Osteoporosis due to which electrolyte imbalance

These substances are present in your blood, bodily fluids, and urine. An electrolyte disorder occurs when the levels of electrolytes in your body are either too high or too low. Electrolytes need to be maintained in an even balance for your body to function properly.

Otherwise, vital body systems can be affected. Severe electrolyte imbalances can cause serious problems such as coma, seizures , and cardiac arrest. Mild forms of electrolyte disorders may not cause any symptoms. Symptoms usually start to appear once a particular disorder becomes more severe. Electrolyte disturbances can become life-threatening if left untreated. Electrolyte disorders are most often caused by a loss of bodily fluids through prolonged vomiting, diarrhea, or sweating.

They may also develop due to fluid loss related to burns. Certain medications can cause electrolyte disorders as well. In some cases, underlying diseases, such as acute or chronic kidney disease , are to blame.

Calcium is a vital mineral that your body uses to stabilize blood pressure and control skeletal muscle contraction. Hypercalcemia occurs when you have too much calcium in the blood.

This is usually caused by:. Hypocalcemia occurs due to a lack of adequate calcium in the bloodstream. Causes can include:.

It can happen as a result of:. Magnesium is a critical mineral that regulates many important functions, such as:. Hypermagnesemia means excess amounts of magnesium. Hypomagnesemia means having too little magnesium in the body. Common causes include:. The kidneys , bones, and intestines work to balance phosphate levels in the body. Phosphate is necessary for a wide variety of functions and interacts closely with calcium. Hyperphosphatemia can occur due to:. Low levels of phosphate, or hypophosphatemia , can be seen in:.

Potassium is particularly important for regulating heart function. It also helps maintain healthy nerves and muscles. Hyperkalemia may develop due to high levels of potassium.

This condition can be fatal if left undiagnosed and untreated. Hypokalemia occurs when potassium levels are too low. This often happens as a result of:. Sodium is necessary for the body to maintain fluid balance and is critical for normal body function. It also helps to regulate nerve function and muscle contraction.

Abnormally high levels of sodium may be caused by:. A high calcium level may result from a problem with the parathyroid glands, as well as from diet, cancer, or disorders affecting Merck and Co. From developing new therapies that treat and prevent disease to helping people in need, we are committed to improving health and well-being around the world.

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Common Health Topics. Electrolyte Balance. Test your knowledge. The endocrine system is made up of glands and organs that regulate and control many bodily functions by producing and secreting hormones, chemicals that affect various bodily activities.

More Content. Click here for the Professional Version. Formation of bone and teeth. Parathyroid hormone. Was This Page Helpful? AQP1 might be expressed in breast cancer cells and it is associated with aggressive behavior. In fact, it correlates with higher grading, CK14 expression, smooth muscle actin expression, basal-like group, and poor prognosis [ 16 ]. They have been described during CRC progression and in liver metastases [ 17 ].

AQP5 over-expression was demonstrated to be associated with worse TNM stage, grading, and lymph node involvement [ 18 ]. AQP3 expression is positively regulated by endothelial growth factor pathway and it is associated with lymph node involvement, metastasis, and tumor differentiation [ 19 ].

Furthermore, a recent study showed that reduced AQP9 gene expression is associated with a lack of response to adjuvant chemotherapy [ 20 ]. AQP3 and AQP5 are also over-expressed in esophageal cancer cells compared to normal tissue and their co-expression seems to have a negative prognostic role [ 21 ].

The co-expression of AQP3 and AQP5, also described in gastric cancer, is associated with lymph node involvement and intestinal type [ 22 ]. Moreover, the damage is proportional to the severity of hyponatremia and concerns the recovery phase of VGSC.

On the other hand, hypernatremia increases the excitability of the membrane, reducing the response time of the channel. However, the effect of hyponatremic condition seems to be less destructive compared to situation of hyponatremia on the activity of Na ion channel [ 23 ]. Syndrome of inappropriate antidiuresis SIAD is a rare cancer paraneoplastic syndrome causing hyponatremia.

It is associated with overexpression of AQP in renal cells. These data suggest that alterations in serum sodium concentration might play an important role on the functionality of tumor cells that overexpress sodium channels and AQPs.

