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					                                             Hepatitis

Glossery

Albumin [al BYOO min]: a protein in the serum that transports substances
Such as drugs and prevents leakage of fluid into the surrounding tissues.
 Alkaline phosphata se [AL kuh lin FAHS fah tays]: protein found in bile duct cell membranes;
blood levels may be increased in any liver disease, but more markedly with cholestasis.

Alpha 1 - antitrypsin [AL fah -1 an tigh TRIP sin]: plasma protein produced by the liver that
inhibits the activity of trypsin and other proteolytic enzymes; inherited deficiency leads to
emphysema and sometimes cirrhosis.

Aminotransferase [ah MEE noh TRANS fir ays]: hepatocyte enzyme that modifies proteins;
blood levels increas e in the setting of hepatocellular necrosis (hepatocyte death). The two
aminotrans ferases important in liver disease are AS T (aspartate aminot rans ferase) and ALT
(alanine aminotrans ferase).

Antibodie s: proteins produced in respons e to a specific antigen, which can then combine with
that antigen and neutralize it.

Antigens: a molecule with a specific configuration that is recognized by the immune system;
usually part of a protein or sugar. It stimulates the formation of a specific antibody and can elicit
an allergic reaction, or otherwise trigger an immune response.

Asci tes [uh SIGH teez]: accumulation of fluid in the abdominal cavity, usually secondary to liver
scarring and inc reas ed sinusoidal pressure. Intractable ascites is unresponsive to treatment and
continually recurs.

Autoimmunity [AW toh im MEW N it ee]: a state or disease in which the body's immune system
attacks the body's own tissues.

Bile: greenish fluid formed by the liver and emptied into the small intestine via the bile ducts;
contains bilirubin, bile salts, phospholipids, and cholesterol.

Bilirubin [BIL ee roo bin]: a bile pigment cleared from the bolld by the liver; formed as a
breakdown product of old red blood cells; marked increas e in blood levels can lead to jaundice
from deposition of bilirubin in skin, mucous membranes, and whites of the eyes.

Caput medusae [KAP medusae [KAP ut muh DOO see]: literally "Medusa's head"; dilated,
varicose veins around the umbilicus, which may be seen in patients with cirrhosis of the liver.

Ceruloplasmin [suh ROO loh PLAZ min]: copper transporter protein; blood levels are usually
decreased in Wilson's disease.

Cholesta si s [hoh luh STAY si s]: blockage or suppression of bile flow, from either intrahepatic or
extrahepatic causes.

Cirrhosi s [sur ROH si s]: pat hologically-defined disease characterized by diffuse, irreversible
fibrosis of the liver surrounding regenerative nodules.
Coagulopathy [koh AG yoo LAH puh thee]: increased bleeding tendency due to decreased
hepatic synthesis of clotting factors.

Decompensation: failure of the liver to compensate for damage or injury, resulting in a decrease
in liver functions.

Dysplasia [di s PLAY zhuh]: alteration in size, shape, and organization of cells; may be
precursor of cancer.

Encephalopathy [en SEF uh LAH puh thee]: alteration in sleep patterns and ment al status,
ranging from forgetfulness and mild confusion to coma; may be caus ed by circulating gut -derived
brain-toxic proteins not cleared by a dysfunctional liver.

Fibrosi s [figh BROH si s]: the formation of fibrous tissue, or scarring.

Fulminant: running a speedy course, with rapid worsening.

Hemochromatosi s [HEE moh KROH mah TOH si s]: toxic accumulation of iron in organs
leading to dysfunction, including cirrhosis; may be genetic (inherited increase in gut iron
absorption) or a result of massive blood trans fusions.

Hepatitis [HEP uh TIGH ti s]: inflammation and damage to the liver; generally considered acute if
duration is less than 6 mont hs, chronic if great er than 6 mont hs.

Hepatocellular necrosi s: localized tissue death of hepatic cells.

Hepatocellular carcinoma (HCC): a primary liver tumor more common in patients with cirrhosis.

Hepatocyte s: liver cells.

Hepatorenal [HEP uh togh REE nahl] syndrome: poorly understood terminal kidney failure in
the setting of hepatic disease.

Homeosta si s [HOH mee oh STAY si s]: tendency of the body to maintain a stable internal
environment, using a variety of counterbalancing control systems.

Hyperbilirubinemia [HIGH pur BIL ee roo bin EE mee uh]: abnormally high levels of bilirubin in
the blood.

Icterus: see Jaundic e.

Idiopathic [ID ee oh PATH ik]: autoimmune chronic active hepatitis (IACAH): chronic hepatitis of
unknown origin; associated with a variety of anti-self antibodies; progresses to cirrhosis and
decompensation unless treated with corticosteroids.

Jaundice [JAHN di s]: hyperbilirubinemia, with deposition of bile pigment in the skin, mucous
membraes, and sclerae (whites of eyes ), resulting in a yellow appearanc e of the patient; also
called icterus.

Kayser-Fleischer rings: golden-brown rings in the corneas due to copper deposition in Wilson's
disease.
Kupffer cells: "scavenger" cells that remove foreign matter, worn-out blood cells, and bacteria
from the liver.

Limiting plate: layer of hepatocytes surrounding each portal triad and separating it from the
surrounding sheets of hepatocytes.

Lobule [LAHB yool]: "structural" unit of the liver; shaped like a hexagon on cross section, with
six portal triads at the periphery and a cent ral vein.

Portal hypertension [P OR tahl HIGH per TEN shun]: abnormal increase in portal blood
pressure, usually due to obstruction of, or increased resistance to, portal blood flow.

Portal system: includes all the veins that drain the small and large intestines, stomach, and
spleen and that converge into the portal vein to drain into the liver.

Portal triad (or tract): consists of three components: branch of the hepatic artery, branch of the
portal vein, and a biliary duct, all held tightly together by a limiting plate of hepatocytes at the
periphery of the lobule.

Portosystemic [POR toh si s TEM ick] shunting: development of blood vessels that connect
the portal and systemic circulation while bypassing the liver.

Prognosi s: prediction as to the probable outcome of a disease.

Prothrombin [proh THRAHM bin] time (PT): laborat ory test that measures the clotting of blood
in seconds; abnormally increas ed P T signifies bleeding risk due to deficient synthesis of clotting
proteins.

Pruritus: itching.

Seroconversion: appearance of specific antibodies in the blood, indicating recovery from
infection or successful vaccination.

Sinusoids: tunnels through hepatic tissue allowing exchange of nutrients and ot her substances
between blood and hepatocytes.

Spider angiomas: red capillary tufts in the skin that blanch on pressure; often found in patients
with cirrhosis.

Spontaneous bacterial peritonitis (S BP): bacterial infection of ascitic fluid.

Steatorrhea [STEE uh toh REE uh]: decreased absorption of dietary fats, resulting in their
passage to the distal bowel which causes foul-smelling diarrhea; can be caused by deficiency of
bile salts.

Transaminase: see Aminotransferase.

Varices [VAYR ih seez]: dilated veins; lower esophageal varices form as collaterals from portal
hypertension and can rupture, leading to massive bleeding.

Wilson's di sea se: inherited metabolic disorder in which copper accumulates in the liver and in
the central nervous system, causing hepatitis, cirrhosis, and neuropsychiatric symptoms.
Key Concepts
The liver is located in the right upper quadrant of the abdominal cavity and comprises right and
left lobes.

. The liver receives a unique dual blood supply: systemic (body) via the hepatic artery and portal
(gut) via the port al vein.

3. Microscopically, the liver is organized into structural units, or lobules, with six peripheral portal
triads and a central vein.

4. One of the unique capacities of the liver is its ability to regenerate after partial removal or
damage, although severe damage can lead to irreversible scarring.

5. The liver is import ant in the synthesis and secretion of key proteins (such as albumin and blood
clotting proteins) and the storage of glucose and many vit amins and minerals.

6. Bile, which is important for the digestion and absorption of fats, is synthesized by the liver and
enters the int estine via the bile ducts.

7. The liver plays a major role in the purification, transformation, and clearance of waste products
(such as ammonia), drugs, and toxins.


A. Structure
 The liver, the largest organ in the body, is located below the diaphragm in the right upper
quadrant of the abdominal cavity, as shown in Figure 1; it is sheltered by the rib cage. In an adult,
the liver normally weights about 3 pounds and extends approximately from the right fifth rib to the
lower border of the rib cage (along an imaginary line extending down from the middle of the collar
bone). When the patient inhales, the liver edge may be felt 1 to 2 cm below the right edge of the
rib cage.

Liver structure has several unique aspects. This section discusses its gross anatomy and blood
supply, its cellular organization, and its capacity to regenerate.

