Acute liver failure

Summary

Acute liver failure (MONDO:0019542) is a disease with 2 cohort genes and 64 clinical trials. Top therapeutic interventions include acetylcysteine, mannitol, and adefovir dipivoxil.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 2
• Phenotypes (HPO): 50
• Clinical trials: 64

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	20	Europe	Validated

Signs & symptoms

Clinical features (HPO)

50 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000952	Jaundice	Very frequent (80-99%)
HP:0001404	Hepatocellular necrosis	Very frequent (80-99%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Very frequent (80-99%)
HP:0012115	Hepatitis	Very frequent (80-99%)
HP:0000712	Emotional lability	Frequent (30-79%)
HP:0000713	Agitation	Frequent (30-79%)
HP:0000846	Adrenal insufficiency	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0001289	Confusion	Frequent (30-79%)
HP:0001350	Slurred speech	Frequent (30-79%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0001943	Hypoglycemia	Frequent (30-79%)
HP:0001987	Hyperammonemia	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002018	Nausea	Frequent (30-79%)
HP:0002329	Drowsiness	Frequent (30-79%)
HP:0002605	Hepatic necrosis	Frequent (30-79%)
HP:0002614	Hepatic periportal necrosis	Frequent (30-79%)
HP:0002615	Hypotension	Frequent (30-79%)
HP:0002793	Abnormal pattern of respiration	Frequent (30-79%)
HP:0002795	Abnormal respiratory system physiology	Frequent (30-79%)
HP:0003225	Reduced coagulation factor V activity	Frequent (30-79%)
HP:0003256	Abnormality of the coagulation cascade	Frequent (30-79%)
HP:0008151	Prolonged prothrombin time	Frequent (30-79%)
HP:0008169	Reduced factor VII activity	Frequent (30-79%)
HP:0008321	Reduced factor X activity	Frequent (30-79%)
HP:0030977	Increased factor VIII activity	Frequent (30-79%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000988	Skin rash	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001259	Coma	Occasional (5-29%)
HP:0001298	Encephalopathy	Occasional (5-29%)
HP:0001892	Abnormal bleeding	Occasional (5-29%)
HP:0001919	Acute kidney injury	Occasional (5-29%)
HP:0001941	Acidosis	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0001948	Alkalosis	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002181	Cerebral edema	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0002311	Incoordination	Occasional (5-29%)
HP:0002516	Increased intracranial pressure	Occasional (5-29%)
HP:0002625	Deep venous thrombosis	Occasional (5-29%)
HP:0002883	Hyperventilation	Occasional (5-29%)
HP:0007021	Pain insensitivity	Occasional (5-29%)
HP:0012417	Hypocapnia	Occasional (5-29%)
HP:0031273	Shock	Occasional (5-29%)
HP:0031844	Euphoria	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	acute liver failure
Mondo ID	MONDO:0019542
MeSH	D017114
Orphanet	90062
NCIT	C84396
SNOMED CT	197270009
UMLS	C0162557
MedGen	58125
GARD	0019112
MedDRA	10000804
Is cancer (heuristic)	no

Also known as: acute hepatic failure · fulminant hepatic failure

Data availability: 2 ClinVar variants.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › acute disease › acute liver failure

