Could taurine supplementation improve graft functions after liver transplantation? A randomized clinical trial among liver transplant recipients.

Ad Integrum Functional and Volumetric Recovery in Right Lobe Living Donors: Is It Really Complete 1 Year After Donor Hepatectomy?

INTRODUCTION Among patients who have undergone liver transplantation, liver enzymes (aminotransferases, bilirubin, and alkaline phosphatase) provide an important indicator of graft function, anatomic and biliary complications, and immunologic response. The pattern of elevation in conjunction with the timing and clinical context can offer insight into the mechanism of injury.1 Frequently, an elevation in liver enzymes is the first indicator of graft pathology, providing an opportunity to intervene clinically to preserve allograft function. PATTERNS OF LIVER ENZYME ELEVATION Across the lifetime of a post-transplant patient, complications directly affecting the liver allograft typically fall into several broad categories: early operative injury, vascular and biliary complications, immune-mediated injury, drugs, infectious complications, and recurrence of primary liver disease (Tables 1–3). Cholestatic and hepatocellular liver enzyme patterns can be suggestive of specific diagnoses, but, in many cases, post-transplant complications demonstrate a relatively nonspecific mixed liver enzyme pattern.2 Management of patients, therefore, often relies on a careful clinical history and a nuanced understanding of symptoms, culture data, serologic tests, and imaging. Ultrasound with Doppler, cross-sectional imaging, endoscopic retrograde cholangiopancreatography, and liver biopsy are among the most frequent tools used in the evaluation of post-transplant elevated liver enzymes. In addition, the rate of rise in liver enzymes often portends more potential harm to the liver allograft and can require rapid diagnostic evaluation to guide appropriate intervention. Dynamic physiological and immunologic changes, particularly early post-transplant, can often lead to co-occurring processes that can complicate the identification of otherwise characteristic liver enzyme pattern presentations.3 Therefore, while the pattern of liver enzyme elevation and rate of rise is important, these changes must also be interpreted in a clinical context to allow prompt diagnosis. TABLE 1 - Perioperative, vascular, and biliary causes of abnormal liver enzymes after LT Category Diagnosis Definition Timing Pattern Risk factors Evaluation Treatment Perioperative complications Ischemia reperfusion injury/preservation injury Hepatocellular graft damage that results from perioperative cold and warm ischemic time as well as reperfusion of the donor liver Post-transplant rise in liver enzymes; typically peaks in the first 2–7 d and spontaneously regresses AST/ALT 5-20X ULNDelayed rise in total bilirubin can occur Typically seen to varying degrees in all patients after transplant None Observation PNF Widespread hepatocellular necrosis and hemorrhage, evolving into post-transplant liver failure.PNF Defined as:1.AST > 30002.INR > 2.53.Within 7 d of transplantation Within first 7 d AST >3000 IU/ML and INR > 2.5 within 7 d post-LT DCD allograft>12 h cold ischemic time>90 min warm ischemic time Imaging to rule out vascular obstruction Retransplant (listed status 1A) Fluid collection, abscess Perioperative fluid collections can become infected in the absence of source control First 1–2 wk post-transplant Mild liver enzyme pattern, cholestasis of sepsis Hematoma or biloma formationReoperation/take-back Cross-sectional imaging, labs Drainage of collection Vascular complications Early HAT Acute thrombosis of the hepatic artery associated with a wide range of clinical manifestations including fever, sudden liver enzyme rise, fulminant hepatic failure Median 7 d, within first 2–3 wk after transplantation Acute ischemic injury with sharp rise in ALT and AST typically >10× ULN Arterial reconstructionDelayed reperfusionMultiple anastomoses Urgent duplex ultrasound or CT angiogram Endovascular intervention, occasionally retransplant Late HAT Narrowing of the transverse diameter of HA by 50%, with resistive index <0.5, peak systolic velocity >400 Can be early or late post-transplant, often insidious. Median 3 mo post-transplant Cholestatic pattern due to diffuse biliary stricturing with elevation in AP +/− TB Intraoperative factors (clamp injury, intimal dissection) and donor anatomy Doppler ultrasound Endovascular interventionSurgical revision Biliary complications Biliary stricture (anastomotic and diffuse type) Focal stricturing at the biliary anastomoses or the diffuse stricturing of large intrahepatic or extrahepatic bile ducts of the donor liver. Within first 2–3 wk after transplantation AP 2–5× ULN with elevated TB (predominantly direct) Surgical technique, ischemic time, hypotension ERCP Endoscopic stenting or balloon dilation. May require revision to Roux-en-y. Bile leak Biliary anastomotic leak, typically producing a fluid collection. Reduced drainage from biliary drain. Most commonly within 30 d Tbili elevation No specific risk factors CT to evaluate collection ERCP vs IR guided stenting and drainage Acute cholangitis Rising bilirubin related to obstruction and infection in the bile ducts, often related to stricturing Any time, often within 1–2 wk Tbili and alk phos predominant rise, leukocytosis Duct anastomosis without drainLDLT MRCP ERCP or PTBD tube Drug related complications DILI Multiple postoperative drug exposures including antibiotics, steroids, TPN, and IS (cyclosporine and azathioprine) Following drug administration cholestatic injury common, less common hepatocellular injury but state dependent on agent Drug exposures Liver biopsy, but nonspecific Removal of causative drug Abbreviations: ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; ERCP, endoscopic retrograde cholangiopancreatography; HA, hepatic artery; HAT, hepatic artery thrombosis; INR, international normalized ratio; IR, interventional radiology; IS, immunosuppression; LDLT, living donor liver transplantation; LT, liver transplantation; MRCP, magnetic resonance cholangiopancreatography; PNF, primary nonfunction; PTBD, percutaneous transhepatic biliary drainage; TB, total bilirubin; TPN, total parenteral nutrition; ULN, upper limit of normal. TABLE 2 - Immune-mediated causes of abnormal liver enzymes after LT Category Diagnosis Definition Timing Pattern Risk factors Evaluation Treatment T-cell mediated complications Acute T-cell mediated rejection T-cell mediated inflammatory infiltrate causing damage to the bile ducts, portal tract, and endothelium (endotheliitis), not associated with low IS levelsLater episodes typically occur in the setting of inadequate IS Median 7–10 d post-transplant, most commonly within the first 90 d AST/ALT typically 5–15× ULNMild elevation in AP 2–5× ULNElevation in bilirubin only seen in severe ACR Immune-mediated liver diseaseInadequate ISInfection, viremia Liver biopsy Short term increase in IS +/− steroid burst depending on severity Chronic T-cell mediated rejection Destruction and loss of bile ducts (vanishing bile duct) with obliteration of the small hepatic arteries. Often preceded by ACR which does not respond to increased IS. 6 wk–6 m after LT AP elevation to 2–5× ULN +/− elevation in TB Inadequate IS levels or compliance Liver biopsy Increased IS Antibody-mediated complications Acute AMR Rapid graft failure caused by preformed circulating antibodies directed against donor antigens. Causes endothelial damage and necrosis. Rare in liver transplant. Typically only if ABO mismatch.4 pathologic criteria