Changes in gene expression in liver tissue from patients with fulminant hepatitis E

Table 1 Characteristics of study subjects in the three groups

Characteristic	Healthy controls (n = 6)	Fulminant hepatitis B (n = 6)	Fulminant hepatitis E (n = 5)
Age (yr)	52 (30-58)	24 (16-60)	28 (18-32)
Gender (Male:Female)	4:2	4:2	1:4
Duration of illness before death (d)	-	9 (6-14)	10 (7-13)
Maximum total serum bilirubin (mg/dL)	0.7 (0.4-1.4)	21 (13.1-41.4)	25 (5.4-32.0)
Serum ALTa (IU/L)	30 (21-58)	1939 (524-5795)	770 (240-1302)
Serum AST (IU/L)	28 (18-35)	859 (250-2345)	458 (332-1000)
Alkaline phosphatase (IU/L)	-	257 (131-427)	306 (164-561)
Serum albumin (g/dL)	-	2.8 (2.0-3.3)	2.8 (2.1-3.2)

Data are shown as median (range), except for gender distribution; patients with fulminant hepatitis B and fulminant hepatitis E were comparable in all variables except serum ALT levels (^aP < 0.05, Mann-Whitney U test). ALT: Alanine aminotransferase.

Table 2 Gene Ontology analysis (biological processes) for gene entities differentially expressed in liver tissue from fulminant hepatitis E as compared to normal liver tissue, as well as in fulminant hepatitis B as compared to normal liver tissue

