Introduction

Body fluids and electrolytes

• Total body mass: 45%–60% water
  • Intracellular fluid (ICF)
  • Extracellular fluid (ECF):
    • Interstitial compartment (majority of ECF)
    • Intravascular compartment
• Electrolytes:
  • Minerals with an electric charge
  • Electrolytes dissociate into cations (positively charged) and anions (negatively charged) when dissolved in water.

Electrolyte balance

The ICF and ECF compartments have different and unequal electrolyte distribution to maintain physiological function.

Intracellular fluid:

• K⁺: main intracellular cation
• Mg²⁺
• Phosphates (HPO₄²^–/H₂PO₄^–) electrically balance the intracellular cations along with the negatively charged proteins.

Extracellular fluid:

• Na⁺: 
  • Main extracellular cation
  • Important in determining serum osmolarity (solutes/L)
  • Controls ECF volume and water distribution in the body
• Calcium (Ca²⁺)
• Chloride and HCO₃^–: 
  • Chloride is the most abundant anion in the ECF.
  • Anions balance the extracellular cations.

Sodium

Overview

• Normal range: 135–145 mEq/L
• 95% of the ingested Na⁺ is absorbed by the gut.
• Excretion: 
  • 90%–95% excreted by the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys
  • Remainder through feces and sweat
• Functions:
  • Establishes osmotic pressure
  • Na⁺ transcellular gradient:
    • Regulated by ATP-dependent cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane channels: Na⁺-K⁺ ATPase
    • Essential in maintaining the resting membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential
  • Transient influx of Na⁺ generates action potential that leads to:
    • Nerve conduction
    • Muscle contraction
    • Cardiac conduction
    • Activation of intracellular signaling pathways

Regulation

• Na⁺ homeostasis: 
  • Regulated through the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys (majority in the proximal tubules)
  • Occurs by sensing changes in the effective circulating volume (ECV):
    • ↑ Na⁺ causes ↑ ECV
    • ↓ Na⁺ causes ↓ ECV
• RAAS:
  • Juxtaglomerular apparatus and carotid sinus/ aortic arch Aortic arch The branchial arches, also known as pharyngeal or visceral arches, are embryonic structures seen in the development of vertebrates that serve as precursors for many structures of the face, neck, and head. These arches are composed of a central core of mesoderm, which is covered externally by ectoderm and internally by endoderm. Branchial Apparatus and Aortic Arches baroreceptors trigger renin release from kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys when ECV ↓
  • If Na⁺ is low: ↓ ECV → renin → angiotensin (causing vasoconstriction) → aldosterone is secreted: 
    • Na⁺ reabsorption from the renal tubules
    • Promotes K⁺ secretion in urine
• Natriuretic peptides:
  • Includes atrial natriuretic peptide and BNP
  • If Na⁺ is high: ↑ ECV → cardiac baroreceptors sense an ↑ in ECV → natriuretic peptide is secreted 
    • Stimulates urinary Na⁺ excretion (natriuresis)
    • Also promotes excretion of water
    • Inhibits angiotensin II production

Related disorders

• Hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia: Na⁺ > 145 meq/L
• Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia: Na⁺ < 135 meq/L

Potassium

Overview

• Normal range: 3.5–5.2 mEq/L
• Excretion: 90% is excreted in the urine, 10% in feces
• Functions: 
  • ٌResting cellular membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential and the propagation of action potentials
  • Hormone secretion and action
  • Vascular tone
  • Systemic BP control
  • GI motility
  • Glucose and insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin metabolism
  • Concentrating ability of kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys and pH regulation

Regulation

• Kidneys are responsible for 90%–95% of the overall K⁺ regulation.
  • ↑ ECF K⁺ level triggers mechanisms for renal K+ excretion
  • Aldosterone:
    • Stimulates Na+-K⁺ ATPase
    • Increases K+ excretion into distal tubules and collecting ducts 
• Transcellular shifting (mediated by insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin and sympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System) prevents the excessive increase in ECF K⁺ levels.
  • β2 receptor activation:
    • Stimulates K⁺ uptake into cells (primarily into muscle and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver cells)
    • β2 antagonists block K⁺ uptake and cause hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia.
    • α1 receptor activation causes a shift of K⁺ out of the cells. 
  • Insulin:
    • Stimulates Na⁺-K⁺ ATPase
    • Increases K⁺ uptake into cells
    • Responsible for dietary uptake of K⁺ into cells after a meal
• Other factors:
  • Acid-base status:
    • Acidosis causes K⁺ to move out of cells.
    • Alkalosis causes K⁺ to move into cells.
  • Exercise: moves K⁺ out of muscle cells

