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					         AARO Training & Consulting                                           Page 31
          Bloodborne Pathogens
          Module 4: Anatomy, Physiology and
          Pathophysiology of the Liver

Job Description – Liver:
Organization:    Digestive system

Title:                Liver

Objectives:           To find the most suitable candidate to fill an essential position in
                      a vibrant active body cavity.

Duties and            Produce plasma proteins that will regulate blood pressure and
responsibilities:     blood.

                      Filter toxic substances such as poisons, drugs, pesticides and
                      environmental pollutants, and remove them from circulation in
                      bile and urine, without complaint.

                      Manufacture appropriate amounts of lipoproteins, cholesterol
                      and phospholipids used to construct cell membranes.
                      Candidates with experience in LDL production and HDL
                      suppression will receive preference.

                      Assist in regulation of body temperature control by warming
                      circulating blood without becoming intimately involved. Produce
                      plasma proteins that will regulate blood pressure and blood.

                      Filter toxic substances such as poisons, drugs, pesticides and
                      environmental pollutants, and remove them from circulation in
                      bile and urine, without complaint.

                      Manufacture appropriate amounts of lipoproteins, cholesterol
                      and phospholipids used to construct cell membranes.
                      Candidates with experience in LDL production and HDL
                      suppression will receive preference.

                      Assist in regulation of body temperature control by warming
                      circulating blood without becoming intimately involved.

Qualifications        Successful candidate must demonstrate in-depth knowledge of
and                   the overall system, as well as partner organs, and the
requirements:         importance of the role of each in the successful operation of
                      the overall system.

                      Successful candidate must be detail and process-oriented.

                      Previous experience with carbohydrate, fat and protein
                      metabolism is essential. Special preference will be given to
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     Module 4: Anatomy, Physiology and
     Pathophysiology of the Liver

                  candidates with      advanced     training   in   fat   metabolism
                  management.

                  Ability to store fats and amino acids converting them into
                  glucose when needed. Candidates with creative approaches to
                  storing fats will be given preference.

                  Ability to produce blood coagulation proteins and maintain a
                  balance between overproduction leading to excessive
                  bleeding, and underproduction leading to increased potential
                  for clot production and stroke.

                  Must willingly accept exposure to toxins as an integral part of
                  the job. Employer attempts to comply with the Occupational
                  Health and Safety Act with respect to Workplace Hazardous
                  Materials Information System; however, risks are unpredictable
                  and not within the control of the employee. Successful
                  candidate must take responsibility for “personal” personal
                  protection.

Lines of          Excellent communication skills required.
Communication:
                  Successful candidate must be an effective leader, motivating,
                  mentoring and encouraging team players.

                  Successful candidate must demonstrate ability to build strong
                  lines of communication with other organs and system.

Orientation and   Orientation date will depend on date of delivery.
training:
                  On-the-job training program.

 Times needed     Position is permanent full-time (24-hour shifts back to back, 7-
and               days per week) with no vacations or holidays for a maximum of
 place of work:   about 105 years.

                  All work will be performed in a location below the diaphragm
                  and over the stomach.

Commitment        It is expected that the successful candidate be committed to a
required:         long-term relationship.

                  Failure to perform responsibilities effectively may ultimately
                  result in job dislocation and replacement.
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      Module 4: Anatomy, Physiology and
      Pathophysiology of the Liver




Benefits:         Honour of contributing and sharing in the success of other
                  organs and organizations.

                  Room and board, the support of the team and access to body
                  resources for the duration of the assignment.

                  Pride associated with providing service that results in
                  maintenance of a quality system.

                  Lasting relationships and sense of belonging.

Frustrations:     Note: if you are claustrophobic in closed conditions, this is not
                  the job for you.

                  Lasting friendships and relationships preceding your
                  involvement in the workplace may result in rejection; however,
                  counseling and therapy is provided to ensure effective
                  functioning of the 'new' team.

                  Discouragement may be encountered following entry of
                  substances and diseases that have the potential to damage the
                  infrastructure resulting in sloppy productivity, lack of morale,
                  and resulting failure.

Satisfactions:    Interaction with other organs and organizations.

