1 Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, 2 Renal Division, St Michael's Hospital, University of Toronto, Toronto, Canada and 3 Nephrology Unit and Department of Internal Medicine, University of Stellenbosch, Cape Town, South Africa
Abstract
Background. Events in the gastrointestinal tract that might contribute to a high absorption of calcium were simulated in vitro to evaluate why only a small proportion of individuals who ingest alkaline calcium salts develop hypercalcaemia, hypokalaemia and metabolic alkalosis.
Methods. A patient who chewed and swallowed around 40 betel nuts daily developed hypercalcaemia, metabolic alkalosis, hypokalaemia with renal potassium wasting, and renal insufficiency. The quantities of calcium and alkali per betel nut preparation were measured. Factors that might increase intestinal absorption of calcium were evaluated.
Results. Hypercalcaemia in the index case was accompanied by a high daily calcium excretion (248 mg, 6.2 mmol). Circulating levels of 1,25-dihydroxyvitamin D3 and parathyroid hormone were low. Hypokalaemia with a high transtubular K+ concentration gradient, metabolic alkalosis, a low excretion of phosphate and a very low glomerular filtration rate were prominent features.
Conclusions. Possible explanations for the pathophysiology of metabolic alkalosis and hypokalaemia are provided. We speculate that a relatively greater availability of ionized calcium than inorganic phosphate in the lumen of the intestinal tract could have enhanced dietary calcium absorption.
Keywords: bicarbonate; calcium; hypokalaemia; milk-alkali syndrome; phosphate
Introduction
The triad of hypercalcaemia, metabolic alkalosis, and renal insufficiency characterizes the milk-alkali syndrome [1]. In the past, its most common presentation was in patients with peptic ulcer disease who took large amounts of milk and calcium carbonate (CaCO3). With the advent of better antacid therapy such as H2 blockers and gastric H+ pump inhibitors, the incidence of this syndrome has decreased. Recently, features of the milk-alkali syndrome have been described in patients who take alkaline calcium salts and vitamin D supplements to treat osteoporosis [2]. Another predisposing cause, betel nut chewing, is an under-estimated source of oral alkaline calcium salts [3]. Betel nuts are the main ingredient of a masticatory drug used in the Far East, Asia, and the South Pacific by an estimated 600 million people [4]. To overcome their bitter taste, alkaline calcium salts are included in the oral preparation.
To understand why only a few of the many individuals who ingest alkaline calcium salts develop hypercalcaemia, hypokalaemia and metabolic alkalosis, we simulated events in the gastrointestinal tract that could contribute to excessive intestinal absorption of calcium. This involves an interplay between the products of bacterial fermentation and the relative proportions of alkaline calcium salts and inorganic phosphate in segments of the intestinal tract where passive, paracellular, non-regulated absorption of ionized calcium occurs [5].
Subjects and methods
Case
A 60-year-old male patient who developed hypercalcaemia, metabolic alkalosis, hypokalaemia with renal potassium (K+) wasting, and renal insufficiency associated with a heavy consumption of betel nuts was examined.
Analysis of betel nut paste
Samples of betel nut paste were obtained from vendors in Toronto, Canada, and in Taipei, Taiwan, to determine the amounts and nature of its calcium compounds. Single preparations were weighed and added to 10 ml of distilled water (n=6) or 0.9% saline (n=5). Prior to centrifugation, the mixture was vortexed vigorously at room temperature until the pH of the supernatant became constant (12.4). The clear aqueous phase was assayed for ionized calcium. To obtain an estimate of its total calcium content, the entire preparation was dissolved in 1 N HCl prior to assay for calcium. A portion of the aqueous HCl extract was titrated back to the original pH with 0.1 N NaOH to determine whether some of the alkali in that solution was CaCO3 rather than calcium hydroxide (Ca(OH)2) or calcium oxide. If fewer H+ ions were to remain in solution after HCl addition, this would indicate that some of the anions accompanying calcium were bicarbonate and/or carbonate (CO32-) (a total CO2 analysis by titration [6]). The quantity of chloride (Cl-) and sodium (Na+) added was verified by direct assay.
A solution containing 1 mmol of CaCO3 and 2.5 mmol of phosphate buffer (pH 7.4) was incubated for up to 12 h at room temperature. The 2.5-fold excess of phosphate over calcium was selected to represent a typical dietary composition [7]. The aqueous phase was assayed for calcium and phosphate, and the quantity of precipitate was also determined.
