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Liver

The liver is a vital organ in vertebrates, serving as the largest glandular organ and a central hub for metabolic, digestive, and detoxifying processes in the human body. Located predominantly in the upper right quadrant of the abdomen, beneath the diaphragm and partially protected by the rib cage, it weighs approximately 1.4 kilograms in adults, comprising about 2% of total body weight. This reddish-brown, wedge-shaped structure performs over 500 essential functions, including the metabolism of nutrients such as carbohydrates, proteins, and lipids; the detoxification and biotransformation of drugs, toxins, and hormones; the production and secretion of bile to aid fat digestion; the synthesis of plasma proteins, cholesterol, and clotting factors; the storage of glycogen, vitamins (A, D, E, K, and B12), and minerals like iron and copper; and the regulation of blood glucose, amino acid levels, and overall blood volume. Anatomically, the liver is divided into four lobes—the larger right lobe, the left lobe, the caudate lobe posteriorly, and the quadrate lobe anteriorly—separated by ligaments such as the falciform ligament, which anchors it to the abdominal wall. Functionally, it is organized into eight segments based on vascular and biliary divisions, allowing for precise surgical resections. The organ receives a unique dual blood supply: approximately 75% from the nutrient-rich portal vein draining the gastrointestinal tract and 25% from the oxygen-rich hepatic artery, together delivering about 25% of the heart's output at rest despite comprising only 2% of body weight. Blood is filtered through sinusoids lined by hepatocytes (the primary functional cells) and Kupffer cells (resident macrophages that phagocytose pathogens and debris), before draining via three major hepatic veins into the inferior vena cava. Microscopically, the liver's basic unit is the hepatic lobule, a hexagonal arrangement of hepatocyte plates radiating from a central vein, with portal triads (containing branches of the portal vein, hepatic artery, and bile duct) at the corners facilitating nutrient exchange and bile flow. Bile produced by hepatocytes is collected in canaliculi and excreted through intrahepatic ducts to the gallbladder or duodenum, essential for emulsifying dietary fats. The liver's regenerative capacity is remarkable; it can restore up to 70% of its mass within weeks following partial hepatectomy, driven by hepatocyte proliferation. This organ's multifaceted roles underscore its indispensability, as liver failure can lead to life-threatening complications like coagulopathy, encephalopathy, and metabolic derangements.

Anatomy

Gross anatomy

The liver is the largest solid organ in the human body, situated in the right upper quadrant of the abdomen, predominantly beneath the right hemidiaphragm and protected by the rib cage.^[1] It typically weighs between 1.4 kg in females and 1.8 kg in males, accounting for approximately 2% of total body weight, and measures about 15 cm in height, 15 cm in width, and 10 cm in thickness. The organ has a wedge-shaped form with a smooth, brown external surface and is partially covered by visceral peritoneum, except for the bare area on its posterior surface where it directly contacts the diaphragm. Anatomically, the liver is divided into four lobes: the right lobe (the largest, comprising about 60% of the liver's mass), the left lobe, the caudate lobe (positioned posteriorly between the inferior vena cava and the left lobe), and the quadrate lobe (located on the inferior surface anterior to the porta hepatis).^[1] The falciform ligament, a thin peritoneal fold, extends from the liver to the anterior abdominal wall and diaphragm, separating the right and left lobes while containing the ligamentum teres (a remnant of the fetal umbilical vein) within the umbilical fissure.^[2] Additional ligaments include the coronary ligaments (superior and inferior reflections attaching the liver to the diaphragm), triangular ligaments (lateral extensions of the coronary ligaments), and the lesser omentum (comprising the hepatogastric and hepatoduodenal ligaments, which connect the liver to the stomach and duodenum, respectively).^[2] The liver features two main surfaces: the diaphragmatic surface (convex, facing superiorly and anteriorly, molded to the diaphragm's contour) and the visceral surface (concave inferiorly, in contact with abdominal viscera and bearing impressions from adjacent organs like the right kidney, colon, and duodenum).^[1] The porta hepatis, an H-shaped fissure on the visceral surface, serves as the primary entry and exit point for vessels and ducts; it contains the portal vein posteriorly (supplying 70-75% of the liver's blood flow from the gastrointestinal tract), the hepatic artery proper medially (providing the remaining 25-30% of oxygenated blood, typically branching from the celiac trunk), and the common hepatic duct laterally (draining bile).^[2] Venous drainage occurs via three main hepatic veins (right, middle, and left) that empty directly into the inferior vena cava.^[2] The gallbladder is embedded in a fossa on the visceral surface of the right lobe, adjacent to the quadrate lobe.^[1]

Microscopic anatomy

The liver's microscopic anatomy is characterized by a complex arrangement of epithelial and mesenchymal elements organized into repetitive functional units known as hepatic lobules and acini. The classic hepatic lobule is a roughly hexagonal prism, approximately 1-2 mm in diameter, centered on a terminal hepatic venule (central vein) with plates of hepatocytes radiating outward toward portal tracts at the periphery.^[3] In contrast, the acinar model emphasizes metabolic zonation, with diamond-shaped acini centered on the portal triad (hepatic arteriole, portal venule, and bile duct) and extending to the terminal hepatic venule, divided into three zones based on oxygen and nutrient gradients: zone 1 (periportal, oxygen-rich), zone 2 (intermediate), and zone 3 (pericentral, oxygen-poor).^[3] These units are not strictly delineated by connective tissue in humans, allowing for a three-dimensional interconnectivity that facilitates efficient blood flow and metabolic exchange.^[4] Hepatocytes, the primary parenchymal cells comprising 60-80% of the liver's cell population, are polygonal cells measuring 20-30 μm in diameter with a large, centrally located round nucleus and abundant eosinophilic cytoplasm rich in organelles such as mitochondria, rough endoplasmic reticulum, and glycogen granules.^[3] They are arranged in single-cell-thick plates (cords) separated by vascular sinusoids, forming a spongy parenchyma that constitutes the bulk of the liver's mass.^[4] Hepatocytes perform diverse functions, including protein synthesis, glycogen storage, and bile production, with their polarity evident in the basolateral (sinusoidal) and apical (canalicular) domains.^[3] The sinusoidal network consists of wide, irregular channels (10-15 μm in diameter) lined by specialized fenestrated endothelial cells lacking a continuous basement membrane, allowing direct exchange between blood and hepatocytes via the subendothelial space of Disse.^[3] Kupffer cells, resident macrophages derived from monocytes, adhere to the sinusoidal endothelium and comprise approximately 15% of the total liver cell count, functioning in phagocytosis and immune surveillance.^[4] Hepatic stellate cells (Ito cells), located in the space of Disse, store vitamin A as retinyl esters and produce extracellular matrix components, playing a key role in fibrosis when activated.^[3] The biliary drainage system begins at the microscopic level with bile canaliculi, narrow channels (0.5-1 μm wide) formed by the apices of adjacent hepatocytes, which collect bile and converge into the canals of Hering—ductular structures lined by cholangiocytes (bile duct epithelial cells) that connect to larger interlobular bile ducts within portal tracts.^[3] Cholangiocytes, cuboidal to columnar in shape and expressing cytokeratins 7 and 19, modify bile composition through secretion and absorption and constitute about 3% of liver cells.^[4] Portal tracts, composed of loose connective tissue, house the accompanying hepatic artery branches and portal veins, which deliver oxygenated and nutrient-rich blood, respectively, to the sinusoids.^[3]

