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Cells maintain their structure and function by adapting to environmental changes.[1] However, when subjected to severe stress, exposure to harmful agents, or intrinsic defects, cells may reach a threshold where adaptation is no longer possible, leading to cell injury.[2] This process involves various cellular and metabolic disruptions and can follow a trajectory from reversible injury to irreversible damage and cell death.[3] Reversible Cell Injury In the early or mild stages of injury, cellular damage remains reversible if the stressor is removed. Although there may be noticeable structural and functional impairments during this phase, the cell retains the capacity to recover and restore normal function. This stage is characterized by alterations in metabolic pathways and organelles without permanent loss of cell viability.[4] If the harmful stimulus persists, the damage may progress beyond the point of repair, resulting in irreversible injury and ultimately cell death. These stages are central to understanding the cellular responses to various pathological conditions.[5] Cell Necrosis Irreversible injury to cells due to encounters with noxious stimuli invariably leads to cell death. Such noxious stimuli include infectious agents (bacteria, viruses, fungi, parasites), oxygen deprivation or hypoxia, and extreme environmental conditions such as heat, radiation, or exposure to ultraviolet irradiation. The resulting death is known as necrosis, a term usually distinguished from the other major consequences of irreversible injury, known as cell death by apoptosis.[6] Apoptosis is a programmed or organized cell death that could be physiological or pathological. Additional information regarding this form of cell death is outside this chapter's scope. Necrosis, a cell death, is almost always associated with a pathological process.[7]

Irreversible injury to cells due to encounters with noxious stimuli invariably leads to cell death. Such noxious stimuli include infectious agents (bacteria, viruses, fungi, parasites), oxygen deprivation or hypoxia, and extreme environmental conditions such as heat, radiation, or exposure to ultraviolet irradiation. The resulting death is known as necrosis, a term usually distinguished from the other major consequences of irreversible injury, known as cell death by apoptosis.[6] Apoptosis is a programmed or organized cell death that could be physiological or pathological. Additional information regarding this form of cell death is outside this chapter's scope. Necrosis, a cell death, is almost always associated with a pathological process.[7] When cells die by necrosis, they exhibit 2 major types of microscopes or macroscopic appearance. The first is liquefactive necrosis, also known as colliquative necrosis, which is characterized by partial or complete dissolution of dead tissue and transformation into a liquid, viscous mass. The loss of tissue and cellular profile occurs within hours in liquefactive necrosis. In contrast to liquefactive necrosis, coagulative necrosis, the other major pattern, is characterized by maintaining normal architecture of necrotic tissue for several days after cell death.[8] Liquefaction derives from the slimy, liquid-like nature of tissues undergoing liquefactive necrosis.[9] This morphological appearance is partly attributable to hydrolytic enzymes' activities, which cause the dissolution of cellular organelles in a necrosis cell. The enzymes responsible for liquefaction are derived from bacterial or lysosomal hydrolytic enzymes.[10][11] Other types of Necrosis In addition to liquefactive and coagulative necrosis, the other morphological patterns associated with cell death by necrosis are: Caseous Necrosis Fat Necrosis Gangrenous Necrosis Fibrinoid Necrosis The other types of necrosis listed above do not represent distinct pathological entities. Rather, they are descriptive terms widely used to describe necrosis occurring in specific clinical scenarios or organ damage. Coagulative Necrosis This is the default pattern of necrosis associated with ischemia or hypoxia in every organ except the brain.[8][12] Gross Appearance: Tissue is firm, and architecture is maintained for days after cell death Microscopic: Preserved cell outlines without nuclei Liquefactive Necrosis

The other types of necrosis listed above do not represent distinct pathological entities. Rather, they are descriptive terms widely used to describe necrosis occurring in specific clinical scenarios or organ damage. Coagulative Necrosis This is the default pattern of necrosis associated with ischemia or hypoxia in every organ except the brain.[8][12] Gross Appearance: Tissue is firm, and architecture is maintained for days after cell death Microscopic: Preserved cell outlines without nuclei Liquefactive Necrosis The pattern of necrosis is seen with infections. Also, the pattern is seen following ischemic injury in the brain. While the reason for liquefactive necrosis following ischemic injury in the brain is poorly understood, the release of digestive enzymes and constituents of neutrophils is the reason for liquefaction in infections.[13][14] Gross Appearance: The tissue is liquid and sometimes creamy yellow because of pus formation Microscopic: Inflammatory cells with numerous neutrophils Caseous Necrosis A unique type of cell death is seen with tuberculosis. Gross Appearance: White, soft, cheesy-looking (caseating) material Microscopic: A uniformly eosinophilic center (necrosis) surrounded by a collar of lymphocytes and activated macrophages (giant cells, epithelioid cells) The entire structure formed in response to tuberculosis is known as a granuloma.[15] Fat Necrosis Fat necrosis occurs from acute inflammation affecting tissues with numerous adipocytes, such as pancreas and breast tissue. Damaged cells release digestive enzymes, which break down lipids to generate free fatty acids.[16] Gross Appearance: Whitish deposits as a result of the formation of calcium soaps Microscopic: Anucleated adipocytes with calcium deposits (seen on H&E as areas of bluish stains) Fibrinoid Necrosis This is a pattern associated with vascular damage (autoimmunity, immune-complex deposition, infections (viruses, spirochetes, rickettsiae).[17] Gross Appearance: Usually not grossly discernible Microscopic: Deposition of fibrin within blood vessels Gangrenous Necrosis Clinically, this describes ischemic necrosis of the lower limbs (sometimes upper limbs or digits).[18] Gross Appearance: Black skin with varying degrees of putrefaction Microscopic: Combination of coagulative necrosis due to ischemia (dry gangrene); and liquefactive necrosis (wet gangrene) if a bacterial infection is superimposed