Related subtypes (118): encephalopathy, acute, infection-induced, seminal vesicle acute gonorrhea, acute diarrhea, acute hydrops keratoconus, acute pericementitis, purulent acute otitis media, acute otitis externa, acute eustachian salpingitis, acute cervicitis, acute gonococcal epididymo-orchitis, acute salpingitis, acute respiratory failure, acute conjunctivitis, acute laryngopharyngitis, acute orbital inflammation, acute dacryocystitis, acute sphenoidal sinusitis, acute proliferative glomerulonephritis, acute cystitis, acute tympanitis, acute closed-angle glaucoma, acute gonococcal prostatitis, acute poststreptococcal glomerulonephritis, acute diffuse glomerulonephritis, acute retrobulbar neuritis, acute frontal sinusitis, acute cholangitis, acute thyroiditis, acute maxillary sinusitis, acute kidney injury, acute transudative otitis media, acute myocarditis, subacute glomerulonephritis, acute pyelonephritis, acute urate nephropathy, acute stress disorder, acute inflammation of lacrimal passage, acute endometritis, acute cor pulmonale, acute intestinal ischemia, subacute delirium, acute laryngitis, acute myocardial infarction, acute ethmoiditis, acute dacryoadenitis, acute female pelvic peritonitis, acute quadriplegic myopathy, severe acute respiratory syndrome, acute hypotension, acute coronary syndrome, acute chest syndrome, acute pancreatitis, acute retinal necrosis syndrome, subacute bacterial endocarditis, necrotizing encephalomyelopathy, subacute, of Leigh, adult, acute intermittent porphyria, leukemia, acute myelocytic, with polyposis coli and colon cancer, surfactant metabolism dysfunction, pulmonary, 1, myoglobinuria, acute recurrent, autosomal recessive, acute leukemia, acute insulin response, alcohol sensitivity, acute, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome, acute transverse myelitis, subacute cutaneous lupus erythematosus, acute lung injury, subacute inflammatory demyelinating polyneuropathy, Marburg acute multiple sclerosis, acute pure sensory neuropathy, autoimmune autonomic ganglionopathy, acute sensory ataxic neuropathy, acute fatty liver of pregnancy, acute neonatal citrullinemia type I, acute endophthalmitis, acute zonal occult outer retinopathy, acute annular outer retinopathy, poliomyelitis, acute generalized exanthematous pustulosis, acute opioid poisoning, acute encephalopathy with biphasic seizures and late reduced diffusion, acute tricyclic antidepressant poisoning, acute poisoning by drugs with membrane-stabilizing effect, recurrent acute pancreatitis, bilateral acute depigmentation of the iris, idiopathic acute eosinophilic pneumonia, acute ackee fruit intoxication, acute interstitial pneumonia, acute adrenal insufficiency, encephalitis, acute inflammatory demyelinating polyradiculoneuropathy, acute motor and sensory axonal neuropathy, acute motor axonal neuropathy, acute graft versus host disease, acute pharyngitis, sudden hearing loss disorder, acute bronchiolitis, acute tonsillitis, acute rheumatic heart disease, acute cholinergic dysautonomia, acute mountain sickness, acute lymphoblastic leukemia congenital sporadic aniridia, acute lichenoid pityriasis, leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate, acute radiation syndrome, acute bilirubin encephalopathy, acute mast cell leukemia, subacute bursitis, acute papillary necrosis, acute posterior multifocal placoid pigment epitheliopathy, acute idiopathic urticaria, acute macular neuroretinopathy, acute flaccid myelitis, acute hepatitis B virus infection, acute hepatitis C virus infection, acute fibrinous and organizing pneumonia, acute transplant rejection

Subtypes (1): acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
252958	NM_007215.4(POLG2):c.544C>T (p.Arg182Trp)	POLG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
523307	NC_012920.1(MT-CO3):m.9355A>T	MT-CO3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MT-CO3	Orphanet:104	Leber hereditary optic neuropathy
MT-CO3	Orphanet:254905	Isolated cytochrome C oxidase deficiency
MT-CO3	Orphanet:550	MELAS
MT-CO3	Orphanet:99845	Genetic recurrent myoglobinuria
POLG2	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MT-CO3	HGNC:7422	ENSG00000198938	P00414	Cytochrome c oxidase subunit 3	clinvar
POLG2	HGNC:9180	ENSG00000256525	Q9UHN1	DNA polymerase subunit gamma-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MT-CO3	Cytochrome c oxidase subunit 3	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
POLG2	DNA polymerase subunit gamma-2	Accessory subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MT-CO3	Other/Unknown	no		Cyt_c_oxidase-like_su3, Cyt_c_oxidase_su3_a-hlx, Cyt_c/ubiquinol_Oxase_su3
POLG2	Enzyme (other)	yes	2.7.7.7	Anticodon-bd, Gly-tRNA_synthase/POLG2, Anticodon-bd_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endocervix	1
rectum	1
zone of skin	1
left testis	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MT-CO3	134	ubiquitous	marker	zone of skin, endocervix, rectum
POLG2	249	ubiquitous	marker	secondary oocyte, oocyte, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MT-CO3	1,791
POLG2	1,557

