Recurrent elevated liver transaminases and acute liver failure in two siblings with novel bi-allelic mutations of NBAS

BackgroundAcute liver failure (ALF) in children can be life-threatening. Although many causes are known, ALF remains unexplained in about half of the cases. Recently, bi-allelic mutations in NBAS were reported to underlie recurrent episodes of elevated liver transaminases (ELT) and ALF in the context of diverse extrahepatic phenotypes.Methods and ResultsWe here describe two sisters, born to non-consanguineous Portuguese parents, who had short stature and presented with recurrent episodes of severe ELT triggered by febrile respiratory viral infections since early childhood. Patient 1 had mild facial dysmorphism and died during the second ELT crisis at 3–11/12 years of age. Patient 2, currently 9 years old, had multiple episodes of ELT (>30), twice with ALF, often accompanied by extensive urticaria and facial angioedema. Whole-exome and Sanger sequencing revealed that both patients carried previously undescribed compound heterozygous mutations of NBAS (NM_015909.3): c.680A > C (p.His227Pro), affecting an evolutionarily conserved residue, and c.1749G > A (p.Trp583*), causing a premature stop codon. Both mutations are predicted to be highly damaging. The parents and two younger siblings are healthy and heterozygous for one or another mutant allele.ConclusionThe multiplex kindred reported herein expands the genotypic and phenotypic spectrum of this recently described clinical syndrome due to autosomal recessive NBAS deficiency.     

Structural changes in the liver of mice infected with avian influenza virus subtype H5N1

Intranasal infection of male outbred rats with isolate of influenza A virus subtype H5N1 (A/Gs/Krasnoozerskoye/627/05) from the Novosibirsk region was followed by high mortality of experimental animals. Morphological study of liver samples revealed subtotal destructive changes in the liver parenchyma (proteinosis and centrolobular necroses), which was related to hemodynamic disorders and cytokine dysregulation. The decrease in reparative activity of hepatocytes was probably followed by hepatocellular failure and contributed to high mortality rate from this infection (up to 85%). Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 146, No. 8, pp. 210–212, August, 2008     

Host immunological response and factors associated with clinical outcome in patients with the novel influenza A H7N9 infection

In March 2013, an influenza outbreak caused by the novel avian-origin H7N9 influenza A virus emerged in eastern China and had caused 43 fatalities by 31 July 2013, although the basis for disease pathogenesis still remains unclear. To assess the immunological and viral factors associated with disease severity, viral RNA and inflammatory cytokines were quantified for 18 H7N9 patients in Shanghai, China. Detailed clinical information was collected and clinical laboratory investigations were performed for all patients. H7N9 infection is characterized by high pharyngeal virus load and frequent detection of viral RNA in blood. High pharyngeal virus load persisted through the first 10 days of antiviral therapy in fatal cases. Genetic characterization of the H7N9 virus revealed an Arg292Lys mutation in the neuraminidase gene associated with oseltamivir-resistance. Pronounced lymphopenia and high chemokine and cytokine levels were observed in H7N9-infected patients, particularly in those where disease was fatal. Serum levels of interleukin-6 (IL-6), IL-8 and macrophage inflammatory protein-1β in our subjects also correlated positively with pharyngeal virus load. Lymphocyte counts <0.5 × 10⁹ cells/L, and serum IL-6 >97 pg/mL, IL-8 >40 pg/mL and C-reactive protein >90 mg/L were identified as being connected with adverse clinical outcome through univariate logistic analysis. Significant survival differences were also observed between patients with serum C-reactive protein <90 mg/L or creatinine <90 µmol/L and those with higher levels. Our data demonstrated that high viral load, and the resulting intense inflammatory responses, played an important role in H7N9 pathogenesis. Though immunomodulatory treatment has potential benefits, the focus of clinical management should be on preventing the intense cytokine response by early diagnosis and effective antiviral treatment.     

