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Ann Indian Acad Neurol
Ann Indian Acad Neurol
AIAN
Ann Indian Acad Neurol
Annals of Indian Academy of Neurology
0972-2327
1998-3549
Wolters Kluwer - Medknow India

AIAN-27-460
10.4103/aian.aian_159_24
Letters to the Editor
Type 1 Renal Tubular Acidosis in Wilson’s Disease
Swain Abinash
Bhoi Sanjeev Kumar
Jha Menka
Samal Priyanka
Naik Suprava 1
Mishra Biswamohan
Pradhan Nikilesh
Saharia Gautom Kumar 2
Department of Neurology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
1 Department of Radiodiagnosis, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
2 Department of Biochemistry, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
Address for correspondence: Dr. Sanjeev Kumar Bhoi, Department of Neurology, All India Institute of Medical Sciences, Bhubaneswar - 751 019, Odisha, India. E-mail: sanjeev_bhoi@rediffmail.com
Jul-Aug 2024
01 8 2024
27 4 460462
05 3 2024
17 6 2024
21 6 2024
Copyright: © 2024 Annals of Indian Academy of Neurology
2024
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pmcDear Editor,

Wilson’s disease (WD) is characterized by the abnormal excretion of copper from the body. It results in excessive accumulation of copper in the liver, brain, and other organs.[1] Numerous case reports indicate that patients with WD display renal osteodystrophy as a result of type 1 renal tubular acidosis (RTA).[234] Hypercalciuria and nephrolithiasis have been described as the other characteristics of type 1 RTA.[567] In this case series, we intend to study the occurrence of occult type 1 RTA in WD by ammonium chloride test.

The study evaluated seven patients with WD. None of the patients showed symptoms of type 1 RTA, such as osteodystrophy, hypocalcemia, or renal stones. To confirm the occurrence of type 1 RTA, ammonium chloride challenge test was performed with the following procedure. Patients were advised to fast overnight. They were asked to take ammonium chloride powder 0.1 g/kg orally with breakfast at 9 am over 15 min. Urine and blood samples were collected at baseline, at 1 h, and thereafter every 2 h till 4 pm. The urine sample was sent for pH analysis and the blood sample for arterial blood gas (ABG) analysis. At least one specimen should show urine pH below 5.5 in a normal person. In type 1 RTA, the urine pH does not fall below 5.5. Type 1 RTA diagnosis is confirmed if the urine pH is not below 5.5, despite the presence of metabolic acidosis.

The ammonium chloride test showed that three out of seven patients (42%) could not acidify their urine to a pH level lower than 5.5 after receiving ammonium chloride, despite a drop in serum bicarbonate in ABG, which suggests type 1 RTA. Among these three patients, two were drug naive and one patient was an asymptomatic sibling. However, these three patients did not have typical symptoms of type 1 RTA or a urine pH above 5.5 at baseline, suggesting occult type 1 RTA. Table 1 provides a summary of the characteristics of seven patients, and Table 2 provides a summary of the findings of the study.

Table 1 Demography, clinical and radiological parameters of patients with Wilson’s disease (n=7)

Parameters	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6	Case 7	
Age (in years)/gender	14/F	11/F	17/F	19/F	15/F	14/M	21/M	
Age at onset (in years)	12	10	11	13	13 (age at diagnosis)	13	9	
Duration of illness	1 year	6 months	5 years	5 years	-	6 months	11 years	
Number of family members affected	1	1	2	2	2	0	0	
Siblings	Siblings			
Presentation	Neurologic	Hepatic	Neurologic	Neurologic	Asymptomatic	Neurologic	Neurologic	
Symptoms	Tremors, dystonia, seizure, decline in scholastic performance and cognition	Jaundice, abdominal swelling	Dystonia, psychiatric and cognitive decline, decrease in scholastic performance	Tremor, dystonia	Asymptomatic	Tremor, dystonia, decline in scholastic performance and cognition	Tremor, dystonia	
Seizure	Yes (generalized)	Absent	Absent	Absent	Absent	Absent	Absent	
Jaundice history	Yes	Yes	No	No	No	No	No	
Skeletal deformity	Knock knee (genu valgum)	Nil	Nil	Nil	Nil	Nil	Nil	
K-F ring	Present	Present	Present	Present	Present	Present	Present	
Serum ceruloplasmin (mg/dl) (20-60)	7.72	3.2	20	6.3	6.6	9	8.1	
24-h urinary copper excretion (μg/d) (3-50)	285	192	591	166	31.6	102.9	645	
MRI of the brain (T2/FLAIR hyperintensity)	Bilateral basal ganglia, thalamus, pons, midbrain, frontal WM, cerebellum	Bilateral basal ganglia	Bilateral basal ganglia, thalamus, pons, midbrain, frontal WM	Bilateral basal ganglia, thalami, pons, midbrain	Normal	Bilateral basal ganglia	Bilateral basal ganglia, thalami, pons, midbrain	
USG of the abdomen and pelvis	Hepatic parenchymal disease with diffuse nodularity, splenomegaly	CLD, splenomegaly, ascites	CLD, splenomegaly	Hepatic parenchymal disease with micronodularity, splenomegaly	Normal	CLD, splenomegaly, ascites	CLD, splenomegaly, ascites	
Serum calcium (ionized) (1-1.4) mmol/l	0.67	1.11	1.14	1.01	1.16	1.0	1.04	
Ammonium chloride test	Positive	Negative	Negative	Positive	Negative	Positive	Negative	
CLD=chronic liver disease, FLAIR=fluid attenuated inversion recovery, K-F=Kayser-Fleischer, MRI=magnetic resonance imaging, USG=ultrasonography, WM=white matter

