Multiple, large intra-abdominal cystic lesions and iron deficiency anaemia as the presenting symptoms of SDHD gastrointestinal stromal tumour (GIST) in a young sub-Saharan woman.

We report the case of a 27-year-old female patient from sub-Saharan Africa who presented with non-specific abdominal complaints, iron deficiency anaemia and multiple, large intra-abdominal cystic lesions on imaging. The lesions appeared to be a most unusual presentation of gastrointestinal stromal tumour (GIST). GIST is a sarcomatous tumour that comprises only 0.2% of all gastrointestinal (GI) tumours; it is the most common mesenchymal malignancy of the GI tract. Our patient had the succinate dehydrogenase-deficient (SDHD) subtype, identified in some 5%-10% of patients with GIST only, commonly found in women and younger patients. The differential diagnosis of intra-abdominal cystic lesions is briefly discussed, including the relevance of a correct pathological diagnosis. This impacts medical and surgical management decisions, including predicting response to targeted therapy. Tyrosine kinase inhibitor therapy has been a breakthrough in the treatment of GISTs, although with extensive disease, and certainly in case of the SDHD subtype, long-term outcome remains disappointing.

Ethical and Legal Aspects of Pandemics During COVID-19 and Beyond for the Hepatology Community.

Content available: Author Interview and Audio Recording.

WGO Guidance for the Care of Patients With COVID-19 and Liver Disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the least deadly but most infectious coronavirus strain transmitted from wild animals. It may affect many organ systems. Aim of the current guideline is to delineate the effects of SARS-CoV-2 on the liver. Asymptomatic aminotransferase elevations are common in coronavirus disease 2019 (COVID-19) disease. Its pathogenesis may be multifactorial. It may involve primary liver injury and indirect effects such as "bystander hepatitis," myositis, toxic liver injury, hypoxia, and preexisting liver disease. Higher aminotransferase elevations, lower albumin, and platelets have been reported in severe compared with mild COVID-19. Despite the dominance of respiratory disease, acute on chronic liver disease/acute hepatic decompensation have been reported in patients with COVID-19 and preexisting liver disease, in particular cirrhosis. Metabolic dysfunction-associated fatty liver disease (MAFLD) has a higher risk of respiratory disease progression than those without MAFLD. Alcohol-associated liver disease may be severely affected by COVID-19-such patients frequently have comorbidities including metabolic syndrome and smoking-induced chronic lung disease. World Gastroenterology Organization (WGO) recommends that interventional procedures such as endoscopy and endoscopic retrograde cholangiopancreatography should be performed in emergency cases or when they are considered strictly necessary such as high risk varices or cholangitis. Hepatocellular cancer surveillance may be postponed by 2 to 3 months. A short delay in treatment initiation and non-surgical approaches should be considered. Liver transplantation should be restricted to patients with high MELD scores, acute liver failure and hepatocellular cancer within Milan criteria. Donors and recipients should be tested for SARS-CoV-2 and if found positive donors should be excluded and liver transplantation postponed until recovery from infection.

Histology of portal vascular changes associated with idiopathic non-cirrhotic portal hypertension: nomenclature and definition.

Idiopathic non-cirrhotic portal hypertension (INCPH) is a rare vascular liver disease that has attracted new interest in recent years. It is characterised by clinical signs of portal hypertension in the absence of cirrhosis or severe fibrosis and any known cause of portal hypertension. As much uncertainty exists about INCPH pathophysiology, and no definite diagnostic tests are available, liver biopsy is an essential tool for achieving a definite diagnosis. Unfortunately, the histological diagnosis of INCPH is not always straightforward, as the characteristic lesions are unevenly distributed, vary greatly in their severity, are often very subtle, and are not all necessarily present in a single case. Furthermore, specifically for the characteristic portal vessel changes observed in INCPH, the terminology and definition are ambiguous, which adds complexity to the already complex clinicopathological scenario. An international study group of liver pathologists and hepatologists pursued a consensus on nomenclature for the portal vascular lesions of INCPH. Such standardisation may assist pathologists in the recognition of such lesions, and will possibly facilitate further advancement in this field.

