Efficacy of zinc monotherapy in a Wilson’s disease adolescent with unusual renal onset: a case report and review of literature

Abstract

Background

Wilson’s disease (WD) is a rare genetic disorder of copper metabolism that typically presents with hepatic, ophthalmologic, neurological, or psychiatric symptoms. Signs of renal involvement usually do not dominate the initial clinical picture of WD. For this category of patients affected by WD, there is no clear indication for first-line treatment nor on which parameters to evaluate therapeutic efficacy.

Case presentation

A 17-year-old patient was referred to our clinic because of lower back pain and gross haematuria. The laboratory exams showed kidney function decline and renal proximal tubular dysfunction, likely due to Fanconi syndrome. Abdominal ultrasound revealed bilateral renal microlithiasis, hepatosplenomegaly and a multinodular hepatic echotexture despite normal liver enzyme levels. A thorough investigation ruled out infectious, autoimmune, neoplastic and haematological disorders. WD was suspected based on kidney injury complicated by Fanconi syndrome combined to signs of chronic liver disease. Serum ceruloplasmin was undetectable, and 24 h-urinary copper excretion was markedly elevated. Slit-lamp examination identified bilateral Kayser–Fleischer rings, and brain MRI revealed classical WD changes with only clinical evidence of mild hypomimia. The diagnosis of WD was genetically confirmed. Monotherapy with zinc acetate resulted in improvement in renal function and hypomimia and a reduction in urinary copper excretion over a 2-year follow-up period. From a hepatic and ophthalmological point of view, the patient remained stable with no signs of progression. Starting from the peculiarities of this case, a literature review was performed focusing on cases of WD with renal manifestations at onset and the behaviour of Kayser–Fleischer rings following pharmacological therapy.

Conclusions

A high index of clinical suspicion for WD is recommended in adolescents with unexplained renal impairment, including Fanconi syndrome, even in the absence of abnormal liver tests. A critical assessment of the patient’s outcome, based on the integration of multiple clinical, laboratory, and imaging parameters, showed that zinc monotherapy may represent a safe and effective first-line treatment in these patients.

Background

Wilson’s disease (WD) is an autosomal recessive disorder caused by mutations in the ATP7B gene, leading to impaired copper excretion with a wide spectrum of manifestations ranging from hepatic abnormalities to ophthalmologic, neurological and psychiatric symptoms [1–4]. The classic ophthalmological manifestation of WD is the Kayser-Fleischer (KF) ring [5], it is rarely observed in WD children with hepatic manifestations, while it is more common in neurological forms and in adults [6–8].

Renal involvement occurs in approximately 10–25% of WD patients and includes tubular dysfunction (e.g., proximal or distal renal tubular acidosis, aminoaciduria, glycosuria, proteinuria, hyperphosphaturia, hypercalciuria), nephrocalcinosis and nephrolithiasis [9, 10]. Severe renal manifestations are observed in WD patients with fulminant hepatic onset in which the accumulation of copper above a toxic threshold induces hepatocellular necrosis with subsequent release of the metal into circulation, resulting in kidney injury, neurological symptoms, and hemolysis [11]. When renal abnormalities are mild or nonspecific, diagnosis may be challenging.

There are no univocal therapeutic indications for the treatment of WD with prevalent renal involvement. Chelators are the first-line therapy for all forms of WD, with a few exceptions, including presymptomatic cases identified by screening, children with mild liver disease, and more recently neurological patients [12–14]. Specific guidance for WD patients with renal manifestations is lacking; in clinical practice, chelators, particularly D-penicillamine, tend to be preferred. These agents, especially D-penicillamine, have a potential nephrotoxicity that zinc does not [15–18]. The efficacy of pharmacological therapy in WD is established according to guidelines, but specific attention to nephrological manifestations are missing [5, 12–14]. It has been reported that the KF ring in patients with WD may disappear after treatment. Most of this information is reported with chelators [19, 20]. Corneal copper clearance likely follows a slower kinetic pattern than hepatic mobilization, making the KF ring a historical rather than dynamic marker of copper load.