                  Opportunity to motivate and mentor other organs and
                  organizations involved in ensuring success of the overall
                  system.
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     Bloodborne Pathogens
     Module 4: Anatomy, Physiology and
     Pathophysiology of the Liver

Anatomy and Physiology of the Liver

The liver is located under the diaphragm and over the stomach, and is the largest
gland in the human body. It measures approximately 8 inches (20 cm) x 6 inches
(15 cm) x 4 inches (10 cm), and weighs approximately 3 pounds (1.5 kg).

Link to GI tract anatomy – the real thing - Liver Pathology - http://www-
medlib.med.utah.edu/WebPath/LIVEHTML/LIVER001.html

The liver has four lobes: a large right lobe, smaller left lobe, small quadrate lobe
on the visceral surface left of the gallbladder, and a small caudate lobe left of the
inferior vena cava. Individual hepatocytes (liver cells) within each lobe radiate in
irregular rows outward from a central vein, forming groups also known as lobules.

Lobules are separated by connective tissue. Nerves and vessels enter and leave
the liver through a channel known as the porta hepatic, located between the
caudate and quadrate lobes.

Link     to     Lobes    of     liver   (WebPath)                 -      http://www-
medlib.med.utah.edu/WebPath/LIVEHTML/LIVER002.html

The liver receives blood from the hepatic artery (40%) and the hepatic portal vein
(60%), which enter side by side and branch into the right and left sides of the
liver.

Oxygenated blood is supplied directly via a branch of the aorta to the hepatic
artery, which carries it to the liver.

The hepatic portal vein transports blood to the liver from the intestinal tract and
the spleen. Two veins join outside the liver to form the portal vein - the
mesenteric veins, which carry deoxygenated blood rich in nutrients from the
intestinal tract, and the splenic vein, which carries red cell breakdown products
from the spleen.

Blood travels from the hepatic artery and the portal vein through arterioles and
venules, and eventually both empty into sinusoids among the hepatocytes. Blood
enters liver lobules through the portal triads where a hepatic artery branch, portal
vein branch and bile duct all group. In the sinusoids, arterial and portal venous
bloods mix and then migrate toward the center of the lobule, emptying into a
central vein. Blood travels from the central vein in each lobule to larger veins,
which eventually lead to one of three veins and on to the inferior vena cava.

Sinusoids act much like capillaries do in other body tissues, but they are much
wider than capillaries (up to 5 times), and have pores and gaps between the cells
of the endothelium to allow blood cells and proteins to pass through.
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     Module 4: Anatomy, Physiology and
     Pathophysiology of the Liver


The hepatic portal vein carries blood rich in nutrients from capillaries in the
digestive tract and pancreas, as well as hemoglobin breakdown from the spleen,
and delivers it to the sinusoids. Hepatocytes absorb nutrients and non-nutrients
from the sinusoids, and release products into the sinusoids to be carried to the
central vein.

Even when large numbers of the hepatocytes are not working well, the liver can
operate. Damaged hepatocytes are also capable of regeneration.

Bile is one of the substances produced by hepatocytes. Bile is formed through
the metabolism of bilirubin, a breakdown product of hemoglobin. As bile is
synthesized, it is secreted from the hepatocytes, collected by tiny channels called
canaliculi, which then drain into ductules. From the ductules, bile is transported
via the right or left hepatic duct to the common hepatic duct, and on to the
gallbladder where it is concentrated and stored. Approximately 800 mL of bile is
secreted daily.

Bile is composed largely of water, ions, phospholipids, bile salts, bilirubin and
other bile pigments, and cholesterol. Bile salts are the only substance in bile
involved in the digestive process, and the remaining contents of bile are waste
products excreted from the liver for removal from the body. Bile salts are
powerful detergents that lower the surface tension between water and fats, and
help break down large fat globules contained in food to small fat globules, so that
lipases in the intestinal tract can digest them.

The common hepatic duct is the excretory duct of the liver. It leaves the liver and
is joined by the cystic duct of the gallbladder. The gall bladder is located in the
groove between the right and quadrate lobes on the visceral surface of the liver.
The gall bladder temporarily stores bile until it is required in the duodenum to
assist in the breakdown of fat. The hepatic and cystic ducts join, and continue as
the common bile duct back to the duodenum.

Bile is concentrated in the gall bladder by reducing water (~ 90%) until it reaches
a mucous consistency. Following a meal, the gallbladder contracts to release bile
into the common bile duct where it is transported to the duodenum with
bicarbonate and digestive enzymes from the pancreas.

