SKELETAL FLUOROSIS RELATED TO HABITUAL TEA CONSUMPTION: LONG-TERM FOLLOW-UP AFTER REDUCTION AND DISCONTINUATION OF TEA

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1 Case Report SKELETAL FLUOROSIS RELATED TO HABITUAL TEA CONSUMPTION: LONG-TERM FOLLOW-UP AFTER REDUCTION AND DISCONTINUATION OF TEA Sina Jasim, MD 1 ; Doris Wenger, MD 2 ; Robert A. Wermers, MD 1 ABSTRACT Objective: Systemic fluorosis due to excessive tea consumption is a cause of acquired osteosclerosis. Reversibility of systemic fluorosis and long-term outcome data are essentially limited to a few case reports and has never been reported in the context of fluorosis due to chronic excessive tea intake. Methods: We previously reported on 4 patients with fluoride excess due to habitual tea consumption with a wide disease spectrum, including skeletal fluorosis, gastrointestinal symptoms, lower extremity pain, and renal insufficiency. Herein, we report long-term follow-up on two of those subjects. Results: Reduction and discontinuation of tea intake was associated with rapid improvement of bone pain, renal function, and gastrointestinal symptoms. Reversibility of osteosclerosis and reductions in bone mineral density were also observed over several years after reduction and elimination of the fluoride source. An initial decrease in plasma fluoride levels occurred, followed by a plateau at abovenormal levels persisting up to 11.5 years thereafter. Submitted for publication April 12, 2017 Accepted for publication June 28, 2017 From the 1 Division of Endocrinology, Diabetes, Metabolism, and Nutrition and Department of Medicine, and 2 Department of Radiology, Mayo Clinic, Rochester, Minnesota. Address correspondence to Dr. Robert A. Wermers, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN wermers.robert@mayo.edu. DOI: /EP CR To purchase reprints of this article, please visit: Copyright 2018 AACE. Conclusion: Elimination of retained skeletal fluoride from chronic excessive tea ingestion may take longer than previous estimates, although specific patient-related factors including reduced renal function may have also contributed to the continued plasma fluoride elevations. (AACE Clinical Case Rep. 2018;4:e98-e103) Abbreviations: BMD = bone mineral density; DXA = dual-energy X-ray absorptiometry; FN = femoral neck; LS = lumbar spine INTRODUCTION Acquired osteosclerosis due to trabecular bone coarsening is rare, with multiple potential causes, including malignancy, vitamin A or D excess, hepatitis C infection, and fluorosis (1). Skeletal fluorosis is the most common and severe presentation of fluorosis among adults and reported to occur when more than 10 mg/day of fluoride is consumed for 10 years or longer (2). It often results in osteosclerosis, which can lead to significant long-term disabilities, including limited spine mobility, kyphosis, and lower extremity pain (3). There are multiple environmental sources of fluoride; however, skeletal fluorosis from chronic ingestion of large volumes of instant or brewed tea is an uncommon and lessrecognized cause. Although fluoride-related bone disease due to excessive brick tea consumption is endemic in some parts of the world, it is less common in the United States (4). However, given that tea is a readily available source of fluoride, excessive chronic intake can result in significant clinical consequences which can be unrecognized (4). Reversibility of systemic fluorosis and long-term outcome data are limited to a few case reports (5-7) and has never been reported with chronic excessive tea e98 AACE CLINICAL CASE REPORTS Vol 4 No. 2 March/April 2018 Copyright 2018 AACE