1. Gross Anatomy. Figure 2 shows the gross anatomy of the liver. Visual examination reveals
that the liver is separat ed into two lobes, the right and the left (Figure 2a), separated by the
falciform ligament. The right lobe is about six times the size of the left and contains two lesser
lobes (Figure 2b).

The porta hepatis is the entry way for supplying blood ves sels (the portal vein and the hepatic
artery ) as well as the exit site of ducts that drain bile formed in the liver. Bile leaves the liver via
the right and left hepatic ducts, which then unite to form the common hepatic duct. The common
hepatic duct in turn joins with the cystic duct from the gallbladder to form the common bile duct.
Bile is stored in the gallbladder (a pear-shaped bag), and then it flows through the cystic duct into
the common bile duct and empties into the intestine.

2. Hepatic Circulation. Figure 3 summarizes the blood flow to and from the liver. As mentioned
above, the liver receives a dual blood supply. The portal vein supplies blood (from the portal
system, the network of veins and capillary beds draining the intestines and spleen) that is rich in
nutrients and absorbed dietary substances but poor in oxygen. This provides 75% of the liver's
blood supply. The hepatic artery supplies oxygenated blood from the systemic circulation (ao rta)
and provides the remaining 25% of the liver's blood supply.

Within the liver, both the portal vein and the hepatic artery branch within the lobes and eventually
converge together into tunnels, or sinusoids Figure 4, that run parallel to rows of hepatocyte s
(liver cells). Sinusoids allow the exchange of substances bet ween the blood and hepatocytes and
merge to form central veins, which drain blood from the liver into the hepatic vein and then back
to the right heart and lungs via the inferior vena cava.

3. Cellular Architecture. The most abundant and metabolically active cells in the liver are the
hepatocytes. They lie together in cords, or sheets, in close association with bile ducts and
sinusoids Figure 4. The sinusoids are lined by a single lay er of endothelial cells, where oxygen,
nutrients, and poisons are removed from the blood, and products made by hepatocytes for use
elsewhere in the body are secreted into the blood. Kupffer cells, found in the sinusoids, are
specialized "scavengers" that can engulf foreign particulate matter, worn -out blood cells, and
bacteria.

Microscopically, the liver is organized into polyhedral units called lobule s. When viewed on a cut
section, a lobule is hexagonal with six portal triads at the periphery see Figure 5. Each portal
triad contains a branch of the portal vein, a branch of the hepatic artery, and a bi le duct, all held
tightly together by a layer of hepatocytes, called a limiting plate, that surrounds the portal triad
and separates it from the sheets of hepatocytes that radiate outward. In the center of the hexagon
is a central vein. Blood flows through sinus oids from portal triads toward the central veins
(peripheral to central), while bile flows outward toward the peripheral portal triads.

4. Regenerative Capacity. Hepatocytes rarely divide, but they have a unique capacity to
reproduce in response to an appropriate stimulus, such as the removal of a portion of liver. This
process involves controlled hyperplasia, or inc reased cell division, that usually restores the liver
to within 5 to 10% of its original weight. Hepatic injury or partial removal leads to both systemic
(e.g., in the blood and other tissues) and local (within the liver) release of growth factors that
stimulate hepatocyte replication.

Because all hepatocytes can perform the necessary hepatic functions and all have an equal
ability to replicate, the liver can undergo compensatory growth and restore its size. Liver
regeneration plays an important role aft er surgical removal of a portion of liver (partial
hepatectomy) and after injuries that destroy portions of the liver, such as viral, toxi c, or ischemic
damage. However, excessive damage can reach a "point of no return," and normal tissue will be
replaced with scar tissue. The liver's ability to regenerate is also compromised by pre-existing or
repeated liver damage or disease




Figure 1
Figure 2
Figure 3
The Liver in Health


    The characteristic structure and organization of the liver enables it to perform vital roles in
regulating, synthesizing, storing, secreting, transforming, and breaking down many different
substances in the body. In addition, the liver's ability to regenerate lost tissue helps maintain
these functions, even in the face of moderate damage. This section of the module focuses on the
structural aspects of the liver and its ability to regenerate.

B. Liver Functions
The body depends on the liver to perform a number of vital functions Figure 6), and although
there is substantial overlap, they can be divided into three basic categories:

· regulation, synthesis, and secretion of many substances important in maintaining the body 's
normal state
· storage of important nutrients such as glycogen (glucose), vitamins, and minerals
· purification, trans formation, and clearance of waste products, drugs, and toxins
Disease or traumatic injury can greatly reduce the liver's ability to carry out these normal
activities. Thus, most of the clinical manifestations of liver dysfunction (discussed later in this
module) stem from cell damage and impairment of the normal liver capacities. For example, viral
hepatitis causes damage and death of hepatocytes. In this case, manifestations may include
increased bleeding (due to decreased synthesis of clotting factors ), jaundice (yellow
pigmentation due to decreased clearance of bilirubin ), and increased levels of circulating
hepatocyte enzymes (released from dead live r cells).

1. Regulations, Synthesi s, and Secretion. Hepatocytes are metabolically active cells that serve
many functions. For example, they take up glucose, minerals, and vitamins from portal and
systemic blood and store them. In addition, hepatocytes can produce many important substanc es
needed by the body, such as blood clotting factors, transporter proteins, cholesterol, and bile
components. Finally, by regulating blood levels of substances such as cholesterol and glucose,
the liver helps maintain body homeosta si s.

a. Glucose. The liver plays a major role in maintaining blood concentrations of glucose, by
storing or releasing glucose as needed.

b. Proteins. Most blood proteins (except for antibodies) are synthesized and secreted by the
liver. One of the most abundant serum proteins is albumin. Impaired liver function that results in
decreased amounts of serum albumin may lead to edema, swelling due to fluid accumulation in
the tissues.

The liver also produces most of the proteins responsible for blood clotting, called coagulation or
clotting factors. If the blood cannot clot normally due to a decrease in the production of these
factors, excessive bleeding may result.

c. Bile. Bile is a greenish fluid synthesized by hepatocytes and secreted into biliary ducts. It then
leaves the liver to be temporarily stored in the gallbladder before emptying into the small
intestine. The major components of bile include cholesterol, phospholipids, bilirubin (a metabolite
of red blood cell hemoglobin), and bile salts. Importantly, bile salts act as "detergents" that aid in
the digestion and absorption of dietary fats. Liver damage or obstruction of a bile duct (e.g.,
gallstone) can lead to chole sta si s, (the blockage of bile flow, which causes the malabsorption of
dietary fats), steatorrhea (foul-smelling diarrhea caused by non-absorbed fats), and jaundice.

d. Lipids. Cholesterol, a type of lipid, is a substance found in cell membranes that helps maintain
the physical integrity of cells. The liver synthesizes cholesterol, which is then packaged and
distributed to the body to be sued or excreted into bile for removal from the body. Increased
cholesterol concentrations in bile may predispose to gallstone formation.

The liver also synthesizes lipoprot eins, which are made up of cholesterol, triglycerides (containing
fatty acids), phospholipids, and proteins. Lipoproteins circulate in the blood and shuttle
cholesterol and fatty acids (an energy source) bet ween the liver and body tissues. Most liver
diseases do not significantly affect serum lipid levels, with the exception of cholestatic diseases,
which may be associated with increased levels.

2. Storage. As mentioned above, the liver is designed to store important substances such as
glucose (in the form of glycogen). The liver also stores fat-soluble vitamins (vitamins A, D, E and
K), folate, vit amin B 12 , and minerals such as copper and iron. However, excessive accumulation
of certain substances can be harmful. For example, patients with an inherited condition known as
Wilson's di sea se cannot secrete copper into bile normally and usually have a low blood level of
the copper-binding prot ein ceruloplasmin. Retained copper accumulates in the liver (leading to
cirrhosi s and in the central nervous system (resulting in neuropsychiat ric symptoms).

