Liver

The liver is a wedge-shaped organ that is located underneath the diaphragm in the right upper abdominal quadrant. It is covered by a capsule and connected to surrounding structures via ligaments. The porta hepatis structures are found in a fissure between two of the four liver lobes. The hepatic artery proper and the portal vein provide the liver with a dual blood supply. Microscopically, the liver is divided into lobules, each with a central vein and a portal triad. Each portal triad consists of an artery, vein, and bile ductule, and is accompanied by lymphatic vessels and a branch of the vagus nerve. Liver parenchyma consists of hepatocytes and hepatic sinusoids. Hepatic sinusoids drain into the central vein of each lobule. The liver is responsible for energy metabolism, synthesis of various substances (e.g., glucose, ketones, bile acid), glucose homeostasis regulation, nutrient storage, and the clearance/excretion of toxins (e.g., ethanol) and waste products. In fetuses, the liver is the site of erythropoiesis from 6 weeks' gestation until birth. During embryogenesis, the liver originates from the endoderm. The ligamentum teres forms from the obliterated umbilical vein and is located in the free edge of the falciform ligament.

General structure

• Largest gland in the body
  • Weight: ∼ 1.2–1.5 kg in adults (2.6–3.3 pounds) ^[1][2]
• Wedge-shaped
• Consists of four lobes:
  • Right (largest)
  • Left
  • Quadrate
  • Caudate
• Typically divided into 8 segments
• Surrounded by the hepatic capsule (two layers)
  • Outer serous layer derived from peritoneum, which covers the entire liver (except the bare area of the liver)
  • Fibrous inner layer (the Glisson capsule) that covers the entire liver (including the bare area of the liver), the hepatic artery, portal vein, and bile ducts
• Porta hepatis structures
  • Common hepatic duct (leaving)
  • Hepatic artery proper (entering)
  • Hepatic portal vein (entering)
  • Hepatic nerve plexus and lymphatic vessels

Location

• Location: under the diaphragm in the right upper abdomen.
  • Extends from the fifth intercostal space to the right costal margin in the midclavicular line
  • Percussed at the fifth intercostal space: see abdominal examination

Ligaments

• Falciform ligament
  • Connects liver to abdominal wall
  • Divides liver into right (larger) and left (smaller) lobes
  • Contains round ligament of liver
• Hepatoduodenal ligament
  • Connects liver to duodenum
  • Contains portal triad (proper hepatic artery, portal vein, common bile duct)
    • Clinical correlate: in cases of liver hemorrhage, temporary clamping of the hepatoduodenal ligament (Pringle maneuver) can help to achieve hemostasis
• Gastrohepatic ligament
  • Connects liver to lesser curvature of the stomach
  • Contains gastric arteries

Vasculature

As part of the liver's dual blood supply, the portal vein allows tissue to remain oxygenated and preserve function in the event of an obstructed hepatic artery.

Innervation

• Glisson capsule and serosa: lower intercostal nerves
• Parenchyma: hepatic plexus

Distention of the capsule results in well-localized, sharp pain, as seen in ascites, inflammation, or hepatic cancer.

References:^[3][4][5][6]

• Visceral peritoneum: serosa that covers the liver
• Hepatic lobules: Sheets of connective tissue divide the liver into small hexagonal units called lobules. These consist of:
  • A central hepatic vein in the middle
  • Portal triads at the vertices
    • A portal triad consists of:
      • Branch of hepatic artery proper
      • Branch of portal vein
      • Bile ductule
    • Each portal triad is accompanied by the following structures:
      • Lymphatic vessels
      • Branch of the vagus nerve
• Parenchyma
  • Mostly consists of hepatocytes
    • Contain large amounts of smooth endoplasmic reticulum, which is involved in detoxification
    • The basolateral surface of hepatocytes faces the sinusoids. .
    • The apical surface of hepatocytes faces the lumen of the bile canaliculi.
      • Hepatocytes secrete bile into the canaliculi → secretions flow parallel to the sinusoids, but in the opposite direction of blood → bile canaliculi form the intrahepatic bile ducts → common bile duct (delivers bile into the duodenum)
  • Hepatic sinusoids; are large capillaries lined with highly fenestrated endothelial cells: Blood flows through the sinusoids and empties into the central vein of each lobule.
• Functions
  • Absorption of nutrients from blood and secretion of products synthesized by special carriers into the blood
  • Kupffer cells (a type of macrophage) are housed in the sinusoids. These cells phagocytize foreign particles, bacteria, and damaged, old blood cells.
  • The plasma-filled space between the sinusoids and hepatocytes is called the perisinusoidal space (of Disse): contains hepatic stellate cells (Ito cells), which store vitamin A and are the main source of extracellular matrix production in liver injury (formation of scar tissue → fibrosis)
• Histological zones:
  • Zone 1: The periportal zone
    • Is best oxygenated and, therefore, is most resistant to ischemia.
    • Affected first in viral hepatitis and toxic substance ingestion, e.g., cocaine.
  • Zone 2: intermediate zone (liver): affected in yellow fever
  • Zone 3: pericentral vein/centrilobular zone
    • The least oxygenated zone, and thus most susceptible to ischemia
    • Most sensitive to metabolic toxins (e.g., ethanol, CCl4, halothane, rifampin, acetaminophen)
    • Has the highest amount of cytochrome P-450

Zone 1 is first and zone 3 is last to receive O₂.

