Dear Editor,
We read with great interest the recent review on acute-on-chronic liver failure (ACLF), which comprehensively described its clinical features, pathogenesis, and therapeutic strategies, including plasmapheresis [
1]. The article emphasized the role of systemic inflammation and cytokine storm in the progression of ACLF. Plasmapheresis was highlighted as a therapeutic option capable of removing triggers of hyper-immune activation and circulating cytokines, underscoring its potential as a disease-modifying treatment. Nevertheless, its impact on transplant-free survival remains controversial, and it is still primarily regarded as a bridging therapy to liver transplantation (LT) [
1,
2]. A similar therapeutic consideration applies to Wilson’s disease (WD), an autosomal recessive disorder caused by mutations in the
ATP7B gene, leading to impaired copper excretion and toxic copper accumulation in multiple organs, including the liver [
3,
4]. Unless LT is performed, patients with WD require lifelong monitoring mainly to assess liver and neurological involvement.
As highlighted in the WD guideline, anti-copper therapy with zinc, D-penicillamine, or trientine is considered initially [
5]. When first-line treatment is insufficient and acute liver failure (ALF) develops, LT should be considered. Plasmapheresis may serve as a bridging therapy to LT in patients with persistent copper overload and ALF [
6,
7]. Plasmapheresis is also recommended as a rescue therapy in patients unresponsive to pharmacological treatment [
8], but its long-term efficacy remains uncertain. Therefore, the guidelines recommend subsequent LT despite improvement after plasmapheresis.
Here, we report a case of a WD patient with ALF that showed sustained clinical improvement after plasmapheresis, without undergoing LT. A 44-year-old man from Korea presented to the emergency room with jaundice and neurological symptoms including tremor, dysarthria, and gait disturbance. Laboratory tests revealed low serum ceruloplasmin (8.6 mg/dL) and markedly elevated 24-hour urinary copper (6,351 μg/day). Radiologic examinations demonstrated advanced liver cirrhosis, bilateral symmetric lesions involving the basal ganglia, and severe diffuse cortical atrophy. Genetic testing confirmed the diagnosis of WD with a homozygous ATP7B mutation in exon 18 (c.3809A>G [N1270S]). At presentation, the patient had ALF with elevated total bilirubin (17.42 mg/dL), prolonged international normalized ratio (INR, 1.64), and decreased albumin (3.4 g/dL). He had no other underlying disease, no history of alcohol use, and preserved renal function, and was enlisted for LT.
On hospital day (HD) 3, the patient showed significant aggravation of ALF, with a further rise in total bilirubin (20.11 mg/dL), ammonia (123 mcg/dL), prolongation of INR (1.80) and decrease in albumin (2.5 g/dL). Plasmapheresis was immediately initiated and performed for three consecutive days, during which liver function improved, with a decrease in total bilirubin (8.22 mg/dL), and INR (1.59). After a 1-day interruption, liver function again deteriorated, with a re-increase in total bilirubin (11.41 mg/dL) and INR (1.65); therefore, plasmapheresis was restarted for two more days. Following this, liver function recovered and remained stable (albumin, 3.3 g/dL; ammonia, 101 mcg/dL), and the patient was started on D-penicillamine. On HD 15, the patient was discharged and showed further improvement in outpatient visit 20-days after discharge (albumin, 3.2 g/dL; ammonia, 49 mcg/dL). Serial changes in bilirubin and INR are depicted in
Figure 1A.
During the episode of ALF, the patient’s white blood cell (WBC) count rose from 5.0 ×10
9/L at pre-admission to 12.6×10
9/L by HD 3 suggesting an active inflammatory or immune-mediated process contributing to liver failure. Therefore, cytokines known to play a role in tissue inflammation and immune-mediated liver injury were selected for measurement [
9-
12]: interleukin (IL)-6, secreted predominantly by activated macrophages, promoting immune activation and inflammation; IL-2, produced mainly by activated T cells, promoting T-cell proliferation and cytotoxic activity; IL-12, stimulating T cells and natural killer (NK) cells to enhance cytotoxic activity; interferon-gamma, secreted by cytotoxic T cells and NK cells, contributing to hepa- tocyte injury; IL-17, derived from T helper 17 (Th17) cells, promoting tissue inflammation and neutrophil recruitment; tumor necrosis factor-alpha (TNF-α), secreted by macrophages and T cells, mediating hepatocellular injury and systemic inflammatory responses; IL-10, an immunomodulatory cytokine. Serial measurements of selected cytokines revealed marked initial elevations of IL-12, IL-6, IL-10, and TNF-α. Plasmapheresis effectively reduced these cytokines, with the most pronounced decrease observed in IL-12, which declined to 8.3% of baseline after 3 days of plasmapheresis. At the same day, the WBC count was also normalized to 8.0×10
9/L. These reductions of cytokines and WBC count were maintained after discharge, and the cytokine kinetics closely paralleled the course of ALF. Similarly, serial measurements of 24-hour urinary copper demonstrated improvement after 5 days of plasmapheresis and showed a marked decline over the subsequent course. Serial changes in cytokine levels and urinary copper are depicted in
Figure 1B.