3. Purification, Transformation, and Clearance. The liver removes harmful substances

(such as ammonia and toxins) from the blood and then breaks them down or transforms them into
less harmful compounds. In addition, the liver metabolizes most hormones and ingested drugs to
either more or less active products.

a. Ammonia. The liver converts ammonia to urea, which is excreted into the urine by the kidneys.
In the presence of severe liver disease, ammonia accumulat es in the blood bec ause of bot h
decreased blood clearance and decreased ability to form urea. Elevated ammonia levels can be
toxic, especially to the brain, and may play a role in the development of hepatic encephalopathy.
b. Bilirubin. Bilirubin is a yellow pigment formed as a break down product of red blood cell
hemoglobin. The spleen, which destroys old red cells, releases "unconjugated" bilirubin into the
blood, where it circulates in the blood bound to albumin (Figure 7). The liver efficiently takes up
bilirubin and chemically modifies it to "conjugated," or water-solube, bilirubin that can be excreted
into bile. Increas ed production or decreased clearance of bilirubin results in jaundice, a yellow
pigmentation of the skin and eyes from bilirubin accumulation.

c. Hormone s. Since the liver plays important roles in hormonal modification and inactivation,
chronic liver disease may cause hormonal imbalances. For example, the masculinizing hormone
testosterone and the feminizing hormone estrogen are metabolized and inactivated by the liver.
Men with cirrhosis, especially those who abuse alcohol, have increased circulating estrogens
relative to testosterone derivatives, which may lead to body feminization.

d. Drugs. Nearly all drugs are modified or degraded in the liver. In particular, oral drugs are
absorbed by the gut and transported via the portal circulation to the liver. In the liver, drugs may
undergo first-pass metabolism, a proc ess in which they are modified, activated, or inactivated
before they enter the systemic circulation, or they may be left unchanged.

Alcohol is primarily metabolized by the liver, and accumulation of its products can lead to cell
injury and death.

In patients with liver disease, drug det oxification and excretion may be dangerously altered,
resulting in drug concentrations that are too low or too high or the production of toxic drug
metabolit es. Therefore, medications that are metabolized by the liver must be used with caution
in patients with hepatic disease; these patients may need lower doses of the drug.

e. Toxins. The liver is generally responsible for detoxifying chemical agents and poisons,
whet her ingested or inhaled. Pre-existing liver disease may inhibit or alter detoxification
processes and thus increase the toxic effects of these agents. Additionally, exposure to
chemicals or toxins may directly affect the liver, ranging from mild dysfunction to severe and life -
threat ening damage.


Summary
From its sheltered position in the abdominal cavity, the liver filters blood from both the portal and
systemic circulations. The body depends on the liver to regulate, synthesize, store, and secret e
many important proteins and nutrients and to purify, trans form, and clear toxic or unneeded
substances. To carry out these functions, hepatocytes are organized for optimal contact with
sinusoids (leading to and from blood vessels) and bile ducts. A special feature of the liver is its
ability to regenerate, but this capacity can be exceeded by repeated or extensive damage.


Figure 6
Figure 7
                                    The Liver in Disease

Key Concepts
 1. Hepatitis, or inflammation of the liver, has numerous potential causes: infections wi th viruses,
bacteria, fungi, or protozoa; exposure to toxins such as alcohol, drugs, or chemical poisons; and
autoimmunity.

2. Portal hypertension involves an increase in port al blood pressure due to obstruction of, or
increased resistance to, blood flow, and it can lead to ascites, rupture of esophageal varices, and
portosystemic shunting.

3. Metabolic diseases such as Wilson's disease, hemochromatosis, and alpha        1   - antitrypsin
deficiency can lead to liver damage.

4. The liver can compensat e for a significant amount of damage, but eventually liver function will
decline markedly (decompensation), as manifested by diminished synthesis, abnormal clearance
and excretion, ascites, and portal hypertension.

5. Acute hepatitis may resolve without significant s equelae, but unresolved inflammation that
persists for longer than six months is termed chronic hepatitis. Chronic hepatitis may be caused
by ongoing infection and associated inflammation or by repeated exposure to toxins, such as
alcohol. Whatever the offending agent, chronic inflammation may lead to irreversible liver scarring
and fibrosis, a condition known as cirrhosis of the liver. Occasionally, acute infection results in
massive tissue destruction and high risk of death (fulminat hepatitis).

6. Chronic persistent hepatitis and chronic active hepatitis are histologic designations developed
for autoimmune chronic hepatitis; they do not carry any prognostic value in chronic viral hepatitis.

7. Jaundice is related to increased levels of serum bilirubin (hyperbilirubinemia) that lead to a
yellow appearance of the skin and whit es of the ey es.

8. Jaundice may involve unconjugated or conjugated hyperbilirubinemia; the latter may be due to
hepatocellular or cholestatic disorders.

9. Cirrhosis is pathologically defined as irreversible, diffuse fibrosis (or scarring) of the liver that is
a common endpoint for many chronic liver diseases; it carries an inc reased risk of liver
decompensation, hepatic failure, and the development of hepatocellular carcinoma.

10. Hepatocellular carcinoma is often associated with cirrhosis and with chronic viral hepatitis; it
is usually diagnosed at an advanced stage, wit h very poor prognosis.

11. Hepatic failure is marked by severe impairment of liver functions and is usually

accompanied by encephalopathy; death occurs in over 50% of cases.

12. Cirrhosis, hepatocellular cancer, and hepatic failure can all occur as a result of chronic viral
hepatitis.


A. Causes of Liver Dysfunction
Liver disease has numerous causes, ranging from microbial infections and neoplasms (tumors) to
metabolic and circulatory problems.

I. Inflammatory Disorders (Hepatitis). Hepatitis involves inflammation and damage to the
hepatocytes. This type of insult may result from infectious agents, toxins, or imm unologic attack
see Figure 8. In addition, other disorders such as Wilson's disease can cause hepatitis, and some
diseases such as alpha 1 -antitrypsin deficiency can imitate hepatitis. However, the most
common cause of hepatitis is viral infection.

a. Infection. Infection is a very important cause of hepatitis, since primary viral infection of the
liver is common and viruses cause the majority of liver infections. Three major viruses cause
hepatitis in the United States: hepatitis viruses A, B, and C. Together, they infect nearly 500,000
people in the United States every year. Viral hepatitis will be discussed in detail in Module 2.

In addition, bacteria, fungi, and prot ozoa can infect the liver, and t he liver is almost inevitably
involved to some extent in all blood-borne infections.

b. Toxins. Toxins such as alcohol, drugs, or poisons can cause hepatitis directly (by damaging
liver tissue) or indirectly (by reducing defenses or stimulating an aut oimm une response), but the
exact mechanism is not always clear.
Alcohol. Alcohol is primarily metabolized by the liver, and these met abolites can cause liver
damage. The risk of hepatic toxicity increases if more than 40 grams, or about four drinks, are
consumed per day.

Drugs. Numerous medications can damage the liver, ranging from mild, asymptomatic alteration
in liver chemistries to hepatic failure and death. Liver toxicity may or may not be dose-related.
Dilantin (an anti-convulsant) and isoniazid (an anti-tuberculosis agent) are examples of drugs that
can cause " viral-like" hepatitis.

Chemicals/Poisons. Both environmental and industrial toxins can cause a wide variety of changes
in the liver. Hepatic damage is not nec essarily dose-dependent and can range from mild,
asymptomatic inflammation to fulminant failure or progressive fibrosi s and cirrhosis.

c. Immunologic mechanisms. The immune system functions primarily to rec ognize " foreign" or
'non-self" antigens, for example, invading viruses, bacteria, and their proteins. These antigens
may be recognized by antibodies, proteins that can specifically bind to them and help remove
them from the body. Occasionally, autoimmunity develops, whereby the immune system
incorrectly reacts against "self" antigens, (one's own cells). This occurs in autoimmune hepatitis
and primary biliary cirrhosis, two diseases in which the immune system attacks and destroys
portions of the liver. If unchecked, persistent inflammation can eventually lead to cirrhosis.

2. Vascular Di sorders. Obstruction of portal blood flow that drains the intestines, stomach and
spleen results in portal hypertension (elevation in portal blood pressure). Think of the liver as a
sieve that filters portal blood; with scarring from repeated injury, the holes of the sieve become
progressively smaller, resisting flow. Resistance to blood flow can also occur before the portal
blood reaches the liver, or after leaving the liver see Figure 9.

Portal hypertensi on can lead to ascite s, an accumulation of fluid that fills and distends the
abdomen. Two serious consequences of portal hypertension include:

· rupture of dilated esophageal blood vessels ( varice s) causing massive bleeding

· portosystemic shunting, in which substances from the gut (including drugs, bacteria, and toxic
substances such as ammonia) bypass the liver and thus have access to other body tissues (for
example, hepatic encephalopathy due to brain exposure to ammonia or other nitrogen -cont aining
materials )

3. Metabolic Disorders. Problems wit h metabolic processes in the liver can be either congenital
(present at birth) or acquired. Some of these disorders, such as Wilson's disease and
hemochromatosi s, can present as hepatitis or cirrhosis and must be distinguished from other
causes of these forms of liver disease.

As explained earlier, Wilson's diseas e is a rare inherited condition, mostly affecting young people,
that is characterized by an inability to excrete copper into bile, resulting in the t oxic accumulation
of copper in the liver and nervous system. Manifestations include liver disease (including
fulminant hepatitis, chronic active hepatitis, and cirrhosis) and neuropsychiatric symptoms.

