Exam III Liver / Gall Bladder

Question 1

Selective Liver Cells

Answer 1

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

Question 2

Liver circulation overview

Answer 2

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%*

Question 3

Liver Microcirculation

Answer 3

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

Question 4

Pathogenesis of liver injury in Circulatory failure

Answer 4

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*

Question 5

Clinical Settings: Increasing the Risk of Ischemic Injury

Answer 5

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

Question 6

Major Functions of the Liver

Answer 6

Metabolic

Synthetic

Detoxification

Excretory

Secretory

Storage

Question 7

Major Metabolic Functions of the Liver: Blood Glucose

Answer 7

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

Question 8

Major Metabolic Functions of the Liver: Protein

Answer 8

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

Question 9

Major Metabolic Functions of the Liver: Fat

Answer 9

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*

Question 10

Formation of Coagulation Factors

Answer 10

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*

Question 11

Excretory Functions

Answer 11

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

Question 12

Vascular Functions of the Liver

Answer 12

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

Question 13

Secretory Functions

Answer 13

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

Question 14

Liver secretory function: Bilirubin

Answer 14

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*

Question 15

Urobilinogen

Answer 15

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*

Question 16

Clinical Significances of Bilirubin

Answer 16

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*

Question 17

Jaundice Classifications

Answer 17

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*

Question 18

Unconjugated Hyperbilirubinemia in the Newborn

Answer 18

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 95^th 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*

Question 19

Liver Regeneration

Answer 19

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*

Question 20

Acute Liver Failure

Answer 20

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

Question 21

Acute Liver Failure Mnemonic: The ABCs

Answer 21

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

Question 22

Acute Liver Failure Clinical Course

Answer 22

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*

Question 23

Pathophysiology of Hepatic Encephalopathy

Answer 23

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

Question 24

Acetaminophen-Induced Liver Injury

Answer 24

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

Question 25

Acetaminophen-Induced Hepatotoxicity

Answer 25

Liver damage from acetaminophen ingestion can happen in 3 circumstances:

• Excessive intake of acetaminophen*
• Excessive cytochrome P450*
• Decreased capacity for glucuronidation or sulfation*

Proposed Mechanism of mitophagy in APAP-induced hepatotoxicity

• A toxic dose of APAP is metabolized to NAPQI in the liver*
• NAPQI can deplete hepatic GSH and bind to proteins-> increased ROS & mitochondrial damage*
• Damaged mitochondria necrotic cell death and more ROS production*
• DAMP-> activation of inflammatory responses*

Question 26

Hepatic Alcohol Metabolism

Answer 26

Liver Alcohol metabolism:

• The primary hepatic pathway generates acetaldehyde in the liver via by the enzyme alcohol dehydrogenase (ADH)*
• The acetaldehyde-> acetate by acetaldehyde dehydrogenase (ALDH)*

Acetaldehyde may be a potential accelerant to liver injury

Gastric alcohol metabolism:

• The stomach has sufficient ADH activity*
• Helicobacter pylori and gastritis can reduce the activity of gastric ADH*

Question 27

Spectrum of alcoholic Liver disease (ALD)

Answer 27

Spectrum of ALD

Heavy ethanol consumption -> wide spectrum of hepatic lesions:

• Fatty liver (i.e. steatosis)*
• Hepatitis*
• Fibrosis/Cirrhosis*

Steatosis

IS the earliest most common response in problem drinkers (4-5 standard drinks per day over decades)

Reversable condtion with good prognosis

Alcoholic Hepatitis

A more severe inflammatory type

Fibrosis and its late stage, cirrhosis

The deposition of abnormal amounts of ECM proteins, mainly by activated stellate cells

Question 28

Pathogenesis of ALD

Answer 28

Mechanisms involved in alcoholic steatosis:

• Alcohol accelerates hepatic lipogenesis*
• Alcohol decelerates hepatic lipid breakdown*
• Alcohol causes defective hepatic lipid export*

Mechanisms involved in alcoholic steatohepatitis:

• Alcohol-induced hepatocyte damage and apoptosis -> apoptotic bodies ->stimulate Kupffer cells to secrete TNFa and TNFy*
• NK cells attracted to the liver to worsen the inflammatory process*
• Activated stellate cells secrete ECM proteins -> destroying the liver’s internal structure and functions*

Question 29

Cirrhosis

Answer 29

Definition of cirrhosis:

• A late stage of progressive hepatic fibrosis*
• Characterized by distortion of the hepatic architecture*
• Irreversible in its advanced stages, at which point the only treatment option: liver transplant*

Note: Liver failure in Chronic liver disease is most often associated with Cirrhosis

Etiology:

• Chronic Viral Hep (B/C(worse))*
• ALD*
• Hemochromatosis*
• Nonalcoholic fatty liver disease*

Question 30

Mechanism of Fibrosis

Answer 30

The ECM in the fibrotic liver is made of insoluble scar

The composition of the hepatic scar is similar in all forms of fibrosing liver injury

The hepatic stellate cell is the main source of the ECM in hepatic fibrosis, including ALD.