Functional anatomy

The functional anatomy of the liver is characterized by its organization into microscopic units that integrate vascular, biliary, and parenchymal components to support its diverse metabolic roles. The liver's parenchyma is arranged in repeating hexagonal lobules, each centered on a terminal hepatic venule (central vein) that drains into larger hepatic veins. Hepatocytes within the lobule form radial plates separated by sinusoids, which are specialized capillaries lined by fenestrated endothelial cells allowing efficient exchange of nutrients, oxygen, and waste products between blood and hepatocytes. This structure facilitates the liver's high-capacity processing of blood, with approximately 1.5 liters per minute flowing through the organ under normal conditions.^[1] Complementing the lobular model is the acinar architecture, which emphasizes functional zones based on blood perfusion gradients from portal triads. The acinus is a rhomboid unit bounded by three adjacent central veins, with portal triads (containing branches of the hepatic artery, portal vein, and bile duct) at its center. Blood from the dual vascular supply—75% from the oxygen-poor portal vein carrying nutrient-rich venous blood from the gastrointestinal tract and 25% from the oxygen-rich hepatic artery—mixes in the sinusoids and flows toward the periphery. This gradient creates three metabolic zones: Zone 1 (periportal), optimized for oxidative processes like gluconeogenesis and bile synthesis due to higher oxygen levels; Zone 2 (intermediate), supporting mixed functions; and Zone 3 (pericentral), specialized for detoxification, glycolysis, and lipogenesis but more susceptible to hypoxia.^[5]^[6] The biliary system is integral to this functional layout, with hepatocytes forming a network of bile canaliculi that collect bile secreted at their apical surfaces. These canaliculi drain into progressively larger ducts within the portal triads, forming the biliary tree that converges into right and left hepatic ducts. This countercurrent flow to blood circulation enables efficient bile transport for digestion while preventing mixing with sinusoidal contents. Resident cells enhance functionality: Kupffer cells in sinusoids act as macrophages for immune surveillance and pathogen clearance; hepatic stellate cells (Ito cells) in the space of Disse store vitamin A and regulate fibrosis; and endothelial cells maintain permeability via fenestrae.^[1]^[5] Macroscopically, the liver's functional divisions align with vascular territories, as described by Couinaud's segmental classification into eight segments based on portal and hepatic venous branching. This allows precise delineation for procedures like resection, where each segment functions semi-autonomously with independent inflow and outflow. The caudate lobe, for instance, often has dual biliary drainage (70-80% to both right and left ducts), reflecting adaptive vascular integration. Overall, this architecture ensures the liver's regenerative capacity and metabolic efficiency, processing over 1,400 mL of blood per minute to maintain homeostasis.^[6]

Gene and protein expression

The human liver exhibits a rich transcriptome, with approximately 13,563 genes (67% of the human proteome) detected as expressed based on RNA sequencing data from normal liver tissue.^[7] Among these, 978 genes display elevated expression specific to the liver, categorized into 263 tissue-enriched genes (showing at least four-fold higher mRNA levels compared to other tissues), 178 group-enriched genes (shared with 2-5 other tissues such as kidney or intestine), and 537 tissue-enhanced genes (at least four-fold above the average across tissues).^[7] These expression patterns underscore the liver's specialized roles in metabolism, detoxification, and protein synthesis, with normalized transcript per million (nTPM) values ranging widely; for instance, the apolipoprotein A-II gene (APOA2), involved in lipid transport, reaches an exceptionally high nTPM of 34,742.6.^[7] Key liver-enriched genes include ALDOB (aldolase B), which encodes an enzyme critical for fructose metabolism in hepatocytes, and AHSG (alpha-2-HS-glycoprotein), a plasma protein with nTPM of 5,638.7 that modulates insulin resistance and bone mineralization.^[7] Another prominent example is SPP2 (secreted phosphoprotein 2), with an nTPM of 502.9 and a tissue specificity score of 4,403, functioning in extracellular matrix organization and immune response.^[7] Genome-wide association studies of liver expression quantitative trait loci (eQTLs) have identified over 6,000 significant associations between single nucleotide polymorphisms (SNPs) and gene expression levels, revealing both cis-acting (3,210 traits near the gene, affecting 3,043 genes) and trans-acting (491 traits genome-wide, affecting 474 genes) regulatory effects at a false discovery rate below 10%. For example, variants near RPS26 explain up to 40% of its expression variance and link to type 1 diabetes susceptibility. At the protein level, the liver proteome mirrors this transcriptomic diversity, with 13,563 proteins detected via mass spectrometry and immunohistochemistry, aligning closely with mRNA abundance for most genes.^[7] Liver-specific proteins predominate in metabolic pathways, such as those for glucose homeostasis (ALDOB) and lipoprotein assembly (APOA2), while others like CFH (complement factor H) support immune regulation and show strong cis-eQTL associations (p = 6.94 × 10⁻²²).^[7] These expression profiles not only highlight the liver's functional zonation—higher metabolic gene expression in periportal hepatocytes—but also inform disease mechanisms, as variations in eQTLs for genes like SORT1 and CELSR2 contribute to coronary artery disease risk through altered lipid metabolism. Overall, such data from integrated genomic and proteomic atlases facilitate targeted research into liver physiology and pathology.^[7]

