the liver growth and the hepatocyte proliferation were already high. This suggests that these stimulants are not complete mitogenic stimuli and need cofactors which are present during the spontaneous growth or, alternatively, that the effect of stimulants is opposed by an inhibitory mechanism present in the adult rat.

Topics: Acute-Phase Reaction; Age Factors; Alanine Transaminase; Albumins; Androgen Antagonists; Animals; Animals, Suckling; Bilirubin; Caseins; Cell Division; Chelating Agents; Chemical and Drug Induced Liver Injury; Cyproterone; Energy Metabolism; Glycogen; Hepatectomy; Hepatocytes; Liver; Liver Diseases; Liver Regeneration; Male; Organ Size; Rats; Rats, Wistar

Whole body catabolism as the result of intrahepatic metabolic derangement is common in liver transplant candidates. However, individual nutritional assessment parameters lack sensitivity and specificity in determining energy status of these patients. Recently, serum hepatocyte growth factor (HGF) has been shown to reflect the recovery of hepatic energy metabolism after liver transplantation.. The relation between preoperative levels of serum HGF and metabolic variables was investigated to clarify the clinical value of measuring HGF in evaluations of the catabolism.. Blood samples were obtained from 30 liver transplant recipients, and biopsy specimens were taken from each recipient's rectus muscle and the explanted liver. Preoperative serum concentration of HGF was determined. Whole body energy metabolism was assessed by measuring glycogen contents of biopsy specimens and plasma or serum levels of glucose, insulin, total ketone bodies, total carnitine, and amino acids.. Serum HGF concentration was elevated in 22 of 30 patients and correlated with the Child-Pugh score. It showed a negative association with muscle glycogen content, and a positive correlation with serum levels of glucose, total carnitine, and total ketone bodies. Patients with elevated serum HGF concentrations had higher preoperative plasma levels of aromatic amino acids and branched chain amino acids, associated with lower branched chain to aromatic amino acid ratios.. The elevated serum concentration of HGF in liver transplant candidates reflected inhibition of peripheral glucose storage, enhanced lipid oxidation, and increased peripheral release of branched chain amino acids, and thus extensive energy catabolism.

Topics: Adult; Aged; Amino Acids; Amino Acids, Branched-Chain; Biomarkers; Blood Glucose; Carnitine; Case-Control Studies; Glycogen; Hepatocyte Growth Factor; Humans; Ketone Bodies; Liver; Liver Diseases; Liver Transplantation; Middle Aged; Muscle, Skeletal

Although discontinuous total parenteral nutrition (d-TPN) has recently been favored for clinical use over continuous total parenteral nutrition (c-TPN) to ameliorate liver dysfunction, mechanisms for the protection against postoperative liver dysfunction remain unknown. This study aimed to examine differences in mitochondrial function in d-TPN- and c-TPN-pretreated livers during ischemia-reperfusion. Rat livers pretreated with d-TPN or c-TPN were perfused with Krebs-Ringer buffer and were exposed to 25% low-flow hypoxia followed by reperfusion. Intrahepatic mitochondrial membrane potential (triangle up) and cell viability were assessed by dual-color digital microfluorography using rhodamine 123 (Rh123) and propidium iodide (PI), respectively. In response to hypoxia, livers pretreated with c-TPN, d-TPN, and an ordinary chow diet exhibited a significant triangle up reduction among the entire lobules. Upon reperfusion, the regional triangle up values further decreased in the c-TPN liver, whereas those in the d-TPN-treated or chow-treated livers displayed a rapid recovery toward the control levels. The severity of cell injury did not differ among the groups, showing that the reperfusion-induced triangle up drop in the c-TPN-pretreated liver is not a consequence of cell injury. Differences in the triangle up drop among the groups appear to occur irrespective of those in the glycogen storage, because the livers undergoing d-TPN display a marked triangle up recovery even when reperfused at the end of a fasted state. These results indicate that c-TPN, but not d-TPN, jeopardizes mitochondrial re-energization and suggest that a circadian pattern of the TPN serves as a potentially beneficial strategy to reduce the risk of postischemic mitochondrial dysfunction in the liver.