Acute-on-chronic liver failure 2018: a need for (urgent) liver biopsy?

INTRODUCTION: 'Acute-on-Chronic-Liver Failure (ACLF)' entered hepatology practice by the end of the 20th century. Although we lack precise and universally agreed definitions, acute decompensation of chronic liver disease with jaundice and deranged clotting, multi-organ failure and high, short-term mortality are hallmarks of the syndrome. Timely recognition and and treatment, including urgent liver transplantation, may save the life of certain patients. The diagnosis and management are mostly based on clinical features, but some have suggested to incorporate histopathology (liver biopsy). This may add to the differentiation between acute and chronic disease, primary and concomitant etiologies, and identify prognostic determinants. Areas covered: A review of the literature on ACLF and the outcome of the discussions at a topical international meeting on specific histopathological aspects of diagnosis and prognosis of the syndrome. Expert commentary: There is a lack of standardized descriptions of histopathological features and there is limited prospective experience with the role of pathology of ACLF. It is important for the clinical hepatologist to understand the potential and limitations of (transjugular) liver biopsy in ACLF and for the pathologist to help address the clinical question and recognise the histopathological features that help to characterize ACLF, both in terms of diagnosis and prognosis.

Role of aetiology in the progression, regression, and parenchymal remodelling of liver disease: implications for liver biopsy interpretation.

Clinicopathological concepts on acute and chronic liver disease have evolved rapidly during the last few years, with advances in general and specific treatment options and improved patient outcomes. The old paradigm of 'irreversibility' of cirrhosis had been challenged in major ways, and the validity of the usage of the term 'cirrhosis' has come into question. This paper addresses aetiology-based clinicopathological concepts and features that may deserve attention because they may determine disease outcome and, specifically, patterns of regression and remodelling. A variety of therapeutic interventions may influence remaining disease features after elimination of damaging agents (virus, alcohol, etc.), and determine the final clinical outcome including the risk of hepatocellular carcinoma (HCC). New concepts create new responsibilities and opportunities for the pathologist to contribute to the understanding of liver pathology and communicate this with clinical colleagues and researchers.

Hepatic steatosis estimated microscopically versus digital image analysis.

BACKGROUND & AIMS: Evaluate in liver biopsies: (i) interobserver agreement of estimates of fat proportionate area (eFPA) and steatosis grading, (ii) the relationship between steatosis grades and measured fat proportionate area (mFPA, digital image analysis), (iii) the accuracy of eFPA, (iv) to present images to aid standardization and accuracy of eFPA. METHODS: Twenty-one liver biopsies were selected from the Royal Free Hospital (RFH) histopathology archive to represent the full range of histopathological steatosis severity. As many non-overlapping fields of parenchyma as possible were photographed at ×20 objective magnification from the biopsies (n = 651). A total of 15 sample images were selected to represent the range of steatosis seen. Twelve hepatopathologists from 11 sites worldwide independently evaluated the sample images for steatosis grade [normal (none)/mild/moderate/severe], and eFPA (% area of liver parenchyma occupied by fat). RESULTS: The hepatopathologists had good linear correlation between eFPA and mFPA for sample images (r = 0.924, P < .001) and excellent concordance (kappa = 0.91, P < 0.001). Interobserver concordance of steatosis grade showed 'substantial agreement' (kappa = 0.64). There was significant difference between eFPA and mFPA in the sample images for mild, moderate and severe steatosis (P = 0.024, P < 0.001, P < 0.001 respectively): the observers consistently over-estimated the eFPA. CONCLUSION: Hepatopathologists showed 'excellent' interobserver agreement in eFPA and 'substantial' agreement in assigning steatosis grade (precision was high). However, compared with mFPA, eFPA was inaccurate. eFPA systematically exceeds mFPA; generally the overestimation increases with severity of steatosis. Considering that non-invasive technologies for estimating liver fat utilize histopathology as reference, such assessments would benefit from quantitative validation of visually estimated microscopic liver fat percentages.

Beyond "cirrhosis": a proposal from the International Liver Pathology Study Group.