Liver Function
The liver is important for nutrient processing, much like a processing plant that
receives raw products and processes them to a useable form for consumers. And
much like the processing plant, the liver also removes waste and detoxifies
foreign substances that were absorbed in the intestinal tract before the product
goes to market.
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     Module 4: Anatomy, Physiology and
     Pathophysiology of the Liver

The liver is involved in metabolism and storage of nutrients obtained from the
digestive system so they are ready for distribution and use in the body, and
disposal of metabolic wastes so that they do not harm the body.

The liver orchestrates the metabolism of fats, carbohydrates, and proteins in
conjunction with the circulatory system, the lymphatic system, and the endocrine
system.

Fat metabolism
The liver converts:
    excess glucose into fat
    saturated fat into unsaturated fat for use by body cells in metabolic
       processes
    fat into specialized fatty substances like cholesterol and phospholipids
       used in cellular structure, and fatty acids to be used by cells for energy

Generally speaking, our bodies prefer sugars (glucose) for energy over fatty
acids and keto-acids. If we ingest more glucose than our body requires for
energy, it is converted into fat.

Glucose requires insulin, a hormone produced by the pancreas, for effective
transport into body cells where it can be used. When glucose is not available, our
body cells shift gears to derive energy from fat (sort of like a car that runs on
electricity and switches to gasoline when the battery runs dead).

As blood glucose concentrations fall, so does insulin secretion, which in turn
causes release of fatty acids by fat cells into the blood. Reduced carbohydrate
availability also causes increased secretion of cortisol by the adrenal glands,
which activates cellular lipase and subsequently results in increased release of
fatty acids.

Phospholipids are composed of glycerol, fatty acids, and a phosphate side chain.

Cholesterol is composed mainly of a sterol nucleus synthesized from acetic acid,
an end-product of fatty acid breakdown.

Both phospholipids and cholesterol are synthesized mainly by hepatocytes,
although all body cells have some function in the synthesis of these substances.
Phospholipids and cholesterol are major components of cell membranes, and
membrane-forming structures within the cell. Cholesterol is necessary for many
other functions as well, particularly sex hormones and steroids such as cortisone.
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     Module 4: Anatomy, Physiology and
     Pathophysiology of the Liver

Carbohydrate metabolism
The liver maintains normal glucose levels in conjunction with two hormones –
insulin and glucagon. Excess glucose is converted into fat, or is stored in
hepatocytes as glycogen. When carbohydrate intake is low, glycogen is
metabolized to glucose and released by the hepatocytes into the sinusoids,
which carry it to the central vein and eventually into the inferior vena cava as
described earlier.

Protein metabolism
The liver produces all proteins except for the immunoglobulins synthesized by
the immune system. Protein synthesis is accomplished through assembly of
amino acids into proteins.

The two major categories of proteins produced by the liver are albumins and
globulins:

Albumin:

 - helps maintain fluid pressure in the arteries, veins and tissues acts as a
   carrier protein for calcium, vitamins, hormones, fatty acids, drugs, and
   bilirubin in the blood

Globulins

 - involved in iron, copper and lipid transport act as precursors to fibrin
   (fibrinogen), act as antibodies or immunoglobins (gamma globulins - IgG,
   IgE, IgA, IgD, IgM)

Several proteins involved with blood coagulation are also produced by the liver:
    fibrinogen
    prothrombin
    factor VII
    factor IX
    factor X

Detoxification

Drug detoxification is a complex process that occurs in the endoplasmic
reticulum of the hepatocytes.

Offending drugs are inactivated and eliminated from the body through the
kidneys, or secreted into bile and passed in the feces.
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       Module 4: Anatomy, Physiology and
       Pathophysiology of the Liver

 In addition, some metabolic processes result in toxic waste products. Ammonia,
 one of the by-products of digestion and metabolism of amino acids from protein,
 is detoxified by conversion into a compound called urea, which is then excreted
 by the kidneys.

 Liver Function Tests

 Liver disease requires early intervention to prevent life-threatening complications,
 but diagnosing liver disease can be challenging, as patients may be
 asymptomatic in the early stages of disease. The insidious nature of early
 disease allows for progressive organ destruction long before symptoms appear.
 However, much of the morbidity and mortality associated with liver disease can
 be prevented with early recognition. Numerous laboratory tests can be used to
 help detect abnormal liver function, although for the most part biochemical tests
 do not define the cause of dysfunction.

