ABSTRACT
Objective: To explore the clinical features of hepatocerebral mitochondrial DNA depletion syndrome (MDS). Methods: The clinical data of 6 hepatocerebral MDS patients diagnosed in the Jinshan Hospital of Fudan University from January 2012 to December 2019 were retrospectively collected and analyzed. Related literature published before January 2020 were searched with the key words of "DGUOK""MPV17""POLG""C10orf2" in PubMed, China national knowledge infrastructure (CNKI) and Wanfang database. Results: All the 6 hepatocerebral MDS cases were male. The age of onset ranged from 3 days to 8 months. The most common initial symptoms were cholestasis and developmental retrogression. The main clinical manifestations included hepatomegaly (4 cases), hypotonia (3 cases), growth retardation (4 cases), cholestasis (5 cases), coagulopathy (5 cases), hypoalbuminemia (3 cases), hypoglycemia (4 cases), hyperlactacidemia (5 cases), and abnormal blood metabolism screening (6 cases). The isotope hepatobiliary imaging revealed no gallbladder and intestinal tract development within 24 hours in 2 patients. Regarding the cranial imaging examination, the head CT found widening of the extracranial space in 1 case, the brain magnetic resonance imaging (MRI) found ventricular enlargement in 2 cases, and the brain ultrasound found peripheral white matter injury in 1 case. Two cases were lost to follow-up, one died of liver failure, and three died of multiple organ failure due to aggravated infection. Among the 6 cases, there were 3 with MPV17 variation (c.182T>C and c.279G>C were novel), 1 with POLG variation (c.2993G>A was novel), 1 with DGUOK variation (c.679G>A homozygous mutation, parthenogenetic diploid of chromosome 2) and 1 with C10orf2 variation (c.1186C>T and c.1504C>T were novel). The literature review found that 129, 100, 51 and 12 cases of hepatocerebral MDS were caused by DGUOK, MPV17, POLG and C10orf2 gene variations, respectively. And the most common clinical manifestations were liver dysfunction presented with cholestasis and elevated transaminase, metabolic disorders including hypoglycemia and hyperlactacidemia, and diverse neurologic symptoms including developmental retardation, hypotonia, epilepsy and peripheral neuropathy. Besides, 1/3 of the patients with C10orf2 variation developed renal tubular injury. Conclusions: Hepatocerebral MDS mainly present with liver dysfunction, metabolic disorder and neuromuscular impairment. Different genotypes show specific clinical manifestations.
Subject(s)
Female , Humans , Infant , Male , Cholestasis , DNA, Mitochondrial/genetics , Hypoglycemia/genetics , Liver Diseases/genetics , Mitochondrial Diseases , Muscle Hypotonia , Retrospective StudiesABSTRACT
With the increasing incidence of hepatobiliary diseases, it is particularly important to understand the role of molecular, cellular and physiological factors in the clinical diagnosis and treatment with traditional Chinese medicine(TCM) in the development of liver disease. Appropriate animal models can help us identify the possible mechanisms of relevant diseases. Danio rerio(zebrafish) model was traditionally used to study embryonic development, and has been gradually used in screening and evaluation of liver diseases and relevant drug in recent years. Zebrafish embryos develop rapidly and the digestive organs of 5-day-old juvenile fish are all mature. At this stage, they may develop hepatobiliary diseases induced by developmental defects or compounds. Zebrafish liver is similar to human liver in cell composition, function, signal transduction, response to injury and cell process mediating liver disease. Furthermore, due to the high conservation of genes and proteins between humans and zebrafish, zebrafish becomes an alternative system for studying basic mechanisms of liver disease. Therefore, genetic screening could be performed to identify new genes involving specific disease processes, and chemical screening could be made for drugs in specific processes. This paper briefly introduced the experimental properties of zebrafish as model system, emphasized the study progress of zebrafish models for pathological mechanism of liver diseases, especially fatty liver, and drug screening and evaluation, so as to provide ideas and techniques for the future liver toxicity assessment of TCM.
