ABSTRACT
This year's Laskerâ¼Debakey Clinical Medical Research Award honors Ralf Bartenschlager, Charles Rice, and Michael Sofia, pioneers in the development of curative and safe therapies for the 170 million people with hepatitis C virus infection.
Subject(s)
Awards and Prizes , Clinical Medicine , Hepacivirus , Hepatitis C, Chronic/drug therapy , Antiviral Agents/therapeutic use , Disease Progression , Drug Discovery , End Stage Liver Disease/virology , Hepacivirus/genetics , Hepacivirus/isolation & purification , Hepacivirus/physiology , Hepatitis C, Chronic/epidemiology , Hepatitis C, Chronic/prevention & control , HumansABSTRACT
The 2012 Lasker-DeBakey Clinical Medical Research Award will be conferred on Thomas Starzl of the University of Pittsburgh School of Medicine in Pittsburgh, Pennsylvania, USA and Roy Calne of the University of Cambridge in Cambridge, UK. They are recognized for pioneering the development of liver transplantation, an intervention that saves 20,000 lives world-wide each year.
Subject(s)
Awards and Prizes , Liver Transplantation/history , History, 20th Century , Humans , Immunosuppressive Agents/therapeutic use , Liver/physiology , Liver Failure/therapy , Liver Transplantation/immunology , Tissue and Organ Procurement , United Kingdom , United StatesABSTRACT
In the last decade, the utility of whole-exome sequencing in uncovering genetic aetiologies of a variety of liver diseases has been demonstrated. These new diagnoses have guided the management, treatment, and prognostication of previously undiagnosed patients, largely thanks to improved insight into the underlying pathogenesis of their conditions. Despite its clear benefits, the uptake of genetic testing by hepatologists has been limited, in part due to limited prior genetic training and/or opportunities for continuing education. Herein, we show that Hepatology Genome Rounds, an interdisciplinary forum highlighting hepatology cases of clinical interest and educational value, are an important venue for integrating genotypic and phenotypic information to enable accurate diagnosis and appropriate management, dissemination of genomic knowledge within the field of hepatology, and ongoing education to providers and trainees in genomic medicine. We describe our single-centre experience and discuss practical considerations for clinicians interested in launching such a series. We foresee that this format will be adopted at other institutions and by additional specialties, with the aim of further incorporating genomic information into clinical medicine.
Subject(s)
Gastroenterology , Liver Diseases , Humans , Genomics , Genetic Testing , Liver Diseases/diagnosis , Liver Diseases/genetics , Liver Diseases/therapy , Exome SequencingABSTRACT
Fulminant viral hepatitis (FVH) caused by hepatitis A virus (HAV) is a life-threatening disease that typically strikes otherwise healthy individuals. The only known genetic etiology of FVH is inherited IL-18BP deficiency, which unleashes IL-18-dependent lymphocyte cytotoxicity and IFN-γ production. We studied two siblings who died from a combination of early-onset inflammatory bowel disease (EOIBD) and FVH due to HAV. The sibling tested was homozygous for the W100G variant of IL10RB previously described in an unrelated patient with EOIBD. We show here that the out-of-frame IL10RB variants seen in other EOIBD patients disrupt cellular responses to IL-10, IL-22, IL-26, and IFN-λs in overexpression conditions and in homozygous cells. By contrast, the impact of in-frame disease-causing variants varies between cases. When overexpressed, the W100G variant impairs cellular responses to IL-10, but not to IL-22, IL-26, or IFN-λ1, whereas cells homozygous for W100G do not respond to IL-10, IL-22, IL-26, or IFN-λ1. As IL-10 is a potent antagonist of IFN-γ in phagocytes, these findings suggest that the molecular basis of FVH in patients with IL-18BP or IL-10RB deficiency may involve excessive IFN-γ activity during HAV infections of the liver. Inherited IL-10RB deficiency, and possibly inherited IL-10 and IL-10RA deficiencies, confer a predisposition to FVH, and patients with these deficiencies should be vaccinated against HAV and other liver-tropic viruses.