"Cirrhosis" is a morphologic term that has been used for almost 200 years to denote the end stage of a variety of chronic liver diseases. The term implies a condition with adverse prognosis due to the well-known complications of portal hypertension, hepatocellular carcinoma, and liver failure. However, recent advances in the diagnosis and treatment of chronic liver diseases have changed the natural history of cirrhosis significantly. This consensus document by the International Liver Pathology Study Group challenges the usefulness of the word cirrhosis in modern medicine and suggests that this is an appropriate time to consider discontinuing the use of this term. The role of pathologists should evolve to the diagnosis of advanced stage of chronic liver disease, with emphasis on etiology, grade of activity, features suggestive of progression or regression, presence of other diseases, and risk factors for malignancy, within the perspective of an integrated clinicopathologic assessment.

A 56-year-old man with sudden onset of portosystemic encephalopathy years after severe electrocution trauma.

A 56-year-old white male painter, with a history of major electrocution and deep thermal injury, developed mental status changes initially ascribed to an acute neurological event. Unexpectedly, magnetic resonance imaging (MRI) of the head showed areas of high signal intensity in the basal ganglia, which can be observed in advanced liver disease. An electroencephalogram (EEG) suggested metabolic encephalopathy and coexistent elevation of ammonia, indicative of significant liver disease. The patient had had a long history of right upper quadrant pain and fluctuation in liver tests following the electrocution trauma. For these symptoms, he underwent surgery 7 years prior to his current presentation of portosystemic encephalopathy, and was found to have a gangrenous acalculous cholecystitis. Intraoperative cholangiogram suggested possible strictures within the right hepatic ducts. Multiple liver biopsies, however, showed only steatosis. Current evaluation including liver biopsy, MRI, magnetic resonance angiography (MRA), and magnetic resonance cholangiopancreatography (MRCP), revealed progression to biliary cirrhosis with large bile duct obstruction, and hepatic artery thrombosis/occlusion with evidence of left lobe atrophy and right lobe compensatory hypertrophy. The pathobiology of ischemic bile duct injury is discussed herein. The case is an example of serious late sequelae of an occupational injury.

A clinical and histopathologic perspective on evolving noninvasive and invasive alternatives for liver biopsy.

Noninvasive or minimally invasive alternatives are proposed as substitutes for liver biopsy and include clinical indices, cross-sectional imaging, serum biomarkers, liver stiffness measurement, and portal pressure measurement. Most alternatives to liver biopsy assess one aspect of liver disease and translate this into a numeric score. Overlap between categories may limit applications. Liver biopsy provides information about numerous variables: tissue architectural changes; necroinflammatory injury; fibrotic stage; alterations of parenchyma and bile duct epithelium; accumulation of fat, copper, and iron; and molecular and genetic changes. Liver biopsy may identify multiple disease etiologies. A single numeric score cannot be a substitute for complete histologic assessment. However, within defined clinical contexts, noninvasive assessment is an attractive alternative for many patients given the ease, avoidance of risk from invasive procedures, and validated contribution to clinical management. Serum biomarkers and liver stiffness assessment may become indispensable in longitudinal studies and to document outcome of treatments. The accuracy of the more reliable techniques is typically around 80%. Neither liver biopsy nor any single alternative option represents an absolute assessment of liver disease. Biopsy and alternatives are not mutually exclusive options. Liver biopsy and the noninvasive alternatives require a clear understanding of significance and limitations of each investigation. This places a responsibility on the clinician to consider fully the results of any of the investigative options used within the diagnostic and prognostic context of each individual patient, and to choose critically the most appropriate investigations for the patient's needs.

Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria.