CaCO3 (1 mmol) was exposed to increasing amounts of HCl (total volume adjusted to 10 ml with distilled water, n=24). Control solutions (n=6) consisted of 1 mmol CaCO3 in a total volume of 10 ml H2O. The clear aqueous phase was aspirated and assayed for ionized calcium. The quantity of HCl added was verified by direct measurement of Cl-.
Analytical techniques
Calcium was measured by an ion-selective electrode (Model 9720, Orion Research Inc., Beverley, MA, USA), and pH was measured by an Orion pH meter (perpHect Log R meter, Model 370, Orion Research Inc.). The concentration of Cl- was measured by a Cl- titrator (Radiometer, Model CMT-10) and Na+ and K+ were measured by flame photometry as previously described [8].
Results
Case synopsis
The 60-year-old male sought medical attention because of anorexia and constipation that were more marked over the past several weeks. He had lost 7 kg of weight in this period. There was no other pertinent past medical history. He denied any consumption of vitamin D supplements. By habit, he chewed approximately 40 betel nuts from Areca catechu on a daily basis, and had done so for more than 40 years. These nuts were wrapped in the leaves of Piper betle along with a calcium-containing paste. He had developed a psychological and physical dependence on this stimulant. Typically, he swallowed the saliva and the remainder of the betel nut preparation. The calcium content of samples that were estimated to represent the amount of paste used in one preparation (0.1 g dry weight) was 1.4±0.06 mmol. Therefore, he consumed approximately 50 mmol of calcium per day in the 40 betel nuts. Back-titration with NaOH confirmed that the alkali was Ca(OH)2 rather than CaCO3. The solubility of the Ca(OH)2 paste at room temperature was 11.3±0.64 mmol/l in water (n=6) and 12.5±0.57 mmol/l in 0.9% saline (n=5); the pH of the latter solution was 12.4. In contrast, CaCO3 was very sparingly soluble in water so its calcium and alkali load would have depended almost exclusively on swallowing if it had been the oral alkaline salt.
On physical examination, the patient was conscious and alert with a supine blood pressure of 114/70 mmHg, heart rate of 80 beats/min, respiratory rate of 14 breaths/min, and his body temperature was 36.6°C. In the upright position, his blood pressure fell to 102/64 mmHg and his pulse rate rose to 94 beats/min. The jugular veins were flat and there was no peripheral oedema. Cardiopulmonary and abdominal examinations were unremarkable. There were no focal neurological deficits except for bilateral hyporeflexia. His tongue, oral mucosa and the angles of his mouth were stained brick-red by the betel nut juice.
The most striking features revealed by the laboratory examination were hypercalcaemia (12.8 mg/dl, 3.2 mmol/l), metabolic alkalosis (plasma pH 7.47, bicarbonate 36 mmol/l), and a very high plasma creatinine and BUN level (calculated creatinine clearance was 8.1 ml/min) (Table 1). Serum intact parathyroid hormone (PTH) (2.7 pg/ml) and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) levels (8.2 pg/ml) were below the normal range (PTH, 1065 pg/ml; 1,25-(OH)2D3, 16.442.4 pg/ml). Hypokalaemia (3.2 mmol/l) was present and accompanied by a urine K+ concentration of 21 mmol/l, a urine K+/creatinine ratio of 2.3 and a transtubular K+ concentration gradient (TTKG) of 7. The urinary excretion of calcium was high (248 mg/day, 6.2 mmol/day, calcium/creatinine 0.64 vs our upper limit of normal being 0.4 in mmol terms), and the urinary excretion of inorganic phosphate was very low (65 mg/day, 2.1 mmol/day).
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Soft tissue calcification was not seen on a chest X-ray, abdominal X-rays or a 99mTC-diphosphonate whole body bone scan. Abdominal sonography revealed normal-sized kidneys, and nephrocalcinosis was not detected. There was no evidence of parathyroid gland enlargement on sonography. Band keratopathy was not seen on slit lamp examination. Panendoscopy did not reveal any malignancy.
