Exam III Liver / Gall Bladder Flashcards
Selective Liver Cells
Hepatocytes:
- The major parenchymal cells in the liver*
- Play pivotal roles in metabolism, detoxification, and protein synthesis*
Kupffer Cells:
- The resident Macrophages in the liver*
- Critical mediators of both liver injury and repair*
- Can be protective*
- Dysregulation can cause chronic inflammation in the liver*
Stellate cells:
Their activation in damaged liver causes secretion of collagen and formation of scar tissue -> chronic fibrosis or cirrhosis
Liver circulation overview
Dual Blood supply:
- The Portal Vein provides 60-80% of hepatic blood flow via Splenic and Mesenteric artery*
- The Hepatic Artery supplys remaining 20-40%*
Liver Microcirculation
The Acinar model defines areas as Zones
The Center of the acinus (peri-portal) is Zone 1:
Main functions include gluconeogenesis, oxidation of fatty acids, amino acid catabolism, ureagenesis, cholesterol synthesis, and bile acid secretion.
The periphery (peri-venular) as Zone 3:
- Particularly vulnerable to a circulatory failure*
- More involved in glycolysis and lipogenesis*
The region between as Zone 2
Pathogenesis of liver injury in Circulatory failure
Regulation of blood flow:
Hepatic Oxygen delivery is related to the oxygen content of blood going to the liver and total hepatic blood flow
Blood flow under systemic stress:
In sepsis: insufficient cardiac output cannot supply demands of the brain -> hepatocellular hypoxia (in zone 3)
Reperfusion injury:
- Mediated by generation of ROS once ischemic hepatocytes are re-exposed to Oxygen -> cell injury*
- Kupffer cells produce cytokines*
Clinical Settings: Increasing the Risk of Ischemic Injury
PTs who have:
Preexisting liver disease and portal HTN are particularly susceptible.
Chronic Liver disease makes them vulnerable to decompensation
PTs who have:
Preexisting passive congestion of the liver
Elevated central venous pressure (as occurs with HF) -> atrophy of hepatocytes in zone 3
Major Functions of the Liver
Metabolic
Synthetic
Detoxification
Excretory
Secretory
Storage
Major Metabolic Functions of the Liver: Blood Glucose
Excess glucose after meal converted to Glycogen: Glycogenesis
Decreased Glucose between meals stimulates breakdown of glycogen: Glycogenolysis
Exhaustion of Glycogen reserves stimulates the Glucose production from amino acids and sugars: Gluconeogenesis
Major Metabolic Functions of the Liver: Protein
Transamination -> Keto acids
Deamination -> Ammonia
Removal of ammonia by synthesis of urea
Where does Ammonia come from?
Bacterial degradation of amines, amino acids, purines, and urea in gut
Formation of Plasma proteins
Synthesis of non-essential amino acids
Major Metabolic Functions of the Liver: Fat
Lipogenesis -> carbohydrates converted to fatty acids
Fatty acid oxidation
Triglycerides -> glycerol and fatty acids
Lipoprotein synthesis
Phospholipid and cholesterol synthesis
- Bound to lipoproteins*
- Excreted through bile as cholesterol*
- Converted to Bile acids*
Formation of Coagulation Factors
Liver requires Vitamin K to manufacture prothrombin, Factors VII, IX, X
The etiology of abnormal hemostasis caused by abnormal liver function:
- Abnormal coagulation factor synthesis*
- Synthesis of dysfunctional coagulation factors*
- Increased consumption of coagulation factors*
- Platelet disorders*
Excretory Functions
Liver excretes and then reabsorbs (from the small intestine) 95% of the bile salts.
