During infection with the hepatitis A virus (HAV), most patients develop mild or asymptomatic disease. However, a small number of patients develop serious, life-threatening hepatitis. We investigated this variability in disease severity by examining 30 Argentinean patients with HAV-induced acute liver failure in a case-control, cross-sectional, observational study. We found that HAV-induced severe liver disease was associated with a 6-amino-acid insertion in TIM1/HAVCR1 (157insMTTTVP), the gene encoding the HAV receptor. This polymorphism was previously shown to be associated with protection against asthma and allergic diseases and with HIV progression. In binding assays, the TIM-1 protein containing the 157insMTTTVP insertion polymorphism bound HAV more efficiently. When expressed by human natural killer T (NKT) cells, this long form resulted in greater NKT cell cytolytic activity against HAV-infected liver cells, compared with the shorter TIM-1 protein without the polymorphism. To our knowledge, the 157insMTTTVP polymorphism in TIM1 is the first genetic susceptibility factor shown to predispose to HAV-induced acute liver failure. Furthermore, these results suggest that HAV infection has driven the natural selection of shorter forms of the TIM-1 protein, which binds HAV less efficiently, thereby protecting against severe HAV-induced disease, but which may predispose toward inflammation associated with asthma and allergy.

IntroductionHepatitis A virus (HAV) infection is a vaccine-preventable disease. The most severe complication in children is fulminant hepatic failure (FHF), estimated to occur in 0.4% of cases; patients with FHF often require a liver transplant (LT). Following another outbreak of HAV infection in Argentina during 2003–2004, a one-dose HAV universal immunization (UI) program was started in 2005, resulting in a reduction in the incidence of HAV infection. We have investigated the impact of HAV UI on the trends in the occurrence of FHF and LT in children.MethodsAll pediatric cases of FHF admitted to four pediatric centers in Buenos Aires during March 1993–July 2005 were retrospectively reviewed, and data of cases during August 2005–December 2008 were collected. Information about demography, HAV infections and vaccination status, diagnostic data for FHF using the Pediatric Acute Liver Failure criteria, clinical laboratory results, encephalopathy, the severity of liver disease using the Pediatric End Stage Liver Disease score, assessment of patients on the LT waiting list using King’s College Criteria for LT, treatment given for FHF (pre- and post-transplant), and clinical outcome were collected using a case report form. The frequency and outcomes of HAV-associated FHF and LT cases before and after UI were analyzed.ResultsDuring the pre-immunization period, March 1993–July 2005, 54.6% (N = 165) of FHF cases were caused by HAV; HAV-associated FHF cases peaked during 2003–2004. During the post-immunization period, August 2005–December 2008, only 27.7% (N = 18) of FHF cases were caused by HAV infection; only one of these patients had received the HAV vaccine (one dose only). The number of HAV-associated FHF cases decreased from 2005, and no cases were reported from November 2006–December 2008. Multivariate analyses showed that the association of FHF with HAV infection rather than other etiologies decreased with increasing age (P = 0.03), UI against HAV (P = 0.002), and anti-actin antibodies (P = 0.002), and increased with increasing weight (P = 0.0004).ConclusionsThe number of children with HAV-associated FHF in Argentina has strongly decreased since the initiation of the UI program. Further monitoring is required to confirm the long-term health and economic benefits of UI against HAV infection.

After the implementation of universal hepatitis A virus vaccination inArgentina, the outcome of pediatric acute liver failure (PALF) remains unknown. We aimed to identify variables associated with the risk of liver transplantation (LT) or death and to determine the causes and short-term outcomes of PALF in Argentina. We retrospectively included 135 patients with PALF listed for LT between 2007 and 2016. Patients with autoimmune hepatitis (AIH), Wilson's disease (WD), or inborn errors of metabolism (IEM) were classified as PALF-chronic liver disease (CLD), and others were classified as "pure" PALF. A logistic regression model was developed to identify factors independently associated with death or need of LT and risk stratification. The most common etiologies were indeterminate (52%), AIH (23%), WD (6%), and IEM (6%). Overall, transplant-free survival was 35%, whereas 50% of the patients underwent LT and 15% died on the waiting list. The 3-month risk of LT or death was significantly higher among patients with pure PALF compared with PALF-CLD (76.5% versus 42.5%; relative risk, 1.8 [1.3-2.5]; P < 0.001), and 3 risk factors were independently associated with worse outcome: international normalized ratio (INR) ≥3.5 (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.3-7.2]), bilirubin ≥17 mg/dL (OR, 4.4; 95% CI, 1.9-10.3]), and pure PALF (OR, 3.8; 95% CI, 1.6-8.9). Patients were identified by the number of risk factors: Patients with 0, 1, or ≥2 risk factors presented a 3-month risk of worse outcome of 17.6%, 36.6%, and 82%, respectively. In conclusion, although lacking external validation, this simple risk-staging model might help stratify patients with different transplant-free survival rates and may contribute to establishing the optimal timing for LT. Liver Transplantation 26 268-275 2020 AASLD.

In July 2005, Argentina switched from a categorical liver allocation system to a MELD/PELD-based policy for patients with CLD. To analyze WL outcomes and survival after LT in children. From January 2000 to December 2010, 923 children were registered. Two consecutive five-yr periods were analyzed and compared: Era I (January 2000-July 2005) (n = 379) and Era II (July 2005-December 31, 2010) (n = 544). All data were prospectively collected and analyzed using the Kaplan-Meier method. After adopting the MELD/PELD system, WL registrations increased by 44% (from 379 to 544) and the number of LT increased by only 24% (from 278 to 365). However, three-month WL mortality rate (32% to 18%, p < 0.0001, HR 2.002 CI 95% 1.5-2.8) decreased significantly. No significant differences were observed between Era 1 and II in one-yr post-LT survival (77.5% vs. 84.1%, p = 0.3053) and in acute re-LT rate (9% vs. 5%, p = 0.1746). Under the MELD/PELD-based allocation system in Argentina, mortality on the WL significantly decreased in children with CLD without affecting post-LT survival, although reduced access to LT was observed.