Subject(s)
Hepatitis, Viral, Human , Interleukin-10 , Humans , Interleukin-10/genetics , Siblings , Interferon-gamma/geneticsABSTRACT
BACKGROUND AND AIMS: Most of the genetic basis of chronic liver disease remains undiscovered. APPROACH AND RESULTS: To identify genetic loci that modulate the risk of liver injury, we performed genome-wide association studies on circulating levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin across 312,671 White British participants in the UK Biobank. We focused on variants associated with elevations in all four liver biochemistries at genome-wide significance (P < 5 × 10-8 ) and that replicated using Mass General Brigham Biobank in 19,323 European ancestry individuals. We identified a genetic locus in mitochondrial glycerol-3-phosphate acyltransferase (GPAM rs10787429) associated with increased levels of ALT (P = 1.4 × 10-30 ), AST (P = 3.6 × 10-10 ), ALP (P = 9.5 × 10-30 ), and total bilirubin (P = 2.9 × 10-12 ). This common genetic variant was also associated with an allele dose-dependent risk of alcohol-associated liver disease (odd ratio [OR] = 1.34, P = 2.6 × 10-5 ) and fatty liver disease (OR = 1.18, P = 5.8 × 10-4 ) by International Classification of Diseases, 10th Revision codes. We identified significant interactions between GPAM rs10787429 and elevated body mass index in association with ALT and AST (P = 7.1 × 10-9 and 3.95 × 10-8 , respectively), as well as between GPAM rs10787429 and weekly alcohol consumption in association with ALT, AST, and alcohol-associated liver disease (P = 4.0 × 10-2 , 1.6 × 10-2 , and 1.3 × 10-2 , respectively). Unlike previously described genetic variants that are associated with an increased risk of liver injury but confer a protective effect on circulating lipids, GPAM rs10787429 was associated with an increase in total cholesterol (P = 2.0 × 10-17 ), LDL cholesterol (P = 2.0 × 10-10 ), and HDL cholesterol (P = 6.6 × 10-37 ). Single-cell RNA-sequencing data demonstrated hepatocyte-predominant expression of GPAM in cells that co-express genes related to VLDL production (P = 9.4 × 10-103 ). CONCLUSIONS: Genetic variation in GPAM is associated with susceptibility to liver injury. GPAM may represent a therapeutic target in chronic liver disease.
Subject(s)
Acetyltransferases/genetics , Chemical and Drug Induced Liver Injury/genetics , Mitochondria, Liver/enzymology , Acetyltransferases/metabolism , Genetic Association Studies , Genetic Variation/genetics , Genome-Wide Association Study , Humans , Mitochondria, Liver/metabolismABSTRACT
The clinical relevance of the Human Genome Project and next-generation sequencing technology was demonstrated for the first time in 2009, when whole-exome sequencing (WES) provided the definitive diagnosis of congenital chloride diarrhea in an infant with presumed renal salt-wasting disease. Over the past decade, numerous studies have shown the utility of WES for clinical diagnosis as well as for discovery of novel genetic disorders through analysis of a single or a handful of informative pedigrees. Hence, advances in improving the speed, accuracy, and computational analysis combined with exponential decrease in the cost of sequencing the human genome is transforming the practice of medicine. The impact of WES has been most noticeable in pediatric disorders and oncology, but its utility in the liver clinic is recently emerging. Here, we assess the current status of WES for clinical diagnosis and acceleration of translation research to enhance care of patients with liver disease.
