Foundations: The Cell, ABGs & Genetics

Before any organ can fail, something goes wrong at the level of the cell, the fluids around it, or the genes that built it. This opening chapter lays the foundation the rest of the book stands on — how cells cope and die, how water and electrolytes stay in balance, how the body defends its pH, and how traits and disorders pass down through families.

Section 1Cells: injury, adaptation & death

Every cell in your body is a tiny, hard-working machine, and like any machine it needs fuel and it needs to get rid of waste. Two supplies matter most: oxygen and glucose. Cells burn glucose with oxygen in the mitochondria to make ATP, the energy currency that runs every pump, every repair, and every heartbeat's worth of work. Take away the oxygen and the whole factory starts to fail. That is why the single most common cause of cell injury is a lack of oxygen.

When the fuel runs out: hypoxia and ischemia

Hypoxia means low oxygen reaching the tissue. Ischemia is a specific, more dangerous flavor of it: blood flow itself is blocked, so the cell loses not only oxygen but also glucose and its ability to wash away waste. Without ATP, the sodium-potassium pump quits, sodium and water rush in, and the cell swells (cellular edema, the earliest visible change). If oxygen returns quickly, the cell recovers. This is reversible injury. But if the insult drags on, mitochondria rupture, calcium floods in, enzymes start digesting the cell from the inside, and the damage becomes irreversible.

Free radicals and oxidative damage

Injury also comes from unstable molecules called free radicals (reactive oxygen species) that carry an unpaired electron and grab electrons from anything nearby, damaging membranes, proteins, and DNA. This oxidative stress underlies radiation injury, reperfusion damage, and aging. The body defends itself with antioxidants and enzymes, but when radicals outrun the defenses, the cell is harmed.

Five ways cells adapt

Before cells give up, they try to adjust to chronic stress. There are five classic adaptations:

• Atrophy - shrinking. A leg in a cast for weeks loses muscle bulk from disuse.
• Hypertrophy - cells get bigger. The heart wall thickens against high blood pressure; a weightlifter's muscles enlarge.
• Hyperplasia - more cells. The uterus grows a thicker lining each cycle under hormones; the liver regenerates.
• Metaplasia - one mature cell type is swapped for a tougher one. In a smoker's airway, delicate ciliated cells become flat squamous cells; in the reflux-damaged lower esophagus the change runs the other way, as the squamous lining is replaced by columnar cells (Barrett esophagus).
• Dysplasia - disordered, abnormal-looking cells. This is not a normal adaptation; it signals trouble and can be a precancerous change, as on an abnormal Pap smear.

Two ways cells die

When adaptation fails, cells die by one of two very different routes. Apoptosis is programmed, tidy cell death - the cell shrinks, packages itself into neat fragments, and is quietly cleared without spilling its contents. It is normal and useful (it sculpts fingers in the womb and removes worn-out cells). Necrosis is messy, unplanned death from injury - the cell bursts, spills its enzymes, and provokes inflammation in the surrounding tissue.

Necrosis comes in patterns worth knowing:

• Coagulative - firm, preserved outline; the classic look after an ischemic infarct (heart, kidney).
• Liquefactive - tissue melts into liquid; typical of the brain after a stroke and of bacterial abscesses.
• Caseous - a crumbly, cheese-like center; the hallmark of tuberculosis.

Signs of chronic stress inside the cell

Cells under long-term strain often show accumulations - substances that pile up because the cell cannot process or export them, such as fat in liver cells (steatosis) or brown lipofuscin, the "wear-and-tear" pigment of aging. Cells and dead tissue may also undergo calcification, laying down calcium salts. When it happens in already-damaged or dead tissue while the blood calcium is normal, it is dystrophic calcification; when a high blood calcium drives deposits into otherwise-normal tissue, it is metastatic. Both are quiet fingerprints of injury the body has been fighting for a long time.

The five adaptations can be hard to keep straight in words - explore the interactive figure below to see atrophy, hypertrophy, hyperplasia, metaplasia, and dysplasia side by side.

