1 Chair of Nephrology, Department of Internal Medicine,2 Chair of Internal Medicine, San Luigi,3 Diabetic Care Unit, Department of Internal Medicine, University of Turin, Italy Email: gbpiccoli{at}hotmail.com; gbpiccoli{at}yahoo.it
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At his clinic visit, A.Z. was a sporty, well nourished person, in good clinical condition (weight 75.3 kg, height 180 cm, body mass index 23), and normotensive (blood pressure 110/75 mmHg; heart rate 64 beats/min). The only pathological finding was modest ankle oedema.
His clinical history, beside poorly controlled diabetes and his report of occasional hand and foot swelling, was unremarkable. He denied alcohol or drug abuse, as well as any self-prescribed medications. His therapy consisted only of injections of insulin, four times daily. He recently had developed severe depression after the death of one of his two daughters, which he reported to have been due to a congenital neuromuscular problem, though he was not able to recall the diagnosis precisely.
According to his wife, he recently had lost interest in living, changed his habits, stopped playing sport and gained weight. In the same 68 month period, his hypoglycaemic crises changed in pattern: he reported being disoriented in space and time, and becoming aggressive, before losing consciousness (blood glucose 2030 mg/dl).
Tests for diabetic end-organ damage revealed: background retinopathy; neuropathy with reduction of vibratory sensibility; no sign of vasculopathy; and normotension.
Under the working diagnosis of a non-diabetic renal disease, the patient was hospitalized for a renal biopsy.
During hospitalization, he suffered a severe hypoglycaemic episode preceded by aggressive behaviour (blood glucose <30 mg/dl). The neurologist suggested a functional component to account for his mild ideomotor slowing and his aggressive behaviour. Electroencephalography revealed non-specific metabolic alterations.
After the hypoglycaemic episode, he reported muscular aches, which he admitted had been present for a few months, but were acutely exacerbated. Suspecting a link with the unspecified problem of his daughter, muscle enzymes were tested. His creatinine phosphokinase and lactic dehydrogenase levels were high (CPK 1960 U/l and LDH 1018 IU/l).
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Answer to the quiz on the preceding page |
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The muscle aches were the symptoms leading to the correct diagnosis. They had been overlooked initially by the patient, who reported them only after his last severe hypoglycaemic crisis. The simple explanation, attributing them to severe hypoglycaemia, was not fully satisfactory, in particular in the absence of severe neuropathy [1]. A metabolic cause was suspected, and thyroid hormones were tested.
His free-T3 and free-T4 levels were below the detection limits of the assay (free-T3 <1.19 pg/ml, free-T4 <1.8 pg/ml), with a high thyroid-stimulating hormone (TSH) level (57.5 IU/ml). Positivity to thyroid autoantibodies confirmed the immunological pathogenesis of his conditionantithyroxin peroxidase >1000 U/ml (normal range 050); antithyroid microsome 4970 IU/ml (normal 0100).
Thyroxin therapy was started, with rapid reversal of the thyroid hormone deficit (free-T3 3.28 pg/ml, free-T4 10.74 pg/ml, TSH 27.0 IU/ml 1 month later). Subsequent to the initiation of treatment, his renal function returned to normal (serum creatinine 1 mg/dl, creatinine clearance 96 ml/min), haemoglobin increased (12.8 g/dl), no more hypoglycaemic crises were reported and he lost weight (6.3 kg).
The link between thyroid hormones and renal function has been known for decades, and the presence of reduced renal clearance in severe hypothyroid states has been confirmed repeatedly. While the rhabdomyolysis induced by extreme hypothyroidism may precipitate acute renal failure, complex effects on glomerulo-tubular balances are described in milder cases [2].
A search on Medline and Embase (September 5, 2003, combining Mesh, Emtree and free terms relating to hypothyroidism and those indicating renal function and kidney failure) retrieved 232 titles, 16 of which dealt with cases or series of cases of reversible renal dysfunction due to hypothyroidism. Most reported cases were of unexplained worsening of pre-existing renal failures of different aetiologies; none, however, was in the context of long-standing diabetes.
Upon re-evaluation of our case, we identify some elements that might have pointed towards hypothyroidism:
In addition to recalling the association between renal and thyroid function, this case is of interest in that it underlines the link between autoimmune diseases and type 1 diabetes.
In the WHO classification (WHO, 1999), type 1 diabetes is characterized by autoimmune destruction of Langhans insulae. It has been associated with various autoimmune diseases, including complex pluriglandular syndromes [4]; the association with autoimmune hypothyroidism is also known as APS type 3a, and may be more common than previously recognized [4].
In the cases so far reported in the literature of renal dysfunction and severe hypothyroidism, thyroid disease was often overlooked because of the overlap between uraemic symptoms and hypothyroid ones. In A.Z., there also was a subtle overlap with the signs and symptoms of long-standing diabetes, which further hindered a timely diagnosis.
While some endocrine authorities propose thyroid function screening in all hospitalized patients, screening in the general population remains controversial [3,4]. However, several authors suggest that the rapid or unexplained worsening of renal failures reported are the tip of the iceberg of an under-diagnosed association, and they recommend performing TSH testing in all patients with the unexplained appearance or progression of kidney failure. This may be particularly important in high-risk populations, such as type 1 diabetics, in whom thyroid function tests should probably be included in the usual nephrological work-up [4].
Conflict of interest statement. None declared.
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