Extrahepatic Pathology Research Articles

Incidental findings during donor liver assessment: Single center experience

Intraoperative consultation of donor liver is an important part of transplant evaluation and determination of liver eligibility. In this study, we describe incidental pathologic findings discovered during the pretransplant evaluation of liver donors in our Institution from 1/2010 to 12/2022. During this 13-year period 369 intraoperative consultations from 262 liver donors were performed. Of those cases, incidental findings were identified in 22 cases (5.9 %) from 19 donors (7.3 %); two donors had more than one lesion. The median age of this subset of patients was 53 years (range: 18–70) and females predominated (63 %). Sixteen of the donors had abnormal findings in the liver: 6 bile duct hamartoma (BDH), 5 hyalinized nodule with Histoplasma capsulatum, 5 focal nodular hyperplasia (FNH), 2 bile duct adenomas (BDA), 1 biliary cyst and 1 hemangioma. One donor had both FNH and a BDH. One BDH and 1 BDA case was misdiagnosed as malignancy during the frozen section evaluation. Three donors had extrahepatic pathologies: a pancreatic tail schwannoma, a low-grade appendiceal mucinous neoplasm, and a lymph node with metastatic endometrial endometrioid adenocarcinoma. Of the 19 livers, the final organ disposition was available for 9: 6 were transplanted (67 %) and 3 were discarded (33 %). Two of the 3 discarded organs were misdiagnosed BDH and BDA cases, and one was incorrectly reported as having 90 % microvesicular steatosis during the frozen assessment. We present the clinicopathologic characteristics of liver donors with incidental findings during the pre-transplant evaluation which could lead to unwarranted graft dismissal if misdiagnosed. Additionally, incidental fungal infections can have implications for immunosuppressive therapy and the decision to use or reject the graft.

Metabolic associated liver disease.

In real practice the patient with liver disease is often the carrier of multiple etiological factors such as metabolic syndrome (MS) and alcohol consumption (AC). Their copresence is often underestimated and AC is not adequately studied. Traditionally to diagnose non-alcoholic fatty liver disease (NAFLD), AC must not exceed 30 gr for men and 20 gr for women per day. This limit should still be reduced, especially in relation to the AC and fibrogenesis ratio and also frequent misestimation of AC or unrecognized MS may underestimate multi caused liver injury. AC is a contributing cause of MS and alcoholic and non-alcoholic liver disease have a substantially overlapping histopathological picture. Moreover, AC and MS are cause and contributing cause of extra-hepatic morbidity and mortality. It can be concluded that the possible simplification of terminology at metabolic associated liver disease (MALD) makes clinical activity more usable and immediate, facilitates better communication and cooperation between scientific societies and specialists who apparently deal with different medical sectors, facilitates early identification of related hepatic and extra-hepatic pathology, allows to "see the person in a unitary way," to create more streamlined care pathways, to reduce the hospitalization rate with relative cost-benefit advantage and to create unitary prevention and health promotion policies.

The Role of Bile Acids in the Human Body and in the Development of Diseases.

Bile acids are specific and quantitatively important organic components of bile, which are synthesized by hepatocytes from cholesterol and are involved in the osmotic process that ensures the outflow of bile. Bile acids include many varieties of amphipathic acid steroids. These are molecules that play a major role in the digestion of fats and the intestinal absorption of hydrophobic compounds and are also involved in the regulation of many functions of the liver, cholangiocytes, and extrahepatic tissues, acting essentially as hormones. The biological effects are realized through variable membrane or nuclear receptors. Hepatic synthesis, intestinal modifications, intestinal peristalsis and permeability, and receptor activity can affect the quantitative and qualitative bile acids composition significantly leading to extrahepatic pathologies. The complexity of bile acids receptors and the effects of cross-activations makes interpretation of the results of the studies rather difficult. In spite, this is a very perspective direction for pharmacology.

Commentary: Metabolic associated liver disease: an inevitable terminological evolution in real practice.