Gene ontology accession	Gene Ontology term	P value
GO:0055114	Oxidation-reduction process	2.68E-40
GO:0006082	Organic acid metabolic process	4.75E-39
GO:0043436	Oxoacid metabolic process	2.17E-38
GO:0019752	Carboxylic acid metabolic process	4.09E-38
GO:0006629	Lipid metabolic process	3.94E-28
GO:0044281	Small molecule metabolic process	9.06E-27
GO:0032787	Monocarboxylic acid metabolic process	3.56E-22
GO:0016054	Organic acid catabolic process	4.22E-19
GO:0046395	Carboxylic acid catabolic process	4.22E-19
GO:0044255	Cellular lipid metabolic process	1.35E-17
GO:0044282	Small molecule catabolic process	5.16E-17
GO:0044712	Single-organism catabolic process	5.16E-17
GO:0006631	Fatty acid metabolic process	2.71E-16
GO:0006520	Cellular amino acid metabolic process	4.43E-16
GO:0044711	Single-organism biosynthetic process	8.25E-14
GO:1901605	Alpha-amino acid metabolic process	1.07E-13
GO:0044283	Small molecule biosynthetic process	1.60E-13
GO:1901564	Organonitrogen compound metabolic process	2.46E-11
GO:0009063	Cellular amino acid catabolic process	4.46E-11
GO:0008610	Lipid biosynthetic process	8.46E-11
GO:0072376	Protein activation cascade	3.87E-10
GO:0008202	Steroid metabolic process	4.10E-10
GO:0016053	Organic acid biosynthetic process	6.26E-10
GO:0046394	Carboxylic acid biosynthetic process	6.26E-10
GO:1901566	Organonitrogen compound biosynthetic process	1.94E-08
GO:0008152	Metabolic process	4.34E-08
GO:1901606	Alpha-amino acid catabolic process	4.58E-08
GO:0072329	Monocarboxylic acid catabolic process	1.40E-07
GO:0007596	Blood coagulation	1.98E-07
GO:0050817	Coagulation	1.98E-07
GO:0007599	Hemostasis	2.83E-07
GO:1901615	Organic hydroxy compound metabolic process	4.14E-07
GO:0042060	Wound healing	4.86E-07
GO:0006956	Complement activation	6.77E-07
GO:0009062	Fatty acid catabolic process	1.71E-06
GO:0006066	Alcohol metabolic process	1.82E-06
GO:0008652	Cellular amino acid biosynthetic process	2.42E-06
GO:0050878	Regulation of body fluid levels	5.46E-06
GO:0051186	Cofactor metabolic process	5.50E-06
GO:0006694	Steroid biosynthetic process	8.32E-06
GO:0044242	Cellular lipid catabolic process	1.09E-05
GO:0005996	Monosaccharide metabolic process	0.000012
GO:0051346	Negative regulation of hydrolase activity	1.28E-05
GO:0005975	Carbohydrate metabolic process	1.35E-05
GO:0010876	Lipid localization	5.30E-05
GO:0044710	Single-organism metabolic process	5.82E-05
GO:0006732	Coenzyme metabolic process	6.57E-05
GO:0010951	Negative regulation of endopeptidase activity	7.22E-05
GO:0019318	Hexose metabolic process	7.95E-05
GO:0006869	Lipid transport	8.02E-05
GO:0065008	Regulation of biological quality	8.96E-05
GO:0010466	Negative regulation of peptidase activity	0.0001
GO:0006006	Glucose metabolic process	0.0001
GO:0042558	Pteridine-containing compound metabolic process	0.0002
GO:0043648	Dicarboxylic acid metabolic process	0.0002
GO:0006958	Complement activation, classical pathway	0.0004
GO:0006091	Generation of precursor metabolites and energy	0.0004
GO:0044262	Cellular carbohydrate metabolic process	0.0004
GO:0006575	Cellular modified amino acid metabolic process	0.0005
GO:0016051	Carbohydrate biosynthetic process	0.0005
GO:0072330	Monocarboxylic acid biosynthetic process	0.0006
GO:00024551	Humoral immune response mediated by circulating immunoglobulin	0.0010
GO:0044723	Single-organism carbohydrate metabolic process	0.0010
GO:0019320	Hexose catabolic process	0.0011
GO:0016052	Carbohydrate catabolic process	0.0014
GO:0044724	Single-organism carbohydrate catabolic process	0.0014
GO:0006820	Anion transport	0.0016
GO:0006007	Glucose catabolic process	0.0017
GO:0046365	Monosaccharide catabolic process	0.0018
GO:0046835	Carbohydrate phosphorylation	0.0020
GO:1901617	Organic hydroxy compound biosynthetic process	0.0020
GO:00022531	Activation of immune response	0.0021
GO:0016125	Sterol metabolic process	0.0022
GO:0006096	Glycolysis	0.0023
GO:0019395	Fatty acid oxidation	0.0037
GO:0034440	Lipid oxidation	0.0037
GO:0046165	Alcohol biosynthetic process	0.0038
GO:00069591	Humoral immune response	0.0042
GO:0009611	Response to wounding	0.0044
GO:0006957	Complement activation, alternative pathway	0.0044
GO:0006760	Folic acid-containing compound metabolic process	0.0044
GO:00450871	Innate immune response	0.0053
GO:0052548	Regulation of endopeptidase activity	0.0077
GO:0046364	Monosaccharide biosynthetic process	0.0077
GO:0006790	Sulfur compound metabolic process	0.0078
GO:0051179	Localization	0.0079
GO:0052547	Regulation of peptidase activity	0.0083
GO:0046942	Carboxylic acid transport	0.0083
GO:0015849	Organic acid transport	0.0095
GO:0016042	Lipid catabolic process	0.0113
GO:0015711	Organic anion transport	0.0113
GO:0051234	Establishment of localization	0.0113
GO:0006810	Transport	0.0119
GO:0044092	Negative regulation of molecular function	0.0126
GO:0019319	Hexose biosynthetic process	0.0131
GO:0072378	Blood coagulation, fibrin clot formation	0.0132
GO:0006558	L-phenylalanine metabolic process	0.0146
GO:0006559	L-phenylalanine catabolic process	0.0146
GO:0000038	Very long-chain fatty acid metabolic process	0.0146
GO:0051289	Protein homotetramerization	0.0146
GO:00022521	Immune effector process	0.0153
GO:0008203	Cholesterol metabolic process	0.0153
GO:0009074	Aromatic amino acid family catabolic process	0.0212
GO:0048806	Genitalia development	0.0212
GO:00160641	Immunoglobulin mediated immune response	0.0214
GO:0050819	Negative regulation of coagulation	0.0214
GO:0043086	Negative regulation of catalytic activity	0.0224
GO:0034754	Cellular hormone metabolic process	0.0243
GO:00197241	B cell mediated immunity	0.0263
GO:0051262	Protein tetramerization	0.0279
GO:00507781	Positive regulation of immune response	0.0292
GO:00507761	Regulation of immune response	0.0341
GO:0006633	Fatty acid biosynthetic process	0.0372
GO:0003333	Amino acid transmembrane transport	0.0389
GO:0016126	Sterol biosynthetic process	0.0416
GO:0006811	Ion transport	0.0420
GO:0006094	Gluconeogenesis	0.0474
GO:0001676	Long-chain fatty acid metabolic process	0.0474

¹These pathways are related to immune responses.