2 Copyright 2018 AACE Tea-Associated Fluorosis, AACE Clinical Case Rep. 2018;4(No. 2) e99 intake. With elimination of excess fluoride from the body via continuous remodeling of the skeleton, fluorosis is thought to be slowly reversible (8). We previously reported 4 patients with osteosclerotic bone disease due to excessive tea consumption (4). Herein, we report longterm (8 and 11.5 years) follow-up of two of these individuals to better understand the natural history of fluorosis due to chronic excess tea intake after reduction and elimination of tea. METHODS Fluoride in plasma was quantified using a La Motte ph PLUS Direct ph/mv/ise/temp meter equipped with a fluoride-specific electrode (Orion Research, Cambridge, MA). The fluoride electrode consists of a single-crystal lanthanum fluoride membrane and an internal reference bonded into an epoxy body. The crystal is an ionic conductor in which only fluoride ions are mobile. A TISAB reagent (1% acetic acid, 6% sodium chloride, 8% sodium acetate, and <1% 1,2-cyclohexane diaminetetraacetic acid in water) was used to buffer the sample prior to ion-selective electrode analysis. Experience in the Mayo Clinical laboratory associated with evaluation of patients exposed to fluoride from common sources including the diet, beverages, drinking water, and the normal use of fluoride toothpastes indicates plasma fluoride is consistently within the range of 0 to 4 µmol/l. CASE REPORT Case 1 A 67-year-old woman with multiple stress fractures had a dual-energy X-ray absorptiometry (DXA) bone mineral density (BMD) measurement that unexpectedly revealed an increased BMD with a Z-score of +4.7 at the lumbar spine (LS) and a femoral neck (FN) Z-score of +0.4, leading to referral to the Metabolic Bone Disease Clinic. She underwent menopause in her early forties and had not utilized hormone replacement therapy. Her medical history was remarkable for multiple gastrointestinal complaints, lower extremity pain, and anorexia nervosa with ongoing restriction of energy intake relative to requirement, fear of weight gain, and concerns with her body shape. Her fracture history was only significant for several stress fractures of her feet. Physical examination revealed a body mass index of 15.2 kg/m 2. Laboratory studies identified an elevated bone alkaline phosphatase fraction of 149 U/L (normal, 11 to 67 U/L) (Table 1). Radiographs of the thoracic and LS showed diffuse osteosclerosis (Fig. 1 A and B). Plasma fluoride was 15.4 µmol/l (normal, 0 to 4 µmol/l). The patient confirmed consumption of an estimated 10 to 16 cups of black tea daily, with an estimated fluoride intake of 13 mg/ day (typically 2.5 mg/day). In the context of her eating disorder, she had difficulty in completely eliminating tea intake and over the Table 1 Baseline Laboratory Evaluation in Fluoride-Associated Metabolic Bone Disease Cases a Test Case 1 Case 2 Normal range Hemoglobin (g/dl) Leukocytes ( 10 9 /L) Sedimentation rate (miu/hour) 6 Not performed 0-29 TSH (miu/l) Calcium (mg/dl) Phosphorus (mg/dl) Total alkaline phosphatase (normal range) Bone alkaline phosphatase fraction (normal range) 206 U/L ( U/L) 149 U/L (11-67 U/L) 70 U/L ( U/L) 14 (<22 µg/l) 25-hydroxyvitamin D (ng/ml) PTH, 1-84-intact (normal range) 37 pg/ml (10-55 pg/ml) 65 pg/ml (11-67 pg/ml) Hepatitis serologies Negative for B & C Negative for B & C Urine heavy metals (arsenic, lead, mercury, cadmium) Negative Negative Serum fluoride (µmol/l) Estimated fluoride intake (mg/day) Abbreviations: PTH = parathyroid hormone; TSH = thyroid-stimulating hormone. a Adapted in part from (4). Typical consumption 2.5 mg daily

3 e100 Tea-Associated Fluorosis, AACE Clinical Case Rep. 2018;4(No. 2) Copyright 2018 AACE A B C Fig. 1. Baseline and follow-up skeletal surveys in case 1 with fluoride excess due to excessive chronic tea consumption and renal insufficiency after reduction and discontinuation of tea intake. Anterior posterior radiograph of the lumbar spine and pelvis (A) and lateral radiograph (B) of the thoracic spine with diffuse osteosclerosis of the visualized bones. Follow-up lateral radiograph of the thoracic spine (C) shows diffuse significant demineralization of the bones with secondary chronic anterior wedging of multiple thoracic vertebral bodies. There was also a displaced and angulated fracture of the sternum in 2014 and thoracic kyphosis (arrow). first 9 years admitted to consuming 2 cups of brewed tea each morning from a single tea bag that was used over a 4 day period. She completely eliminated brewed tea 2.5 years prior to the last plasma fluoride measurement. After reducing and subsequently eliminating tea consumption, her pain and gastrointestinal symptoms improved. Over the ensuing 10 years, her BMD demonstrated a remarkable progressive