Development

Embryonic development

The embryonic development of the liver begins during the third week of gestation, around days 22–24, when the hepatic diverticulum emerges as an outgrowth from the ventral endoderm of the distal foregut.^[8] This structure arises from definitive endoderm cells that have acquired hepatic competence through the action of transcription factors such as Foxa2, Gata4, Gata6, and Hhex, which open chromatin to allow responsiveness to inductive signals.^[8] The hepatic endoderm is located adjacent to the developing heart and septum transversum, setting the stage for essential signaling interactions.^[9] By days 24–28 (Carnegie stage 11–12), the hepatic diverticulum elongates into the septum transversum mesenchyme, forming the liver bud or hepatic primordium, as hepatoblasts—bipotent progenitor cells—delaminate from the endodermal epithelium and migrate into the surrounding mesoderm.^[8] This migration is driven by signals from the cardiac mesoderm, including fibroblast growth factor (FGF) from the heart, and bone morphogenetic protein (BMP) from the septum transversum, which specify the hepatic fate and promote proliferation.^[8] The septum transversum provides a supportive stroma, including extracellular matrix components, while endothelial cells from the developing vitelline veins begin to invade the liver bud, facilitating early vascularization and further hepatoblast expansion.^[9] Genes such as Prox1 and Onecut1/2 regulate this delamination and bud morphogenesis.^[8] During weeks 4–6 (Carnegie stages 13–15), the liver bud grows rapidly, dividing into cranial and caudal portions that form the future left and right lobes, respectively, and hepatic cords organize into trabeculae that establish the basic lobular architecture.^[9] Sinusoids emerge as primitive vascular channels lined by endothelial cells, derived from mesodermal angioblasts, which interact with hepatoblasts to promote their survival and differentiation.^[8] Hematopoiesis initiates around week 5, as the liver becomes a transient site for blood cell production, colonized by mesoderm-derived hematopoietic stem cells from the yolk sac and later the aorta-gonad-mesonephros region.^[10] This function peaks in the fetal period but begins embryonically, underscoring the liver's early multifunctional role.^[9] Hepatoblast differentiation commences around week 6–7, influenced by pathways such as Hnf4α for hepatocyte maturation and Notch signaling for biliary epithelial cell specification, leading to the formation of primitive ductal plates by week 8.^[8] These processes involve reciprocal endoderm-mesoderm signaling, with Wnt and TGFβ pathways modulating cell fate decisions.^[8] By the end of the embryonic period (week 8), the liver occupies a significant portion of the upper abdomen, with its portal triad structures beginning to take shape, though intrahepatic bile duct remodeling occurs later in fetal development.^[10] Disruptions in these early stages, such as mutations in Hhex or Gata4, can lead to congenital anomalies like biliary atresia.^[8]

Fetal development

The fetal liver continues its development after the embryonic period (week 9 onward), building on the rapid growth from weeks 5–10, by which point it constitutes approximately 10% of the fetal body weight.^[11] During the fetal period, the liver expands through proliferation of hepatic progenitor cells, driven primarily by WNT/β-catenin signaling pathways that promote differentiation into hepatocytes.^[11] The organ achieves histological maturity by the early fetal period, around the 9th week, featuring organized lobules and the establishment of basic vascular and biliary structures.^[11] A hallmark of fetal liver development is its role as the primary site of hematopoiesis, continuing from its embryonic initiation and peaking between the 6th and 7th months, with hematopoietic cells occupying up to 70% of the liver parenchyma during stage III of development, dominated by erythropoiesis and supported by pluripotent stem cells expressing markers like CD34+.^[11] As gestation advances into the third trimester, hematopoiesis gradually regresses, with the proportion of hematopoietic cells dropping to less than 30% by stage IV, coinciding with the bone marrow assuming dominance postnatally.^[11] Vascularization in the fetal liver progresses concurrently, with endothelial cells facilitating the formation of sinusoids that ensure nutrient and oxygen delivery to support rapid organ growth and hematopoietic activity.^[8] These sinusoidal networks mature by the mid-second trimester, enabling efficient blood flow through the hepatic portal system and vena cava connections.^[12] Biliary development during this period involves the differentiation of hepatoblasts near portal veins into cholangiocytes, leading to the remodeling of the ductal plate into functional intrahepatic bile ducts by the late second trimester.^[8] Towards term, the fetal liver undergoes functional maturation, shifting emphasis from hematopoiesis to metabolic roles such as glycogen storage and gluconeogenesis, influenced by a late gestational surge in cortisol that upregulates enzymes like phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase).^[12] Alpha-fetoprotein expression, prominent in early fetal stages, declines as hepatocytes acquire adult-like metabolic zonation, with periportal regions favoring gluconeogenesis and perivenous areas supporting glycolysis.^[12] This transition prepares the liver for neonatal independence, though environmental factors like placental insufficiency can impair vascular perfusion and overall growth if hypoxia occurs.^[12]

