Liver transplantation (LT) is vital for patients with end-stage cirrhosis, but survival is compromised by recurrent graft cirrhosis in 25% of recipients due to de novo or recurrent disease. This study aims to understand the trajectory, predisposing factors, and complications of graft cirrhosis to improve management in this patient population. We retrospectively reviewed 454 LT recipients diagnosed with graft cirrhosis from January 1, 1985, to December 31, 2019. We collected demographic, clinical, laboratory, imaging, endoscopic, and histological data. Statistical analysis was done with univariate and multivariate analyses. Graft cirrhosis was frequently due to recurrent primary disease, with hepatitis C (49.2%) and graft rejection (9.6%) being primary contributors. Signs of decompensation, including primarily ascites, were seen in 12% of patients, with an 18% mortality rate at first decompensation. MELD-Na >15 was found in 62% of patients, driven by creatinine levels. Of note, 42% experienced portal hypertensive complications before deterioration in their synthetic function. Predictors of mortality included lower serum sodium, elevated aspartate transaminase, and older donor age. Only two patients developed de novo hepatocellular carcinoma (HCC). The Baveno VII criteria for varices needing treatment showed high sensitivity (100%) with moderate specificity (46.7%). Portal hypertensive complications often precede synthetic dysfunction in graft cirrhosis patients. Clinicians should screen for portal hypertensive complications, de novo HCC, and biochemical decompensation following graft cirrhosis. Early intervention can improve outcomes and prolong survival in LT recipients with graft cirrhosis. Liver transplantation is a life-saving treatment for patients with advanced liver disease. However, in about 25% of liver transplant recipients, the transplanted liver can develop scarring over time, known as graft cirrhosis. This may occur due to recurrence of the original liver disease or a new injury to the transplanted liver. Understanding how graft cirrhosis develops and progresses is important to improve long-term outcomes after transplantation. In this study, we reviewed 454 liver transplant recipients diagnosed with graft cirrhosis between 1985 and 2019. We analyzed clinical data, laboratory tests, imaging, endoscopy, and liver biopsy findings to identify causes, complications, and factors associated with survival. We found that most cases of graft cirrhosis were caused by recurrence of the original disease, particularly hepatitis C, although rejection was another important cause. Many patients had relatively preserved liver function at diagnosis, yet complications from portal hypertension, which results from increased pressure in the blood vessels from cirrhosis, were common. Importantly, 42% of patients developed complications such as fluid accumulation in the abdomen or enlarged esophageal veins before their laboratory tests showed significant liver dysfunction. When patients experienced overt liver decompensation, outcomes were poor, with an 18% mortality rate after the first episode. Lower blood sodium levels, higher liver enzyme levels, and older donor age were associated with increased risk of death. New liver cancer after transplant was rare. These findings highlight the importance of early screening for portal hypertension and close monitoring to enable timely intervention in patients with graft cirrhosis.
Ketamine-related cholangiopathy is increasingly being described in America, Europe, and Asia, paralleling increases in ketamine use globally. However, ketamine-related cholangiopathy has not been described in Canada previously. We report three cases of ketamine-related cholangiopathy in Calgary, Alberta. Between May 2024 and April 2025, three patients were assessed by the University of Calgary Liver Unit in Calgary, Alberta, Canada. Case 1 was a 28-year-old female referred for elevated liver enzymes and features concerning for sclerosing cholangitis identified on magnetic resonance cholangiopancreatography. Case 2 was a 40-year-old male referred due to features of sclerosing cholangitis identified on magnetic resonance cholangiopancreatography. Case 3 was a 33-year-old female referred for elevated liver enzymes with biliary dilation on abdominal CT scan. In all cases, a history of chronic ketamine use and a negative comprehensive workup for other etiologies strongly suggested ketamine as the cause of their presentations. Case 1 had normalization of liver enzymes and marked improvement of radiographic biliary changes at 3-month follow-up after complete cessation of ketamine. Case 2 reduced ketamine use by 50% and experienced similar clinical improvement at 3-month follow-up. Case 3 continued using ketamine, resulting in worsening liver enzyme elevations and persistent biliary tree imaging abnormalities. Chronic ketamine use should be considered in patients presenting with liver enzyme elevation and/or imaging evidence of biliary dilation. Increased awareness in Canada is essential to ensuring health care providers consider ketamine-related cholangiopathy in patients presenting with these clinical findings, as with ketamine cessation liver injury and biliary abnormalities are potentially reversible. Ketamine is a drug that can be used clinically to treat chronic pain and severe depression. However, ketamine is increasingly being used recreationally due to its hallucinogenic and dissociative side effects. Multiple adverse effects can develop with prolonged use of ketamine, including liver and biliary injuries, which have been termed ketamine-related cholangiopathy. Patients with ketamine-related cholangiopathy may present with liver disease occurring from bile flow obstruction and can be associated with marked abnormalities of the bile ducts on ultrasound and magnetic resonance imaging. Some patients have been reported to develop advanced forms of liver disease from ketamine, including cirrhosis. Importantly, if identified early, the liver injury and biliary changes seen on imaging often appear to be reversible with ketamine cessation. Increased awareness of the potential liver and biliary complications that can arise with ketamine use will be critical for preventing this reversible cause of bile duct and liver damage.