Topics: Animals; Bile; Cell Survival; Fluorescent Dyes; Glycogen; Intracellular Membranes; Ischemia; Liver; Liver Diseases; Male; Membrane Potentials; Mitochondria, Liver; Nutritional Status; Parenteral Nutrition, Total; Phagocytosis; Rats; Rats, Wistar; Reperfusion Injury; Rhodamine 123

Although, diet restriction (DR) has been shown to substantially increase longevity while reducing or delaying the onset of age-related diseases, little is known about the mechanisms underlying the beneficial effects of DR on acute toxic outcomes. An earlier study (S. K. Ramaiah et al., 1998, Toxicol. Appl. Pharmacol. 150, 12-21) revealed that a 35% DR compared to ad libitum (AL) feeding leads to a substantial increase in liver injury of thioacetamide (TA) at a low dose (50 mg/kg, i.p.). Higher liver injury was accompanied by enhanced survival. A prompt and enhanced tissue repair response in DR rats at the low dose (sixfold higher liver injury) occurred, whereas at equitoxic doses (50 mg/kg in DR and 600 mg/kg in AL rats) tissue repair in AL rats was substantially diminished and delayed. The extent of liver injury did not appear to be closely related to the extent of stimulated tissue repair response. The purpose of the present study was to investigate the time course (0-120 h) of liver injury and liver tissue repair at the high dose (600 mg TA/kg, i.p., lethal in AL rats) in AL and DR rats. Male Sprague-Dawley rats (225-275 g) were 35% diet restricted compared to their AL cohorts for 21 days and on day 22 they received a single dose of TA (600 mg/kg, i.p.). Liver injury was assessed by plasma ALT and by histopathological examination of liver sections. Tissue repair was assessed by [3H]thymidine incorporation into hepatonuclear DNA and proliferating cell nuclear antigen (PCNA) immunohistochemistry during 0-120 h after TA injection. In AL-fed rats hepatic necrosis was evident at 12 h, peaked at 60 h, and persisted thereafter until mortality (3 to 6 days). Peak liver injury was approximately twofold higher in DR rats compared to that seen in AL rats. Hepatic necrosis was evident at 36 h, peaked at 48 h, persisted until 96 h, and returned to normal by 120 h. Light microscopy of liver sections revealed progression of hepatic injury in AL rats whereas injury regressed completely leading to recovery of DR rats by 120 h. Progression of injury led to 90% mortality in AL rats vs 30% mortality in DR group. In the surviving AL rats, S-phase DNA synthesis was evident at 60 h, peaked at 72 h, and declined to base level by 120 h, whereas in DR rats S-phase DNA synthesis was evident at 36 h and was consistently higher until 96 h reaching control levels by 120 h. PCNA studies showed a corresponding increase in cells in S and M phase in the AL and DR groups. DR resulted in

Topics: Animals; Carcinogens; Cell Division; Chemical and Drug Induced Liver Injury; Diet; Glycogen; Liver; Liver Diseases; Liver Function Tests; Liver Regeneration; Male; Rats; Rats, Sprague-Dawley; Thioacetamide

Foci of altered hepatocytes (FAH) represent preneoplastic lesions, as shown in various animal models of hepatocarcinogenesis, but their significance in the human liver has not been established. The cellular composition, size distribution and proliferation kinetics of FAH in 163 explanted and resected human livers with or without hepatocellular carcinoma (HCC) and their possible association with small-cell change of hepatocytes (SCC) were therefore studied. FAH, including glycogen-storing foci, were found in 84 of 111 cirrhotic livers, demonstrating higher incidences in cases with (29/32) than in those without HCC (55/79). FAH were observed more frequently in HCC-free cirrhosis associated with hepatitis B or C virus or chronic alcoholic abuse (high-risk group) (37/47) than in that due to other causes (low-risk group) (12/21). MCF, predominant in cirrhotic livers of the high-risk group, were more proliferative, larger and more often involved in formation of nodules of altered hepatocytes (39.3%) than were GSF (8.5%). The results suggest that the FAH are preneoplastic lesions, MCF being more advanced than GSF. Oncocytic and amphophilic cell foci were also observed, but their significance remains to be clarified. Two types of SCC, namely diffuse and intrafocal SCC, were identified, but only intrafocal SCC was found to be related to increased proliferative activity and more frequent nodular transformation of the FAH involved, suggesting a close association with progression from FAH to HCC.

