BHS 116.2: Physiology II
Notetaker: Stephanie Cullen
Date: 1/30/12
Page: 1
WARNING: These notes are only what I could get in class due to mediasite being down. There was
also no mp3 recording. I think I got most of it, but there were a few spots I wanted to revisit and
was not able to.
Regeneration
- The liver has enormous functional reserve and regeneration occurs in all but the most severe
hepatic diseases
o Good since we abuse the liver with alcohol or prescription drugs, etc.
- In a normal individual, removal of 75% of the liver will result in minimal hepatic impairment
o Regeneration will restore the liver mass within a few weeks
- If massive hepatocellular necrosis occurs that leaves the connective tissue framework intact,
almost perfect restitution can occur in the patient can survive all of the metabolic insults
Objective: Describe how the liver responds to injury.
Responses to Injury
- Inflammation
o Injury to hepatocytes associated with an influx of acute or chronic inflammatory cells is
hepatitis
- Degeneration
o Occurs w/ persistent inflammation
o Damage from toxic or inflammatory insult may cause hepatocytes to take on a swollen
appearance with a large clear cytoplasm (ballooning degeneration), a diffuse, foamy
swollen appearance (foamy degeneration), or the cell may swell due to fat accumulation
(steatosis) – fatty liver
- Cell death (necrosis)
o Hepatocyte destruction due to significant insult (persistent toxic insult)
- All of the steps above are reversible
o New hepatocytes will take the place of destroyed ones
- Fibrosis
o Fibrous tissue is formed in response to inflammation or direct toxic insult to the liver
o Over time, fibrous strands link regions of the liver (portal-to-portal, portal-to-central,
central-to-central) in a process called bridging fibrosis
o Unlike all of the other lesions of the liver, fibrosis is generally considered irreversible
- Cirrhosis
o With continuing fibrosis and cellular injury, the liver is subdivided into nodules of
regenerating hepatocytes by intact connective tissue surrounded by scar tissue (fibrotic
bands)
Objective: Describe the key lab tests for liver disease.
Lab Tests and Clinical Consequences of Liver Disease
- Hepatocyte integrity
o Aminotransferase in the blood
- Biliary excretory function
o Bilirubin in the blood
- Hepatocyte function
o Decreased albumin
o Increased clotting time
BHS 116.2: Physiology II
Notetaker: Stephanie Cullen
Date: 1/30/12
Page: 2
Objective: Describe the various pathophysiologies, structural changes, and symptoms of the liver
diseases (jaundice and cholestatis, portal HTN, cirrhosis, liver failure, viral hepatitis, and alcoholic
liver disease).
Pathophysiology of Jaundice (yellowing of the skin)
- Bilirubin Metabolism
o Bilirubin is the end product of heme degradation derived from erythrocytes
o Binds to albumin in the blood and is carried to the liver (via hepatic artery)
for processing
 Glucuronidation (conjugation) and transport to the gall bladder in the
bile for use in digestion (excrete)
 Makes bile yellow
- Jaundice is the systemic accumulation of unconjugated bilirubin and/or bilirubin
glucuronides (conjugated bilirubin) in tissues giving rise to yellow discoloration
o Unconjugated = hasn’t made it to the liver for processing
o Conjugated = has been processed by the liver
o Develops in patients with hyperbilirubinemia
o Bilirubin gives bile its brilliant yellow color
o Most common causes are hemolytic anemias, hepatitis, and obstruction of
bile flow
- Yellowing of the sclera can also be called icterus, but it’s usually referred to as
jaundice
o Early: scleral conjunctiva
o Late: sclera
- In the normal adult, serum bilirubin levels vary between 0.3-1.2
mg/dl
o Jaundice becomes evident at levels above 2.0-2.5 mg/dl
o Levels can reach 30-40 mg/dl in severe disease states
- Hyperbilirubinemia arises in 2 forms
o Predominantly unconjugated
 Excess production of bilirubin (usually blood
related)
 Reduced hepatic uptake
 Impaired bilirubin conjugation
o Predominantly conjugated
 Decreased hepatic excretion