Post-transplant immunosuppression increases malignancy risk. Gastric cancer is one of the most common post-transplant malignancies among high-risk groups including Asian patients. Helicobacter pylori is a known risk factor for gastric cancer; however, pre-transplant screening is not standard. This retrospective study assesses the frequency with which patients with end-stage liver disease, prior to liver transplant, are screened for H. pylori using endoscopic or non-endoscopic methods. We conducted a retrospective chart review of 127 patients who underwent upper endoscopy prior to liver transplant. Data were collected for age, ethnicity, indications for endoscopy, endoscopic findings, endoscopic treatment, gastric biopsy results, and antibiotic/proton pump inhibitor use. Non-endoscopic H. pylori testing within 5 years before transplant was recorded. Among 127 patients, 15 were of Asian and 9 were of Indigenous heritage. The most common indication for endoscopy was variceal surveillance (83 patients), then gastrointestinal bleeding (33 patients). Thirty-nine patients had biopsies taken for H. pylori, with four testing positive. Twenty patients had non-endoscopic testing, with three testing positive. Seventy-six patients (60%) underwent no form of testing. In Asian patients, 8 of 15 (53%) had no form of testing. Indigenous and Asian patients demonstrated high positivity rates, with 50% and 14% testing positive, respectively. H. pylori testing was performed in under 40% patients awaiting liver transplant. When tested, positivity was 10% by biopsies and 15% by other methods. Given high prevalence of H. pylori positivity, routine screening via endoscopic or non-endoscopic methods should be employed to mitigate post-transplant gastric malignancy risk. Liver transplant offers a life-saving treatment for many patients with advanced liver disease. However, patients who have received a liver transplant require long-term immunosuppressive medications. Such medications come with side effects that may increase a patient's susceptibility to infections and various cancers. Stomach cancer is one of the more common cancers after transplant, with higher incidences observed in certain ethnic groups, including Asian populations. Helicobacter pylori (H. pylori) is a well-established risk factor for stomach cancer. Currently, routine screening for this bacterium is not standard practice before liver transplant. Our study looked at patients who underwent liver transplantation over a 2-year period. We examined the frequency of testing, methods of testing, and infection rates of H. pylori in liver transplant recipients to better understand current screening practice. We identified that H. pylori infection rate was higher in Asian and Indigenous patients; however, screening remained underutilized despite these patients’ increased risks. Our findings highlight a potential gap in pre-transplant care and suggest that hospitals should consider including routine H. pylori screening as part of standard pre-transplant workup. Detection and early treatment of this infection may decrease the risk of stomach cancers and improve the long-term outcomes of people receiving liver transplants.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in people with HIV (PWH), yet its impact on health-related quality of life (HRQoL) remains poorly characterized. We evaluated the association between MASLD and both generic and liver-specific HRQoL. We conducted a cross-sectional analysis within a national multicenter cohort of PWH. MASLD was defined as hepatic steatosis (controlled attenuation parameter >248 dB/m) plus at least metabolic comorbidity and significant liver fibrosis as liver stiffness measurement ≥8 kPa on FibroScan. Generic HRQoL was assessed using the Short Form-36 and liver-specific HRQoL using the Chronic Liver Disease Questionnaire (CLDQ). Adjusted estimated mean differences were estimated using multivariable linear regression. Among 519 participants, the prevalence of MASLD and significant liver fibrosis was 41.4% and 7.2%, respectively. MASLD was independently associated with lower generic HRQoL, including reduction of physical functioning (-4.6; 95% confidence interval [CI] -9.12 to -0.01) and general health (-4.5; 95% CI -8.58 to -0.48) on the Short Form-36. Liver-specific HRQoL was more affected; MASLD was associated with a lower overall CLDQ score (-0.29; 95% CI -0.49 to -0.09), driven by worse fatigue, systemic symptoms, emotional symptoms, and worry. Among PWH with MASLD, increasing metabolic comorbidity burden was associated with a dose-response decline in physical HRQoL, whereas liver-specific HRQoL did not differ across comorbidity strata. Significant fibrosis was associated with lower CLDQ activity (-0.62; 95% CI -1.20 to -0.05) and worry (-0.60; 95% CI -1.15 to -0.05). In PWH, MASLD is associated with impaired HRQoL, particularly fatigue, systemic symptoms, and emotional well-being. Greater metabolic burden and liver fibrosis further worsen patient-reported outcomes.
