Liver

Development

• Develops from the 3rd to 8th week during embryogenesis
  • Originates from the foregut endoderm
  • Appears as the hepatic diverticulum, which later becomes the liver and the gallbladder
• The falciform ligament is called the ventral mesentery during the fetal period.
• The round ligament contains the umbilical vein during gestation, which is the main fetal blood source (see table below).

Gross Anatomy

Location

The liver is the largest gland in the body. It extends from the right to the left hypochondriac region (¾ of the liver is in the right superior quadrant).

• Immediately adjacent to the inferior surface of the diaphragm → location is breath-dependent (rises during exhalation, lowers during inhalation)
• Superior limit: height of the 5th intercostal space during exhalation
• Inferior limit: curve of the right costal arch during inhalation 
• Surfaces: diaphragmatic and visceral
  • Intraperitoneal except for the bare area, porta hepatis, and gallbladder fossa 
  • Enclosed in the Glisson capsule (external layer of fibrous connective tissue)
• Weight: 1.5 kg (average)

Four lobes

• Superficially divided by fissures and ligaments
• Functionally determined by the left and right branches of the hepatic vein and Cantlie’s line (an imaginary line that crosses the gallbladder fossa and inferior vena cava)

1. Right lobe: largest
2. Left lobe: separated from the right by the falciform ligament on the diaphragmatic surface
3. Caudate lobe: between the venous ligament and groove for the inferior vena cava (IVC)
4. Quadrate lobe: between the round ligament and the gallbladder fossa

Impressions of adjacent structures and organs

• Gastric: left lobe, anterior to the esophageal impression
• Colic: inferior margin of the right lobe (right colic flexure)
• Duodenal: right lobe, lateral to the gallbladder (1st segment of the duodenum)
• Renal: center of the right lobe (superior pole of the right kidney)
• Suprarenal: superior to the renal impression (right adrenal gland)

Eight segments (Couinaud classification)

• Based on a transverse plane through the bifurcation of the main portal vein
  • Exception: Caudate lobe receives blood flow from both vascular branches.
• 8 functionally independent segments, each with its own vascular inflow, outflow, and biliary drainage 
• Segment I is the caudate lobe and can only be seen from the posterior view.
• Segments can be surgically resected without affecting the viability of the remaining liver.

Porta hepatis

The porta hepatis (also called the hepatic portal) is a transverse fissure that separates the caudate and quadrate lobes and serves as a passageway for the following: 

• Common hepatic bile duct (exits the liver, located anteriorly and laterally)
• Hepatic artery proper (enters the liver, located anteriorly and medially) 
• Hepatic portal vein (enters the liver, located posteriorly, between the duct and artery)
• Hepatic nerve plexus (contains postganglionic sympathetic innervation from the celiac plexus and preganglionic parasympathetic innervation from the vagus nerve)
• Lymphatic vessels of the liver

Ligaments of the liver

Definition: Ligaments of the liver are double layers of visceral peritoneum that fix the position of the liver by attaching it to the surrounding structures.

Microscopic Anatomy

Hepatic (classical) lobule

• Small hexagonal units of the liver, measuring 1–2.5 mm each, separated by thin strands of connective tissue
• Central vein: Each lobule has a vein in the center that receives mixed blood from the sinusoids (via branches from the portal vein and hepatic artery), drains into the hepatic veins, and leaves the liver via the IVC.
• Portal triad: cluster of vessels located at the 6 vertices of each hepatic lobule:
  • Interlobular branch of the portal vein: supplies the lobule with deoxygenated blood, rich in nutrients
  • Interlobular branch of the hepatic artery proper: supplies the lobule with oxygenated blood
  • Interlobular bile duct: drains the bile from the biliary ductules in the opposite direction of blood flow
  • Additionally: lymphatic vessels and a branch of the vagus nerve

Portal vein lobule

• The portal vein lobule is a lobule viewed from a 2nd perspective, with the portal triad in the center and the central veins at the 3 vertices
• Shaped like a triangle
• Functional unit for bile transport
• Bile is drawn to the center of the triangle, into the interlobular bile duct.

Hepatic acinus

• The hepatic acinus is a lobule viewed from a 3rd perspective, with the central veins and portal triads at the 4 vertices.
• Diamond-shaped
• Functional unit for blood exchange
• Blood moves from the triads to the vein through 3 zones:
  1. Zone 1: the periphery of the hepatic lobule, highest nutrient/oxygen levels
  2. Zone 2: transitional zone
  3. Zone 3: the center of the hepatic lobule, lowest nutrient/oxygen levels
     • Most sensitive to ischemic damage

Hepatocytes

• Polyhedral cells organized into plates separated by sinusoids
• Shape and number of the nuclei vary
• Each cell has an apical biliary pole, which drains into 1 or more bile canaliculi, and a basolateral blood pole, which receives blood from the sinusoids.

