Hypophosphatemia: Clinical manifestations of phosphate depletion

INTRODUCTION — When combined with phosphate depletion (that is, when not due solely to phosphate movement into cells), hypophosphatemia can cause a variety of symptoms and clinical manifestations [1,2]. The manifestations depend, in large part, upon the severity and chronicity of the phosphate depletion, with the plasma phosphate concentration usually being below 1 mg/dL (0.32 mmol/L) in symptomatic patients.

The major conditions associated with symptomatic hypophosphatemia are chronic alcoholism, intravenous hyperalimentation without phosphate supplementation, urinary phosphate-wasting syndromes (such as Fanconi syndrome or tumor-induced osteomalacia), and the chronic ingestion of antacids or other phosphate binders. Significant hypophosphatemia is also observed in patients receiving continuous kidney replacement therapies, yet the clinical relevance of this finding remains uncertain. (See "Hypophosphatemia: Causes of hypophosphatemia".)

Severe hypophosphatemia can also be seen during treatment of diabetic ketoacidosis and with prolonged hyperventilation; however, symptoms are unusual in these settings since the hypophosphatemia is acute and there is no preexisting chronic phosphate depletion [3]. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", section on 'Phosphate depletion'.)

Except for the effects on calcium and magnesium metabolism, the clinical manifestations of hypophosphatemia are primarily due to the consequences of intracellular phosphate depletion, which can affect many organ systems. The symptoms and organ-specific pathologies related to hypophosphatemia will be reviewed here. The diagnostic approach to and treatment of hypophosphatemia are discussed separately. (See "Hypophosphatemia: Evaluation and treatment".)

EFFECTS OF HYPOPHOSPHATEMIA ON MINERAL METABOLISM AND BONE — Prolonged hypophosphatemia results in defects in both kidney mineral handling and bone architecture. Distal tubular reabsorption of calcium and magnesium are inhibited, and striking hypercalciuria ensues. This response to phosphate depletion is dramatic, but the mechanism is unknown. Not uncommonly, patients with idiopathic hypercalciuria have mild hypophosphatemia, and it has been suggested that impaired phosphate balance may be the primary abnormality, with enhanced calcium excretion representing a secondary effect. Chronic hypercalciuria increases the risk of crystalluria and kidney stone formation. Not surprisingly, patients with this disorder can exhibit microscopic or macroscopic hematuria and flank pain.

The initial response of bone to hypophosphatemia is increased resorption; the associated release of bone calcium contributes to the hypercalciuria. This effect may be mediated, in part, by the phosphate depletion-induced rise in the synthesis of calcitriol (1,25-dihydroxyvitamin D) (see "Overview of vitamin D", section on 'Metabolism'). More prolonged hypophosphatemia, over a period of months to years, leads to rickets and osteomalacia, due to decreased bone mineralization. These patients with prolonged phosphate depletion can experience significant musculoskeletal pain, bone deformities, and are at substantial long-term risk for fractures.

EXTRASKELETAL EFFECTS OF PHOSPHATE DEPLETION — Most of the extra-skeletal effects of hypophosphatemia are due to two consequences of prolonged intracellular phosphate depletion, which impact virtually all organ systems. These include:

●A reduction in red blood cell 2,3-diphosphoglycerate (DPG) levels, thereby increasing the affinity of hemoglobin for oxygen and reducing oxygen release at the tissue level [4].

●Decreased intracellular concentrations of adenosine triphosphate (ATP), leading to a failure of cellular functions dependent upon this energy-rich phosphate compound.

Central nervous system — Severe hypophosphatemia, defined as a phosphate concentration below 1 mg/dL (0.32 mmol/L), can lead to metabolic encephalopathy that results from ATP depletion. A broad spectrum of neurologic symptoms have been associated with prolonged phosphate depletion, ranging from mild irritability and paresthesias to more severe manifestations such as delirium, generalized seizures, and coma [2,5,6]. Severe phosphate depletion is also speculated to contribute to the development of central and extrapontine myelinolysis [7-9]. However, given that the clinical conditions that commonly result in total body phosphate depletion can have diverse central nervous system (CNS) effects that appear independent of abnormalities in phosphate homeostasis, it is difficult to decipher the independent contribution of prolonged hypophosphatemia to this CNS pathology.

