Wilson’s disease (WD) is a genetic metabolic disease strictly associated with liver cirrhosis. In this review, the genetic bases of the disease are discussed, with emphasis on the role of ATP7B (the ...Wilson disease protein) dysfunction as a determinant factor of systemic copper overload.
Regarding the different multiple mutations described in WD patients, the peculiarity of Sardinian population is highlighted, Sardinians carrying a rare deletion in the promoter (5′ UTR) of the WD gene.
The role of epigenetic changes in the clinical presentation and evolution of liver disease in WD patients is also discussed, nutrition probably representing a relevantly risk factor in WD patients. The role of transmission electron microscopy in the diagnosis of WD-related liver disease is underlined. Mitochondrial changes, increased peroxisomes fat droplets, lipolysosomes and intranuclear glycogen inclusions are reported as the most frequent ultrastructural changes in the liver of WD carriers.
The role of histochemical stains for copper is analyzed, and the Timm's method is suggested as the most sensitive one for revealing hepatic copper overload in all stage of WD.
The marked variability of the histological liver changes occurring in WD is underlined simple steatosis may represent the only pathological changes, frequently associated with glycogenated nuclei.
Mallory-Denk bodies lipogranulomas alcoholic and non-alcoholic fatty liver disease ending with bridging fibrosis and cirrhosis. Finally, the reversal of fibrosis as a possible therapeutic objective in WD is discussed.
This article highlights the molecular mechanisms underlying copper trafficking inside the hepatocyte, focusing on the role of hCtr1 (the copper transporter 1) and the copper metallochaperone Atox1 in copper transfer from the sinusoidal lumen toward the Golgi Apparatus where the ATP7B (Wilson disease protein) is located. Display omitted
•Altered copper metabolism and liver overload•Open questions regarding the relationships between copper storage and liver disease•Morphology role is to identify the structural and ultrastructural aspects.•Liver histology and Wilson disease, non-alcoholic fatty liver disease, viral hepatitis
Magnesium is an essential trace metal and a necessary factor for multiple biochemical functions in humans. Its role in biology is fundamental in over 600 enzymatic reactions implicated in protein ...synthesis, mitochondrial functions, neuromuscular activity, bone formation, and immune system competence. Magnesium status is relevant in fetal development during gestation and in the newborn growth during the perinatal period. Moreover, magnesium is able to influence fetal programming and disease presentation in childhood or adulthood. The aim of this review is to focus on this metal homeostasis, analyzing its normal values, the causes of hypomagnesemia, the interaction with drugs and other conditions, and the diseases associated with magnesium value alteration during pregnancy, in order to study its role in fetal programming of adult diseases. The data here reported clearly indicated the existence of a connection between magnesium status and human pathology starting from intrauterine life and extending into childhood and adulthood.
The authors report their experience regarding parotidectomy performed under a three-dimensional-high-definition (3D-HD) exoscope, with the aim of evaluating its effectiveness in parotid surgery. This ...is a prospective study on nine patients treated by the same surgeon. All patients underwent parotidectomy for extrafacial primary tumours without preoperative involvement of the skin or of the facial nerve from March 2019 to June 2019 with the use of a 3D-HD exoscope. Magnification was variable from 8x to 30x with direct vision supplied by a 3D monitor. Six men and three women, mean (range) age 47.8 (19-74) years underwent parotidectomy. No patient experienced postoperative complications or definitive facial palsy. The mean (range) time of surgery was 149.4 (115 - 210) minutes. The 3D exoscope represents a valid alternative to the operative microscope or surgical loupe for parotid surgery. It is a light instrument allowing for precise surgical dissection of the parotid region by reducing the risks for iatrogenic lesions of the facial nerve using a real 3D magnification of the anatomical structures in HD. Furthermore, its use does not prolong the operative time and shows high potential for training and educational purposes since the operating room staff can better perceive the procedure and the surgeon’s fine gestures. Although the preliminary applications show promising results, there is still a need for wider scientific validation.