Sinusoids

• Capillaries with discontinuous endothelium between hepatocyte plates
• Receive oxygen-rich blood from the interlobular arteries and nutrient-rich blood from the interlobular veins and conducts in toward the central veins
• Kupffer cells: specialized macrophages between the endothelial cells, which phagocytose old or damaged erythrocytes
• Pit cells: liver-specific natural killer cells that adhere to the endothelium, are dependent on Kupffer cells, and have tumor cell-lysing capability 
• Perisinusoidal or space of Disse: space filled with blood plasma that lies between the sinusoids and hepatocytes
  • Contains Stellate or Ito cells: store vitamin A and play a role in collagen production (important in the development of cirrhosis)

Neurovasculature

Blood supply

The liver has a special dual blood supply that provides a mix of oxygenated, deoxygenated, and nutrient-rich blood. 

• Hepatic artery proper (HAP): supplies 25% of the liver’s blood supply and carries oxygenated blood 
  • Abdominal aorta → celiac trunk → common hepatic artery →  HAP
• Portal vein: supplies 75% of blood supply, carries oxygen-poor, nutrient-rich blood drained from the abdominal organs
  • Formed most commonly by the union of the splenic and superior mesenteric veins
  • Additional tributaries: inferior mesenteric, cystic, and left and right gastric veins

Venous drainage

• Sinusoids → central vein of each lobule → hepatic veins → IVC
• Portosystemic anastomoses: alternative routes of circulation ensuring venous drainage of abdominal organs even if blockage occurs in portal system. Anastomosis between:
  • The left gastric veins and the lower esophageal veins 
  • The superior rectal veins and the inferior and middle rectal veins
  • The paraumbilical veins and the small epigastric veins
  • The intraparenchymal hepatic branches of the right division of the portal vein and the retroperitoneal veins 
  • The omental and colonic veins with the retroperitoneal veins
  • The ductus venosus and the IVC 

Lymphatic drainage

Hepatic lymph nodes: located around the porta hepatis → celiac cluster of lymph nodes → cisterna chyli (dilated sac that receives lymph from the gastrointestinal [GI] trunk and 2 lumbar lymphatic trunks) → thoracic duct 

Innervation

• Hepatic plexus (travels with the hepatic artery and portal vein)
• Sympathetic fibers from the celiac plexus and superior mesenteric plexus
• Parasympathetic fibers from the anterior and posterior vagal trunks
• Glisson capsule innervated by the most inferior intercostal nerves
• HAP has α and β adrenergic receptors innervated by splanchnic nerves

Biliary drainage

Bile canaliculi → intrahepatic bile ducts → left and right hepatic ducts → common hepatic duct → common bile duct → duodenum

Functions of the Liver

Detoxification

The liver eliminates degradation products obtained via resorption from the GI tract. It makes fat-soluble substances water-soluble through enzymatic modification. This allows for excretion via biliary tracts or through urine.

• Cytochrome p450 system: inactivates orally administered drugs via the first-pass effect
• Degradation of ammonia into urea
• Ethanol breakdown
• Breakdown of bilirubin (glucuronidation) → excretion into bile

Metabolism

• Carbohydrates:
  • Gluconeogenesis (synthesis of glucose from amino acids, lactate, or glycerol)
  • Glycogenesis (synthesis of glycogen from glucose)
  • Glycogenolysis (breakdown of glycogen into glucose)
  • Glycolysis (breakdown of glucose into pyruvate, producing adenosine triphosphate (ATP))
• Proteins: 
  • Production of albumin; globulins; acute phase proteins; transaminases; coagulation factors I (fibrinogen), II (prothrombin), V, VII, VIII, IX, X, XI, XII, and XIII; protein C; protein S; and antithrombin
  • Amino acid degradation
• Lipids:  
  • Lipogenesis (storage of free fats as triglycerides) 
  • Ketogenesis (synthesis of ketone bodies) 
  • Fatty acid synthesis and degradation 
  • Production of bile acids, lipoproteins, and cholesterol

Storage

• Glycogen 
• Lipoproteins 
• Vitamins A, K, B12, B9 (folate), E, and D 
• Iron and copper

Hormone production

• Thrombopoietin
• Insulin-like growth factor 1
• Angiotensinogen

Erythropoiesis

• Site of fetal RBC production from week 6 of gestation until birth
• Extramedullary erythropoiesis may occur in adulthood after bone marrow irradiation, in various bone marrow disorders (e.g., myelofibrosis, myelodysplastic syndrome, polycythemia vera), and chronic anemias (e.g., thalassemia, sickle cell disease).