Hemochromatosis is an iron overload syndrome causing iron deposits and consequent damage
to various organs, including the liver (cirrhosis), heart (heart failure), pancreas (diabetes), and
pituitary gland (decreased sex drive and impotence). The disease may be due to an inherit ed
increase in gut absorption of iron or to multiple blood transfusions, since iron is normally found in
circulating red blood cells. Alpha 1 - antitrypsin deficiency is an inherit ed disease that predisposes
the affected person toemphysema (or lung destruction), especially
predisposes the affected person toemphysema (or lung destruction), especially with smoking.
Alpha 1 - antitrypsin inactivates other enzymes, causing damage to organs if left unchecked. The
lung is the most severely affected organ in patients with this disease, but appr oximately 10% of
adult patients will also develop cirrhosis.

4. Neoplastic Di sorders. Benign (non-cancerous) hepatic tumors are generally asymptomatic.
The most common are hemangiomas, blood-filled vascular channels which occur more oft en in
women and are present in about 5% of the population.

The liver is the most frequent site for blood -borne malignant tumor metastases, including
colorectal, breast, lung, stomach, pancreas, and ovarian cancers, and malignant melanoma (a
skin cancer), among others. Prima ry malignant liver cancer - hepatocellular carcinoma (HCC) -
most commonly occurs in patients with cirrhosis from viral infection, alcoholism,
hemochromatosis, or alpha 1 - antitrypsin deficiency. Men are affected more frequently than
women, and the prognosis is dismal, with an average survival of about six months after
symptoms begin. Hepat ocellular carcinoma will be discussed in more detail later in Section II - B-
5.

5. Liver Involvement in Extrahepatic Disorders. The liver may be affected by numerous
conditions, particularly autoimmune disorders, in which the immune system attacks the body's
own normal tissues. Some examples include rheumatic diseases (such as systemic lupus
erythematosus and rheumat oid art hritis) and inflammatory bowel dis eases (such as ulcerative
colitis and Crohn's disease).

Systemic infections, such as tuberculosis, candidiasis, and toxoplasmosis, may spread to the
liver. In addition, heart failure can lead to liver congestion, scarring, and ascites, because blood
cannot drain from the liver properly when the heart is not pumping effectively.

Clinical Manifestations of Liver Dysfunction

A variety of insults can damage the liver, but their signs and symptoms are similar and may be
due to hepatic dysfunction and/or obstruction to bloo d or bile flow. These manifestations include
symptoms and signs of hepatitis, jaundice, cirrhosis, hepatocellular carcinoma, and hepatic
failure.

1. Natural History of Hepatic Di sease. Hepatocyte injury, such as occurs in acute viral hepatitis
infection, stimulates an inflammatory response designed to try to eliminate the cause of the injury.
Hepatocytes are frequently damaged and destroyed during the course of the inflammation; the
death of thes e cells is termed hepatocellular necrosi s. This type of injury may be initially well
tolerated due to a large reserve of functioning hepatic tissue (compensat ed liver disease), and the
injury may be repaired by regeneration with minimal loss.

However, with severe, continuing, or repeated damage, such as in chronic hepatitis,
compens atory regeneration eventually fails to repair the whole injury (it may be too large and/ or
the framework may have been destroyed), and the destroyed hepatocytes are replaced by scar
tissue (fibrosis), leading to cirrhosis. The liver is a resilient organ and can tolerate a certain
amount of cell loss, but eventually a threshold is reached and liver function declines markedly.
Such decompensation may be manifested by the following:

· synthetic defect - fewer normally functioning liver cells reduce the amounts of serum albumin
and coagulation factors (a marked abnormality in blood clotting is associated with a poor
prognosis)
· abnormal clearanc e - decreased hepatic clearance of gut -absorbed proteins and ammonia can
produce hepatic encephalopathy, a poisoning of the brain with symptoms ranging from confusion
to coma

· abnormal excretion - accumulation of serum bilirubin, which is normally taken up by the liver and
excreted into bile, resulting in jaundice

· ascites - increased sinusoidal pressure, as with severe inflammation or scarring of the liver,
leads to fluid accumulation in the abdomen that becomes more difficult to control with progressive
decompensation

· portal hypertension - scarred liver tissue acts as a barrier to blood flow an d causes increased
portal blood pressure; a major risk is the rupture of esophageal varices, resulting in massive
bleeding that may be fatal

2. Inflammation/Hepatitis. As described previously, hepatitis involves inflammation and damage
of normal liver cells and is most commonly associated with viral and toxic insults. In general, the
diagnosis is often made by excluding various viral, toxic, and metabolic etiologies until only one
remains. For hepatitis B and hepatitis C, however, tests are available that may definitively detect
the presence of virus in the blood.

a. Acute hepatitis. Clinically, patients with hepatitis may be completely asymptomatic and
without jaundice. More commonly, they complain of such symptoms as anorexia (loss of
appetite), nausea, weakness, headache, muscle aches, altered small or taste, aversion to foods
or tobacco, fever, abdominal pain, and jaundice. Hepatitis is generally considered acute if it
resolves without sequelae (long-term changes ) within six months. Serological tests for hepatitis A
IgM should be positive if the person has acute hepatitis A. If the pers on has acute hepatitis B, the
serological mark ers that may be positive include hepatitis B surface antigen, hepatitis B e antigen
or hepatitis B IgM core antibody.

b. Fulminant hepatitis. Rarely, a severe hepatitis results in acute, massive destruction of large
portions of the liver or the entire organ. The most common causes are virus es and drug reactions.
Decompensation rapidly occurs, manifested by encephalopathy, fever, marked jaundice, and
either an enlarged tender liver or a shrunken liver, with a severe decline in liver function. The risk
of death is high, and survival depends on the ability of the liver to regenerate. If patients recover,
they do so fully. Hepatitis B is most likely to cause fulminant hepatitis; hepatitis C is a less
frequent cause, while A causes fulminant hepatitis only rarely.

c. Chronic hepatiti s. Chronic hepatitis implies ongoing liver inflammation that has existed for
more than six months. Chronic hepatitis is most likely caused by hepatitis B or C, if there is an
infectious etiology. The anti-HCV test will be positive in the case of the latter, and HBsAg test
positive in the former. The presence of HBEAG is indicative of ongoing hepatitis B infection.
Symptoms vary greatly and may include fatigue, abdominal pain, and jaundice. A symptomatic or
mildly symptomatic patients may escape diagnosis until a routine checkup reveals abnormal liver
chemistries or an enlarged liver. Importantly, such persistent inflammation may lead to
progressive liver scarring and cirrhosis.

Historically, histologic patterns such as chronic persistent hepatitis (CPH) and chronic active
hepatitis (CAH) were used to predict disease progression and prognosi s. These classifications
were originally developed to describe types of idiopathic autoimmune chronic active hepatitis
(IACAH). It has since been recognized that in chronic viral hepatitis, histological activity is not
directly related to prognosis. Instead, the presence and replicative activity of the virus are most
important in determining disease progression. Although histologic examination is still important in
clinical assessment, it has been propos ed that chronic hepatitis be classified primarily by etiology
see Figure 10., without using histology to imply prognosis.

d. Carrier state. Carriers are completely asymptomatic individuals who harbor the virus without
evidence of liver inflammation or damage. Liver chemistries and tissue biopsies are normal.
Lifespan is considered normal, barring additional independent insults to the liver. The carrier state
most commonly occurs with hepatitis B infection, in about 5% of those infected as adults.

3. Jaundice. A patient with jaundice has a yellow appearance, due to increased serum bilirubin
(hyperbilirubinemia) , with deposition of bile pigment in the skin, mucous membranes, and
sclera (whites of the eyes).

Jaundice does not occur until the serum bilirubin exceeds 2 to 2. 5 mg/dL and is generally
asymptomatic. However, a jaundiced person may complain of pruritus , or itching of the skin; this
is more common with chronic cholestasis. In addition, stools may be "clay -colored" (due to
decreased biliary pigment excreted into the gut) and urine may be dark (due to increased bilirubin
excreted in the urine).

4. Cirrhosi s. Cirrhosis is the common endpoint of many chronic liver diseases, since
inflammation and cell death eventually yield to fibrosis, or scar formation. Cirrhosis in volves
irreversible damage to the lobular architecture, wit h diffus e fibrous bands of scar tissue
surrounding nodules of regenerating hepatocytes. A pathologic diagnosis based on liver biopsy,
cirrhosis is described as micronodular if the nodule diameter is less than 3 mm and macronodular
if it is more than 3 mm.

Patients with cirrhosis have signific antly shortened life spans and are at risk for dec ompensation
decompensation and hepatic failure, as well as the development of hepatocellular carcinoma.