Topics: Adolescent; Adult; Aged; Carcinoma, Hepatocellular; Cell Division; Child; Child, Preschool; Female; Glycogen; Hepatitis; Humans; Immunohistochemistry; Infant; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Precancerous Conditions; Proliferating Cell Nuclear Antigen

Swelling with nonlipid cytoplasmic vacuolation of diffusely distributed hepatocytes is seen consistently after mild acute and subacute liver injury. Several lines of evidence point to the possibility that this change may reflect a cellular adaptation beneficial to the host, rather than a degenerative change. The nature and significance of this morphological manifestation were tested in batches of albino rats given small doses of a variety of hepatotoxins, some of which were subsequently challenged with a large highly necrogenic dose of carbon tetrachloride (CCl4). Morphological and biochemical investigations showed that cytoplasmic vacuolation of liver cells following low doses of toxins was due to excess accumulation of glycogen, predominantly of the monoparticulate form. These cells lacked features of degeneration or regeneration and were much less susceptible to injury by the large dose CCl4, as assessed by structural and serum enzyme analyses. This tolerance to toxic damage seemed to be associated with excess accumulation of intracellular glycogen. We conclude from these and other observations on animal and human livers that many of the vacuolated hepatocytes seen in liver injury are cells adaptively altered to resist further insult rather than cells undergoing hydropic degeneration, as is commonly believed.

Topics: Adaptation, Physiological; Aflatoxin B1; Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride; Carcinogens; Chemical and Drug Induced Liver Injury; Cytoplasm; Drug Tolerance; Fasting; Formic Acid Esters; Glycogen; Liver; Liver Diseases; Male; Microscopy, Electron; Rats; Rats, Wistar; Vacuoles

The present study describes light and electron microscopic changes in the liver of Atlantic salmon during the development of infectious salmon anemia (ISA). Atlantic salmon postsmolts weighing 80-100 g were infected by intraperitoneal injections, and liver samples were collected sequentially between day 0 and day 25 post infection (p.i.), with time intervals of 3-4 days. At each collection time, livers from five infected fish and two control fish were examined. Changes involving the perisinusoidal macrophages were observed by transmission electron microscopy, from day 4 p.i. Large vacuoles, containing a fine-granular material with low electron density, accumulated in the cytoplasm. These changes persisted and became more severe throughout the investigation, leading to a considerable increase in the size of the cells. At day 14 p.i., degenerative features of the sinusoidal endothelium were observed. By day 18 p.i., areas of the liver were devoid of a sinusoidal endothelial lining, bringing hepatocytes in direct contact with blood cells. At this stage, the sinusoids were moderately congested. From day 21 p.i., heavy sinusoidal congestion, peliosis hepatis, and degeneration of the hepatocytes were observed. No virus was observed in any of the inhabitant cell types of the liver. Gross and light microscopic changes were first recorded at day 18 p.i., as was a significant decrease in the hematocrit values. By day 25 p.i., characteristic multifocal, confluent, hemorrhagic necroses were present. Results of the present investigation suggest that the liver lesions observed with ISA are not the result of the development of an anemia alone or caused by direct viral damage to hepatocytes. Hepatocellular degeneration succeeded changes in the perisinusoidal macrophages and degeneration of the sinusoidal endothelium. These changes may have impeded the sinusoidal blood flow and hence caused an ischemic hepatocellular necrosis.