In this case, we report the efficacy of zinc monotherapy in an adolescent with WD whose clinical onset was dominated by renal involvement. In addition to renal improvement, resolution of hypomimia was observed, which was the only overt neurological manifestation despite copper accumulation on neuroimaging. Liver and ophthalmological findings remained stable. Based on the peculiarities of this case, a literature review was conducted, focusing on cases with renal manifestations at the onset of WD and on ophthalmological changes during drug therapy.

Search strategy and selection criteria

In this narrative review, a systematic literature search was conducted in PubMed, Cochrane, and Google Scholar for all the literature published. The used keywords were “Wilson’s disease” and “Wilson disease” combined with additional terms including “zinc therapy”, “kidney injury”, “renal involvement” to identify relevant studies. The reference lists of the identified articles were also evaluated to verify their relevance for the purposes of our study. Articles in languages other than English, animal studies, and abstracts presented only in conference proceedings were excluded.

Case presentation

A 17-year-old South Asian male, born to consanguineous parents, was referred to our Pediatric Unit for macroscopic haematuria, lumbar pain, arthralgia and fatigue. Laboratory investigations revealed kidney injury (serum creatinine 1.59 mg/dl, estimated glomerular filtration rate-eGFR 65 ml/min/1.73 m² CKD-EPI), thrombocytopenia (50,000/µL) and leukopenia (3700/µL), hypovitaminosis D with parathyroid hormone in normal range and hypouricemia. Liver enzymes and coagulation parameters resulted within normal limits. The subsequent urinalysis showed mild proteinuria, hyperphosphaturia, glucosuria, albuminuria, and alkaline urine. Arterial blood gas analysis revealed non-anion gap metabolic acidosis. Autoimmune screening resulted negative, and bone mineral densitometry revealed normal bone mineralization compared to reference values for sex and age. These findings were strongly suggestive of Fanconi syndrome.

The family history was notable for the early death of a brother due to a suspected blood disorder. Physical examination revealed good general condition, a flat abdomen with hepatosplenomegaly. Nutritional status was adequate. Abdominal ultrasound confirmed hepatomegaly, revealing a multinodular echotexture, splenomegaly; kidneys presented normal volume and echogenicity and bilateral renal microlithiasis. Although liver enzymes were normal, based on splenomegaly with associated leuko-thrombocytopenia, portal hypertension was suspected. Esophagogastroduodenoscopy did not detect presence of esophageal varices. Further tests ruled out infectious, metabolic, autoimmune, biliary, neoplastic, and haematological disorders. No potentially toxic medications or substances had been taken.

WD was suspected due to the presence of unexplained kidney injury associated to renal tubulopathy combined to signs of chronic liver disease. Serum ceruloplasmin was undetectable (< 0.0243 g/L), and 24-hour urinary copper excretion (24 h-UCE) was markedly elevated (512.72 µg/day; normal values < 40 µg/day).

Slit-lamp examination revealed the presence of a bilateral KF ring, more evident inferiorly and temporally. On neurological examination, the patient presented mild hypomimia without other neurological symptoms. Brain MRI studies revealed bilateral T2/FLAIR hyperintensity in the globus pallidus, red nuclei, substantia nigra, dentate nuclei, and corticospinal tracts, consistent with WD. Transcranial magnetic stimulation, paired-pulse protocols, showed normal electrophysiological responses.

A Leipzig score of 8 confirmed the diagnosis of WD [21]. Given the presence of nephropathy and neurological involvement, treatment with oral zinc acetate (50 mg three times daily) was started. Chelators, which are potentially nephrotoxic and can cause a worsening of neurological symptoms in patients with WD, were not preferred.

Genetic testing revealed a homozygous pathogenic variant (c.813 C > A; p.Cys271*) in ATP7B gene, previously associated with early-onset multisystemic WD in South Asian populations [22].