 Chronic viral hepatitis, chronic autoimmune hepatitis, and alcoholic liver disease are the
predominant causes of cirrhosis in the Unit ed States. Viral infection can be investigated by
checking specific blood tests, such as serum antigens or antibodies (discus sed in Section III).
Autoimmune liver disease may be detected by discovering certain autoimmune antibodies in the
blood. Alcoholic cirrhosis can usually be inferred from a history of chronic alcohol consumption. A
liver biopsy may be helpful in distinguishing causes, but in some patients, an exact etiology
cannot be determined (crypt ogenic cirrhosis). Cirrhosis may also be caused by metabolic
diseases (Wilson's disease, hemochromatosis, and alpha 1 - antitrypsin deficiency, all of which
can be diagnosed by laboratory tests and/or liver biopsy) or toxins (diagnosed by positive history
for drugs, environmental or industrial toxins, and confirmatory lab investigation).

Cirrhosis may be clinically silent for many years except for progressive weight loss, fatigue, and
chronic jaundice. E ventually, liver failure and portal hy pert ension develop, with deepening
jaundice, bleeding from esophageal varices, intractable ascites, and encephalopathy. Death
usually occurs as a result of bleeding, hepatic coma, infections (such as spontaneous bacterial
peritonitis, or infection of ascitic fluid), or kidney failure.

5. Hepatocellular Carcinoma. Primary malignant Primary malignant cancer of the liver, or
hepatocellular carcinoma (HCC), is associated with a dismal prognosis si nce it is usually
diagnosed at a late stage. Cirrhosis often progresses to the development of this tumor; in fact,
about 75% to 95% of patients who develop HCC have cirrhosis. This tumor is also associated
with certain hepatitis viruses (B and C), as indicated by its prevalence in certain areas of the
world where the incidence of viral hepatitis is high.
a. Etiology/epidemiology. HCC is most common in A frica, the Far East (Taiwan, southeast
China, Japan), and southern Europe, probably due to the high incidence of chronic viral hepatitis
in these areas.

In the United States, approximately 3 people per 100, 000 develop HCC each year. HCC is more
common in men, particularly in their 50s and 60s. It generally occurs in those with long -standing
cirrhosis associated wit h alcoholism, post-viral hepatitis B and and C, hemochromatosis, or alpha
1 - antitrypsin deficiency. HCC rarely develops in patients with cirrhosis due to Wilson's disease or
primary biliary cirrhosis.

b. Pathogenesis. Chronic inflammat ory diseases of the liver, as in other tissues, may increase
the risk of developing cancer. Nodular regeneration in cirrhotic livers may lead to cellular
dyspla sia (alteration in shape, size, and organization of cells), since errors are more likely to be
made in more actively dividing cells. This is most likely an intermediate step in the progression to
carcinoma, the proliferation of mutated cells. Additionally, excessive cell turnover probably
increases the susceptibility to carcinogens (agents that may induce canc er) and may promote the
expression of oncogenes ("cancer geners"). Hepatitis B genomic material (fragments of hepatitis
B virus DNA) has been found integrated in cancer cells, but the significance of this finding is not
clear.

c. Clinical features and prognosi s. Hepatocellular carcinoma is usually well advanced by the
time patients present with symptoms, which include right -upper quadrant pain (often a "dull
ache"), weight loss, anorexia, nausea, fever, or sudden worsening of jaundice or ascites. Severe
pain may be associated wit h bleeding into the liver or abdomen. On physical exam, the liver may
be stony hard. Unfortunately, the prognosis is dismal, primarily because the diseas e is at an
advanced stage at diagnosis (extensive hepatic enlargement and/or metastatic spread to the
lungs). Complete surgic al removal of the affected tissue offers the only potential cure.
Chemotherapy is ineffective, and most patients die within 3-6 months of present ation (primarily
from liver failure or bleeding).

6. Hepatic Failure. Hepatic failure involves the systemic complications associated with severe
liver injury and dysfunction. It may occur in a patient without pre -existing liver disease or may be
superimposed on chronic liver injury. The diagnosis of acute liver failure requires the presence of
symptoms, including jaundice and encephalopathy. Mortality exceeds 50%, even in the best
circumstances. Management involves general supportive measures until the liver can regenerate
and resume function. In acute liver failure without pre-existing disease, liver transplant may be
life-s aving.

a. Underlying conditions. About 2000 patients a year develop fulminant hepatic failure in the
United States. The most common cause is viral hepatitis, followed by hepatotoxic drugs.

b. Clinical features. Fulminant hepatic failure impairs all liver functions, causing decreased
bilirubin metabolism (jaundice), dec reased clearance of ammonia and gut -derived proteins
(encephalopathy), and decreased clotting factor production (coagulopathy ). It may also cause
kidney failure (such as hepatorenal syndrome respiratory failure (due to infection, water
accumulation, or inflammation of the lungs), shock (severe fall in blood pressure), and sepsis
(systemic infection, probably a result of decreased clear ance of portal bacteria by the liver).

Without a liver transplant, more than 50% of patients will die, usually from a combination of the
above conditions. However, if patients survive without transplantation, their livers may regenerate
to normal functional capacity, especially if the liver was healthy before failure began.


Summary
Liver disease may have a variety of origins. Inflammation, or hepatitis, may be caused by
infection (especially viral infection), exposure to toxins (including alcohol and drugs), or
autoimmune reactions. Portal hypertension and metabolic diseases, such as Wilson's
disease and hemochromatosis, can also cause significant liver problems. In addition to
benign primary tumors and malignant metastases, the liver may develop hepatocellular
carcinoma, which carries a dismal prognosis. The liver may also become involved in a
number of systemic conditions, including autoimmune disorders, infections, and heart
failure.

Regardless of the specific cause, liver disease frequently presents similar clinical
manifestations. Initially, symptoms may be mild, since this resilient organ can
compensate for a certain amount of damage. However, eventually decompensation
occurs, characterized by a marked decline in liver functions and the development of
ascites and portal hypertension.

Hepatitis may be acute (with recovery within six months), fulminant (acute critical illness
with high mortality rate), or chronic (persistent disease for more than six months).
Manifestations of hepatic desease include jaundice (hyperbilirubinemia), cirrhosis
(irreversible fibrosis and scarring), hepatocellular carcinoma (primary malignant cancer
of the liver), and hepatic failure (severe decline in all liver functions).

Figure 8




                                        Figure 9
                            Click on image to go back to paper.
Figure 10




Types of hepatitis :
  Hepatitis A : what is it ?
        Hepatitis A is the most prevalent type of hepatitis. Hepatitis A and hepatitis E are mainly
transmitted through the fecal -oral route, while hepatitis B, C, and D are spread through blood or
other body fluids.

  Source: PR News wire

  Hepatitis A (HAV) is a highly contagious virus that attacks the liver. It is the seventh most
commonly reported infectious disease in the United States (behind gonorrhea, chicken pox,
syphilis, AIDS, salmonellosis, and shigellosis). HAV accounts for as many as 65 percent of all
viral hepatitis cases in the U.S. each year.

In 1996, approximately 29,000 cases of HAV were report ed in the U.S. However,the Federal
Cent ers for Disease Control for Disease Control and Prevention (CDC) estimate that there are
approximately 143,000 HAV infections in the United States each year. Worldwide, there are an
estimated 1.4 million cases reported annually.

There are several types of hepatitis. Hepatitis A is the . Hepatitis A is the most prevalent.
Hepatitis A and hepatitis E are mainly transmitted through the fec al-oral route, while hepatitis B,
C, and D are spread through blood or other body fluids.


Common Symptoms of Hepatitis A
-- fatigue

-- nausea

-- vomiting

-- fever/chills

-- jaundice

-- pain in the liver area

-- dark urine

-- light -colored stools

-- abdominal pain

There is currently no treatment for hepatitis A, although rest and proper nutrition can relieve some
symptoms. The most important factor affecting the severity of the disease is age. Children less
than a year old rarely show clinical signs of the illness. This means that parents and child -care
work ers handling soiled diapers can catch or transmit the disease without knowing they have
been exposed.

Clinical manifestations of hepatitis A often pass unrecognized in children younger than two years
of age. Overt hepatitis develops in the majority of infected older children and adults. In adults,
approximately 22 percent will be hospitalized.

An estimated 100 deaths occur in the U.S. each year from hepatitis A. In out breaks, three peop le
died in northern California in December, 1995, and another person died in Canada in January,
1996.

The incubation period for hepatitis A ranges from 20 to 50 days , which means that infectious
patients, such as food handlers or children, can spread the disease well before they are even
aware they have it. Incubation is shorter with increasing age.