Finally, the importance of sodium in oncology is also underlined by another potential development field, sodium magnetic resonance imaging 23 NaMRI. Currently, the most promising application areas of 23 NaMRI are the early diagnosis of brain tumors and breast cancer [ 24 ]. It can arise rapidly within 48 h acute hypernatremia or, more frequently, slowly chronic hypernatremia. It represents the most common tumor-related electrolyte disorder. In particular, hyponatremia seems associated to poorer performance status [ 28 ] and reduced survival in patients with lung cancer [ 29 ] , renal cell carcinoma [ 30 ] , malignant pleural mesothelioma [ 31 ] , gastric cancer [ 32 ] , colon-rectal cancer [ 33 ] , and lymphoma [ 34 ].

Furthermore, hyponatremia seems to also have a negative role in hospitalized patients, as it was demonstrated to be associated with a longer length of hospital stay, inducing a negative impact on quality of live and prognosis and an increase in hospitalization costs [ 37 ]. In cancer patients, several causes might induce hyponatremia [ 1 ] :.

Cancer: paraneoplastic syndromes such as SIAD, brain metastasis, adrenal metastasis, and kidney metastasis can cause hyponatremia. Cancer-treatment: it can cause hyponatremia as a direct effect of their mechanism of action vinca alkaloids might induce SIAD; platinum derivates are frequently associated to hyponatremia; and target therapies, in particular antiangiogenetic agents, seem to induce hyponatremia, despite the underlying mechanism being unknown or as a result of side effects such as gastrointestinal losses vomiting and diarrhea caused by most of chemotherapeutic agents, target therapies, and immunotherapy , kidney loss, and heart failure cardiotoxic drugs such as anthracyclines and target therapies such as anti HER-2, anti-ALK, and anti-MEK.

Immunotherapeutic agents might cause direct damage to adrenal or pituitary gland, favoring hyponatremia development.

Concomitant drugs: diuretics, antibiotics, non-steroidal anti-inflammatory drugs NSAIDs , opioids, antidepressants, and neuroleptics can induce hyponatremia. Concomitant diseases: heart failure, kidney failure, thyroiditis, hypercortisolism, liver cirrhosis, pneumonia, and inflammatory lung or brain diseases can induce hyponatremia.

However, in most cases, more than one of the aforementioned factors might induce hyponatremia in cancer patients. These causes can be traced back to two different basic mechanisms: excessive free water for increased intake or reduced elimination or, rarely, sodium loss reduced intake or increased loss.

The knowledge of these two different mechanisms is fundamental for the differential diagnosis between the potential causes in order to set a correct therapeutic approach. Extracellular volume ECV status is fundamental to distinguishing the mechanism underlying hyponatremia. According to ECV status, hyponatremia can be classified in [Table 1] :.

Hypovolemic hyponatremia is often due to water loss, namely gastrointestinal loss vomiting, diarrhea , renal losses, bleeding, and cerebral salt wasting, caused by a dysfunction of hypothalamic-renal axis. Euvolemic hyponatremia, despite being rare, is an important and frequent condition in cancer patients. Several mechanisms induce euvolemic hyponatremia such as adrenal insufficiency, hypothyroidism, and SIAD.

It is characterized by a deregulated AVP activity, which induces a lower free water excretion. The relative free water surplus leads to serum euvolemic hypo-osmolar hyponatremia. It is often due to a paraneoplastic syndrome, related to several kinds of tumors. It is most frequently reported in patients with small-cell lung cancer, but it is also described in patients with non-small-cell lung cancer, head and neck cancer, and, rarely, other malignancies [ 26 ].

SIAD may be caused by [ 38 ] :. Although paraneoplastic syndrome is the most frequent cause of SIAD, it should be considered that many conditions might lead to an inappropriate release of AVP in cancer patients [ 39 , 40 ] :. Hypervolemic hyponatremia is characterized by an excess of both total body sodium and water. It occurs in edematous conditions such as cirrhosis, chronic kidney disease, nephrotic syndrome, and congestive heart failure [ 42 ].

According to serum osmolality status, hyponatremia can be divided into [ 43 , 44 ] :. This condition might be induced by an excessive water intake e. A correct and timely diagnosis of hyponatremia is essential to setting up a rapid therapy and improving the prognosis of cancer patients. Hyponatremia symptoms are often absent or generic and closely related to hyponatremia grade and onset speed [ 1 ].

Diagnosis of hyponatremia requires routine laboratory tests. For a correct therapeutic approach, it is crucial to identify the underlying causes, thus lab assessment should also include plasma and urine osmolality, ECV status evaluation, and urinary sodium concentration to obtain a correct differential diagnosis [Figure 1]. Figure 1. Hyponatremia management algorithm [ 38 , 44 - 48 ].