Zone II is affected in yellow fever.

References:^[3][5]

For laboratory parameters for each of the functions, see “Parameters of hepatocellular damage,” “Parameters of cholestasis,” and “Parameters of hepatic synthesis” in “Liver function tests.”

References:^[7][8][9]

Breakdown of ethanol

Example of zero-order elimination (for alcohol dehydrogenase); : A constant amount of alcohol is metabolized per unit time (∼ 1 ounce of alcohol/hour). NAD⁺ is the limiting reactant for this pathway.

1. Oxidation of ethanol to acetaldehyde by alcohol dehydrogenase
   • Fomepizole: competitively inhibits alcohol dehydrogenase; used in the treatment of methanol and ethylene glycol poisoning to prevent the formation of toxic metabolites ^[8]
   • Alternatively, ethanol can be given, as it will compete for alcohol dehydrogenase and thereby limit the formation of formaldehyde.
2. Oxidation of acetaldehyde to acetate by acetaldehyde dehydrogenase
   • Disulfiram competitively inhibits acetaldehyde dehydrogenase, which is useful in the treatment of alcohol use disorder: Acetaldehyde builds up quickly after alcohol consumption and causes hangover symptoms, which usually discourages patients from drinking. ^[9]
   • Other drugs (e.g., metronidazole) have a disulfiram-like effect, which is why the concomitant use of alcohol and antibiotics is not recommended.
3. Ligation of acetate and coenzyme A to acetyl-CoA by thiokinase under ATP consumption

When large quantities of alcohol are consumed, acetaldehyde builds up faster than it can be metabolized by acetaldehyde dehydrogenase. Excess acetaldehyde plays a major role in hangover symptoms.

Female individuals are more susceptible to ethanol intoxication than male individuals, even when consuming similar levels of alcohol. This is mainly because they have lower total body water and alcohol dehydrogenase activity than male individuals of comparable size. These physiological factors result in higher and more prolonged blood alcohol concentration, leading to faster intoxication. ^[10];
FOMEpizole: For Overdosing on Methanol or Ethylene glycol!

It is DISgusting to drink alcohol when taking DISulfiram!

Metabolic consequences of heavy ethanol consumption

When ethanol is metabolized, there is an increase in the NADH/NAD⁺ ratio in the liver. Heavy ethanol consumption and consequently excess NADH result in:

• Anion gap metabolic acidosis
  • Lactic acidosis: increased conversion of pyruvate to lactate by lactate dehydrogenase → ↑ lactate
  • Ketoacidosis: Acetyl-CoA is shunted into the ketogenesis pathway instead of the TCA cycle (increased NADH/NAD⁺ ratio inhibits the TCA cycle, leading to a buildup of acetyl-CoA) → ↑ ketone bodies
• Fasting hypoglycemia
  • ↑ NADH/NAD⁺ ratio → inhibition of conversion of cytosolic malate to oxaloacetic acid (OAA), increased conversion of OAA to malate → impaired gluconeogenesis, inhibition of TCA cycle
• Hepatosteatosis
  • In the glycolysis pathway, ↑ NADH/NAD+ ratio leads to increased conversion of DHAP to glycerol-3-phosphate
  • ↑ NADH/NAD⁺ratio → inhibition of TCA → ↑ acetyl-CoA → ↑ fatty acid synthesis
  • ↑ Fatty acids and ↑ glycerol-3-phosphate → ↑ triglycerides → hepatic steatosis

• Endoderm origin ^[11]
• Derived from junction of foregut and midgut ^[11]
• Ligamentum teres: formed from the obliterated umbilical vein ^[11]

• Hepatic inflammation
  • Alcoholic hepatitis
  • Non-alcoholic steatohepatitis
  • Autoimmune hepatitis
  • Fitz-Hugh-Curtis syndrome
• Hepatic infection
  • Differential diagnosis of viral hepatitis
  • Liver abscesses (e.g., due to Klebsiella or amebic liver abscess)
  • Parasitic infection (e.g., Plasmodium vivax and P. ovale have hypnozoite forms that reside in the liver)
• Hepatic tumors
  • Hepatocellular carcinoma
  • Angiosarcoma (e.g., due to arsenic or vinyl chloride exposure)
  • Colon cancer metastases
  • Benign liver tumors and hepatic cysts
  • Hepatic adenoma
  • Hydatid cyst disease
• Hereditary diseases
  • Hemochromatosis: iron overload
  • Wilson disease: copper overload
  • Von Gierke's Disease: increased liver glycogen
  • Black liver due to Dubin-Johnson syndrome
• Others
  • Fatty liver
  • Hepatomegaly (e.g., due to right heart failure or schistosomiasis)
  • Budd-Chiari syndrome
  • Ischemia (typically affects central vein zone)
  • Cirrhosis