for diagnosis: microvascular inflammation and portal edema, elevated DSA, C4d deposition, exclusion of other liver diseases Usually within first 3–4 wk post-transplant AST/ALT typically 5–15× ULNMild elevation in AP 2–5× ULNElevation in bilirubin only seen in severe ACR ABO mismatch Serum evaluation for DSALiver biopsy with staining for C4d IVIG treatmentRituximabPlasmapheresisBortezumib Chronic AMR Can be associated with graft injury and/or advanced fibrosis, abnormal liver enzymes after weaning ISPathologic features: mild portal inflammation, mild interface hepatitis, dense portal fibrosis. Positive DSA within 3 mo of biopsy. Focal C4d positivity ( >10% portal tracts). Exclusion of other causes Any time after the first month after transplantation Similar to early AMR but typically more subtle ABO mismatch Serum evaluation for DSALiver biopsy with staining for C4d Retransplant Other rejection Plasma cell rich rejection A manifestation of allograft rejection with positive C4d staining of portal capillaries. Rapid progression of fibrosis resistant to IS. Any time after transplant AP elevation Unknown C4d staining of portal capillaries Retransplant Abbreviations: ACR, acute cellular rejection; ALT, alanine aminotransferase; AMR, antibody-mediated rejection; AP, alkaline phosphatase; AST, aspartate aminotransferase; DSA, donor-specific antigen; IS, immunosuppression; IVIG, intravenous immunoglobulin; LT, liver transplantation; TB, total bilirubin; ULN, upper limit of normal. TABLE 3 - Infectious causes of abnormal liver enzymes after LT Category Diagnosis Findings Timing Pattern Risk factors Evaluation Treatment Viral infections CMV infection Fever, leukopenia, elevated liver enzymes, diarrhea Most common in the first 1–6 mo after transplantation AST/ALT 5–15× ULN Most common in CMV D + /R− combinations Serum CMV PCRColonoscopy with biopsies PPX: valganciclovirTreatment: valganciclovir HBV (donor-derived or reactivation) Mild elevation in liver enzymes, fever, or asymptomatic Transmission within 3–5 d AST/ALT 1–3× ULN Known infections in donor Day 3 PCR, Day 7 PCR, weekly thereafter Entecavir or Tenofovir for suppression Donor-derived HCV Mild elevation in liver enzymes, fever, or asymptomatic Transmission most commonly 3–5 d, can occur in 3–6 mo AST/ALT 1–3× ULN Known infections in donor Day 3 PCR, Day 7 PCR, weekly thereafter Early initiation of DAA HSV Fever, fatigue, severely elevated liver enzymes, leukopenia; note that rash is not required Most common in the first 3 mo after transplantation AST/ALT 5–15× ULN Most common in new HSV acquisition HSV serum PCR Valacyclovir SARS-CoV-2 Fever, liver injury, upper respiratory symptoms Anytime AST/ALT 1–3× ULN Metabolic syndrome SARS-CoV-2 PCR Monoclonal antibodyRemdesivir, prednisone Bacterial infections CDI Diarrhea, fulminant colitis Higher risk in the first 3 mo Elevation in liver enzymes only if severe colitis, dehydration present Exposure to multiple antimicrobial agents, prior CDI C.diff EIA and toxin FidaxomicinPO VancomycinMetronidazole Liver abscess Abdominal pain, fevers, intrahepatic collections Anytime Alk phos/ Tbili 5–10× ULN Ischemic injury, bile leak CT or MRI IR drainage and IV antibiotics Ascending cholangitis Abdominal pain, fevers, biliary stricture and biliary dilatation Anytime Alk phos/ Tbili 5–10× ULN Anastomotic stricture MRCP or ERCP ERCP vs percutaneous drainage Cholestasis of sepsis Hypotension, tachycardia, localizing infectious symptoms Anytime Alk phos/ Tbili 5-10x ULN Sepsis of any kind (urinary, SSTI, abscess, PNA) None Treatment of underlying source infection Fungal infections Invasive candidal infections Candidemia (sepsis)line infection, peritonitis, endophthalmitis First 3 mo Typically elevations are associated with cholestasis of sepsis CMV infection Line and blood cultures, fluid culture Fluconazole (mild-moderate infection, CNI interaction)Echinocandin (moderate-severe infection) Aspergillus CT chest: nodular opacity with halo sign, 50% of the time aspergillus becomes invasive First 30 d Typically elevations are associated with cholestasis of sepsis Pretransplant colonization Sputum cultureChest imagingB-D-glucanGalactomannan Voriconazole Endemic Mycoses(Histoplasmosis, Coccidiomycosis, Blastomycosis) Pneumonia, 30% with disseminated disease: hepatosplenomegaly, GI involvement, sepsis First 3 mo Elevation of Tbili/Alk phos related to hepatic parenchymal invasion or cholestasis of sepsis Pretransplant exposure through endemic location or donor-derived infection Serologic testingCross-sectional imaging ItraconazoleAmphotericin B Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CDI, Clostridium Difficile infection; CMV, cytomegalovirus; CNI, calcineurin inhibitor; DAA, direct-acting antiviral; EIA, enzyme immunoassay; ERCP, endoscopic retrograde cholangiopancreatography; GI, gastrointestinal; HSV, Herpes simplex virus; IR, interventional radiology; LT, liver transplantation; MRCP, magnetic resonance cholangiopancreatography; PO, per os; PPX, prophylaxis; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ULN, upper limit of normal. TIMING OF LIVER ENZYME ELEVATION The length of time since transplant is among the most distinguishing features of post-transplant elevated liver enzymes (Figure 1). Although several complications, such as DILI and infection, can occur at any time, a majority of the presentations occur within a very specific window post-transplant.4 Findings can be categorized as immediate (first week), early (first month), intermediate (1–12 mo), and late complications (>1 y).FIGURE 1: Causes of liver enzyme elevations over the post-transplant period. The causes of liver enzyme elevations post-transplant are shown relative to the time from transplant, during which these causes are most likely to occur. Abbreviations: CMV, cytomegalovirus; HAT, hepatic artery thrombosis; HSV, Herpes simplex virus; IS, immunosuppression; LT, liver transplantation.IMMEDIATE PERIOD (DAYS 0–7) During the first week after the transplant, almost all patients experience a transient elevation in liver enzymes. This is attributed to a combination of operative "preservation injury" and ischemic reperfusion injury – injury to the donor liver resulting from cold and warm ischemic time and vascular reperfusion.5 Classically, preservation injury is an AST/ALT predominant pattern, which rises steadily over ~7 days to 5–20x the ULN, often with a delayed elevation in bilirubin.5 The challenge in the immediate postoperative period is to distinguish preservation injury from other more acute complications requiring urgent intervention: primary nonfunction, hepatic artery thrombosis, biliary complications, and early acute cellular rejection (ACR) (Tables 1, 2). Early Doppler ultrasound to evaluate vascular patency is appropriate in the first 24 hours after transplant and after any acute change in graft function.6 Improving the international normalized ratio distinguishes rising liver enzymes of preservation injury from graft-threatening complications, including primary nonfunction and hepatic artery thrombosis.7 Other immediate complications include biliary leaks, which occur in 2%–25% of patients after transplant.6 An early isolated bilirubin elevation, often in combination with abdominal pain, leukocytosis, and fevers should prompt cross-sectional imaging to look for fluid collections requiring endoscopic or percutaneous drainage. Hemodynamic complications, including bleeding and volume overload, can also lead to mixed elevations in liver enzymes driven by perioperative hypotension, ischemia, and hepatic congestion. In addition, resorption of hematomas and transfusion