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG2	Q9UHN1	38
MT-CO3	P00414	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Strand-asynchronous mitochondrial DNA replication	1	571.0×	0.012	POLG2
Complex IV assembly	1	114.2×	0.019	MT-CO3
Transcriptional activation of mitochondrial biogenesis	1	102.0×	0.019	POLG2
Cytoprotection by HMOX1	1	92.1×	0.019	MT-CO3
TP53 Regulates Metabolic Genes	1	64.9×	0.021	MT-CO3
Mitochondrial translation termination	1	54.9×	0.021	MT-CO3
Respiratory electron transport	1	47.6×	0.021	MT-CO3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
respiratory chain complex IV assembly	1	1203.7×	0.003	MT-CO3
positive regulation of DNA-directed DNA polymerase activity	1	1053.2×	0.003	POLG2
mitochondrial DNA replication	1	766.0×	0.003	POLG2
mitochondrial electron transport, cytochrome c to oxygen	1	383.0×	0.005	MT-CO3
DNA-templated DNA replication	1	280.9×	0.006	POLG2
cellular respiration	1	216.1×	0.006	MT-CO3
mitochondrion organization	1	75.9×	0.015	POLG2
in utero embryonic development	1	36.0×	0.028	POLG2

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Acetylcysteine	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Ornithine, Sodium Chloride.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MT-CO3	0	0
POLG2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MT-CO3	1	Binding:1
POLG2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POLG2	2.7.7.7	DNA-directed DNA polymerase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	POLG2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MT-CO3