Table 3 Results of Gene Ontology analysis (biological processes) for gene entities differentially expressed in liver tissue from fulminant hepatitis E as compared to normal liver, but not in that from fulminant hepatitis B as compared to normal liver

Gene Ontology term	P value
Immune system process1	1.67E-11
Immune response1	4.81E-09
Regulation of immune system process1	5.06E-08
Positive regulation of immune system process1	2.72E-06
Defense response	1.04E-05
Response to wounding	1.90E-05
Signaling	7.78E-05
Adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains1	2.40E-04
Adaptive immune response1	2.40E-04
Response to stimulus	3.53E-04
Regulation of cell activation	4.65E-04
Inflammatory response1	6.89E-04
Cell adhesion	0.0010
Biological adhesion	0.0010
Positive regulation of immune response1	0.0015
Cell activation	0.0018
Signal transduction	0.0019
Regulation of leukocyte activation1	0.0020
Activation of immune response1	0.0021
Oxidation reduction	0.0021
B cell mediated immunity1	0.0023
Leukocyte mediated immunity1	0.0026
Positive regulation of response to stimulus	0.0027
Regulation of locomotion	0.0028
Regulation of immune response1	0.0030
Phospholipid efflux	0.0032
Lymphocyte mediated immunity1	0.0032
Regulation of cell migration1	0.0048
Regulation of cell motility1	0.0048
Response to stress	0.0050
Regulation of lymphocyte activation1	0.0056
Regulation of cellular component movement	0.0064
Signal transmission	0.0067
Immunoglobulin mediated immune response1	0.0067
Signaling process	0.0067
Small molecule metabolic process	0.0083
Cholesterol efflux	0.0124
Immune effector process1	0.0154
Negative regulation of apoptosis	0.0161
Positive regulation of cell activation	0.0176
Positive regulation of leukocyte activation1	0.0176
Regulation of response to stimulus	0.0177
Negative regulation of cell death	0.0179
Negative regulation of programmed cell death	0.0179
Regulation of lipid metabolic process	0.0180
Signaling pathway	0.0206
Acute inflammatory response1	0.0241
Phospholipid transport	0.0257
Regulation of fatty acid metabolic process	0.0273
Alcohol metabolic process	0.0282
Cholesterol transport	0.0310
Sterol transport	0.0472

¹These pathways are related to immune responses.

Table 4 Pathways whose genes were found to be over-represented among entities differentially expressed in both fulminant hepatitis E and fulminant hepatitis B, and in fulminant hepatitis E but not in fulminant hepatitis B (derived using BioCarta through DAVID resource)

BioCarta pathway	Gene count	P value
In both FH-B vs normal, and FH-E vs normal
Complement pathway	10	0.0002
Intrinsic prothrombin activation pathway	10	0.0002
Nuclear receptors in lipid metabolism and toxicity	13	0.0022
Alternative complement pathway	6	0.0069
Extrinsic prothrombin activation pathway	6	0.0113
Lectin induced complement pathway	6	0.0172
Classical complement pathway	6	0.0172
Acute myocardial infarction	6	0.0248
Vitamin C in the brain	4	0.0385
CBL mediated ligand-induced downregulation of epidermal growth factor receptors	5	0.0543
Catabolic pathways for methionine, isoleucine, threonine and valine	3	0.0955
In FH-E vs normal but not in FH-B vs normal
T cytotoxic cell surface molecules	7	0.0005
T helper cell surface molecules	6	0.0043
Cytotoxic T lymphocyte mediated immune response against target cells	7	0.0022
Co-stimulatory signal during T-cell activation	7	0.0085
Role of epidermal growth factor receptor transactivation by G protein-coupled receptors in cardiac hypertrophy	6	0.0092
T cell receptor signaling pathway	10	0.0049
Lck and Fyn tyrosine kinases in initiation of T cell receptor activation	5	0.0187
Interleukin-7 signal transduction	5	0.0446
Mitochondrial carnitinepalmitoyltransferase system	3	0.0529
T cell receptor and CD3 complex	3	0.0529
Interleukin-17 signaling pathway	5	0.0562