of red blood cells can result in transient rises in indirect bilirubin that does not reflect allograft dysfunction. Because of the complex physiological changes that occur in the first-week post-transplant, empiric treatment of complications is not uncommon (eg, escalation of glucocorticoids for empiric treatment of ACR). EARLY PERIOD (<1 MONTH) ACR most frequently occurs in the first 30 days after transplant with a mixed elevation in liver enzymes. Liver enzymes that do not decline after the first postoperative week or rise again after a period of improvement should prompt evaluation for ACR with liver biopsy. Attempts to identify serum biomarkers for ACR are in the early stages, and liver biopsy remains the gold standard. A 2022 study by Levitsky et al8 demonstrated the validity of a 59-gene biomarker, which succeeds in distinguishing transplant recipients with acute rejection. Since the introduction of tacrolimus-based regimens, published estimates of the incidence of ACR range from 15% to 45%.4,9,10 A 2016 prospective study by Shindoh et al11 observed a median time to ACR of 17 days (range 5–83 d) after transplantation. Early ACR, most commonly defined as occurring within the first 6 weeks post-transplant, occurs in an estimated 30%–35% of patients.12 Early ACR is treated effectively with a burst of steroids or escalation of immunosuppression (IS).13,14 While initial studies demonstrated that ACR had no impact on patient and graft survival, more recent data refute that assertion. A 2019 study by Jadlowiec et al, however, demonstrated that 17% of patients experienced late ACR episodes after the first 6 weeks post-transplant.12 Episodes of late ACR were associated with a higher rate of chronic rejection and graft failure.15,16 In addition, Levitsky et al10 demonstrated that, in 2 large national databases, biopsy-proven ACR was associated with an increased risk of both graft loss and death in the 12 months after diagnosis. The incidence of ACR is substantially higher in individuals with autoimmune etiology of liver disease, and it is important to recognize that early ACR is not prevented by adequate serum IS levels.4 In patients refractory to treatment, antibody-mediated rejection and plasma-cell–rich rejection should be considered with additional diagnostic testing to include donor-specific antigen testing and C4d liver tissue staining (in addition to routine hematoxylin and eosin liver tissue staining). Because IS takes some time to reach maximum efficacy, the first postoperative month is the highest risk for ACR and lowest risk for opportunistic infections. During the early postoperative period, a majority of infections are bacterial complications of the operation and hospitalization itself: wound infections, acute cholangitis, abdominal fluid collections, urinary infections, and Clostridium difficile colitis.2 Other early complications include anastomotic biliary stricture and obstructive jaundice, with or without acute cholangitis.6 If there is a high degree of suspicion for stricture, cross-sectional imaging with CT or MRI is typically followed by endoscopic retrograde cholangiopancreatography for endoscopic stenting. Some patients may ultimately require revision to roux-en-y anatomy to achieve long-term resolution of obstruction. INTERMEDIATE PERIOD (1–12 MONTHS) Beginning at ~2–3 months post-transplant, antimicrobial prophylaxis and immunosuppressive regimens begin to be weaned. This phase of post-transplant management demands careful attention to the balance between the simultaneous risks of infection and rejection, requiring an individualized approach guided by patient response. Stepwise de-escalation of IS should be combined with careful monitoring of liver enzymes. During this phase, late-onset ACR often occurs in patients who are young, female, or have an autoimmune history.4 In contrast to early ACR, late rejection is associated with immunosuppressive levels and should be suspected if even very mild elevations in liver enzymes develop after a change in immunosuppressive medication dosing. At the same time, the risk of developing an opportunistic infection increases with the tapering of prophylaxis. Viral infections, particularly cytomegalovirus, carry an important risk of activating the host's innate immune response and triggering an episode of ACR. Elevations in liver enzymes during this phase should, therefore, also prompt consideration of cytomegalovirus and other viral infections depending on the clinical context. Candidiasis, aspergillosis, P. jirovecii pneumonia, and endemic mycoses are other important causes of post-transplant opportunistic infection but present typically with pulmonary or tissue-invasive disease and so are less likely to increase a patient's liver enzymes in the absence of disseminated disease.2 Finding a careful balance between immune-mediated and infectious complications is critical to long-term graft survival Early disease recurrence, particularly NASH, is also common; liver biopsy may be required to distinguish this from rejection. Biliary complications frequently arise during this time period and include both anastomotic and nonanastomotic strictures. LATE PERIOD (>12 MONTHS) After ~12 months post-transplant, elevations in liver enzymes become less common as the patient's immune response and immunosuppressive dosing stabilize. In patients with chronically low IS, ductopenic rejection causes rising bilirubin with progressive bile duct loss on liver biopsy, often irreversible. Chronic rejection involves the loss of at least 50% of portal tracts and classic foam cell obliterative arteriopathy.15 This type of immune-mediated duct loss is irreversible and occurs in an estimated 2%–5% of transplant recipients.17 Given advances in immunosuppressants, chronic rejection is frequently associated with poor medication adherence and should, therefore, prompt evaluation of medication-related issues, such as access and affordability.15 In addition to rejection, post-transplant alcohol use and weight gain represent a significant risk to allograft function. Studies suggest that about 10% of patients use alcohol heavily after transplant, regardless of whether the patient's original liver disease was alcohol-associated.18 Elevated liver enzymes of unclear etiology post-transplant should, therefore, prompt additional substance use history and alcohol biomarker testing. It is important to educate patients in advance that both alcohol use and recurrent NASH can cause the rapid development of allograft cirrhosis.19 Autoimmune liver diseases may also reoccur or develop de-novo in a post-transplant patient. Autoantibody testing is not reliable due to IS, so identifying autoimmune liver disease requires a high index of clinical suspicion and judicious use of liver biopsy for confirmation.20 PSC, in particular, is associated with an increased risk of severe recurrence; an estimated 30% of those with recurrent PSC will ultimately require re-transplantation.21 As patients progress into the second and third decades after transplant, the risks of graft dysfunction decrease, allowing for lower levels of IS and reduced frequency of lab monitoring over time. CONCLUSION Liver enzymes provide the most reliable noninvasive method for evaluating clinical status after liver transplantation. Regular monitoring is required throughout the lifetime of a liver transplant recipient. It is critical that clinicians managing post-transplant patients recognize the most common presentations of liver enzyme elevations and the appropriate first steps in evaluation, diagnosis, and treatment to preserve long-term allograft function.