During the subsequent 24 months of follow-up, a gradual improvement in renal function and tubular dysfunction was observed. Blood pressure remained normal. The patient continued zinc monotherapy along with vitamin D supplementation. Urinary copper excretion decreased to 93.3 µg/day with satisfactory adherence to therapy, except for the evaluation after 22 months of treatment in which the patient declared non-optimal adherence to zinc therapy with evidence of 24 h-UCE > 100 µg/day and concomitant increase in liver enzymes (Table 1).

Table 1.

Longitudinal biochemical course over 24 months showing renal stabilization and improved copper metabolism under zinc therapy

Parameter	At onset	2 months	5 months	8 months	12 months	14 months	20 months	22 months	24 months	Normal range
Creatinine, mg/dL	1.59	1.44	1.31	1.31	1.4	1.31	1.26	1.36	1.3	0.6–1.2
Cistatin C, mg/l	1.58	-	-	1.36	-	1.18	-	-	1.1	0.61–0.95
Albumin, g/dL	4.6	4.7	5.1	4.8	4.6	4.5	4.7	4.7	4.5	3.8–5.4
Uric acid, mg/dL		2.3	3.2	3.4	3.6	2.8	3.6	3.8	3.5	2.6-6.0
BUN, mg/dl	30	33	38	29	26	29	35	33	37	16.6–48.5
Ca, mg/dl	9.3	9.3	9.9	9.7	9.0	9.6	9.2	9.5	9.7	9–11
P, mg/dl	9.0	2.8	3.6	3.0	2.4	2.2	2.2	3.2	2.4	3.1-6
25-OH D, ng/ml				14			15.5		65.6
Hb, g/dl	13.0	13.3	13.5	14.4	14.2	13.3	14.5	13.9	13.1	11.5–14
Platelets (x 103/µL)	55	63	57	75	68	40	41	51	68	130–400
TB, mg/dL	0.47	0.40	0.39	0.52	0.41	0.59	0.45	0.42	0.21	0.2–1.2
DB, mg/dL	0.47	0.16	0.19	< 0.08	0.17	0.23	0.17	0.19	0.09	0-0.50
AST, IU/L	16	29	31	-	30	29	34	44	44	0–34
ALT, IU/L	15	38	53	-	36	37	65	92	68	0–55
ALP, IU/L	100	170	163	168	137	142	129	153	117	56–167
GGT, IU/L	15	9	13	11	9	10	14	17	12	9–36
CHE, IU/L		-	-	-	-	-	5553	5977	5509	5320–12,920
PT INR	1.15	1.13	1.17	1.16	1.14	1.17	1.11	1.11	1.08	0.8–1.20
24 h -UCE, µg/die	512.7	-	144.04	113.6	173.6	126	79.2	176	93.3	< 100 (target under zinc therapy)
24 h urinary zinc, µg/die		-		3534	6133	5485	4226	3685	5652	> 2000
Serum copper, µg/dL	45.1	-	17.1	37.7	21.7	13.6	11.8	14.1	25.8	35–75
Serum zinc, µg/dL		-	214.9	481	288.7	268.7	353.2	297.3	280.6	> 125
Ceruloplasmin, g/L	< 0.0231	< 0.0231	< 0.0231	< 0.0231	< 0.0243	< 0.0243	< 0.026	-	< 0.023	0.2–0.6
Proteinuria, mg/24 h	382	341	210	-	159	138	-	-	110	< 150
24 h-urinary calcium excretion, mg/24 h	499	-	210	208	-	-	160	-	140	0-300

Abbreviations: ALP, Alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, urea; Ca, serum calcium; CHE, cholinesterase; DB, direct bilirubin; GGT, gamma-glutamyl transferase; Hb, haemoglobin; P, serum phosphate; TB, total bilirubin; 24 h-UCE, 24-hour urinary copper excretion (< 40 µg/24 h represents the diagnostic threshold for Wilson’s disease, whereas < 100 µg/24 h indicates the target range under zinc therapy¹³), 25-OH D, 25-Hydroxyvitamin D

No adverse effects related to zinc treatment were observed, including clinical or laboratory signs of copper depletion.

