Liver

Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

Editors

  • Nancy C. Tkacs, PhD, RN

  • Linda L. Herrmann, PhD, RN, AGACNP-BC, GNP-BC, ACHPN, FAANP
    © Springer Publishing Company, LLC.

Chapter 14: Liver

Key Concepts

  • Anatomy

    • Blood Supply

    • Most blood flow comes from the portal vein, which drains the intestines, pancreas, and spleen.

    • Oxygenated blood is supplied by the hepatic artery.

    • The liver experiences a high rate of blood flow.

  • Physiology

    • The liver is the major metabolic organ of the body, regulating substrate flow during both fed and fasted states.

    • Functions include:

    • Producing bile, which contains bile salts essential for fat digestion and absorption.

    • High rate of protein synthesis, including the majority of plasma proteins.

    • Biotransformation of bilirubin and drugs to facilitate excretion.

    • Susceptibility to infections (e.g., hepatitis), damage from alcohol and obesity, and drug toxicity.

Liver Disorders

  • Jaundice

  • Liver Fibrosis

  • Drug-Induced Liver Injury

  • Acute Liver Failure

  • Acetaminophen Toxicity

  • Cholestasis

  • Acute Hepatitis

  • Chronic Hepatitis

  • Viral Hepatitis (types A, B, C, D, and E)

  • Cirrhosis

  • Portal Hypertension

  • Portal-Systemic Shunting

  • Hepatic Encephalopathy

  • Hepatorenal Syndrome

  • Alcoholic Liver Disease

  • Nonalcoholic Fatty Liver Disease

  • Hereditary Hemochromatosis

  • Hyperbilirubinemia

  • Biliary Atresia

  • Hepatocellular Carcinoma

Liver Histology

  • Blood enters the liver through the portal vein and hepatic artery, then flows through large, highly permeable capillaries known as sinusoids, which lie between hepatocyte plates.

  • Immune surveillance is performed by resident macrophages and dendritic cells.

  • The interstitial space, called the space of Disse, is occupied by stellate cells and is continuous with lymph vessels.

Liver Blood Supply

  • The liver weighs approximately 2.5% of total body weight.

  • Receives about 20% to 25% of cardiac output.

  • Portal vein contributes 75% to 80% of liver blood flow, rich in nutrients and hormones absorbed from the gut and pancreas.

  • The hepatic artery is the primary source of oxygen for the liver.

Liver Blood and Bile Flow

  • Blood flows into the central vein of the liver lobule.

  • The liver has relatively low tissue oxygenation due to deoxygenation of portal vein blood compared to other organs.

  • Bile flows from hepatocytes to bile ductules.

Liver Cell Structure and Function

  • Hepatocytes are polarized with a brush border facing the space of Disse and sinusoids.

  • Tight junctions surround the bile canaliculus, which prevents bile from mixing with blood.

  • The liver contains abundant smooth and rough endoplasmic reticulum (ER), Golgi apparatus, and storage granules for glycogen and lipids.

Bile Duct Anatomy

  • The common hepatic duct joins the cystic duct leading to the gallbladder.

  • The common bile duct drains the gallbladder and liver, merging with the pancreatic duct before emptying into the duodenum under the sphincter of Oddi's control.

Liver Cell Metabolic Functions

  • Energy Metabolism

    • Postprandial: Fuel storage; portal vein blood is rich in absorbed nutrients and insulin.

    • Glucose is stored as glycogen (glycogenesis).

    • Excess glucose transforms into triglycerides, forming very low-density lipoproteins (VLDL).

    • Fasting:

    • Glucose is generated from glycogen (glycogenolysis) and new glucose synthesis (gluconeogenesis).

  • Lipid Metabolism

    • The liver synthesizes cholesterol, high-density lipoproteins (HDL), and processes intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL).

Liver Cell Synthetic Functions

  • Bile Salts

    • Amphipathic molecules essential for fat digestion and absorption in the small intestine.

    • Taken up by ileum transporters, recycled back to the liver 2 to 3 times during a meal.

  • Urea Synthesis

    • Amine groups form through hepatic amino acid metabolism.

    • The urea cycle utilizes amines to synthesize urea, detoxifying ammonia produced from amines.

  • Liver Protein Synthesis

    • Synthesizes plasma proteins (e.g., albumin), coagulation and complement proteins, and carrier proteins such as angiotensinogen, glutathione, and alpha1-antitrypsin.

    • Acute phase proteins synthesized during infections and inflammatory responses.

Summary of Liver Metabolic Processes

  • The liver secretes bile into the small intestine, where nutrients are absorbed and returned to the liver via the portal vein.

  • Other substances are exchanged between the liver and blood.

Bilirubin Metabolism

  • The breakdown of aging red blood cells generates heme, converted to bilirubin.

  • Types of Bilirubin:

    • Unconjugated (indirect): Initially hydrophobic and nonpolar, carried in circulation by albumin.

