Cellular Adaptation & Injury

Atrophy is shrinking. In our own words, the cell gets smaller. The one sourced example is skeletal muscle: "Atrophy of skeletal muscle may result from many things, including disuse, denervation, systemic illness, chronic glucocorticoid use, and malnourishment." The mechanism is a balance tipped toward breakdown — atrophy "is caused by increased proteolysis mediated by the ubiquitin system and decreased protein synthesis, which reduces muscle mass by reducing the diameter of individual muscle fibers." Disuse and long-term steroids are both on that list, which is why an immobilized patient on chronic glucocorticoids loses muscle on two fronts.

Hypertrophy is bigger cells, not more of them. "An increase in the size of individual cells characterizes myocyte hypertrophy." The heart is the model: left ventricular hypertrophy is "a condition in which there is an increase in left ventricular mass, with or without an increase in chamber size," and it can occur "as a response to increased workload or other conditions." Hyperplasia is more cells — "An increase in the number of cells in an organ or tissue. These cells appear normal under a microscope. They are not cancer, but may become cancer." The NCI adds the key clue: "Hyperplasia can be caused by several factors or conditions, including chronic irritation."

Metaplasia swaps one cell type for another. It is "A change of cells to a form that does not normally occur in the tissue in which it is found." The sourced example is Barrett esophagus: long-standing reflux replaces the normal lining with intestinal-type cells — "biopsies showing columnar epithelium and goblet cells indicative of intestinal metaplasia." The trigger is chronic acid and bile: "Most cases are acquired, with the precipitant usually being long-standing gastroesophageal reflux (GERD)," and Barrett "can be found in 5% to 12% of patients with chronic symptoms of GERD." The new lining is where dysplasia and cancer can later arise.

Adaptation starts out helpful and can turn harmful — left ventricular hypertrophy shows both halves. Early on, "The increased mass of muscle fibers or wall thickness initially serves as a compensatory mechanism to maintain contractile forces and counter increased ventricular wall stress." But "The benefits of increased wall thickness to compensate for elevated wall stress are offset by a significant increase in the degree of stiffness of the hypertrophied walls," and "Pathologic LVH, once developed, puts the patient at significant risk for the development of heart failure, dysrhythmias, and sudden death." The usual driver is afterload: "The most common etiologic cause is the heart contracting against an elevated afterload, as seen in hypertension and also seen in valvular aortic stenosis." That is why "Hypertension remains the most important preventable cause of LVH."

The NCI names the steps before cancer. "Before cancer cells form in tissues of the body, the cells go through abnormal changes called hyperplasia and dysplasia." Each step is defined by what the cells look like. In hyperplasia, "the cells and the way the tissue is organized still look normal under a microscope." Dysplasia is the first step where the cells look wrong: "Dysplasia is a more advanced condition than hyperplasia. In dysplasia, there is also a buildup of extra cells. But the cells look abnormal and there are changes in how the tissue is organized. In general, the more abnormal the cells and tissue look, the greater the chance that cancer will form."

Dysplasia is still not cancer. "Dysplasia is not cancer, but it may sometimes become cancer. Dysplasia can be mild, moderate, or severe, depending on how abnormal the cells look under a microscope and how much of the tissue or organ is affected." A familiar example is on the skin: "A dysplastic nevus can turn into melanoma, although most do not." And "Some types of dysplasia may need to be monitored or treated, but others do not." Carcinoma in situ is the last stop before invasion: "Although it is sometimes called stage 0 cancer, it is not cancer because the abnormal cells do not invade nearby tissue the way that cancer cells do. But because some carcinomas in situ may become cancer, they are usually treated."

Cancer is defined by invasion. "Cancer is a disease in which some of the body’s cells grow uncontrollably and spread to other parts of the body." Malignant tumours invade — "Cancerous tumors spread into, or invade, nearby tissues" — while "Benign tumors do not spread into, or invade, nearby tissues." Two sourced examples show the whole road. In the endometrium, hyperplasia "results from estrogenic stimulation of the endometrial tissue with a relative deficiency of progesterone" (the unopposed-estrogen pattern seen with anovulatory cycles, PCOS, obesity, estrogen therapy and tamoxifen), and "Endometrial hyperplasia, in atypical forms, is the precursor lesion for endometrioid adenocarcinoma of the endometrium." In the esophagus, Barrett metaplasia "predisposes patients to developing dysplasia and esophageal adenocarcinoma, a cancer with high morbidity and mortality." Both can go backwards if the stimulus is removed early — for the endometrium, "Spontaneous resolution can occur if reversible causes of estrogen excess are corrected."

