Itai Itai Disease

Itai itai disease (Japanese for "it hurts, it hurts") is chronic cadmium poisoning characterised by renal proximal tubular dysfunction with Fanconi type features and severe osteomalacia with osteoporosis and multiple fractures. It was first described in the Jinzu River basin of Toyama, Japan, where rice irrigated with water contaminated by mine effluent accumulated cadmium. The patients were mainly post-menopausal women with multiple pregnancies and low calcium, vitamin D and protein intake.

Cadmium accumulates in the renal cortex with a biological half life of 10 to 30 years. Tubular injury produces low molecular weight proteinuria, glycosuria, aminoaciduria, phosphaturia, hypercalciuria and acidosis. Renal phosphate wasting and impaired activation of vitamin D (loss of 1-alpha hydroxylase activity) cause osteomalacia, which is aggravated by direct cadmium effects on bone.

Other sources of cadmium are nickel cadmium batteries, electroplating, smelting, pigments, contaminated rice and shellfish, and tobacco smoke. The tubular lesion is irreversible once urine beta-2-microglobulin exceeds 1000 micrograms/g creatinine.

• Bone pain in the lumbar spine, hips, and long bones, worse on weight bearing and walking, giving a waddling gait.
• Multiple pathological fractures (ribs, vertebrae, long bones), height loss, spinal deformity.
• Muscle weakness, proximal myopathy.
• Polyuria, polydipsia, thirst, urinary calcium stones.
• Anaemia, anosmia, yellow tooth rings (cadmium line) in occupational exposure.
• Chronic kidney disease with proteinuria.
• Red flags: new vertebral or hip fracture, hypophosphataemia, fall in eGFR, lung symptoms in industrial exposure (cadmium emphysema and lung cancer).

• Exposure history: rice, shellfish, offal, tobacco, occupational contact.
• Urine cadmium (normal below 1 microgram per gram creatinine; over 5 micrograms per gram indicates tubular risk) and blood cadmium (below 5 micrograms/L; reflects recent exposure).
• Urine beta-2-microglobulin or retinol binding protein (over 300 micrograms/g creatinine marks tubular dysfunction), urine N-acetyl-beta-D-glucosaminidase.
• Serum: low phosphate (below 0.8 mmol/L), low or normal calcium, raised alkaline phosphatase, raised parathyroid hormone, low 25-hydroxy vitamin D (below 50 nmol/L), low bicarbonate, low urate, normal or reduced eGFR.
• Urine: glycosuria with normal blood glucose, generalised aminoaciduria, phosphate wasting (tubular reabsorption of phosphate below 80 percent).
• Radiographs: Looser zones (pseudofractures), biconcave vertebrae, reduced bone density; DXA shows low bone mineral density.
• Exclude other causes of Fanconi syndrome and osteomalacia (hereditary, myeloma, tenofovir toxicity, nutritional vitamin D deficiency, tumour induced osteomalacia), lead poisoning, and primary osteoporosis.

• Remove the cadmium source: change the food or water supply, remove from industrial exposure, stop smoking.
• Chelation is not effective and edetate calcium disodium is nephrotoxic with cadmium; it is avoided.
• Osteomalacia: vitamin D3 (cholecalciferol) 50 000 units orally once weekly for 8 weeks, then 1000 to 2000 units daily; for impaired activation use calcitriol 0.25 to 0.5 micrograms orally once daily, adjusting every 2 to 4 weeks by serum calcium, aiming for a normal calcium; monitor calcium and phosphate every 2 weeks for 3 months, then every 3 months.
• Phosphate replacement: oral phosphate 750 to 1500 mg elemental phosphorus daily in 3 to 4 divided doses for hypophosphataemia, together with calcitriol, to avoid secondary hyperparathyroidism; stop if diarrhoea or raised parathyroid hormone.
• Calcium 1000 to 1200 mg daily (diet and supplements) with 800 to 1000 IU vitamin D; dietary protein 1 g/kg.
• Metabolic acidosis: sodium bicarbonate 500 mg to 1 g orally 3 times daily to keep serum bicarbonate at 22 mmol/L or more.
• Bisphosphonates are used only after osteomalacia is corrected (vitamin D and calcium replete), because they can worsen osteomalacia.
• Analgesia: paracetamol 1 g orally every 6 hours; avoid non-steroidal anti-inflammatory drugs in tubular disease; short course opioid for fractures. Orthopaedic treatment of fractures, with bracing.
• Kidney: manage chronic kidney disease with ACE inhibitors, blood pressure control, and renal replacement therapy as required.
• Follow up: bone profile every 3 months; DXA yearly; urine beta-2-microglobulin yearly.
• Prevention: limit cadmium in food and water, monitor mining effluent and irrigated crops, and public health surveillance.