reduction of 40% at the LS and 35.1% at the FN (Fig. 2 A and B). Evaluation for secondary causes of accelerated BMD loss was unrevealing. Despite rapid loss of BMD, plasma fluoride levels plateaued, and upon last measure 11.5 years later, was 9.2 μmol/l (Fig. 2 C). Her Cockcroft Gault estimated glomerular filtration rate (egfr) improved and stabilized from 24 ml/min at baseline to 41 ml/min (serum creatinine 0.5 mg/dl), and her total alkaline phosphatase was significantly lower at 107 U/L compared to baseline at last follow-up. Radiographs of the thoracic and LS after a decade showed diffuse demineralization of the bones with thoracic kyphosis (Fig. 1 C). Case 2 A 62-year-old female was referred for an elevated DXA BMD with Z-scores of +7.2 at the LS and +2.0 at the FN. She had nonspecific bilateral lower-extremity pain but no prior history of fractures. Her medical history was remarkable for mild chronic renal insufficiency and ongoing estrogen replacement therapy after hysterectomy. She admitted to consuming excessive amounts of ice tea (30 to 40 eight-ounce glasses of tea/day) for about 30 years, with an estimated daily fluoride intake of 14 mg/day. Physical examination was unremarkable. She had a serum creatinine of 1.7 mg/dl and a plasma fluoride level of 17.3 μmol/l (normal, 0 to 4 μmol/l) (Table 1). Radiographic skeletal survey demonstrated diffuse osteosclerosis and cortical thickening of the axial and appendicular skeleton as well as multifocal ligamentous ossification (Fig. 3 A-C). Upon confirmation of her diagnosis, the patient completely eliminated ice tea intake. Over 8 years of follow-up after tea discontinuation, her DXA BMD declined by 11.4% at the LS and 2.6% at the FN (Fig. 2 A and B). Plasma fluoride level plateaued at 3 years after tea discontinuation at 7.2 μmol/l and upon last measure at year 8 was 7.4 μmol/l (Fig. 2 C). Her egfr rapidly improved and stabilized from 35 ml/min at baseline to 46 ml/min (serum creatinine 1.2 mg/dl), and her total alkaline phosphatase was similar to baseline (74 U/L) at year 8. Follow-up lateral radiographs of the thoracic spine 8 years later showed resolution of osteosclerosis with normal to slight decrease in skeletal mineralization (Fig. 3 D). DISCUSSION Fluoride-related bone disease due to excessive chronic tea intake has been rarely reported in the United States (4,8-11). Although tea is historically perceived to promote health, chronic excessive amounts of ingested fluoride can be harmful. Indeed, processed tea is fluoride rich, and skeletal fluorosis is prevalent in some regions of Asia where poor-quality brick tea is brewed using mature leaves, twigs, and berries of the tea plant, Camellia sinensis. Black tea also contains a significant amount of fluoride (12), and its preparations (e.g., brewed tea and instant tea) are popular in the United States, but to date, only a few cases of skeletal fluorosis due to chronic instant (4,8,11) and brewed (4,9,10) tea consumption have been reported. The half-life of fluoride in the adult skeleton is estimated to average 7 years or longer and increases with advanced age (3,5). The skeleton contains ~99% of the

4 Copyright 2018 AACE Tea-Associated Fluorosis, AACE Clinical Case Rep. 2018;4(No. 2) e101 A B Fig. 2. Change from baseline in dual-energy X-ray absorptiometry bone mineral density (BMD) at the lumbar spine (A) and femoral neck (B) and plasma fluoride levels (μmol/l) (C) in 2 patients with fluoride excess due to excessive chronic tea consumption and renal insufficiency after reduction and discontinuation of tea. C D body burden of fluoride, which substitutes for the hydroxyl ion in hydroxyapatite to form hydroxyfluorapatite crystals, which are more compact, less soluble, and more stable than hydroxyapatite and cause resistance to bone remodeling (13). Therefore, fluoride remains in the system for prolonged periods of time, and it may take longer than 2 years after the elimination of the fluoride source to see a significant reduction in bone density or a change in skeletal radiographs (14). After fluoride withdrawal, BMD has been observed to decrease, reversing the increase in BMD previously seen due to osteoblast stimulation (4). In