COVID-19 in Liver Transplant Recipients: An Initial Experience From the US Epicenter

To compare isolated liver transplantation (LT) for cystic fibrosis (CF) versus other indications and versus combined liver-lung transplantation (CLLT) for CF in children and identify factors associated with survival. We compared clinical and survival data after first isolated LT for CF versus other indications and versus CLLT for CF in children (<18 years) using United Network for Organ Sharing data (02/2002-12/2024). A total of 157 pediatric CF transplant recipients were included (LT: 145; CLLT: 12). Isolated CF LT recipients had higher total bilirubin (TB) than CLLT (median 1.6 vs. 0.7 mg/dL, p = 0.02). A higher proportion of CF transplant recipients with high TB levels (≥1.5 mg/dL) had ascites, encephalopathy, and required life support compared to those with low TB levels (<1.5 mg/dL). CF LT demonstrated superior patient survival versus CF CLLT (log-rank test, p = 0.02; 5-year: 89.1% vs. 72.2%), but inferior versus non-CF LT (log-rank test, p < 0.001; 5-year: 91.5%). Multivariable Cox regression showed increased risk of patient mortality and liver graft loss in CF CLLT recipients compared to isolated CF LT recipients (hazard ratio [HR] = 2.92, 95% confidence interval [95% CI]: 1.20-7.07, p = 0.02 and HR = 2.56, 95% CI: 1.09-5.98, p = 0.03, respectively) and recipients with higher TB levels (HR = 1.05, 95% CI: 1.01-1.10, p = 0.008 and HR = 1.05, 95% CI: 1.01-1.09, p = 0.008, respectively), when adjusting for recipient age, albumin and international normalized ratio (INR) at time of LT, ICU status, and liver graft type. Multivariable Cox regression of isolated LT recipients showed increased risk of patient mortality (HR = 2.03, 95% CI: 1.41-2.93, p < 0.001) and liver graft loss (HR = 1.54, 95% CI: 1.13-2.11, p = 0.006) for CF compared to non-CF etiologies, when adjusting for recipient age, albumin, INR, and TB at time of LT, ICU status, and liver graft type. Isolated LT for CF was associated with superior survival compared to CLLT for CF, but inferior survival compared to LT for non-CF indications. Higher TB in CF may be a marker of inferior outcomes post-LT.