Section 2Fluid balance & edema

Your body is mostly water, and where that water sits matters just as much as how much you have. In a healthy adult, water makes up roughly 60% of body weight. A handy memory trick is the 60-40-20 rule: about 60% of body weight is total water, about 40% sits inside cells, and about 20% sits outside them.

The fluid compartments

Think of two big rooms. The intracellular fluid (ICF) compartment is all the water inside your cells, and it holds the majority, roughly two-thirds of body water. The extracellular fluid (ECF) compartment is everything outside the cells, the remaining one-third. The ECF splits again into two parts: the interstitial fluid that bathes the spaces between cells, and the intravascular fluid, which is the plasma inside your blood vessels. Fluid is always shifting between these spaces, and keeping it balanced is what keeps cells alive and blood pressure steady.

Osmosis and tonicity

Water follows solute. Osmosis is the movement of water across a semipermeable membrane from an area of lower solute concentration to higher, chasing the particles it cannot easily follow. Tonicity describes how a solution affects cell volume, and it is one of the highest-yield concepts you will use at the bedside when hanging IV fluids.

Starling forces: the tug-of-war at the capillary

At every capillary, two opposing pressures decide whether fluid leaks out or gets pulled back in. This push-pull is described by the Starling forces. Hydrostatic pressure is the outward push of fluid against the vessel wall, essentially the pressure of blood being pumped, and it drives fluid out into the tissues. Oncotic pressure (also called colloid osmotic pressure) is the inward pull created mostly by albumin, the large protein that stays in the bloodstream and draws water back in. Normally, fluid pushes out at the arterial end and gets reabsorbed at the venous end, with the lymphatic system mopping up the small leftover. When this balance tips, fluid piles up in the tissues, and that is edema.

The four mechanisms of edema

Edema is not one problem, it is any disruption of that Starling balance or the drainage system. Four mechanisms cause it:

• Increased hydrostatic pressure. Too much outward push forces fluid into tissues. This is classic in heart failure (blood backs up) and venous obstruction like a DVT, causing dependent swelling in the ankles and feet.
• Decreased plasma oncotic pressure. Low albumin means a weak inward pull, so fluid stays out. Seen in cirrhosis, nephrotic syndrome, and severe malnutrition.
• Lymphatic obstruction. If the lymph channels that normally drain leftover fluid are blocked, protein-rich fluid backs up as lymphedema, often after lymph node removal or radiation in cancer treatment.
• Sodium and water retention. Where sodium goes, water follows. When the kidneys hold onto sodium (often driven by aldosterone or renal failure), the extra volume raises hydrostatic pressure and expands the ECF, causing generalized swelling.

Third spacing

Third spacing is fluid that shifts out of the vessels and interstitium and gets trapped in a space where it does no useful work, such as the abdomen (ascites), the pleural cavity, or the bowel wall after surgery or in sepsis. This matters clinically because that fluid is lost to circulation: the patient can look puffy and swollen while actually being intravascularly dry, with a low blood pressure, rising heart rate, and poor urine output. You may be giving fluids to someone who appears fluid-overloaded, which is why assessing perfusion, not just appearance, is essential. Explore the compartments and these shifts in the interactive figure below.

Section 3The electrolytes that matter most

Think of electrolytes as the tiny charged particles dissolved in your body's water that make nerves fire, muscles squeeze, and the heart beat on rhythm. Because they carry an electrical charge, even small shifts in their concentration change how excitable your cells are. The body works hard to keep them in a narrow range, and when it can't, the nervous system and the heart are usually the first to complain. Let's walk through the big three, plus a quiet helper.

Sodium: the master of water balance

Sodium (normal roughly 135 to 145 mEq/L) is the main electrolyte outside your cells, and where sodium goes, water follows. That single rule explains almost every symptom. Because sodium controls where water sits, sodium problems are really water problems, and the brain feels them most because it is packed inside a rigid skull.