The correct management of hyponatremia and its treatment require the detection of its cause. Plasmatic osmolarity and ECV evaluation are necessary to recognize the origin of hyponatremia. Symptomatic hyponatremia should be treated with hypertonic saline solution. Tolvaptan should be considered in hyponatremia due to SIAD. In particular, due to different therapeutic options, it is fundamental to exclude SIAD. SIAD diagnosis is diagnosis of exclusion, for which the main criteria are:.

The therapeutic approach depends on etiology, presence of symptoms, and grade of hyponatremia [Figure 1]. Treatment options include fluid restriction, diuretics, saline solution administration, and vaptans selective vasopressin receptor antagonists. Fluid restriction is a difficult therapeutic choice since it is associated with poor compliance because cancer patients often need abundant hydration for oncological therapies.

Furthermore, several days are required to correct serum sodium concentrations. In the case of ECV, isotonic saline infusion should be preferred. In the case of hyponatremia secondary to SIAD, the use of Tolvaptan, a selective V2 receptor antagonist, should be considered [ 46 ]. In fact, has shown an important efficacy to correct and stabilize serum sodium concentration, favoring the beginning and prosecution of anticancer treatments without delay. Furthermore, it seems to reduce the risk of hyponatremia development as chemotherapy adverse event [ 47 ].

Tolvaptan schedule requires starting dose of 15 mg once daily and it should be administrated first in a hospital department to monitor the therapeutic response and any adverse event.

Other approved therapeutic agents are urea and Demeclocycline. However, due to their toxicity and poor patient compliance, they are no longer employed in clinical practice. It is important to monitor the rate of correction of hyponatremia since an excessive speed of rising sodium levels might cause the development of central pontine myelinolysis, an irreversible condition that leads to death.

Therefore, it is recommended to monitor plasma sodium levels in the first 24 h at regular intervals of h, in order to control the correction speed [ 49 ]. In cancer patients, several causes might induce hypernatremia [Table 2] [ 51 , 52 ] :. Cancer: anorexia and cancer cachexia, kidney damage, brain metastasis inducing diabetes insipidus, and gastrointestinal disorders due to cancer infiltration e.

Cancer treatment: adverse events such as vomiting and diarrhea common to most anti-cancer agents chemotherapy, TKIs, and immunotherapies associated with reduced thirst stimulation might cause hypernatremia. Elevated serum sodium concentration might be induced also by bowel direct damage due to antiangiogenetic agents or immunotherapy.

Furthermore, some chemotherapeutic agents such as ifosfamide might induce an iatrogenic diabetes insipidus. Concomitant drugs: osmotic diuretics, corticosteroids, enteral or parenteral nutrition, and hypertonic saline infusion can induce hypernatremia.

Two different basic mechanisms might be involved in hypernatremia development: water loss for reduced introduction euvolemic hypernatremia or increased elimination hypovolemic hypernatremia , or, rarely, accumulation of sodium often on iatrogenic basis, hypervolemic hypernatremia.

Understanding these mechanisms is crucial for a correct differential diagnosis among potential causes of hypernatremia. The most frequent mechanism underlying hypernatremia is total body water loss due to impaired thirst stimulation. It is often associated with altered mental status conditions, such as older age, brain tumors, damage, or surgery, causing a deficit in thirst and osmoregulation [ 51 ].

Water loss can also be due to renal or extra renal disorders [ 52 ]. Renal water loss usually is caused by osmotic diuresis e.

Rarely, renal water loss can be induced by insipidus diabetes, a deficit of the vasopressin-ADH-receptor system, which can have a central or a nephrogenic origin.

Central insipidus diabetes is characterized by a reduced secretion of AVP, often related to a central nervous system damage e. Nephrogenic insipidus diabetes instead depends on renal resistance to the action of AVP. It is a rarely congenic condition, more frequently related to iatrogenic effect of amphotericin B, lithium, ifosfamide, foscarnet, and streptozocin on tubular reabsorption of water [ 53 ]. Extra-renal water loss is often related to gastrointestinal diseases vomiting, nasogastric drainage, and diarrhea.

Rarely, hypernatremia can be caused by excessive salt intake. This condition is often iatrogenic and induced by parenteral administering of hypertonic solutions or chronic nutrition support with hyperosmolar or high protein feeds [ 55 ]. Hypernatremia causes neurological symptoms, for which severity is correlated with both grade and onset speed. In most cases, patients refer non-specific symptoms such as thirst, anorexia, restlessness, nausea, muscle weakness, and confusion.

