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Journal of Postgraduate Medicine, Vol. 52, No. 3, July-September, 2006, pp. 201-203 Case Report Increasing thyroxine requirements in primary hypothyroidism: Don't forget the urinalysis! Junglee NA, Scanlon MF, Rees DA Centre for Endocrine and Diabetes Sciences, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW Code Number: jp06065 Abstract Rising thyroid stimulating hormone (TSH) levels in patients being treated for primary hypothyroidism usually indicate poor compliance with thyroxine therapy. In rare instances, drugs or diseases affecting absorption of thyroxine or drugs that accelerate thyroxine metabolism can manifest in a similar fashion. Nephrotic syndrome is a rare cause of such a presentation though its presence can rapidly be suspected by dipstick urine testing. In this report we describe a patient with long-standing primary thyroid failure whose thyroxine dose requirements increased upon development of massive proteinuria. Biochemical testing and renal biopsy subsequently demonstrated nephrotic syndrome and amyloid deposition in association with myeloma. Dipstick urine testing should be considered in all hypothyroid patients with rising TSH levels, where good compliance with thyroxine therapy is likely.Keywords: Hypothyroidism, nephrotic syndrome, urinalysis Primary hypothyroidism is a common condition with an estimated prevalence varying from 2-7% worldwide.[1] Faced with an elevation in the TSH level in patients with treated disease, clinicians are taught to check compliance with therapy before increasing the thyroxine dose. However, in rare instances drugs or diseases affecting thyroxine absorption (e.g., coeliac disease) and drugs which accelerate thyroxine metabolism (e.g., carbamazepine) lead to a similar rise in TSH. We report in this paper that urinary protein loss is another unusual but important cause of rising TSH levels in such patients, illustrating the importance of dipstick urine testing as a rapid screening procedure in the outpatient clinic. Case History A 62-year-old woman treated for primary thyroid failure was referred to the endocrinology clinic with increasing thyroxine requirements. She was diagnosed ten years prior with primary hypothyroidism on the basis of low serum free T 4 (1.8 pmol/l; normal range 9.8-23.1 pmol/l) and elevated serum TSH (53 mU/l; normal range 0.35-5.50 mU/l) levels although the anti-thyroid peroxidase (anti-TPO) antibody titre was low (19.6 kU/l; normal range < 32 kU/l). She was started on 100 micrograms of thyroxine daily and her symptoms resolved. Her thyroid function remained stable for ten years until routine tests demonstrated a rise in serum TSH to 6.1 mU/l. She maintained that she was fully compliant with therapy and her daily thyroxine dose was therefore increased to 125 micrograms. However, the TSH concentration continued to rise, despite progressive escalation of the thyroxine dose [Figure - 1]. This eventually returned into the normal range with a total daily dose of 200 micrograms [Figure - 1]. On the basis of these changes she was referred for review in the endocrinology clinic. Upon presentation, the patient weighed 78.6 kg and measured 160 cm in height. Physical examination confirmed the presence of mild periorbital swelling and peripheral edema but no palpable goitre with normal findings on general examination. She was noted to be hypertensive (140/90 mmHg). Dipstick urine testing demonstrated +3 protein, suggesting the presence of nephrotic range proteinuria. Subsequent 24-hour urine collections revealed up to 13.5 g of protein in 24 hours along with a parallel decrease in serum albumin (28 g/l; normal range 35-50 g/l). A marked mixed dyslipidaemia (cholesterol 9.3 mmol/l, triglycerides 10.2 mmol/l) was present in keeping with the nephrotic syndrome. Thyroid function tests showed a normal free T 4 concentration (17.3 pmol/l) with a TSH value at the upper end of the normal range (5.17 mU/l). Anti-TPO antibodies were absent and an autoantibody screen (including anti-nuclear, anti-double stranded DNA and anti-neutrophil cytoplasmic antibodies) was negative. IgA anti-TTG antibody titres were within normal limits (< 10.0 u/ml). A renal biopsy was then performed, which on Congo Red staining demonstrated numerous deposits of fibrillary material in various