Sarcopenia is associated with increased mortality in patients with cirrhosis, but this association remains unclear when adjusted for portal hypertension. We investigated the association of muscle mass and portal hypertension on liver-related events. This retrospective study (2012-2022) included adult patients with cirrhosis and available hepatic venous pressure gradient (HVPG). Total cross-sectional skeletal muscle index (SMI) and subcutaneous adipose tissue index (SATI) at the third lumbar vertebrae (L3) were measured at the time of HVPG using CT imaging. Sarcopenia is defined as L3-SMI <39 cm2/m2 in female and <50 cm2/m2 in male patients. Logistic regression analyses assessed sarcopenia predictors; Cox regression analyses assessed liver-related events and mortality predictors. A total of 121 patients were included (sarcopenia: 46%, female: 62%, mean age: 58.3 years, MASLD: 34%, median HVPG: 10 mmHg, median MELD score: 13, prior decompensation: 55%). Sarcopenia was more likely in patients with prior decompensation (70% versus 43%, p < 0.003), lower alanine aminotransferase (ALT) (21 versus 40 U/L, p < 0.001), and lower SATI (37.4 versus 76.4 cm2/m2, p < 0.001). After age, prior decompensation, and ALT adjustments, SATI remained an independent predictor of sarcopenia (adjusted odds ratio aOR 0.98 [95% CI 0.97-0.99]). Over a median follow-up of 14.5 months, 59% had liver-related events and 29% died. After HVPG and MELD adjustments, which were significant factors, L3-SMI remained a predictor of liver-related events (adjusted hazard ratio [aHR] 0.98 [95% CI 0.95-0.99]) and mortality (aHR 0.96 [95% CI 0.92-0.99]). Our study demonstrates that low muscle mass predicts liver-related events and mortality independently of portal hypertension and liver disease severity. Low muscle mass is frequent in people with cirrhosis. Our study shows that low muscle mass is linked to an increased risk of liver-related events and mortality after adjusting for the presence of portal hypertension, an important cause of liver events. This supports the need to screen and treat low muscle mass in patients with cirrhosis and prevent the occurrence of liver-related complications.
Liver transplantation from donors following medical assistance in dying (MAiD) is a novel practice with emerging Canadian outcomes data. We sought to compare donor and recipient outcomes after liver transplantation following donor MAiD, circulatory death (DCD), or brain death (DBD). We conducted a scoping review and a single-centre retrospective cohort study. The 5 retrospective studies identified found comparable short-term liver graft and patient survival between MAiD, DCD, and DBD liver recipients, with no differences in vascular complications or primary nonfunction. One study noted higher biliary complications among MAiD liver recipients. Our single-centre retrospective cohort reporting included 177 liver transplant recipients between 2018 and 2024 (19 MAiD, 14 DCD, and 144 DBD donors). Among donors, MAiD (mean age 59 yr) and DBD (mean age 57 yr) donors were older than DCD donors (mean age 37 yr; p < 0.001) and had lower median body mass index than other donors (MAiD 20, DCD 22, DBD 26; p < 0.001). Cold ischemia times were longest for DBD grafts (6.6 h v. 6.2 h DCD and 5.8 h MAiD; p = 0.02), with no other intraoperative differences. Rates of mortality within 90 days (p = 0.7), complications (Clavien-Dindo grade ≥ 3; p = 0.4), and retransplant (p = 0.6) were comparable across groups. Biliary strictures affected 42% MAiD, 35% DCD, and 13% DBD livers (p = 0.005), mostly extrahepatic and anastomotic strictures. Kaplan-Meier analysis found no significant difference in graft survival between donor groups (p = 0.7), Cox regression identified portal vein thrombosis (hazard ratio [HR] 23.98, 95% confidence interval [CI] 2.41 to 238.15), hepatic artery thrombosis (HR 8.14, 95% CI 1.72 to 38.54), and biliary complications (HR 11.93; 95% CI 2.31 to 61.76) as independent predictors of graft loss. Liver transplantation from donors who underwent MAiD was not associated with higher graft loss or mortality than in those who underwent DCD or DBD. Its continued use is safe, and larger multicentre studies are warranted for validation. La transplantation d’un foie provenant d’une personne donneuse d’organe après qu’elle a reçu l’aide médicale à mourir (AMM) est une nouvelle pratique pour laquelle on commence à obtenir des données canadiennes sur les résultats. Nous avons voulu comparer les résultats liés aux personnes donneuses d’organe ainsi que ceux liés aux personnes receveuses d’organe à la suite d’une transplantation hépatique suivant le décès par AMM, le décès par arrêt cardiorespiratoire ou la mort cérébrale de la personne donneuse d’organe. Nous avons effectué une revue exploratoire ainsi qu’une étude de cohorte rétrospective menée dans un seul centre. Les 5 études rétrospectives repérées ont révélé une survie à court terme semblable du greffon et des personnes greffées qui ont reçu un foie après un décès par AMM, un décès par arrêt cardiorespiratoire ou une mort cérébrale; aucune différence n’a été relevée en ce qui concerne les complications vasculaires ou la non-fonction primaire. Une étude a révélé un nombre accru de complications biliaires chez les personnes ayant reçu un foie à la suite d’un décès par AMM. Notre étude de cohorte rétrospective menée dans un seul centre comprenait 177 personnes ayant reçu un foie entre 2018 et 2024 (19 à la suite d’un décès par AMM, 14 à la suite d’un décès par arrêt cardiorespiratoire et 144 à la suite d’une mort cérébrale). Les personnes donneuses d’organe ayant reçu l’AMM (âge moyen 59 ans) et celles ayant subi une mort cérébrale (âge moyen 57 ans) étaient plus âgées que les personnes décédées à la suite d’un arrêt cardiorespiratoire (âge moyen 37 ans; p < 