Distinct changing profiles of hepatitis A and E virus infection among patients with acute hepatitis in Mongolia: The first report of the full genome sequence of a novel genotype 1 hepatitis E virus strain

In January 2012, Mongolia started a hepatitis A vaccination program, which has not yet been evaluated. The first occurrence of autochthonous acute hepatitis E in 2013, caused by genotype 4 hepatitis E virus (HEV), suggests the need for a routine study to monitor its prevalence. One hundred fifty‐four consecutive patients who were clinically diagnosed with acute hepatitis between 2014 and 2015 in Ulaanbaatar, Mongolia were studied. By serological and molecular testing followed by sequencing and phylogenetic analysis, only one patient (0.6%) was diagnosed with acute hepatitis A, caused by genotype IA hepatitis A virus (HAV), and 32 (20.8%) patients were diagnosed with acute hepatitis E, caused by genotype 1 HEV. The 32 HEV isolates obtained in this study shared 99.5‐100% nucleotide identity and were grouped into a cluster separated from those of subtypes 1a to 1f. Upon comparison of p‐distances over the entire genome, the distances between one representative HEV isolate (MNE15‐072) and 1a‐1f strains were 0.071‐0.137, while those between 1b and 1c were 0.062‐0.070. In conclusion, the prevalence of acute hepatitis A has decreased in Mongolia since the start of the vaccination program, while the monophyletic genotype 1 HEV strain of a probably novel subtype has been prevalent.     

Clinical impact of A/H1/N1/09 influenza in patients with cirrhosis: Experience from a nosocomial cluster of infection

A/H1N1/09 influenza is associated with a high risk of complications in patients with chronic diseases, but data on morbidity and mortality in patients with cirrhosis are limited. A cluster of A/H1N1/09 infection in 48 patients admitted to a Gastro‐Hepatology Unit is reported. Nosocomial spread, clinical outcome, and viral characteristics of A/H1N1/09 strains from a study group of 48 inpatients (21 and 27 with and without cirrhosis, respectively) were compared with those from a control group of 44 outpatients with mild influenza‐like illness and without cirrhosis. A/H1N1/09 infection was confirmed in 8/48 (17%) inpatients. A/H1N1/09 infection rate did not differ in patients with and without cirrhosis (4/21, 19%; 4/27, 15%), but three patients with cirrhosis died of pneumonia and acute respiratory distress syndrome, with fungal or bacterial superinfection in two cases, despite antiviral treatment. None of patients without cirrhosis died. Viral sequences showed the presence of hemagglutinin mutation D222G in two out of three fatal cases and S183P in seven out of eight infected patients. These mutants were not detected in the outpatients group. Even if A/H1N1/09 infection rate in hospitalized patients with and without cirrhosis was not significantly different, cirrhosis and D222G/S183P substitutions were significantly associated with severe disease and poor outcome, also suggesting fungal or bacterial superinfection and portal hypertension as risk factors for A/H1N1/09 disease severity in patients with cirrhosis. Vaccination, preventive and early treatment and a strict control of nosocomial spread should be activated carefully in patients with cirrhosis during epidemics influenza. J. Med. Virol. 85:1–7, 2012. © 2012 Wiley Periodicals, Inc.     

Risk assessment on the epidemics of human infection with a novel avian influenza A (H7N9) virus in Jiangsu Province, China

A novel avian influenza A (H7N9) virus was discovered in February 2013 in China and has resulted in more than 100 comfirmed human infections including 26 fatal cases as of May 2, 2013. The situation raises many urgent questions and global public health concerns. In this study, epidemiologic characteristics of infected human cases in Jiangsu province were analyzed and risk assessment was undertaken based on the information available. Briefly, it is highly unlikely that a pandemic of human infection with avian influenza A (H7N9) virus will happen in Jiangsu Province in the near future. In the end, some measures are recommended to prevent the situation from becoming worse.     

Characterization of eleven novel mutations (M45L, R119H, 544delG, G145V, H154Y, C184Y, D289V, 862+5A, 1172delC, R411X, E459K) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with severe hypophosphatasia. Mutations in brief no. 217. Online

Hypophosphatasia is a rare inherited disorder characterized by defective bone mineralization and deficiency of serum and tissue liver/ bone/kidney tissue alkaline phosphatase (L/B/K ALP) activity. We report the characterization of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 9 families affected by severe hypophosphatasia. Fourteen distinct mutations were found, 3 of which were previously reported in the North American or Japanese populations. Seven of the 11 new mutations were missense mutations (M45L, R119H, G145V, C184Y and H154Y, D289V, E459K), the four others were 2 single nucleotide deletions (544delG and 1172delC), a mutation affecting donor splice site (862 + 5A) and a nonsense mutation (R411X).