Metabolic bone disease heralding the diagnosis of Wilson’s disease

Abstract

We report a short-statured, young man in his 20s presenting with bilateral cataract, recurrent kidney stones, history of refractory rickets and bone deformity. He had been consuming calcium and vitamin D supplements and had been operated for cataract and renal stone disease, prior to reporting in our clinic without any significant laboratory or clinical improvement. The patient was diagnosed as having Fanconi’s syndrome attributable to Wilson’s disease. This patient highlights that in case of resistant rickets, a high index of suspicion must be invoked for Wilson’s disease. Timely recognition of this entity results in prompt ministrations and prevention of disability.

Background

Wilson’s disease (WD) is a rare disorder of copper metabolism due to autosomal recessive mutation of ATP7B gene on chromosome 13q14-21.¹ This gene codes for a copper-transporting ATPase (Cu(2þ)-transporting beta polypeptide, ATP7B). This protein is expressed mainly in the hepatocyte and is responsible for the incorporation of copper in serum ceruloplasmin (the main copper transport protein) and also its elimination in bile. The loss of function of this gene causes a toxic accumulation of copper in the hepatocyte and neurological damage.² So, patients primarily present with neurologic or hepatic symptoms. Less common manifestations are renal calculi, haemolytic anaemia, ocular signs (bilateral cataracts and Kayser-Fleischer (KF) ring) and bone pathologies.^3–5 Renal involvement is in the form of renal tubular defects (renal tubular acidosis (RTA) types 1 and 2 or Fanconi’s syndrome).^{5 6} The musculoskeletal manifestations may vary from calf pain, arthropathy to refractory osteomalacia, osteoporosis and recurrent fractures.⁷ Here, we report an interesting case of metabolic bone disease leading to the diagnosis of Wilsons’s disease.

Case presentation

A young man in his 20s born out of non-consanguineous marriage had presented with deformity of right leg that was noticed after a traumatic fracture of right femur. The fracture was sustained 2 years back after fall from bicycle. It was managed with internal fixation and the implant (intramedullary nail) was removed 1 year later, following which he sustained fragility fracture at the same site in right femur. Hence, redo fixation was done and the nail was left in-situ permanently. This deformity was associated with difficulty in walking and pain but there was no muscle weakness. He had significant history of decreased vision for which he underwent bilateral cataract surgery 1 year back. During preoperative evaluation, he was also found to have bilateral nephrolithiasis with shrunken right kidney and gross left hydroureteronephrosis. Nephrolithiasis was managed with ureteroscopic stone removal and a double J (DJ) stent was placed. He also had intermittent knee arthralgia requiring analgesics. At 8 years of age, he developed prolonged jaundice (3 months) which gradually resolved with conservative treatment. He was a developmentally normal child with no history of delayed dentition, dental abcesses, failure to thrive or poor scholastic performance. He had adequate calcium intake and sunlight exposure. There was no history of recurrent pain abdomen or loose stools. No family history of pathologic fractures was noted. On examination; his height was 158 cm (height SD score=−2.6), Body MAss Index=24.4 kg/m². He had bilateral KF ring and bilateral pseudophakia. There was right genu varus deformity, depressed posterior fontanelle, lumbar scoliosis to the left (figure 1).

Figure 1.

(A) Genu varus deformity of the right leg. (B) Radiographs showing rarified bones with thin cortices, (C) provisional lines of calcification, (D) scoliosis, left side renal stones, (D) right femur with implant in situ and (F) skull with depressed posterior fontanelle.