In hyponatremia (low sodium), the blood outside cells becomes dilute, so water moves into cells by osmosis and they swell. In brain cells this means cerebral edema, which is why patients get headache, confusion, lethargy, and in severe or rapid cases, seizures. In hypernatremia (high sodium), the outside is too salty, so water is pulled out of cells and they shrink. The brain literally dehydrates, causing thirst, restlessness, irritability, and altered mental status. Notice the pattern: sodium imbalances are neurologic because they move water in and out of neurons.

Potassium: the heart's electrolyte

Potassium (normal about 3.5 to 5.0 mEq/L) is the major electrolyte inside cells, and it sets the electrical resting membrane potential that lets heart muscle depolarize and repolarize on cue. This is why potassium is often called the most dangerous electrolyte: both too little and too much can stop the heart, and the danger shows up on the ECG.

In hypokalemia, cardiac cells become sluggish to repolarize, producing flattened T waves, ST depression, and U waves, along with muscle weakness and risk of lethal arrhythmias. In hyperkalemia, cells depolarize too easily at first, giving the classic peaked (tall, tented) T waves, then a widening QRS, and finally a sine-wave pattern that can slide into ventricular fibrillation or asystole. Because both extremes are arrhythmogenic, potassium sits at the top of the emergency list.

Calcium: nerves, muscles, and PTH

Calcium (total normal roughly 8.5 to 10.5 mg/dL) stabilizes nerve and muscle membranes and is guarded by parathyroid hormone (PTH), which raises calcium by pulling it from bone, saving it in the kidney, and activating vitamin D. Here the rule flips: low calcium makes cells more excitable.

In hypocalcemia, membranes become twitchy and fire too easily, causing tetany, muscle cramps, tingling, and the two bedside signs: Trousseau sign (carpal spasm when a blood-pressure cuff is inflated) and Chvostek sign (facial twitch when you tap the cheek over the facial nerve). In hypercalcemia, often from too much PTH or from cancer, membranes are over-stabilized, so things slow down: "stones, bones, groans, and psychiatric moans" means kidney stones, bone pain, constipation and abdominal pain, and lethargy or confusion.

Magnesium: the quiet partner

Magnesium (normal about 1.7 to 2.4 mg/dL, which is roughly 1.4 to 2.0 mEq/L) tends to travel with potassium and calcium. Low magnesium makes potassium hard to replace and worsens low calcium, so you often cannot fix a stubborn hypokalemia until you correct the magnesium first. Think of it as the electrolyte that keeps the other two honest.

Which imbalances are true emergencies? The ones that threaten the heart or brain fastest: severe hyperkalemia and hypokalemia (lethal arrhythmias within minutes), symptomatic hyponatremia with seizures (brain swelling), and severe hypocalcemia that can cause laryngospasm. Explore the interactive figure below to see how each imbalance shifts.

Section 4Acid-base balance & the ABG

Your blood is fussy about one thing above almost all others: its pH. Every enzyme, every heartbeat, every nerve signal depends on the blood staying in a narrow window of 7.35 to 7.45. That is only barely on the alkaline (basic) side of neutral, and your body guards it obsessively. Slip below 7.35 and we call it acidosis; drift above 7.45 and it is alkalosis. Push much past 6.8 or 7.8 in either direction and cells simply stop working. So the body runs two teams whose whole job is defending that pH.

Two defenders: the lungs (fast) and the kidneys (slow)

Think of pH as a seesaw between an acid and a base. The acid side is carbon dioxide (CO2), a waste gas that dissolves into carbonic acid. The base side is bicarbonate (HCO3), the buffer that soaks up extra acid. The lungs control the CO2 side and they are fast - breathe harder and you blow off CO2 (less acid) within minutes; breathe slower and CO2 builds up. The kidneys control the bicarbonate side and they are slow, taking hours to days to hold onto or dump HCO3. Fast lungs, slow kidneys - remember that and half of ABGs make sense.