Dual-energy X-ray absorptiometry (DEXA) scan of the lumbar spine (L2-L4) revealed a Z-score of -1.0, indicative of normal bone mineralization. Follow-up esophagogastroduodenoscopy confirmed the absence of esophageal varices, and serial FibroScan assessments demonstrated stable liver stiffness at 5.8 kPa. The hypomimia gradually resolved and no other neurological symptoms appeared over the months. Follow-up examinations at 6 months, one year and two years after treatment initiation confirmed the presence of KF ring, with no relevant change in intensity or extension (Fig. 1).

Fig. 1.

Kayser–Fleischer ring at two-year evaluation in a Wilson disease patient on zinc monotherapy. Slit-lamp photograph taken two years after diagnosis showing a stable peripheral brownish–greenish Kayser–Fleischer ring (black arrows), which remained unchanged over follow-up despite marked systemic improvement on zinc treatment

Serial Scheimpflug corneal densitometry, available from baseline and throughout follow-up, showed mild, non-directional fluctuations over time, without a consistent reduction in peripheral corneal density values (Table 2).

Table 2.

Serial corneal densitometry measurements from treatment initiation

Timepoint	Eye	2–6 mm	6–10 mm	10–12 mm
Baseline	OD	9.4	14.0	19.5
Baseline	OS	8.6	13.4	20.8
6 months	OD	9.8	13.9	20.0
6 months	OS	8.8	13.8	21.8
1 year	OD	9.5	14.2	20.8
1 year	OS	10.1	15.4	22.6
2 years	OD	10.8	15.6	21.5
2 years	OS	10.8	12.7	22.2

Screening of family members showed that the younger brother was also affected by WD, with genetic testing demonstrating the pathogenic ATP7B variant c.813 C > A – p.(Cys271*) in the homozygous state. In retrospective evaluation, the premature death of another brother at the age of 18, previously attributed to an undefined hematological disease, was considered likely related to undiagnosed WD with hypersplenism.

Discussion and conclusions

WD is clinically associated with hepatic, ophthalmologic, neurological and psychiatric symptoms, while renal manifestations usually do not dominate the clinical picture at presentation, except in fulminant cases where renal failure and red urine due to massive hemolysis are commonly found [4]. Furthermore, WD can remain clinically silent for a long time and manifest itself when the disease has already reached an advanced stage of copper accumulation in various organs. It is usually unpredictable in which organ WD will manifest clinically. In general, in WD copper deposition within the renal tubules can lead to a spectrum of abnormalities, including Fanconi syndrome, renal tubular acidosis, nephrocalcinosis and nephrolithiasis [23, 24]. This case is peculiar because the patient was recruited for macroscopic haematuria in the absence of overt hepatic or neurological symptoms that typically orient the diagnostic suspicion toward WD diagnosis. Along with gross haematuria, laboratory findings revealed renal tubular dysfunction consistent with Fanconi syndrome, likely secondary to copper-induced proximal tubular toxicity. Macroscopic haematuria has been rarely described in WD and mostly attributed to D-penicillamine therapy [15] or IgA nephropathy [24]. In our case, gross haematuria was explained with mechanical trauma to the urothelium caused by microliths, in the setting of an underlying copper-induced proximal tubulopathy. Spontaneous resolution of haematuria without immunosuppressive treatment further supported its mechanical aetiology related to urinary microlithiasis. The absence of systemic blood hypertension, stable renal function, and increased sodium urinary excretion over time supported a primarily tubular, rather than glomerular aetiology [1, 9].

The severity of tubular injury correlates with the degree of copper deposition, as confirmed by experimental models. Renal involvement in WD was first described by Litin in 1959, who identified hypercalciuria as a subclinical marker that may precede WD diagnosis by years [25] and contribute to stone formation, nephrolithiasis, nephrocalcinosis, and progressive renal damage. Combined calcium and phosphate wasting, together with poor nutritional status, may also lead to osteomalacia and increased fracture risk [26]. Recent literature indicates that nephrolithiasis may occur at or even before the diagnosis of WD, suggesting that early tubular copper toxicity promotes hypercalciuria and lithogenesis (Table 3).