Related disorders

• Hyperkalemia: K⁺ > 5.2 mEq/L
• Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia: K⁺ < 3.5 mEq/L

Chloride

Overview

• Normal range: 96–106 mEq/L

• Rapidly and almost totally absorbed by the GI tract
• Excretion: through GI tract, urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract, and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
• Functions:
  • Follows Na⁺ across cellular membranes to maintain charge neutrality
  • Maintenance of cell homeostasis 
  • Transmission of action potentials in neurons
  • Maintenance of ECF osmolarity (together with Na⁺), thus regulating:
    • Blood volume
    • BP 
  • Acid-base balance
  • Synthesis of gastric hydrochloric acid 
  • Control of epithelial fluid transport

Regulation

Chloride homeostasis:

• Mainly by the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys (through reabsorption in the tubules)
• Affected by acid-base disorders:
  • ↑ Chloride: associated with acidosis
  • ↓ Chloride: associated with alkalosis 
• Affected by changes in Na⁺ levels. Reabsorption is mediated by cation cotransporters in combination with Na⁺.

Related disorders

• Hyperchloremia (chloride > 106 mEq/L): 
  • From pure water loss (electrolyte-free fluid), such as hypotonic dehydration 
  • Administration of NaCl-containing fluids or hypertonic feeding
  • Acidosis:
    • Renal tubular acidosis Renal Tubular Acidosis Renal tubular acidosis (RTA) is an imbalance in physiologic pH caused by the kidney's inability to acidify urine to maintain blood pH at physiologic levels. Renal tubular acidosis exist in multiple types, including distal RTA (type 1), proximal RTA (type 2), and hyperkalemic RTA (type 4). Renal Tubular Acidosis
    • Small bowel diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea 
    • Pancreatic fistula
  • Drugs (acetazolamide)
• Hypochloremia (< 96 mEq/L):
  • Inadequate NaCl intake
  • Loss of chloride:
    • Vomiting: loss of hydrochloric acid in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach, leading to hypochloremic hypokalemic metabolic alkalosis Metabolic alkalosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic alkalosis also occurs when there is an increased loss of acid, either renally or through the upper GI tract (e.g., vomiting), increased intake of HCO3-, or a reduced ability to secrete HCO3- when needed. Metabolic Alkalosis
    • Gastric lavage
    • Burns Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns
    • Excessive use of diuretics or osmotic diuresis
    • In combination with hyponatremia

Calcium

Overview

• Normal range: 8.5–10.5 mg/dL
• Ca²⁺: metabolically active form (normal range 4.65–5.25 mg/dL)
• Most abundant mineral in the human body with 99% found in the skeleton
• Functions: 
  • Enzyme activity
  • Cellular functions related to cell division, exocytosis, communication
  • Muscle contraction
  • Cardiac contractility
  • Nerve conduction
  • Blood coagulation
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones mineralization

Regulation

• Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones, intestine, and kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys are involved in homeostasis.
• Key elements of Ca²⁺ regulation:
  • Parathyroid hormone (PTH) from parathyroid glands Parathyroid glands The parathyroid glands are 2 pairs of small endocrine glands found in close proximity to the thyroid gland. The superior parathyroid glands are lodged within the parenchyma of the upper poles of the right and left thyroid lobes; the inferior parathyroid glands are close to the inferior tips or poles of the lobes. Parathyroid Glands:
    • ↑ Vitamin D production in the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys 
    • ↑ Ca²⁺ reabsorption in the distal tubules and ↑ Ca²⁺ absorption in the intestines
    • ↑ Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones resorption (release of Ca²⁺ and HPO₄²^–/H₂PO₄^– from bones)
  • Vitamin D:
    • Activates osteoclasts to release Ca²⁺ and phosphorus
    • ↑ Intestinal Ca²⁺ and HPO₄²^–/H₂PO₄^– absorption
  • pH: 
    • ↑ pH (alkalosis) → ↑ binding to albumin = ↓ ionized Ca²⁺
    • ↓ pH (acidosis) → ↓ binding to albumin = ↑ ionized Ca²⁺
  • Albumin:
    • Every 1 g/dL ↓ in albumin → ↓ in Ca²⁺ by 0.8 mg/dL
    • Corrected Ca²⁺ (mg/dL) = measured total Ca²⁺ (mg/dL) + [0.8 x (4.0 – albumin concentration (g/dL))]
  • Other factors:
    • Calcitonin from the thyroid gland Thyroid gland The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland (opposes PTH →↓ Ca²⁺)
    • Hyperphosphatemia (↑ HPO₄²^–/H₂PO₄^– binding, ↓ Ca²⁺)
    • Hypomagnesemia (↓ PTH release → ↓ Ca²⁺)