Functions

Vascular functions

The liver receives a dual blood supply, with approximately 75–80% of its total blood flow derived from the portal vein and 20–25% from the hepatic artery, resulting in a total hepatic blood flow of about 100 mL per minute per 100 g of liver tissue under normal conditions.^[13] The portal vein transports nutrient-rich, deoxygenated blood from the gastrointestinal tract, spleen, and pancreas at low pressure (6–10 mmHg), enabling the liver to process absorbed nutrients, hormones, and microbial products before they enter the systemic circulation.^[13] In contrast, the hepatic artery delivers oxygenated blood from the aorta via the celiac trunk, ensuring adequate oxygen supply despite the portal vein's low oxygenation (saturation around 75%).^[13] These two inflows converge in the hepatic sinusoids, low-pressure capillary-like structures lined by liver sinusoidal endothelial cells (LSECs), where blood mixes and facilitates exchange with hepatocytes.^[14] The hepatic arterial buffer response (HABR) is a key regulatory mechanism that maintains total hepatic blood flow constancy by inducing reciprocal changes: a decrease in portal venous flow triggers hepatic arterial vasodilation, compensating for 25–60% of the reduction, while an increase in portal flow leads to arterial vasoconstriction.^[13] This response, primarily mediated by adenosine washout from the space of Disse and modulated by factors like nitric oxide and hydrogen sulfide, preserves hepatic clearance efficiency for substrates such as drugs and nutrients, and supports oxygenation during physiological stresses like digestion or hemorrhage.^[13] LSECs play a central role in vascular homeostasis by regulating vascular tone through production of vasodilators like nitric oxide and vasoconstrictors such as endothelin and prostanoids, thereby influencing intrahepatic resistance and portal pressure.^[14] Their fenestrated structure, with pores of 100–150 nm and no basement membrane, enables selective filtration of plasma components, including chylomicron remnants and small immune complexes, while preventing larger particles from accessing the parenchyma.^[15] Additionally, LSECs exhibit potent scavenger functions via receptor-mediated endocytosis, clearing waste macromolecules such as hyaluronan (88% of circulating load removed by the liver within 19 minutes), denatured collagen fragments (approximately 0.5 g/day), oxidized low-density lipoproteins, and microbial products like lipopolysaccharide, using receptors including stabilins-1/2, mannose receptor, and FcγRIIb.^[15] This clearance, occurring at rates exceeding 100 million virus-like particles per minute in models, maintains blood purity and prevents systemic inflammation without triggering immune activation.^[15] The liver's vascular system also serves as a dynamic blood reservoir, storing 25–30 mL of blood per 100 g of tissue, which can be mobilized during hypovolemia to support systemic circulation, contributing to overall cardiovascular homeostasis.^[13] In scenarios like partial hepatectomy, increased portal flow post-resection (e.g., doubling after 60% liver removal) is buffered by HABR to promote regeneration while avoiding overperfusion.^[13] These vascular adaptations underscore the liver's integration of local perfusion control with whole-body physiological demands.^[14]

Biliary functions

The liver's biliary functions primarily involve the synthesis, secretion, and modification of bile, a complex fluid essential for digestion and waste elimination. Hepatocytes in the liver produce approximately 500 to 600 mL of bile per day, which is initially secreted into the canaliculi between liver cells.^[16]^[17] Bile production is divided into bile salt-dependent and bile salt-independent components, with the former accounting for about 50% of the flow (roughly 225 to 300 mL/day) driven by the active transport of bile salts, while the latter is facilitated by the secretion of organic solutes like glutathione and bicarbonate.^[17] Bile composition reflects its dual roles in solubilization and excretion; it is isosmotic with plasma and consists mainly of water (about 97%), electrolytes such as sodium and bicarbonate, conjugated bile salts (derived from cholesterol via the enzyme cholesterol 7α-hydroxylase, yielding primary bile acids like cholic and chenodeoxycholic acids), phospholipids (primarily lecithin), cholesterol, conjugated bilirubin (a breakdown product of heme), and trace proteins.^[16]^[17] Hepatocytes conjugate bile acids with glycine or taurine to enhance their solubility and detergent properties, and these conjugated forms, along with secondary bile acids formed by gut bacteria (e.g., deoxycholic acid), constitute the bile salt pool of 2 to 4 grams in adults.^[17] Secretion begins with active transport across the canalicular membrane of hepatocytes via ATP-dependent pumps, including the bile salt export pump (BSEP) for bile salts and multidrug resistance-associated protein 2 (MRP2) for bilirubin and glutathione; this creates an osmotic gradient that draws water and electrolytes into the canaliculi.^[17] The bile then flows through a network of ductules and intrahepatic bile ducts lined by cholangiocytes, which modify it by secreting bicarbonate-rich fluid (up to 25% of total bile volume) in response to hormones like secretin, thereby alkalinizing and diluting the bile to protect the ductal epithelium and enhance its flow.^[16]^[17] From the hepatic ducts, bile enters the common bile duct, where it is either stored in the gallbladder or released into the duodenum upon stimulation by cholecystokinin (CCK) during meals.^[17] In terms of physiological roles, bile salts act as emulsifiers in the small intestine, forming micelles that solubilize dietary fats and fat-soluble vitamins (A, D, E, K), thereby facilitating their digestion by lipases and absorption by enterocytes.^[16]^[17] Additionally, bile serves an excretory function by eliminating excess cholesterol (preventing its accumulation in the liver), conjugated bilirubin (to avoid toxicity), and metabolic waste products like drugs and heavy metals.^[16]^[17] Efficiency is maintained through enterohepatic circulation, where 90 to 95% of bile salts are reabsorbed in the terminal ileum via the apical sodium-dependent bile acid transporter (ASBT) and returned to the liver via the portal vein, recycling the pool 10 to 12 times daily and minimizing de novo synthesis needs.^[16]^[17] This circulation conserves energy, as only 5% of bile salts are lost in feces each cycle, requiring the liver to synthesize about 0.2 to 0.6 grams daily to replenish the pool.^[17]