Investigations

On investigations, he had mild transaminitis and deranged renal function test. Serum calcium and 25 (OH) vitamin D levels were normal, potassium and phosphate were low, parathormone and total alkaline phosphatase were elevated (table 1). There was glucosuria on 24 hours urinary examination but no hypercalciuria (Table 2). TmP/GFR was low (0.98 mg/dL) suggestive of phosphaturia. Arterial blood gas analysis showed non-anion gap metabolic acidosis (pH=7.26, HCO₃=8.9, anion gap=12). Ultrasound abdomen revealed coarsened hepatic echotexture and multiple left renal calculi (9 mm) in pelvi-calyceal system with DJ stent in situ. Transient elastography (Fibroscan) showed increased liver stiffness (LSM=15.4 kPa, IQR=1.8kPa, CAP=238dB/m). Densitometry revealed decreased bone mineral density (BMD) at lumbar spine (BMD=0.731 g/cm², Z score=−3) and neck of femur (BMD=0.419 g/cm², Z score=−4). Radiographs showed lucency at metaphyseal ends of long bones with provisional lines of calcification (figure 1). CEMRI brain was normal. In view of non-anion gap metabolic acidosis with glucosuria, urine pH (7.0), hypophosphatemia and MBD, a possibility of RTA was considered. Presence of jaundice, transaminitis, coarsened liver echotexture, bilateral KF ring, cataract pointed to WD as an aetiology for RTA. Serum ceruloplasmin was normal and 24 hour urinary copper levels were >40 µg (table 2). Due to high suspicion, liver biopsy was performed for copper content, which confirmed the diagnosis of WD. Genetic analysis could not be done due to financial constraints.

Table 1.

Baseline biochemical parameters

Parameter	Value	Reference range
Haemoglobin (g/L)	12.8	12.0–16.0
TLC (total leucocyte count) (x109/L)	5100	4.0–11.0
Platelets (x109/L)	145 000	150–450
Serum sodium/potassium (Meq/L)	140/3.1	135–145/3.5–5
RFT (urea/creatinine) (mg/dL)	26/2.33	10–50/0.5–1.2
T. protein/albumin (g/dL)	7.70/4.47	6.4–8.3/3.4–4.8
AST/ALT (units/L)	55/64.4	2–40
Total/conjugated bilirubin (mg/dL)	0.74/0.37	0.2–1.2/0–0.3
Alkaline phosphatase (U/L)	649	42–128
GGT	12
Calcium (mg/dL)	9.1	8.6–10.2
Phosphate (mg/dL)	2.5	2.5–4.5
Albumin (g/dL)	4.1	3.5–5
Alkaline phosphatase U/L	649	40–129
25 (OH)Vitamin D (ng/mL)	45	30–100
Parathormone (iPTH) (pg/mL)	242	15–65

Table 2.

24 hours urinary profile of patient

Calcium (50–300) mg/TV	172.5
Phosphate (400–1300) mg/TV	511.5
Glucose	+++
Fractional excretion of copper (FePO4) (<50 µg/dL)	0.577

Table 3.

Copper metabolism parameters

Serum ceruloplasmin (22–58) µg/dL	32.1
24 hours urine copper (3–40) µg	44.52
Liver dry weight copper (<45 µg/g)	262

Treatment

He was advised low copper diet and was initiated on oral zinc, sodium bicarbonate, cholecalciferol, calcium and active vitamin D supplementation. Potassium replacement was also needed initially but not later on due to underlying chronic kidney disease (CKD.

Outcome and follow-up

Post 2 years of management, transaminitis has resolved and BMD has improved (Lumbar spine BMD=0.895, Z score=−1.6; neck of femur BMD=0.526, Z score=−3.5).

Discussion

Here, we present a young man with WD, presenting as rickets due to RTA. The index patient had been symptomatic since long but it was only during evaluation for rickets/osteomalacia that he was diagnosed to have RTA secondary to WD. MBD is known in WD but it is rare for a patient to present primarily with skeletal involvement. Cavallino et al reported a 12-year-old man who was being managed as vitamin D resistant rickets since 8 years of age. Detailed neurological evaluation revealed subtle neurological signs and on further evaluation, he was diagnosed to have WD.⁸ Shin reported a 25-year-old man who had recurrent fractures, low BMD and mild transaminitis. He was observed to have WD on evaluation for osteopenia, work-up did not reveal any RTA or neurologic involvement.⁹ Indians tend to have higher predeliction for rickets, especially as a presenting manifestation of WD, in the absence of hepatic or CNS manifestation.^10–17 Wadia et al first drew attention in this regard and observed that rickets could be the striking manifestations of WD.¹⁰ A case of 12-year-old girl who had progressive genu valgum in the absence of any CNS/hepatic manifestations and was subsequently found to have renal rickets due to RTA secondary to WD was recently reported.¹¹ Another reported case was of 13‐year‐old boy with knock‐knee deformity, which progressed over 8 years without any other manifestations. He was diagnosed to have RTA secondary to WD.¹² Palkar et al reported a case of two sisters presenting with progressive bowing of legs, humerus fracture in the elder one; who were found to have RTA secondary to WD. Both had coarsened hepatic echotexture, but neither had CNS manifestations.¹³