Cholangiocarcinoma of the intrahepatic and extrahepatic bile ducts develops through a multistep histopathologic sequence. Premalignant or non-invasive neoplastic lesions of bile ducts have been historically called biliary dysplasia or atypical biliary epithelium. To this date, no standard terminology or classification system has been offered for these lesions. In 2005, a conceptual framework and diagnostic criteria for biliary intraepithelial neoplasia (BilIN) were proposed using the livers of patients with hepatolithiasis. We report herein an international interobserver agreement study on the diagnosis of biliary non-invasive neoplastic lesions with the goal to obtain a consensus on the terminology and grading. Seventeen pathologists from the United States, Europe and Asia participated in this study. They shared a digital file containing histological pictures of 30 foci of non-invasive neoplastic lesions selected from the biliary system of patients suffering from primary sclerosing cholangitis, choledochal cyst or hepatolithiasis. In the criteria, we proposed in 2005, BilIN was classified into three categories based on the degree of atypia: BilIN-1, BilIN-2 and BilIN-3. In this study, consensus was reached for the terminology of BilIN and the three-grade classification system. Interobserver agreement on the diagnosis was moderate (kappa-value=0.45). On the basis of the suggestions and opinions obtained from the 17 participants, the original criteria for BilIN were revised. We now propose a new consensus classification of BilIN that may assist in allowing a more uniform terminology for the diagnosis of biliary non-invasive neoplastic lesions. This classification should help to advance clinical and research applications.

Ethical, social and legal implications of genetic testing in liver disease.

Advances in molecular genetics challenge the hepatology community to understand and implement genetic knowledge. Despite excitement about the potential benefits of new genetic information, concerns have been raised about the inappropriate use of genetic testing, clinicians' incorrect ordering and misinterpretation of test results, and discrimination in employment and insurability based on tests results. Among the public there is fear and mistrust, in part based on horrifying historical events that were gross violations of medical ethical standards. Clinicians, scientists, patient advocacy groups, and government agencies worldwide are debating the optimal legal protections to prevent abuse. In addition, these groups are developing clinical guidelines for optimal use. Traditional ethical and legal standards of confidentiality between physicians and their patients are under scrutiny. A new principle, "the duty to warn," is emerging that has applications specific to genetic testing and may conflict with the duty to maintain patient confidentiality. Emerging ethical, legal, and social issues involve the appropriate use and protection of confidential data in tissue and serum banks. Education of the profession and the public at many levels will increase the likelihood that the unraveling of the human genome will maximally benefit society. If fear of genetic testing can be alleviated, selection bias in research could be reduced. Professional and lay organizations concerned with liver disease should consider a more active role in the public and professional debate, and foster education at all levels.

Liver biopsy 2005: when and how?

Clinical imaging and serologic testing are increasingly replacing biopsy for diagnosing hepatic diseases. However, more biopsies are being done to stage and grade hepatitis C and fatty liver disease, to diagnose space-occupying lesions (typically with fine-needle aspiration biopsy), and to assess response to therapy. If biopsy is planned, it is important to evaluate its indications and risks and, if other physicians are involved, who is responsible for what.

Association of CTLA4 polymorphisms with sustained response to interferon and ribavirin therapy for chronic hepatitis C virus infection.

Cytotoxic T lymphocyte antigen-4 (CTLA4) suppresses cytotoxic T lymphocyte activity. We examined the associations of CTLA4 single-nucleotide polymorphisms (SNPs) at promoter site -318 and exon-1 site 49 with clearance of hepatitis C virus (HCV) after treatment with combination interferon-alpha plus ribavirin (IFN-alpha+R) therapy in 79 white sustained responders (SRs) and 79 nonresponders (NRs). SRs had higher frequencies of 49G, alone (odds ratio [OR], 2.3; P=.042) and tightly linked with -318C in a haplotype (OR, 2.4; P=.030). Homozygosity for the -318C-49G haplotype was even more frequent among SRs (OR, 5.2; P=.049). Comparably strong associations persisted after multivariable analysis. Relationships were not seen with non-1 genotype viruses (OR, 0.93-1.25; P>.25). Virus load also declined more rapidly in carriers of both 49G (P=.0095) and the -318C-49G haplotype. CTLA4 49G in exon 1 alone and in a haplotype with -318C promoter is associated with sustained IFNalpha+R response in white patients with HCV genotype 1 infection.

Video-assisted thoracoscopic surgery with talc pleurodesis in the management of symptomatic hepatic hydrothorax.