In real practice, the patient with liver disease is often the carrier of multiple etiological factors, such as metabolic syndrome (MS) and alcohol consumption (AC). Their co-presence is often underestimated as AC is not adequately studied. AC is a contributing cause of MS and alcoholic and nonalcoholic liver disease have a substantially overlapping histopathological picture. Moreover, AC and MS are the cause (and the contributing cause) of extra-hepatic morbidity and mortality. It can be concluded that the possible simplification of terminology at metabolic associated liver disease (MALD) facilitates better communication and cooperation between scientific societies and specialists belonging to different medical sectors, facilitates early identification of related hepatic and extra-hepatic pathology, allows to "see the person in a unitary way", to create leaner healthcare pathways, to reduce the hospitalization rate with relative cost-benefit advantage and to create unitary prevention and health promotion policies.

HCV-RELATED VASCULITIS

Up to 3% of people in the world are infected with HCV, and 75-80% of them have chronic currency of infection. In the clinical picture of HCV infection, a significant place is given to extrahepatic manifestations - more than half of patients suffer from lesions of the skin, kidneys, heart, blood vessels, autoimmune and lymphoproliferative syndromes associated with HCV. Usually, mortality from chronic hepatitis C is associated with liver cirrhosis and hepatocellular carcinoma, but in fact, more patients die from complications associated with the development of cryoglobulinemic vasculitis - chronic renal failure and cardiovascular catastrophes. 40-60% of patients with chronic HCV infection suffer from cryoglobulinemic vasculitis in a wide range of clinical manifestations: from minimal to life-threatening. The pathogenesis of mixed cryoglobulinemia syndrome is based on polyclonal activation of lymphocytes.The systemic nature of the lesion, which is observed in HCV infection, reflects its generalized nature with the involvement of many organs and tissues in the pathological process, which complicates timely diagnosis and treatment. A variety of systemic extrahepatic pathology, which often outstrips the clinical picture of hepatitis itself, masquerading as another disease means that a specialist of any profile can meet with chronic HCV infection and its consequences.

The role of Epstein-Barr viral infection and hepatitis B and C in liver pathology.

A review of scientific literature data on clinical and epidemiological characterization of viral hepatitis B, C and Epstein-Barr viral infection is presented. Scopus, Web of Science, MedLine, The Cochrane Library, PubMed, CyberLeninka, RSCI databases were used to find the necessary literature. It was shown that Epstein-Barr virus along with hepatitis B and C viruses plays a significant role in the development of virus-mediated autoimmune liver diseases, as well as other organs (intestine, heart, kidneys, thyroid gland, etc.). The similarity of these nosologies is also evident in the nature of the course of the disease: the presence of a primary infection in a manifest or latent form, with possible subsequent chronization of the process and its periodic reactivation. Wide distribution of pathogens in the human population determines the possibility of mixed infections with Epstein-Barr virus and hepatitis B and C viruses, however, this problem has not been adequately described in the scientific literature. The review suggests that the role of Epstein-Barr virus in the development of liver diseases and extrahepatic pathology should not be ignored, and the combination of this pathogen with hepatitis B and C viruses required further in-depth studies.

Extrahepatic complications of non-alcoholic fatty liver disease: Its impact beyond the liver.

Non-alcoholic fatty liver disease (NAFLD) is currently one of the main causes of chronic liver disease in Western countries, with a 25% prevalence reported in the general population worldwide. Visceral adiposity and liver fat promote a state of systemic inflammation, predisposing individuals with NAFLD to the extrahepatic pathologies of cardiovascular disease (the most common cause of death in patients with NAFLD), diabetes mellitus, chronic kidney disease, hypothyroidism, polycystic ovary syndrome, obstructive sleep apnea, and an increased risk for presenting with gastrointestinal and extraintestinal neoplasias. Different mechanisms between NAFLD and its association with extrahepatic diseases have been reported, and lipotoxicity is the main cause of inflammatory pathway activation that results in extrahepatic tissue damage.