 Table 1: Significance and normal values of biochemicals used in assessing
 liver function

<b> Biochemical                      Significance                                      Normal values </b>
Aspartate-aminotransferase (AST)     Enzyme released by the liver, heart muscle,       1-36 U/L
(previously called serum glutamic    skeletal muscle, pancreas and kidneys into
oxaloacetic transaminase [SGOT])     the blood stream when disease or injury
                                     occurs.
                                     Found in the cytoplasm of hepatocytes.
                                     Increases suggest possible hepatocellular
                                     damage or necrosis.
Alanine-aminotransferase (ALT)       Enzyme found in high concentrations in the        1-45 IU/L
(previously serum glutamic pyruvic   cytoplasm of hepatocytes (liver), and at lower
transaminase [SGPT])                 concentrations in the heart, kidney and           Males:
                                     skeletal muscle.                                  10-40 U/L
                                     Found in relatively low numbers in the            (0.17-0.68 kat/L)
                                     peripheral blood.
                                     Increases suggest possible hepatocellular         Females:
                                     obstruction, damage or necrosis.                  7-35 U/L
                                     More specifically related to liver cell injury    (0.12-0.06 kat/L)
                                     than AST.
Alkaline phosphatase                 Produced in liver, intestine, kidney, placenta    38-111 U/L
(ALP)                                and bone.                                         (0.65-1.89 kat/L)
                                     Serum levels increase during bone formation
                                     or with liver and biliary tract disorders.
                                     Increased levels are a non-specific indicator
                                     of liver or bone disease.
Ammonia                              By-product of protein metabolism – converted      11-32 mol/L
(NH3)                                to urea by liver.                                 (15-45 g/dL)
                                     Elevated in severe liver disease.
                                     Increased levels in cirrhosis, acute hepatitis,
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       Module 4: Anatomy, Physiology and
       Pathophysiology of the Liver

                                  necrosis, and obstruction of blood flow to
                                  liver.
Bilirubin:                        Reflects liver’s ability to absorb, conjugate 5-21 mol/L
Conjugated (~ 30% of total)       and excrete bilirubin in bile.                (0.3-1.2 mg/dL)
Total
Gamma-glutamyl-transferase        Found in liver, pancreas and kidney.             5-55 IU/L
(GGT/GGTP)                        Elevated with many forms of liver injury.
                                  Too sensitive and nonspecific to be helpful in
                                  diagnosis of specific liver disease.
Lactic dehydrogenase              Present in many tissues – liver, cardiac         100-210 U/L
(LD/LDH)                          tissue, kidneys and erythrocytes.                (1.7-3.6 kat/L)
                                  Serum levels elevated with cellular injury.
                                  related to any of these tissues.
                                  Highly nonspecific.
Prothrombin time                  Most coagulation proteins are produced in the    11-15 seconds
(PT/APTT/INR)                     liver.
                                  PT can help assess liver function although
                                  changes in coagulation proteins are not
                                  specific for liver disease.
Serum alpha1-fetoprotein          Major protein of normal fetal plasma; found in   < 15 g/L
(AFP)                             very low levels in serum of nonpregnant
                                  adults.
Serum protein electrophoresis     Used with serum total protein levels to detect   Albumin 3.9 g/dL
                                  and quantify albumin, alpha1, alpha2, beta       alpha 1 0.2-0.4 g/dL
                                  and gamma globulins to differentiate different   alpha 2 0.4-0.8 g/dL
                                  disease processes.                               beta 0.5-1.0 g/dL
                                                                                   gamma 0.6-1.3 g/dL
5’-nucleotidase                   Liver related enzyme used to help assess
                                  cholestatic/biliary obstruction..                2-17 U/L
                                  Elevated serum levels in association with
                                  elevated ALP level is specific for hepatobiliary
                                  disease.
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          Module 4: Anatomy, Physiology and
          Pathophysiology of the Liver

  Table 2: Liver biochemicals levels as diagnostic indicators


Analyte                  Increased Levels

                         Mild/Slight                 Moderate              High </b>
                         (2-3x normal)               (3-20x normal)

Alpha1       fetoprotein Hepatic disorders attended by hepatocyte regenerative activity, hepatoma,
(AFP)                    germ cell derived tumors