Subject(s)
Animals , Humans , Drug Evaluation, Preclinical , Liver , Liver Diseases/genetics , Medicine, Chinese Traditional , Zebrafish/geneticsABSTRACT
Abstract Objectives: The aims of the study were to determine the frequency of hepatobiliary disease in patients with cystic fibrosis and to describe the sociodemographic, clinical, and laboratory profile of these patients. Methods: This was a retrospective, descriptive, and analytical study of 55 patients diagnosed with cystic fibrosis, aged between 3 months and 21 years, followed-up from January 2008 to June 2016 in a referral center. Medical records were consulted and sociodemographic, clinical and laboratory data, including hepatobiliary alterations, imaging studies, genetic studies, liver biopsies, and upper digestive endoscopies were registered. Results: Hepatobiliary disease was diagnosed in 16.4% of the patients and occurred as an initial manifestation of cystic fibrosis in 55.6% of these cases. The diagnosis of hepatopathy occurred before or concomitantly with the diagnosis of cystic fibrosis in 88.9% of the children. All patients with hepatobiliary disease were considered non-white, with a predominance of females (77.8%) and median (IQR) of 54 (27-91) months. Compared with the group without hepatobiliary disease, children with liver disease had a higher frequency of severe mutations identified in the CFTR gene (77.8% vs. 39.6%, p = 0.033) and severe pancreatic insufficiency (88.9% vs. 31.6%, p = 0.007). Conclusion: The frequency of hepatobiliary disease was high, with a very early diagnosis of the disease and its complications in the studied series. A statistical association was observed between the occurrence of hepatobiliary disease and the presence of pancreatic insufficiency and severe mutations in the CFTR gene. It is emphasized that cystic fibrosis is an important differential diagnosis of liver diseases in childhood.
Resumo Objetivos: Os objetivos do estudo foram determinar a frequência da doença hepatobiliar em pacientes com fibrose cística e descrever o perfil sociodemográfico, clínico e laboratorial destes. Métodos: Estudo retrospectivo, descritivo e analítico de 55 pacientes com diagnóstico de fibrose cística, entre três meses e 21 anos, acompanhados de janeiro de 2008 a junho de 2016 em um centro de referência. Foi realizada consulta aos prontuários médicos, registrando-se os dados sociodemográficos, clínicos e laboratoriais, incluindo-se alterações hepatobiliares, exames de imagem, estudos genéticos, biópsias hepáticas e endoscopias digestivas altas. Resultados: A doença hepatobiliar foi diagnosticada em 16,4% dos pacientes e ocorreu como manifestação inicial da fibrose cística em 55,6% destes casos. O diagnóstico da hepatopatia ocorreu antes ou concomitante ao diagnóstico da fibrose cística em 88,9% das crianças. Todos os pacientes com doença hepatobiliar foram considerados não brancos, havendo predominância do sexo feminino (77,8%) e mediana (I.I.Q) de idade de 54 (27-91) meses. Em comparação com o grupo sem doença hepatobiliar, as crianças com hepatopatia tiveram maior frequência de mutações graves no gene CFTR identificadas (77,8% vs 39,6%; p = 0,033) e de insuficiência pancreática grave (88,9% vs 31,6%; p = 0,007). Conclusão: A frequência de doença hepatobiliar foi elevada, observando-se um diagnóstico muito precoce da mesma e de suas complicações na casuística estudada. Houve associação estatística entre a ocorrência de doença hepatobiliar e a presença de insuficiência pancreática e de mutações graves do gene CFTR. Enfatiza-se que a fibrose cística represente um importante diagnóstico diferencial de hepatopatias na infância.