Objective To investigate the correlation between the elastographic characteristics of liver and postoperative function of liver allografts. Methods Forty-eight cases of liver transplantation from The First Affiliated Hospital of Sun Yat-sen University were analyzed, Shear wave elastography (SWE) was performed before operation or at one week or one month post-operation.Liver function was evaluated by measuring alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), γ-glutamine transferase (GGT), albumin (ALB), alkaline phosphatase (ALP), prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR). Early allograft dysfunction (EAD) was also analyzed with reference to SWE among liver transplant recipients. Results SWE at one week after transplantation was significantly correlated with TBIL (r=0.525 6, P<0.01), APTT (r=0.668 3, P<0.000 1), PT (r=0.593 7, P=0.000 1), INR (r=0.609 6, P<0.000 1) and prealbumin (r=-0.464 1, P<0.01). However, no significant correlation was observed between pre-operative SWE and parameters of post-operative liver function.SWE in EAD patients was higher than that of patients without EAD (17.60±1.09 kPa vs.13.38±0.99 kPa, P<0.01). The optimal cut-off value of SWE at one week post-operation was 14.85 kPa. Conclusion Postoperative SWE is significantly correlated with postoperative liver function tests and EAD, suggesting SWE is a potential test for evaluating the quality of liver allografts. Key words: Ultrasonic examination; Shear wave elastography; Liver transplantation; Early allograft dysfunction

BACKGROUND: Prior studies have assessed risk factors and clinical outcomes in liver transplant (LT) recipients infected with COVID-19 globally; however, there is a paucity of Canadian data. Our multicentre study aims to examine the characteristics and clinical outcomes of LT patients with COVID-19 infection in Canada. METHODS: Adult LT recipients with reverse transcription-polymerase chain reaction (RT-PCR) confirmed COVID-19, from Canadian tertiary care centres between March 2020 and June 2021 were included. RESULTS: A total of 49 patients with a history of LT and COVID-19 infection were identified. Twenty-nine patients (59%) were male, median time from LT was 66 months (IQR 1-128), and median age was 59 years (IQR 52-65). At COVID-19 diagnosis, the median alanine transaminase (ALT) was 37 U/L (IQR 21-41), aspartate aminotransferase (AST) U/L was 34 (IQR 20-37), alkaline phosphatase (ALP) U/L was 156 (IQR 88-156), total bilirubin was 11 μmol/L (IQR 7-14), and international normalized ratio (INR) was 1.1 (IQR 1.0-1.1). The majority of patients (86%) were on tacrolimus (monotherapy or combined with mycophenolate mofetil); median tacrolimus level at COVID-19 diagnosis was 5.3 μg/L (IQR 4.0-8.1). Immunosuppression was modified in eight (16%) patients post-infection. Eighteen patients (37%) required hospitalization, and three (6%) required intensive care unit (ICU) admission and mechanical ventilation. Four patients (8%) died from complications related to COVID-19 infection. On univariate analysis, neither age, sex, comorbidities, nor duration post-transplant were associated with risk of hospitalization or ICU admission. CONCLUSIONS: LT recipients with COVID-19 have high rates of hospitalization but fortunately have low rates of ICU admission and mortality in this national registry.

Michael R. Lucey, Norah Terrault, Lolu Ojo, J. Eileen Hay, James Neuberger, Emily Blumberg, and Lewis W. Teperman Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI; Gastroenterology Division, Department of Medicine, University of California San Francisco, San Francisco, CA; Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, MI; Mayo Clinic, Rochester, MN; Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom; Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, PA; and Department of Surgery, NYU Transplant Associates, New York, NY