 Impaired intrahepatic and/or extrahepatic bile flow
Cholestasis
- Systemic retention of not only bilirubin, but also other solutes
eliminated in bile (particularly bile salts and cholesterol)
o Jaundice + other solute
- This condition results from hepatocellular dysfunction or intrahepatic/extrahepatic biliary
obstruction
- Can present as jaundice because there is retention of bilirubin as well
- Symptoms
o Pruritus
 Itching which could be due to the accumulation of excess bile salts under the skin
 Jaundice + itching = cholestasis
BHS 116.2: Physiology II
Notetaker: Stephanie Cullen
Date: 1/30/12
Page: 3
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Skin xanthomas
 Focal accumulations of cholesterol as a result of hyperlipidemia and impaired
cholesterol excretion
 Jaundice + xanthomas = cholestasis
o Elevated serum alkaline phosphatase
 The characteristic finding for cholestasis
 AP is an enzyme present in the plasma membrane of bile duct epithelium and the
plasma membrane of hepatocytes
 Shows that the epithelium in lysing when AP is in the blood
Morphology
o Enlarged hepatocytes with accumulation of bile pigment
o Dilated bile canaliculi
 Obstruction somewhere down the line
o Kupffer cells containing bile pigments
 Sinusoid defensive cells
o Bile duct proliferation
 Help get rid of and divert flow
o Bile pigment retention in the bile duct
Cirrhosis
- Among the top 10 causes of death in the Western world
- Frequent causes:
o Alcoholic liver disease (60-70%)
o Viral hepatitis (10%)
o Biliary diseases (5-10%)
 2nd leading cause of known causes
o Cryptogenic cirrhosis (10-15%)
 Unknown cause
 Overall 2nd leading cause
- Typically the end stage of liver disease and is defined by 3
characteristics
o Bridging fibrous septa within or around liver lobules
 Bands of fibrous tissue or broad scars
 Structure is disrupted
 See picture- red areas are normal hepatocytes and
purple areas are fibrous bands
 Bands encircle regenerating regions and
push the cell out forming nodules on the
surface
 Ruins the organization of the liver
o Decreases the function
o Parenchymal nodules created by regeneration of hepatocytes encircled by the fibrous
bands
 Micronodules (less than 3mm)
 Macronodules (several cm)
 See picture- very nodular
o Disruption of the architecture of the entire liver
BHS 116.2: Physiology II
Notetaker: Stephanie Cullen
-
Date: 1/30/12
Page: 4
Pathogenesis
o 3 major pathologic mechanisms that combine to create cirrhosis:
 Hepatocyte death
 Can be caused by various insults (toxins, disease, viral infection, etc)
 Hepatocyte regeneration
 Normal response to hepatocyte death
 Progressive fibrosis
 As cells die, some regeneration occurs while fibrosis takes the place of
the rest of the dead cells
 Excessive deposition of collagen by stellate cells
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In cirrhosis, excess amounts of types I and III collagen are deposited in all portions of the
liver lobule (particularly the Space of Disse) and the sinusoidal endothelial cells lose their
porosity
 Thus, the sinuses are converted from a low pressure, free flowing route of
exchange between plasma and hepatocytes to high pressure channels
 Higher resistance to blood which increases the blood pressure in the liver
o The major source for this excess collagen secretion appears to be the stellate cells
 Stimuli may include, chronic inflammation with TNF secretion, cytokine
production by injured Kupffer cells, endothelial cells, or hepatocytes, or direct
stimulation of stellate cells by a toxin
Symptoms
o Can be clinically silent
o Some non-specific symptoms include:
 Anorexia
 Weight loss
 Weakness
 Debilitation in advanced disease
o Ultimate mechanism of death is one or a combination of the following:
 Progressive liver failure
 Complication related to portal hypertension
 This will cause symptoms to occur
 Development of hepatocellular carcinoma
 Regeneration of hepatocytes could damage DNA and cause a tumor
Portal Hypertension
- Due to an increased resistance to blood flow
- May develop from a variety of causes:
o Prehepatic