Subject(s)
Humans , Male , Female , Child, Preschool , Child , Adolescent , Exocrine Pancreatic Insufficiency/etiology , Cystic Fibrosis/complications , Liver Diseases/etiology , Mutation/genetics , Exocrine Pancreatic Insufficiency/genetics , Socioeconomic Factors , Retrospective Studies , Cystic Fibrosis/genetics , Genotype , Liver Diseases/geneticsABSTRACT
BACKGROUND/AIMS: We tried to investigate the expression characteristics of KAI1, a suppressor of wide-spectrum tumor metastasis, and vascular endothelial growth factor (VEGF), the most common angiogenesis factor, and then to analyze their diagnostic value for hepatocellular carcinoma (HCC). METHODS: The protein and mRNA expression levels of KAI1 or VEGF in HCC tissues and in self-controlled para-carcinoma tissues were analyzed by Western blot and real-time polymerase chain reaction, respectively. Serum levels of KAI1 and VEGF in the patients with HCC, benign liver disease or in healthy controls were quantitatively detected by enzyme-linked immunosorbent assay. RESULTS: The expression level of KAI1 was downregulated, while the expression level of VEGF was upregulated in the tissues or serum of the patients with HCC. The expression level of serum KAI1 in HCC patients was correlated with TNM staging, intrahepatic metastasis, lymph node or peritoneal metastasis, and portal vein thrombus. In addition to the factors that were correlated with KAI1 expression, VEGF expression was also closely related to the alpha-fetoprotein level of the patients. The area under the receiver operating characteristic curve for the diagnosis of HCC was 0.907 for KAI1 and 0.779 for VEGF. The sensitivity of serum KAI1 levels in the diagnosis of HCC was 86.96%; the accuracy was 83.06%, while the sensitivity, the accuracy and the negative predictive value were improved to 91.86%, 84.68%, and 78.79% according to the combined detection of KAI1 and VEGF, respectively. CONCLUSIONS: A combined detection of KAI1 and VEGF may greatly improve the efficiency of diagnosis and form a reliable panel of diagnostic markers for HCC.
Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Kangai-1 Protein/blood , Carcinoma, Hepatocellular/blood , Case-Control Studies , Gene Expression Regulation , Liver Diseases/genetics , Liver Neoplasms/blood , Vascular Endothelial Growth Factor A/blood , alpha-Fetoproteins/analysisABSTRACT
BACKGROUND/OBJECTIVES: Hepatitis B virus (HBV) genotypes may differ in pathogenicity. However, the interplay between different virus characteristics such as genotypes, mutants and virus loads has not been well studied . We investigated the association between HBV genotype, presence of 1896 precore mutation and HBV viral loads in patients with HBV-related liver disease. METHODS: One hundred and sixteen HBV DNA-seropositive patients attending a gastroenterology outpatient clinic and 107 HBV DNA-seropositive blood donors were recruited. The subjects were stratified as those with normal (Group I, n=164) and elevated (Group II, n=59) ALT levels. The HBV genotype and the presence of the 1896 precore mutation were determined, and plasma HBV DNA levels measured. RESULTS: Genotype C was more common in Group II than in Group I (10 (17%) vs. 4 (2.4%); p< 0.005). There was no relationship between the 1896 precore mutation and the HBV DNA levels. Subjects with genotype C (n=14) had higher HBV DNA levels than those with genotypes A (n=33) or D (n=158). CONCLUSIONS: The infecting genotype, but not the presence of 1896 precore mutation, correlates with HBV load. The association of genotype C with higher virus loads and with elevated ALT may point to a greater pathogenicity of this genotype.
Subject(s)
Adult , Cross-Sectional Studies , Female , Genotype , Hepatitis B/genetics , Hepatitis B virus/genetics , Humans , India , Liver/physiopathology , Liver Diseases/genetics , Logistic Models , Male , Middle Aged , Multivariate Analysis , Mutation/genetics , Statistics, Nonparametric , Viral LoadABSTRACT
El cáncer primario de hígado es en el mundo la quinta neoplasia más común en hombres y la octava en mujeres, con gran impacto debido a su alta mortalidad, ya que representa la tercera causa de mortalidad relacionadacon cáncer en población masculina. Se ha descrito una fuerte asociación con factores de riesgo como las hepatitis virales crónicas, las hepatopatías de origengenético, el consumo de alcohol, el tabaquismo y enfermedades metabólicas, entre otras. En este artículo se analizan publicaciones originales y de revisión en las que se evalúan dichos factores y su asociación con el carcinoma hepatocelular (CHC).Además, se recopila información actualizada sobre datos epidemiológicos por regiones del mundo.