Metabolic functions

The liver serves as a central hub for systemic energy homeostasis, orchestrating the metabolism of carbohydrates, lipids, and proteins to maintain blood glucose levels, provide energy substrates, and support biosynthetic needs across the body.^[5] In the fed state, it promotes anabolic processes such as glycolysis, glycogenesis, and lipogenesis, primarily driven by insulin signaling, while in fasting, catabolic pathways like gluconeogenesis, glycogenolysis, and fatty acid β-oxidation predominate under glucagon and glucocorticoid influence.^[18] These functions are zonated within the liver lobule, with periportal zone 1 hepatocytes favoring oxidative processes like gluconeogenesis and β-oxidation, and pericentral zone 3 cells supporting glycolysis and lipogenesis due to differences in oxygen and nutrient gradients.^[5] In carbohydrate metabolism, the liver maintains euglycemia by storing excess glucose as glycogen postprandially through glycogenesis, catalyzed by glucokinase and glycogen synthase in zone 3 hepatocytes.^[5] During fasting or exercise, it releases glucose via glycogenolysis, breaking down glycogen stores to yield up to 80% of hepatic glucose output initially, and sustains production through gluconeogenesis, synthesizing glucose from non-carbohydrate precursors like lactate, glycerol, and amino acids in zone 1.^[19] This process, accounting for the majority of endogenous glucose after prolonged fasting, is transcriptionally regulated by factors such as CREB, FoxO1, and PGC-1α, which are activated by glucagon to suppress insulin-mediated inhibition.^[18] Dysregulation, as seen in insulin resistance, elevates gluconeogenesis and contributes to hyperglycemia in type 2 diabetes.^[18] Lipid metabolism in the liver involves both synthesis and breakdown to balance energy storage and utilization. In the fed state, excess calories from carbohydrates are converted to fatty acids via de novo lipogenesis in zone 3, involving acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and transcription factor SREBP-1c, with the resulting triglycerides packaged into very low-density lipoproteins (VLDL) for export to adipose tissue.^[5] During fasting, zone 1 hepatocytes perform β-oxidation of fatty acids to generate acetyl-CoA for the tricarboxylic acid (TCA) cycle and ATP production, while excess acetyl-CoA is shunted to ketogenesis, producing ketone bodies like acetoacetate and β-hydroxybutyrate as alternative fuels for the brain and muscles.^[19] The liver also synthesizes cholesterol endogenously from acetyl-CoA via HMG-CoA reductase and produces bile acids from cholesterol to aid dietary fat absorption, with PPARα regulating fasting-induced oxidation.^[5] Protein and amino acid metabolism are dominated by the liver's role in nitrogen handling and plasma protein production. It catabolizes amino acids in zone 1, incorporating their carbon skeletons into gluconeogenesis or the TCA cycle for energy, while detoxifying ammonia through the urea cycle, which converts it to urea for renal excretion.^[5] Hepatocytes synthesize approximately 85-90% of circulating plasma proteins, including albumin for oncotic pressure and transport, clotting factors like fibrinogen, and acute-phase proteins during inflammation, with glutamine synthesis occurring in zone 3 to buffer acidosis.^[19] Transcription factors such as C/EBPα and hormonal signals like insulin maintain these synthetic rates, ensuring amino acid homeostasis.^[18] Beyond macronutrients, the liver metabolizes and stores vitamins and hormones to support broader physiological needs. It stores glycogen alongside fat-soluble vitamins (A, D, E, K) in hepatocytes and stellate cells, performing 25-hydroxylation of vitamin D via CYP2R1 and regulating vitamin E forms through selective secretion with lipoproteins.^[5] For hormones, it deiodinates thyroxine (T4) to active triiodothyronine (T3) and metabolizes sex steroids, while synthesizing carrier proteins like sex hormone-binding globulin.^[5] These endocrine-like functions, including hepatokine secretion such as fibroblast growth factor 21 during fasting, further integrate the liver into metabolic regulation.^[19]

Detoxification and other roles

The liver serves as the primary organ for detoxification, processing and neutralizing a wide array of xenobiotics, including drugs, alcohol, environmental toxins, and metabolic byproducts, to prevent systemic toxicity.^[5] This process occurs predominantly in hepatocytes through a two-phase enzymatic system: phase I involves oxidation, reduction, or hydrolysis primarily via cytochrome P450 (CYP450) enzymes in the smooth endoplasmic reticulum, generating reactive intermediates that are more polar; phase II follows with conjugation reactions using agents like glucuronate, glutathione, or sulfate to produce water-soluble metabolites for excretion via urine or bile.^[5] These reactions are concentrated in zone III of the liver acinus, near the central vein, and can be influenced by factors such as age, genetics, diet, and disease states, with some metabolites potentially hepatotoxic if not efficiently processed.^[5] Additionally, phase III involves active transport of conjugates across hepatocyte membranes into bile canaliculi or bloodstream.^[5] Beyond detoxification, the liver plays crucial roles in immune surveillance and modulation, acting as a frontline barrier against pathogens entering via the portal vein from the gut.^[20] Kupffer cells, resident macrophages comprising 80-90% of the body's fixed tissue macrophages, phagocytose bacteria, debris, and apoptotic cells in the sinusoidal space, while liver sinusoidal endothelial cells scavenge small particulates and antigens through endocytosis.^[20] Natural killer (NK) cells, including liver-specific "pit cells," and natural killer T (NKT) cells bridge innate and adaptive responses, producing cytokines to regulate inflammation and tolerance; the liver's innate immunity is robust, producing 80-90% of circulating acute-phase proteins and complement components via hepatocytes.^[20] This setup promotes immune tolerance to harmless gut-derived antigens but can shift to strong responses against infections, contributing to conditions like viral hepatitis.^[20] The liver also exhibits endocrine functions, synthesizing and metabolizing hormones to maintain homeostasis.^[21] It produces hepatokines such as fibroblast growth factor 21 (FGF21), which enhances insulin sensitivity and glucose uptake in adipose tissue, and angiotensinogen, the precursor to angiotensin II for blood pressure regulation.^[21] Key metabolic roles include deiodination of thyroxine (T4) to active triiodothyronine (T3) via type 1 deiodinase, inactivation of glucagon-like peptide-1 (GLP-1) by dipeptidyl peptidase-4, and processing of steroid hormones like estrogens and cortisol through phase I/II pathways.^[21] Furthermore, the liver stores fat-soluble vitamins (A, D, E, K) in Ito cells and hepatocytes, releasing them as needed, and supports hematopoiesis during fetal development, producing blood cells from the sixth week of gestation.^[5] These diverse roles underscore the liver's integration across physiological systems, with disruptions often leading to multisystem effects.^[5]