Clinically, this describes ischemic necrosis of the lower limbs (sometimes upper limbs or digits).[18] Gross Appearance: Black skin with varying degrees of putrefaction Microscopic: Combination of coagulative necrosis due to ischemia (dry gangrene); and liquefactive necrosis (wet gangrene) if a bacterial infection is superimposed These represent morphological patterns that are visible grossly and microscopically. Fibrinoid necrosis is usually visible only microscopically. In subsequent paragraphs, we discuss the gross and microscopic findings in liquefactive necrosis.

The cause of cell death, the organ affected, and the duration of cell death determine patterns of necrosis (liquefactive or coagulative).[19] Liquefactive necrosis is a pattern of cell death caused by several etiological factors. Major Causes of Liquefactive Necrosis In all solid organs of the body: Infectious agents (bacteria, fungi, viruses, parasites) In the brain Infectious agents Hypoxia/Ischemia (the occurrence of liquefaction as a pattern of necrosis in response to hypoxic injury in the brain is an exception to observed findings in the rest of the body Tissues in all other mammalian body systems usually undergo cell death by coagulative necrosis in response to hypoxia. The reason for this difference is poorly understood).[20]

Liquefactive Necrosis Three major factors contribute to liquefactive necrosis: Enzymatic digestion of cellular debris in dead or dying tissues Enzymatic digestion of surrounding tissues Denaturation of cellular proteins Because infectious agents are rich in digestive enzymes and likely to elicit an inflammatory response, they can rapidly increase cellular digestion. This manifests as liquefactive necrosis. Cellular dissolution and digestion are brought about by several enzymes, some from the infecting organism and some from the lysosome of the dying cells.[21] Enzymes involved in liquefaction include: Proteases (collagenases, elastases) Deoxyribonuclease Lysosomal enzymes Coagulative Necrosis A major difference between liquefactive and coagulative necrosis is that in liquefactive necrosis, the enzyme system of the necrotic tissue is intact and can commence the process of cellular digestion almost immediately via autolysis. In addition to self-digestion (autolysis), heterolysis occurs due to a release of enzymes and inflammatory cells from the invading organism.[22] Cellular digestion is principally dependent on heterolysis in coagulative necrosis since a hypoxic injury would have damaged the enzymes of the cells undergoing ischemic necrosis. This partly explains the late onset of digestion and removal of dead tissues in this type of necrosis.[23] Caseous Necrosis This pattern is almost unique to tuberculosis. Certain fungi can also exhibit caseous necrosis. In tuberculosis, the organism is partially resistant to digestion and phagocytosis by tissue macrophages, leading to the activation of the macrophages to form giant cells and epithelioid cells. This sets off several steps that lead to the recruitment of more macrophages and inflammatory cells, the production of cytokines, and slow degradation of the mycobacteria. Mycolic acid and other lipid constituents of the mycobacteria cell wall confer a characteristic "cheese-like" appearance on the tubercle of tuberculosis, hence the descriptive term "caseous."[24] Fat Necrosis

This pattern is almost unique to tuberculosis. Certain fungi can also exhibit caseous necrosis. In tuberculosis, the organism is partially resistant to digestion and phagocytosis by tissue macrophages, leading to the activation of the macrophages to form giant cells and epithelioid cells. This sets off several steps that lead to the recruitment of more macrophages and inflammatory cells, the production of cytokines, and slow degradation of the mycobacteria. Mycolic acid and other lipid constituents of the mycobacteria cell wall confer a characteristic "cheese-like" appearance on the tubercle of tuberculosis, hence the descriptive term "caseous."[24] Fat Necrosis The release of lipases and amylases from the pancreatic cells is the major trigger for fat necrosis in the pancreas. This process is usually triggered by several factors leading to pancreas inflammation or pancreatitis.[25] Causes of acute pancreatitis include alcohol, gallbladder stones, poisoning, and insect bites. Since an inadvertent release of enzymes triggers fat necrosis in the pancreas, this process is also called enzymatic fat necrosis.[26] Breast tissues can also give rise to fat necrosis. The trigger for this is usually trauma.[27] Fibrinoid Necrosis This is a pattern that is not grossly discernible but can be seen microscopically. Fibrinoid necrosis is a pattern of cell death characterized by endothelial damage and exudation of plasma proteins (especially fibrin).[17] Gangrenous Necrosis See the description in the introduction above; this is not a true pathological type; rather, it is a clinical term describing coagulative necrosis (dry gangrene) or sometimes liquefactive necrosis (wet gangrene) affecting the extremities.