Subject(s)
Aflatoxins/adverse effects , Carcinoma, Hepatocellular , Diabetes Mellitus , Ethanol , Risk Factors , Hepacivirus , Hepatitis B virus , Epidemiology , Liver Diseases/genetics , Obesity , NicotianaABSTRACT
Hepatocyte mitochondrion functions as a cause and as a target of liver injury. Since the mitochondria are under dual control of nuclear DNA and mitochondrial DNA (mtDNA), mutations in genes of both classes have been associated with inherited mitochondrial hepatopathies. Point mutations, deletions, insertions, rearrangements, DNA depletion--all have been identified. Many factors influence the prevalence of mitochondrial disorders, including the mutations rate, inheritance pattern, population structure, and the genetic background. In primary disorders, mitochondrial defect is the primary cause of liver disease often producing fatal hepatic failure in infancy or childhood. In secondary disorders, insult to mitochondria is caused by either a gene defect that affects non-mitochondrial proteins or by an exogenous injury to mitochondria. Diagnosis should be suspected in cases of liver disease with neuromuscular symptoms, multisystem involvement that cannot be explained by a single pathology or rapidly progressive liver failure in early childhood. Laboratory findings in the blood and urine show an altered redox status. Various antioxidants, vitamins, cofactors, and electron acceptors have been for proposed but none is effective. Presence of neuromuscular or extraintestinal involvement in primary disorder precludes the use of liver transplantation.
Subject(s)
DNA Mutational Analysis , DNA, Mitochondrial , Humans , Liver Diseases/genetics , Mitochondria, Liver/pathology , Mitochondrial Diseases/genetics , Point MutationABSTRACT
Novel and exciting techniques have been developed for the genetic modification of hepatocytes. There are five broadly defined indications for direct gene transfer in liver therapy: 1] Gene replacement therapy, 2] Gene expression therapy, 3] Viral enzyme prodrug therapy, 4] Inhibition of gene expression, and 5] Repair of abnormal genes. The two main methods of gene delivery to the liver are: 1] viral vectors including Retroviruses, Adenoviruses, Adeno-associated, Simian virus 40, hybrid virus vectors, and 2] non-viral methods involving attachment of a therapeutic gene to a carrier. These may be either polymer based cationic carriers [conjugates] or lipid based vectors [liposomes]. The last decade of the second millennium has seen a lot of research work done in the field of genetics. Based on the many advances in the field, we hope that there is bright future for clinical applications of gene therapy for hepatic diseases
Subject(s)
Humans , Gene Transfer Techniques , Liver Diseases/genetics , Genetic Vectors , Genetic Engineering , Hepatocytes/transplantationABSTRACT
Recent molecular studies have resulted in the identification of genetic alterations underlying several hereditary disorders of the liver. Cloning of disease genes are increasing our understanding of the basic defects in liver diseases. This review focuses on selected inherited liver diseases such as hyperbilirubinemic syndromes, hemochromatosis, Wilson disease and genetic cholestatic syndromes and illustrate the knowledge gained on these disorders from molecular studies. Potential implications of the identification of disease genes such as practical applications for diagnosis, information on prognosis and the possibility to design new therapies are discussed
Subject(s)
Humans , Liver Diseases/genetics , Molecular Biology , Cholestasis/genetics , Hemochromatosis/genetics , Hyperbilirubinemia/genetics , Hepatolenticular Degeneration/geneticsABSTRACT
Alpha1 antitrypsin [alpha1 AT] deficiency is a relatively common genetic cause of liver disease among Caucasians. It is an autosomal recessive disorder characterized by reduced serum levels of alpha1 AT, a 52 KD glycoprotein that functions as an atiprotease. The deficiency state is caused by mutations in the alpha1 AT gene on chromosome 14.alpha1 AT shows considerable genetic variability, having more than 75 genetic variants [pi types]. The piz allele is the most common deficiency variant. Pizz homozygotes have 15-20% of the normale plasma levels of alpha1 AT. The deficiency is due to lack of secretion of Z alpha1 AT from the hepatocyte, where inclusions are formed in the endoplasmic reticulum. Homozygous alpha1 AT deficiency [pizz] is known to predispose to emphysema and chronic liver disease. This review outlines the clinical manifestations and treatment of alpha1 AT deficiency associated liver disease, focusing on recent advances in the pathogenic mechanism of liver disease in this genetic disorder
Subject(s)
Humans , Liver Diseases/geneticsABSTRACT
A alfa-antitripsina é a principal glicoproteína circulante com a funçäo de inibir a açäo das proteases séricas, tais como a elastase produzida pelos glóbulos brancos e a tripsina pelo pâncreas. A quantidade produzida pelo fígado é controlada pro fenômenos inflamatórios e hormonais, com o intuito de balancear a açäo das proteases e seus inibidores em nível vascular e extravascular. A deficiência de alfa 1AT é geralmente designada pelo fenótipo anormal desta glipcoproteína polimórfica. Em torno de 2 a 30 por cento dos indivíduos de certas populaçöes apresentam outro fenótipo Pi (inibidor de protease) que näo o MN, que é o mais comum. A maioria dos fenótipos apresenta níveis...