Cells are injured by a short list of causes. Hypoxia ("This can occur due to ischemia, shock, or respiratory failure"), physical agents such as trauma, temperature extremes, radiation or electric shock, chemical agents including poisons, drug toxicities and recreational drugs, biological agents (bacteria, viruses, fungi) and immunologic reactions such as autoimmunity.

Whatever the cause, energy failure comes first. "ATP depletion or decreased synthesis is the first biochemical change observed in injury." Without ATP, the membrane pumps stop: "This lack of ATP results in the failure of the energy-dependent sodium pump in the plasma membrane, causing an influx of calcium and water, leading to cell swelling and detachment of ribosomes from the endoplasmic reticulum." Then "Increased cytosolic calcium and oxidative stress lead to mitochondrial damage." When blood flow stops, the same chain runs: "Whenever there is impairment of blood flow to the tissues, there is tissue hypoxia, which triggers anaerobic respiration resulting in depletion of cellular ATP reserves."

Time decides whether the cell recovers. "Whether this cellular injury is irreversible or reversible will depend on the duration for which the cell remained in a hypoxic state." Once injury is irreversible the cell dies: "Irreversible cell injury and eventual cell death due to pathological processes are termed necrosis." The membranes fail and "Both these mechanisms lead to disruption of the plasma membrane leading to the spilling of intracellular contents into the surrounding tissue." This is why every ischemia protocol — chest pain, stroke, a cold limb — is a race against the clock.

Necrosis is uncontrolled and inflammatory. "It is an uncontrolled cell death that results in swelling of the cell organelles, plasma membrane rupture and eventual lysis of the cell, and spillage of intracellular contents into the surrounding tissue leading to tissue damage." It happens "due to overwhelming noxious stimulus from outside the cell and is almost always associated with inflammatory responses." Under the microscope the cell and nucleus swell, with karyolysis (nuclear dissolution), karyorrhexis (nuclear fragmentation) or nuclear pyknosis.

Apoptosis is programmed and quiet. "Apoptosis is a tightly regulated form of programmed cell death essential for normal development and tissue maintenance." It is "a genetically programmed, adenosine triphosphate (ATP)-dependent, enzyme-mediated mechanism that enables the orderly dismantling of cells without provoking significant inflammation or injury to surrounding tissues." Enzymes called caspases run it: "The apoptotic process is primarily mediated by caspases, a family of cysteine proteases activated through intrinsic and extrinsic signaling pathways." The cell shrinks and breaks into apoptotic bodies, and "Notably, the plasma membrane remains intact throughout the process." So "apoptosis does not provoke an inflammatory response, in contrast to necrosis, necroptosis, pyroptosis, and ferroptosis, all of which involve plasma membrane rupture, cell swelling, and release of proinflammatory intracellular contents."

Keep the contrast, but do not make it absolute. Some necrosis is also regulated: "different types of regulated necrosis have been described, such as necroptosis, pyroptosis, and ferroptosis." And apoptosis is normal — it is "critical during embryogenesis, immune system regulation, and the preservation of tissue homeostasis throughout adulthood." When apoptosis goes wrong, disease follows in both directions. "Evasion of apoptosis is a defining feature of malignant transformation" — cells that should die keep dividing. Too much apoptosis kills cells that should live: "Excessive neuronal apoptosis is a central pathologic feature of Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis." In a stroke, "both necrosis and apoptosis contribute to neuronal death, with apoptosis predominating in the ischemic penumbra."

Coagulative — "Ischemia in most organs except the brain can lead to coagulative necrosis." The outline of the dead cells is kept. Liquefactive — "This morphology is most commonly observed in the central nervous system." The dead cells are digested into a liquid mass, and "This morphology also occurs in most bacterial infections, and the accumulation of such necrotic material is called pus." So an ischemic stroke liquefies, while ischemia in most other organs coagulates.