In the case of rapid onset or severe hypernatremia, patients might present lethargy, hyperreflexia, until convulsions, and coma [ 56 ]. Clinical suspicion of hypernatremia should be confirmed by laboratory exam. The correct diagnosis and the detection of specific causes or predisposing factors are crucial for a correct management [Figure 2]. Figure 2. The treatment of hypernatremia in cancer patients is based on the correction of the cause. For the differential diagnosis, the evaluation of volume and urinary sodium are fundamental.

DI: diabetes insipidus; EVC: extracellular volume. For a correct differential diagnosis between hyponatremia caused by excess of sodium intake and hyponatremia caused by loss of free water, the assessment of urine osmolality, urine sodium concentration, and urine volume should be obtained [ 57 ].

Concentrated urine is usually related to insufficient water intake or extra-renal losses. Conversely, hypernatremia is associated to elevated serum osmolality and low urine osmolality renal damage with deficient capacity of urinary concentration [ 56 ].

Hypernatremia associated to polyuria e. Once hypernatremia diagnosis is confirmed, the optimal management requires the removal of the cause and the correction of the electrolyte disorder based on the total ECV, restoring intravascular volume and free water. In collaborating and asymptomatic patients without gastrointestinal dysfunction, oral hydration is effective, and should be preferred.

In patients with severe hypernatremia or unable to intake fluid orally due to vomiting or neurological changes , intravenous hydration should be considered. Loop diuretics should be considered in the case of pure sodium gain natriuresis. In patients with chronic hypernatremia or when time of onset is unknown, the correction should be obtained within 48 h, with a reduction of serum osmolality of no more than 0.

Monitoring serum sodium levels at regular intervals of 4 h is highly recommended to control the correction speed [ 59 ]. Patients experiencing central insipidus diabetes should receive nasal or oral desmopressin. Nephrogenic insipidus diabetes should be treated with a combination of thiazide diuretics and low sodium-low protein, removing potential precipitation factors [ 60 ].

Calcium is an extracellular cation and the normal serum calcium concentration range is 2. Most of the calcium content is deposited in the organic matrix by hydroxyapatite crystals of bones.

Acid-base status influences the binding between calcium and serum proteins. In particular, alkalosis favors the binding while acidosis induces the ionized calcium form.

Calcium derives from diet and it is excreted by kidney. Calcium reabsorption in kidney occurs mainly in the proximal tubules, and a small share in the ascending loop of Henle, thus loop diuretics decrease tubular calcium resorption, whereas thiazide diuretics improve its resorption [ 62 ]. Calcium metabolism requires a steady interaction between bone and ECF.

Several hormones are involved in calcium homeostasis. Parathyroid hormone PTH , whose secretion is mediated by reduced serum calcium levels, acts on bone, favoring osteoclastic-mediated bone resorption and promoting calcium leakage and it induces the synthesis of active vitamin D and calcium intestinal absorption. Vitamin D also plays a crucial role in serum calcium homeostasis, favoring increased intestinal calcium absorption and bone calcium storage [ 64 ]. Several studies demonstrated a crucial role of calcium-mediated signaling pathways in carcinogenesis, dedifferentiated into cancer stem cells, cellular motility favoring tumor invasion and metastasis, and the regulation of apoptosis [ 65 ].

Several calcium channels are involved and expressed in cancer cells. Calcium channels are also described in androgen-responsive prostate cancer. In fact, they mediate androgen-induced effects [ 67 ]. Transient receptor potential cation channel TRPC , subfamily C, is a group of channels expressed in cancer cells. In prostate cancer, TRPM8 expression is regulated by androgens.

In fact, it is not expressed in the healthy prostate cells and benign prostatic hyperplasia. Furthermore, its expression correlates with Gleason score and presence of metastases [ 69 ]. Several causes can induce hypocalcemia in cancer patients [Table 3] :. Cancer: malnutrition due to anorexia, cancer cachexia or bowel obstruction, malabsorption related to bowel tumor infiltration or previous intestinal surgery, abnormal liver function due to liver metastasis might promote the development of hypoalbuminemia and subsequent hypocalcemia [ 70 ].

Furthermore, malabsorption and malnutrition might frequently cause vitamin D deficiency and then hypocalcemia in cancer patients [ 70 ]. Another condition leading to hypocalcemia is PTH deficiency.

It is a common condition of patients undergoing total thyroidectomy with subtotal or total parathyroidectomy for cancer [ 71 ]. Paraneoplastic disorders are also involved in hypocalcemia in cancer syndrome. Such as tumor lysis syndrome or the hungry bone syndrome.