Topics: Anemia; Animals; Communicable Diseases; Endothelium; Fish Diseases; Glycogen; Hematocrit; Injections, Intraperitoneal; Liver; Liver Diseases; Microscopy, Electron; Salmon; Tissue Fixation

In addition to the infantile lethal form of glycogen storage disease with cardiomyopathy (GSD Type IIa, Pompe disease) 1,4 glucosidase or acid maltase deficiency has been reported in a few children and adults (GSD Type IIb or IIc) erroneously thought to have muscular dystrophies. The clinical heterogeneity of the muscle involvement in these latter cases is illustrated in a 12-year-old boy presenting with a right lumbar mass, growth retardation, muscular weakness including difficulty in walking, and marked elevations of muscle and liver enzymes. Light- and electron-microscopic examination of specimens from the lumbar mass, apparently normal skeletal muscle and liver, showed typical changes consistent with the biochemical and enzymatic features of acid maltase deficiency. GSD Type IIb and IIc are more frequent than suspected, may present as local pseudohypertrophy and should be considered in patients with progressive muscle disease and abnormal serum enzymes.

Topics: alpha-Glucosidases; Back; Child; Diagnosis, Differential; Glucan 1,4-alpha-Glucosidase; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type II; Humans; Liver Diseases; Male; Muscular Diseases

Previous studies have shown that a chlorinated pesticide, chlordecone (Kepone), greatly potentiates carbon tetrachloride (CCl4) hepatotoxicity and lethality (Curtis, L.R., Williams, W.L., and Mehendale, H.M. (1979). Toxicol. Appl. Pharmacol. 51, 283-293; Curtis, L.R., and Mehendale, H.M. (1980). Drug Metab. Dispos. 8, 23-27). The present study describes sequential morphologic changes which occurred in livers of rats given a "nontoxic" level of chlordecone (10 ppm for 15 days) followed by a single injection of CCl4 (0.1 ml/kg). The hepatic alterations were examined 1 to 36 hr after exposure of the rats to CCl4. Those changes were compared to hepatic alterations which occurred in rats that received the same dose of chlordecone (10 ppm for 15 days) or a single injection of CClr (0.1 ml/kg) alone. The only change noted in livers from rats that received chlordecone alone was focal increase in smooth endoplasmic reticulum (SER) of hepatocytes at 24 hr and continuing throughout the time course of the experiment. Livers from animals that received CCl4 alone showed morphologic changes at 6 hr consisting of glycogen loss, increase in SER, and dilatation of rough endoplasmic reticulum (RER) in pericentral hepatocytes. Accumulation of small lipid droplets was also noted in midzonal hepatocytes. After 6 hr, there was no further increase in severity of injury. At 12 hr recovery was noticeable and, by 36 hr, livers from the CCl4 group appeared normal. Prior administration of chlordecone greatly potentiated pathologic changes in livers of animals that received CCl4. By 4 hr, there was total loss of glycogen in hepatocytes throughout the entire lobule. Small lipid droplets were present in pericentral, midzonal and periportal hepatocytes. Hepatocytes with extremely dilated RER were randomly scattered throughout the entire lobule. At 6 hr, there was further accumulation of lipid in the form of large droplets in hepatocytes. Focal, necrotic cells surrounded by polymorphonuclear leukocytes were randomly distributed throughout the lobule. The number of necrotic foci had progressively increased at the 12- and 24-hr intervals. By 36 hr, confluent areas of necrosis in pericentral and midzonal areas were observed in livers of some animals. This study indicates that although the combination of chlordecone and CCl4 produces much greater hepatic injury resembling damage due to a massive dose of CCl4, histologically, some differences in the progression and distribution of hepatocellul

Topics: Animals; Carbon Tetrachloride; Cell Nucleus; Chemical and Drug Induced Liver Injury; Chlordecone; Cytoplasm; Drug Synergism; Endoplasmic Reticulum; Glycogen; Insecticides; Kinetics; Liver; Liver Diseases; Male; Microscopy, Electron; Rats; Rats, Inbred Strains

