Yếu toàn thể do Hạ calci máu và Giảm phosphate máu từ ức chế acid mạnh

Abstract

Potent gastric acid suppression can disrupt mineral homeostasis. An older woman receiving alfacalcidol developed weakness accompanied by profound hypophosphatemia with hypocalcemia and secondary hyperparathyroidism after initiation of the potassium-competitive acid blocker vonoprazan. Laboratory findings showed an elevated intact parathyroid hormone level and renal phosphate wasting, whereas her serum magnesium level was 2.7 mg/dL (reference range, 1.7–2.6 mg/dL) and her intact fibroblast growth factor 23 was 41.7 pg/mL (reference range, 19.9–52.9 pg/mL). The patient’s weakness and calcium–phosphate abnormalities resolved with mineral repletion and switching from vonoprazan to a proton-pump inhibitor. This case highlights that strong acid suppression may precipitate significant calcium–phosphate derangements despite active vitamin D therapy. Early evaluation of mineral metabolism and reassessment of acid-suppressive therapy are especially important in patients with unexplained weakness.

Background

Proton pump inhibitors (PPIs) are widely used for acid-related diseases 1. Profound acid suppression may reduce calcium bioavailability and disturb calcium–phosphate homeostasis. This could predispose susceptible patients to hypocalcemia with secondary hyperparathyroidism and renal phosphate wasting 1, 2. Potassium-competitive acid blockers (P-CABs) such as vonoprazan provide more potent and sustained acid suppression than PPIs but may exacerbate these disturbances 3.

Active vitamin D analogs, such as alfacalcidol, are commonly prescribed for osteoporosis 4. However, they may not prevent calcium–phosphate derangements when mineral availability is limited by poor intake or by depleted vitamin D stores 5.

We report a patient receiving alfacalcidol who developed weakness accompanied by hypocalcemia, profound hypophosphatemia, and secondary hyperparathyroidism after initiation of vonoprazan. The abnormalities resolved with calcium and phosphate repletion and switching from a P-CAB to a PPI.

Case Report

A 78-year-old woman with osteoporosis had anorexia with reduced oral intake and decreased outdoor activity for approximately 1 month before the current presentation. She developed melena and was admitted to an acute care hospital 22 days before the current presentation. Endoscopy revealed a bleeding peptic ulcer with high-risk stigmata. She received intravenous omeprazole and fluids. Eighteen days before the current presentation, she resumed oral intake and was given oral vonoprazan for acid suppression. After approximately 10 to 14 days of treatment with vonoprazan, she developed generalized weakness, and there was no improvement in activities of daily living. She was transferred to a subacute care hospital for rehabilitation.

The patient’s medical history included hypertension, dyslipidemia, type 2 diabetes mellitus, osteoporosis, and constipation. Medications included vonoprazan, alfacalcidol, irbesartan, amlodipine, bisoprolol, metformin, atorvastatin, and magnesium oxide. She continued taking home medications, including alfacalcidol; vonoprazan was the only newly initiated drug. Metformin was held during the initial hospitalization.

On admission, the patient’s vital signs were stable. Her muscle strength was normal on examination despite subjective weakness. Laboratory testing revealed a corrected calcium level of 7.5 mg/dL (reference range, 8.2–10.0 mg/dL), phosphate level of 0.8 mg/dL (reference range, 2.5–4.5 mg/dL), magnesium level of 2.7 mg/dL (reference range, 1.7–2.6 mg/dL), and creatinine level of 0.46 mg/dL (reference range, 0.46–0.82 mg/dL; Table 1). At original hospital admission (22 days before transfer), her calcium and phosphate levels were 9.2 mg/dL and 4.6 mg/dL, respectively; they were not reassessed thereafter. Her intact parathyroid hormone (iPTH) level was 252 pg/mL (reference range, 10–65 pg/mL) with a fractional excretion of phosphate (FEPO₄) of 47% (reference range, <20%). Given profound hypophosphatemia, weakness due to hypophosphatemia was suspected. The combination of hypocalcemia, elevated iPTH, and high FEPO₄ was consistent with secondary hyperparathyroidism with renal phosphate wasting. We continued alfacalcidol and administered intravenous sodium phosphate plus oral calcium aspartate. Her calcium and phosphate levels rapidly normalized with symptomatic improvement (Figure 1), followed by normalization of her iPTH level (46 pg/mL) and FEPO₄ (6.9%). Additional testing showed a 25-hydroxyvitamin D level of 15.6 ng/mL (reference range, 30–50 ng/mL) and 1,25-dihydroxyvitamin D level of 168 pg/mL (reference range, 18–78 pg/mL). The patient’s parathyroid hormone–related peptide level was <1.0 pg/mL (reference range, ≤1.1 pg/mL) and intact fibroblast growth factor 23 (FGF-23) level was 41.7 pg/mL (reference range, 19.9–52.9 pg/mL).

Vonoprazan was the only newly initiated medication; thus, impaired calcium absorption from potent acid suppression was suspected. We therefore changed her treatment from vonoprazan to lansoprazole on hospital day 10. No further calcium and phosphate repletion was required, and she was discharged on hospital day 20. In Japan, a 25-hydroxyvitamin D prescription is not available. Therefore, she was advised to start over-the-counter 25-hydroxyvitamin D supplementation at a dose of 1000 IU daily after discharge with outpatient follow-up, consistent with the 2024 Endocrine Society guideline recommending 800 to 2000 IU/day for older adults (6).