Clinical significance

Liver diseases

Liver diseases refer to a diverse group of disorders that damage the liver's structure or impair its functions, ranging from acute infections to chronic progressive conditions. These diseases affect millions worldwide and are a leading cause of death, with liver diseases contributing to over 2 million deaths annually, representing about 4% of all global deaths; cirrhosis and other chronic liver diseases account for approximately 1.4 million of these (as of 2021).^[22]^[23] The major etiologies include viral infections, excessive alcohol use, metabolic factors, autoimmune processes, genetic abnormalities, and toxins, often leading to inflammation (hepatitis), fat accumulation (steatosis), scarring (fibrosis), and eventual cirrhosis or liver failure. Early detection and management are crucial, as many liver diseases are asymptomatic until advanced stages. Viral hepatitis, caused by hepatitis viruses A, B, C, D, and E, is a primary infectious cause of liver disease, with hepatitis B and C being the most significant contributors to chronic infections and cirrhosis globally. Hepatitis A and E are typically acute and transmitted via contaminated food or water, while B, C, and D lead to persistent infection through blood or sexual contact, affecting an estimated 304 million people with chronic hepatitis B or C (plus about 15 million with D) as of 2022.^[24] Alcoholic liver disease, resulting from prolonged heavy alcohol consumption, progresses from fatty liver to alcoholic hepatitis and cirrhosis, and remains significant in high-income countries, though MASLD has become the leading cause of chronic liver disease worldwide, including in high-income countries. Nonalcoholic fatty liver disease (NAFLD), recently reclassified as metabolic dysfunction-associated steatotic liver disease (MASLD), arises from obesity, insulin resistance, and metabolic syndrome, and has become the most common chronic liver condition worldwide, affecting up to 30% of the global population and driving the increasing burden of cirrhosis. Autoimmune liver diseases occur when the immune system mistakenly attacks liver tissue, including autoimmune hepatitis (affecting hepatocytes), primary biliary cholangitis (targeting small bile ducts), and primary sclerosing cholangitis (involving larger bile ducts). These conditions are more prevalent in women and can lead to cirrhosis if untreated. Genetic disorders, such as hemochromatosis (iron overload) and Wilson's disease (copper accumulation), cause liver damage through toxic metal buildup and account for a small but significant portion of early-onset cirrhosis cases. Drug-induced liver injury, from medications like acetaminophen or certain antibiotics, represents another common cause, often reversible but potentially acute and severe. Liver cancer, primarily hepatocellular carcinoma, frequently develops as a complication of underlying chronic liver diseases like viral hepatitis or cirrhosis, with global incidence of approximately 866,000 cases in 2022; projections indicate that new cases will nearly double to 1.52 million by 2050 if current trends continue.^[25]^[26] Other notable conditions include vascular disorders like Budd-Chiari syndrome (hepatic vein blockage) and alpha-1 antitrypsin deficiency, a genetic cause of emphysema and liver disease. Common symptoms across these diseases include jaundice, fatigue, abdominal pain and swelling, easy bruising, and itchy skin, though many remain silent until decompensated cirrhosis ensues with ascites, encephalopathy, or variceal bleeding. Diagnosis typically involves liver function tests, imaging (ultrasound, CT, MRI), and biopsy, while treatment varies by etiology—antivirals for hepatitis, abstinence and nutrition for alcoholic disease, weight loss for MASLD, immunosuppressants for autoimmune types, and liver transplantation for end-stage failure. Prevention strategies emphasize vaccination for hepatitis A and B, moderation of alcohol intake, obesity control, and safe injection practices.

Symptoms and diagnosis

Liver diseases often remain asymptomatic in their early stages, particularly conditions like nonalcoholic fatty liver disease or early cirrhosis, and may only be detected during routine medical examinations or tests for unrelated issues.^[27]^[28] As the disease progresses, common symptoms emerge, including jaundice, which manifests as yellowing of the skin and the whites of the eyes due to bilirubin buildup; this sign may be less noticeable on darker skin tones.^[29]^[30] Other frequent symptoms include persistent fatigue and weakness, abdominal pain or swelling (ascites) from fluid accumulation, and edema causing swelling in the legs, ankles, or feet.^[27]^[29] Patients may also experience itchy skin, nausea, vomiting, loss of appetite, and unintended weight loss.^[27]^[29] Additional signs encompass easy bruising or bleeding, dark-colored urine, pale stools, muscle cramps, and in advanced cases, confusion or sleep disturbances due to hepatic encephalopathy.^[27]^[29] Individuals should seek immediate medical attention for severe abdominal pain, persistent jaundice, or swelling that limits mobility.^[29] Diagnosis typically begins with a thorough medical history and physical examination to identify risk factors such as alcohol use, viral infections, or metabolic conditions.^[28] Blood tests are essential, including liver function tests that measure enzymes like alanine aminotransferase (ALT) and aspartate aminotransferase (AST), bilirubin levels, and albumin to assess liver damage and synthetic function; additional tests can detect specific causes, such as viral hepatitis markers or genetic disorders.^[28]^[30] Imaging studies provide structural insights: abdominal ultrasound is often the initial noninvasive test to visualize liver size, texture, and abnormalities like tumors or fatty infiltration; computed tomography (CT) scans or magnetic resonance imaging (MRI) offer more detailed views for complex cases.^[28] Transient elastography, a specialized ultrasound, evaluates liver stiffness to gauge fibrosis or cirrhosis without invasion.^[28] If needed, a liver biopsy—performed via needle under imaging guidance—provides definitive tissue analysis for confirming diagnoses like cancer or inflammation.^[28]

