Severe acute liver disease in adults: Contemporary role of histopathology.

Liver biopsies have consistently contributed to our understanding of the pathogenesis and aetiologies of acute liver disease. As other diagnostic modalities have been developed and refined, the role of biopsy in the management of patients with acute liver failure (ALF), acute-on-chronic liver failure (ACLF) and acute hepatitis, including acute liver injury (ALI), has changed. Liver biopsy remains particularly valuable when first-line diagnostic algorithms fail to determine aetiology. Despite not being identified as a mandatory diagnostic tool in recent clinical guidelines for the management of ALF or ACLF, many centres continue to undertake biopsies given the relative safety of transjugular biopsy in this setting. Several studies have demonstrated that liver biopsy can provide prognostic information, particularly in the context of so-called indeterminate hepatitis, and is extremely useful in excluding conditions such as metastatic tumours that would preclude transplantation. In addition, its widespread use of percutaneous biopsies in cases of less severe acute liver injury, for example in the establishment of a diagnosis of acute presentation of autoimmune hepatitis or confirmation of a probable or definite drug-induced liver injury (DILI), has meant that many centres have seen a shift in the ratio of specimens they are receiving from patients with chronic to acute liver disease. Histopathologists therefore need to be equipped to deal with these challenging specimens. This overview provides an insight into the contemporary role of biopsies (as well as explant and autopsy material) in diagnosing acute liver disease. It outlines up-to-date clinical definitions of liver injury and considers recent recommendations for the diagnosis of AIH and drug-induced, autoimmune-like hepatitis (DI-AIH).

Hepatic ultrastructural features distinguish paediatric Wilson disease from NAFLD and autoimmune hepatitis.

BACKGROUND AND AIMS: Wilson disease (WD) has diverse presentations that frequently mimic other liver diseases. Distinguishing WD from non-alcoholic fatty liver disease (NAFLD) and autoimmune hepatitis (AIH), can be difficult and has critical implications for medical management. This study aimed to examine the utility of histological features of WD in children compared to those with NAFLD and AIH. METHODS: A review of liver biopsy slides was performed in children with a clinical and/or genetic diagnosis of WD, seen at the Hospital for Sick Children between 1981 and 2019 and compared to controls with NAFLD and AIH. 37 children with WD and 37 disease controls (20 NAFLD; 17 AIH) were included. Three pathologists, blind to clinical details and diagnosis, reviewed all liver biopsies to reach consensus. Clinical and histopathologic features were compared between groups. RESULTS: Most WD cases displayed steatosis or steatohepatitis on histology (34/37), active AIH-pattern in 1 and inactive cirrhosis in 2 cases. Electron microscopy (EM) findings of mitochondrial abnormalities including dilated tips of cristae, pleomorphism, membrane duplication and dense matrix were more frequent in the WD group as compared to disease controls (p < 0.0001). In WD, dilated tips of mitochondrial cristae had a sensitivity of 91% and specificity of 86%, best among EM features. CONCLUSIONS: Light microscopic findings display considerable overlap among children with WD, NAFLD and AIH. Ultrastructural findings of mitochondrial abnormalities are important to distinguish WD from NAFLD and AIH. EM examination should be considered essential in the diagnostic work-up of paediatric liver biopsies.

Designing Clinical Trials in Wilson's Disease.

BACKGROUND AND AIMS: Wilson's disease (WD) is an autosomal-recessive disorder caused by ATP7B gene mutations leading to pathological accumulation of copper in the liver and brain. Adoption of initial treatments for WD was based on empirical observations. These therapies are effective, but there are still unmet needs for which treatment modalities are being developed. An increase of therapeutical trials is anticipated. APPROACH AND RESULTS: The first Wilson Disease Aarhus Symposium (May 2019) included a workshop on randomized clinical trial design. The authors of the article were organizers or presented during this workshop, and this article presents their consensus on the design of clinical trials for WD, addressing trial population, treatment comparators, inclusion and exclusion criteria, and treatment endpoints. To achieve adequate recruitment of patients with this rare disorder, the study groups should include all clinical phenotypes and treatment-experienced as well as treatment-naïve patients. CONCLUSIONS: The primary study endpoint should be clinical or a composite endpoint until appropriate surrogate endpoints are validated. Standardization of clinical trials will permit pooling of data and allow for better treatment comparisons, as well as reduce the future numbers of patients needed per trial.