kidney elements, consistent with amyloid deposition. Numerous dysplastic lambda plasma cells were also observed in the biopsy specimen [Figure - 2]. Serum electrophoresis and bone marrow examination were both normal, but a trace amount of Bence-Jones paraprotein was detected in the urine. These features were consistent with a diagnosis of myeloma-associated amyloidosis and the patient was commenced on chemotherapy with bleomycin. Subsequently, urinary protein excretion and thyroid function tests remained stable on this regime [Figure - 1]. The mixed dyslipidaemia was successfully controlled using statin therapy. Discussion Nephrotic syndrome is an unusual cause of rising thyroxine requirements in primary thyroid failure, but our case serves to illustrate the value of simple dipstick urine testing in such a setting. Nephrotic syndrome is characterised by a marked increase in glomerular permeability to macromolecules and clinically presents with peripheral edema, proteinuria, hypoproteinaemia and hypercholesterolemia. Thyroid function abnormalities, comprising urinary loss of thyroid binding globulin (TBG), free T 4 and free tri-iodothyronine (T 3 ), with consequent falls in serum T 4 , T 3 and TBG levels, are well-documented in children with untreated nephrotic syndrome and are reversible with disease remission or following bilateral nephrectomy and renal replacement therapy.[2],[3],[4] Chronic peritoneal dialysis may also be associated with significant protein loss, including increased TBG excretion, though T 4 and T 3 losses in such patients are usually mild and do not result in significant thyroid failure.[5] Urinary loss of T 4 and T 3 is also apparent in some adult patients and correlates with serum free T 3 and free T 4 concentrations: in a series of ten patients reported by Fonseca and colleagues, those patients with detectable urinary T 4 excretion had significantly lower serum free T 4 and free T 3 concentrations.[6] Rarely, hyperthyroidism and nephrotic syndrome co-exist.[7] In this instance, massive proteinuria may serve to lessen the impact of the thyrotoxic state due to urinary thyroid hormone loss. Although loss of thyroid hormone in the urine seems the likely explanation for the rising TSH levels in our patient, could amyloid infiltration of the thyroid have additionally contributed? We feel this is unlikely since the hypothyroidism was diagnosed ten years previously and repeated clinical examination of our patient during this period consistently reported no palpable goitre. However, studies have demonstrated that some degree of thyroid amyloid deposition occurs in more than 80% of patients with secondary amyloidosis.[8] While most are euthyroid on biochemical testing with only rare reports of symptomatic hypothyroidism, detailed testing in one series of patients with secondary amyloidosis revealed an unexpectedly high incidence of thyroid dysfunction.[8] Glomerular disease giving rise to protein loss with associated endocrine dysfunction is not confined to the thyroid axis and clinicians should be alert to alterations in other hormone systems, notably the hypothalamo-pituitary-adrenal axis and the growth hormone / Insulin-like growth factor-I system.[9] This is exemplified in a recent report demonstrating a false-positive short synacthen test result in a patient with nephrotic syndrome, presumed secondary to urinary loss of cortisol binding globulin.[10] Free serum cortisol levels are likely to be normal in such patients. In summary, we report a case of progressive thyroid failure in a patient who developed nephrotic syndrome and myeloma-associated amyloidosis. Our report highlights the endocrine consequences of massive proteinuria and demonstrates the value of dipstick urine testing as a rapid and cheap screening investigation in the clinic setting. Examination of the urine should form part of the investigation strategy in all compliant patients with rising thyroxine requirements in primary hypothyroidism. Acknowledgement We would like to thank Dr. DFR Griffiths, Consultant Pathologist, for his advice and providing the renal biopsy image.References
Copyright 2006 - Journal of Postgraduate Medicine The following images related to this document are available:Photo images[jp06065f2.jpg] [jp06065f1.jpg] |
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