The present study, conducted over a time course of 36 hr after CCl4 administration, describes sequential morphometric and biochemical changes which occur in livers of rats exposed to a combination of low levels of chlordecone (10 ppm for 15 days) and a single ip injection of CCl4 (0.1 ml/kg). Those changes were compared to hepatic alterations which occur in rats that received the same dose of chlordecone or CCl4 alone. Biochemical studies showed only trivial increases in levels of glutamic-pyruvic transaminase (GPT), glutamic-oxalacetic transaminase (GOT), and moderate but temporary increases in isocitrate dehydrogenase (ICD) after CCl4 alone. The combination of chlordecone and CCl4 resulted in significantly greater elevations of all three serum enzymes at all time intervals examined. Morphometric data showed no difference between normal diet controls and animals exposed to chlordecone alone as far as numerical density of hepatocytes or volume densities of hepatocytes with glycogen, lipid, dilated rough endoplasmic reticulum (RER), pyknosis, or mitoses. Morphometric analysis of livers from animals that received CCl4 alone showed decreases in numerical density, temporary decrease in percentage of hepatocytes containing glycogen, an increase in hepatocytes containing lipid, temporary increase in hepatocytes with dilated RER, and temporary increases in pyknotic nuclei. Soon after the initial hepatic injury was histologically evident between 4 and 6 hr, the number of mitoses increased dramatically and this progressed until complete recovery from CCl4 damage. From all indices of damage, complete recovery was evident by 36 hr after CCl4 administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride; Cell Nucleus; Chemical and Drug Induced Liver Injury; Chlordecone; Drug Synergism; Endoplasmic Reticulum; Glycogen; Insecticides; Isocitrate Dehydrogenase; Kinetics; Lipid Metabolism; Liver Diseases; Male; Mitosis; Rats; Rats, Inbred Strains

Two cases of type III glycogen storage disease are reported in adults; the occurrence of cirrhosis in one case illustrates the potential development of chronic liver disease in this condition. The other was the oldest patient with this condition found in a review of published reports. Electron microscopy of peripheral blood leucocytes to demonstrate excess glycogen was found to be a quick and useful aid to diagnosis. Histology of these adult cases showed a distribution of hepatocyte vacuolation which has not been previously recorded.

Topics: Adult; Aged; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type III; Humans; Leukocytes; Liver; Liver Diseases; Male

Topics: Adolescent; Child; Child, Preschool; Erythrocytes; Glycogen; Glycogen Debranching Enzyme System; Glycogen Storage Disease; Glycogen Storage Disease Type I; Glycogen Storage Disease Type II; Glycogen Storage Disease Type IV; Humans; Infant; Leukocytes; Liver; Liver Diseases; Phosphorylase a

We found marked accumulation of glycogen in the brain in one case of the cerebro-hepato-renal syndrome (CHRS). Glycogen in the form of beta-particles was deposited freely within the nucleus, perikaryon and cell processes of neurons and glial cells. The changes involved the gray matter diffusely but were more prominent in the cerebral cortex. The patient died at the age of 4 months after a clinical course characterized by severe hypotonia, seizures, and apneic episodes. Other neuropathologic findings were developmental malformations of the central nervous systen (CNS) (pachygyria, polymicrogyria, and hypoplasia of the inferior olives), white matter abnormalities (deficiency in myelination and diffuse accumulation of sudanophilic droplets within glial cells), clusters of peculiar "globoid" histiocytes with pleomorphic lipid inclusions, and microglial nodules in gray and white matter. This unusual combination of findings is regarded as characteristic of the CHRS.

Topics: Brain; Brain Diseases; Cerebral Cortex; Glycogen; Histocytochemistry; Humans; Infant; Kidney Diseases; Liver Diseases; Male; Neuroglia; Neurons; Syndrome

Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Experimental; Dogs; Fatty Liver; Female; Glycogen; Humans; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Lipid Metabolism; Liver; Liver Cirrhosis; Liver Diseases; Male; Rabbits; Rats

Liver dysfunction following whole-body Co-60 irradiation has been studied in domestic and desert rat species. A significant elevation in the serum transaminases activity was noticed both in gerbil and house rat. Alkaline phosphatase and plasma cholesterol levels were also increased indicating an early radiation impairment of the liver tissue, which was later confirmed by histological studies. A steady fall in liver glycogen in irradiated gerbils was strikingly in contrast to an increase in irradiated house rat. Drastic depletion in liver glycogen, changes in the serum enzyme levels and the severity of the hepatic necrosis in gerbils point out that desert mammalian species are much more sensitive to radiation hazard as compared with domestic ones.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Cholesterol; Gerbillinae; Glycogen; Liver; Liver Diseases; Necrosis; Radiation Effects; Radiation Injuries; Rats