Excretion of endogenous substances:
- Bilirubin*
- Steroid hormones*
Excretion of exogenous substances:
Drug metabolites
Enterohepatic circulation
Vascular Functions of the Liver
Acts as a reservoir of blood
Synthesizes about 50% of the circulating lymph
The Kupffer cells in the liver axt as macrophages and form part of the phagocytic system in the body
Secretory Functions
The Liver secretes bile containing
- Bilirubin, water*
- Bile acids*
- Electrolytes*
- Phospholipids and cholesterol*
Bile acids: digestion and absorption of fat and fat-soluble vitamins from the small intestine
Liver secretory function: Bilirubin
Formation
By breakdown of heme by heme oxygenase
Conjugation
- Water-insoluble unconjugated bilirubin is associated with all toxic effects of bilirubin*
- Conversion of bilirubin to a water-soluble state is essential for elimination*
Urobilinogen
Formation:
- Urobilinogen: produced by bacterial breakdown of the bilirubin in the bowel*
- It is partly absorbed in the bowel*
- The other fraction excreted in urine*
Urinary urobilinogen excretion may be increased in:
- Excessive bilirubin production*
- Inefficient hepatic clearance of the urobilinogen*
- Excessive exposure of bilirubin to intestinal bacteria*
Urinary urobilinogen excretion can be reduced in:
- Biliary obstruction*
- Severe cholestasis*
Clinical Significances of Bilirubin
Bilirubin in health States:
A balance between production and clearance
Causes of elevated serum bilirubin:
- Overproduction of Bilirubin*
- Abnormal uptake, conjugation or excretion of bilirubin*
- Damaged hepatocytes or bile ducts*
Potential beneficial effects of Bilirubin:
Antioxidant
- INC serum bilirubin levels -> DEC risk of ischemic CAD and cancer mortality*
- Induction of heme oxygenase reduces the replication of hep C virus*
Physiologic mechanisms that protect against bilirubin toxicity:
- Binding to plasma albumin*
- Rapid Uptake*
- Conjugation*
- Clearance*
Jaundice Classifications
For clinical purposes, 2 major categories of hyperbilirubinemia
Plasma elevation of mainly unconjugated bilirubin due to:
- Overproduction of bilirubin*
- Abnormal bilirubin uptake*
- Abnormalities conjugation*
Plasma elevation of both unconjugated and conjugated bilirubin due to:
- Hepatocellular diseases*
- Defective reuptake of conjugated bilirubin*
- Biliary obstruction*
Unconjugated Hyperbilirubinemia in the Newborn
Causes of hyperbilirubinemia can be classified by pathogenesis:
- Increased production of bilirubin*
- Decreased clearance of bilirubin*
- Increased enterohepatic circulation of bilirubin*
Clinical Features:
- Jaundice in the first 24 hours of life*
- Total serum or plasma bilirubin (TB) level greater than the hour: specific 95th percentile*
- Conjugated bilirubin concentration >1 mg/dL*
- Rate of TB rise greater than 0.2 mg/dL per hour*
- Jaundice in a term newborn after 2 weeks of age*
Liver Regeneration
Regeneration in the normal liver:
- Macrophages*
- Hepatic stellate cells*
- Liver sinusoidal cells*
- *Signal hepatocytes to enter mitosis*
- Hepatic Stellate cells are not activated*
Regeneration in the abnormal, chronically damaged liver:
- The hepatic stellate cells are activated to myofibroblasts and excessive scar tissue inhibits regeneration*
- Excessive cellular debris inhibits efficient liver regeneration*
Acute Liver Failure
Definition:
Severe acute liver injury with encephalopathy and elevated prothrombin time in a PT without cirrhosis or preexisting liver disease
Cutoff between acute and chronic Liver failure is a disease duration of <26 weeks
Etiology:
Viral and drug-induced hepatitis (acetaminophen) are the most common causes
Acute Liver Failure Mnemonic: The ABCs
A – Acetaminophen, Hep A, Autoimmune Hep, Amanita Phalloides (mushroom poisoning), Adenovirus
B – Hep B, Budd-Chiari Syndrome
C – Cryptogenic, Hep C, CMV
D – Hep D, Drugs and toxins
E – Hep E, EBV
F – Fatty infiltration – Acute fatty liver of pregnancy, Reye’s Syndrome
G – Genetic – Wilson disease
H – Hypoperfusion (ischemic hep, SOS, Sepsis), HELLP syndrome, HSV, Heat stroke, Hepatectomy, Hemophagocytic lymphohistiocytosis
I – Infiltration by tumor
Acute Liver Failure Clinical Course
By definition: PTs with acute liver failure have:
Severe acute liver injury, leading to liver test abnormalities
Hepatic encephalopathy
Prolonged prothrombin time/INR
Other Clinical manifestations:
- Jaundice*
- Hepatomegaly*
- Right Upper Quadrant Tenderness*
- Coagulopathy*
- Increased portal HTN*
Pathophysiology of Hepatic Encephalopathy
Definition: A reversible syndrome of impaired brain function occurring in PTs with advanced liver failure
Selective pathogenesis:
The synergistic action of ammonia with other toxins may cause:
- The changes in blood-to-vrain transport*
- Oxidative stress*
- Astrocyte swelling*
The above changes may cause abnormal neurotransmission and an increase in ICP
Sepsis/neuroinflammation
Acetaminophen-Induced Liver Injury
The Most common hepatotoxin causing acute liver failure is acetaminophen (N-acetyl-p-aminophenol; APAP; Paracetamol)
Acetaminophen is directly cytotoxic to hepatocytes through its converstion to N-acetyl-p-benzoquinoneimine (NAPQI)
Selective Clinical factors influencing cytotoxicity
Acute alcohol ingestion: is not a risk factor for hepatotoxicity and may even be protective by competing with APAP for CYP450.
Chronic alcohol ingestion: increases CYP450 activity two-fold and reduces glutathione levels