With liver injury these cells undergo an “activation” -> becomes fibrogenic genes in stellate cells

Question 31

The Prognosis of Cirrhosis

Answer 31

Compensated Cirrhosis:

PTs with cirrhosis who have not developed major complications

The median survival of PTs with compensated cirrhosis is >12 years

Decompensated cirrhosis:

PTs who have developed complications of Cirrhosis such as:

• Variceal hemorrhage*
• Ascites*
• Hepatocellular carcinoma*

Have a worse prognosis than those with compensated cirrhosis

Question 32

Portal HTN

Answer 32

Definition:

• The result of resistance to portal blood flow-> variceal bleeding and ascites*
• It is the most commonly caused by cirrhosis*

Pathophysiology:

Structural changes occur in the setting of liver microcirculation

Dynamic changes are caused by increased production of vasoconstrictors and reduced release of vasodilators

Main Selective clinical consequences of portal HTN are:

Ascites

Hepatic encephalopathy

Question 33

Ascites

Answer 33

Definition:

The accumulation of excess fluid in the peritoneal cavity is called Ascites

Etiology

Portal HTN causes profound changes in the splanchnic circulation in the setting of cirrhosis

Question 34

Iron Overload

Answer 34

Normal iron stores:

• Hemoglobin*
• Iron-containing proteins*
• Iron bound to transferrin in plasma*
• Storage iron: ferritin or hemosiderin*

Total body iron content -> balance between dietary iron and iron loss from bleeding

Elimination of Iron excess:

• Intake*
• Loss*
• Recycling: Iron is recycled from the breakdown of senescent RBCs in the macrophages in the liver, spleen, and bone marrow*

Question 35

Clinical consequence of Iron Overload

Answer 35

Organ damage from ROS

Iron burden -> transferrin becomes saturated-> Iron binds to other proteins and molecules

• This iron is referred to as non-transferrin-bound iron (NTBI)*
• NTBI is taken up by the cells of the liver, heart, and endocrine organs*
• NTBI can chemically interact with hydrogen peroxide -> more ROS production -> tissue damage, inflammation and fibrosis*

Question 36

Hereditary Hemochromatosis

Answer 36

Definition:

Most commonly due to HFE gene mutation -> increased intestinal iron absorption

Mechanisms of livery injury:

Lipid peroxidation via iron-catalyzed free radical reactions

Interaction of ROS and iron itself with DNA causing lethal cell injury and predisposition to hepatocellular carcinoma

Stimulation of collagen formation: by activation of hepatic stellate cells

Clinical consequence:

The complications of fibrosis and cirrhosis developing in PTs increase with a significant iron overload, called hepatic iron concentration (HIC) greater than 3x the upper limit of normal

Question 37

Hemochromatosis Pathogenesis

Answer 37

Mutation of the HFE gene:

Hepcidin transcriptional activity is reduced

The effect of reduced levels of circulating hepcidin causes:

• Unchecked iron-export by ferroportin in the macrophage*
• That is responsible for the excess plasma iron load -> Tissue Iron accumulation and tissue damage*

Question 38

Hepatitis A Virus (HAV)

Answer 38

Essentials:

• A self-inflicted illness that does not become chronic*
• Infection confers lifelong immunity and is preventable via vaccine*

Prevention: Vaccination, immune globulin, and attention to hygienic practices

Spread:

• Contaminated water and foods and is shed in the stool*
• Raw or steamed shellfish (oysters, mussels, clams)*

Pathogenesis

Hepatocellular damage and destruction by HAV-specific CD8+ T lymphocytes and NK cells

Interferon-gamma have a main role in helping the clearance of infected hepatocytes

Question 39

Clinical Course of HAV

Answer 39

Typical manifestations:

• The incubation period of HAV: ~28 days*
• Sudden onset of nausea, vomiting, anorexia, fever, malaise and abdominal pain*
• Infected individuals are contagious during the incubation period and for about a week after jaundice appears*
• Complete recovery: six months in nearly all PTs.*

Question 40

Hepatitis B Virus (HBV)

Answer 40

Essentials:

The Clinical outcome depends upon the age at infection, the level of HBV replication and the immune status of the host

Spread:

Blood, semen, or other body fluid infected with the Hep B virus (childbirth, sharing needles)

Pathogenesis of infection

Immune-mediated liver injury:

• Cytotoxic T cell-mediated lysis*
• Direct cytotoxic liver injury*

Role of viral variants:

HBV mutations can potentially affect the severity of liver disease

Development of chronic infection

Question 41

Clinical Course of HBV

Answer 41

Acute Hepatitis Clinical manifestations:

• Mainly have subclinical Hep*
• More Severe in PTs co-infected with other hepatitis viruses or with underlying liver disease*

Phases of Chronic HBV infection:

• Immune tolerance (born with it, no liver disease)*
• Immune-active, HBeAg-positive (active viral replication)*
• Inactive chronic HBV (Carrier of HBV HBeAg negative)*
• Immune-active, HBeAg-negative (older PTs with advanced liver disease)*
• Resolution of chronic HBV infection*

Question 42

Hepatitis C Virus (HCV)

Answer 42

Essentials:

The majority of infected persons are not clinically ill

There is no vaccine for Hepatitis C

Persistent infection and chronic hepatitis are the hallmarks

Spread:

A blood-borne virus

Mostly by sharing needles to inject drugs

Pathogenesis of infection:

Acute hepatitis:

• HCV infection through hepatic artery*
• Viral replication and INF increased expression*

Chronic Hep C

Liver Cirrhosis

Hepatocellular carcinoma

Question 43

Model for HCV-Associated Carcinogenesis

Answer 43

Hepatocellular carcinoma results from a combination of indirect host-mediated and direct HCV-mediated mechanisms:

• HCV disturbs hepatocellular homeostasis by driving several cancer hallmarks*
• HCV-induced inflammatory responses indirectly drive hepatocarcinogenesis*