Clinical Relevance

Clinical evaluation

• Abdominal examination: The examination of the liver is mostly based on palpation and percussion. The purpose of liver palpation is to approximate liver size and feel for tenderness and masses. The purpose of liver percussion is to measure the liver size.
• Liver function tests: can be divided into 3 categories:
  • Parameters of hepatocellular damage (transaminases, glutamate dehydrogenase, and AST/ALT ratio)
  • Parameters of cholestasis (e.g., γ-glutamyl transpeptidase, alkaline phosphatase, and direct and indirect bilirubin)
  • Parameters of hepatic synthesis (albumin, cholinesterase, and coagulation factors)
• Normal abdominal imaging: Imaging is essential for accurately detecting focal liver lesions (e.g., abscess, tumor), but is limited in detecting and diagnosing diffuse hepatocellular disease (e.g., hepatitis, cirrhosis).
  The types of imaging used are:
  • Hepatobiliary ultrasonography
  • Ultrasound elastography
  • Doppler ultrasonography
  • Computed tomography (CT) scan
  • Radionuclide liver scanning
  • Abdominal radiography
  • Magnetic resonance imaging (MRI)

Disorders

Neoplasms

• Benign liver tumors: cavernous hemangiomas, hepatocellular adenomas, and focal nodular hyperplasia. 
• Liver cancer: hepatocellular carcinoma; intrahepatic cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemangioendothelioma; liver metastases from GI, breast, and lung malignancies; and rare hepatic tumors (carcinosarcomas, teratomas, yolk sac tumors, carcinoid tumors, and lymphomas). 

Infections

• Viral hepatitis: mainly caused by primarily hepatotropic viruses A, B, C, D, and E, resulting in targeted inflammation of the liver. Patients develop non-specific symptoms, such as nausea, vomiting, anorexia, and abdominal pain. Other viruses may cause hepatitis, including the Epstein-Barr virus, cytomegalovirus, and yellow fever virus.
• Bacterial infections:
  • Pyogenic liver abscess (caused by many different types of pyogenic bacteria)
  • Diffuse involvement, such as by Salmonella enterica serotype typhi, Mycobacterium tuberculosis
• Fungal infections, including Candida spp., Histoplasma capsulatum
• Parasitic infections, including Schistosoma spp. (schistosomiasis), Plasmodium spp. (malaria)

Inflammatory disorders

• Alcoholic liver disease: progressive disease characterized by inflammation and damage of the liver due to long-term excessive alcohol abuse.
• Nonalcoholic fatty liver disease: progressive disease of the liver characterized by the accumulation of fat in the liver without the excessive intake of alcohol; often associated with obesity, diabetes, and elevated triglycerides.
• Autoimmune hepatitis: progressive necroinflammatory process leading to chronic hepatitis or cirrhosis. Characterized by the presence of circulating autoantibodies and high serum globulin concentrations. 
• Fitz-Hugh-Curtis syndrome (perihepatitis): characterized by inflammation of the liver capsule that occurs in women as a rare complication of pelvic inflammatory disease (PID).

Hereditary disorders

• Hemochromatosis: a genetic autosomal recessive disorder due to a mutation of the HFE gene, resulting in increased intestinal iron absorption. Presents with hepatomegaly, liver cirrhosis, bronzed skin, diabetes mellitus, arthralgia, and cardiomyopathy.
• Wilson’s disease: an autosomal recessive metabolic disorder in which copper excretion is impaired, leading to copper accumulation in the liver.
• Dubin-Johnson syndrome: a rare, autosomal recessive disorder that involves elevated levels of conjugated bilirubin in the serum that lead to a melanin-like pigment depositing in the liver, causing what is known as “black liver.”

Miscellaneous disorders

• Portal hypertension: an increase in the pressure in the portal vein. Most commonly caused by cirrhosis, schistosomiasis, and portal vein thrombosis, but may be idiopathic.
• Cirrhosis: a condition caused by chronic damage to the liver. Cirrhosis is characterized by hepatic parenchymal necrosis, which ultimately leads to fibrosis and liver insufficiency.
• Budd–Chiari syndrome: a rare condition resulting from hepatic vein obstruction that leads to hepatomegaly, ascites, and abdominal discomfort.