Most patients begin recovery within three weeks, although some have prolonged or relapsing
symptoms for up to six months.
How Is Hepatitis A Spread?
The hepatitis A virus is transmitted by the fecal-oral rout e, through close person-to-person
contact, or by ingesting cont aminat ed food or water. Infection has been shown to be spread by:

-- close personal contact with someone infected with hepatitis A.

-- eating foods contaminated by infected food handlers.

-- contact with infected children (who do not usually show symptoms), who can then infect non-
immune children or adults at home or in child -care centers.

-- ingesting raw or undercooked shellfish (e.g. oysters, clams, mussels) from waters
contaminated wit h the hepatitis A virus.

-- ingesting contaminated food or water during travel to underdeveloped areas.

-- transmission through blood trans fusions or sharing needles with infected people using
injectable drugs.

In the United States and other developed countries, people potentially susceptible to catching
hepatitis A include:

-- those who travel to less developed areas of the world where hepatitis A is common. These
areas include A frica, Asia (except Japan), the M editerranean basin, Eastern Europe, the Middle
East, Central and South American, Mexico andparts of the Caribbean.

-- military personnel

-- individuals living in areas where hepatitis A is endemic

-- certain ethnic and geographic populations that experienc e cyclic epidemics

-- male homosexuals and others who engage in high-risk sexual activity

-- hemophiliacs and other recipients of therapeutic blood products

-- youngsters in child-care facilities, their families, and facility staff

-- food handlers

-- healthcare workers who treat patients infected with the virus

-- institutionalized persons and their caregivers

-- laboratory workers who handle live hepatitis A virus

-- handlers of primates that may harbor hepatitis A.

Also at risk are people who live in fre quently affected communities with poor sanitation or
overcrowded living conditions.
Why Worry About Children?

The highest incidence of hepatitis A is in children. Nearly 30 percent of the reported cases occur
in children younger than 15. Many very young children do not show symptoms, so the unreported
number is likely much higher.

Many health experts suggest that children are a silent source in spreading the disease.
Approximately 45% of persons with HAV cannot identify a recognized risk factor associated with
their disease, but about half of them have children under five years of age living in their
households.

How Can Hepatitis A Be Prevented?

Historically, the most common prevent ative has been immune globulin administration, which is
effective for about three to six months. Now, however,there are t wo vaccines that provide longer-
term protection and eliminate the need for repeated shots. These vaccines typically are
administered as oneinitial shot followed by a booster shot in about six to 18 months.

Prior infection with hepatitis A confers lifetime prot ection against a second attack. If in doubt, a
blood test can determine if an individual has had hepatitis A in the past or needs protection.


What Is The Economic Impact Of Hepatitis A?
The annual direct and indirect costs of treating cases and cont rolling outbreaks of hepatitis A in
the United States are estimated to be $200 million. Additional economic costs are incurred when
adults who contract the disease miss an average of 27 days of work, which translates into
approximately $2600 in lostwages for each adult case ($2600 x 150,000 cases annually = $390
million in losttime). These estimates do not include business losses in the restaurant ortourist
industries related to outbreaks of the disease.




Question: I s the new hepatitis A vaccine effective and who needs it?

  :
Yes, the new hepatitis A vaccine (Havrix) is very effective. It induces protective titres of anti -
bodies in greater than 95%, and 99% of people after the first and second doses, respectively. I f
time does not permit two doses six months apart, then a single Havrix -1440 (double strength)
dose may be given. The first dose of the vaccine probably requires at least three weeks to induce
significant antibodies, so those travellers who did not have the foresight to have the first dose
administered at least three weeks before departure to a high-endemic area should also have
standard gammaglobulin to assure protection. Protective antibody titres to the vaccine last at
least three years. At this time the need for booster doses is unclear, but it's likely that, similar to
hepatitis B, they will be unnecessary. The vaccine should be administered as an IM injection into
the deltoid. Children can be given half-strength (0. 5 mL) doses.

Although the manufacturer has suggested a very broad range of people to be target ed for
vaccination, the National Advisory Committee on Immunization (NACI) only recommends
vaccinating:
1) long-term or frequent travellers to endemic regions (which means basically everywhere except
Canada, USA, Western Europe, Japan, Australia, and New Zealand).
2) residents of communities wit h high endemic rates of recurrent out breaks of hepatitis A, and
3) residents and staff of institutions for the mentally handicapped.

Who Should Receive Hepatitis A Vaccination?

Long-term or frequent travellers to endemic regions
Residents of communities with high endemic rates of hepatitis A
Residents and staff of institutions for the mentally handicapped

Question: I s there any role for standard gammaglobulin in viral hepatitis prophylaxis?

Answer:

Basically no. (See the answer above for one last small indication. ) Development of highly
effective hepatitis A vaccines has obviated the need for gammaglobulin. Note that standard
gammaglobulin is useless for immunoprophylaxis against hepatitis B and C.

Question: What is uni versal hepatitis B vaccination?

Answer:
This refers to vaccination of the entire population, usually at the neonatal or childhood level. The
rationale for this is that targeted vaccination of high-risk groups has failed to achieve its aims,
because most people in these risk groups are unaware or unwilling to be vaccinated. Moreover,
30% to 40% of hepatitis B virus (HBV ) infections occur in people who deny any known risk factor.

Question: How is universal HBV vaccination being implemented in Canada?

Answer:
As of this writing, eleven provinces and territories have opted for elementary schoolchild (grades
4 to 6) vaccination, and only four of the eleven have also targeted neonates. This i s despite the
recommendations of the Canadian Paediatric Society, NACI, and the American Public Health
Service, that the first priority in univers al vaccination should be neonates. Recently a consensus
statement prepared by the Canadian Association for the Study of Liver (CASL) also endorsed a
similar strategy of neonatal univers al vaccination, with catch-up programs for school-aged
children if funding permits.

Why then have provincial health authorities, against the recommendations of their own experts,
implemented childhood vaccination schedules? It may be that most provincial health ministries
followed the misguided example set by British Columbia, which start ed by targeting children in
grade six. British Columbia was experiencing relatively high rates o f acute hepatitis B in
teenagers and young adults, especially around the greater Vancouver region, and in this age
group, almost all acute HBV is transmitted through sexual contact or intravenous drug use.
Accordingly, with schoolchild vaccination, one could observe tangible reduction in acute HBV
infections within only a few years, rather than within 15 to 20 years with the neonatal program.
However, most health ministries have apparently not distinguished between preventing disease
versus preventing mortality. Although acute hepatitis B in teenagers and adults causes some
morbidity, it is rarely fat al (approx. 0.3% fatality rate), and the risk of developing chronic carriage
of HBV, which is widely quoted as 5% to 10% based on older literature, now seems to have been
over-estimated. Recent studies, including an important study that followed up American soldiers
                                                          1
acutely infected with HBV during a 1942 epidemic, have found a carrier rate following acut e
                                1-3
HBV of only 0.3% to 0.9%
On the other hand, if infection occurs in neonates, it is well known that the chronic carriage rat e is
greater than 90%, and in early childhood (1 to 6 years), the chronicity rates following acute
exposure to HBV are 10% to 80% in an inverse age-dependent manner. Therefore, to pre vent
chronic HBV carriage, with its attendant sequelae of cirrhosis and hepatocellular carcinoma, one
must aim to prevent neonates and infants from being infected by HBV. Although this is partially
addressed by universal screening of all pregnancies with hepatitis B immune globulin (HB IG) and
vaccination for infants born to HBV-positive mothers, this approach is not completely effective
because of high intrafamilial transmission rates. In households where the mother is negative for
HBsAg, but at least one child is already infected, there is a 26% transmission rate between
          4
siblings.

In a static low-endemic population, childhood vaccination will eventually reduce the population
pool of chronic HBV carriers, but in Canada the continuing influx of immigrants, the vast majority
from high-endemic countries, defeats this strategy. The bottom line is that in immunocompetent
individuals, the risk of chronic hepatitis is high before age five, and very low after age ten. Hence
it makes sense to give the vaccine at a time when the chance of preventing chronic infection is
highest. So, what is the answer to the question regarding the rationale for the current approach to
childhood vaccination ? Beats me !

Question: What is the schedule for neonatal protection if the mother is a hepatitis B
carrier?

Answer:
For this patient, hepatitis B vaccine 0.5 mL i.m. is administered within the first 12h after birth,
along with HB IG, 1 mL, at the same time (but different injection site). The second dose of vaccine
should be given at one week, and the third at one to six months. Without intervention, the
replicative HBV carrier (HB eAg-positive) mot her has a greater than 80% chanc e of transmitting
the infection to the newborn, while the HB eAg negative mother still has 15% to 20% rates .
Because protection is not totally effective even with this immunoprophylaxis, there is still a 5% to
10% transmission rate of HBV.