Topics: Aged; Carbohydrate Metabolism; Child; Diabetes Complications; Drug-Related Side Effects and Adverse Reactions; Fatty Liver; Female; Glycogen; Humans; Lipid Metabolism; Liver Diseases; Male; Metabolic Diseases; Oxygen Consumption; Proteins

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Contrast Media; Glycogen; Golgi Apparatus; Humans; L-Lactate Dehydrogenase; Leucyl Aminopeptidase; Liver; Liver Diseases; Male; Microscopy, Electron; Mitochondria, Liver; Phagocytosis; Pinocytosis; Radiography; Rats

Topics: Acid Phosphatase; Animals; Chemical and Drug Induced Liver Injury; Esterases; Female; Glycogen; Histocytochemistry; L-Lactate Dehydrogenase; Lanthanum; Liver; Liver Diseases; Malate Dehydrogenase; Male; Phosphorylase Kinase; Rats; Succinate Dehydrogenase

Topics: Cells, Cultured; Culture Media; DNA; Fibroblasts; Glucosidases; Glucosyltransferases; Glycogen; Glycogen Storage Disease; Glycogen Synthase; Glycoside Hydrolases; Heart Diseases; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Liver Diseases; Methods; Muscular Diseases; Phosphorylases; Proteins

Topics: Bone Marrow; Glucose Tolerance Test; Glucose-6-Phosphatase; Glucosidases; Glucosyltransferases; Glycogen; Glycogen Storage Disease; Glycogen Synthase; Humans; Infant; Leukocytes; Liver; Liver Diseases; Liver Glycogen; Male; Microscopy, Electron; Molecular Weight; Myocardium; Phosphoglucomutase; Phosphorylase Kinase

Topics: Adenosine Monophosphate; Child; Diagnosis, Differential; Glycogen; Glycogen Storage Disease; Hepatomegaly; Humans; Leukocytes; Liver; Liver Diseases; Liver Glycogen; Male; Phosphorylase Kinase; Phosphorylases

Topics: Adolescent; Blood Glucose; Electrophoresis, Polyacrylamide Gel; Forearm; Glucose Tolerance Test; Glucosidases; Glycogen; Glycogen Storage Disease; Humans; Iodine; Lactates; Liver Diseases; Magnetic Resonance Spectroscopy; Male; Microscopy, Electron; Muscle Proteins; Muscles; Muscular Diseases; Physical Exertion; Spectrophotometry, Infrared

Topics: Amylases; Amylopectin; Child; Chromatography, Gel; Glucosyltransferases; Glycogen; Glycogen Storage Disease; Humans; Liver Diseases; Male; Molecular Conformation

Topics: Carbohydrate Metabolism; Chronic Disease; Epinephrine; Fatty Acids, Nonesterified; Glycogen; Humans; Lipid Mobilization; Liver Diseases

Topics: Adenosine Triphosphatases; Alkaline Phosphatase; Animals; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cold Temperature; Drug Tolerance; Glutamate Dehydrogenase; Glycogen; Histocytochemistry; Lipid Metabolism; Liver; Liver Diseases; Mice; Necrosis; Staining and Labeling; Time Factors

Topics: Autoradiography; Blood Glucose; Carbon Isotopes; Erythrocytes; Female; Galactose; Glucagon; Glucosidases; Glycogen; Glycogen Storage Disease; Humans; Infant; Leukocytes; Liver; Liver Diseases; Male; Muscles; Pedigree; Syndrome; Transferases

Topics: Biopsy; Child, Preschool; Glucosidases; Glycogen; Glycogen Storage Disease; Humans; Infant; Liver; Liver Diseases; Microscopy, Electron; Mitochondria, Liver; Muscles; Myofibrils

Topics: Animals; Biopsy; Carbohydrate Metabolism, Inborn Errors; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Endoplasmic Reticulum; Fructose; Galactose; Glucose; Glycogen; Golgi Apparatus; Humans; Liver; Liver Diseases; Male; Mannitol; Mannose; Microscopy; Microscopy, Electron; Rats; Rats, Inbred Strains; Ribosomes