Subject(s)
Humans , Infant, Newborn , Infant , Child, Preschool , Child , alpha 1-Antitrypsin/deficiency , Liver Diseases/genetics , alpha 1-Antitrypsin/metabolism , Liver Diseases/diagnosis , Liver Diseases/therapy , Lung Diseases/therapyABSTRACT
Aflatoxin B1 (AFB1), a fungal toxin produced by Aspergillus flavus, is known to be a possible hepatocarcinogen. But the molecular biologic changes which may occur following exposure to AFB1 are not known and thus the carcinogenesis is not yet understood. This study was performed to examine the expressions of c-myc, c-fos and TGF-alpha genes and to investigate the possible role of those molecular biologic changes in hepatic regeneration and in the development of hepatocellular carcinoma (HCC). Sprague-Dawley rats were divided into 3 groups: Carbon tetrachloride (CCl4) only was administered to group I, AFB1 only was administered to group II and a combination of AFB1 and CCl4 was administered to group III. The animals were sacrificed at 0.5, 1, 2, 6, 12, 24, 48, and 72 hours after treatment. In addition to the examination of the hematoxylin-eosin stained sections, hepatic regeneration and apoptosis were analyzed quantitatively by bromodeoxyuridine (BrdU)-anti-BrdU immunohistochemistry and TUNEL assay utilizing apoptosis kit, respectively. The hepatic expressions of c-myc, c-fos and transforming growth factor-alpha (TGF-alpha) were examined by immunohistochemistry and studied by Western blot. The number of BrdU labelled cells and the degree of necrosis/apoptosis were comparable among the different groups. Livers of the group II rats showed nearly normal histology without regeneration and necrosis/apoptosis. In groups I and III, the number of BrdU- labelled cells showed an increase at 48 hours after treatment, and the increment was significantly higher in group I than in group III. Most BrdU-labelled cells were mature hepatocytes in group I, whereas in group III they appeared to be less mature. In group I, apoptosis showed an increase at around 24 hours, but appeared in group III as early as 12 hours after treatment and persisted through 48 hours. The expression of c-myc and c-fos were also different between the experimental groups. The expression intensity of c-myc in group I was highest at 1 hour and decreased thereafter. In groups II and III, the expressions were much more intense than in group I, except at 1 hour, and the increased intensity persisted throughout the experiment. Group II in particular showed a peak intensity at 30 minutes and at 6 hours after treatment. In group I, c-fos was strongly expressed only at 24 hours, but in group III, there was progressively increased expression with peak intensity at 24 hours. TGF-alpha was expressed in similar intensities in all groups throughout the experiment. These results suggest that AFB1 may evoke an intense and protracted expression of c-myc, provocating the CCl4-induced necrosis of hepatocytes, and a prolonged expression of c-fos, including persistent signals for regeneration which in turn may activate the replication of immature cells. These findings will aid further investigation of molecular biologic and histologic characteristics of the hepatotoxic and hepatocarcinogenic mechanism of AFB1 in rats. And these results in rats, together with clinico-epidemiologic and molecular biologic investigations in humans and other animals, suggest that AFB1 may supply hepatocarcinogenic background in early exposure time in AFB1-contaminated areas of China and Korea.