Question: What are the immunoprophylaxis recommendations for household contacts if
an individual is found to be positive for HBsAg or develops acute hepatitis B?

Answer:
All household contacts should be screened for HBsAg and anti-HBs. If the spouse or sexual
partner is negative for both, then he or she should be given 5 mL of HB IG and a course of
vaccine, if the index case has acute hepatitis B, whereas vaccine alone should suffice for
partners of chronic HBsAg carriers. Other household contacts, if serologically negative, require
only a course of vaccination. In Canada, almost all public health units will carry out the above or
slightly variant programs when notified of a positive HBsAg result.

Question: I have a general practice with very little ER work; why should I be vaccinated for
HBV?

Answer:
If your practice involves no work in emergency rooms, hospital wards, insti tutions for the
handicapped and no administration of needles or minor surgery, and you never have hangnails,
minor cuts and abrasions on your hands, then it is likely that you would not be susceptible to
occupationally-acquired hepatitis B. There are very few practices that fit this description, and all
other physicians would benefit from this safe and effective vaccine. Or, put another way, there
has been several cases of unvaccinated physicians who died from occupationally -acquired acute
hepatitis B; isn't your life worth the $150. 00 cost of a course of vaccine?
Question: I had a standard course of three deltoid injections of full -dose hepatiti s B
vaccination, but failed to make protective antibody titres.

What does thi s mean and what should I do now?
Answer:
Lesser response rates to HBV vaccination are associated with age, increased body mass and
smoking. For example, only 60% to 80% of those aged over 60 years make protective antibody
titres. No one can reverse aging, but it you are overweight and smoke, losing weight and quitting
smoking, followed by revaccination, might be effective. E ven in healthy immunocompetent adults,
about 5% will not develop protective antibodies after a course of vaccination. Recent work has
discovered that the immune res ponse to hepatitis B surface epitopes is genetically determined.
For your interest, you probably have HLA haplotypes B8, DR3, SCO1; or B44, DR7, FC31. If a
second complete course of vaccinations fails to induce protective titres, you will have to sadly
accept that you are not protected against hepatitis B. You can blame your parents for giving you
these bad genes.

Question: I s a booster dose needed after five or ten years for recipients of hepatiti s B
vaccination?

Answer:
No. If you originally demonstrated an a dequat e antibody response, even though anti-HBs titres
may gradually fall below the critical 10 IU/L level, the immune system will mount a sufficiently
                                                                  5-6
protective anamnestic response if rechallenged with hepatitis B.

Question: I s there anything on the horizon for a vaccine against hepatiti s C?

Answer:
No. Effects to develop an effective HCV vaccine have been frustrated by:
1) initial diffic ulties in actually identifying the virus responsible for hepatitis C (although we knew
its molecular structure in 1989, it was not until 1996 that a putative HCV was identified),
2) difficulties in establishing stable cultures of the virus in a cell line, and
3) high mutability of the HCV, which like HIV, mutates at a high rate.

Question: What should be done in case of a needle stick injury?

Answer:
Management will slightly differ depending on whether the recipient (usually a healthcare worker)
has previously been vaccinated for HBV. If vaccinated, then the recipient (as a baseline) and the
source patient, should be tested for anti-HCV and anti HIV. If not vaccinated, then HBsAg should
be added to the tests for the source patient, and both HBsAg and anti-HBs added to the
recipient's bloodwork. Since this article is focussed on hepatitis, we will only deal with the HB V
and HCV -positive scenarios 1) Source is HBsAg-positive, recipient unvaccinated (and negative
for both HBsAg and HBs): give recipient HB IG, 5 mL, i.m., and first dose of hepatitis B vaccine.
Complete the standard dosing protocol of vaccine at zero, one, and six months. Without
intervention, there is about a 20% chance of the recipient contracting acute hepatitis B, and this
figure is a composite of approximately a 50% to 80% chance if the source is HBeAg -positive
(replicating, with high viral load), and a 10% to 15% chance if the source is HBeA g-negative.
2) Source is anti-HCV-positive, recipient anti-HCV -negative: test the recipient for ALT at baseline
(as soon as possible aft er needlestick), and HCV-RNA by polymerase chain reaction and ALT at
six to eight weeks after exposure. If HCV RNA is negative at this time, the chance of contracting
acute hepatitis C is essentially zero. If the HCV -RNA test is not available locally, then the ALT
should be repeated at three and six months, and the anti-HCV at six months. If they remain
normal or negative at at six months, the likelihood of developing HCV will be nil.
If HCV -RNA turns positive at six to eight weeks, this heralds the ons et of acute hepatitis C, and
these patients should be treated with a - interferon at a dos e of three million units s.c. thrice
weekly for 24 weeks. In centres where HCV-RNA is not available, the diagnosis of acute HCV
can be made using a combination of the ALT and anti-HCV serology, realizing that the
development of anti-HCV-positivity, even with third generation enzyme immunoassays,
sometimes lags behind the acute hepatitis by a month or more. Therefore, before embarking on
interferon therapy with its cost and side effects, I would recommend confirming the diagnosis by
HCV -RNA which can be sent out to a lab in a larger centre. Fortunately, acute HCV developing
after needle stick injury is uncommon. Several series have indicated that the risk of this occurring
is approximately 5% to 10%.




Hepatitis B:The Complexities

Hepatitis B Virus: A Complex Structure

The hepatitis B viron consists of a surface and a core. The core contains a DNA polymerase and
the e antigen. The DNA structure is double stranded and circular. There are four major
polypeptide reading frames (genes): the S (surface), the C (core), the P (polymerase) and the X
(transcriptional transactivating). The S gene consists of three regions, the pre -S1, pre-S2 and
encodes the surface proteins (HBsAg). Very rarely a mutation may occur in the S gene and may
abort the HBsAg with the result that a person may be HBsAg negative but still have virus present
as determined by HBV DNA. The C gene is divided into two regions, the pre-core and the core,
and codes for two different proteins, the Core antigen (HBcAg) and the e antigen (HBeA g). A not
uncommon mutant is the pre-c ore mutant, which may stop production of HB eAg, and these
persons will be HBsAg positive, HBV DNA positive, but HB eAg negative. A third mutant which
appears to have a mutant in the core , the Core antigen (HBcAg) and the e antigen (HBeAg). A
not uncommon mut ant is the pre-core mutant, which may stop production of HBeAg, and these
persons will be HBsAg positive, HBV DNA positive, but HB eAg negative. A third mutant which
appears to have a mutant in the core has been described and is referred to as HBV2. These
patients are HBsAg positive, but lack HBeAg and HBV DNA, thus also anti -HBc. Another mutant,
the YMDD mutant, will be described at a later date.

To make it even more complex, the HBsAg particles are antigenically complex and these
antigenic determinants have been identified. There is a single common determinant designated a,
and four major subdeterminants designated d,y,w and r. Thus, the four major determinants are:
adw, adr, ayw and ayr.

Multiple Tests are Available
Because of the complexity and the antigenic differences of the virus, there are a number of tests
available for hepatitis B:

Antigens
HBsAg = presence of the virus
HBcAg = not detected in blood
HBeAg = correlates with the viral replication and infectivity

Antibodie s
anti-HBs = antibodies to the surface
anti-HBc = antibodies to the core can be either IgM (acute) or IgG (chronic)
anti-HBe = antibodies to e and indicat es low infectivity and probable recovery

Other Markers
HBV DNA = indicates virus presence and activity
DNA polymerase = determines the presence of HBV DNA
HBsAg in liver cells (Orcein stain = Shakata cells) = HBsAg inside hepatocytes

Hep B:The Complexities

Carrier Rates Vary Greatly




Hepatitis B is a serious disease caused by the hepatitis B virus (HBV)
that attacks the liver and can be spread to others . HEPATITS B GET VACcINATED
You cannot get HBV from:
* sneezing or coughing .
*Kissing or hugging .
*Breast feeding .
 * food or water .
*casual contact (such as an office setting .
* sharing eating utensils or drinking glasses .
 erson d pi ted in these ma t rials a e mode s and us d or illus rative purpose only.
How do you now if you have HEPA ITI B?
Only blood test can tell or sure. See your doctore to if you have symptoms of hepatitis
 (extreme tiredness, loss of appetite , joint pain, yellow skin or eyes), or if you think you had
direct contact with someone who has hepatitis B.
its is very important that all pregnant women get a blood test for hepatitis B early in their pregnancy since a
woman who ha s hepatitis B can spread the virus to her baby during birth .
Is HEPATITIS B a serious problem?
Yes. Each year, thousands of people of all ages get hepatitis B and about 5,000 die of
chronic (life-long) liver problems caused by hepatitis B virus (HBV) infection. If you have
had other types of hepatitis, such as hepatitis A or hepatitis C, you can still get hepatitis B.