Topics: Cell Nucleus; Child; Cytoplasm; Diabetes Mellitus; Gluconeogenesis; Glycogen; Glycosuria; Humans; Liver; Liver Diseases; Microscopy; Prediabetic State; Time Factors

Topics: Alcoholism; Animals; Cholangitis; Dogs; Glucose; Glycogen; Humans; Hypoglycemia; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Rabbits; Rats

Topics: Adenosine Triphosphate; Adenylyl Cyclases; Glucose; Glucosyltransferases; Glycogen; Glycogen Storage Disease; Humans; Liver Diseases; Male; Phosphorylase Kinase; Phosphorylases

Topics: Brain; Chronic Disease; Ganglia; Glycogen; Histocytochemistry; Humans; Liver Cirrhosis; Liver Diseases; Microscopy, Electron; Polysaccharides; Staining and Labeling

Topics: Animals; Biopsy; Carcinoma, Hepatocellular; Cell Membrane; Cell Nucleolus; Cell Nucleus; Cytoplasm; Endoplasmic Reticulum; Glycogen; Golgi Apparatus; Humans; Inclusion Bodies; Liver; Liver Diseases; Liver Neoplasms; Microscopy, Electron; Mitochondria, Liver; Neoplasms, Experimental

Topics: Acid Phosphatase; Adenosine Triphosphatases; Alkaline Phosphatase; Animals; Carcinogens; Carcinoma, Hepatocellular; Fluorenes; Glucose-6-Phosphatase; Glucuronidase; Glycogen; Histocytochemistry; Hyperplasia; L-Lactate Dehydrogenase; Liver Diseases; Liver Neoplasms; Male; Neoplasms, Experimental; Phosphorylase Kinase; Rats; Succinate Dehydrogenase

Topics: Child; Child, Preschool; Fatty Acids, Nonesterified; Female; Fructose-Bisphosphatase; Gluconeogenesis; Glucosidases; Glucosyltransferases; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type I; Growth Hormone; Humans; Hydrocortisone; Infant; Insulin; Liver; Liver Diseases; Male; Phosphofructokinase-1

Topics: Autopsy; Biopsy; Cardiomyopathies; Glucosidases; Glycogen; Glycogen Storage Disease; Glycoside Hydrolases; Humans; Infant; Kidney; Kidney Diseases; Liver; Liver Diseases; Microscopy, Electron; Muscles; Muscular Diseases; Myocardium; Ultracentrifugation

Topics: Adolescent; Bile; Body Weight; Carbohydrate Metabolism, Inborn Errors; Child; Child, Preschool; Cystic Fibrosis; Female; Galactosemias; Glycogen; Hepatitis A; Hepatolenticular Degeneration; Humans; India; Infant; Infant Nutritional Physiological Phenomena; Liver Diseases; Male; Tyrosine

Topics: Biopsy; Female; Glycogen; Glycogen Storage Disease; Heterozygote; Humans; Leukocytes; Liver; Liver Diseases; Phosphorylase Kinase

Topics: Adult; Child; Child, Preschool; Consanguinity; Glucosidases; Glycogen; Glycogen Storage Disease; Humans; Infant; Liver Diseases; Liver Glycogen; Male; Muscular Diseases; Pedigree

Topics: Carbon Isotopes; Glucose; Glucosidases; Glucosyltransferases; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type I; Glycoside Hydrolases; Hepatitis; Humans; Jaundice, Chronic Idiopathic; Liver Diseases; Liver Glycogen; Molecular Weight; Muscular Diseases; Phosphorylases; Ultracentrifugation

Topics: Aflatoxins; Animals; Body Weight; Chemical and Drug Induced Liver Injury; Glycogen; Liver Diseases; Male; Necrosis; Rabbits; Skin Absorption; Time Factors

Topics: Chronic Disease; Epinephrine; Fatty Acids, Nonesterified; Glycogen; Glycolysis; Humans; Liver Diseases

Three cases of nuclear glycogenosis in the liver of diabetic patients have been studied by electron microscopy. In addition to the glycogen deposits described by others, an unusual intranuclear glycogen-filled body was found in all three cases. This body occurred alone or in close contact with the major glycogen deposit.