    • Conjugated (direct): Liver conjugates bilirubin with glucuronic acid, allowing free travel in the blood.

  • Bilirubin contributes to bile color; stercobilin is responsible for fecal color, while cholestasis may lead to pale stools.

Liver Cell Biotransformation Reactions

  • Targets nonpolar endogenous and exogenous compounds.

  • Bilirubin Process: Bilirubin bound to albumin taken by the liver for conjugation. Conjugated bilirubin, now water-soluble, is secreted into bile and excreted by kidneys.

  • Drug Metabolism:

    • Cytochrome P450 enzymes in smooth ER attach a chemically reactive "handle" to molecules.

    • Conjugating enzymes add a water-soluble group, enabling filtering and secretion by kidneys.

Outcomes of Drug Metabolism

  • Oxidation and conjugation reactions yield metabolites, which may be nonpolar (excreted via bile) or polar (excreted by kidneys).

Liver First-Pass Drug Metabolism

  • The liver's high blood flow facilitates injury from chemical exposures (the liver exposome).

  • Orally administered medications undergo first-pass through the liver via the portal vein, subject to metabolic enzymes acting on them.

  • Some drugs are metabolized into inactive forms, while others (prodrugs) are activated by liver metabolism, affecting effective circulating drug concentration.

Additional Liver Characteristics

  • The reticuloendothelial system includes Kupffer cells in sinusoids that phagocytize bacteria translocating from the gut.

  • Vitamin and Mineral Storage: Includes vitamins A, E, B12, and iron as ferritin, along with synthesis of iron-binding proteins like transferrin and hepcidin.

  • The liver exhibits regenerative capacity after acute damage from conditions like drug-induced liver injury or hepatitis A, allowing recovery and growth.

Liver Assessment Tools

  • Liver cell necrosis results in the release of liver proteins:

    • Alanine Aminotransferase (ALT): Most specific liver marker.

    • Aspartate Aminotransferase (AST)

    • Gamma-Glutamyl Transferase (GGT): Increases with alcohol-induced damage.

    • Alkaline Phosphatase (ALP): Often reflects cholestasis but may indicate bone turnover.

  • Protein Synthesizing Markers:

    • Albumin levels

    • Prothrombin Time (PT) reflects coagulation protein production.

  • Biomarkers for uptake and biotransformation include indirect and direct bilirubin levels, and assessment of fibrosis through imaging techniques like ultrasound, MRI, CT, elastography, or biopsy.

Acute Liver Injury

  • In the United States, more than 50% of acute liver injury cases are drug-induced liver injuries (DILI).

  • Acetaminophen is a common culprit; other drugs, including various antibiotics, may also cause acute liver injury.

  • Signs and symptoms of acute liver injury often begin with a subtle prodrome of fatigue and nausea, potentially resolving spontaneously, followed by jaundice in severe cases.

  • Acetaminophen Overdose Mechanism: Generates the toxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI), which must be conjugated to glutathione to be detoxified. Excessive acetaminophen reduces liver glutathione, requiring N-acetylcysteine as a treatment to replenish glutathione levels.

Acute Cholestasis

  • Defined as the blockage of bile flow due to various causes, including:

    • Bile duct blockage from gallstones, neoplasms, or pancreatic inflammation.

    • Reactions to certain pharmaceuticals.

    • Commonly associated with pregnancy.

  • Findings: Jaundice and hyperbilirubinemia, elevated GGT, ALP, and 5' nucleotidase; increased circulating bile salts causing pruritus; pale stools and dark urine from bile secretion failure.

Hepatitis

  • General term for liver inflammation, can be acute or chronic, induced by alcohol exposure, obesity, or viral infection.

  • Hepatitis A Virus: Transmitted via the fecal-oral route, prevalent globally, typically resolves after acute infection, and vaccines are available. Diagnosis relies on the detection of immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies against hepatitis A antigens.

Hepatitis B Virus Infection

  • A DNA virus leading to chronic infection due to host genome integration. Transmission occurs through blood and sexual contact, and vaccines are available.

  • Hepatitis B Virus (HBV) Antigens:

    • Surface (HBsAg)

    • Envelope (HBeAg)

    • Core (HBcAg)

Hepatitis B Virus Laboratory Evaluation

  • Anti-HBs, HBsAg, Anti-HBcAg, Anti-HBeAg interpretation shows:

    • Markers for acute HBV infection, chronic HBV infection, immunity from vaccination or prior infection, etc.

Chronic Liver Disease—Vascular Changes

  • Normal sinusoids are highly permeable and low-resistance, while chronic liver inflammation leads to:

    • Activated Kupffer and stellate cells, lymphocyte infiltration contributing to fibrosis.

    • Increased extracellular matrix protein, narrowing vessel lumens, and endothelial cells losing fenestrations impacting protein exchange.

  • Portal hypertension arises due to increased vascular resistance.

Liver Cirrhosis

  • Resulting from prolonged liver damage progressing to extensive fibrosis and resulting portal hypertension.