0,001), et leur indice de masse corporelle médian était inférieur (AMM 20, arrêt cardiorespiratoire 22, mort cérébrale 26; p < 0,001). Les périodes d’ischémie froide les plus longues ont été notées pour les greffons des personnes ayant subi une mort cérébrale (6,6 h par rapport à 6,2 h pour les décès par arrêt cardiorespiratoire et à 5,8 h pour les décès par AMM; p = 0,02), sans aucune autre différence sur le plan peropératoire. Les taux de mortalité dans les 90 jours (p = 0,7), de complications (grade ≥ 3 à la classification de Clavien–Dindo; p = 0,4) et de retransplantation (p = 0,6) étaient comparables entre les groupes. Des sténoses biliaires ont été constatées chez 42 % des foies provenant de personnes décédées par AMM, 35 % de personnes décédées d’un arrêt cardiorespiratoire et 13 % de personnes ayant subi une mort cérébrale (p = 0,005), la plupart étant des sténoses extrahépatiques ou anastomotiques. Une analyse selon la méthode de Kaplan–Meier n’a révélé aucune différence significative quant à la survie du greffon entre les groupes de personnes donneuses (p = 0,7); le modèle de régression de Cox a permis de repérer les facteurs prédictifs indépendants de perte du greffon suivants : thrombose de la veine porte (rapport de risque [HR] 23,98, intervalle de confiance [IC] à 95 % 2,41 à 238,15), thrombose de l’artère hépatique (HR 8,14, IC à 95 % 1,72 à 38,54) et complications biliaires (HR 11,93, IC à 95 % 2,31 à 61,76). La transplantation d’un foie provenant de personnes donneuses d’organe ayant eu recours à l’AMM n’a pas été associée à une perte accrue du greffon ou à une mortalité accrue par rapport à la transplantation d’un foie provenant de personnes décédées d’un arrêt cardiorespiratoire ou ayant subi une mort cérébrale. Le recours continu à cette technique est sûr, et de plus grandes études multicentriques sont nécessaires pour valider celle-ci.
Alcohol-associated liver disease (ALD) is a growing health care concern, with alcohol use disorder (AUD) being a contributor to liver-related morbidity and mortality. This study examines the practices, perspectives, and challenges faced by Canadian health care providers in managing AUD within the context of ALD. A nationally representative survey was conducted among health care providers involved in ALD management. The survey evaluated practices related to AUD screening, prescribing pharmacotherapy, addiction services referral, and perceived barriers. Alcohol use screening was common (75%), but standardized tools were rarely used (<10%), with barriers including time constraints (61%) and resource limitations (60%). Less than 15% of patients received AUD pharmacotherapy, with lack of training identified as a key barrier. Notably, 47% of providers had never prescribed AUD pharmacotherapy due to low comfort levels (78%). Early and mid-career providers were more likely to prescribe AUD pharmacotherapy compared to their senior counterparts (71% versus 61%, p = 0.02). Acamprosate and naltrexone were the most frequently prescribed medications. Behavioural therapy referrals were reported by 57% of respondents, although patient reluctance (70%) and financial barriers (53%) hindered access. Knowledge gaps regarding AUD pharmacotherapies were prevalent. This study reveals significant gaps in AUD management within ALD care, marked by insufficient screening, underuse of pharmacotherapies, and limited referrals to addiction services. Addressing these issues requires urgent attention through enhanced provider education, integration of addiction care, and systemic reforms. Collaborative efforts among all health care providers are essential to improving care delivery and outcomes for individuals with ALD and AUD. North America, including Canada, is witnessing a concerning increase in the prevalence of alcohol use disorder (AUD) and alcohol-associated liver disease (ALD). As a result, ALD has emerged as a significant contributor to liver-related morbidity and mortality. This study aims to investigate the present state of practice in the management of ALD among health care providers across Canada. By exploring the attitudes, practices, and challenges faced by health care providers, the study seeks to identify existing gaps in the delivery of services related to ALD care and generate evidence-informed insights that address clinical practice concerns specific to the Canadian context. A nationally representative survey was conducted among health care providers involved in ALD management to evaluate practices related to AUD screening, prescribing pharmacotherapy, addiction services referral, and perceived barriers. Providers including specialists in addiction and psychiatry, gastroenterology, and hepatology, as well as social work, were included in the survey. Our results suggest alcohol use screening is common (75%) among health care providers. However, standardized tools were rarely used (<10%), with barriers including time constraints (61%) and resource limitations (60%). Notably, 47% of providers had never prescribed AUD pharmacotherapy due to low comfort levels (78%). Early and mid-career providers were more likely to prescribe AUD pharmacotherapy compared to their senior counterparts (71% versus 61%, p = 0.02). Behavioural therapy referrals were reported by 57% of respondents, although patient reluctance (70%) and financial barriers (53%) hindered access. Our study demonstrated significant gaps in AUD management within ALD care, marked by insufficient screening, underuse of pharmacotherapies, and limited referrals to addiction services. Collaborative efforts among all health care providers are essential to improve care delivery and outcomes for individuals with ALD and AUD. Our study shows that in Canada, we need to have increased provider education, integration of addiction care, and systemic reforms.