Related disorders

• Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia: Ca²⁺ > 10.5 mg/dL
• Hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia: Ca²⁺ < 8.5 mg/dL

Magnesium

Overview

• Normal range: 1.5–2.2 mg/dL

• 4th most abundant cation in the body
• Mg²⁺ distribution in the body:
  • Skeleton: 55%
  • Soft tissue: 45%
  • ECF: 1% (about 55% free, with the remainder complexed with anions or protein)
• Functions:
  • Cofactor for enzymatic reactions involved in ATP and/or DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure synthesis
  • Cellular replication and biochemical processes (i.e., glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. Glycolysis)
  • Linked with Ca²⁺ and K⁺ homeostasis
  • Neuromuscular excitability:
    • Smooth muscle contraction and relaxation
    • Stabilization of cardiac muscle
  • Coagulation

Regulation

• Maintaining Mg²⁺ levels in the serum varies and depends on:
  • Intake
  • GI absorption
  • Renal reabsorption and excretion
• Kidneys will conserve Mg²⁺ when the levels are low and excrete the excess when the intake is high.
• Key elements:
  • Increased Mg²⁺ absorption in the presence of:
    • PTH
    • Vitamin D
    • Na⁺ in the diet
    • Thyroid hormone
  • Decreased Mg²⁺ absorption in the presence of:
    • Ca²⁺
    • Aldosterone (promotes excretion of Mg²⁺ with K⁺, and retention of Na⁺)

Related disorders

• Hypermagnesemia (Mg²⁺ > 2.2 mg/dL):
  • Overuse of Mg²⁺-containing laxatives Laxatives Laxatives are medications used to promote defecation. Most often, laxatives are used to treat constipation or for bowel preparation for certain procedures. There are 4 main classes of laxatives: bulk-forming, stimulant, osmotic, and emollient. Laxatives or antacids
  • Renal failure
  • Features: 
    • Generalized muscle weakness, nausea
    • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension 
    • Cardiac rhythm abnormalities (especially if Mg²⁺ > 6 mg/dL): prolonged PR, wide QRS, peaked T waves
  • Management includes calcium gluconate, diuresis, and dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Overview and Types of Dialysis.
• Hypomagnesemia (Mg²⁺ < 1.5 mg/dL): 
  • Alcoholism (most common electrolyte change is ↓ Mg²⁺)
  • Diarrhea and GI disease
  • Diuretic use
  • Proton pump inhibitor therapy
  • Common cause of refractory hypokalemia

Phosphate

Overview

• Normal range: 2.5–4.5 mg/dL (higher in children)
• 2 forms in the serum (depending on the acid-base status):
  •  Dihydrogen phosphate (H₂PO₄^–) 
  • Monohydrogen phosphate (HPO₄²^–)
• 85% of the total body phosphate is in the bones and teeth Teeth Normally, an adult has 32 teeth: 16 maxillary and 16 mandibular. These teeth are divided into 4 quadrants with 8 teeth each. Each quadrant consists of 2 incisors (dentes incisivi), 1 canine (dens caninus), 2 premolars (dentes premolares), and 3 molars (dentes molares). Teeth are composed of enamel, dentin, and dental cement. Teeth in the form of hydroxyapatite.
• Only 1% in the ECF
• Functions:
  • Required for cellular function and skeletal mineralization
  • Component of many metabolic intermediates (ATP) and nucleotides
  • Aerobic and anaerobic energy metabolism
  • O₂ delivery to tissues

Regulation

• Maintained by dietary intake, mobilization from the bone, and renal excretion
• Key elements:
  • Vitamin D: 
    • Increases HPO₄²^–/H₂PO₄^– reabsorption and release from bones
    • Renal tubular reabsorption: in proximal tubules through Na⁺-dependent phosphate (Na/Pi) cotransporter
  • PTH: increased HPO₄²^–/H₂PO₄^– excretion by the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys
  • Fibroblast growth factor (FGF)-23: 
    • Produced by osteocytes
    • Inhibits renal production of vitamin D →↓ HPO₄²^–/H₂PO₄^– reabsorption
    • Inhibits GI HPO₄²^–/H₂PO₄^– absorption