Regeneration and transplantation

The liver possesses a remarkable capacity for regeneration, enabling it to restore its mass and function after injury or surgical resection. This process primarily occurs through the proliferation of existing hepatocytes in response to acute damage, such as partial hepatectomy or toxin-induced injury, where the organ can regain up to 70-80% of its original mass within weeks.^[31] In cases of chronic liver disease, regeneration may involve liver progenitor cells (LPCs) or transdifferentiation of biliary epithelial cells into hepatocytes when hepatocyte proliferation is impaired.^[32] The initiation of regeneration is triggered by mechanical signals like increased portal blood flow and hemodynamic changes, which activate growth factors such as hepatocyte growth factor (HGF) and epidermal growth factor (EGF).^[31] Regeneration proceeds in three phases: priming, proliferation, and termination. During the priming phase, cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) prepare hepatocytes for division via pathways including JAK/STAT3 and NF-κB, often mediated by non-parenchymal cells such as Kupffer cells and liver sinusoidal endothelial cells.^[32] The proliferative phase involves hepatocyte replication driven by HGF/c-Met, EGF/EGFR, Wnt/β-catenin, and Hippo/YAP signaling, which promote cell cycle progression and inhibit apoptosis.^[31] Termination is regulated by transforming growth factor-beta (TGF-β) and Hippo pathway components to prevent overgrowth and restore the liver-to-body weight ratio, a concept known as the "hepatostat."^[32] Key cellular interactions include hepatic stellate cells providing extracellular matrix remodeling and immune cells like macrophages secreting IL-6 to coordinate the response.^[31] In progenitor-dependent regeneration, activated in chronic settings like fibrosis, Notch and Hedgehog pathways guide LPC expansion and differentiation into hepatocytes or cholangiocytes.^[32] Disruptions in regeneration, often due to underlying conditions like cirrhosis or non-alcoholic steatohepatitis, can lead to liver failure, necessitating transplantation as the definitive treatment for end-stage disease. Liver transplantation involves surgically replacing the diseased liver with a healthy graft from a deceased or living donor, a procedure first successfully performed in 1967 by Thomas Starzl.^[33] The surgery, lasting 6-12 hours under general anesthesia, includes removing the recipient's liver, implanting the graft, and reconnecting vascular and biliary structures; living donor liver transplantation (LDLT) uses a portion of the donor's liver, which regenerates in both parties within weeks.^[34] In 2024, the United States performed 11,458 liver transplants, reflecting a continued increase from 10,659 in 2023, with a 71% rise over the past decade amid rising demand from conditions like hepatocellular carcinoma and metabolic dysfunction-associated steatotic liver disease.^[35]^[36] Post-transplant outcomes have improved with advancements like machine perfusion for graft preservation and refined immunosuppression protocols. One-year patient survival rates for adult deceased donor transplants reached 93.5% in 2023, with five-year survival at 81.0%; pediatric outcomes were even higher at 91.1% and 90.3%, respectively.^[36] LDLT offers comparable or superior short-term survival, with about 75% of recipients living at least five years overall, though challenges persist including organ shortage—leading to 15% waitlist mortality globally—and complications like rejection or biliary strictures.^[34]^[33] Emerging therapies, such as regulatory T-cell modulation and ex vivo normothermic perfusion, aim to expand donor pools and enhance long-term graft function.^[33]

Society and culture

Culinary and nutritional aspects

The liver, as an organ meat, is renowned for its exceptional nutritional density, providing a concentrated source of essential vitamins, minerals, and proteins in a relatively low-calorie package. A 100-gram serving of raw beef liver contains approximately 135 calories, 20 grams of high-quality protein, 3.6 grams of fat (including beneficial polyunsaturated fatty acids), and negligible carbohydrates, making it a valuable component for balanced diets.^[37] It is particularly rich in vitamin A, with over 4,900 micrograms retinol activity equivalents (RAE) per 100 grams—exceeding the recommended daily intake for adults by several times—supporting vision, immune function, and skin health. B vitamins abound, including 59 micrograms of vitamin B12 (over 2,400% of the daily value), which aids red blood cell formation and neurological function, alongside riboflavin (2.75 milligrams, about 200% daily value) for energy metabolism and folate (290 micrograms, 73% daily value) for DNA synthesis. Minerals like iron (4.9 milligrams, 27% daily value) combat anemia, while selenium and copper contribute to antioxidant defenses and connective tissue health. Similar profiles hold for other animal livers, such as chicken or pork, though beef liver often leads in vitamin A and B12 content. In culinary traditions worldwide, liver is valued for its versatility and umami-rich flavor, often transformed through preparation techniques to mitigate its metallic taste and firm texture. Common methods include soaking slices in milk or buttermilk for 30–60 minutes to tenderize and reduce bitterness, followed by quick pan-frying or braising to an internal temperature of 160°F (71°C) to ensure tenderness and food safety. In French cuisine, duck or goose liver features prominently in foie gras, a delicacy produced by force-feeding birds to enlarge the liver, then gently cooked or pâtéed for smooth texture.^[38] Jewish culinary heritage highlights chopped liver, a spread made by sautéing calf or beef liver with onions and hard-boiled eggs, originating from Eastern European resourcefulness during times of scarcity.^[39] British and American dishes frequently pair beef liver with caramelized onions and bacon, as in the classic liver and onions recipe, where dredging in flour before frying adds a crispy exterior. In Asian contexts, such as Chinese or Filipino stir-fries, pork or chicken liver is thinly sliced and cooked rapidly with ginger, soy sauce, or vegetables to balance its richness. These preparations not only enhance palatability but also preserve nutritional integrity when avoiding overcooking, which can degrade heat-sensitive vitamins like C and B-complex. Despite its benefits, liver consumption requires moderation due to potential health risks. Its high preformed vitamin A (retinol) content can lead to hypervitaminosis A if intake exceeds 3,000 micrograms daily over time, causing symptoms like nausea, liver enlargement, and bone pain, particularly in pregnant women where excess poses teratogenic risks.^[40] A single 100-gram serving provides enough vitamin A to meet weekly needs, so limiting to 1–2 servings per week is advisable.^[41] Additionally, liver contains elevated cholesterol (about 275 milligrams per 100 grams) and may accumulate environmental toxins like heavy metals in wild game, though levels in commercially raised animals are typically safe when sourced responsibly. Pathogen risks, including Campylobacter or Salmonella, necessitate thorough cooking, as undercooked liver has been linked to infections.^[42] Overall, when incorporated judiciously, liver offers a sustainable, nutrient-packed option that aligns with dietary guidelines for organ meats in moderation.^[43]