Cancer treatment: hypocalcemia is also reported in cancer patients receiving bisphosphonates or denosumab, an anti-RANKL receptor activator of nuclear factor kappa B ligand monoclonal antibody, employed in cancer patients with bone metastasis in order to delay or prevent skeletal-related events. In fact, they promote calcium deposition in the bones, reducing blood calcium concentration [ 73 ].

Therefore, checking calcium serum level before these treatments and implementation of calcium and vitamin D oral intake are recommended [ 74 ]. Furthermore, several drugs, such as chemotherapeutic agents, target therapies, immunotherapies can induce hypocalcemia in cancer patients, through different mechanisms: kidney injuries, iatrogenic magnesium-deficiency, gastrointestinal damage, pancreatitis [ 75 ].

In particular, monoclonal anti EGFR antibodies can cause hypomagnesemia with consequent hypocalcemia [ 75 ]. Concomitant drugs: diuretics and parenteral nutrition can induce hypocalcemia [ 70 ]. Concomitant diseases: kidney failure, autoimmune disorders causing PTH deficiency, sepsis, and pancreatitis can induce hypocalcemia [ 70 ].

Clinical manifestations of hypocalcemia are closely related to severity and time of onset. Symptoms and signs are influenced by other factors such as acid-base status, hypomagnesemia, and over-activity of sympathetic system [ 76 ]. Clinical disorders due to hypocalcemia depend on altered electrical potential of cell membrane, and it appears as an imbalanced neuromuscular excitability.

Chronic and mild hypocalcemia are often asymptomatic or they can present with muscle cramps, ectopic calcifications, parkinsonism, dementia, depression, psychosis, dry skin, and cataract. Severe or acute hypocalcemia might cause tetanic spasms, laryngospasm until generalized convulsions, and coma [ 76 ]. Severe hypocalcemia might also provoke cardiac alteration such as arrhythmias or heart block.

ECG shows typical alteration such as prolongation of the QTc and ST interval, altered repolarization, T-wave pointed shape, or inversion [ 77 ]. Since serum calcium is partially bound to proteins, it is suggested to correct total serum calcium concentrations with albumin levels [e. Alternatively, ionized calcium can be evaluated. For a correct differential diagnosis, serum albumin, total protein, urinary calcium, phosphate, vitamin D, plasma PTH, and parathyroid, renal, and liver function should be evaluated [Figure 3] [ 78 ].

Figure 3. Algorithm of hypocalcemia management [ 48 , 78 - 86 ]. For a correct diagnostic classification of hypocalcemia, it is essential to distinguish between hypoparathyroidism and other causes through the dosage of blood parathyroid hormone. In the case of high parathormone concentrations, dosage of vitamin D is useful to exclude deficiency. PTH: parathyroid hormone.

Treatment of hypocalcemia depends on severity, clinical manifestation, and underlying causes. When possible, it is always advisable to correct the cause of hypocalcemia [ 78 ]. To avoid adverse events, calcium gluconate should be infused slowly e. In fact, a rapid correction of hypocalcemia might increase the risk of cardiac arrhythmias, especially in patients receiving digoxin, thus cardiac activity should be monitored with ECG and correction rate of hypocalcemia should be checked every h during intravenous calcium gluconate infusion [ 79 ].

Moreover, concomitant hypomagnesemia or alkalosis should be corrected [ 80 ]. In the case of hypoparathyroidism, the treatment aims to control symptoms, maintaining adequate serum calcium levels 2.

Calcitriol, a vitamin D analog, is usually used with a starting dose of 0. Thiazide diuretics associated with a low phosphate diet could be considered [ 82 ]. It is recommended to monitor weekly serum calcium, phosphorus concentration, and creatinine during initial administration to obtain a correct stabilization of the dose [ 83 ]. In the case of chronic hypocalcemia, oral supplementation of calcium calcium carbonate or calcium citrate and vitamin D is recommended.

In the case of hypomagnesemia, it should be corrected [ 84 ]. Vitamin D insufficiency requires supplementation with oral or intramuscular ergocalciferol vitamin D2 or oral cholecalciferol vitamin D3. When hypocalcemia is secondary to vitamin D malabsorption, it is important to correct the underlying cause e. Patients receiving bisphosphonates or anti-RANKL should receive oral calcium and vitamin D supplementation to prevent hypocalcemia [ 86 ].