Portal hypertension in children

Abstract Portal hypertension (PH) is an important complication of chronic liver disease. It can also be caused by a wide range of extrahepatic pathologies in children, and is often clinically silent. Acute variceal haemorrhage (VH) is the most serious consequence of portal hypertension associated with significant morbidity and mortality. Management of PH in children consists of medical, endoscopic and surgical approaches which are mainly focused on acute treatment as well as reducing the risk of variceal haemorrhage. Current treatment strategies for children with PH are mostly based on extrapolation of data from adult studies and expert opinion and consensus. A structured protocol, consisting of surveillance endoscopy with primary and secondary prophylactic therapy by endoscopic variceal ligation or sclerotherapy, is increasingly becoming the standard of care. This article discusses the causes and current treatment options for PH in childhood.

151 - RNA-Dependent RNA Polymerase Activity of HCV NS5B Protein Is Modulated by Glutathionylation

Hepatitis C virus (HCV) is a human blood-borne pathogen that causes chronic liver disease. Chronic hepatitis C often leads to development of liver fibrosis, cirrhosis and hepatocellular carcinoma as well as other hepatic and extrahepatic pathologies. HCV genome is presented by a short positive strand RNA encoding ten structural and non-structural proteins. Among these non-structural protein 5B (NS5B) exhibits RNA-dependent RNA-polymerase activity capable of replicating genomic RNA de novo thus acting as a key component of HCV replicase. Investigation of mechanisms of regulation of HCV replication was focused mostly on search for NS5B-interacting viral and cellular proteins. Much less attention was given to metabolic alterations in the infected cells. It was already shown that HCV triggers massive reactive oxygen species (ROS) production, and virus replication can be inhibited by extracellular H 2 O 2 . Our aim was to explore possible redox modifications of NS5B protein as a link between these events. Using antibodies against glutathionylated proteins we showed that the recombinant NS5B protein of 1b or 2a genotypes, expressed in E.coli , contain glytathione residues. Treatment of NS5B with oxidized glutathione increases degree of glutathionylation, whereas reduced glutathione causes opposite effect. Increase of NS5B glutathionylation degree was accompanied by inhibition of its enzymatic activity both in primer-dependent and primer-independent ( de novo ) systems. MALDI MS analysis revealed that glutathionylation of the recombinant protein of 2a genotype occurs at cysteine residues at positions 89, 146, 274, and 279/295, and GSSG treatment affected residues 170, 223, and 521. Construction of a panel of NS5B mutants with substitution of any single cysteine by serine demonstrated that C279S mutant lost its enzymatic activity, whereas other mutant forms retained sensitivity to glutathione and reducing agents. Currently these data are being verified in HCV cellular replicon system. Acknowledgements This study was supported by Russian Science Foundation (grant #14-14-01021).

Antiviral therapy: why does it fail in HCV-related chronic hepatitis?

HCV infection is a very common cause of chronic viral hepatitis. It is a worldwide health problem with approximately 170 million persons infected and areas of high endemicity in which the percentage of the population infected reaches 30%. It is a progressive disease that can lead to complications such as severe liver fibrosis and cirrhosis, ascites, esophageal varices, gastrointestinal bleeding and, in 30–50% of patients with cirrhosis, hepatocellular carcinoma. Extrahepatic pathologies such as mixed cryoglobulinemia, non-Hodgkin lymphoma and membrano-proliferative glomerulonephritis have been associated with HCV infection. Effective treatment exists, and is based on IFN-α. Sustained disappearance of the virus (sustained virological response) radically changes the natural history of chronic hepatitis C, with reduced or no disease progression and complications. Interferon-based treatment has improved over the years owing to the association with ribavirin and subsequently with ‘pegylation’ of interferon molecules. The present standard of care results in a response rate of up to 80% in some subpopulations. Nevertheless, some patients do not respond to this therapy. Several factors predicting nonresponse to interferon therapy have been investigated since it became available. These factors include the characteristics of the virus and of the subject infected, and the therapy used. The aim of this article is to provide an overview of these factors, and insights into the newly recognized causes of nonresponse to help clinicians select the most appropriate therapy for HCV viral hepatitis.

