18 research outputs found
Problems in grading and staging of nonalcoholic steatohepatitis: A study of 597 cases by Turkish National Working Group of Hepatopancreatobiliary Pathology
WOS: 00024945460081
Comparison of different chronic hepatitis scores with respect to interobserver variability: A study of Turkish National Working Group of Hepato-pancreato-biliary Pathology
fibrinogen gamma chain mutations provoke fibrinogen and apolipoprotein B plasma deficiency and liver storage
p.R375W (Fibrinogen Aguadilla) is one out of seven identified mutations (Brescia, Aguadilla, Angers, Al du Pont, Pisa, Beograd, and Ankara) causing hepatic storage of the mutant fibrinogen γ. The Aguadilla mutation has been reported in children from the Caribbean, Europe, Japan, Saudi Arabia, Turkey, and China. All reported children presented with a variable degree of histologically proven chronic liver disease and low plasma fibrinogen levels. In addition, one Japanese and one Turkish child had concomitant hypo-APOB-lipoproteinemia of unknown origin. We report here on an additional child from Turkey with hypofibrinogenemia due to the Aguadilla mutation, massive hepatic storage of the mutant protein, and severe hypo-APOB-lipoproteinemia. The liver biopsy of the patient was studied by light microscopy, electron microscopy (EM), and immunohistochemistry. The investigation included the DNA sequencing of the three fibrinogen and APOB-lipoprotein regulatory genes and the analysis of the encoded protein structures. Six additional Fibrinogen Storage Disease (FSD) patients with either the Aguadilla, Ankara, or Brescia mutations were investigated with the same methodology. A molecular analysis revealed the fibrinogen gamma p.R375W mutation (Aguadilla) but no changes in the APOB and MTTP genes. APOB and MTTP genes showed no abnormalities in the other study cases. Light microscopy and EM studies of liver tissue samples from the child led to the demonstration of the simultaneous accumulation of both fibrinogen and APOB in the same inclusions. Interestingly enough, APOB-containing lipid droplets were entrapped within the fibrinogen inclusions in the hepatocytic Endoplasmic Reticulum (ER). Similar histological, immunohistochemical, EM, and molecular genetics findings were found in the other six FSD cases associated with the Aguadilla, as well as with the Ankara and Brescia mutations. The simultaneous retention of fibrinogen and APOB-lipoproteins in FSD can be detected in routinely stained histological sections. The analysis of protein structures unraveled the pathomorphogenesis of this unexpected phenomenon. Fibrinogen gamma chain mutations provoke conformational changes in the region of the globular domain involved in the "end-to-end" interaction, thus impairing the D-dimer formation. Each monomeric fibrinogen gamma chain is left with an abnormal exposure of hydrophobic patches that become available for interactions with APOB and lipids, causing their intracellular retention and impairment of export as a secondary unavoidable phenomenon
Problems in grading and staging of nonalcoholic steatohepatitis: A study of 597 cases by Turkish National Working Group of Hepatopancreatobiliary Pathology
Hepatocellular adenomas in the Turkish population: reclassification according to updated World Health Organization criteria
Aims Hepatocellular adenoma (HCA) is an uncommon liver neoplasm, and studies of HCA subtypes have been primarily limited to France, the USA, and Japan. The aim of this study was to describe the clinicopathological features of HCA subtypes in Turkey
Recurrent Recessive Mutation in Deoxyguanosine Kinase Causes Idiopathic Noncirrhotic Portal Hypertension
Despite advances in the diagnosis and management of idiopathic
noncirrhotic portal hypertension, its pathogenesis remains elusive.