Initial therapy included intravenous isotonic saline to re-expand his extracellular fluid (ECF) volume. His plasma calcium concentration fell between days 1 and 3 to 7.0 mg/dl (1.8 mmol/l); his plasma PTH level was 10-fold higher when he became hypocalcaemic. These data suggest that the fall in calcium input and the expanded ECF volume may have led to hypocalcaemia. At this point, his PTH level rose to 32 pg/ml. The degree of rise in PTH was less than reported by previous workers [9] and may represent the degree of PTH reserve or down-regulation that may occur with chronic hypercalcaemia. Nevertheless, either this degree of rise in PTH and/or a decreased rate of calcium excretion led to the subsequent rise in his plasma calcium concentration to the normal range (Table 2). Hypercalcaemia and metabolic alkalosis resolved completely within 1 week (Table 2
). Although the patient's renal function improved considerably in this time interval, his GFR remained significantly depressed on discharge; serum creatinine declined initially from 9.7 to 3.0 mg/dl (844 to 251 µmol/l) (Table 2
). The progress of his recovery in GFR could not be documented because he was lost to medical follow-up. The patient was advised to stop chewing betel nuts and, while in our care, he decreased his consumption to fewer than five nuts per day.
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Additional studies
Exposure of a calcium carbonate precipitate to an inorganic phosphate buffer
This experiment was designed to simulate events in the intestinal tract downstream from the duodenum. When 1 mmol of CaCO3 was added to 2.5 mmol of inorganic phosphate at pH 7.4 for 12-h, much of the flaky CaCO3 precipitate was converted to a hard, white precipitate of insoluble calcium phosphate (Ca3(PO4)2) over 12 h despite the absence of added H+. There was no detectable ionized calcium remaining in the solution. The content of inorganic phosphate fell progressively to 2.1 mmol as more precipitate formed, implying that 60% of the CaCO3 was converted to Ca3(PO4)2 at this time point.
Calcium carbonate exposure to HCl
When increasing amounts of HCl were added to a solution containing 1 mmol CaCO3, ionized calcium was released in a linear and equivalent fashion by the added H+ (Figure 1). Hence, 100 mEq H+ would need to be produced by bacterial fermentation in the lower intestinal tract to convert the total amount (50 mmol) of ingested CaCO3 to ionized calcium. Much smaller amounts of H+ would be needed to dissolve only a portion of the CaCO3; the patient only excreted 6 mmol of calcium in 24 h.
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Discussion
Our aim was to identify the risk factors leading to the development of the major electrolyte abnormalities, including hypercalcaemia, metabolic alkalosis, and hypokalaemia, in association with excessive calcium and alkali intake. Considerable emphasis was placed on the case synopsis because it illustrates an under-emphasized cause being a high intake of alkaline calcium salts in conjunction with a low absorption of inorganic phosphate.
Hypercalcaemia
Calcium is absorbed in the duodenum by a highly regulated transcellular route, and downstream in the intestinal tract both by a regulated and by a passive non-regulated paracellular route, provided that calcium is in its ionized form [5]. The major regulator of intestinal ionized calcium absorption is 1,25-(OH)2D3; ionized calcium is formed when Ca(OH)2 or CaCO3 reacts with HCl secreted in the stomach (Figure 2). Calcium remains ionized until sufficient sodium bicarbonate is secreted into the duodenum to form a luminal CaCO3 precipitate.
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If the CaCO3 precipitate formed in the duodenum were to remain intact downstream in the intestinal tract, there might be little further absorption of calcium. However, CaCO3 can be converted to ionized calcium in the lumen of the lower intestinal tract if there is a local source of H+ (Figure 3) [5]. Bacterial fermentation of undigested carbohydrates can provide 300 mmol of H+ per day [12]. Only a few mmol of H+ would be needed to dissolve enough CaCO3 to yield a luminal ionized calcium concentration exceeding that of plasma. This would permit passive calcium absorption if anions, such as inorganic phosphate, that could remove ionized calcium by precipitation were not present in the lumen of the intestinal tract, as shown by Equation 1:
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Metabolic alkalosis
The ingestion of CaCO3 could provide an absorbable form of alkali if organic acids were produced in the lumen of the intestinal tract, provided that their conjugate bases (acetate, proprionate and butyrate) were absorbed and metabolized to yield neutral metabolic end-products plus bicarbonate ions [19] (Figure 3). In fact, hypercalcaemia might augment the formation of organic acids and enhance the absorption of ionized calcium by slowing GI motility. One can obtain a crude estimate of how much alkali was absorbed along with calcium in our index case by examining the rate of excretion of calcium, at least in one 24 h urine collection period [7]. For the alkali accompanying calcium to remain as a bicarbonate in the body, calcium must remain in an ionic form or be excreted with an anion other than bicarbonate (e.g. Cl- from NaCl). Therefore the alkali load attributed to the net absorption of Ca(OH)2 is equal to the daily renal excretion of ionized calcium (12 mEq/day). Because our patient was excreting more than 12 mEq of bicarbonate per day in his urine (pH 7.5, volume 1.1 l/day), another source of alkali would be needed to be in positive alkaline balance. Given his urine pH and GFR, the alkaline source was likely to have been a non-renal one because low excretion of ammonium means little addition of new bicarbonate to the body [20]. As shown in Figure 3
and Equation 1, the patient could, in theory, convert two-thirds of the alkali (carbonate) from the poorly absorbable CaCO3 into absorbable alkali by precipitation reactions in the intestinal tract.