Alkaline                 Cirrhosis,                Viral hepatitis              Primary    or     metastatic
phosphotase (ALP)        cholestasis,                                           cancer, fungal and other
                         inflammatory        liver                              pathogen liver infiltration
                         disease,     infiltrative
                         liver disease, chronic
                         alcoholism


Aminotransaminase        Fatty            liver,    Acute     or      chronic   Acute viral hepatitis, drug
s(ALT and AST)1          nonalcoholic               hepatitis       including   reaction, acetaminophen
                         steatohepatitis,           alcoholic hepatitis and     toxicity,   other    toxins,
                         chronic viral hepatitis,   non-alcoholic               ischemic injury (shock),
                         early    stages       of   steatohepatitis             Wilson’s disease
                         hemochromatosis


Ammonia                  Liver disease, UTI with distension and stasis, Reye’s syndrome


Bilirubin:               Bile duct blockage, cirrhosis, chronic alcoholism, viral hepatitis, cholangitis,
Total                    hepatic lesions, neoplasia, biliary obstruction, infectious mononucleosis,
                         lymphocytosis, etc.


Gamma-glutamyl-          Cirrhosis, chronic alcoholism, viral hepatitis, hepatoma, carcinoma of
transferase              pancreas, systemic lupus erythematosus, primary biliary cirrhosis,
(GGT)                    hyperthyroidism, drugs, renal failure, pancreatic disease, etc.


Lactic                                              Cirrhosis  and    viral
dehydrogenase (LD)                                  heptatis,      chronic
                                                    alcoholism


Prothrombin time                                                                Fulminant hepatic liver
(PT/INR)                                                                        disease due to infectious
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       Module 4: Anatomy, Physiology and
       Pathophysiology of the Liver

                                                                            or toxic origin


Serum         protein Liver disease (albumin, alpha2)
electrophoresis


5’-nucleotidase        Metastatic liver neoplasia, primary biliary cirrhosis, biliary obstruction from
                       calculi and tumor

 1 ALT may also be elevated in individuals with cirrhosis, hepatocyte disease, Reye’s syndrome,
 hemochromatosis, chemical liver injury and cholescystitis.

 The three most common blood tests used to assess liver function are bilirubin,
 alanine-aminotransferase (ALT) and aspartate-aminotransferase (AST).

 Pathophysiology of the Liver

 ALL POINTS BULLETIN
 On January 1, 2004, at about 2am, a ”the system” was violated by an unidentified
 assailant who may have gained entry. Preliminary sketches suggest that the
 suspect has ties with the infamous “Hepatitis group” – connected with numerous
 crimes of bioterrorism (vandalism, property destruction, murder). The group
 includes 6 members (A, B, C, D, E and G). Some of them are known to be armed
 and dangerous. Personnel are asked to be on the lookout for any signs of
 suspicious activity, especially in the liver. Personnel are asked not to try to
 apprehend suspects without backup. Please follow the communication algorithm
 and appropriate chain of command. If you have any information on these
 suspects including last known whereabouts, please contact - Chief of Operations
 – Immune system.


 Introduction
 The liver is vulnerable to injury by numerous sources - liver damage can be
 caused by drugs, toxins, alcohol, inherited diseases, certain metabolic diseases
 and viruses.

 Causes of liver damage:
    viruses
    bacteria
    drugs/chemicals
    toxins

 Liver damage may result in hepatocyte necrosis and/or accumulation of fat in the
 cytoplasm of hepatocytes. When liver injury is mild, liver cells usually recover and
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     Module 4: Anatomy, Physiology and
     Pathophysiology of the Liver

liver function is restored to normal. However, multiple episodes of mild liver injury
may cumulatively lead to scarring and permanent impairment.

When injury is severe, large numbers of liver cells may be destroyed and the liver
may not be able to sustain life. If the individual survives, severe scarring and
permanent impairment may occur.

The most common types of liver disease characterized by hepatocellular injury
are viral hepatitis and alcoholic liver disease. Chronic hepatocellular injury may in
turn be followed by cirrhosis - diffuse scarring throughout the liver.

Hepatitis

Commonly, hepatitis refers to viral hepatitis. There are a wide variety of viruses
that can cause hepatitis, but the most common are the viruses designated A, B,
C, D, E (WHO/CDC) and G (Health Canada).

Viral Hepatitis

Viral hepatitis refers to one of several clinically similar but distinct infections –
hepatitis A, B, C, D, E and G are all currently known to cause hepatitis.