case 1, we observed a continuous and prolonged period of accelerated BMD loss from the thoracic and LS, which was more dramatic than the decline that was seen in other reports (6,7) and also supported her described reduction and elimination of tea. Decline in BMD after discontinuing fluoride was also observed with fluoride therapy for osteoporosis (15). The BMD in case 2 was likely better maintained by estrogen replacement therapy, an observation that is consistent with a report by Cundy et al (6) which demonstrated a slower rate of LS BMD decline over 9 years (~0.8% per year) and 10-fold increase in the rate of fall in LS BMD (~8% per year) after stopping estrogen replacement. Reversibility of osteosclerosis following cessation of exposure is reported to be variable in patients with skeletal fluorosis (5). Baseline skeletal radiographs in our patients showed characteristic findings of skeletal fluorosis, including diffuse osteosclerosis, cortical thickening, as well as multifocal ligamentous ossification. The follow-up Fig. 3. Baseline and follow-up skeletal surveys in case 2 with fluoride excess due to excessive chronic tea consumption and renal insufficiency after discontinuation of tea intake. Baseline anterior posterior radiograph of the lumbar spine and pelvis (A) and lateral radiograph of the thoracic spine (C) demonstrate diffuse osteosclerosis and cortical thickening of the visualized bones. Baseline anterior posterior radiographs of the right (R) and left (L) forearm demonstrate osteosclerosis, cortical thickening and ossification of portions of the interosseous membrane (asterisks) bilaterally (B). Follow-up lateral radiograph of the thoracic spine (D) shows normal to slight decrease in skeletal mineralization. There is slight interval progression of the degree of chronic anterior wedging of several mid thoracic vertebral bodies. radiographs showed resolution of the osteosclerosis and cortical thickening, with development of varying degrees of reduction in BMD in both cases (Figs. 1 C and 3 D). Improvement in joint pain was also observed after discontinuation of fluoride ingestion. This is consistent with other reports of prompt improvement and resolution of musculoskeletal pain associated with fluoride excess even with shorter-term fluoride exposure (16), emphasizing the importance of recognizing the often insidious features of fluoride toxicity. We observed that despite reduction and elimination of excessive fluoride, plasma fluoride levels dropped rapidly and then plateaued at an approximately twice normal level in both individuals at 11.5 and 8 years, respectively, for cases 1 and 2. This is despite the fact that case 1 had an average annual BMD loss at the LS of 4%, consistent with high turnover, compared to a lesser amount of bone loss over time in case 2. This differs from the only other longterm follow-up of systemic fluoride levels in an individual with fluorosis likely related to fluoridated toothpaste expo-

5 e102 Tea-Associated Fluorosis, AACE Clinical Case Rep. 2018;4(No. 2) Copyright 2018 AACE sure, where serum fluoride levels were in the normal range within the first year after avoidance of fluoridated dental products (7). However, this individual s urinary fluoride levels took longer to approximate the normal range. Although we did not measure 24-hour urinary fluoride levels, they are typically proportional to plasma concentrations and can also be affected by the amount of fluoride exposure, the rate of fluoride absorption, gastric acidity, and the rate of skeletal and renal clearance of fluoride (17). In addition, Kurland et al (7) performed an iliac crest bone biopsy 8.5 years after stopping fluoridated toothpaste, which still demonstrated significantly elevated bone fluoride content, although it was reduced from baseline. Our results suggest that chronic excessive fluoride ingestion can be associated with long-term elevated plasma fluoride levels due to retained skeletal fluoride after reduction and discontinuation of its consumption. There are several factors which may influence the rate of fluoride elimination from the skeleton. First, continued ingestion of fluoride, albeit at lesser amounts, could sustain