Liver cirrhosis may present in different stages with distinct prognoses. Commonly used models for predicting liver-related decompensation and mortality have several limitations. Ammonia was proposed as a possible alternative or complementary tool. Our primary objective was to explore the predictive role of plasma ammonia levels regarding liver-related outcomes. Our secondary aim was to validate a new measure that corrects baseline ammonia levels to the upper limit of normal (AMM-ULN) as a predictor of liver-related outcomes. In this retrospective single-centre study, 278 patients with cirrhosis and an ammonia measurement were included. Relevant outcomes (liver-related decompensation and mortality) were evaluated in the compensated and decompensated groups, and AMM-ULN was assessed as a predictor. Plasma ammonia levels and AMM-ULN were predictors of hepatic decompensation (hazard ratio [HR] 1.453, 95% CI 1.085-1.945, p = 0.012) and mortality (HR 1.010, 95% CI 1.003-1.017, p < 0.001) at 12 months in the compensated cirrhosis group. These parameters were not predictors of further decompensation and mortality in already decompensated patients. AMM-ULN ≥ 1.4 identified patients at higher risk of liver-related decompensation (p = 0.009) and mortality (p = 0.020) at 12 months in the compensated cohort. Both ammonia levels and AMM-ULN were predictors of hepatic decompensation and liver-related mortality in compensated patients at 12 months of follow-up. Different stages of liver cirrhosis exist. Prediction models are important to evaluate the associated risk of decompensation and mortality. Plasma ammonia levels have been proposed as a predictor. In this study, ammonia was an independent predictor of decompensation and mortality at 12 months in patients with compensated cirrhosis.
Advanced fibrosis (F2-F4) drives morbidity and mortality in metabolic dysfunction-associated steatotic liver disease (MASLD). Population-wide screening is impractical due to patient volume and health care costs. We hypothesized that machine learning (ML) algorithms trained on routine demographic and clinical data could identify patients at risk of significant fibrosis, reducing reliance on blood draws or transient elastography (TE). As part of the Liver Beware study, 4,193 patients prospectively underwent TE. Clinical and demographic data, such as age, BMI, race, diabetes, and hypertension, were collected immediately prior to elastography. Data were split into training (60%), validation (20%), and test (20%) sets. Six ML algorithms were evaluated: logistic regression, logistic regression with SMOTE, XGBoost, random forest, SVM, and ensemble voting classifier. Performance was assessed by accuracy, sensitivity, specificity, precision, and area under the curve (AUC). XGBoost had the most well-balanced test performance with 72.2% accuracy, 59.7% sensitivity, 73.4% specificity, 17.4% precision, and AUC of 0.72. Random forest had the highest accuracy (91.1%) but low sensitivity (1.4%). XGBoost identified obesity, diabetes, and hypertension as the leading predictors of risk of fibrosis. ML algorithms based on readily available demographic and clinical data can identify patients at high risk of fibrosis with acceptable accuracy. This scalable approach enables triaging for further testing such as TE, trading marginal AUC reduction for maximal accessibility compared with biomarker-dependent scores (eg, SAFE, Agile 4/3+). Implementation and cost-effectiveness studies are needed to refine referral thresholds and evaluate real-world impact. Metabolic liver disease (MASLD) is becoming more common and can lead to serious liver damage if not caught early. We used machine learning to predict serious liver damage (fibrosis) in people with fatty liver disease using common health data such as age, weight, and diabetes status. Our best model, XGBoost, showed promising accuracy and could help physicians identify at-risk patients to intervene earlier and prevent worsening liver disease.