Subject(s)
Exome Sequencing , Liver Diseases/diagnosis , Gastroenterologists , Genome, Human , Humans , Liver Diseases/therapy , Precision MedicineABSTRACT
BACKGROUND/AIMS: Very few studies have been performed to evaluate cranio-maxillofacial trauma diagnosed in hospitals in children and adolescents. The aim of this study was to perform an analysis of oral and cranio-maxillofacial trauma in the aforementioned population. MATERIALS AND METHODS: A hospital-based retrospective study, which reviewed 1438 patient records, was conducted at the "Teresina Emergency Hospital", Brazil. Data regarding demographics, day of the week on which trauma occurred, type of injury, etiology, anatomic trauma site, time of hospital admission, and associated comorbidities (or injuries) were collected. RESULTS: There were 1092 (75.9%) males and 346 (24.1%) females. The largest group was adolescents aged between 13 and 18 years (956, 66.5%). The majority lived in urban areas (69%). Trauma occurred most frequently during the week. The most prevalent etiology was road traffic accidents involving motorcycles (771, 53.6%) causing facial and skull fractures (598, 41%). The most prevalent soft tissue lesions were facial abrasions (49%), followed by injuries to the cheek (16.7%). Comorbidities associated with craniofacial trauma were present in 82%, with complications from traumatic brain injuries being the most prevalent (65.6%) Dental trauma was recorded in only 81 cases (5.6%). CONCLUSION: Male adolescents living in urban areas were most affected by craniofacial trauma. The most common cause was road traffic accidents involving motorcycles, resulting in facial and skull fractures. Complications from traumatic brain injuries were the most common associated injuries.
Subject(s)
Maxillofacial Injuries/epidemiology , Skull Fractures/epidemiology , Accidents, Traffic , Adolescent , Brazil/epidemiology , Child , Female , Humans , Male , Retrospective StudiesABSTRACT
BACKGROUND & AIMS: Adult patients suffering from liver disease of unknown cause represent an understudied and underserved population. The use of whole-exome sequencing (WES) for the assessment of a broader spectrum of non-oncological diseases, among adults, remains poorly studied. We assessed the utility of WES in the diagnosis and management of adults with unexplained liver disease despite comprehensive evaluation by a hepatologist and with no history of alcohol overuse. METHODS: We performed WES and deep phenotyping of 19 unrelated adult patients with idiopathic liver disease recruited at a tertiary academic health care center in the US. RESULTS: Analysis of the exome in 19 cases identified 4 monogenic disorders in 5 unrelated adults. Patient 1 suffered for 18â¯years from devastating complications of undiagnosed type 3 familial partial lipodystrophy due to a deleterious heterozygous variant in PPARG. Molecular diagnosis enabled initiation of leptin replacement therapy with subsequent normalization of liver aminotransferases, amelioration of dyslipidemia, and decreases in daily insulin requirements. Patients 2 and 3 were diagnosed with MDR3 deficiency due to recessive mutations in ABCB4. Patient 4 with a prior diagnosis of non-alcoholic steatohepatitis was found to harbor a mitochondrial disorder due to a homozygous pathogenic variant in NDUFB3; this finding enabled initiation of disease preventive measures including supplementation with antioxidants. Patient 5 is a lean patient with hepatic steatosis of unknown etiology who was found to have a damaging heterozygous variant in APOB. CONCLUSIONS: Genomic analysis yielded an actionable diagnosis in a substantial number (â¼25%) of selected adult patients with chronic liver disease of unknown etiology. This study supports the use of WES in the evaluation and management of adults with idiopathic liver disease in clinical practice. LAY SUMMARY: We performed whole-exome sequencing in 19 adult patients with unexplained liver disease after an unrevealing conventional work-up performed by a hepatologist. In 5 cases, genomic analysis led to a diagnosis and informed treatment and management of the disease. Therefore, we suggest using whole-exome sequencing in the evaluation and management of adults with unexplained liver disease.
Subject(s)
Exome Sequencing , Liver Diseases/genetics , ATP Binding Cassette Transporter, Subfamily B/deficiency , ATP Binding Cassette Transporter, Subfamily B/genetics , Adult , Aged , Cholestasis, Intrahepatic/genetics , Female , Genomics , Humans , Lipodystrophy, Familial Partial/genetics , Male , Middle Aged , PPAR gamma/geneticsABSTRACT
Acyl CoA Oxidase 2 (ACOX2) encodes branched-chain acyl-CoA oxidase, a peroxisomal enzyme believed to be involved in the metabolism of branched-chain fatty acids and bile acid intermediates. Deficiency of this enzyme has not been described previously. We report an 8-y-old male with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Exome sequencing revealed a previously unidentified homozygous premature termination mutation (p.Y69*) in ACOX2 Immunohistochemistry confirmed the absence of ACOX2 expression in the patient's liver, and biochemical analysis showed marked elevation of intermediate bile acids upstream of ACOX2. These findings define a potentially treatable inborn error of bile acid biosynthesis caused by ACOX2 deficiency.