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MT-CO3	1	—
POLG2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 64.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	43
PHASE2	10
PHASE4	3
PHASE3	2
PHASE2/PHASE3	2
PHASE1/PHASE2	2
PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00896025	PHASE4	TERMINATED	Study of N-Acetylcysteine in Acute Liver Failure (ALF)
NCT02375867	PHASE4	COMPLETED	Steroids in Fulminant Hepatitis A in the Pediatric Age Group
NCT03667157	PHASE4	COMPLETED	Liver Function After Intravenous Methylprednisolone Administration
NCT00004467	PHASE3	COMPLETED	Randomized Study of Acetylcysteine in Patients With Acute Liver Failure Not Caused by Acetaminophen
NCT00248625	PHASE3	COMPLETED	N-acetylcysteine in Non-Acetaminophen Pediatric Acute Liver Failure
NCT01452295	PHASE2/PHASE3	WITHDRAWN	Registry Protocol for Tracking Trial Subjects After VTI-206 Study Completion
NCT02786836	PHASE2/PHASE3	COMPLETED	13C-Methacetin Breath Test for the Prediction of Outcome in in ALI or ALF
NCT04862221	PHASE2	RECRUITING	TReatment for ImmUne Mediated PathopHysiology
NCT05491135	PHASE1/PHASE2	NOT_YET_RECRUITING	Hepatocyte Microbeads for Acute Liver Failure
NCT05689645	PHASE2	RECRUITING	F573 for Injection for the Treatment of Liver Injury/Failure
NCT00030225	PHASE2	COMPLETED	Phase 2 Evaluation of the ELAD System in the Management of Acute Liver Failure
NCT00470314	PHASE2	UNKNOWN	Therapeutic Efficacy of L-Ornithine L-Aspartate Infusion in Patients With Acute Liver Failure
NCT00832728	PHASE2	WITHDRAWN	Safety and Efficacy of the Extracorporeal Liver Assist Device (ELAD®) In Patients With Fulminant Hepatic Failure (FHF)
NCT01548690	PHASE2	COMPLETED	Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure/Severe Acute Liver Injury
NCT01690845	PHASE2	UNKNOWN	Molecular Adsorbent Recirculating System (MARS®) in Hypoxic Hepatitis
NCT01875874	PHASE2	TERMINATED	Safety and Efficacy of the ELAD System (ELAD) to Treat Acute Liver Failure (ALF)
NCT01937130	PHASE2	TERMINATED	Pharmacokinetic and Pharmacodynamic Study of IDN-6556 in ACLF
NCT03882346	PHASE2	UNKNOWN	Study to Evaluate Safety and Efficacy of LifeLiver in Acute or Acute-on-Chronic Liver Failure Patients
NCT05940610	PHASE1/PHASE2	WITHDRAWN	The Safety and Efficacy of MSC-EVs in Acute/Acute-on-Chronic Liver Failure
NCT03629015	PHASE1	WITHDRAWN	Safety Study of Stemchymal® in Acute Liver Failure
NCT06285253	PHASE1	COMPLETED	miroliverELAP® for the Treatment of Acute Liver Failure: A Phase 1 Trial
NCT02833064	Not specified	ACTIVE_NOT_RECRUITING	Biomarkers in Liver Failure
NCT05146336	Not specified	RECRUITING	CytOSorb TreatMent Of Critically Ill PatientS Registry
NCT05413083	Not specified	ACTIVE_NOT_RECRUITING	Evaluation of Cardiac Function in Acutely Decompensated Cirrhosis
NCT06515145	Not specified	NOT_YET_RECRUITING	High-volume Versus Standard Volume Plasma Exchange in Patients With Acute Liver Failure With Cerebral Edema
NCT06698991	Not specified	NOT_YET_RECRUITING	Daily Versus Alternate Day Plasma Exchange in Wilson Disease With Acute Liver Failure in Children
NCT06778941	Not specified	NOT_YET_RECRUITING	Etiology and Prognostic Analysis of Acute Liver Failure in Chinese Children
NCT06831643	Not specified	RECRUITING	Standard Volume vs. High Volume Plasma Exchange in Pediatric Acute Liver Failure
NCT06872372	Not specified	ACTIVE_NOT_RECRUITING	Role of N-Acetylcysteine in Non-Acetaminophen-Induced Acute Liver Failure
NCT06893042	Not specified	ENROLLING_BY_INVITATION	Clinical Study of Pediatric Acute Liver Failure
NCT06987604	Not specified	ENROLLING_BY_INVITATION	Continuous Renal Replacement Therapy Intensity in Hyperammonemia
NCT07131969	Not specified	NOT_YET_RECRUITING	Transcriptional Analysis of Mechanisms in Liver Failure and Sepsis
NCT07329036	Not specified	RECRUITING	ALSS - DPMAS and Therapeutic Plasma Exchange (TPE), Its Effect on Primary Coagulation, Inflammation and the Function of Vital Organs in ALF or ACLF
NCT07556055	Not specified	NOT_YET_RECRUITING	Etiology and Prognostic Factors in Patients With Acute Liver Failure
NCT07585890	Not specified	RECRUITING	Establishing a Reference Framework for Outcomes After Machine-Preserved Liver Transplantation in Europe
NCT00059267	Not specified	COMPLETED	Prevention of Recurrent Hepatitis B After Liver Transplantation
NCT00245310	Not specified	COMPLETED	Indocyangreen Elimination in Cirrhosis and Acute Liver Failure
NCT00282542	Not specified	WITHDRAWN	Hepatocyte Transplantation as a Life Support Bridge
NCT00518440	Not specified	COMPLETED	A Multi-Center Trial to Study Acute Liver Failure in Adults
NCT00655304	Not specified	COMPLETED	The Effect of Prometheus (R) Liver Support Dialysis on Cerebral Metabolism in Acute Liver Failure

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ACETYLCYSTEINE	4	3
MANNITOL	4	2
ADEFOVIR DIPIVOXIL	4	1
DIPHENHYDRAMINE	4	1
METHYLPREDNISOLONE	4	1
PREDNISOLONE	4	1
ORNITHINE	3	3
ASPARTIC ACID	3	1
ANTILYMPHOCYTE IMMUNOGLOBULIN (HORSE)	2	1
EMRICASAN	2	1
CHEMBL5435500	0	3
CHEMBL507900	0	1