Hepatitis A (formerly infectious hepatitis) and Hepatitis B (formerly serum
hepatitis) have been recognized since the early 1940’s.

Hepatitis A infection occurs following ingestion of food or drinking water or
ingesting improperly cooked seafood from water that has been contaminated by
the feces of people infected with the hepatitis A virus. Hepatitis A can also be
spread through close personal contact. The incubation period (time from
exposure to the virus to the time that symptoms develop) ranges from 15 to 50
days. The infection is generally self-limiting and is not associated with chronic
infection or carrier states.

Hepatitis B will be discussed in more detail in Module 5.

Subsequently, a third type of viral hepatitis was recognized, originally designated
non-A, non-B hepatitis, and later named Hepatitis C (HCV). Hepatitis C will be
discussed in more detail in Module 6.

The hepatitis D (delta) virus (HDV), identified in 1977, is a defective virus that
requires the presence of HBV to exist.

Hepatitis E was not recognized as a distinct human disease until 1980. Hepatitis
E has been associated with epidemics of hepatitis E in Central and South-East
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      Module 4: Anatomy, Physiology and
      Pathophysiology of the Liver

Asia, North and West Africa, and in Mexico, in areas where fecal contamination
of drinking water is common.

The incubation period for HEV infection ranges from 3 to 8 weeks. The clinical
presentation of hepatitis E is like that of hepatitis A and infections are usually
self-limited as they are with hepatitis E infection. As with hepatitis A, hepatitis E is
not associated with chronic disease or carrier states.

Hepatitis A and E are excreted in the feces of infected individuals, beginning 1-2
weeks before symptoms start.

Hepatitis G is a virus without a disease. It was originally discovered in a search
for other causes. It is frequently present in the sera of individuals with chronic
hepatitis but is also found in individuals without disease. It is not considered a
pathogen as it is not associated with illness.

Transmission is mainly by way of the oral-fecal route for hepatitis A and E, and
percutaneous exposure to body fluids, including sexual intercourse, for hepatitis
B, C, and D. Chronic infection and severe complications occur mainly for
hepatitis, B, C, and D.

Historical

Outbreaks of epidemic jaundice were reported in Greek and Roman times.
Hepatitis was first recognized as a clinical entity in the U.S. and Europe during
late 18th, early 19th centuries.

During WW2, two types of hepatitis were distinguished, later designated as
hepatitis A (formerly infectious hepatitis) and hepatitis B (formerly serum
hepatitis).

Subsequently, a third type of viral hepatitis was recognized - non-A, non-B
hepatitis. The causative agent of non-A, non-B hepatitis was discovered in 1989
and is now referred to as Hepatitis C virus (HCV).

HAV, HBV, and HCV account for most cases of viral hepatitis.

Hepatitis D (delta hepatitis) occurs as a coinfection or superinfection of HBV.
Hepatitis E has also been recognized, and although it contributes to infection in
developing countries, it is infrequent in North America.
Global Prevalence

The prevalence of HBV carriers is highest in developing countries – those with
primitive or limited medical facilities – and lowest in countries with the highest
standards of living – Great Britain, Canada, United States, Scandinavia, and
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     Pathophysiology of the Liver

some other European countries. The WHO estimates HBV carriers rates of 0.2-
0.5% of the populations of Northern, Western, and Central Europe, North
America, Australia; 2-7% in Eastern Europe, the Mediterranean, Russia and the
Russian Federation, Southwest Asia, Central and South America; and anywhere
from 7-20% in parts of China, Southeast Asia, and tropical Africa. In areas of
Africa and Asia, widespread infection may occur in infancy and childhood.

Link       to          distribution     map          http://www.who.int/emc-
documents/hepatitis/docs/whocdscsrlyo20022/disease/world_distribution.html

The WHO also estimated that 170 million persons are chronically infected with
HCV worldwide, and 3 – 4,000,000 persons are newly infected each year. HCV is
spread primarily by direct contact with human blood, and the major causes of
HCV infection worldwide unscreened blood transfusions and re-use of needles
and syringes that have not been adequately sterilized.

Reference: World Health Organization (WHO). 2003. Hepatitis C Facts Sheet
retrieved from http://www.who.int/mediacentre/factsheets/fs164/en/ on August 4,
2004.