Subject(s)
Ataxia/enzymology , Bile Acids and Salts/biosynthesis , Cognitive Dysfunction/enzymology , Liver Cirrhosis/enzymology , Oxidoreductases/deficiency , Transaminases/metabolism , Ataxia/complications , Ataxia/genetics , Bile Acids and Salts/chemistry , Child , Cognitive Dysfunction/complications , Cognitive Dysfunction/genetics , Homozygote , Humans , Infant , Infant, Newborn , Liver/pathology , Liver Cirrhosis/complications , Liver Cirrhosis/genetics , Loss of Function Mutation/genetics , Male , Mutation/genetics , Oxidation-Reduction , Oxidoreductases/geneticsABSTRACT
Human protothecosis is a rare microalgae infection, and its dissemination typically occurs in immunocompromised individuals, but no specific immune defect has been reported. Here, we describe an 8-year-old daughter of a consanguineous union with abdominal pain and bloody diarrhea for 3 months who was found to have pancolitis with numerous microalgae identified as Prototheca zopfii. In the absence of a known immunodeficiency, exome sequencing was performed, which uncovered a novel recessive frameshift mutation in CARD9 (p.V261fs). This report highlights that CARD9 deficiency should be investigated in patients with unexplained systemic/visceral protothecosis and suggests a new mechanistic insight into anti-Prototheca immunity.
Subject(s)
CARD Signaling Adaptor Proteins/genetics , Candidiasis, Chronic Mucocutaneous/complications , Colitis/genetics , Colitis/pathology , Prototheca/isolation & purification , Child , Female , Frameshift Mutation , HumansSubject(s)
Genomic Medicine , Liver Diseases , Genomics , Humans , Liver Diseases/genetics , Liver Diseases/therapy , Precision MedicineABSTRACT
Hepatocellular adenoma (HCA) is a rare benign liver tumor, predominantly seen in young women. Its major complications are malignant transformation, spontaneous hemorrhage, and rupture. We describe a case of a young female with no underlying liver disease who presented with acute abdominal pain and was found to have a 17cm heterogeneous mass in the left lobe of the liver. She underwent left hepatectomy and pathology revealed a 14cm moderately differentiated hepatocellular carcinoma (HCC) arising in a shell of a HCA. At that time, vascular invasion was already present. She rapidly developed recurrent multifocal hepatic lesions and subsequent spread to the brain, leading to her death 18months after surgery. To investigate the underlying genetic events occurring during hepatocellular adenoma-carcinoma transition and extra-hepatic dissemination, we performed whole exome sequencing of DNA isolated from peripheral blood leucocytes, HCA, HCC, tumor thrombus and brain metastasis. Our data show a step-wise addition of somatic mutations and copy number variations with disease progression, suggesting a linear tumor evolution, which is supported by clonality analysis. Specifically, using a model based clustering of somatic mutations, one single founding clone arising in the HCA, which included catenin beta 1 (CTNNB1) and IL6ST driver mutations, was identified and displayed an increasing clonality rate in HCC, tumor thrombus and brain metastasis. Our data highlight the feasibility of performing whole exome capture, sequencing and analysis using formalin-fixed paraffin-embedded (FFPE) samples, and we describe the first genomic longitudinal study of hepatocellular adenoma-carcinoma transition, vascular invasion and brain metastasis with detailed clinicopathologic annotation.