Hepatitis C virus (HCV) infection is a global health problem affecting 170 million individuals worldwide. In the United States, there are approximately 7 million adults and 100,000 children chronically infected with HCV (1,2). The importance of HCV infection stems from its proclivity to cause insidious liver damage over many years, including chronic hepatitis, cirrhosis, and liver cancer. In adults, HCV infection is a leading cause for liver cancer worldwide (3). The financial burden of this viral infection is staggering, with projected medical costs of $10.7 billion in adults from 2010 to 2019 and approximately $426 million during the next 10 years in children (4,5). The epidemiology, clinical outcome, and risk factors associated with progression of HCV-related liver disease are fairly well characterized in adults. Although the natural history of childhood HCV infection is poorly defined, it appears to be an indolent disease in most children (6–13); however, progressive liver disease, including chronic hepatitis and cirrhosis necessitating liver transplantation, can occur in children (14,15). Unlike in adults, liver cancer, particularly hepatocellular carcinoma (HCC), is rare in children (16), but it was described in 2 young adults infected with HCV during childhood (17). Herein we extend these observations and present 2 children with chronic hepatitis C who developed HCC as adolescents. To our knowledge, they are the youngest HCV-infected patients to be reported as having this complication. These cases illustrate the potentially ominous course of HCV infection, and highlight the importance of remaining vigilant for complications via periodic evaluation in young patients with this infection. We performed a retrospective chart review of 2 adolescents with HCV infection who developed HCC. This work was exempt from approval by the institutional review boards of all of the participating centers. PATIENT 1 The child was a 13-year-old white girl who had received a T cell–depleted allogeneic stem cell transplant for recurrent acute myelogenous leukemia 7 years earlier, in May 1986. The stem cell transplant preconditioning regimen included Cytoxan and fractionated total body irradiation. Her posttransplant course was complicated by Escherichia coli urinary tract infection, hemorrhagic cystitis, and graft-versus-host disease involving her skin. Two months after stem cell transplant, she was hospitalized for Varicella zoster infection of the trigeminal nerve and results of liver tests were abnormal: total bilirubin 7.5 mg/dL (direct reacting fraction 2.5 mg/dL), aspartate aminotransferase (AST) 1206 IU/L (normal < 40 IU/L), and alanine aminotransferase (ALT) 1880 IU/L (normal < 40 IU/L). Her serological evaluation excluded infection with Epstein-Barr virus, hepatitis B virus, cytomegalovirus, and Toxoplasma gondii. Abdominal sonogram yielded normal results. Values of AST and ALT remained intermittently abnormal and were ascribed to possible chronic graft-versus-host disease. She subsequently developed aseptic necrosis of the right ankle, as well as growth hormone deficiency, hypothyroidism, attention deficit disorder, and hypertension, for which she was prescribed a short course of growth hormone (discontinued because of liver dysfunction), L-thyroxine, methylphenidate, and propranolol, respectively. In May 1993, 7 years after her stem cell transplant, she experienced an episode of hematemesis and melena for which she received packed red blood cells and was prescribed cimetidine by her general physician. Melena recurred 3 days before a scheduled routine visit with pediatric oncologists at the University of Florida; she then had an episode of hematemesis in the oncology clinic and she was hospitalized for further management. The family history was significant for cancer of the stomach, pancreas, and lung, as well as peptic ulcer disease. On initial examination, the patient was a teenager in no acute distress. The heart and respiratory rates were 160 beats and 32 breaths per minute, respectively, and blood pressure was 127/55 mmHg. The remainder of the physical examination was normal except for a systolic heart murmur and the presence of black, tarry stools that were guaiac positive. In particular, neither liver nor spleen was enlarged and there were no other stigmata of chronic liver disease. Initial laboratory evaluation revealed a hemoglobin concentration of 4.5 g/dL, white blood cell count 17.5 × 106/L, and platelets 210 × 106/L; results of routine serum electrolytes, blood urea nitrogen, creatinine, glucose, calcium, phosphorus, alkaline phosphatase, total bilirubin, and direct bilirubin were normal; the AST and ALT were elevated at 89 IU/L and 55 IU/L (normal < 40 IU/L), respectively. Hepatitis A and B virus serology were negative; α1-antitrypsin and ceruloplasmin levels were normal as were the results of prothrombin and partial thromboplastin time. Her serum tested positive for HCV by enzyme immunoassay (optical density > 5.5); nucleic amplification tests were not commercially available at the time, but she had detectable HCV RNA by an in-house polymerase chain reaction assay (18). An abdominal sonogram again yielded normal findings except for ascites, and esophagogastroduodenoscopy revealed Candida esophagitis and varices in the distal esophagus and gastric fundus without active bleeding. Histological review of liver tissue obtained by percutaneous needle biopsy showed focal chronic portal and lobular inflammation with mild portal fibrosis and macrovesicular steatosis. The patient was treated with packed red blood cells, fluconazole, and famotidine, and was subsequently discharged home. During the next 4 months, and despite the addition of propranolol to the medical regimen, she had several episodes of hematemesis. Sclerotherapy of the esophageal varices led to no further bleeding but variceal size remained unchanged. While the patient was being evaluated for liver transplantation at 13 years of age, in February 1994 the α-fetoprotein (AFP) concentration was noted to be elevated (2740 ng/mL; normal < 8.9 ng/mL); computerized axial tomography (CT) scan of the abdomen revealed 2 low-attenuation lesions in the right lobe of the liver, measuring approximately 4 and 6 cm in largest diameter, respectively. There were no abnormalities noted on the CT scan of her chest and bone scan and she underwent a right hepatectomy. Histological review of the excised liver revealed chronic active hepatitis, cirrhosis, and multinodular HCC with the margins of the sample free of tumor. The AFP levels initially decreased but then increased by the end of June 1994 (Fig. 1A) and several low-attenuation lesions were noted in the left lobe of the liver via abdominal CT scan. The cholestasis worsened and repeat CT scan of the abdomen in September 1994 showed bile duct dilatation; the AFP was 6470 ng/mL. The patient underwent palliative biliary stent placement and died at home shortly thereafter.FIG. 1: Biochemical profiles of (A) patient 1 and (B) patient 2. AFP = α-fetoprotein.PATIENT 2 The child was a 14-year-old African American girl who presented with anasarca and liver dysfunction in September 2001. She was the product of a cesarean section from a mother infected with HCV and human immunodeficiency virus (HIV). This patient presented to an outside hospital 4 months earlier with pedal edema and mild respiratory distress. Laboratory studies at that time revealed liver dysfunction with an AST and ALT of 158 IU/L and 146 IU/L, respectively (normal < 40 IU/L for both); the serum albumin concentration was 2.5 g/dL, and the prothrombin time was 14.4 seconds (normal <12 seconds). The hemoglobin concentration was 11.6 g/dL, white blood cell count 4.2 × 106/L, and platelet count 81 × 106/L. She had detectable HCV RNA in serum at 83200 IU/mL (Amplicor V2.0, Roche Diagnostics, Indianapolis, IN) and the HCV genotype was 1a. The AFP concentration was mildly elevated at 39.8 ng/mL (normal <8.9 ng/mL; Fig. 1B). Hepatitis A and B virus and HIV serology were negative and other potential causes of liver dysfunction including α1-antitrypsin deficiency, autoimmune hepatitis, and Wilson disease were excluded with appropriate serological tests. She was prescribed spironolactone, furosemide, ursodeoxycholic acid, and vitamin K and referred to our liver center for consideration of antiviral treatment and liver transplantation. At the time of presentation, findings on a physical examination were normal except for the presence of ascites and a firm liver edge that was palpable 8 cm below the right costal margin at the midclavicular line. Results of liver tests were persistently abnormal: AST, ALT, and total bilirubin concentrations were 156 IU/L, 112 IU/L, and 4.9 mg/dL, respectively; the serum albumin level was 2.8 mg/dL, the prothrombin time was 18.1 seconds, and the plasma ammonia concentration was 95 mg/dL. Histological examination of liver tissue obtained by a transjugular approach showed minimal portal lymphocytic infiltration, intrahepatic cholestasis, and rare foci of piecemeal necrosis, but no significant lobular inflammation, fibrosis, or steatosis. She was prescribed a salt-restricted diet, neomycin, lactulose, and monthly parenteral vitamin K. There was concern that antiviral therapy would precipitate further worsening of her advanced liver disease and she