Topics: Diabetes Complications; Diabetes Mellitus; Female; Glycogen; Glycogen Storage Disease; Histocytochemistry; Humans; Liver Diseases; Male; Microscopy, Electron

Topics: Child; Female; Glucosidases; Glycogen; Glycogen Storage Disease; Humans; Liver; Liver Diseases; Muscles; Muscular Diseases

Topics: Adult; Anemia, Hemolytic; Cardiovascular Diseases; Chronic Disease; Diabetes Mellitus; Female; Gastrointestinal Diseases; Gestational Age; Glycogen; Humans; Hyperthyroidism; Infant, Newborn; Liver Diseases; Neoplasms; Nephritis, Interstitial; Postpartum Period; Pregnancy; Respiratory Tract Diseases

Topics: Blood Cells; Erythrocytes; Follow-Up Studies; Glycogen; Humans; Infant; Leukocytes; Liver; Liver Diseases; Male; Phosphorylase Kinase

Topics: Brain Diseases; Glycogen; Humans; In Vitro Techniques; Liver Diseases; Staining and Labeling

Topics: Glucosidases; Glycogen; Glycogen Storage Disease; Humans; Hyperplasia; Hypertrophy; Infant; Liver Diseases; Metabolic Diseases; Metabolism; Muscular Diseases

Topics: Glycogen; Hepatocytes; Humans; Liver Diseases

Topics: Alcoholic Intoxication; Carbohydrate Metabolism; Fructose; Glycogen; Humans; Liver Diseases; Liver Glycogen

Topics: Glycogen; Humans; Liver Diseases

Topics: Biopsy; Glycogen; Hepatitis; Histocytochemistry; Humans; Liver; Liver Cirrhosis; Liver Diseases; Liver Glycogen; Liver Neoplasms; Phosphorylases; Phosphotransferases

Topics: Glycogen; Liver; Liver Diseases; Phosphorylases

Topics: Glycogen; Humans; Liver; Liver Diseases; Reproducibility of Results

Topics: Glycogen; Hepatolenticular Degeneration; Humans; Liver; Liver Diseases

Topics: Diabetes Complications; Diabetes Mellitus; Glucagon; Glycogen; Humans; Liver Diseases

Topics: Child; Glucose; Glucose-6-Phosphatase; Glycogen; Humans; Infant; Liver Diseases; Phosphoric Monoester Hydrolases; Pupil Disorders; Siblings

Topics: Diabetes Complications; Glycogen; Glycogen Storage Disease; Humans; Iatrogenic Disease; Liver Diseases

Topics: Animals; Fatty Liver; Glycogen; Humans; Liver Diseases; Liver Glycogen; Rabbits

Topics: Glycogen; Glycogen Storage Disease; Humans; Liver Diseases

Topics: Glycogen; Humans; Liver Diseases; Phosphoric Monoester Hydrolases

Topics: Child; Glycogen; Glycogen Storage Disease; Glycogenolysis; Hepatomegaly; Humans; Infant; Liver Diseases

Topics: Glycogen; Glycogenolysis; Humans; Liver Diseases; Liver Glycogen

Topics: Fatty Liver; Glycogen; Humans; Keto Acids; Ketones; Lactates; Liver Diseases; Pyruvates

Topics: Choline; Glycogen; Glycogenolysis; Humans; Liver Diseases

Topics: Blood Glucose; Glucagon; Glycogen; Hormones; Humans; Liver Diseases; Pancreas

Topics: Glycogen; Hepatomegaly; Humans; Liver Diseases

Topics: Glycogen; Glycogenolysis; Humans; Liver Diseases; Liver Glycogen

Topics: Glycogen; Glycogenolysis; Humans; Liver; Liver Diseases; Liver Regeneration; Mitosis

Topics: Glycogen; Glycogenolysis; Humans; Liver; Liver Diseases

Topics: Glycogen; Humans; Liver Diseases; Liver Glycogen

Topics: Glycogen; Humans; Liver Diseases; Muscles

Topics: Glycogen; Humans; Liver Diseases