Fifty years of impact on liver pathology: a history of the Gnomes.

Professional societies play a major role in medicine and science. The societies tend to be large with well-developed administrative structures. An additional model, however, is based on small groups of experts who meet regularly in an egalitarian model in order to discuss disease-specific scientific and medical problems. In order to illustrate the effectiveness of this model, the history and practices are examined of a long-standing successful example, the International Liver Pathology Group, better known as the Gnomes. The history shows that groups such as the Gnomes offer a number of important benefits not available in larger societies and nurturing such groups advances science and medicine in meaningful ways. The success of the Gnomes' approach provides a road map for future small scientific groups.

Hepatitis C in 2020: A North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Position Paper.

In 1989, a collaboration between the Centers for Disease Control (CDC) and a California biotechnology company identified the hepatitis C virus (HCV, formerly known as non-A, non-B hepatitis virus) as the causative agent in the epidemic of silent posttransfusion hepatitis resulting in cirrhosis. We now know that, the HCV genome is a 9.6 kb positive, single-stranded RNA. A single open reading frame encodes a 3011 amino acid residue polyprotein that undergoes proteolysis to yield 10 individual gene products, consisting of 3 structural proteins (core and envelope glycoproteins E1 and E2) and 7 nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B), which participate in posttranslational proteolytic processing and replication of HCV genetic material. Less than 25 years later, a new class of medications, known as direct-acting antivirals (DAAs) which target these proteins, were introduced to treat HCV infection. These highly effective antiviral agents are now approved for use in children as young as 3 years of age and have demonstrated sustained virologic responses exceeding 90% in most genotypes. Although tremendous scientific progress has been made, the incidence of acute HCV infections has increased by 4-fold since 2005, compounded in the last decade by a surge in opioid and intravenous drug use. Unfortunately, awareness of this deadly hepatotropic virus among members of the lay public remains limited. Patient education, advocacy, and counseling must, therefore, complement the availability of curative treatments against HCV infection if this virus is to be eradicated.

Pediatric Wilson Disease Presenting as Acute Liver Failure: An Individual Patient Data Meta-analysis.

OBJECTIVES: Wilson disease (WD) presenting as acute liver failure (ALF) is rare and typically fatal without liver transplantation (LT). Its rarity has hindered comprehensive studies. We undertook an individual patient data meta-analysis to characterize a cohort of pediatric patients presenting with ALF whose final diagnosis was WD to examine outcomes and identify predictors of poor outcomes. METHODS: Database searches were conducted in PubMed, ScienceDirect, and Google Scholar, restricted to English-language articles published between January 1984 and May 2018. Articles were excluded if pediatric (<18 years old) data were not extractable or if LT was not readily available at reporting institutions. Extracted data included clinical and biochemical characteristics, genotype, treatment, and outcome. RESULTS: Data were available on 249 subjects from 52 articles, plus 7 additional subjects identified from our institution's WD database (N = 256). Females represented 69% (n = 170/245). Median age at presentation was 13.4 years (n = 204, range 4.0-17.9). Of the total 256 subjects, 87% underwent LT, 11% achieved spontaneous recovery and 2% died before LT. International normalized ratio >2.0 at presentation was a predictor of LT/death (odds ratio 7.6, 95% confidence interval 1.5-28), with a trend observed for hepatic encephalopathy (HE) (odds ratio 4.18, 95% confidence interval 0.99-18). Arithmetic diagnostic scores proved inferior in the pediatric age-bracket compared to adults. CONCLUSIONS: This large international pediatric cohort has permitted an individual patient data analysis of WD presenting as ALF. Notably, 11% of subjects achieved spontaneous survival; the rest required LT. Coagulopathy (international normalized ratio >2:0) and HE at presentation heralded poor outcomes. Further prospective studies may identify additional early predictors of outcomes.

Management of Wilson Disease Diagnosed in Infancy: An Appraisal of Available Experience to Generate Discussion.