Subject(s)
Adenoma/pathology , Carcinoma, Hepatocellular/pathology , Exome , Liver Neoplasms/pathology , Adult , Carcinoma, Hepatocellular/genetics , DNA Copy Number Variations , Female , Humans , Liver Neoplasms/genetics , Mutation , Neoplasm InvasivenessSubject(s)
Genomics/methods , Non-alcoholic Fatty Liver Disease , Thinness , Genomic Medicine/trends , Humans , Non-alcoholic Fatty Liver Disease/diagnosis , Non-alcoholic Fatty Liver Disease/epidemiology , Non-alcoholic Fatty Liver Disease/genetics , Thinness/diagnosis , Thinness/epidemiology , Thinness/geneticsABSTRACT
UNLABELLED: Despite advances in the diagnosis and management of idiopathic noncirrhotic portal hypertension, its pathogenesis remains elusive. Insight may be gained from study of early-onset familial idiopathic noncirrhotic portal hypertension, in which Mendelian mutations may account for disease. We performed exome sequencing of eight subjects from six kindreds with onset of portal hypertension of indeterminate etiology during infancy or childhood. Three subjects from two consanguineous families shared the identical rare homozygous p.N46S mutation in DGUOK, a deoxyguanosine kinase required for mitochondrial DNA replication; haplotype sharing demonstrated that the mutation in the two families was inherited from a remote common ancestor. All three affected subjects had stable portal hypertension with noncirrhotic liver disease for 6-16 years of follow-up. This mutation impairs adenosine triphosphate binding and reduces catalytic activity. Loss-of-function mutations in DGUOK have previously been implicated in cirrhosis and liver failure but not in isolated portal hypertension. Interestingly, treatment of patients with human immunodeficiency viral infection with the nucleoside analogue didanosine is known to cause portal hypertension in a subset of patients and lowers deoxyguanosine kinase levels in vitro; the current findings implicate these effects on deoxyguanosine kinase in the causal mechanism. CONCLUSION: Our findings provide new insight into the mechanisms mediating inherited and acquired noncirrhotic portal hypertension, expand the phenotypic spectrum of DGUOK deficiency, and provide a new genetic test for a specific cause of idiopathic noncirrhotic portal hypertension. (Hepatology 2016;63:1977-1986).
Subject(s)
Hypertension, Portal/genetics , Phosphotransferases (Alcohol Group Acceptor)/genetics , Adolescent , Amino Acid Sequence , Animals , Cattle , Child , Child, Preschool , DNA Mutational Analysis , Dogs , Female , Genes, Recessive , Homozygote , Humans , Infant , Liver Failure/genetics , Male , Molecular Sequence Data , Pedigree , Principal Component Analysis , Rats , Young AdultABSTRACT
BACKGROUND: The effectiveness of interferon-free direct-acting antivirals (DAA) in treating chronic hepatitis C virus (HCV) is limited by low screening and treatment rates, particularly among people who inject drugs (PWIDs). METHODS: To evaluate the levels of screening and treatment with interferon-free DAAs that are required to control HCV incidence and HCV-associated morbidity and mortality, we developed a transmission model, stratified by age and by injection drug use, and calibrated it to epidemiological data in the United States from 1992 to 2014. We quantified the impact of administration of DAAs at current and at enhanced screening and treatment rates, focusing on outcomes of HCV incidence, prevalence, compensated and decompensated cirrhosis, hepatocellular carcinoma, liver transplants, and mortality from 2015 to 2040. RESULTS: Increasing annual treatment of patients 4-fold-from the approximately 100 000 treated historically to 400 000-is predicted to prevent 526 084 (95% confidence interval, 466 615-593 347) cases of cirrhosis and 256 315 (201 589-316 114) HCV-associated deaths. By simultaneously increasing treatment capacity and increasing the number of HCV infections diagnosed, total HCV prevalence could fall to as low as 305 599 (222 955-422 110) infections by 2040. Complete elimination of HCV transmission in the United States through treatment with DAAs would require nearly universal screening of PWIDs, with an annual treatment rate of at least 30%. CONCLUSIONS: Interferon-free DAAs are projected to achieve marked reductions in HCV-associated morbidity and mortality. Aggressive expansion in HCV screening and treatment, particularly among PWIDs, would be required to eliminate HCV in the United States.