Cardiopulmonary system — Myocardial contractility may be impaired with ATP depletion [10], and phosphate administration appears to improve cardiac function, especially in patients with severe hypophosphatemia, defined as a plasma phosphate below 1 mg/dL (0.32 mmol/L) [11,12]. In addition, hypophosphatemia has been associated with a higher incidence of ventricular arrhythmias in the setting of acute myocardial infarction [13] and an increased requirement of vasoactive drug support following cardiac surgery [14]. Thus, in patients presenting with otherwise unexplained symptoms of heart failure (eg, dyspnea, orthopnea, edema), it may be reasonable to screen for phosphate deficiency.

Pulmonary function can also be directly impacted by prolonged hypophosphatemia. Diaphragmatic contractility can be substantially impaired in this setting [15], and several studies suggest that hypophosphatemia is associated with prolonged ventilator dependency in critically ill patients [16,17].

Skeletal and smooth muscle — Hypophosphatemia-induced manifestations of muscle dysfunction include a proximal myopathy (affecting skeletal muscle) [18], dysphagia, and ileus (affecting smooth muscle), which can manifest as patient complaints of muscle weakness, inability or difficulty swallowing, or abdominal distension or pain, respectively.

In addition, acute hypophosphatemia superimposed upon preexisting severe phosphate depletion can lead to rhabdomyolysis [19,20]. Although creatine phosphokinase (CPK) elevations are not uncommon in hypophosphatemia, clinically significant rhabdomyolysis has been described most commonly in patients with a history of alcohol use disorder, poorly controlled diabetes mellitus, or those who are severely malnourished and receiving hyperalimentation without adequate phosphate supplementation [20-22].

The development of rhabdomyolysis with the associated release of phosphate from the damaged muscle cells has two clinical consequences: It may mask the underlying hypophosphatemia and may therefore protect against the development of other hypophosphatemic symptoms [19,20]. The demonstration of a low plasma phosphate concentration before or after the peak muscle breakdown may be the only clue to the underlying phosphate depletion.

Hematologic dysfunction — Hypophosphatemia can also affect each of the components of the hematopoietic system.

Red blood cells — A reduction in intracellular ATP levels increases erythrocyte rigidity, predisposing to hemolysis, which can be seen when the plasma phosphate concentration falls below 0.5 mg/dL (0.16 mmol/L) [23,24]. However, clinically evident hemolysis due solely to hypophosphatemia is rare.

White blood cells — Diminished intracellular ATP levels reduce both phagocytosis and granulocyte chemotaxis [25]. This complication is also rare and only seen with severe hypophosphatemia. It is unclear how any potential alterations to white blood cell biology may translate to overall immune function or clinical manifestations.

Platelets — Defective clot retraction and thrombocytopenia can occur, which can aggravate mucosal hemorrhage. As with the effects on red blood cells, the effects of platelet dysfunction related to phosphate deficiency likely occur only with profound hypophosphatemia.

SUMMARY

●General principles – The manifestations of hypophosphatemia depend upon the severity and chronicity of the phosphate depletion. Most symptomatic patients have a plasma phosphate concentration below 1 mg/dL (0.32 mmol/L).

The effects of hypophosphatemia may be categorized into those that arise from associated alterations to mineral metabolism and those due to intracellular phosphate depletion. (See 'Introduction' above.)

●Effects on mineral metabolism and bone – Hypophosphatemia-induced changes in mineral metabolism include a decrease in distal tubular reabsorption of calcium and magnesium and increased bone resorption, both resulting in hypercalciuria. Increased bone resorption is likely mediated by the phosphate depletion-induced rise in the synthesis of calcitriol (1,25-dihydroxyvitamin D). Prolonged hypophosphatemia may lead to rickets and osteomalacia. (See 'Effects of hypophosphatemia on mineral metabolism and bone' above.)

●Extraskeletal effects

•Decreased intracellular ATP levels may cause metabolic encephalopathy, impaired myocardial contractility, respiratory failure due to weakness of the diaphragm, a proximal myopathy, dysphagia, and ileus. (See 'Central nervous system' above and 'Cardiopulmonary system' above and 'Skeletal and smooth muscle' above.)

•Acute hypophosphatemia superimposed upon preexisting severe phosphate depletion may cause rhabdomyolysis. Due to the release of intracellular phosphate from damaged muscle cells, rhabdomyolysis may mask underlying hypophosphatemia and therefore protect against the development of other hypophosphatemic symptoms. (See 'Skeletal and smooth muscle' above.)

•The hematologic effects of a hypophosphatemia-induced decrease in intracellular ATP levels include an increased predisposition to hemolysis, a decrease in both phagocytosis and granulocyte chemotaxis, and defective clot retraction and thrombocytopenia. (See 'Hematologic dysfunction' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Zalman S Agus, MD, who contributed to an earlier version of this topic review.