Caseous is the tuberculosis pattern — "This necrosis takes place in tuberculous infection, and the necrotic area is referred to as a granuloma." Fat necrosis — "This type of necrosis occurs in acute pancreatitis." and "Fat necrosis also occurs in breast tissue due to fat saponification." Fibrinoid — "This type of necrosis occurs in blood vessels due to the deposition of immune complexes in blood vessel walls leading to leakage of fibrin."

Gangrenous necrosis is a bedside term, not a microscope pattern. "This is not a morphological pattern but rather a clinical term for ischemic necrosis of the limbs. It has two types i) dry (ischemia leading to coagulative necrosis), and ii) wet (ischemia with superimposed bacterial infection leading to liquefactive necrosis)." The clinical examples tie it together: "Ischemia of the heart leading to myocardial injury, ischemia of the brain leading to stroke, and ischemia of the limbs leading to gangrene are all clinical examples of necrosis." The treatment rule follows: "Most of the time, identifying the cause of necrosis and treating it is more important than removing the dead tissue." In a heart attack, "treatment is targeted at opening the coronary vessels either by thrombolysis or PCI to restore blood supply."

The paradox. Reperfusion injury is a concept "where reperfusion can occasionally exacerbate the cellular damage already caused by ischemia/hypoxia." When blood returns, "there is a sudden increase in blood and oxygen flow that triggers the activation of the inflammatory process, release of cytokines, and results in further damage to cells and their membranes." Three mechanisms drive it: more reactive oxygen species, vasoconstriction in the small vessels, and neutrophils sticking to the vessel lining and releasing cytokines. "The rate at which ROS are formed exceeds the rate at which they can be detoxified."

None of this is a reason to delay reperfusion. "The first line of treatment is always thrombolytic therapy or an invasive revascularization procedure." and "The main concern remains that early revascularization should be achieved in order to prevent initial extensive cellular damage." Protective strategies are still research-stage: pre- or post-conditioning, antioxidants and controlled reperfusion "appear to decrease the degree of reperfusion injury," but "Various studies are being done on animals to ascertain the efficacy of these treatment modalities."

What reperfusion injury looks like at the bedside. It "can present as acute heart failure, cerebral dysfunction, SIRS (systemic inflammatory response system), and multi-organ failure." In the heart, "The most common presentation of reperfusion in the heart is ventricular arrhythmias, myocardial wall rupture, microvasculature abnormalities, and myocyte death." In the brain, hemorrhagic transformation or cerebral edema shows up as "focal neurological deficits." In a limb: "With limb ischemia, pain that is out of proportion to the physical findings, decreased pulses, skin changes, and decreased sensations are all indicative of a possible reperfusion injury." The swelling can go further — "This can eventually result in acute compartment syndrome." That is why "Following an episode of ischemia that has been treated with revascularization; the patient should be placed under strict observation."

Gangrene is dead tissue at the bedside. "Gangrene is a condition characterized by tissue necrosis resulting from ischemia or infection. The condition is commonly classified into dry, wet, and gas gangrene." Dry gangrene is slow ischemia: "Dry gangrene typically results from progressive ischemia and is most pronounced in the digits, often causing circumferential necrosis. The affected tissue becomes dry and may undergo autoamputation." It usually marks the end of peripheral arterial disease — "Dry gangrene is most commonly secondary to atherosclerosis and progressive occlusion of arterial perfusion to distal tissue, marking an end stage of peripheral vascular disease. The risk is higher in individuals with diabetes, hypertension, hyperlipidemia, and those who smoke."

Wet gangrene is dead tissue plus infection. "Wet gangrene refers to necrotic tissue complicated by secondary infection and is typically seen in the lower extremities. The condition presents with edema, erythema, and purulent drainage." Gas gangrene is the emergency: "Gas gangrene is a rapidly progressive, life-threatening necrotizing infection caused by gas-forming bacteria, most commonly Clostridium species. Clinical features include edema, crepitance, and dishwater drainage" and it "carries a high mortality rate, particularly in patients with leukocytosis, hyperglycemia, or sepsis."

Once it is established, the tissue does not come back. "Once ulcers progress to dry gangrene, full tissue recovery is unlikely, but medical and surgical interventions can help minimize tissue loss." Treatment "ranges from debridement and advanced wound care to amputation and revascularization." The patient may not feel it coming: "Diabetic neuropathy may reduce awareness of developing gangrene." — so the nurse’s foot and limb assessment is often the first warning.