Subject(s)
Male , Rats , Aflatoxin B1/pharmacology , Animals , Carbon Tetrachloride , Carcinogens/pharmacology , Gene Expression/drug effects , Genes, Immediate-Early/drug effects , Liver Diseases/metabolism , Liver Diseases/genetics , Liver Diseases/chemically induced , Rats, Sprague-Dawley , Transforming Growth Factor alpha/metabolismSubject(s)
Humans , Gastrointestinal Diseases/genetics , Liver Diseases/genetics , Histocompatibility Antigens/immunology , Gastrointestinal Diseases/etiology , Gastrointestinal Diseases/physiopathology , Gastrointestinal Diseases/prevention & control , Genetic Techniques , Liver Diseases/immunology , Liver Diseases/therapyABSTRACT
To investigate the prevalence of point mutation in the pre-core (pre-C) region of hepatitis B virus (HBV) DNA, we performed dot blot hybridization and sequencing of enzymatically amplified HBV DNA from the sera of 25 patients with HBeAg-positive and 32 patients with HBeAg-negative chronic liver diseases. The pre-C region of HBV DNA was successfully amplified by polymerase chain reaction (PCR) from 55 (96.5%) of 57 sera. According to the status of serum HBeAg, HBV DNA was amplified from all 25 sera of HBeAg-positive patients and 30 (93.8%) of 32 sera of HBeAg-negative patients. All amplified DNA from the sera of 25 patients with HBeAg-positive and that from 28 (93.3%) of 30 patients with HBeAg-negative chronic liver diseases hybridized with the wild type probe. In addition, that from 5 (20.0%) among 25 patients with HBeAg-positive and 16 (53.3%) among 30 patients with HBeAg-negative chronic liver diseases hybridized also with the mutant type probe. These results suggest that the prevalence of point mutation in the pre-C region of HBV DNA is relatively high in patients with HBeAg-negative chronic liver diseases and further study is mandatory to identify the significance of this mutation.
Subject(s)
Humans , Base Sequence , Chronic Disease , DNA, Viral/genetics , Hepatitis B virus/genetics , Liver Diseases/genetics , Molecular Probes/genetics , Molecular Sequence Data , MutationABSTRACT
Se estudiaron 110 niños con diversas enfermedades del hígado: 16 hepatitis aguda viral, 8 hepatitis crónica persistente, 31 hepatitis crónicas activa, 5 esteatosis hepática, 11 cirrosis hepática, 24 colestasis del lactante, 3 enfermedad de Wilson, 2 fibrosis hepática congénita, 5 enfermedades metabólicas y 5 de otras causas, con edades comprendidas entre 2 meses y 14 años, a los que se determinó el fenotipo del sistema Pi por enfoque isoeléctrico en geles ultrafinos de poliacrilamida según el método de Kueppers, con modificaciones como pesquisaje de alfa-1-antitripsina (A1-AT), realizándose los niveles en suero a los que presentaban el fenotipo Pi ZZ, biopsia hepática con coloración de P.A.S. con digestión de diastasa y estudio familiar del fenotipo. Se halló un 3.6% de positividad del fenotipo Pi ZZ en los niños estudiados, presentando disminución sérica de A1-AT y la presencia de inclusiones P.A.S. positivas resistente a diastasa en el citoplasma de los hepatocitos, teniendo 3 de ellos antecendentes de ictericia en la etapa postnatal y el cuarto paciente hepatomegalia como forma de presentación. El estudio del fenotipo a los padres resultó un patrón heterocigótico (MZ) y los hermanos normales (MM). Se insiste en la importancia del diagnóstico de la deficiencia de A1-AT y el valor diagnóstico de la determinación del fenotipo del sistema Pi en toda enfermedad hepática en la infancia y adolescencia