Increased access to molecular genetic testing is changing the demographics for diagnosing inherited disorders and imposing new challenges for medical management. Wilson disease (WD), typically diagnosed in older children and adults, can now be detected in utero and in infants (children younger than 24 months, including neonates) via genetic testing. An evidence-based approach to management of these neonates and extremely young children, who are typically asymptomatic, has been hampered by lack of clinical experience. We present a case of an infantile diagnosis of WD, review available experience, and discuss current trends in antenatal genetic testing of parents and fetus that may lead to a very early diagnosis of WD. Based on physiological and nutritional considerations, we propose an algorithmic approach to management of infantile WD as a starting point for further discussion. Future collaboration amongst specialists is essential to identify evidence-based approaches and best practice for managing treatment of infants with genetically diagnosed WD.

The Canadian Liver Foundation celebrates 50 years of commitment to hepatology.

Founded in 1969, the Canadian Liver Foundation (CLF) was the first foundation worldwide to support research and education relating specifically to the liver and liver diseases. This year marks its 50th anniversary. It has been highly effective in promoting hepatology in Canada.

Update on the Diagnosis and Management of Wilson Disease.

PURPOSE OF REVIEW: Exciting developments relating to Wilson disease (WD) have taken place with respect to both basic biological and clinical research. This review critically examines some of these findings and considers their implications for current thinking about WD. It is not a comprehensive review of WD as a clinical disorder. RECENT FINDINGS: The structure of the gene product of ATP7B, abnormal in WD, is being worked out in detail, along with a broader description of how the protein ATP7B (Wilson ATPase) functions in cells including enterocytes, not only in relation to copper disposition but also to lipid synthesis. Recent population studies raise the possibility that WD displays incomplete penetrance. Innovative screening techniques may increase ascertainment. New strategies for diagnosing and treating WD are being developed. Several disorders have been identified which might qualify as WD-mimics. WD can be difficult to diagnose and treat. Insights from its pathobiology are providing new options for managing WD.

Wilson disease in children.

Wilson disease (WD) is an inherited disorder mainly of hepatocellular copper disposition, due to dysfunction of the Wilson ATPase, a P1B-ATPase encoded by the gene ATP7B. In children, as in older age brackets, clinical disease is highly diverse. Although hepatic disease is the common presentation in children/adolescents, neurologic, psychiatric, and hematologic clinical presentations do occur. Very young children may have clinically evident liver disease due to WD. Early diagnosis, preferably when the child/adolescent is asymptomatic, is most likely to result in near-normal longevity with generally good health so long as the patient tolerates effective medication, is adherent to the lifelong treatment regimen, and has consistent access to the medication. Apart from a lively index of clinical suspicion on the part of physicians, biochemical tests including liver tests, serum ceruloplasmin, and basal 24-hour urinary copper excretion and genotype determination are key to diagnosis. Oral chelation treatment remains central to medical management, although zinc appears to be an attractive option for the presymptomatic child. Pediatric patients presenting with Wilsonian fulminant hepatic failure must be differentiated from those with decompensated cirrhosis, since the latter may respond to intensive medical interventions and not require liver transplantation. Recently identified WD-mimic disorders reveal important aspects of WD pathogenesis.

Early Posthepatoportoenterostomy Predictors of Native Liver Survival in Biliary Atresia.

OBJECTIVES: Most infants with biliary atresia (BA) require liver transplantation (LT) after hepatoportoenterostomy (HPE), including those who initially clear jaundice. The aim of the present study was to identify clinical and routine laboratory factors in infants with BA post-HPE that predict native liver survival at 2 years. METHODS: A retrospective cohort study was conducted in 217 patients with BA undergoing HPE in Sydney, Australia and Toronto, Canada between January 1986 and July 2009. Univariate and multivariate logistic regression using backwards-stepwise elimination identified variables at 3 months after HPE most associated with 2-year native liver survival. RESULTS: Significant variables (P < 0.05) on univariate analysis included serum total bilirubin (TB) and albumin at 3 months post-HPE, bridging fibrosis or cirrhosis on initial liver biopsy, ascites of <3 months post-HPE, type 3 BA anatomy, age at HPE of >45 days, change in length z scores within 3 months of HPE, and center. On multivariate analysis, TB (P < 0.0001) and albumin (P = 0.02) at 3 months post-HPE, and center (P = 0.0003) were independently associated with native liver survival. Receiver operating characteristic analysis revealed an optimal cut-off value of TB <74 µmol/L (4.3 mg/dL; area under the receiver operating characteristic curve 0.8990) and serum albumin level >35 g/L (3.5 mg/dL; area under the receiver operating characteristic curve 0.7633) to predict 2-year native liver survival. TB and albumin levels 3 months post-HPE defined 3 groups (1: TB ≤74 µmol/L, albumin >35 g/L; 2: TB ≤74 µmol/L, albumin ≤35 g/L; 3: TB >74 µmol/L) with distinct short- and long-term native liver survival rates (log-rank P < 0.001). Length z scores 3 months post-HPE were poorer for group 2 than group 1 (-0.91 vs -0.30, P = 0.0217) with similar rates of coagulopathy. CONCLUSIONS: Serum TB and albumin levels 3 months post-HPE independently predicted native liver survival in BA when controlling for center. Serum albumin level <35 g/L in infants with BA who were no longer jaundiced at 3 months post-HPE was a poor prognostic indicator. Poorer linear growth and absence of significant coagulopathy suggest a role for early aggressive nutritional therapy in this group.