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Patient-partnered basic and translational research is the most productive and meaningful approach to developing informed research questions, generating high-quality data, and producing impactful work. While several organizations have published guidelines for patient-partnered research, few experiential reports in basic science are written from both the patient and researcher perspectives and comment on real-time practical challenges and approaches that ensure the establishment and maintenance of a non-tokenistic, organized, and successful research partnership with patient partners. We describe patient partners' and researchers' experiences working together in a basic science and translational research team studying the drivers of primary sclerosing cholangitis, a rare liver disease for which liver transplantation remains the only treatment to disrupt disease progression. We outline approaches used to support meaningful communication, collaboration, and shared output among project stakeholders, drawing on the perspectives of both basic science researchers and patient representatives involved in long-standing joint research projects. Several practical elements support the success of patient partnership in basic and translational science, including structured communication, clear role definition, mutual respect, sustained engagement, and intentional mechanisms to support patient partners' meaningful contributions. We highlight challenges and strategies used to address them in real time, offering insight into how patient-researcher partnerships can be maintained in an organized, authentic, and non-tokenistic way. This review highlights a patient-partnered research team's experiential insights to bridge the gap between published guidance and real-world practice, reinforcing how authentic patient-researcher partnerships can drive more inclusive and impactful basic and translational science. Involving patients as active partners in research leads to better questions, stronger data, and more meaningful results. While many organizations have created guidelines for including patients in research, there are still very few reports and reviews that describe what this looks like in real time, especially in basic science and translational research in rare liver disease. In this article, we share the experience of both patient partners and researchers working together on a project focused on primary sclerosing cholangitis, a rare liver disease for which liver transplant is the only treatment that can stop progression. We describe how we built and maintained a true partnership by using practical strategies for communication, collaboration, and shared decision making. This work offers lessons learned by both researchers and patient partners and shows how strong patient–researcher relationships can lead to better science and greater impact.
Multiple North American and European societies now endorse a combined serological and imaging-based clinical care pathway for non-invasive risk stratification of patients with metabolic dysfunction-associated steatotic liver disease (MASLD). A multidisciplinary group of Canadian radiologists, hepatologists, family physicians, and other health professionals have recently published consensus guidelines for identification and risk stratification of patients with suspected MASLD. Screening should be performed with the FIB-4 score, and those with an indeterminate FIB-4 (between 1.32.67) should undergo imaging-based liver stiffness evaluation either with transient elastography (FibroScan), ultrasound shear wave elastography, or magnetic resonance elastography as a second step. While the implementation of these techniques for measuring liver stiffness differ, there is no clinically significant difference in their diagnostic performance. This narrative review, intended for Family Physicians, summarizes recommendations for serological investigations and imaging modalities of liver steatosis and stiffness. Practical guidance includes an algorithm with thresholds. We discuss current challenges and future directions of risk-stratifying patients with MASLD in the community.
Postmortem perfusion is a procedure which provides in-vivo fixation of the human body and prevents organ and tissue decomposition after biological death occurs. Formaldehyde-based embalming solutions influence nucleic acid degradation, which reduces the quality and quantity of DNA extracted and the effectiveness of short tandem repeat (STR) typing. This research is a 1-year study aimed at determining the timeframe within which viable DNA profiles can be generated from different tissue types, post-embalming. Samples from the bone marrow (tibia), trapezius and quadriceps muscles, liver, and brain tissues were collected before embalming and at seven time points post-embalming. DNA extraction and quantification were performed on each sample to assess whether sufficient DNA was available for testing. Samples with DNA quantities over 0.05 ng/μL underwent amplification and STR analysis to produce DNA profiles. Quantification values and profile quality were compared across tissue types and time points. Results showed that prolonged exposure to embalming solutions significantly reduced DNA quality, leading to less discernible profiles. Statistically significant differences were detected among all tissue types at all time periods. Liver and brain samples retained more DNA than bone marrow, trapezius, and quadricep muscle samples. Qualitative evaluation of ski slope patterns in liver STR profiles demonstrated increasing signal degradation over time and was consistent across loci, suggesting predictable fragment length-dependent decline. This study suggests that after embalming, the liver is the preferential tissue for recovering DNA for forensic analysis, as the liver samples were the most robust and the only sample type to yield DNA profiles up to 1 year.
The liver is composed of diverse cell populations that coordinate essential metabolic and immune functions. Single-cell transcriptomics has advanced characterization of liver cellular composition, but dissociation of tissue to single-cells can introduce biases through the enrichment or depletion of cell types. Spatial transcriptomics is a complementary approach to avoid inherent bias for cell populations and to add important spatial context. The Visium HD spatial transcriptomics technology from 10X Genomics enables high-resolution spatial mapping of gene expression in tissue samples with a bin width of 2 µm enabling quantification of transcripts at a sub-cellular resolution. We applied Visium HD to three healthy human liver donor samples, from two adult and one pediatric donor. We identified cell types by clustering 8 µm bins and integration with single-cell reference maps. Differential expression analyses identified spatially distinct gene expression resulting in development of a high-resolution map of the liver. This resource provides cell-level and spatially-resolved insights into the cellular and anatomical heterogeneity of the liver to serve as a resource for researchers to identify disease-specific spatial signatures and novel therapeutic targets.