Iron and copper ions play important roles in many physiological functions of our body, even though the exact mechanisms regulating their absorption, distribution and excretion are not fully ...understood. Metal-related human pathology may be observed in two different clinical settings: deficiency or overload. The overload in liver cells of both trace elements leads to multiple cellular lesions. Here we report the main pathological changes observed at transmission electron microscopy in the liver of subjects affected by Beta-thalassemia and by Wilson's disease. The hepatic iron overload in beta-thalassemia patients is associated with haemosiderin storage both in Kupffer cells and in the cytoplasm of hepatocytes. Haemosiderin granules are grouped inside voluminous lysosomes, also called siderosomes. Other ultrastructural changes are fat droplets, proliferation of the smooth endoplasmic reticulum and fibrosis. Apoptosis of hepatocytes and infiltration of sinusoids by polymorphonucleates is also detected in beta-thalassemia. Ultrastructural changes in liver biopsies from Wilson's disease patients are characterized by severe mitochondrial changes, associated with an increased number of perossisomes, cytoplasmic lipid droplets and the presence of lipolysosomes, characteristic cytoplasmic bodies formed by lipid vacuoles surrounded by electron-dense lysosomes. In patients affected by Wilson's disease, nuclei are frequently involved, with disorganization of the nucleoplasm and with glycogen inclusions. On the contrary, no significant changes are detected in Kupffer cells. Our data show that iron and copper, even though are both transition metals, are responsible of different pathological changes at ultrastructural level. In particular, copper overload is associated with mitochondrial damage, whereas iron overload only rarely may cause severe mitochondrial changes. These differences underlay the need for further studies in which biochemical analyses should be associated with ultrastructural data, in order to better understand the molecular ways associated with iron- and copper-related pathology at subcellular level.
In human pathology, SARS-CoV-2 utilizes multiple molecular pathways to determine structural and biochemical changes within the different organs and cell types. The clinical picture of patients with ...COVID-19 is characterized by a very large spectrum. The reason for this variability has not been clarified yet, causing the inability to make a prognosis on the evolution of the disease.
PubMed search was performed focusing on the role of ACE 2 receptors in allowing the viral entry into cells, the role of ACE 2 downregulation in triggering the tissue pathology or in accelerating previous disease states, the role of increased levels of Angiotensin II in determining endothelial dysfunction and the enhanced vascular permeability, the role of the dysregulation of the renin angiotensin system in COVID-19 and the role of cytokine storm.
The pathological changes induced by SARS-CoV-2 infection in the different organs, the correlations between the single cell types targeted by the virus in the different human organs and the clinical consequences, COVID-19 chronic pathologies in liver fibrosis, cardiac fibrosis and atrial arrhythmias, glomerulosclerosis and pulmonary fibrosis, due to the systemic fibroblast activation induced by angiotensin II are discussed.
The main pathways involved showed different pathological changes in multiple tissues and the different clinical presentations. Even if ACE2 is the main receptor of SARS-CoV-2 and the main entry point into cells for the virus, ACE2 expression does not always explain the observed marked inter-individual variability in clinical presentation and outcome, evidencing the complexity of this disorder. The proper interpretation of the growing data available might allow to better classifying COVID-19 in human pathology.
The development of the human central nervous system represents a delicate moment of embryogenesis. The purpose of this study was to analyze the expression of multiple immunohistochemical markers in ...the stem/progenitor cells in the human cerebral cortex during the early phases of development. To this end, samples from cerebral cortex were obtained from 4 human embryos of 11 weeks of gestation. Each sample was formalin-fixed, paraffin embedded and immunostained with several markers including GFAP, WT1, Nestin, Vimentin, CD117, S100B, Sox2, PAX2, PAX5, Tβ4, Neurofilament, CD44, CD133, Synaptophysin and Cyclin D1. Our study shows the ability of the different immunohistochemical markers to evidence different zones of the developing human cerebral cortex, allowing the identification of the multiple stages of differentiation of neuronal and glial precursors. Three important markers of radial glial cells are evidenced in this early gestational age: Vimentin, Nestin and WT1. Sox2 was expressed by the stem/progenitor cells of the ventricular zone, whereas the postmitotic neurons of the cortical plate were immunostained by PAX2 and NSE. Future studies are needed to test other important stem/progenitor cells markers and to better analyze differences in the immunohistochemical expression of these markers during gestation.