The patient’s peripheral blood mononuclear cell (PBMC) was obtained at HD 3 (ALF) and HD 10 (convalescent phase) and single-cell RNA sequencing (scRNA-seq) was performed. After preprocessing (Scanpy v1.9.8) and batch correction (Harmonypy v0.0.6), the cells were projected in uniform manifold approximation and projection (UMAP) and the cell types were annotated using Celltypist (v1.7.1) and canonical marker genes (
Fig. 1C). To investigate cell-level differences according to disease status, the composition of PBMC subsets were examined. Notably, in ALF, classical monocytes, non-classical monocytes, and type 2 conventional dendritic cells (cDC2) were markedly expanded with monocytes being dominant. These subtypes were almost depleted during the convalescent phase. In contrast, NK cells, T cells, and B cell subtypes showed comparable proportions between the two conditions (
Fig. 1D). Consistently, cytokines elevated in peripheral blood during ALF were found to be highly expressed in monocytes (
Fig. 1E). To validate these findings at the protein level, we performed flow cytometry, which revealed a significant increase in CD14
+ HLA-DR
+ monocytes during ALF (
Fig. 1F). Furthermore, additional gating for CD80 expression demonstrated that the proportion of activated CD80
+ monocytes was markedly higher during ALF compared with the convalescent phase, consistent with previous studies reporting that copper activates monocytes and inflammation [
13].
This case highlights that plasmapheresis followed by anti-copper therapy, may be considered as an effective therapeutic option in WD-associated ALF accompanied by marked leukocytosis. The patient showed rapid clinical improvement after plasmapheresis, with sustained recovery of liver function without transplantation. Cytokine profiling, scRNA-seq, and flow cytometry demonstrated that activated monocytes play a central role in the immunopathogenesis of ALF in WD, with plasmapheresis potentially contributing to the reduction of key mediators involved in this process. While current guidelines emphasize LT as the ultimate curative treatment, this case suggests that in selected patients presenting with WD-ALF and prominent leukocytosis, an adequate course of plasmapheresis may provide durable clinical benefit. Although a single case cannot confirm the therapeutic efficacy or mechanism of plasmapheresis in WD-associated ALF, clinicians should remain aware of this potential option. Further studies are warranted to elucidate the underlying pathophysiology and to identify patient subgroups most likely to benefit, particularly in relation to specific immune cell populations and cytokine drivers highlighted in this study.
Clinical information and laboratory test results were obtained through review of the hospital electronic medical records. Cytokine levels were measured in parallel with routine laboratory tests during the patient’s hospitalization. For research purposes, additional sampling of PBMCs was performed to conduct scRNA-seq and flow cytometry analyses. The study protocol was approved by the Institutional Review Board of Seoul St. Mary’s Hospital (approval No. KC25TISI0662), and written informed consent was obtained from the patient.
FOOTNOTES
-
Authors’ contribution
Pil Soo Sung contributed to clinical patient care, the concept, revision of the letter, and approved the final version of this manuscript.
Kwon Yong Tak contributed to the drafting, revision of the letter, single-cell RNA-seq analysis, and clinical patient care.
Min Seo Park contributed to patient’s sample management, data production, and flow cytometry analysis.
-
Acknowledgements
This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (Ministry of Science and ICT) (No. RS-2024-00337298).
-
Conflicts of Interest
The authors have no conflict of interest to disclose.
Figure 1.Clinical course and profiling of blood cells in a patient with Wilson’s disease. (A) Serial changes in blood laboratory tests showing improved liver function after plasmapheresis. Plots show total bilirubin, direct bilirubin, and international normalized ratio (INR) across the clinical course. Shaded areas indicate periods of plasmapheresis; arrows denote admission and discharge. (B) Serial changes of blood cytokine levels and 24-hour urinary copper. Shaded areas indicate plasmapheresis. (C-E) scRNA-seq analysis of PBMC from acute liver phase (ALF) and convalescent phase. (C) Processed scRNA-seq data illustrating condition-wise differences and cell type clusters. Left, UMAP visualization colored by condition. Middle, UMAP visualization annotated by cell type clusters. Right, dot plot of representative marker genes defining each subtype. (D) Comparison of cell type proportions between ALF and convalescent phase. (E) Expression of cytokine-related genes by cell type. Cell types dominant in ALF exhibit higher expression of these genes. (F) Flow cytometry gating of monocytes (CD14+ HLA-DR+) and subsequent assessment of CD80 expression at ALF and convalescent phase. Corresponding bar plots show proportions of monocytes among live cells (top) and CD80+ cells among monocytes (bottom). IL, interleukin; IFN-γ, interferon-gamma; TNF-α, tumor necrosis factor-alpha; HD, hospital day; PDD, postdischarge day; UMAP, uniform manifold approximation and projection; DC, dendritic cell; NK cells, natural killer cells; MAIT, mucosal-associated invariant T cell; Tcm, central memory T cell; Tem, effector memory T cell; HSC, hematopoietic stem cell; MPP, monocyte plasmapheresis phase; MO, monocyte; HLA-DR, human leukocyte antigen-DR; CP, convalescent phase; scRNA-seq, single-cell RNA sequencing; PBMC, peripheral blood mononuclear cell.
Abbreviations
acute-on-chronic liver failure
type 2 conventional dendritic cells
international normalized ratio
peripheral blood mononuclear cell
single-cell RNA sequencing
tumor necrosis factor-alpha
uniform manifold approximation and projection
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