Sepsis is a common complication of parenteral nutrition therapy for infants with intestinal failure, due to the presence of a central venous catheter and impairment of gut barrier function. Intestinal failure-associated liver disease (IFALD) is another complication, often attributed to the type of intravenous lipid emulsion delivered and this is commonly studied in pre-clinical animal models. Animal studies frequently overlook sepsis as a confounding factor, potentially biasing the results. We retrospectively reviewed 14-day studies of total parenteral nutrition (TPN) in piglets in our laboratory from 2011 to 2025, to determine if sepsis is an independent predictor of key liver outcomes relevant to IFALD research. Sepsis was defined as positive blood culture. A total of 86 piglets (76 male; aged 2-5 days) were eligible for inclusion across four experimental studies. In total, 44 (51%) were suspected to have sepsis on the basis of clinical signs, 4 had missing blood cultures, and of these 28/40 (70%) had a positive blood culture. Septic piglets had higher mortality compared to those not suspected to be septic or having a negative blood culture (43% vs. 9%, p < 0.001). Septic piglets showed significantly lower bile flow (p < 0.001) and higher serum total bilirubin (p < 0.001) compared to non-septic piglets. The risk of developing sepsis was reduced in piglets with older age (OR = 0.42, p = 0.007) and increased when given a pure soy-oil compared to pure fish-oil emulsion (OR = 10.77, p = 0.05). Multivariate analysis showed the independent predictors of bile flow were both sepsis (negative) and higher body weight at study entry (positive) (R2 = 0.42, p < 0.001), while sepsis and use of a soy-based lipid emulsion were independent positive predictors of total bilirubin (R2 = 0.34, p < 0.001). Sepsis is associated with reduced bile flow, elevated total bilirubin and increased mortality in PN fed neonatal piglets. As sepsis can be a confounding factor in liver outcomes, researchers should both introduce refinements to mitigate sepsis as well as consistently report on the number of animals with sepsis within treatment groups and their outcomes.
Post-transplant malignancy (PTM) contributes substantially to late morbidity and mortality after liver transplantation (LT), yet contemporary data on cancer spectra across cirrhosis etiologies remain limited. We assessed PTM prevalence, determinants, and cancer-type distribution by pre-LT etiology in a Canadian cohort to inform risk-adapted surveillance in routine practice. We conducted a retrospective cohort study of adults undergoing LT at a tertiary Ontario center (2007-2018) with 60-month follow-up. De novo and recurrent malignancies were ascertained through June 2023 using institutional cancer registries. Time-to-event associations with post-LT cancers were evaluated using Cox proportional hazards models. Among 575 recipients (mean age 53.6 ± 11.0 years; 30.1% women), etiologies included alcohol-associated liver disease (22.9%), HCV (20.8%), MASLD (16.2%), PSC (11.1%), and others. Maintenance immunosuppression was predominantly tacrolimus with or without mycophenolate. Overall, 55 patients (9.5%) developed non-HCC cancers at 27.3 ± 19.1 months; the most frequent were non-melanoma skin cancer (3.4% of the cohort; 36.4% of cancers), head and neck (10.9%), PTLD (9.1%), and gastrointestinal (9.1%). Post-LT HCC occurred in 3.4% (90% recurrences). Overall cancer incidence was similar across etiologic groups, but cancer-type distributions differed (p = 0.049). In multivariable Cox models, age, sex, smoking, alcohol use, and immunosuppression class were not associated with non-HCC cancer risk, whereas pre-LT HCC independently increased risk (HR 2.66; 95% CI 1.40-5.08; p = 0.003). PTM was common after LT and overall showed etiology-linked cancer spectra. These findings support universal dermatologic surveillance and intensified, individualized screening for recipients with pre-transplant HCC, incorporating underlying liver disease etiology to optimize early detection and long-term outcomes.
Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist under investigation for treating obesity and related diseases. The SYNCHRONIZE-MASLD phase 3, randomized, double-blind, placebo-controlled trial included 216 adults (131 female and 85 male) with obesity (defined as a body mass index ≥30 kg m-2 or ≥27 kg m-2 with at least one obesity complication) and at-risk metabolic dysfunction-associated steatotic liver disease (MASLD), defined by MASLD with evidence of liver inflammation and/or fibrosis by noninvasive tests (NITs) or biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH). Participants were randomized (2:1) and treated with once-weekly subcutaneous injections of survodutide 6.0 mg (n = 146) or placebo (n = 70). The co-primary endpoints, ≥30% reduction in magnetic resonance imaging-proton density fat fraction (MRI-PDFF)-assessed liver fat content (LFC) and percentage change in body weight (both baseline to week 48), were met. In total, 84.2% of survodutide-treated patients versus 24.3% of placebo-treated patients had ≥30% reduction in LFC using the efficacy estimand (P < 0.0001; treatment regimen estimand: 68.5% versus 28.6%, respectively; P < 0.0001). Mean percentage change in body weight was -12.2% with survodutide and -1.0% with placebo using the efficacy estimand (P < 0.0001; treatment regimen estimand: -8.7% versus -1.4%, respectively; P < 0.0001). The most frequently reported adverse events with survodutide were gastrointestinal, commonly occurring during dose escalation, and were generally of mild-to-moderate severity. In adults with obesity and at-risk MASLD, survodutide treatment was statistically and clinically superior to placebo for reductions in MRI-PDFF-assessed LFC and body weight. Limitations included short trial duration (48 weeks) and limited global reach (participants recruited in the United States and Spain).