Discussion

Under strong acid suppression, reduced intestinal calcium availability can trigger secondary hyperparathyroidism, which promotes renal phosphate wasting and may culminate in severe hypophosphatemia. Hypophosphatemia should be considered in the differential diagnosis of unexplained generalized weakness, as it may be overlooked and is not routinely assessed in clinical practice.

Profound gastric acid suppression, particularly with P-CABs, may impair calcium bioavailability and disrupt mineral homeostasis. Gastric acidity is required for solubilization of dietary calcium salts, a substantial proportion of which exist as relatively insoluble forms such as calcium carbonate or calcium phosphate. It must be ionized into absorbable Ca²⁺ before small-intestinal uptake 1. Proton pump inhibitors have been shown to reduce calcium absorption by increasing intragastric pH 5. One group reported a 40% reduction after 14 days of omeprazole in women 7. Potassium-competitive acid blockers maintain higher intragastric pH longer than PPIs 3; thus, a stronger effect on calcium bioavailability is thought to be biologically plausible. In our patient, calcium and phosphate levels were normal at initial admission. However, those levels declined after initiation of vonoprazan, a temporal association that is compatible with this mechanism.

Secondary hyperparathyroidism provides a clinically actionable explanation for the coexistence of hypocalcemia and severe hypophosphatemia. Proton pump inhibitor–associated hypocalcemia with compensatory elevations in PTH levels has been previously described (2), and an increased PTH level promotes renal phosphate wasting through enhanced urinary phosphate excretion (8). In our patient, profound hypophosphatemia was accompanied by a markedly elevated iPTH level and a high FEPO₄, which supports PTH-mediated renal phosphate wasting as the proximate mechanism. Alternative causes of renal phosphate wasting were considered less likely because the patient’s FGF-23 level was not elevated, and there were no features of proximal tubular dysfunction, such as Fanconi syndrome (8). In addition, her serum magnesium level did not decrease, making hypomagnesemia-related disturbances in parathyroid hormone secretion unlikely in this case (9). The mildly elevated magnesium level was likely related to the patient’s use of magnesium oxide. Following calcium and phosphate repletion, her iPTH level and FEPO₄ normalized, which supports transient secondary hyperparathyroidism–driven phosphaturia as the primary mechanism. Although hypocalcemia and hypophosphatemia are classically associated with osteomalacia (5), several features in this case argue against a chronic bone mineralization disorder. Specifically, her alkaline phosphatase level was not elevated and her 1,25-dihydroxyvitamin D level was elevated. In addition, the patient’s calcium and phosphate concentrations were normal at the initial hospital admission, which supports an acute, reversible disturbance of mineral metabolism.

Low 25-hydroxyvitamin D levels are common in older adults, which may predispose them to disturbances in mineral metabolism. Causes of vitamin D insufficiency are multifactorial, which include diminished cutaneous synthesis, limited sun exposure, reduced dietary intake, and the effects of medication 5. With reduced sunlight exposure and intake, 25-hydroxyvitamin D levels can gradually fall over weeks to months 10. Gastric acid suppression has been proposed as a contributor to vitamin D insufficiency, but available evidence remains inconsistent 11. In our patient, anorexia preceding hospitalization, subsequent fasting, and reduced outdoor activity likely contributed to depleted vitamin D stores. This may have lowered the threshold for clinically apparent hypocalcemia and secondary hyperparathyroidism in the setting of potent acid suppression.

Active vitamin D analog therapy does not necessarily prevent hypocalcemia or hypophosphatemia when intestinal mineral availability is constrained. Active vitamin D analogs have greater biologic potency than 25-hydroxyvitamin D and are thought to enhance intestinal calcium and phosphate absorption while suppressing parathyroid hormone secretion (12). However, in the present case, hypocalcemia, hypophosphatemia, and markedly elevated iPTH levels developed despite continued alfacalcidol therapy, which suggested that pathophysiologic processes overriding the effects of exogenous active vitamin D were present. Importantly, after cessation of calcium and phosphate supplementation and switching from a P-CAB to a PPI, serum calcium and phosphate levels remained stable. This supports restoration of intestinal mineral availability as the primary driver of improvement.

Hypophosphatemia should be considered in the differential diagnosis of patients presenting with unexplained generalized weakness. Severe hypophosphatemia, defined as a serum phosphate level below 0.9 mg/dL, is known to frequently cause clinical symptoms 13. Muscle weakness is a common manifestation, partly attributable to impaired adenosine triphosphate production 13. Although the differential diagnosis of generalized weakness is broad, our patient lacked findings suggestive of other conditions that could account for the weakness. The rapid improvement after phosphate supplementation supports hypophosphatemia as the primary cause of the generalized weakness.

Potent acid suppression, particularly with P-CAB therapy, may be associated with disturbances in calcium–phosphate homeostasis. This may be especially possible in susceptible patients through secondary hyperparathyroidism and renal phosphate wasting. Active vitamin D therapy alone may be insufficient when intestinal mineral availability is limited. Early evaluation of calcium–phosphate metabolism and reassessment of acid suppression are warranted in symptomatic patients.