Related disorders

• Hyperphosphatemia (HPO₄²^–/H₂PO₄^– > 4.5 mg/dL):
  • Renal failure
  • Hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Hypoparathyroidism
  • Tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome
  • Rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis
  • Vitamin D toxicity
• Hypophosphatemia (HPO₄²^–/H₂PO₄^– < 2.5 mg/dL):
  • Decreased intake ( malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion, alcoholism)
  • Hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism
  • Refeeding syndrome (patients who are malnourished experience sudden insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin release with parenteral nutrition, shifting HPO₄²^–/H₂PO₄^– intracellularly)

Bicarbonate

Overview

• Normal range: 22–28 mEq/L
• Functions:
  • Indirect indicator of total CO₂ level in serum
  • Vital component of pH regulation
  • HCO₃^– buffer system: the balance between carbonic acid (H₂CO₃), HCO₃^–, and CO₂, which maintains blood pH:

                                      CO₂ + H₂O ⇆ H₂CO₃ ⇆ H⁺ + HCO₃^–

Regulation

To maintain homeostasis, the following mechanisms are triggered to keep the pH in the physiological range (7.35–7.45):

• Respiratory compensation: 
  • Changes in ventilation compensate for changes in the blood HCO₃^– levels.
  • Lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs respond to metabolic acidosis by ↑ ventilation
  • Lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs respond to metabolic alkalosis by ↓ ventilation
• Renal compensation: 
  • Kidneys regulate the secretion of H⁺ into the urine, and, at the same time, reabsorb HCO₃^– (normally 100% is absorbed).
  • Kidneys respond to respiratory acidosis by increasing serum HCO₃^– levels through ↑ secretion of H⁺
  • Kidneys respond to respiratory alkalosis by decreasing serum HCO₃^– through ↓ secretion of H⁺ and urinary excretion of HCO₃^–

Related disorders

• Metabolic disorders: primarily caused by abnormal HCO₃^– levels
  • Metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis
  • Metabolic alkalosis
• Respiratory disorders: primarily caused by abnormal CO₂ levels
  • Respiratory acidosis Respiratory acidosis The respiratory system is responsible for eliminating the volatile acid carbon dioxide (CO2), which is produced via aerobic metabolism. In the setting of hypoventilation, this acid load is not adequately blown off, and respiratory acidosis occurs. Renal compensation occurs after 3-5 days, as the kidneys attempt to increase the serum bicarbonate levels. Respiratory Acidosis
  • Respiratory alkalosis Respiratory alkalosis The respiratory system is responsible for eliminating the volatile acid carbon dioxide (CO2), which is produced via aerobic metabolism. When hypoventilation occurs, excess carbon dioxide is blown off and respiratory alkalosis develops. The kidneys respond by decreasing serum bicarbonate (HCO3-) through increased HCO3- excretion or decreased excretion of H+. Respiratory Alkalosis

Clinical Relevance

Disorders related to sodium levels

• Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia: a condition defined as Na⁺ < 135 mmol/L. Severe hyponatremia is defined as Na⁺ < 120 mEq/L. Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia occurs in the case of severe diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea (with both Na⁺ and water losses) and SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) (increased total body water). Symptoms can be absent, mild, or severe (confusion, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma). Acute severe hyponatremia and neurologic or hemodynamic compromise require an urgent supplementation of serum Na⁺, which is best accomplished using hypertonic (3%) NaCl. If untreated, the complications include acute cerebral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema and osmotic demyelination syndrome. In all other cases, the gradual correction of Na⁺ levels is preferred.
• Hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia: a condition defined by serum Na⁺ > 145 mEq/L. The vast majority of cases are chronic where there is a slow rise in plasma tonicity. Increased Na⁺ levels are seen in diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea (hypovolemic) and diabetes insipidus Diabetes Insipidus Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of DI: central DI (CDI) and nephrogenic DI (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. Diabetes Insipidus (euvolemic). Neurologic (lethargy, altered mental status, irritability, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures) features are mainly observed. Hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia can also cause muscle cramps and decreased deep tendon reflexes. The initial treatment for severe hypovolemic hypernatremia is isotonic 0.9% saline. Once the volume deficit has been restored, patients are switched to half-normal (0.45%) saline.

Disorders related to potassium levels

• Hyperkalemia: a condition defined by serum K⁺ > 5.2 mEq/L. Severe hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia is seen in acute renal failure and can be catastrophic as it causes respiratory paralysis, generalized muscle paralysis, and cardiac arrest Cardiac arrest Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest. Drugs such as ACEi are a common cause of hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia.
• Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia: a condition defined by plasma K⁺ < 3.5 mEq/L. Features of hypokalemia include muscle weakness and general fatigue. Hyperpolarization affects excitability and delays the repolarization of cardiac muscles. The ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) findings include low T wave and presence of U wave. Diuretic use, thyrotoxicosis Thyrotoxicosis Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism, and other conditions (Liddle’s syndrome, Bartter’s syndrome) lead to low K⁺.