The spectrum of MBD in WD is wide; including rickets, osteomalacia, osteoporosis, spontaneous fractures, osteoarthritis, osteochondritis dessicans and chondrocalcinosis.^{7 17} The main characteristic of MBD is bone demineralisation, reported in 24%–88% of the patients.^{7 18 19}Radiologic skeletal case series have reported osteomalacia in 14%–35%.^20–22 When evaluated by densitometry (DEXA); the prevalence of low bone mass was 43% in adult cohort (mean age 30 years) and 67.7% in paediatric cohort (mean age 9 years).^{23 24} Fractures have been reported in 7%–35% patients.²⁵ No specific fracture site or triggering mechanism has been described and the fractures heal without any complication. Spinal radiological abnormalities, especially osteochondritis, lumbar osteoarthritis and squaring of vertebrae have been occasionally reported in radiological case-series. Dorsolumbar scoliosis has also been described in seven out of 32 studied patients.⁷ Articular symptoms (monarthritis, polyarthritis and arthralgia) are usually spontaneous or of mechanical type, affecting mainly the large joints, especially the knees (16%–77% depending on the series, mean 33%).^{17 26}

Pathogenesis of MBD is multifactorial. RTA leads to hypercalciuria, phosphaturia and systemic acidosis, leading to impaired mineralisation and increased resorption. Additionally, direct effect of copper has been reported. In vitro studies on chick embryo found that copper levels between 5 and 20 mg/mL lead to interrupted osteoblastogenesis and reduced thickness of bone matrix.²⁷ Hepatic failure due to cirrhosis and poor dietary intake as a result of neurological disease could also contribute to the same.²⁸The index patient had evidence of both proximal RTA (glucosuria, hypophosphatemia) and distal RTA (nephrolithiasis), leading to rickets—osteomalacia and bilateral renal stones. Nephrolithiasis has been reported in upto 40% Wilson disease patients. Its pathogenesis is related to hypercalciuria, direct damage to glomeruli and tubular epithelium by free copper and urinary acidification defects.^{3 29 30} Zare et al reported a 39-year-old man presenting with recurrent kidney stones, refractory rickets and bone deformity, eventually diagnosed to have WD, similar to our index patient.³⁰ Nephrolithiasis in our patient resulted in CKD, thereby begetting CKD related MBD in the face of Wilson’s related MBD.

Diagnosis of WD is based on a combination of clinical findings and biochemical testing.³¹Mutation analysis by whole-gene sequencing is recommended if the diagnosis is difficult to establish by clinical and biochemical testing.³¹ This patient had normal levels of serum cerulopasmin despite multiple clinical signs, which can occur in 10% of patients.⁷ Hence, liver biopsy was sought to establish the diagnosis. Management armamentarium includes low copper diet, copper chelating medical treatment (zinc, trientine and tetrathiomolybedate) and liver transplantation.³¹ The choice of therapy depends on clinical manifestation and its severity. Monitoring is done for efficacy of treatment and drug specific side effects.

Conclusion

This case highlights that WD should be considered in the evaluation of MBD. Temporal sequence and clinical history can reveal different etiologies for the same manifestation, as in this case—WD and chronic kidney disease, both leading to MBD.

Learning points.

• Metabolic bone disease is an important cause for bony deformities and fragility fractures.

• Metabolic bone disease may be due to causes other than vitamin D deficiency.

• Wilsons disease is a rare but important cause of metabolic bone disease.

• Wilsons disease can have monosymptomatic presentation as metabolic bone disease in the absence of neurologic or gastrointestinal manifestations.

Ethics statements

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Consent obtained directly from patient(s).