Hypercalcemia is defined as a higher serum calcium concentration total serum calcium over than It is a common electrolyte disorder in patients with advanced malignancies and it correlates with poor prognosis [ 88 ]. Several causes might contribute to the development of hypercalcemia in cancer patients [Table 4] :. Cancer: the main cause of hypercalcemia in cancer patients is hyperparathyroidism. It can be divided into primary and secondary hyperparathyroidism.

Primary hyperparathyroidism, the most common cause of hypercalcemia in the general population, is characterized by inappropriate secretion of PTH provoking elevated serum calcium concentrations. Single parathyroid carcinoma is a frequent cause of primary hyperparathyroidism, sometimes inducing a rare but life-threatening condition, hyperparathyroidism-induced hypercalcemic crisis characterized by elevated PTH concentrations times higher than normal values and serum calcium-levels [ 89 ].

Secondary hyperparathyroidism, instead, is characterized by elevated quantities of PTH, secreted by parathyroids. Several causes might contribute to this mechanism [ 90 ] , in particular malnutrition and cancer anorexia are the most common cancer related causes. Malignancies are an important cause of hypercalcemia. Even though several mechanisms underlay hypercalcemia in cancer patients, it seems to be correlated, especially in some kinds of tumors head and neck, lung, renal cell, ovarian, thyroid, endometrial, colorectal, breast cancer, hepatocarcinoma, cholangiocarcinoma, thymomas, neuroendocrine tumors, gastrointestinal stromal tumor, and leukemias , with the ectopic production of PTH or parathormone-related peptide PTHrP.

These factors seem responsible for osteoclastic activation, through an increased synthesis of RANKL, provoking bone destruction and calcium release.

Furthermore, they determine an increased renal calcium reabsorption, favoring the development of metastatic calcification involving multiple organs, especially lungs, potentially resulting in pulmonary edema [ 92 ]. Moreover, bone metastases, in particular osteolytic ones, are often associated to hypercalcemia due to calcium release from bone.

Bone metastasis releases several local factors, e. Rarely, hypercalcemia might be due to ectopic activity of 1-alpha-hydroxylase resulting in calcitriol production that promotes increased bone resorption with calcium release and intestinal calcium absorption. This mechanism is described in some kinds of tumors such as lymphomas lymphoma-associated calcitriol production and ovarian germ cell tumors [ 88 ].

Finally, immobilization due to bedridden patients, a common condition of advanced cancer, can favor an acceleration of bone resorption resulting in hypercalcemia [ 94 ].

Cancer treatment: antineoplastic drugs can indirectly cause hypercalcemia, for example through kidney damage [ 88 ]. Concomitant drugs: several drugs might cause hypercalcemia.

Thiazide diuretics, vitamin D intoxication, and parenteral nutrition are the most common agents involved in this electrolyte disorder in cancer patients. Concomitant diseases: several pathological conditions might cause hypercalcemia. It may depend on excess of PTH primary hyperparathyroidism due to parathyroid adenoma, familial hypocalciuric hypercalcemia, isolated familial hyperparathyroidism, or most commonly secondary hyperparathyroidism due to renal failure or drugs such as lithium or arise due to mechanisms independent of PTH chronic granulomatous disorders, hyperthyroidism, acromegaly, pheochromocytoma, and adrenal insufficiency [ 88 - 90 ].

To define an effective hypercalcemia, it is important to avoid the presence of concomitant factors that can influence the share of bound and free calcium e. Diagnosis is often incidentally during routine laboratory investigations, as most patients with mild hypercalcemia are asymptomatic [ 88 ]. Chronic hypercalcemia, due to hyperparathyroidism, is often asymptomatic; however, in some cases, this long-lasting electrolyte disorder might cause nephrolithiasis.

Instead, chronic hyperparathyroidism secondary to renal failure and dialysis might cause bone pain related to bone remodeling process, fibrous degeneration, and formation of cysts and nodules of fibrosis.

Clinical presentation depends on grade and time of onset. Most common symptoms are general malaise, thirst, lethargy, and constipation often associated with abdominal pain. Renal symptoms and signs such as polyuria, polydipsia, nycturia, nephrolithiasis, and rarely renal failure and nephrocalcinosis should be also considered.

Furthermore, hypercalcemia might cause cardiac arrhythmias. Renal function and immunoreactive parathyroid hormone analysis are recommended for a complete diagnostic classification that allows making differential diagnosis and to consider potential serious conditions cardiac arrhythmias. Electrocardiography should also be performed in order to avoid presence of cardiac alterations [ 95 ]. Generally, primary hyperparathyroidism is usually characterized by hypercalcemia with high ionized free serum calcium levels , hypophosphatemia, PTH being inappropriately high e.