Nevertheless, ingesting alkaline substances, even in large amounts, is not sufficient to cause the development of chronic metabolic alkalosis in normal subjects [21]. In subjects with marked renal insufficiency, the intake of NaHCO3 could lead to the development of metabolic alkalosis. If this were the sole cause, the ECF volume should be expanded. In contrast, if vomiting provided the bicarbonate load, the ECF volume would remain near its normal value. Given our patients very low GFR, the metabolic alkalosis could be due in part to the input of bicarbonate, and due to a low rate of bicarbonate excretion because of the low filtered load for this ion. Therefore, the presence of calcium in the alkali load or the absence of a large intake of Na+ (in NaHCO3) might play a critical role in the metabolic alkalosis in our index case. Hence renal mechanisms were sought to explain why chronic metabolic alkalosis was present in this patient. Hypercalcaemia and suppressed levels of PTH enhance the renal reabsorption of bicarbonate (left portion of Figure 4) [22] by stimulating the Na+/H+ exchanger [23]. If enhanced proximal reabsorption of bicarbonate were the sole mechanism involved in this process, one would anticipate an expanded rather than a contracted ECF volume, as was seen in our case. Therefore we looked for a link between hypercalcaemia, metabolic alkalosis and a low ECF volume.
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Renal failure
Hypercalcaemia can cause arteriolar vasoconstriction within the kidney, a reduction in the ultrafiltration coefficient, a reduction in tubular Na+ reabsorption, acute tubular necrosis, nephrocalcinosis, and tubulointerstitial fibrosis, all of which can result in renal dysfunction via decreased GFR or direct tubular damage [2931]. The coexistence of hyperphosphataemia, hypercalcaemia, ECF volume reduction and metabolic alkalosis could promote renal parenchymal calcification, an important pathological aspect of the syndrome that contributes to the development of renal dysfunction.
Perspectives
Patients who may be at risk of developing hypercalcaemia and secondary metabolic alkalosis include those individuals given CaCO3 and vitamin D supplements to delay the development of osteoporosis. Risk factors, such as low phosphate intake and factors that might affect the process of bacterial fermentation, should also be considered. These patients may be recognized initially by finding hypercalciuria, subtle symptoms attributable to hypercalcaemia, an unexplained fall in GFR, or by the presence of electrolyte abnormalities such as hypercalcaemia, hypokalaemia and metabolic alkalosis. A high urine calcium:creatinine ratio in a random urine sample might be a reasonable screening test for the detection of a population at risk of these complications.
Patients with renal failure are often treated with CaCO3 to ensure that some of their dietary phosphate is converted to a non-absorbable form. This therapy should not lead to harmful effects related to excessive calcium absorption as long as their intestinal lumen contains more inorganic phosphate plus oxalate than ionized calcium. Notwithstanding, should a rare patient take too much CaCO3, ingest too little dietary phosphate, and/or have an altered bacterial flora that decreases the availability of luminal oxalate, excessive absorption of calcium could occur. In this situation, hypercalcaemia and/or metastatic calcification might develop.
Concluding remarks
Our interpretation of the pathophysiology of hypercalcaemia, hypokalaemia and metabolic alkalosis in the case presented includes roles for the conversion of oral alkaline calcium salts to an absorbable form of ionized calcium due to bacterial production of H+ in the GI tract. Key to this being a potential clinical problem is the presence of a low phosphate intake and/or the presence of phosphate binders in the lumen. Another risk factor is the consumption of the precursors of 1,25-(OH)2D3 that could stimulate calcium absorption in the intestinal tract. At the renal level, hypercalcaemia could cause a Bartter's-like syndrome due to a loop diuretic-like effect contributing to the development of hypokalaemia, a K+ deficit, a contracted ECF volume and an enhanced reabsorption of bicarbonate in the proximal convoluted tubule.
Notes
Correspondence and offprint requests to: Shih-Hua Lin, MD, Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, Number 325, Section 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan. Email: L521116{at}ndmc1.ndmctsgh.edu.tw
References