 Major conditions are an occlusive thrombosis (blood clot) or narrowing of the
portal vein before it divides in the liver
BHS 116.2: Physiology II
Notetaker: Stephanie Cullen
Date: 1/30/12
Page: 5
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Posthepatic
 Major conditions are severe right-sided heart failure, constrictive pericarditis, and
hepatic vein obstruction
 Severe right-sided heart failure causes a back up in the vena cava
o Intrahepatic
 Major cause is cirrhosis
Portal hypertension in cirrhosis results from increased resistance to portal
blood flow at the sinusoidal level and compression of the central veins by
the periventular fibrosis
4 clinical consequences:
o Ascites
 Collection of excess serous (protein-rich) fluid in the
peritoneal cavity
 Due to sinusoidal hypertension driving fluid into the
Space of Disse and then into the lymphatics
 The excess lymph flows into the peritoneal cavity
(normal lymph flow in thoracic duct is 1 L/day but in
cirrhosis it approaches 20 L/day)
 From the high pressure system
o Formation of porto-systemic venous shunts
 Bypasses develop wherever the portal and systemic circulation share capillary
beds
 Principal sites include the rectum (hemorrhoids), cardioesophgeal junction
(esophageal varices), and the periumbilical region (caput medusae)
 Esophageal varices are found in 65% of patients w/ advanced cirrhosis
and result in death by massive bledding in ½ of those cases
o Congestive splenomegaly
 Enlargement of the spleen due to backed up blood flow through the liver
o Hepatic encephalopathy
 A spectrum of disturbances from subtle behavioral abnormalities to confusion
and stupor all the way to coma and death
 Since the blood isn’t getting purified in the liver (causing an elevated level of
toxins in the blood), the brain can be exposed to many toxic substances,
especially ammonia which causes edema and leads to swelling
Liver Failure
- The most severe consequence of liver disease
- It may result from a sudden and massive hepatic destruction or most often it is the end point of
progressive damage to the liver
- 80-90% of hepatic functional capacity must be eroded before hepatic failure ensues
- Clinical signs:
o Jaundice
o Hypoalbuminemia: decreased levels of albumin in the blood
o Hyperammonemia: increased levels of ammonia in the blood
- Liver failure is life-threatening!
o Susceptibility of multiple organ failure due to toxins in the blood
o Coagulopathy (impaired synthesis and secretion of blood clotting factors)
 A lot more bleeding
o Hepatic encephalopathy
o Hepatorenal syndrome (renal failure due to liver failure)
 Can be reversed if liver failure is reversed (transplant)
BHS 116.2: Physiology II
Notetaker: Stephanie Cullen

Date: 1/30/12
Page: 6
Changes in the liver alter blood flow
 Increased flow to intestines and stomach
 Decreased flow to the kidneys (causing ischemia)
Viral Hepatitis
- An inflammation of the liver due to infection by a small group of viruses which cause similar
morphologic patterns of disease
o Hep A and E don’t lead to liver disease
o All are RNA viruses except Hep B
o Hep A is usually caused by shellfish
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Hepatitis B (HBV)
o Major cause of liver disease worldwide
o A DNA virus w/ an incubation period of 4-26 weeks
 Present in all physiologic body fluids except stool
o Blood transmission and sexual transmission are the most common routes of infection
o Acute disease can last many weeks to months
o 400 million carriers globally but only about 4%
develop chronic hepatitis
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Presence of HBs, HBe antigen, HBV-DNA, and
liver enzymes in the serum signifies infection
and active virus replication
Presence of anti-HBs IgG in the serum signifies
the end of acute infection
 Develop immunity since it is present for a long
period of time
Continued presence of the above antigens and lack of HBs
IgG during this period is a sign of chronic infection
 Some level of symptoms continue to be present
Hepatocyte damage is due to the attack on virus-infected