plasma fluoride at higher levels. Case 1 had an underlying eating disorder which likely reflected her initial difficulty in completely eliminating tea from her diet (4). Indeed, lifestyle factors have been demonstrated to influence adult skeletal fluorosis (18). Differences in gastrointestinal motility could also influence fluoride absorption, since one-fourth of ingested fluoride is absorbed from the stomach, while the rest is absorbed from the proximal small bowel (19). Other factors that can influence fluoride metabolism include acid-base status and other underlying medical conditions. The fluoride source, amount, and chronicity of its intake likely also impact the long-term reduction in plasma fluoride levels after fluoride discontinuation or reduction. As such, with shorter-term exposure to fluoride excess, plasma fluoride levels are noted to more rapidly approximate normal after the fluoride source is eliminated (16). However, in both of our cases, chronic cumulative exposure to excess fluoride likely contributed to skeletal retention of fluoride that was observed. Bone remodeling activity could additionally influence the rate of fluoride efflux from the skeleton. Specifically, the rate at which skeletal fluorosis can be reversed would be expected to be slower with reduced bone turnover, as can be seen with antiremodeling osteoporosis therapy (6). Since half of absorbed fluoride is excreted in the urine, reduced elimination of fluoride due to chronic kidney disease could also predispose individuals to continued elevations in plasma fluoride levels after elimination of the toxic fluoride source, as its renal clearance is directly related to glomerular filtration rate (17). Finally, genetic modifiers and pharmacogenomic variations in metabolism could influence exposure to unbound (ionized) fluoride metabolites, resulting in elevated plasma fluoride levels (20). After elimination of the fluoride source, we also documented improvement in gastrointestinal symptoms as well as improvement and stabilization of renal function in our individuals with fluorosis. Gastrointestinal symptoms such as nausea, abdominal pain, and vomiting are common in patients treated with fluoride and improve shortly after fluoride discontinuation (4). Also, in both of our subjects, serum creatinine levels improved after fluoride cessation, which is consistent with fluoride s known association with renal impairment (4). However, it remains unclear in humans how fluoride leads to renal disease. CONCLUSION These patients represent the first long-term follow-up of tea-related fluorosis after reducing and eliminating fluoride-containing tea intake. Excess tea consumption is an important consideration in the differential diagnosis of high bone mass, and as such, it is essential to ask appropriate history questions in this regard. Reduction and elimination of tea consumption can result in prompt improvement in gastrointestinal symptoms (4), musculoskeletal pain (16), and renal function (4). Reversibility of osteosclerosis and reductions in BMD are also observed after elimination of the fluoride source. The clinical consequences and management of the related bone loss is uncertain. Although plasma fluoride levels rapidly declined after reducing or stopping tea intake in our patients, the levels remained approximately twice normal up to 11.5 years thereafter, suggesting the elimination of retained skeletal fluoride from chronic excessive fluoride ingestion may take longer than previous estimates. However, it is likely that reduced renal function and other patient-specific factors also contributed to the persistence of elevated plasma fluoride levels in these cases. Long-term follow-up of fluoride levels in additional patients identified with fluorosis should help further clarify the natural history of this disorder. DISCLOSURE The authors have no multiplicity of interest to disclose. REFERENCES 1. Whyte MP. Sclerosing bone disorders. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 8th ed. Wiley-Blackwell; US Environmental Protection Agency. Safe Drinking Water Act (SDWA): regulations and guidance. Available at: sdwa. 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