• Adherence
• Diagnosis
• Monitoring
• Treatment
• Wilson disease

• Hepatolenticular Degeneration/surgery
• Hepatolenticular Degeneration/diagnosis
• Liver Transplantation/standards
• Liver Transplantation/adverse effects
• Liver Transplantation/methods
• Humans
• Copper
• End Stage Liver Disease/surgery
• End Stage Liver Disease/mortality
• End Stage Liver Disease/diagnosis
• Treatment Outcome
• Patient Selection
• Waiting Lists/mortality
• Liver Failure, Acute/surgery
• Liver Failure, Acute/diagnosis
• Liver Failure, Acute/etiology
• Liver Failure, Acute/mortality
• Liver Cirrhosis/surgery
• Liver Cirrhosis/complications
• Liver Cirrhosis/diagnosis

• Humans
• Chemical and Drug Induced Liver Injury/diagnosis
• Chemical and Drug Induced Liver Injury/etiology
• Antineoplastic Agents/adverse effects
• Clinical Trials as Topic
• Neoplasms/drug therapy
• Practice Guidelines as Topic
• Liver Function Tests/methods

• acute hepatitis
• acute liver failure
• ceruloplasmin
• copper
• liver transplantation

• Humans
• Hepatolenticular Degeneration/diagnosis
• Hepatolenticular Degeneration/therapy
• Hepatolenticular Degeneration/complications
• Copper

• blood routine examination
• hepatolenticular degeneration
• liver cirrhosis
• machine learning
• wilson disease

The goal of the present work is to provide an overview of the differential diagnosis of Wilson disease.

Wilson disease is a rare condition due to copper accumulation primarily in the liver and brain. Although there is no definitive cure, current anti-copper treatments are associated with better outcomes if initiated early and if the diagnosis is made promptly. However, diagnostic delays are frequent and often Wilson disease represents a diagnostic challenge. The diagnosis ultimately relies on a combination of clinical, laboratory and genetic findings, and it is crucial that clinicians list Wilson disease in their differential diagnosis, especially in patients presenting with a hepatocellular pattern of liver injury. Some biochemical and liver histological features of Wilson disease overlap with those of more common conditions including nonalcoholic fatty liver disease, alcohol-associated liver disease, and autoimmune hepatitis. In particular, hepatic steatosis, hepatocyte glycogenated nuclei, ballooning degeneration, and Mallory-Denk bodies are often identified in Wilson disease as well as more common liver diseases. In addition, the natural history of liver damage in Wilson disease and the risk of developing liver cancer are largely understudied.

We conducted an enlarged review of published papers on Wilson disease focusing on its diagnosis and distinctive clinical and liver pathology features in relation to common non-cholestatic liver diseases with the final goal in aiding clinicians in the diagnostic process of this rare but treatable condition.

Aside from markedly altered copper metabolism, Wilson disease has essentially no pathognomonic features that can distinguish it from more common liver diseases. Clinicians should be aware of this challenge and consider Wilson disease in patients presenting with a hepatocellular pattern of liver injury.

• Wilson disease (WD)
• copper
• diagnosis
• fatty liver
• histology

Wilson’s disease (WD) is a rare autosomal recessive inherited disorder of copper metabolism. Acute liver failure (ALF) and hemolytic anemia represent the most severe presentation of WD in children. No clear genotype-phenotype correlations exist in WD. Protein-truncating nonsense, frame-shift, or splice-site variants may be associated with more severe disease. In contrast, missense variants may be associated with late-onset, less severe disease, and more neurological manifestations. Recently, a gene variant (HSD17B13:TA, rs72613567) with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD.

To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia.

The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed. The clinical manifestations (ALF with non-immune hemolytic anemia or other less severe forms), laboratory parameters, copper metabolism, ATP7B variants, and the HSD17B13:TA (rs72613567) variant were reviewed to analyze the possible genotype-phenotype correlations.

We analyzed the data of 51 patients with WD, 26 females (50.98%), with the mean age at the diagnosis of 12.36 ± 3.74 years. ALF and Coombs-negative hemolytic anemia was present in 8 children (15.67%), all adolescent girls. The Kayser-Fleisher ring was present in 9 children (17.65%). The most frequent variants of the ATP7B gene were p.His1069Gln (c.3207A>G) in 38.24% of all alleles, p.Gly1341Asp (c.4021G>A) in 26.47%, p.Trp939Cys (c.2817G>T) in 9.80%, and p.Lys844Ter (c.2530A>T) in 4.90%. In ALF with hemolytic anemia, p.Trp939Cys (c.2817G>T) and p.Lys844Ter (c.2530A>T) variants were more frequent than in other less severe forms, in which p.His1069Gln (c.3207A>G) was more frequent. p.Gly1341Asp (c.4021G>A) has a similar frequency in all hepatic forms. For 33 of the patients, the HSD17B13 genotype was evaluated. The overall HSD17B13:TA allele frequency was 24.24%. Its frequency was higher in patients with less severe liver disease (26.92%) than those with ALF and hemolytic anemia (14.28%).

It remains challenging to prove a genotype-phenotype correlation in WD patients. In children with ALF and hemolytic anemia, the missense variants other than p.His1069Gln (c.3207A>G) and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants. As genetic analysis is usually time-consuming and the results are late, the importance at the onset of the ALF is questionable. If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease, this could be essential to predict a possible severe evolution.

• Wilson’s disease
• Children
• Acute liver failure
• Hemolytic anemia
• ATP7B variant
• Genotype-phenotype correlation

• Acetamides/administration & dosage
• Acetamides/analysis
• Administration, Oral
• Adolescent
• Adult
• Aged
• Breath Tests/methods
• Carbon Isotopes
• Chemical and Drug Induced Liver Injury/diagnosis
• Chemical and Drug Induced Liver Injury/etiology
• Chemical and Drug Induced Liver Injury/mortality
• Chemical and Drug Induced Liver Injury/surgery
• Clinical Decision-Making/methods
• Disease Progression
• End Stage Liver Disease/epidemiology
• End Stage Liver Disease/pathology
• End Stage Liver Disease/surgery
• Feasibility Studies
• Female
• Humans
• Liver Failure, Acute/diagnosis
• Liver Failure, Acute/mortality
• Liver Failure, Acute/pathology
• Liver Failure, Acute/surgery
• Liver Transplantation
• Male
• Middle Aged
• Point-of-Care Testing
• Prognosis
• ROC Curve
• Risk Assessment/methods
• Risk Assessment/statistics & numerical data
• Severity of Illness Index
• Young Adult

• R01 DK058369 NIDDK NIH HHS
• U01 DK058369 NIDDK NIH HHS

• Acute liver failure
• acute liver injury
• adverse drug reactions
• drug induced liver injury
• safety treatment liver disease

• ATP7B
• Ceruloplasmin
• Chelator
• Copper
• Liver disease
• Wilson´s disease