Pathophysiology

• Liver Structure and Function

  • Metabolic Functions:
  • Produces bile
  • Metabolizes hormones and drugs
  • Synthesizes proteins, glucose, clotting factors
  • Stores vitamins and minerals
  • Changes ammonia to Urea
  • Converts fatty acids to ketones
• Portal Circulation


  • Dual blood supply
  • Venous (portal) supply from digestive tract and abdominal organs
  • Arterial (hepatic artery) supply
  • Can store 500-1000mL blood
  • Lobules, sinusoids
  • Kupffer cells
• Bilirubin Elimination


  1. Liver converts free bilirubin into conjugated

  2. Returned to portal circulation or excreted

  3. Jaundice appears when serum bilirubin > 2 – 2.5 md/dL
• Diagnostic Tests of Hepatobiliary Function


  • Liver function tests: diagnosis, differentiate disorders, determine severity, monitor responses to treatment
  • Liver serum enzymes: alanine aminotransferase (ALT), aspartate aminotransferase (AST)
  • Other tests: Bilirubin, Albumin, Prothrombin time
• Alcohol-Induced Liver Disease


  • Spectrum: Fatty liver disease, Alcoholic hepatitis, Cirrhosis
  • Leads to death due to: Liver failure, Esophageal varices, Kidney failure
  • 10% of alcoholics develop cirrhosis
• Metabolism of Alcohol


  1. Alcohol is absorbed from stomach and metabolized by liver

  2. End products cause liver injury: Acetaldehyde, Free radicals

  3. Age, sex, ethnicity, genetics play a role in metabolism of alcohol and development of alcohol-induced liver disease

  4. Women produce more acetaldehyde, increased risk liver damage
• Toxicity of Alcohol Abuse

  • Abuse of ANY type of alcohol
  • Amount required to produce chronic liver disease varies
  • Damage continues weeks/months after alcohol intake discontinued
  • Steatosis (Figure 38-12): Accumulation of fat in hepatocytes, First stage of toxic effects of alcohol on liver
• Cirrhosis


  • End-stage chronic liver disease
  • Functional liver tissue replaced by fibrous tissue
  • Caused by: Alcoholism, Viral hepatitis, Toxic reactions to drugs, Biliary obstructions, Non-alcoholic fatty liver disease
• Cirrhosis: Pathophysiology


  1. Diffuse fibrosis and nodule formation

  2. Constrictive scarring and bands are formed

  3. Fibrous tissue replaces normally functioning liver tissue

  4. Disrupts flow in the vascular channels and biliary duct systems

  5. Leads to: Portal hypertension, Biliary obstruction, Loss liver cells, Liver failure
• Cirrhosis: Clinical Manifestations


  • Often no symptoms until disease is far advanced
  • Most common signs & symptoms: Weight loss, Weakness, Anorexia, Diarrhea, Hepatomegaly, Jaundice, RUQ abdominal pain
  • Late manifestations: Portal hypertension, Liver cell failure
  • Portal hypertension causes: Splenomegaly, Ascites, Esophageal varices, Hemorrhoids, Caput medusae
• Portal Hypertension


  • Abnormally high BP in the portal venous system
  • Caused by resistance to portal blood flow
  • Causes can be: Intrahepatic, Posthepatic, Prehepatic
  • Complications: Ascites, Splenomegaly, Hepatic encephalopathy, Portosystemic shunts (esophageal varices)
• Ascites


  • Accumulation of fluid in the peritoneal cavity
  • 15L or more
  • Late-stage manifestation of cirrhosis and portal hypertension
  • Manifestations: Abdominal discomfort, Dyspnea, Insomnia, Difficulty walking
  • Paracentesis is common
  • Complications include spontaneous bacterial peritonitis
• Portosystemic shunts


  • Collateral channels develop due to high portal pressure
  • Lead to: Hemorrhoids, Caput medusae, Cyanosis, Esophageal Varices
• Esophageal Varices


  • Thin-walled varicosities
  • Prone to rupture
  • Cause massive hemorrhage
  • Impaired coagulation complicates bleeding
  • High mortality rate
• Liver Failure


  • Most severe consequence is hepatic failure
  • 80-90% of liver function lost before liver failure occurs
  • Manifestations: Fetor hepaticus
  • Leads to Systemic Disorders: Hematologic disorders, Endocrine disorders, Skin disorders, Hepatorenal syndrome, Hepatic Encephalopathy
• Acute kidney injury (AKI)