Differential diagnosis between primary and secondary hyperparathyroidism could be difficult in the case of renal failure, although hyperphosphatemia is often linked to secondary hyperparathyroidism and normal or low phosphorus levels are indicative of primary hyperparathyroidism [ 96 ].

Furthermore, in the presence of secondary hyperparathyroidism, radiographic examination should be useful to detect bone cysts presence and bone reabsorption. It can be produced from breast, lung, and kidney cancer cells.

When possible, the individuation of PTHrP is useful for reach diagnosis of paraneoplastic hypercalcemia [ 88 ]. Treatment depends on clinical manifestation, grade of hypercalcemia, and underlying cause, which should be correct whenever possible [Figure 4]. In the case of mild symptoms, serum calcium levels are below Figure 4.

Algorithm of hypercalcemia management [ 48 , 88 , 94 - ]. To treat hypercalcemia, a correct diagnostic framework is essential, which is based on the parathyroid dosage to distinguish between hyperparathyroidism and other causes. Since hypercalcemia induces polyuria, most patients are dehydrated. Therefore, intravenous isotonic saline solution NaCl 0. In patients with edematogenic syndromes e.

Loop diuretics e. The use of furosemide should be limited in dehydrated patients or in patients presenting other electrolyte abnormalities magnesium and, potassium [ 99 ]. However, due to the risk of tachyphylaxis, the duration of treatment with calcitonin should not exceed 48 h [ ].

The addition of corticosteroids e. Corticosteroids are also use for the treatment of vitamin D intoxication, idiopathic hypercalcemia, and sarcoidosis [ ]. Finally, bisphosphonates, such as ibandronate, pamidronate, and mostly zoledronic acid, have been shown to be effective in reducing serum calcium in approximately 12 h [ ]. Recent evidence demonstrates the activity of denosumab in control malignant hypercalcemia, especially in patients with persistent hypercalcemia despite bisphosphonates.

Furthermore, it could also be used in patients with reduced renal function [ ]. Potassium is the second most abundant cation in the human organism. Normal serum potassium concentration ranges between 3. Many mechanisms act for preserving potassium homeostasis: oral intake, renal elimination, and balance between intracellular and extracellular concentration.

Renal active excretion of potassium in cortical collecting ducts is regulated by aldosterone, through the modification of the epithelial sodium channel into the open configuration and the increase of the number of epithelial sodium channel. This modification favors sodium reabsorption and increases potassium secretion [ ].

This ionic channel creates a concentration gradient across cell membrane, maintaining the potential of cell membrane. Several potassium channels are involved in cancer proliferation. Potassium channels KCN are a large group of proteins involved in potassium transfer. In prostate cancer, several potassium channels are involved.

In fact, it is over-expressed in cancer cells with Gleason score of , and in hormone sensitive phase. KCNK2 seems to be involved in the regulation of cell proliferation [ ].

In particular, over-expression of KCNH2 regulates cell invasion, giving an invasive phenotype to the tumor, and it represents a negative prognostic factor in early stages when associated with the absence of Glut It also seems to confer different chemosensitivity to different drugs; in particular, cells with over-expression of KCNH2 are inhibited by paclitaxel, vincristine, and hydroxy-camptothecin, while they seem to have resistance to doxorubin.

Overexpression of KCNH2 has been also demonstrated to be associated with poorer prognosis in squamous-cell carcinoma of esophagus [ ]. Over-expression of KCNH2 seems to also have a role in pancreatic cancer. In particular, it is involved in EGFR pathway, conferring an aggressive behavior and poorer prognosis [ ].

KCNH2 has also been investigated in gastric cancer. In particular, it has been demonstrated to be negatively correlated with grading, stage of disease, venous invasion, and shorter survival [ ].

Furthermore, it has been demonstrated to modulate VEGF-A secretion and cisplatin-induced apoptosis [ ]. Severe hypokalemia is defined as a potassium level lower than 2. Hypokalemia is a common electrolyte disorder in cancer patients. Several causes might induce hypokalemia in cancer patients [ ] :. Cancer: several conditions related to cancer might induce a reduced potassium intake malnutrition, anorexia, and malabsorption due to cancer bowel infiltration or bowel obstruction.