The four primary disorders

Every simple acid-base problem is a story about one of those two chemicals going wrong. If the trouble starts with CO2 (a breathing problem), it is respiratory. If it starts with HCO3 (a metabolic or kidney problem), it is metabolic.

Reading an ABG in three steps

You do not need to memorize a chart - just walk down three numbers in order. Standard normals are pH 7.35-7.45, PaCO2 35-45 mmHg, and HCO3 22-26 mEq/L.

1. Look at the pH first. Below 7.35 = acidosis. Above 7.45 = alkalosis. This tells you which direction the body is actually in.
2. Look at the CO2. Above 45 is acidic; below 35 is alkalotic (because CO2 is an acid). If the CO2 matches the pH direction, the lungs are the culprit - it is respiratory.
3. Look at the HCO3. Below 22 is acidic; above 26 is alkalotic. If the HCO3 matches the pH direction, the kidneys/metabolism are the culprit - it is metabolic.

Whichever value moves the same way as the pH is your primary problem. Example: pH 7.28 (acidosis) with CO2 60 (acidic) - the CO2 explains it, so this is respiratory acidosis, often from a COPD patient who is retaining CO2.

Compensation: the other team pitches in

Here is the elegant part. When one system fails, the other one tries to drag the pH back toward normal. If the lungs cause an acidosis, the kidneys slowly retain bicarbonate to buffer it. If the kidneys (metabolic) cause an acidosis, the lungs speed up to blow off CO2 - those deep, sighing Kussmaul respirations in DKA are exactly this rescue in action. The compensating system pushes its own number in the same direction as the primary problem. So in a compensated respiratory acidosis you will see high CO2 (the problem) and high HCO3 (the kidney rescue).

Watch the pH to judge how far compensation has gone. If pH is back inside 7.35-7.45, it is fully compensated. If pH is still abnormal but the second value has clearly shifted to help, it is partially compensated. If only the primary system is off and the other has not budged, it is uncompensated. Remember: compensation nudges pH toward normal but rarely overshoots it - the body does not overcorrect past neutral.

Tie it to real patients and it sticks: the vomiting patient loses stomach acid and swings alkalotic (metabolic alkalosis); the panicking, hyperventilating patient blows off CO2 (respiratory alkalosis); the septic or hemorrhaging patient in shock pours out lactic acid (metabolic acidosis); the sedated post-op patient who is barely breathing retains CO2 (respiratory acidosis). Explore the step-by-step ABG interpreter below to practice walking those three numbers yourself.

Section 5Genes & inheritance

Every cell in your body carries a full instruction manual written in DNA. Think of DNA as a long string of just four chemical letters (A, T, C, G). A gene is one meaningful sentence in that manual, and each gene tells the cell how to build one protein. Proteins do almost everything: they form structures, carry oxygen, speed up reactions as enzymes, and open and close channels. The flow is simple to remember: DNA is copied (transcribed) into mRNA, and mRNA is read (translated) into a protein. When the recipe is spelled correctly, the protein works.

What a mutation actually does

A mutation is a spelling change in a gene. Sometimes it is harmless. Other times it swaps one letter and changes one amino acid, so the protein folds wrong or stops working. In sickle cell disease, a single letter change turns normal hemoglobin into a sticky version that warps red cells into a sickle shape. So the whole chain matters: a tiny DNA typo can cascade into a missing or broken protein, and a broken protein shows up as disease. This is why genetic conditions are so consistent within a family - everyone inherits the same misspelled recipe.

Autosomal dominant vs autosomal recessive

You inherit two copies of most genes - one from each parent (these live on the autosomes, chromosomes 1 through 22). Whether a condition appears depends on how many broken copies it takes.

In autosomal dominant inheritance, one faulty copy is enough to show the trait, so it typically appears in every generation and affects males and females equally. Huntington disease is the classic example. In autosomal recessive inheritance, you need two faulty copies to be affected. People with just one copy are healthy carriers - they carry the gene silently and can pass it on. Cystic fibrosis and sickle cell disease follow this pattern, which is why they often seem to skip generations and appear when two carriers have a child.