Lipid nanoparticle (LNP) delivery of RNA therapeutics is constrained by poor tissue selectivity and off-target toxicity. Most high-throughput screening approaches have focused on single-target efficacy while overlooking off-target uptake. Here we report multiobjective LNP engineering with artificial intelligence (MOLEA), a system that integrates high-dimensional lipid representations, cell-type-resolved transfection data and multitask optimization to design ionizable lipids with both high potency and biological selectivity. MOLEA learns structure-function relationships across diverse cellular contexts to identify lipids that preferentially deliver mRNA to target tissue while minimizing hepatocyte transfection. Applying MOLEA to cartilage, we developed K9 LNPs, which achieve >90% transfection efficiency in mouse joint chondrocytes and a 13.5-fold increase in knee-to-liver selectivity compared to the clinical benchmark SM-102. We demonstrate chondrocyte-specific Mmp13 editing in osteoarthritis mouse models, leading to sustained cartilage protection and suppression of disease-associated immune and matrix remodeling. Our findings demonstrate how artificial-intelligence-guided multiobjective optimization can enable precision RNA delivery with potential applications to other tissues.
Liver transplantation (LT) is increasingly performed on patients with comorbidities, including critically ill individuals requiring extended intensive care unit (ICU) care. Little is known about these recipients' long-term functional and neuropsychological outcomes. This study aimed to assess the impact of prolonged ICU stays and mechanical ventilation on LT recipients. We examined 1-year outcomes of LT recipients with prolonged mechanical ventilation (MV) exceeding 7 days in the multicentre RECOVER program (2009-2014). Assessments occurred at 7 days and 3, 6, and 12 months post-ICU discharge, focusing on the functional independence measure (FIM), Medical Research Council (MRC), 6-minute walk test (6MWT), and short-form-36 (SF-36) survey. Psychological assessment used the impact of event scale (IES) and Beck depression inventory-II (BDI-II). Caregivers' psychological outcomes were also evaluated. Fourteen LT recipients (42.9% male; mean age 50 years) with median MV of 16.5 (14.0-25.8) days were included; 13 survived to ICU discharge (median ICU stay 19.5 [15.5-31.2] days). FIM scores showed persistent cognitive and motor function limitations, plateauing at 3 months. At 12 months, total FIM was 87.7 (SD 48.1), indicating moderate assistance need. The 6MWT was 71.6% predicted; SF-36 physical component score was 44.6 SD 9.1. Average BDI-II of 9.9 (SD 13.8) at 1 year indicated minimal depressive symptoms; mean IES score (24.4 SD 28.8) suggested post-traumatic stress disorder symptoms. Caregivers also experienced persistent depressive symptoms. LT recipients with prolonged MV exhibited lasting functional and cognitive limitations at 1-year follow-up, underscoring the potential benefits of targeted rehabilitation interventions for enhanced recovery. Liver transplantation (LT) has greatly extended lives, yet merely increasing lifespan is not enough. As more patients with complex health issues undergo transplant, focusing on post-transplant quality of life is critical. In our study, we followed LT recipients who required over a week of ventilator support after LT to assess their recovery during the first year post-ICU discharge. We evaluated their ability to perform daily tasks, mobility, and endurance, along with signs of depression and post-traumatic stress. We also monitored the emotional well-being of their caregivers. Even 1 year after transplantation, many patients continued to experience physical and cognitive challenges, while caregivers showed ongoing depressive symptoms. Overall, our findings underscore the need for comprehensive support—both medically and emotionally—for patients and caregivers following LT.
Ketamine is a dissociative anesthetic with potential for treating mood, anxiety, and related disorders; however, concerns have emerged regarding hepatotoxicity in the context of chronic treatment. Systematic searches of PubMed, Scopus, and Ovid databases were conducted from inception to August 2025. Eligible studies included randomized controlled trials (RCTs), observational studies, and case reports/series reporting liver function outcomes following therapeutic ketamine administration for mood, anxiety, or related psychiatric disorders. Of 635 screened records, 13 met inclusion criteria: five RCTs, three observational studies, and five case reports/series, encompassing 1017 patients receiving ketamine primarily for major depressive disorder (MDD) and bipolar disorder (BD). Across RCTs (n = 879), 75 hepatic adverse events were reported, predominantly mild and transient aminotransferase elevations, with rare cases of liver impairment, but no cases meeting Hy's Law criteria. Observational studies identified three instances of liver impairment, RCTs identified one case as indicated by elevated bilirubin, and case reports described more severe presentations, including bile duct dilation and gall bladder distention, which improved with dose reduction or discontinuation. Evidence identified here suggests that ketamine at dosing regimens typically used for mood disorders may cause liver enzyme elevations, but impaired liver function and serious hepatotoxicity appears rare. However, considering the instances of impaired liver function identified herein and real-world data associating severe drug-induced liver injury (DILI) with higher exposures, routine liver monitoring remains justified throughout ketamine treatment.