  Rapid decline in kidney function
• Acute kidney injury


  • Causes buildup of nitrogenous waste products
  • Impairs fluid and electrolyte balance
  • Potentially reversible
• Azotemia


  Increased levels of nitrogenous waste products in the blood
• Glomerular filtration rate (GFR)


  Decreased GFR
• Urine formation


  1. Glomerular filtration

  2. Tubular reabsorption and secretion
• Glomerular filtration


  • Filters plasma
  • Glomerular filtration rate (average = 125mL/min or 160L/day)
  • Regulated by afferent and efferent arterioles
• Tubular reabsorption and secretion


  • Passive: water and urea
  • Active transport: Na+, K+, Cl-, Ca2+, phosphate
  • 1mL of glomerular filtrate formed each minute is excreted in urine (60mL/hour)
  • Transport maximum (renal threshold)
• Regulation of urine concentration


  • Depends on osmolarity of interstitial fluids
  • ADH
  • Action of ADH
• Regulation of renal blood flow

  • 1000 to 1300 mL of blood flow per minute
  • 25% of cardiac output
  • Feedback mechanisms keep blood flow constant
  • Neural and Humoral Control Mechanisms
  • Autoregulatory Mechanisms
• Creatinine clearance


  Test of renal function
• Cystatin C


  Test of renal function
• Serum creatinine


  Test of renal function, normal = 0.6 mg/dL - 1.2 mg/dL
• Blood urea nitrogen (BUN)


  Test of renal function, normal = 8 – 20 mg/dL
• Urea


  Formed by liver as end-product of protein metabolism, approximately 50% excreted in urine, necessary for concentration and dilution of urine, eliminated entirely by kidney
• Prerenal AKI


  • Characterized by decreased renal blood flow
  • Caused by decreased vascular volume, impaired perfusion, decreased vascular filling
  • If RBF falls to <20% of normal, ischemic changes occur and GFR falls and metabolism slows
  • Reversible if blood flow restored, or may lead to intrarenal AKI
  • Examples of causes: hemorrhage, heart failure, shock, anaphylaxis, sepsis, drugs, contrast media, NSAIDs
  • Manifestations: decreased urine output, increased BUN
• Intrarenal AKI


  • Acute damage to nephrons
  • Caused by ischemia from prerenal AKI, acute tubular injury/necrosis, acute glomerulonephritis, acute pyelonephritis
  • Acute tubular injury/necrosis caused by prolonged ischemia, sepsis, nephrotoxic effects of drugs, tubular obstruction, toxins from infections
• Acute tubular necrosis (ATN)


  • Ischemia causes severe, irreversible damage and necrosis and sloughing, GFR significantly reduced and does not improve with restoration of RBF, ischemia + nephrotoxin exposure = very high risk ATN, dehydration increases risk
• Postrenal AKI


  • Due to obstruction of urinary outflow
  • Causes: ureteral obstruction, bladder obstruction, urethral obstruction
  • Leads to retrograde pressure that damages nephrons
  • Treatment - restore urine flow
  • Examples of causes: calculi, strictures, tumors, neurogenic bladder, prostatic hyperplasia
• Neurons


  Afferent and efferent neurons, showing the soma or cell body, dendrites, and axon
• The Brain


  • Forebrain, midbrain, & hindbrain
  • Cerebellum
  • Cerebral hemispheres
• The Forebrain


  • Thalamus
  • Subthalamus
  • Hypothalamus
  • internal capsule
  • corpus callosum
  • basal ganglia (caudate nucleus, lentiform nucleus)
  • amygdaloid complex
  • insula
  • parietal cortex
• The Cerebral Cortex


  • Motor and sensory areas of the cerebral cortex
  • Frontal Lobe (4, 8, 6)
  • Parietal Lobe (3, 1, 2, 5, 7)
  • Temporal Lobe (41, 22)
  • Occipital Lobe (17, 18, 19)
• The Limbic System


  • limbic cortex (cingulate gyrus, parahippocampal gyrus, uncus)
  • subcortical structures (thalamus, hypothalamus, amygdala)
• Neurotransmitters


  • Norepinephrine
  • Acetylcholine
  • Dopamine
  • Histamine
  • gamma-aminobutyric acid (GABA)
  • Serotonin
• Synaptic Transmission


  Neurons communicate through chemical synapses via neurotransmitters