Acute liver failure with hemolytic anemia in children with Wilson’s disease: Genotype-phenotype correlations?

Abstract

BACKGROUND 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. AIM To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia. METHODS 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. RESULTS 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%). CONCLUSION 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.

Nutritional Support in Acute Liver Failure

“…Thus, zinc deficiency is strictly linked to hepatic encephalopathy [ 50 ]. Conversely, patients with ALF derived from undiagnosed Wilson disease can present with copper-driven toxicity [ 51 ]. The hydration of individuals with ALF is important in terms of hemodynamic state stability.…”

Wilson’s Disease with Acute Hepatic Onset: How to Diagnose and Treat It

“…It seems reasonable to use zinc in combination with chelators, even if there are no univocal Once the diagnosis has been established, it is crucial to stage the liver disease severity and neurological involvement using the available scores. Patients with an NWI score ≥ 11 must be listed for liver transplantation, but in the meantime, supportive and specific therapy (chelators and zinc) must be started with close monitoring of the patient in order to verify if liver function gradually improves or whether there is a need for urgent liver transplantation [44]. In patients with an NWI score < 11, the chances that medical therapy will avoid liver transplantation are higher.…”

“…Therefore, a practical guide from the British Association for the Study of the Liver recommended that all patients with unexplained Coombs-negative hemolytic anemia and/or movement disorders [42] should be investigated for WD [43]. ALF-WD accompanied by hemolytic crisis is estimated to occur in 30% of children with ALF who require a liver transplant and in 60% of those with unfavorable evolution before transplantation [44].…”

Screening for Wilson’s disease in acute liver failure: A new scoring system in children

“…Coombs-negative hemolytic anemia is another feature of ALF caused by WD, and it can be observed in children with ALF-WD ( 11 , 12 , 20 , 26 ). In the classic case of ALF-WD, the sudden release of copper from the liver leads to high levels of non-ceruloplasmin-bound copper in plasma, resulting in excessive destruction of red blood cells, which further leads to intravascular hemolysis.…”