North American Prevalence
In the United States, approximately 15,000 individuals die from viral hepatitis
annually. The most common causes of viral hepatitis are HAV, HBV, and HCV.

The CDC estimates that there are approximately 1,500,000 Americans who are
chronically infected with HBV; approximately 3.9 million (1.8%) with HCV,
2,700,000 of these are chronic carriers; and almost 1,500,000 carriers of
hepatitis D, which occurs only in combination with HBV infection.
Hepatitis C is the most common reason for liver transplant in the U.S.

Reference: Centers for Disease Control and Prevention (CDC). 2003. Hepatitis
C. Retrieved from http://www.cdc.gov/ncidod/diseases/hepatitis/ on August 4,
2004.

In Canada, endemicity is relatively low.

Reference: Health Canada. 1997. Preventing the transmission of bloodborne
pathogens in health care and public service settings. Retrieved from
http://www.hc-sc.gc.ca/pphb-dgspsp/publicat/ccdr-
rmtc/97vol23/23s3/23s3a_e.html#prev on August 4, 2004.
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The case definition for viral hepatitis as defined by the World Health Organization
(WHO) is:

“…an acute illness typically including acute jaundice, dark urine, anorexia,
malaise, extreme fatigue, and right upper quadrant tenderness. Biologic signs
include increased urine urobilinogen and > 2.5 times the upper limit of serum
alanine-aminotransferase.”

All hepatitis viruses produce similar tissue changes in the liver. These changes
are characterized by diffuse inflammation throughout the liver lobules associated
with liver cell swelling and necrosis of individual liver cells. The clinical
manifestations of viral hepatitis vary corresponding to the extent of liver cell injury
and inflammation, and symptoms may be mild so that infection escapes
detection. Symptoms are reported to occur more often in adults than children.
Despite the absence of symptoms, individuals with acute infection are infectious.

The viral agent responsible for acute hepatitis cannot be determined on the basis
of symptoms as all types of viral hepatitis present similarly. Because of this,
clinical laboratory testing is required for diagnosis of most cases of hepatitis.

Clinical presentation for viral hepatitis may include the following symptoms:
     fatigue
     loss of appetite
     nausea
     abdominal discomfort
     dark urine
     clay-colored bowel movements
     yellowing of the skin and eyes (jaundice)

Acute hepatitis

Acute hepatitis is defined as an acute injury to the liver, resulting in release of
liver cytoplasmic enzymes (i.e. aspartate aminotransferase [AST] and alanine
aminotransferase [ALT]), often accompanied by symptoms of fever, loss of
appetite and abnormal bilirubin metabolism (yellow coloration of skin and eyes),
dark urine and pale stools). Acute hepatitis may be due to factors other than viral
infection such as shock (in response to blood loss, infection or cardiac problems),
and drug reactions. Toxins (i.e. acetaminophen overdose) are a less common
cause of acute hepatitis – toxins are more likely to result in FHF.

Clinical manifestations:

Acute hepatitis is usually self-limiting, but in 10-15% of cases may progress to
chronic hepatitis. In a rare number of cases acute hepatitis may cause severe
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      Pathophysiology of the Liver

liver damage leading to fulminant hepatic failure (FHF) and the need for liver
transplant.

Diagnostic blood tests

Laboratory testing can help differentiate viral hepatitis from other forms of liver
disease. The target of injury in acute hepatitis is the cytoplasm of hepatocytes. In
acute hepatitis, AST is elevated to 1.5 – 2.0 times as much ALT.

Hepatitis results in release of increased levels of ALT and AST into blood and
increased levels of circulating bilirubin due to decreased uptake, conjugation or
secretion by the liver. Often, increases in serum bilirubin, ALT, and/or AST are
the first signs of hepatitis.

In the early stages of acute viral hepatitis, serum AST is generally higher than
ALT; however, because of the shorter half-life of AST, after a few days of illness
ALT is generally higher than AST. Peak ALT and AST levels are generally 8-40
times the upper normal limit.

With shock, rapid, marked increases are seen in serum AST and ALT followed by
a rapid decrease; prolonged PT; and little or no increase in bilirubin. Complete
liver function is usually restored if the individual survives.

A rash often accompanies acute hepatitis caused by drug reactions. Joint or
renal problems, as well as an increased eosinophil count may also accompany
hepatitis related to drug reactions. Laboratory test results are similar to those for
acute viral hepatitis, but ALP is more likely to be increased with drug reactions.
Discontinuation of the offending medication usually results in resolution of
symptoms.