Table 3.

Reported cases of Wilson Disease presenting with renal involvement

Author	Sex, Age (ys)	Renal Presentation	Other Organs at Onset	Diagnostic evidence for WD	Treatment	Outcome
Nakada et al., 1994 [27]	F, 17	Renal colic; distal ureteral stone	None initially. After 2 months, the patient developed jaundice; ascites; Fanconi syndrome	- Serum ceruloplasmin: 15 mg/dl - Serum copper: 308 µg /dl - Presence of KF rings - Genetic investigation: NA	D-Penicillamine	Fatal outcome secondary to liver failure
Kalra et al., 2004 [28]	F, 30	Renal colic; hypercalciuria; RTA	Abnormal LFTs; jaundice	-Serum ceruloplasmin: 16 mg/dl − 24 h–UCE: 340 µg/24 h - Serum copper: 16.4 µmol/l - Absence of KF rings - Genetic investigation: NA	D-penicillamine	Normalization of LFTs. Hypercalciuria persisted after 10 weeks of follow up
Palkar et al., 2011 [29]	Two sisters/ 15 and 13	Difficult in walking; rickets; distal RTA	Splenomegaly; signs of portal hypertension	-Serum ceruloplasmin: 12 and 15 mg/dl - Presence of KF rings in sibling - Genetic investigation: NA	D- Penicillamine plus zinc	Improvement in osteopaenia after 3 months
Di Stefano et al., 2012 [30]	M, 16	Hypercalciuria; nephrocalcinosis; polyuria/polydipsia	Hypertransaminasemia (ALT 81 IU/L, AST 47 IU/L)	-Serum ceruloplasmin: 4 mg/dl − 24 h- UCE: 113.4 µg/24 h - Copper’s content: 270 µg/g dry weight of liver - Absence of KF rings - Genetic investigation: mutation in homozygosis N1270S (belong to exon 18)	D-penicillamine	Resolution of hypercalciuria
Subrahmanyam et al., 2014 [31]	M, 16	Distal RTA; rickets; hypercalciuria; osteoporosis	Portal hypertension (splenomegaly, thrombocytopenia and grade I esophageal varices); gynecomastia; osteoporosis; KF rings	-Serum ceruloplasmin: 15 mg/dl - Presence of KF rings - Brain MRI: symmetrical pallidal hyperintensities on T1 - Genetic investigation: NA	Zinc acetate	After 8 months, subjective improvement in lower limb weakness
Azad et al.; 2018 [32]	M, 22	Distal RTA; rickets	Tremor on both hands; KF rings. Other systemic findings were normal.	-Serum ceruloplasmin: 30 mg/dl − 24 h-UCE: 1359.5 µg/24 h - Presence of KF rings - Genetic investigation: NA	D-penicillamine plus zinc acetate	Significant improvement in muscle weakness and tremor
Saiteja et al., 2024 [33]	F, 11	Distal RTA; severe rickets; hypercalciuria	KF rings Absence of liver and neurological symptoms	-Serum ceruloplasmin: 11 mg/dl − 24 h-UCE: 110 µg/24 h - Presence of KF rings - Genetic investigation: a homozygous single base pair deletion in exon 2 of the ATP7B gene	D-penicillamine plus zinc	Improved metabolic profile
Matti et al. 2024 [34]	F, adolescent	Proximal RTA with isolated phosphaturia; recurrent fractures;	History of jaundice; KF rings: splenomegaly; normal LFTs; RTA with phosphaturia Arterial blood gas showed hyperchloremic metabolic acidosis with an anion gap of 17.3	Fanconi-like pattern -Serum ceruloplasmin: 32 mg/dl -24 h-UCE: >650 µg/24 h -Abdominal ultrasound: hepatosplenomegaly and echotexture suggestive of cirrhotic changes	D-penicillamine plus zinc	Transient D-penicillamine–related dysarthria (resolved); progressive clinical and radiological improvement with normalization of bone density.
Gupta et al., 2025 [35]	M, 8	Nephrotic syndrome; edema; ascites	Splenomegaly, signs of portal hypertension. Abnormal LFTs: AST 233 IU/L, ALT 154 IU/L, GGT 262 IU/L, TB 2.9 mg/dl, DB 1.3 mg/dl, INR 2.7, albumin 2.4 g/dl) No neurological manifestations Presence of KF rings	-Serum ceruloplasmin: 9.88 mg/dl − 24 h-UCE: 536 µg/24 h - Presence of KF rings	D-Penicillamine plus zinc	After six weeks, ascites had reduced, and edema had improved.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; DB, direct bilirubin; F, female; GGT, gamma-glutamyl transferase; KF, Kayser-Fleischer; ys, years; LFTs, liver function; M, male; NA, not available; RTA, Renal tubular acidosis; TB, total bilirubin; 24 h-UCE, 24-hour urinary copper excretion; WD, Wilson disease