Some neuroendocrine tumors might cause hypokalemia through secretive diarrhea, favoring potassium losses. Other tumors induce renal potassium losses through the production of hormones such as adrenocorticotropic hormone ACTH , cortisol, and mineralocorticoids, or through kidney damage, such as multiple myeloma. Cancer treatment: chemotherapeutic agents, target therapies and immunotherapies might cause hypokalemia secondary to diarrhea or vomiting.

Concomitant drugs: thiazide diuretics, insulin, granulocyte growth factors, beta-2 agonists, and glucocorticoids might cause hypokalemia. Concomitant diseases: endocrine dysfunctions causing excess glucocorticoids or mineralocorticoids, toxic epidermal necrolysis, and inflammatory bowel diseases might cause hypokalemia.

Causes of hypokalemia might be resumed substantially in three mechanisms: an inadequate potassium intake, redistribution of potassium among intra- and extracellular compartments, and potassium losses [Table 5].

The passage of potassium into the intracellular compartment might depend on many mechanisms: uptake of potassium by tumor cells, alkalosis, hypothermia, and drugs. For example, granulocyte growth factors, often employed in cancer patients, provoke an acute hematopoietic cell formation, favoring rapid potassium intake by the new cells [ ].

Hypokalemia is similarly induced by rapid cell proliferation in acute leukemia [ ]. Potassium losses can be classified into renal and non-renal losses.

The most common extra-renal losses are gastrointestinal losses due to drugs or cancer-induced diarrhea and vomiting, infections, radiation enteritis, and type of tumors villous adenoma and neuroendocrine neoplasms [ ]. In particular, neuroendocrine neoplasms, although rare, are represented with the carcinoid syndrome characterized by serotonin and kallikrein hypersecretion inducing flushing, severe secretory diarrhea with cramps and hypokalemia, tachycardia, hypotension until heart failure, and bronchial constriction [ ].

Another rare syndrome due to tumor hypersecretion of vasoactive intestinal polypeptide induces important watery diarrhea with hypokalemia and achlorhydria [ ]. Renal losses have several potential causes. Endocrine disorders should be considered in cancer patients. For example, Cushing syndrome can be due in rare cases to ACTH-producing tumors, especially in patients with small-cell lung cancer, medullary thyroid carcinoma, islet cell adenoma or carcinoma, pheochromocytoma, and ganglioneuroma, inducing an excessive production of cortisol able to blind mineralocorticoid receptors inducing hypokalemia [ ].

Another rare cause is primary aldosteronism, due to the excessive and autonomous secretion of aldosterone by adrenal adenomas or carcinoma. This syndrome is characterized by polydipsia, polyuria, resistant hypertension, and severe hypokalemia [ ]. Furthermore, a common cause of potassium renal losses in cancer patients is drug-related tubular toxicity.

Several chemotherapeutic agents, target therapies, and immunotherapeutic drugs [Table 5] might induce renal injury associated to hypokalemia. Renal function should be evaluated before drug administration to avoid further renal damage [ ]. Concomitant therapies such as thiazide diuretics and glucocorticoids can favor potassium renal losses. Finally, some kinds of tumor induce renal damage.

For example, patients with multiple myeloma producing Bence-Jones proteins develop a progressive renal injury leading to hypomagnesemia and hypokalemia. Acute myeloid leukemia, through secretion of lysozyme, induces renal tubular damage [ ]. In hematological patients, especially in those with marked leukocytosis e. Clinical presentation depends on severity of hypokalemia.

Patients are often asymptomatic, especially those with mild hypokalemia [ ]. Symptoms and sign of hypokalemia are non-specific and due to muscular, neurological, or cardiac dysfunction.

The most common clinical manifestation is characterized by weakness, fatigue, myalgia, muscle cramps, and constipation. In the case of moderate or severe hypokalemia, neurological and psychiatric symptoms e.

In particular, cardiac arrhythmias represent life-threatening complications requiring immediate diagnosis and adequate treatment. Therefore, ECG monitoring should be performed in patients with hypokalemia typical alterations are inverted T waves, appearance of U wave, ST depression, and enlarged PR interval [ ].

Diagnosis of hypokalemia is based on detection of low serum potassium levels. For a correct management of hypokalemia, it is important to understand the underlying causes. Presence of pseudo-hypokalemia should be excluded in patients with marked leukocytosis. Furthermore, other laboratory exams should be performed for a correct differential diagnosis.

Blood sugar, acid-base balance, creatinine, magnesium levels, and urine electrolytes concentration should be evaluated [Figure 5] [ ]. In particular, h renal potassium concentration is useful to establish renal or extra-renal potassium losses.