Subject(s)
Antiviral Agents/therapeutic use , Disease Transmission, Infectious/prevention & control , Hepatitis C, Chronic/diagnosis , Hepatitis C, Chronic/drug therapy , Mass Screening/methods , Mass Screening/statistics & numerical data , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Hepatocellular/epidemiology , Carcinoma, Hepatocellular/prevention & control , Child , Female , Hepatitis C, Chronic/epidemiology , Hepatitis C, Chronic/mortality , Humans , Incidence , Liver Failure/epidemiology , Liver Failure/prevention & control , Liver Transplantation , Male , Middle Aged , Prevalence , United States/epidemiology , Young AdultABSTRACT
BACKGROUND & AIMS: In children with liver failure, as many as half remain of indeterminate aetiology. This hinders timely consideration of optimal treatment options. We posit that a significant subset of these children harbour known inherited metabolic liver diseases with atypical presentation or novel inborn errors of metabolism. We investigated the utility of whole-exome sequencing in three children with advanced liver disease of indeterminate aetiology. METHODS: Patient 1 was a 10 year-old female diagnosed with Wilson disease but no detectable ATP7B mutations, and decompensated liver cirrhosis who underwent liver transplant and subsequently developed onset of neurodegenerative disease. Patient 2 was a full-term 2 day-old male with fatal acute liver failure of indeterminate aetiology. Patient 3 was an 8 year-old female with progressive syndromic cholestasis of unknown aetiology since age 3 months. RESULTS: Unbiased whole-exome sequencing of germline DNA revealed homozygous mutations in MPV17 and SERAC1 as the disease causing genes in patient 1 and 2, respectively. This is the first demonstration of SERAC1 loss-of-function associated fatal acute liver failure. Patient 1 expands the phenotypic spectrum of the MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. Patient 3 was found to have syndromic cholestasis due to bi-allelic NOTCH2 mutations. CONCLUSIONS: Our findings validate the application of whole-exome sequencing in the diagnosis and management of children with advanced liver disease of indeterminate aetiology, with the potential to enhance optimal selection of treatment options and adequate counselling of families. Moreover, whole-exome sequencing revealed a hitherto unrecognized phenotypic spectrum of inherited metabolic liver diseases.
Subject(s)
Exome , Liver Failure/diagnosis , Liver Failure/genetics , Amino Acid Sequence , Base Sequence , Carboxylic Ester Hydrolases/genetics , Child , Cholestasis/genetics , DNA Mutational Analysis , End Stage Liver Disease/genetics , Fatal Outcome , Female , Genes, Recessive , Hepatolenticular Degeneration/diagnosis , Hepatolenticular Degeneration/genetics , Heterozygote , Homozygote , Humans , Infant, Newborn , Liver Failure/therapy , Liver Failure, Acute/genetics , Male , Membrane Proteins/genetics , Mitochondrial Proteins/genetics , Molecular Sequence Data , Pedigree , RNA Splice Sites , Receptor, Notch2/genetics , Sequence Homology, Amino AcidABSTRACT
Hepatocellular carcinoma (HCC) rarely occurs in childhood. We describe a patient with new onset of pruritus at 8 months of age who at 17 months of age was found to have a 2.5 cm HCC. To delineate the possible genetic basis of this tumour, we performed whole exome sequencing (WES) of the germline DNA and identified two novel predictably deleterious missense mutations in ABCB11, encoding bile salt export pump (BSEP), confirmed in the parental DNA as bi-allelic and inherited. Although inherited ABCB11 mutations have previously been linked to HCC in a small number of cases, the molecular mechanisms of hepatocellular carcinogenesis in ABCB11 disease are unknown. WES of the HCC tissue uncovered somatic driver mutations in the beta-catenin (CTNNB1) and nuclear-factor-erythroid-2-related-factor-2 (NFE2L2) genes. Moreover, clonality analysis predicted that the CTNNB1 mutation was clonal and occurred earlier during carcinogenesis, whereas the NFE2L2 mutation was acquired later. Interestingly, background liver parenchyma showed no inflammation or fibrosis and BSEP expression was preserved. This is the first study to identify somatic CTNNB1 and NFE2L2 mutations in early childhood arisen in the setting of inherited bi-allelic ABCB11 mutations. Rapid WES analysis expedited this child's diagnosis and treatment, and likely improved her prognosis.