Disorders related to chloride levels

• Cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. Cystic Fibrosis: an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancehereditary disease of the exocrine glands that primarily affects the lungs and digestive system.  Cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. Cystic Fibrosis is due to a spectrum of defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in this gene leads to an inability to properly transport chloride. Given the interlinking functions of chloride with Na⁺, there is a subsequent impairment in Na⁺ and water absorption. A characteristic feature is the abnormally high (> 60 mEq/L) chloride concentration in sweat. Hyperviscous mucus is found in the other glands.

Disorders related to calcium levels

• Hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia: Calcium levels are regulated by the PTH secreted by the parathyroid gland. Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia or hypocalcemia result if the body fails to maintain Ca²⁺ levels within the normal range. The presentation of patients with hypocalcemia can vary from asymptomatic to life-threatening hemodynamic instability. Conditions related to low Ca²⁺ include hypoparathyroidism, CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease, and acute pancreatitis Acute pancreatitis Acute pancreatitis is an inflammatory disease of the pancreas due to autodigestion. Common etiologies include gallstones and excessive alcohol use. Patients typically present with epigastric pain radiating to the back. Acute Pancreatitis.
• Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia: might be mild, moderate, or severe. Principal causes include hyperparathyroidism, thyrotoxicosis Thyrotoxicosis Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism, and cancer. Clinical features include constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation, weakness, confusion, and coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma.
• Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis: a chronic progressive metabolic bone disease characterized by decreased bone density and deterioration of bone strength and integrity. Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis is common in post-menopausal women and older men and is also associated with many chronic conditions.

Disorders related to magnesium levels

• Alcoholism: a chronic (> 12 months), problematic pattern of alcohol use causing significant distress. Hypomagnesemia is the most common electrolyte change in alcoholism (decrease intake, increased renal losses, and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea).

Disorders related to phosphate levels

• Hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism: a condition resulting from elevated PTH levels. The most common cause is a parathyroid adenoma, and other causes include hyperplasia or carcinomas. The presenting features of hyperparathyroidism include nonspecific symptoms (fatigue, constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation), abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, renal stones, bone pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and neuropsychiatric symptoms.
• Hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Hypoparathyroidism: decreased secretion or activity of the PTH. The most common cause of hypoparathyroidism is the iatrogenic removal of the parathyroid glands Parathyroid glands The parathyroid glands are 2 pairs of small endocrine glands found in close proximity to the thyroid gland. The superior parathyroid glands are lodged within the parenchyma of the upper poles of the right and left thyroid lobes; the inferior parathyroid glands are close to the inferior tips or poles of the lobes. Parathyroid Glands during thyroid surgeries. Other causes include autoimmune conditions, congenital absence of the parathyroid glands Parathyroid glands The parathyroid glands are 2 pairs of small endocrine glands found in close proximity to the thyroid gland. The superior parathyroid glands are lodged within the parenchyma of the upper poles of the right and left thyroid lobes; the inferior parathyroid glands are close to the inferior tips or poles of the lobes. Parathyroid Glands, or defective Ca²⁺ sensing. Features include perioral tingling and numbness, muscle cramps, tetany, carpopedal spasms, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures.

Disorders related to bicarbonate levels

• Renal tubular acidosis Renal Tubular Acidosis Renal tubular acidosis (RTA) is an imbalance in physiologic pH caused by the kidney's inability to acidify urine to maintain blood pH at physiologic levels. Renal tubular acidosis exist in multiple types, including distal RTA (type 1), proximal RTA (type 2), and hyperkalemic RTA (type 4). Renal Tubular Acidosis ( RTA RTA Renal tubular acidosis (RTA) is an imbalance in physiologic pH caused by the kidney's inability to acidify urine to maintain blood pH at physiologic levels. Renal tubular acidosis exist in multiple types, including distal RTA (type 1), proximal RTA (type 2), and hyperkalemic RTA (type 4). Renal Tubular Acidosis) II: a condition characterized by impaired proximal tubular acidification mechanism in the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys caused by the reduced reabsorption of HCO₃^– in the proximal tubules. Renal tubular acidosis Renal Tubular Acidosis Renal tubular acidosis (RTA) is an imbalance in physiologic pH caused by the kidney's inability to acidify urine to maintain blood pH at physiologic levels. Renal tubular acidosis exist in multiple types, including distal RTA (type 1), proximal RTA (type 2), and hyperkalemic RTA (type 4). Renal Tubular Acidosis II is seen in multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma, where the excreted light chains produce proximal tubular dysfunction.