X-linked recessive: why males are hit harder

Some genes sit on the X chromosome. Females are XX and males are XY. In X-linked recessive conditions like hemophilia, the faulty gene is on the X. A female has a backup X, so one healthy copy usually covers for the broken one - she is typically a carrier. A male has only one X and no second copy to compensate, so a single faulty gene shows. That is why X-linked recessive disorders affect males far more often. A carrier mother has a 50 percent chance of passing the affected X to each son.

Predicting the odds with a Punnett square

A Punnett square is a simple grid that lays out each parent's possible gene copies and shows the chance of each combination in their children. Use capital letters for dominant and lowercase for recessive. For two carriers of a recessive condition (both Aa), the grid gives four boxes: AA, Aa, Aa, aa. That means about a 25 percent chance of an affected child (aa), a 50 percent chance of a carrier, and a 25 percent chance of neither. Each pregnancy is an independent roll - the odds reset every time. You can explore the patterns and squares in the interactive figure below.

Penetrance and expressivity

Penetrance is whether a gene shows at all - the percentage of people with the gene who actually develop the trait. Expressivity is how strongly it shows - how mild or severe the same gene looks from person to person.

Section 6Chromosomal & congenital disorders

Every cell in your body normally carries 46 chromosomes arranged in 23 pairs: 22 pairs of autosomes plus one pair of sex chromosomes (XX in females, XY in males). You inherit exactly half from each parent. This tidy sorting happens during meiosis, the special cell division that makes eggs and sperm. When meiosis works, each gamete ends up with exactly 23 chromosomes, and fertilization restores the full set of 46. Chromosomal disorders happen when that sorting goes wrong, or when an outside exposure damages a developing embryo. Explore the interactive figure below to see how an extra chromosome reshapes the picture.

Nondisjunction: chromosomes that refuse to separate

The most common mistake is nondisjunction - a pair of chromosomes fails to pull apart during meiosis. One gamete ends up with an extra copy, and the other is left short. If that gamete joins in fertilization, the embryo carries the wrong count, a state called aneuploidy. Getting three copies of a chromosome instead of two is a trisomy; having only one copy is a monosomy. Because chromosomes are packed with genes, even one extra or missing chromosome throws off the dose of hundreds of proteins - which is why these disorders affect so many body systems at once. Nondisjunction becomes more likely with advancing maternal age, which is why the risk of trisomies climbs after about age 35.

Trisomy 21 and its cousins

Trisomy 21 (Down syndrome) is the most common surviving autosomal trisomy - three copies of chromosome 21. Classic features usually include intellectual disability, a flat facial profile with upslanting palpebral fissures, a single palmar (simian) crease, and hypotonia (low muscle tone). Because that extra genetic material affects many systems, congenital heart defects (often an atrioventricular septal defect) are common, along with a higher risk of leukemia and early Alzheimer-type changes. Two rarer, far more severe trisomies are worth knowing: trisomy 18 (Edwards syndrome) and trisomy 13 (Patau syndrome). Both usually cause profound impairment and multiple organ malformations, and most affected infants do not survive past infancy.

When the sex chromosomes are off

Nondisjunction can also hit the sex chromosomes. Turner syndrome (45,X) is a monosomy - a female with only one X. It usually presents with short stature, a webbed neck, ovarian dysgenesis (nonfunctioning ovaries causing infertility and absent puberty without hormone therapy), and often coarctation of the aorta. Klinefelter syndrome (47,XXY) is a male with an extra X. It often shows up around puberty with tall stature and small firm testes: the seminiferous tubules scar over and germ cells are lost, so the semen has no sperm (azoospermia) and the man is infertile. In parallel, the Leydig cells fail, and that reduced testosterone is what produces the gynecomastia and delayed or incomplete puberty. Testosterone replacement fixes the hormonal features but does not restore fertility, because the tubules themselves are gone. Notice the pattern: an extra sex chromosome tends to be better tolerated than an extra autosome, largely because the body naturally silences extra X chromosomes.