Hematemesis Complicating Pregnancy

A rare case of bleeding from esophageal varices complicating pregnancy, without any intrahepatic or extrahepatic pathology has been reported and the differential diagnosis has been discussed

Intestinal Malrotation in Adult Seen on Hepatobiliary Scintigraphy

Hepatobiliary scintigraphy is primarily used to diagnose acute and chronic biliary tract disorders. However, its potential role in diagnosing unsuspected extrahepatic pathology is not well described. We present 2 adult patients with chronic abdominal pain who underwent hepatobiliary scintigraphy for evaluation of cystic duct patency. In both cases, the proximal small bowel was located on the right side of the abdomen, which suggested the diagnosis of malrotation. Retrospective review of abdominal CT scan, upper gastrointestinal series, and subsequent laparotomy confirmed malrotation. The diagnosis of malrotation in both these patients was first suggested on hepatobiliary scintigraphy, which significantly impacted their subsequent management.

Progressive intrahepatic cholestasis: Mechanisms, diagnosis and therapy

Progressive intrahepatic cholestasis (PIHC, also known as progressive familial intrahepatic cholestasis) is a general term encompassing a devastating group of illnesses manifest by severe morbidity and potential mortality. By definition these diseases are characterized by persistent cholestasis that is the result of intra-hepatic rather than extra-hepatic pathology. Recent scientific advances have begun to clarify the molecular basis of many of these disorders. The morbidities of these diseases are primarily the result of profound cholestasis. This cholestasis is often associated with intractable pruritus, which leads to a very poor quality of life. Normal development and sleep are not possible for the affected individual and family dynamics are sometimes irreparably damaged. The cholestasis also leads to complications of fat soluble vitamin malabsorption including osteopenia and pathologic bone fractures, xeropthalmia, and peripheral neuropathy. End-stage liver disease and all of its attendant problems may develop in affected individuals by young adulthood. Optimal therapeutic approaches to PIHC are not well established and disease-specific approaches may be required.

TT virus has a ubiquitous diffusion in human body tissues: analyses of paired serum and tissue samples.

The tissue tropism and possible correlation with liver disease of the TT virus (TTV) as well as its prevalence and genotype distribution remain undefined. TTV-DNA was investigated in paired sera and tissue samples from 144 patients, and sera and cerebrospinal fluids (CSF) from additional six subjects. Of the 144 tissue samples, 128 were liver biopsy specimens from subjects with hepatic disease while 16 were surgically obtained nonliver specimens from patients with extrahepatic disease. TTV cloning, sequencing and genotype analyses were performed on isolates from sera, tissue specimens and peripheral blood mononuclear cells of two patients with hepatic and four patients with extrahepatic pathologies, as well as from sera and CSFs of two subjects. TTV was found in 100% of the examined tissues and in 60.1 and 50% of sera from patients with hepatic and extrahepatic pathologies, respectively. Moreover, TTV was detected in four of the six CSFs analysed but only in two correspondent sera. Genotyping revealed the coexistence of multiple TTV genotypes and genetic variants in each infected individual, and the analysis of TTV mRNA showed the presence of transcripts in all the six different tissues studied. These results indicate that the entire adult population in our area is more likely infected by TTV, although several subjects are not viraemic and that TTV infects many different human tissues and is able to invade the central nervous system.

Investigation of transfusion transmitted viruses in cases clinically suspected of posttransfusion hepatitis with undetermined ethiology