  • Early stages may be reversible with effective management, yet damage may become irreversible requiring transplantation.

  • Characteristics: Hard, shrunken liver with a nodular appearance; complications may vary by stage - compensated or decompensated.

COVID-19 and Liver

  • Hospitalized patients with COVID-19 often exhibit elevated liver enzymes, more severe in older patients and those with obesity.

  • Enzyme elevation severity correlates with disease extent, mechanical ventilation need, and mortality risk.

  • Liver injury may occur through multiple mechanisms despite it not being a primary target, including coagulopathy, hypoxia from ARDS, drug-induced injury, and cytokine storms.

Increased Sinusoid Resistance in Chronic Liver Disease

  • Describes changes associated with chronic liver disease:

    • Increased hepatic sinusoid resistance and decreased splanchnic capillary oncotic pressure leading to portal hypertension and related complications.

    • Resulting consequences include ascites, varices, hepatic encephalopathy, splenomegaly, and hemorrhage with persistence of altered blood flow, and activation of the RAAS and SNS.

Causes of Chronic Liver Disease

  • Alcoholic Liver Disease

    • Leading cause of liver disease globally; ethanol metabolism produces toxic acetaldehyde and increases reactive oxygen species.

    • Causes changes in metabolic pathways, promoting fatty liver and contributing to fibrosis and progression to hepatocellular carcinoma (HCC).

  • Nonalcoholic Fatty Liver Disease (NAFLD)

    • Includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH);

    • Strong correlation to obesity, diabetes, and metabolic syndrome, with insulin resistance exacerbating liver fat accumulation.

    • Managing weight through lifestyle, medications, and surgeries may reverse conditions.

  • Hepatitis B Infection

    • Chronic in children more prone to immune infiltration and HCC development; antiviral regimens help manage progression but cure is often elusive.

  • Hepatitis C Infection

    • Often asymptomatic; chronic cases may remain undetected. Testing and treatment can clear infections based on availability and affordability.

Hereditary Hemochromatosis

  • Autosomal recessive disorder due to reductions in HFE gene product leading to hepcidin activity elevation, promoting iron transport, and subsequent iron accumulation and hepatic damage.

Pediatric Considerations – Liver Development

  • Hepatocytes arise from endoderm, while mesoderm-derived endothelial cells assist vascular formation.

  • Bile acid production, secretion, and enterohepatic circulation matures within the first year of life.

  • Prenatal maturation includes glycogen storage for immediate postnatal blood glucose maintenance and the eventual synthesis of coagulation factors.

  • Drug clearance via phase 2 enzymes does not mature until approximately 2 years old, raising drug toxicity risks.

Pediatric Considerations - Liver Disorders in Infancy

  • Biliary Atresia: Can arise as a congenital defect or acquired disorder, often leads to irreversible bile duct damage demanding transplant.

  • Neonatal Hyperbilirubinemia: Defined as plasma bilirubin >1.2 mg/dL, it can be unconjugated or conjugated; due to impaired bilirubin uptake during fetal development.

  • Commonly physiological, resulting from increased fetal RBC count and decreased RBC lifespan.

Liver Damage Secondary to Alpha Antitrypsin Deficiency

  • Alpha1-Antitrypsin (AAT) is produced by the liver, balancing inflammation.

  • Disease manifestations range from mild enzyme elevation to severe states like hepatitis and cirrhosis;

  • Significant liver disease risk remains low in children, yet severe cases can necessitate transplantation.

Wilson’s Disease

  • Rare autosomal recessive genetic disorder leading to copper metabolism dysfunction, typically diagnoses post-age 5, manifests at adolescence/adulthood.

  • Dietary copper absorption occurs, but genetic mutations restrict its transport into bile; excess copper deposits in the liver and other organs can result in cirrhosis and related complications.

Nonalcoholic Fatty Liver Disease (NAFLD)

  • Most common pediatric liver disease with higher prevalence in males and obese individuals;

  • NAFLD includes conditions progressing to NASH, fibrosis, and potential transplantation needs; diagnosis is often delayed due to symptom absence and inadequate screening tools.

Gerontological Considerations

  • Structural and functional hepatic changes: Increased hepatocyte volume and blood flow decrease, yet liver function tests remain relatively stable with age.

  • Minimal changes in albumin, coagulation factors, and alkaline phosphatase levels; triglyceride levels may rise due to reduced LDL production.

  • Declines in phase I drug metabolism can increase drug-induced liver injury risk, while phase II reactions appear unaffected.

  • Aging liver cells show signs such as decreased telomere length, senescence, increased oxidative stress susceptibility, and DNA repair impairment, which can reduce regenerative capacity during recovery from liver insults.

  • Increased liver blood flow reduction and mass elevates drug injury risk with polypharmacy; older adults may also experience a higher prevalence of autoimmune hepatitis, which requires immunosuppression for management.

  • Primary biliary cholangitis represents an autoimmune disorder affecting bile ducts.