cells by CD8+ cytotoxic T cells
 Why we see an inflammatory response
Hepatitis C (HCV)
o Major cause of chronic liver disease in the Western world
 High rate of progression to cirrhosis
 85% of those w/ an acute infection get chronic hepatitis and of those, 20% get
cirrhosis
 Overall, 7-8% of people w/ an acute
infection die from the virus
o Major routes of transmission are inoculation
(IV drug use) and blood transfusion
o HCV is an RNA virus w/ an incubation period
of 2-26 weeks
BHS 116.2: Physiology II
Notetaker: Stephanie Cullen
Date: 1/30/12
Page: 7
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Detection of HCV-RNA and liver enzymes in the serum are a
sign of infection
o Anti-HCV IgG and IgM are present in the serum following
acute disease while HCV RNA disappears
 75-80% are asymptomatic
o In chronic disease, there are periodic elevations in serum
aminotransferase levels and continued presence of HCV RNA
and HCV IgG
 Rarely see symptoms in the normal symptomatic phase
 Relapses lead to symptoms (jaundice, serum
aminotransferase)
Hepatitis D (HDV)
o Unique RNA virus that is absolutely dependent of HBV
coinfection for multiplication
 It has circular DNA that can’t incorporate itself into host DNA w/o coinfection
o In the USA, HDV is largely restricted to drug addicts and multiply transfused individuals
(hemopheliacs)
o Coinfection rarely results in death or cirrhosis
o Superinfecton is more severe because a person is already infected w/ Hep B
 80% get chronic HBV/HDV hepatitis that leads to cirrhosis
Clinical Syndromes of Viral Hepatitis
- Carrier state
o The individual harbors the virus and can transmit it, but shows little or no outward
symptoms
o Minimal if any liver damage
- Asymptomatic infection
o No symptoms at all, but person has elevated liver enzymes or antiviral antibodies
- Acute viral hepatitis
o Incubation period
o Symptomatic pericteric phase
 Fatigue, nausea, loss of appetite
o Symptomatic icteric phase
 Above symptoms begin to fade
 Jaundice
o Convalescence (recovery)
BHS 116.2: Physiology II
Notetaker: Stephanie Cullen
Date: 1/30/12
Page: 8
Chronic Viral Hepatitis
- Defined as symptomatic, biochemical, or serological
evidence of continuing or relapsing hepatic disease for
more than 6 months, with histologically documented
inflammation and necrosis
o Histologically, the tell tale sign of chronic vs
acute viral hepatitis is the presence of bridging
fibrosis (ballooning) and bridging necrosis in
the chronic disease
- Patients can undergo remission or progress to cirrhosis
o Remission can still leave some permanent irreversible fibrosis
Alcoholic Liver Disease
- Excessive alcohol consumption is the leading cause of liver disease in most Western countries
- More than 10 million Americans are alcoholics
- Alcohol abuse causes 100,000-200,000 deaths annually in the USA
- 3 distinctive yet overlapping forms:
o Hepatic steatosis (fatty liver)
 80% of heavy drinkers
 Reversible
o Alcoholic hepatitis
 10-35% of heavy drinkers
 Reversible
o Cirrhosis
 10% of heavy drinkers
 Micronodular
 Irreversible
o Usually go from steatosis to hepatitis to cirrhosis
 Could skip the hepatitis stage and go right to cirrhosis
- Detrimental effects of alcohol and its byproducts on hepatocellular function:
o Shift away from catabolism of substrates toward lipid biosynthesis resulting in fatty liver
o Free radical generation during ethanol oxidation (necrosis) during detoxification
 Directly effects mitochondrial function
o Neutrophil infiltration is common in alcoholic hepatitis
o Ethanol can alter hepatic proteins so that the body recognizes them as foregin
 Induces an immunologic attack (inflammation and necrosis)
o Induction of cytochrome P450 can augment the transformation of other drugs into toxic
metabolites (necrosis)
 Occurs instead of detoxification
- The most important treatment is abstinence from
alcohol
o Once cirrhosis occurs, those other effects
are irreversible
Clicker Question: Jaundice is caused by an excess of which of the following?
a. Bile salts
b. Bilirubin
c. Cholesterol
d. Ascites