Transfusion transmitted viruses (TTV) were investigated in cardiac surgery cases who were previously transfused with blood and/or blood products and were suspected of having posttransfusion hepatitis (PTH) based on the results of physical examination, clinical findings, biochemical blood test results and in a smaller number, on radiological results. They were identified as having non-A–C hepatitis based on serological or molecular test methods. In this study, out of 90 cases suspected for PTH and non-A–C, 78 (86.7%) were male, 12 (13.3%) were female and their ages were between 17 and 67. Ninety healthy blood donors, who donated blood for the first time and had never had a transfusion, were selected as the control group. They had alanine aminotransferase (ALT) levels <40 U, were seronegative for hepatitis B virus (HBV) and hepatitis C virus (HCV). Seventy-seven were immune, and 13 were seronegative for hepatitis A virus (HAV). In this study, TTV-deoxyribonucleic acid (DNA) investigation was performed by the polymerase chain reaction (PCR) method suggested by Takahashi et al. with 5 ′ GCT ACG TCA CTA ACC ACG TG 3 ′ (T801) and 5 ′ CTG CGG TGT GTA AAC TCA CC 3 ′ (T935) primers. TTV-DNA was found to be positive in 21 (23.3%) of the patient group and 4 (4.4%) of the control group ( p<0.05). In the patients determined to be TTV-DNA positive, the admission time following transfusion was a minimum of 3, and a maximum of 15 (average 7) weeks. The average ALT levels detected at the time of admission did not show a difference between TTV-DNA positive and negative cases ( p>0.05). However the ALT levels had a tendency to rise and reached their highest level nine weeks after transfusion in the TTV-DNA positive cases, although in two cases the ALT levels decreased to normal value after the 13th week. During the 24 month follow up of the TTV-DNA positives all cases except one were positive at the end of this period. The results of this study are the same as those reported in the literature suggesting that TTV-DNA, excluding the main viral agents which are known to cause PTH, can be determined in transfused PTH or non-transfused asymptomatic patients in varying ratios. In order to define the epidemiological properties and hepatic–extrahepatic pathologies more clearly we have looked for evidence of the viral agent, which probably contaminates both by transfusion and non-transfusion routes. It is suggested that, in addition to the case groups in this study, new clinical studies are necessary including transfused but non-PTH patients.

TT virus levels in the plasma of infected individuals with different hepatic and extrahepatic pathology

TT virus levels in the plasma of infected individuals with different hepatic and extrahepatic pathology

TT virus levels in the plasma of infected individuals with different hepatic and extrahepatic pathology

TT virus (TTV) infection is extremely widespread in the general population. A sensitive real-time PCR assay was developed that quantitated accurately the most prevalent TTV genotypes in Italy. When used to test 217 individuals for TTV viraemia, the overall prevalence was 94%. Viraemia levels varied widely amongst individual subjects, with no major differences related to gender or age. The highest TTV titres were in haemophiliacs and in patients with non-A-E hepatitis, but they did not differ from the group with miscellaneous diseases. HIV- and HCV-infected subjects and patients with primary liver diseases had TTV loads similar to those of healthy individuals.

TT virus levels in the plasma of infected individuals with different hepatic and extrahepatic pathologies

TT virus levels in the plasma of infected individuals with different hepatic and extrahepatic pathologies

Divergent evolution of hepatitis C virus in liver and peripheral blood mononuclear cells of infected patients

In infected individuals, hepatitis C virus (HCV) exists as a variably complex population of related genetic variants known as quasispecies. The quasispecies of HCV were studied previously in 10 chronically infected patients by single-strand conformation polymorphism analysis of a segment of the envelope gene E2/NS1 containing the hypervariable region 1 and it was found that certain variants (LC variants) were present both in the liver and in peripheral blood mononuclear cells (PBMC), others (L variants) were present in the liver but not in the PBMC, and still others (C variants) showed the opposite distribution. The sequence data obtained from nine such patients are reported, indicating that, within individual subjects, L and C variants are distinct phylogenetically. Results are described on the growth of HCV in stimulated healthy donor PBMC cultures supporting the concept that genetic divergence might stem, at least in part, from virus adaptation to growth in different cell types. This information may help to understand how HCV persists and produces disease in infected patients, especially with regard to extrahepatic pathology.

Ultrasound examination of the pancreatobiliary system

Among new noninvasive and highly informative methods of liver, extrahepatic bile ducts and pancreas pathology research, ultrasound examination is the most widespread nowadays. In recent years a lot of works have been published, testifying about great diagnostic possibilities of ultrasound in cholelithiasis, as well as in surgical diseases of pancreas.