Table 2 Clinical and laboratory parameters of patients with Wilson’s disease

Parameters	Values (n=7) (%)	
Mean age of onset (years)	11 (range 9-13)	
Male: female	2:5	
Family history	5 patients (71%)	
Movement disorder	5 patients (71%)	
K-F ring	7 patients (100%)	
Mean 24-h urine copper (μg/d)	287 (range 31-645)	
Mean serum ceruloplasmin (mg/dl)	8.7 (range 3-20)	
Positive ammonium chloride test	3 patients (42%)	
Abnormal MRI of the brain (T2/FLAIR hyperintensity)	
    Basal ganglia	6 patients (87%)	
    Thalamus	4 patients (57%)	
    Brainstem	4 patients (57%)	
    Frontal lobe	5 patients (71%)	
K-F=Kayser-Fleischer, FLAIR=fluid attenuated inversion recovery, MRI=magnetic resonance imaging

The mean age of onset of the disease in the present series is comparable to the ages at which the disease first appeared in eastern India[8] and Turkey.[9] However, additional series of studies from Great Britain[10] and Central India[11] have recorded a later age of onset for the condition. The mechanism of type 1 RTA in WD can be explained by typical copper excretion abnormality. Copper is released from the kidney in a bound state to metallothionein (MT) during the process of glomerular filtration. Copper transporter 1 (CTR1), a ubiquitous copper transporter, is located on the luminal surface of kidney cells (proximal convoluted tubules).[12] It reabsorbs the Cu–MT complex that has been expelled. Within the tubular epithelium, the Cu–MT complex is ingested by the lysosome and subsequently destroyed. Copper and MT are both liberated after the Cu–MT complex is broken down. The tubular epithelium is sensitive to the toxicity of both free MT and free Cu. The presence of free copper causes oxidative damage and stimulates the production of further MT, resulting in a vicious cycle. It causes several different types of renal impairment, including RTA type 1. Copper is reabsorbed in the kidney into the bloodstream by ATPases like ATP7A and ATP7B. There is still some confusion over the precise cellular expression of any particular protein in humans. However, both ATP7A and ATP7B of the murine species are expressed in the glomeruli, but only ATP7B is found in the medulla.[13] In response to the concentration of copper in the tubule, kidney cells undergo a process known as intracellular trafficking of ATP7B and ATP7A. Within the cells, ATP7B may play a role in the redistribution of excess copper into vesicles. So, in the absence of ATP7A and ATP7B, copper accumulates in the kidney. This could help explain, at least in part, why patients with WD have a higher concentration of copper in their intrarenal tubules. Copper reabsorption in the loops of Henle requires the involvement of ATP7A and ATP7B. WD is characterized by an inability to produce ATP7B, which results in an abnormal redistribution of copper inside the cells. In addition, it increases the toxicity of copper. All these methods can create type 1 RTA in patients with WD, which is caused by an accumulation of extra MT that is released from the liver and finds its way into kidney cells. Type 1 RTA can cause osteodystrophy and renal stones.[14] One patient in our cohort was asymptomatic at the time of the diagnosis of WD. He was screened because his brother had WD. In conclusion, type 1 RTA can precede the classical presentation of WD, and complications of type 1 RTA, like renal osteodystrophy and nephrolithiasis, can be prevented by screening the urine pH with ammonium chloride test. However, a larger study is needed before using this test as a regular practice.

Informed consent

Written informed consent was obtained from all the participants/or legal guardians for this study.

Financial support and sponsorship

AIIMS Bhubaneswar intramural research grant was received (Rs. 131,000/- for biochemical estimation).

Conflicts of interest

There are no conflicts of interest.

Acknowledgement

We thank Miss. Pritimayee Behera for the secretarial help.
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