Acute hepatitis caused by toxins presents similarly to ischemic hepatitis – peak
serum aminotransferase levels (ALT/AST) are generally 10-100 times the upper
normal limit, AST:ALT ratios > 1 for the first 1-2 days, serum ALP levels are
increased less than twice the upper normal limit, and PT is increased up to 3
seconds more than the upper normal limit of 12 seconds.

In most primary liver disease ALT and AST are increased in a roughly 1:1 ratio.
Alcoholic liver disease is often characterized by an AST:ALT ratio of > 2:1,
although if the ALT level is elevated > 400 U/L, alcoholic liver disease is not likely
the culprit, despite the AST:ALT ratio.

Although biochemical tests are helpful in diagnosing hepatitis, serological
antigen-antibody tests are necessary to determine the specific viral agent
responsible for hepatitis.
    AARO Training & Consulting                                          Page 47
     Bloodborne Pathogens
     Module 4: Anatomy, Physiology and
     Pathophysiology of the Liver

Chronic hepatitis

Chronic liver disease is the 8th leading cause of death in the U.S. (Bach). Alcohol
consumption and viral hepatitis (HBV and HCV) are significant causes of chronic
liver disease, as well as congenital, metabolic, autoimmune, and drug-induced
conditions.

The CDC estimated that 1,250,000 Americans had chronic viral hepatitis, of
whom 20-30% acquired their infection in childhood.

Chronic hepatitis may lead to severe liver injury leading to fulminant hepatic
failure (FHF) and the need for liver transplant.

Symptoms may include:
   weight loss
   malnutrition
   fatigue
   easy bruising (caused by reduced levels of coagulation factors II, VII, IX,
     and X)
   jaundice
   pruritus
   edema
   ascites
   GI bleeding from esophageal varicose veins (caused by portal
     hypertension)
   encephalopathy with muscle tremors
   coma

Clinical Manifestations

Fulminant hepatic failure (FHF)
    develops within 2 weeks
    subfulminant hepatic failure develops within 2-8 weeks of the onset of
      jaundice
    onset of massive hepatocellular necrosis resulting in sudden and severe
      impairment of liver function
    encephalopathy is usually present
    causes include acetaminophen toxicity, viral hepatitis, drug reaction,
      toxins (mushroom poisoning), ischemic hepatitis, Wilson’s disease,
      autoimmune chronic active hepatitis, fatty liver of pregnancy and Reye’s
      syndrome
    requires intensive monitoring and assessment of need for liver transplant
       AARO Training & Consulting                                      Page 48
        Bloodborne Pathogens
        Module 4: Anatomy, Physiology and
        Pathophysiology of the Liver

Cirrhosis
     diffuse process characterized by the formation of islands of regenerated
       liver surrounded by dense fibrosis (abnormal nodules)
     occurs after a protracted insult (such as alcohol, chronic active hepatitis,
       etc.)
     most complications of cirrhosis occur as a result of portal hypertension
       development or decreased synthetic function of the liver
     signs and symptoms of liver failure include change in personality -
       uncooperative and violent behavior is not uncommon, jaundice, odor,
       tremors and hyper-reflex activity, spontaneous bleeding from mucosal
       surfaces
     rigidity with spasms as cirrhosis progresses
     cerebral edema is an important cause of death in patients with fulminant
       hepatic failure

Diagnostic blood tests

        serum albumin is usually normal initially
        hypoglycemia is found in a large percentage of patients with FHF
        lactic acidosis develops in approximately half the patients with grade 3
         coma
        decreased blood sodium and potassium are found especially in later
         stages
        coagulation problems develop due to decreased hepatic synthesis of
         coagulation factors
        prothrombin (PT) time is a good prognostic indicator
        cerebral edema can also lead to respiratory depression and respiratory
         acidosis, therefore, neurologic status and PT/INR should be followed
         closely in patients with FHF
        liver enzymes may be normal in end-stage disease because of the small
         amount of residual hepatic tissue - patients will usually have low serum
         albumin
        anemia and thrombocytopenia may be present
        blood ammonia levels may be elevated
        electrolyte abnormalities include decreased blood sodium, hypokalemia
         and free water overload
        acidosis or alkalosis may also be present

				
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