was listed for liver transplantation. During the next few months she experienced recurrent epistaxis and pedal edema. The concentration of AFP increased to 76.6 ng/mL within 5 months (Fig. 1B), and results of a sonogram and CT of her abdomen yielded normal results except for ascites and a nodular-appearing liver. The patient remained clinically stable during the ensuing 5 months but then developed pancreatitis, E coli bacteremia, and Klebsiella urosepsis, resulting in septic shock necessitating mechanical ventilation, vasopressors, and admission to an outside pediatric intensive care unit. She was transferred to our hospital with grade III encephalopathy. Her clinical course was complicated by renal dysfunction consistent with hepatorenal syndrome requiring hemodialysis. A suitable cadaveric liver allograft became available and she underwent emergent split liver transplant. At the time of surgery, 5 L of ascitic fluid were noted in her abdominal cavity, as was severe portal hypertension. Unfortunately, the transplant procedure was complicated by extensive retroperitoneal bleeding and cardiopulmonary arrest. She was successfully resuscitated, the surgical wound was packed open, and she was returned to pediatric intensive care. She required reoperation a few hours later because massive bleeding persisted and she continued to be unresponsive to large amounts of blood products. The transplanted liver appeared nonfunctional and was removed. Although a portosystemic shunt was constructed, the massive retroperitoneal bleeding continued, and the patient experienced another cardiac arrest and expired despite resuscitation attempts. Histologically, the native explanted liver was cirrhotic and contained multiple foci of lobular necrosis and dysplastic nodules. A single 1.5-cm nodule of well-differentiated HCC also was discovered. DISCUSSION Although chronic hepatitis C is regarded as a major cause of liver morbidity in adults, this viral infection is generally believed to be indolent in children. However, chronic HCV infection leads to significant liver dysfunction in a proportion of children, severe enough to necessitate liver replacement in some (14,15). In addition, hepatocellular carcinoma developed in 2 young adults with transfusion-acquired HCV infection many years after undergoing successful cancer treatment (17). This report of HCC during adolescence further substantiates the notion that HCV infection can lead to devastating consequences even in the second decade of life. Hepatocellular carcinoma is a common cancer in adults and HCV infection accounts for a significant proportion of the cases (3). Hepatitis C virus–related liver cancer usually but not exclusively arises in the context of cirrhosis. Although the pathogenesis of hepatocellular carcinoma is poorly understood, repeated cycles of liver injury with attendant regeneration and repair likely play a pivotal role in its development. Important factors that appear to increase the risk for HCV-related liver cancer in adults include male sex, older age at diagnosis and at acquisition of virus, severity of liver disease at presentation, co-infection with hepatitis B virus or HIV, and excessive alcohol consumption, as well as possibly liver steatosis and diabetes mellitus (3). The occurrence of HCC in children is rare in comparison with adult occurrence, and a predisposing oncogenic cause is identified in only a small minority of cases (16). The detection of serological markers of HCV in adults with hepatocellular carcinoma is generally sufficient to establish a causal relation between this infection and cancer. Therefore, the recognition of HCV antibodies and HCV RNA in serum, in the absence of other predisposing factors, strongly supports this viral infection as the cause of liver cancer in our patients. Secondary malignancies are relatively common among cancer survivors (19), especially in those who receive growth hormone therapy (20) such as our first patient. Interestingly, liver cancer is not reported in large cohorts of patients surviving cancer, even in those prescribed growth hormone (19,20). Therefore, although possible, it is unlikely that either the previous history of malignancy or the use of growth hormone were important predisposing factors for the development of HCC in our first patient, and this more strongly implicates HCV as the major oncogenic factor. It should also be emphasized that this patient received large doses of glucocorticosteroids after stem cell transplantation for the treatment of what was presumed to be graft-versus-host disease–related liver dysfunction. However, HCV tests were unavailable when she initially developed liver dysfunction, 2 months after stem cell transplantation. Therefore, this patient was likely infected with HCV during the transplant process. In retrospect, her liver problem was probably related to chronic HCV infection, which was diagnosed only years afterward, with the advent of virus-specific serological tests. Glucocorticoids are associated with accelerated progression of HCV disease in adults after liver transplantation (21,22) and, therefore, may have promoted the development of liver cancer in this adolescent. Furthermore, based on her family history of cancer, genetic factors may have contributed to the pathogenesis of liver cancer in our first patient. Risk factors associated with progression of liver disease in children with chronic HCV infection are poorly understood. In contrast to our first patient, patient 2 lacked comorbid conditions linked to progressive liver disease in children (23) and adults (24). Our second patient's mother was co-infected with HIV, which negatively affects the long-term clinical outcome in adults with HCV (25). However, patient 2 was not infected with HIV at the time of our evaluation, based on negative serological results for this virus. Nevertheless, it is plausible that in utero or perinatal exposure to HIV led to increased HCV heterogeneity, which is associated with higher serum transaminase levels in small pediatric studies (26,27). Although alcohol consumption, a predictor of ominous disease progression in adults with HCV (24), was not directly elicited in our adolescents, its occult use cannot be completely excluded and may have influenced the development of advanced disease in our patients. In all, the reasons underlying the accelerated rate of liver disease progression in our adolescents, particularly our second patient, remain unclear. Although treating children with HCV infection is challenging, our patients may have benefited from available antiviral therapy. However, HCV was diagnosed in our patients only after developing decompensated liver disease when antiviral treatment was deemed unsafe. Therefore, these adolescents underscore the importance of identifying HCV infection early and support careful serological screening of children at risk for this viral pathogen (28). Although hepatocellular carcinoma is rare in children, it is one of the most common primary liver tumors in this age group, accounting for approximately 20% to 30% of all such lesions (16,29). Indeed, HCC accounted for 87% of all primary liver tumors in adolescents (15–19 years old) reported to the National Center for Health Statistics between 1979 and 1996 (16). Interestingly, the cause of hepatocellular cancer was unknown in the vast majority of these cases. Because reliable serological tests to detect HCV were unavailable during most of the study period in this comprehensive report (16), it is possible that some of these cases of HCC may have been related to this viral infection, as occurred in our patients. Although our 2 patients succumbed to HCC, the outcome of this disease in childhood is not uniformly poor (30). The long-term survival of patients with liver cancer has improved in recent years with the advent of novel therapeutic techniques such as chemoablation and intratumor chemotherapeutic injections, in addition to tumor resection and liver transplantation (31). Favorable outcomes, however, generally correlate with smaller lesions, thus accentuating the need for early detection of HCC. Periodic monitoring of patients with HCV-related histological fibrosis or cirrhosis by serial serological assessment of AFP level and abdominal imaging may improve early diagnosis of liver cancer (32). These diagnostic methods are imperfect screening tools, as observed in our second patient, in whom HCC was detected only after histopathological evaluation of her explanted liver. Screening for HCC in children with chronic HCV infection is particularly difficult because development of tumor appears to be a rare complication in this unique group. At this time, there are no pediatric-specific guidelines to screen for HCC in children chronically infected with HCV. Those children presumably at greater risk (advanced fibrosis or cirrhosis) should undergo periodic surveillance (abdominal sonogram alone or with serum AFP determination every 6 to 12 months) as is currently recommended for adults (32). In conclusion, although HCV infection is an indolent disease in most infected children, potentially ominous sequelae including HCC can occur in the pediatric age group. Our patients highlight the critical importance of remaining vigilant for liver-related complications even in young patients with this viral pathogen.