Systemic bacterial infection induces a hematopoietic response program termed “emergency granulopoiesis” that is characterized by increased de novo bone marrow (BM) neutrophil production. How loss of ...local immune control and bacterial dissemination is sensed and subsequently translated into the switch from steady-state to emergency granulopoiesis is, however, unknown. Using tissue-specific myeloid differentiation primary response gene 88 (Myd88)-deficient mice and in vivo lipopolysaccharide (LPS) administration to model severe bacterial infection, we here show that endothelial cells (ECs) but not hematopoietic cells, hepatocytes, pericytes, or BM stromal cells, are essential cells for this process. Indeed, ECs from multiple tissues including BM express high levels of Tlr4 and Myd88 and are the primary source of granulocyte colony-stimulating factor (G-CSF), the key granulopoietic cytokine, after LPS challenge or infection with Escherichia coli. EC-intrinsic MYD88 signaling and subsequent G-CSF production by ECs is required for myeloid progenitor lineage skewing toward granulocyte-macrophage progenitors, increased colony-forming unit granulocyte activity in BM, and accelerated BM neutrophil generation after LPS stimulation. Thus, ECs catalyze the detection of systemic infection into demand-adapted granulopoiesis.
•ECs express Tlr4 and Myd88 and, after in vivo LPS or E coli stimulation, are the prime sources of G-CSF.•ECs are sensors of systemically spread pathogens and subsequent drivers of BM emergency granulopoiesis.
COVID-19, the newly emerging infectious disease, has been associated with acute liver injury, often related to progression to severe pneumonia. The association between moderate-severe liver injury ...and more severe clinical course of COVID-19 has suggested that liver injury is prevalent in severe than in mild cases of COVID-19, while no difference in liver involvement has been reported between survivors and non-survivors. The spectrum of liver involvement during COVID-19 ranges from an asymptomatic elevation of liver enzymes to severe hepatitis. Only rarely, cases with acute hepatitis have been reported in the absence of respiratory symptoms. Both epithelial and biliary cells possess the angiotensin-converting enzyme-2 receptors that SARS-CoV-2 uses to be internalized. However, to our knowledge, no ultrastructural identification of the virus in liver cells has been reported to date. Here we provide evidence of SARS-CoV-2 in the liver of two patients, a 34-year-old woman and a 60-year-old man with COVID-19.
We investigated two patients with COVID-19 showing several virions within cytoplasmic vacuoles of cholangiocytes and in endothelial cells of hepatic sinusoids. In both patients, we performed histological and ultrastructural examinations by liver biopsy. After two months, both patients were free of symptoms, and the SARS-CoV-2 infection had resolved.
Liver biopsy histological and ultrastructural examination showed liver injury and several virions within cytoplasmic vacuoles of cholangiocytes and in endothelial cells of hepatic sinusoids.
Although most studies in COVID-19 have been focused on the lungs, recently, cholestatic liver pathology has been introduced in the spectrum of pathological changes related to COVID-19. To the best of our knowledge, those presented in this paper are the first images of hepatic SARS-CoV-2 infected liver cells. Our findings suggest a role for cholangiocytes and biliary structures in the COVID-19.
An increasing number of coronavirus disease 2019 (COVID-19) related autoimmune hepatitis (AIH) and autoimmune liver disease (AILD) has been already described so far in the last three years. This rise ...has set up some diagnostic and therapeutic concerns, although steroid therapy has mostly been efficient, avoiding main significant side effects.
We report the case of a 52-year-old subject displaying liver function impairment at the laboratory tests while positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) swab. Needle liver biopsy showed severe portal inflammation, interface hepatitis, lobular inflammation, abundant plasma cells, bridging necrosis, endothelialitis, bile duct vanishing disease, and ductular reaction. The diagnosis of autoimmune liver disease (AILD) was performed. After a month of steroid and ursodeoxycholic acid medications, liver function fully recovered. Azathioprine was introduced, and steroids were gradually reduced.
Probably triggered by the SARS-CoV-2-induced cytokine storm, the association between COVID-19 and autoimmune-related inflammatory injury may display a particular paradigm of AILD pathogenesis.
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