Insight may be gained from study of early-onset familial idiopathic
noncirrhotic portal hypertension, in which Mendelian mutations may
account for disease. We performed exome sequencing of eight subjects
from six kindreds with onset of portal hypertension of indeterminate
etiology during infancy or childhood. Three subjects from two
consanguineous families shared the identical rare homozygous p. N46S
mutation in DGUOK, a deoxyguanosine kinase required for mitochondrial
DNA replication; haplotype sharing demonstrated that the mutation in the
two families was inherited from a remote common ancestor. All three
affected subjects had stable portal hypertension with noncirrhotic liver
disease for 6-16 years of follow-up. This mutation impairs adenosine
triphosphate binding and reduces catalytic activity. Loss-offunction
mutations in DGUOK have previously been implicated in cirrhosis and
liver failure but not in isolated portal hypertension. Interestingly,
treatment of patients with human immunodeficiency viral infection with
the nucleoside analogue didanosine is known to cause portal hypertension
in a subset of patients and lowers deoxyguanosine kinase levels in
vitro; the current findings implicate these effects on deoxyguanosine
kinase in the causal mechanism. Conclusion: Our findings provide new
insight into the mechanisms mediating inherited and acquired
noncirrhotic portal hypertension, expand the phenotypic spectrum of
DGUOK deficiency, and provide a new genetic test for a specific cause of
idiopathic noncirrhotic portal hypertension
Presence and extent of estrogen receptor-alpha expression in patients with simple steatosis and NASH
ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment
Acyl CoA Oxidase 2 (ACOX2) encodes branched-chain acyl-CoA oxidase, a
peroxisomal enzyme believed to be involved in the metabolism of
branched-chain fatty acids and bile acid intermediates. Deficiency of
this enzyme has not been described previously. We report an 8-y-old male
with intermittently elevated transaminase levels, liver fibrosis, mild
ataxia, and cognitive impairment. Exome sequencing revealed a previously
unidentified homozygous premature termination mutation (p.Y69{*}) in
ACOX2. Immunohistochemistry confirmed the absence of ACOX2 expression in
the patient's liver, and biochemical analysis showed marked elevation of
intermediate bile acids upstream of ACOX2. These findings define a
potentially treatable inborn error of bile acid biosynthesis caused by
ACOX2 deficiency
Fibrinogen Gamma Chain Mutations Provoke Fibrinogen and Apolipoprotein B Plasma Deficiency and Liver Storage
p.R375W (Fibrinogen Aguadilla) is one out of seven identified mutations
(Brescia, Aguadilla, Angers, Al du Pont, Pisa, Beograd, and Ankara)
causing hepatic storage of the mutant fibrinogen gamma. The Aguadilla
mutation has been reported in children from the Caribbean, Europe,
Japan, Saudi Arabia, Turkey, and China. All reported children presented
with a variable degree of histologically proven chronic liver disease
and low plasma fibrinogen levels. In addition, one Japanese and one
Turkish child had concomitant hypo-APOB-lipoproteinemia of unknown
origin. We report here on an additional child from Turkey with
hypofibrinogenemia due to the Aguadilla mutation, massive hepatic
storage of the mutant protein, and severe hypo-APOB-lipoproteinemia. The
liver biopsy of the patient was studied by light microscopy, electron
microscopy (EM), and immunohistochemistry. The investigation included
the DNA sequencing of the three fibrinogen and APOB-lipoprotein
regulatory genes and the analysis of the encoded protein structures. Six
additional Fibrinogen Storage Disease (FSD) patients with either the
Aguadilla, Ankara, or Brescia mutations were investigated with the same
methodology. A molecular analysis revealed the fibrinogen gamma p.R375W
mutation (Aguadilla) but no changes in the APOB and MTTP genes. APOB and
MTTP genes showed no abnormalities in the other study cases. Light
microscopy and EM studies of liver tissue samples from the child led to
the demonstration of the simultaneous accumulation of both fibrinogen
and APOB in the same inclusions. Interestingly enough, APOB-containing
lipid droplets were entrapped within the fibrinogen inclusions in the
hepatocytic Endoplasmic Reticulum (ER). Similar histological,
immunohistochemical, EM, and molecular genetics findings were found in
the other six FSD cases associated with the Aguadilla, as well as with
the Ankara and Brescia mutations. The simultaneous retention of
fibrinogen and APOB-lipoproteins in FSD can be detected in routinely
stained histological sections. The analysis of protein structures
unraveled the pathomorphogenesis of this unexpected phenomenon.
Fibrinogen gamma chain mutations provoke conformational changes in the
region of the globular domain involved in the ``end-to-end{''}
interaction, thus impairing the D-dimer formation. Each monomeric
fibrinogen gamma chain is left with an abnormal exposure of hydrophobic
patches that become available for interactions with APOB and lipids,
causing their intracellular retention and impairment of export as a
secondary unavoidable phenomenon