Fulminant hepatic failure from the Budd-Chiari syndrome. A bridge to transplantation with transjugular intrahepatic portosystemic shunt.

Liver transplantation (LT) is considered the only treatment for patients with end-stage liver disease and, despite its incredible impacts on the patients' health status, places them in an immunocompromised state in which opportunistic infection would find a way to present. Latent tuberculosis infection (LTBI) is the most common form of TB and can be diagnosed through tuberculin skin test (TST) or Interferon-Gamma Release Assays (IGRA). LT recipients are at significant risk of TB activation. There is no strict guideline to approaching these cases though, in most centers, Isoniazid (INH) would be prescribed prophylactically. INH is a hepatotoxic medication and can have adverse effects on the transplanted liver. There is no consensus on this issue; therefore, we aimed to survey the potential hepatotoxic effects of INH among LT recipients in Shiraz, Iran. A retrospective cohort study was conducted among LT candidates and recipients at Abu Ali Sina Organ Transplantation Center between 1993 and 2019. All the cases underwent TST and chest X-ray to detect LTBI. All the LTBI were treated with INH from 6-9 months and followed by the level of liver enzymes for quick detection of hepatotoxicity. A control group was selected among LT recipients and matched for age, gender, MELD score, and donor age. Among 4895 medical records reviewed, 55 (1.12%) cases had LTBI. Neither INH-related hepatotoxicity, nor signs and symptoms that were suspicious to TB reactivation were reported. Overall, three deaths were reported, two because of myocardial infarction and one due to pneumonia. Ten patients (18.2%) experienced acute rejection as confirmed with pathology and responded to methylprednisolone. Aspartate aminotransferase (AST) was diminished from pre-LT time to the first time after transplantation; after that, it showed a steady pattern. Meanwhile, Alanine transaminase (ALT) was constant before and one stage later and decreased after that. Statistical analyses only showed significant changes in the total bilirubin titer between the case and control groups. This survey showed prophylactic management of LTBI with INH in LT candidates and recipients was associated with no hepatotoxicity or related death. It seems that INH prophylaxis is safe in LT settings and can efficiently prevent TB activation; however, careful monitoring for adverse effects and liver enzymes elevation is highly recommended.

Hasagawa, Toshimichi; Reyes, Jorge; Nour, Bakr; Tzakis, Andreas G.; Green, Michael3; Todo, Satoru; Starzl, Thomas E. Author Information

Safety and Outcomes in 100 Consecutive Donation After Circulatory Death Liver Transplants Using a Protocol That Includes Thrombolytic Therapy.

Protoporphyria is a genetic disorder of porphyrin metabolism in which a deficiency of ferrochelatase activity causes excessive accumulation and excretion of protoporphyrin (1,2). Protoporphyrin is excreted in bile, and its deposition in the liver impairs hepatic structure and function (3,4). As a co

Statins Are Safe for the Treatment of Hypercholesterolemia in Patients With Chronic Liver Disease

Ischemic Reperfusion Injury–Induced Oxidative Stress and Pro-inflammatory Mediators in Liver Transplantation Recipients