OBJECTIVES: Video-assisted thoracoscopic surgery with talc pleurodesis is a therapeutic option for patients with hepatic hydrothorax that is refractory to medical therapy. We report the outcomes of 15 patients who underwent this procedure for significantly symptomatic disease. METHODS: Data on 15 consecutive patients presenting to our institution between November, 1996, and June, 2000, with refractory hepatic hydrothorax was retrospectively collected. Baseline demographical and clinical characteristics and outcomes after the procedure were analyzed. RESULTS: The mean age of our cohort was 51.5 yr, and eight (53%) of the 15 patients were male. The etiologies of liver disease were hepatitis C virus and/or alcohol (n = 12) and cryptogenic cirrhosis (n = 3). Nine patients were Child-Pugh class C and six class B. Success defined as control of symptomatic hydrothorax in the first 30 days after the procedure was achieved in 11 of 15 patients (73%). Eight of these patients remained asymptomatic at a median follow-up of 5.5 months after the procedure, but three patients experienced symptomatic fluid reaccumulation 45, 61, and 62 days after the initial procedure. After a second VATS procedure, control was achieved in two of these three patients. Complications included pain around the chest tube site, low grade fever with leukocytosis, pleurocutaneous fistula and empyema, all of which responded to medical therapy. Four patients did not respond to the procedure. There were no procedure-related deaths. Overall mortality and baseline clinical characteristics were similar between responders and nonresponders to VATS with pleurodesis. CONCLUSIONS: Symptomatic hepatic hydrothorax can be controlled with a single VATS with pleurodesis in as many as 53% of patients and with two procedures in 73% with no procedure-related mortality. The procedure may be considered as a palliative alternative in patients needing frequent thoracocentesis. It also provides an alternative to transjugular intrahepatic portosystemic shunts and is a bridge toward liver transplantation.

A 38-year-old African-American woman with an unusually rapid progression of "Primary Biliary Cirrhosis": a missed opportunity!

The case discussed is of a 38-year-old African-American woman who developed upper abdominal symptoms and liver test abnormalities. She underwent cholecystectomy for presumed gallstone disease. This was followed by a worsening of her condition, with the development of jaundice in the next 2 weeks. Results of reevaluation included transaminases around 1000 IU/L with minimal elevation of alkaline phosphatase (ALP), an antimitochondrial antibody (AMA) titer of 1:320, and an elevated immunoglobulin M (IgM). The antinuclear antibodies (ANA) level was positive, but titers were not obtained. There was no suggestion of bile duct obstruction. Liver biopsy findings were believed to be consistent with primary biliary cirrhosis (PBC). She was therefore started on, but failed treatment with, ursodeoxycholic acid. She was transferred to a transplant center 8 weeks later after a brief episode of encephalopathy and hypoglycemia. The clinical findings were consistent with subfulminant hepatic failure secondary to autoimmune hepatitis (AIH) with an ANA titer of 1:1280, an anti-smooth muscle antibody (SMA) titer of 1:40, and an elevated IgG. Review of the biopsy showed panlobular inflammation and bridging necrosis consistent with severe AIH. On imaging, she had ascites and a nodular appearance of the liver. An immediate drop in transaminases followed corticosteroid therapy, but her disease was already irreversible, and she underwent successful liver transplantation. The explanted liver was shrunken and noncirrhotic with massive hepatocellular collapse and contained multiple regenerating nodules, explaining the ultrasonographic appearances. The inflammatory component had greatly diminished compared with the earlier biopsy. The case illustrates the importance of knowledge of the natural course of a specific disease and the careful interpretation of clinical data, including autoimmune markers. PBC would rarely cause liver failure in a young woman; it is not a rapidly progressive disease. The original clinical diagnosis was unduly swayed by a positive AMA, which can be seen in up to 20% of patients with AIH. Markedly elevated transaminases with minimal elevation of ALP and positive ANA in a young woman should have pointed toward AIH at an earlier stage. The academic discussion of AMA-positive AIH versus PBC/AIH overlap syndrome remains intriguing, but prompt institution of aggressive immunosuppressive therapy aimed at the AIH component should not be deferred. In retrospect, an opportunity was missed.