Historical and cultural uses

In ancient Mesopotamian civilizations, such as those of the Babylonians and Assyrians, the liver held profound cultural significance as the primary organ for hepatoscopy, a form of divination where priests examined the livers of sacrificed animals, particularly sheep, to interpret omens and predict future events. This practice, documented through clay liver models inscribed with prophetic signs dating back to the second millennium BCE, viewed the liver's shape, markings, and anomalies as direct messages from the gods regarding matters like warfare, harvests, or royal decisions.^[38] The tradition of liver divination extended to other ancient societies, including the Etruscans and Romans, where it evolved into haruspicy, a ritual inspection of animal entrails led by specialized priests known as haruspices. In Etruscan culture, detailed bronze models of livers, such as the Piacenza Liver from the 3rd century BCE, served as educational tools for decoding divine will, emphasizing the liver's role as a cosmic map. Roman adoption of this practice integrated it into state religion, with emperors consulting haruspices before major events, underscoring the liver's symbolic connection to fate and authority.^[44] Medically, the liver was revered in ancient Egyptian practices as a therapeutic agent; texts from the Ebers Papyrus around 1550 BCE describe using roasted ox liver to treat blindness by applying its fluids to the eyes, reflecting early recognition of its nutritional value in combating night blindness due to vitamin A content. In Greek and Roman medicine, Hippocrates in the 5th century BCE identified liver abscesses, while Galen in the 2nd century CE elevated the liver as the body's principal organ, the origin of blood and vital spirits, central to his theory of sanguification and humoral balance. This hepatocentric view, where the liver was seen as the seat of life force and emotion, influenced Western physiology for centuries.^[45]^[46] Culturally, the liver symbolized deep emotional and spiritual qualities across civilizations. In ancient Greek mythology, as in the myth of Prometheus and the lesser-known tale of Tityus, the liver represented the seat of the soul, life, and intelligence, eternally regenerating to signify resilience against divine punishment. Assyrian texts from the 1st millennium BCE portrayed the liver as the source of happiness, radiating warmth and light in moments of joy, contrasting with modern cardiac associations. In Middle Eastern traditions, including Arabic literature, the liver embodied courage, perseverance, and desire, immortalized in phrases like "you are my liver," denoting profound friendship and loyalty.^[47]^[48]^[49]

Comparative anatomy

Liver in other animals

The liver is a defining organ of vertebrates, absent in invertebrates, and exhibits structural and functional variations across vertebrate classes that reflect evolutionary adaptations to diverse physiological demands. While all vertebrate livers share core components such as hepatocytes, sinusoids, and bile canaliculi for metabolic, detoxifying, and synthetic roles, differences in lobation, vascular organization, and histological arrangement distinguish them. These variations influence processes like nutrient processing and toxin clearance, with lower vertebrates often displaying simpler architectures compared to the complex lobular systems in higher forms.^[50] In fish, the liver typically adopts a compact form adapted to aquatic environments, often divided into two or three lobes to fit within the coelomic cavity alongside other viscera. For instance, in teleost species like the Nile tilapia (Oreochromis niloticus), the left lobe is larger and extends across the body, while the right is smaller, with a prominent gallbladder impression on the visceral surface. Histologically, teleost livers feature hepatocytes arranged in anastomosing cords one or two cells thick, surrounded by sinusoids, and bile ducts positioned near but independent of portal veins in a non-portal triad configuration—unlike the integrated triads in tetrapods. This arrangement, classified into cord-like, tubular, or solid hepatocyte-sinusoidal patterns depending on phylogeny, supports efficient oxygen uptake from oxygenated water via the dual blood supply but limits complex compartmentalization seen in land vertebrates. Pancreatic tissue often intermingles with hepatic parenchyma, aiding digestion in the compact abdominal space.^[51]^[52]^[50] Amphibian livers, transitional between aquatic and terrestrial forms, are generally elongate or bilobate organs located ventrally in the abdominal cavity, posterior to the heart and near the stomach. In salamanders such as mountain newts (Neurergus spp.), the liver attaches anteriorly to the transverse septum and extends posteriorly, with two primary lobes that may subdivide further; vascular supply mirrors tetrapods via the hepatic portal vein and artery. Microscopically, hepatocytes form cords separated by sinusoids lined with fenestrated endothelium, accompanied by Kupffer cells and melanomacrophage centers for immune surveillance—features akin to fish but with emerging portal triad structures including periportal bile ducts. This setup facilitates semi-aquatic metabolism, including urea production in some species, though the liver's simpler lobulation compared to amniotes reflects less specialized compartmentalization.^[53]^[50] Reptilian livers maintain a vertebrate-typical design but adapt to ectothermic lifestyles, serving as the largest visceral organ with functions in lipid storage and bile production for fat digestion. In snakes and elongated lizards, the liver is notably linear and diffuse along the body axis, while in turtles and broader lizards, it appears more transverse and compact. Histologically, it features portal triad organization with bile ducts along portal veins and fenestrated sinusoids, similar to amphibians but with greater stromal support; some squamates produce bilirubin, contrasting with biliverdin dominance in other reptiles. These adaptations support intermittent feeding and temperature-dependent metabolism, with a large functional reserve allowing delayed clinical signs of impairment.^[54]^[50] Avian livers, proportional to high metabolic rates for flight, are relatively larger than mammalian counterparts—often comprising 2-3% of body weight—and bilobed without a true lobular structure or extensive connective tissue septa. In species like domestic fowl, the right lobe dominates, spanning the sternum, with a single gallbladder; vascular supply includes dual hepatic inflow, but sinusoids radiate without classic mammalian acini. Hepatocytes are polygonal and arranged in irregular plates around central veins, emphasizing rapid nutrient turnover for egg production and energy demands, though lacking the fibrous Glisson's capsule of mammals. This streamlined architecture enhances efficiency in endothermic, high-output physiology.^[55]^[50]^[56] Among mammals, liver morphology diversifies but generally features multi-lobate designs (e.g., six lobes in dogs, four in humans) with well-defined portal triads at lobule peripheries, enabling zoned metabolic functions like zonation for glycolysis or detoxification. Sinusoids are lined by fenestrated endothelium, and extensive collagen supports the organ's regenerative capacity, adaptations honed for endothermy and varied diets across orders. These traits build on reptilian foundations, with increased complexity correlating to dietary and environmental pressures.^[50]^[56]

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