Controversies and Variation in Diagnosing and Treating Children With Wilson Disease: Results of an International Survey.

OBJECTIVES: Variation in care is more common in settings in which evidence-based approaches are limited. The aims of the present study were to describe consensus and variability in approaches taken by pediatric hepatologists in the management of Wilson disease (WD) in children. METHOD: International case-centered, Internet-based survey of pediatric hepatologists. Survey cases were developed by consensus of the authors and were intended to identify variation in the care of children with WD. RESULTS: One hundred eleven of 253 clinicians responded (44%). Of these, 84% of North American and 41% of European participants used guidelines published in their respective region. Although consensus existed on the first-line diagnostic tools (serum ceruloplasmin and baseline 24-hour urinary copper excretion), survey participants did not agree on how much liver copper content was required for diagnosis: 57% considered >250 µg/g dry weight to be consistent with WD, whereas 25% considered >50 µg/g to be diagnostic. Overall, 50% of practitioners perform genetic testing in all suspected cases, and 81% perform genetic testing once they know the genotype of an index patient. For initial treatment of fulminant WD, 51% of participants chose chelation and 15% chose immediate transplantation; 47% chose listing for transplantation followed by monitoring using a disease-severity score, and then carrying out transplantation only when the score reached a critical cut-off. To treat mildly affected siblings of index patients, 43% of practitioners chose zinc. Most reported that they use chelation to treat patients with hepatic dysfunction; however, 29% of North American participants chose not to use D-penicillamine as primary therapy. CONCLUSIONS: From an international perspective, pediatric hepatologists vary in the approaches they use in the care for children with WD. Regional preferences and accessibility to treatments may generate variation. Unwarranted variation, however, may also contribute to differences in outcome and should be targeted to improve quality of care.

Incidence and Characteristics of Autoimmune Hepatitis.

BACKGROUND AND OBJECTIVES: Autoimmune hepatitis (AIH) is a progressive inflammatory liver disease of unknown etiology, with limited population-based estimates of pediatric incidence. We reported the incidence of pediatric AIH in Canada and described its clinical characteristics. METHODS: We conducted a retrospective cohort study of patients aged <18 years diagnosed with AIH between 2000-2009 at all pediatric centers in Canada. RESULTS: A total of 159 children with AIH (60.3% female, 13.2% type 2 AIH) were identified. Annual incidence was 0.23 per 100000 children. Median age at presentation for type 1 was 12 years (interquartile range: 11-14) versus 10 years for type 2 (interquartile range: 4.5-13) (P = .03). Fatigue (58%), jaundice (54%), and abdominal pain (49%) were the most common presenting symptoms. Serum albumin (33 vs 38 g/L; P = .03) and platelet count (187 000 vs 249 000; P <.001) were significantly lower and the international normalized ratio (1.4 vs 1.2; P <.001) was higher in cirrhotic versus noncirrhotic patients. Initial treatment included corticosteroids (80%), azathioprine (32%), and/or cyclosporine (13%). Response to treatment at 1 year was complete in 90%, and partial in 3%. 3% of patients had no response, and 3% responded and later relapsed. Nine patients underwent liver transplantation, and 4 patients died at a mean follow-up of 4 years. CONCLUSIONS: AIH is uncommon in children and adolescents in Canada. Type 1 AIH was diagnosed 5.5 times more frequently than type 2 AIH. Most patients respond well to conventional therapy, diminishing the need for liver transplantation.