Clinical Examples of Necrosis Infections Abscesses (brain, lungs, liver, skin) Lung infections Skin Infections Wet Gangrene Fournier gangrene Brain abscess Hypoxic Injury Cerebrovascular accident (stroke; liquefactive necrosis)[14] Acute tubular necrosis (kidneys; coagulative necrosis)[28] Acute myocardial infarction (coagulative necrosis)[29]

Appropriate history and physical examination findings would guide diagnosis and management, including which evaluation studies to order. Liquefactive necrosis closely mirrors acute inflammation and the response to an infectious process. The only exception is in the brain, where liquefaction may occur in response to ischemia. Evaluation and management are geared toward effective clinical management, whether medical with either antibiotics or surgical management. Hypoxic injury is the cause of coagulative necrosis. The reestablishment of blood flow or oxygen supply is reperfusion; this is important for management. Hence, for this pattern of tissue damage, studies such as Doppler ultrasound are useful in determining blood flow.[30] Useful Evaluation Physical examination: Monitor vital signs to evaluate overall health and identify any immediate complications. Laboratory investigations: Conduct tests such as complete blood count to check for infection or anemia, blood cultures to detect underlying infections, and urine culture and urinalysis to assess kidney function. Imaging studies: Use x-rays to rule out fractures or other bony injuries. Venous Doppler scan: Focus on venous blood flow, which is essential for detecting deep vein thrombosis. Computed tomography scans: These scans provide detailed images of internal structures, aiding in assessing organ damage. Serum electrolytes: Analyze electrolyte levels to manage metabolic imbalances commonly associated with hypoxic conditions.

Management of Infectious Processes Antibiotics are the mainstay of managing infectious processes.[31] Clinical findings and antibiotic susceptibility would guide the choice of antibiotics.[6] Surgical management is also often indicated and includes: Drainage of abscesses Wound debridement Amputation Management of Ischemic Processes/Stroke Myocardial infarction is the prototype example of coagulative necrosis, which requires urgent management. Early removal of the obstructive lesions in the coronary arteries is a crucial step in the management of myocardial infarction. This is usually achieved medically or by an invasive procedure.[29] Stroke management is a multidisciplinary, multispecialist effort that should consider several factors, including the extent of residual damage, the risk of reoccurrence, and the patient's rehabilitative needs.[32] Management of Caseous Necrosis This requires standard tuberculosis management, including combination antibiotics and close laboratory and clinical monitoring.[33] Management of Gangrenous Necrosis This is a serious medical and surgical situation that requires antibiotics and sometimes necessitates the removal of dead tissues (debridement). In severe, life-threatening cases, an amputation may be necessary.[34]

The prognosis for liquefactive necrosis is influenced by several key factors, including the underlying cause, the specific organ involved, the severity of tissue damage, and the patient's overall health. Infections leading to abscess formation generally have a better outcome with timely antibiotic therapy and drainage. At the same time, ischemic events, particularly in the brain, often result in permanent functional deficits and poorer recovery. Localized necrosis typically heals through fibrosis, while more extensive tissue damage raises the risk of serious complications such as sepsis or multi-organ failure. Factors like age, existing health conditions, and immune system status also play a crucial role in determining recovery chances. Early diagnosis and effective management are essential for enhancing prognosis and improving recovery outcomes.[35]

Some complications can include the following: Abscess formation: This is common in infections and requires drainage or surgical intervention. Sepsis: This is a complication, particularly if caused by pyogenic organisms. Permanent dysfunction: In cases involving liquefactive necrosis, particularly in critical organs such as the brain or spinal cord, there can be lasting functional impairments that are often irreversible.[36] Cyst formation: In brain necrosis, areas may resolve into fluid-filled cysts.

Preventing liquefactive necrosis requires addressing underlying etiologies, such as infections and ischemia, through evidence-based measures. These include maintaining proper hygiene, managing chronic conditions such as diabetes and hypertension, adopting a healthy lifestyle, and ensuring timely administration of vaccines. Early recognition of clinical warning signs, including persistent fever, localized pain or swelling, or acute neurological deficits, is critical for initiating prompt medical intervention. Adherence to prescribed therapeutic regimens, such as completing antibiotic courses, is essential to reduce complications. Furthermore, rehabilitation strategies and psychological support are integral in managing the long-term sequelae of necrosis. Empowering patients through education and fostering effective communication with healthcare providers are key strategies to mitigate risks and improve clinical outcomes.

Several types of necrotic processes occur following injury or infection. The pathologist makes the final diagnosis of the type of necrosis. Sometimes, patients may need to be referred to the surgeon or radiologist for aspiration or debridement of the necrotic tissues. Often, radical debridement is required in cases of Fournier gangrene, and the patient and family should be notified about the possibility of a stoma. If time permits, a stoma nurse should visit patients who are about to undergo an abdominal procedure for gangrene or necrosis.