Nakada et al. reported a 17-year-old girl presenting with renal colic due to ureteral stones who subsequently developed Fanconi syndrome and progressive liver failure, eventually dying from hepatic decompensation [27]. Di Stefano et al. described a 16-year-old boy with hypercalciuria, nephrocalcinosis, and bone fragility, without neurological or ophthalmological signs, who responded to D-penicillamine [30]. Gupta et al. reported an 8-year-old boy presenting with nephrotic syndrome as the initial manifestation of WD, with clinical and biochemical improvement after treatment with D-penicillamine and zinc [35]. These cases were managed primarily with chelators alone or in combination with zinc; only a report of Subrahmanyam et al. described management with zinc monotherapy in an adolescent with renal tubular acidosis and bone disease [31]. However, these authors mainly reported subjective clinical improvement, whereas our case documents objective biochemical evidence of renal and metabolic recovery over longitudinal follow-up.

None of these cases provided detailed information on changes in renal parameters during follow-up and the specific impact on them of the drugs used for WD therapy. The optimal treatment for patients with predominant renal involvement has not yet been established. Although it can appear a deviation from current first-line recommendations based on international guidelines [5, 12–14], the choice of zinc monotherapy as induction therapy in this patient represents a personalized therapeutic choice determined by a patient-specific risk–benefit assessment in a field still matter of debate in the international literature as patients with neurological involvement and without clear recommendation regarding patients with kidney involment. Trientine is generally considered less nephrotoxic than D-penicillamine, and the risk of neurological worsening appears lower and less consistently reported. However, as a chelating agent capable of mobilizing tissue copper, it has been associated, albeit infrequently, with early neurological deterioration, particularly in patients with pre-existing neurological involvement [5, 14].

Zinc has been indicated by guidelines as possible first line of treatment for patients with neurological involvement [14, 36]. Given the presence in our patient of neurological manifestations and the coexistence of renal tubular dysfunction, we opted for zinc as an initial therapeutic strategy due to its more favourable neurological safety profile and its mechanism of action. Zinc therapy was initiated under close clinical and biochemical monitoring. The patient showed progressive neurological and biochemical improvement, and therefore treatment switch to chelators, including trientine, was not required. Most reported cases received chelators, but long-term efficacy data remain scarce. In contrast, our study provides a two-year longitudinal follow-up, documenting stable renal function, no progression of tubular dysfunction, and a progressive decline in 24 h-UCE under zinc monotherapy.

After initiating zinc acetate therapy, 24 h-UCE progressively decreased, coinciding with good adherence to therapy, reaching the desired range according to guidelines. Only in one occasion the 24 h-UCE exceeded 100 µg, related to poor adherence, with a concomitant slight increase in liver enzymes. Renal parameters showed improvement throughout the observation period, with resolution of glycosuria, calciuria, proteinuria, and phosphaturia. These findings strongly suggest that zinc effectively halted copper-induced tubular toxicity, and the high levels of urinary zinc, characteristic of WD therapy which aims to exceed 2000 µg daily, did not negatively impact tubular function. Based on this single case, it is not possible to draw conclusions regarding the potential nephrotoxicity or comparative efficacy of chelators in this setting. It cannot be excluded that even chelation therapy, preferably at a low initial dose, could have had a favourable impact on the patient’s clinical course, but it is a common observation that chelators, following initial copper mobilization, can cause a latent or worsening of the neurological symptoms of WD [37].