Teratogens: when the environment is the culprit

Not every congenital disorder is genetic. A teratogen is any agent that disrupts normal fetal development - a drug, infection, chemical, or radiation. Timing matters enormously. The embryonic period (roughly weeks 3 to 8), when organs are first forming, is the window of greatest vulnerability; an exposure then can cause major structural defects, while later exposure tends to affect growth and function. A key cluster to memorize is the TORCH infections: Toxoplasmosis, Other (including syphilis), Rubella, Cytomegalovirus, and Herpes simplex. These maternal infections can cross the placenta and cause malformations, growth restriction, hearing loss, and neurologic damage. Alcohol is one of the most preventable teratogens; prenatal exposure can produce fetal alcohol spectrum disorder, with characteristic facial features, growth deficits, and lifelong cognitive impairment. There is no known safe amount.

Multifactorial disorders

Finally, many common conditions - neural tube defects, cleft lip and palate, congenital heart disease - are multifactorial, arising from a combination of several genes plus environmental influences rather than a single cause.

ReferenceWords worth knowing

A quick reference for the terms in this chapter — skim it now, or circle back whenever a word trips you up.

Apoptosis

Apoptosis is orderly, programmed cell death in which a cell shrinks and neatly packages itself for removal without spilling its contents, so no inflammation results.

Atrophy

Atrophy is a decrease in the size of cells (and therefore the whole tissue or organ) in response to disuse, denervation, aging, or reduced blood supply, as when a casted limb shrinks.

Autosomal recessive

Autosomal recessive describes an inheritance pattern in which a person must receive two copies of a mutated gene (one from each parent) on a non-sex chromosome to show the disease, so unaffected carriers can silently pass it on.

Compensation (acid-base)

Compensation is the body's attempt to restore normal blood pH by using the system that is not primarily broken, so the lungs adjust CO₂ for a metabolic problem and the kidneys adjust bicarbonate for a respiratory problem.

Dysplasia

Dysplasia is disordered growth in which cells vary in size, shape, and organization; it is not cancer but is often a warning change that can precede it.

Edema

Edema is the buildup of excess fluid in the interstitial space (the tissue between cells), producing visible swelling and sometimes pitting when pressed.

Hyperplasia

Hyperplasia is an increase in the number of cells in a tissue due to increased cell division, such as the endometrium thickening under hormonal stimulation.

Hypertrophy

Hypertrophy is an increase in the size of individual cells (without adding new cells), enlarging the organ, as when heart muscle thickens against high blood pressure.

Hyponatremia

Hyponatremia is a lower-than-normal blood sodium level (usually below about 135 mEq/L) that often reflects too much water relative to sodium and can cause confusion or seizures.

Hypoxia

Hypoxia is an inadequate supply of oxygen reaching the tissues, which starves cells of the fuel they need to make energy.

Ischemia

Ischemia is reduced blood flow to a tissue that limits delivery of both oxygen and nutrients while also letting wastes build up, and it is a common cause of hypoxia.

Metaplasia

Metaplasia is the reversible replacement of one mature cell type by another, tougher one under stress (such as airway cells changing under chronic cigarette smoke); the swap withstands the stress but loses the original tissue's specialized function and can precede dysplasia.

Necrosis

Necrosis is disorderly, unplanned cell death from injury in which cells swell and burst, spilling their contents and triggering inflammation.

Nondisjunction

Nondisjunction is the failure of chromosomes to separate properly during cell division, leaving a cell with an extra or missing chromosome, as in trisomy 21 (Down syndrome).

Oncotic pressure

Oncotic pressure is the inward pull that plasma proteins (mainly albumin) exert to keep fluid inside blood vessels; when it drops, fluid leaks out and edema forms.

Tonicity

Tonicity is how a solution's solute concentration affects a cell's water movement, causing the cell to swell in a hypotonic solution, shrink in a hypertonic one, or stay unchanged in an isotonic one.

DrillFlashcards for this unit

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