In our case, zinc monotherapy, in addition to achieving a gradual reduction in urinary copper excretion and a progressive improvement in renal function, resulted in resolution of mild hypomimia and a stabilization of the hepatic and ophthalmological findings. A limitation of this study is the absence of follow-up brain MRI, which prevents formal assessment of radiological evolution, even if in WD imaging abnormalities may persist despite clinical neurological improvement.

The absence of progression of liver disease was supported by the absence of varices on repeated endoscopy, the lack of liver function worsening, and the unchanged liver stiffness values (5.8 kPa). The discrepancy between a multinodular liver morphology on abdominal ultrasound and a low FibroScan value (5.8 kPa) may appear contradictory, but it has been well described [38]. Indeed, transient elastography is a valuable non-invasive tool, but low liver stiffness values ​​can be detected in heterogeneous or macronodular cirrhosis because only a limited volume of liver parenchyma is sampled. In line with EASL guidelines, liver stiffness measurements should be interpreted in the clinical and morphological context and do not exclude cirrhosis in the presence of signs of portal hypertension as in our patient [39].

Of interest is the stability of corneal copper deposition which showed only slight non-directional fluctuations on serial Scheimpflug densitometry, in line with the slow or absent regression of KF rings reported with zinc monotherapy [19, 40, 41]. The stability of ophthalmic copper accumulation in this case treated with zinc monotherapy does not appear to reproduce the reduction/disappearance of KF reported in WD patients successfully treated with chelators [20]. In this regard, some considerations must be made. The experience with chelators certainly involves a larger number of patients, even if there is a lack of sufficient data on how the reduction/disappearance of KF is associated with the modification of other clinical, laboratory and imaging parameters. The ability of the drugs used in WD (chelators or zinc) to deplete organs is not fully understood. Initially, it was believed that zinc, rather than depleting the liver of copper, promoted the binding of copper to metallothioneins in a non-toxic form. This concept could also be applied to the eye.

More recently, however, it has been reported that zinc, even more than chelators, can lead to a marked copper deficiency with consequent neurological and haematological damage. Data on KF changes in patients with copper deficiency are lacking. On the other hand, studies on liver biopsies of progressors and non-progressors treated with chelators have shown that copper content tends to remain stable over time [42]. Therefore, there does not appear to be a linear correlation between the clinical efficacy of drug therapies and measurable copper accumulation in various organs. This clinical case promotes an evaluation of treatment efficacy based on the integration of multiple parameters and not exclusively on quantitative copper levels or the persistence/disappearance of KF rings. In patients with WD undergoing zinc monotherapy, KF may remain stable despite an improvement in renal and neurological symptoms and a stable liver status. Further studies are desirable to confirm this interpretation and to clarify the most appropriate induction strategy in WD patients with concurrent renal and subtle neurological features.

Abbreviations

WD

Wilson’s disease

KF

Kayser-Fleisher ring

24 h-UCE

24 h-urinary copper excretion

DEXA

Dual-energy X-ray absorptiometry

Author contributions

Iorio R, Delle Cave V, Di Dato F and Iorio F performed the research and wrote the manuscript. Delle Cave V, Iorio F, Di Dato F, Iorio R, Capuano I, and Piscopo R reviewed and edited the manuscript for important intellectual content. All authors have read and approved the final manuscript.

Funding

None.

Data availability

All data generated or analyzed during this study are included in this published article. Additional information is available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This case report was conducted in accordance with the Declaration of Helsinki. No ethical approval was required. Written informed consent to participate was obtained from the patient.

Consent for publication

The patient, now of legal adult age, provided written informed consent for the publication of all clinical information and accompanying images included in this case report. A copy of the signed consent is available for review by the Editor.

Competing interests

The authors declare no competing interests.