HBV is spread by:
• having sex with an infected person
• direct contact with the blood of an infected person
How can you protect yourself from getting infected with HBV?
• Get vaccinated! Hepatitis B vaccine is safe, effective, and your best protection.
• Practice “safer” sex. If you are having sex, but not with one steady partner, use latex
    condoms correctly every time you have sex. The efficacy of latex condoms in preventing
    infection with HBV is unknown, but their proper use may reduce transmission.
• Don’t share anything that might have blood on it.
o Don’t share drugs, needles, syringes, cookers, cotton, water, or rinse cups.
o Don’t share personal care items, such as razors or toothbrushes.
• Think about the health risks if you are planning to get a tattoo or body piercing. Make sure
    the artist or piercer sterilizes needles and equipment, uses disposable gloves, and washes
    hands properly.
• Handle needles and sharps safely. Follow standard precautions if you have a job that
    exposes you to human blood.
If you shoot drugs, get help to stop or get into a treatment program.
Get HEPATITIS B vaccine if:
• you are under 19 years of age
• your sex partner has hepatitis B
• you are a man who has sex with men †
• you recently had a sexually transmitted disease (e.g., gonorrhea, syphilis)
• you have sex with more than one partner
• you shoot drugs †
• you live with someone who has chronic hepatitis B
• you have a job that exposes you to human blood
• you are a kidney dialysis patient
• you live or travel for more than 6 months in countries where hepatitis B is common
† Also get hepatitis A vaccine
Is the vaccine safe?
  Yes. Hepatitis B vaccine is safe and effective. Millions of children and adults have received
the vaccine worldwide since 1982.
Should you get a blood test after the vaccine series to be sure that you are protected?
Most people don’t need to get their blood tested after completing the vaccine series (usually
three shots). You should get a blood test 1 to 2 months after you complete the series if:
• your sex partner has chronic hepatitis B
• your immune system is not working well (e.g., you are on dialysis or you have AIDS)
• you have a job that exposes you to human blood
Should you ever get a booster shot after the vaccine series?
Most people do not need booster shots after getting the vaccine series. After vaccination,
babies born to infected mothers should get their blood tested at 9 to 15 months of age to be
sure that they are protected.
                        Interpretation of the Hepatitis B Panel
          Tests                     Results                           Interpretation
           HBsAg                    negative
          anti-HBc                  negative                             su sceptible
          anti-HBs                  negative
           HBsAg                    negative
          anti-HBc                  positive                   immune due to natural infection
          anti-HBs                  positive
           HBsAg                    negative
          anti-HBc                  negative                immune due to hepatitis B vaccination
          anti-HBs                  positive
           HBsAg                    positive
          anti-HBc                  positive                               acutely
        IgM anti-HBc                positive                              infected
          anti-HBs                  negative
           HBsAg                    positive
          anti-HBc                  positive                             chronically
        IgM anti-HBc                negative                              infected
          anti-HBs                  negative
           HBsAg                    negative                                 four
          anti-HBc                  positive                           interpretations
          anti-HBs                  negative                              possible




                       Medical Nutrition Therapy in Hepatic Disease
                                    by Katherine Phillips

       Four million Americans have Hepatitis C virus and 2.7 million Americans are
chronically infected with Hepatitis C. HCV can lead to cirrhosis and end stage liver
disease; however, proper nutrition and the avoidance of alcohol can delay this
progression. Hepatitis C virus is currently the leading indication for liver transplantation
in the United States. A person with HCV should be educated about a broad array of
nutritional aspects, such as vitamin supplementation, ammonia-rich foods, and the
hepatotoxic effects of alcohol.
       When Hepatitis C does advance to cirrhosis, medical nutrition therapy is
recommended to help combat the nutritional problems. A doctor should make a referral
for the patient to see a Registered Dietitian. The RD can educate the patient on the
proper diet modifications that will ease some of the discomforts of cirrhosis. The most
common nutritional problems associated with cirrhosis are hypoglycemia, fat
malabsorption, steatorrhea, and portal hypertension. A person with cirrhosis should be
under the care of a doctor who will monitor their ammonia levels and ascites. The
Registered Dietitian will educate the client on eating regularly to maintain blood glucose
levels within normal ranges, educate the client about high ammonia foods, educate on
the complications associated with alcohol use, and educate the client on eating a high
calorie, lowfat diet. The RD can also work with the physician to prescribe a special
formula that specifically meets the needs of a hepatic disease patient. Formulas that
meet the needs of a patient with Hepatitis C advanced to cirrhosis would be those that
contain MCT oils. Bile aids in the absorption of dietary fat, since the scarred liver cannot
produce bile easily, MCT oil should be used. The body can absorb medium chain
triglycerides without bile. There are many benefits of a person with cirrhosis consulting
with a Registered Dietitian. As Hepatitis C cases continue to rise in this country, the role
of the RD will become even more important.




    PROTEIN-CONTROLLED DIET FOR ACUTE AND REFRACTORY
                HEPATIC ENCEPHALOPATHY
Descripti on
Adjustment of the amount and type of protein characterizes the Protein -Controlled Diet for Hepatic Encephalopathy.
Energy and protein are provided to attempt maintenance of nitrogen balance and support liver regeneration.

Indications
The diet is used in the treatment of acute and refractory hepatic encephalopathy associated with hepatic disorders,
which may include the following:

   hepatitis
   cholestatic liver d isease
   cirrohosis with acute and/or chronic encephalopathy

     Liver d isease causes numerous metabolic problems that can affect all majo r nutrients and the assessment
parameters common ly used to evaluate nutritional status of the patient with hepatic diseas e. The classic signs of
liver disease are anorexia, weight loss, and nausea with marked deficiencies in energy, protein, vitamins, and
minerals (1,2). Because of the high risk for malnutrition in persons with hepatic diseases the American Society for
Enteral and Parenteral Nutrit ion (ASPEN) recommends protein restriction be no less than 0.6 to 0.8 g/kg and
reserved to those patients during acute or refractory episodes of encephalopathy. Normal protein intake should be
resumed of 1 to 1.2 g/kg after the cause of encephalopathy has been identified and treated (3). The widespread
practice of protein restriction for all patients with cirrhosis is not justified and often leads to iatrogenic protein
malnutrit ion (3).
Although malnutrition does not correlate with the type of liver disease, therapeutic modifications vary according to
the type and severity of hepatic insufficiency. Generally, fatty liver requires little to no nutrition intervention, while
cirrhosis necessitates major changes in the patient’s food intake. A major goal of medical nutrition therapy in liver
disease is to prevent and treat hepatic encephalopathy (1,3).

   Hepatic disease can profoundly affect the nutritional status of the patient because of its effects on carbohydrate,
fat, protein, vitamin, and mineral metabolis m. Metabolic disorders of the following are commonly seen in the
clin ical setting of patients with hepatic insufficiency:

   Carbohydrates: Adverse effects can include hypoglycemia or hyperglycemia. Hypoglycemia is most frequently
    seen in acute hepatitis or fulminant liver disease, probably due to impaired gluconeogenesis (1,3).
    Hyperglycemia is co mmonly observed secondary to counteracting catabolic hormones and insulin resistance
    when superimposed by acute stress and injury (1). Soluble fiber may be beneficial in managing hepatic
    encephalopathy. Soluble fiber is fermented in the colon by the same mechanis m as lactulose, which eliminates
    ammon ia in the form of ammon iu m ion and bacterial proteins (3).
   Fats: Malabsorption may occur because of inadequate production of bile salts. This may lead to steatorrhea,
    which could lead to deficiencies in fat-soluble vitamin and calcium levels. Researchers have found an increase
    in serum lipids, reflect ing lipolysis (1,3).
   Protein: The effect of hepatic injury on protein metabolism is more dramat ic than is carbohydrate or fat
    metabolism. There is a decrease in synthesis of serum albu min, the transportation of proteins, and the clotting
    factors (1,3). The ability of the liver to synthesize urea decreases, which results in an accumulation of ammonia
    and a decrease in serum urea level. Th is derangement in metabolism elevates the serum aro matic amino acids
    (AAAs) (phenylalanine, tryptophan, and tyrosine) and methionine and decreases the serum branched-chain
    amino acids (BCAAs) (valine, isoleucine, and leucine). The only enzymes that metabolize AAAs are located in
    the hepatocytes. In hepatic insufficiency, there is a decrease in hepatic oxidation of AAAs, leading to an
    increase in circulat ion of AAAs in the plasma. In contrast, BCAAs are metabolized primarily by the skeletal
    muscle. There is an increase in BCAA oxidation in the peripheral tissue during stress, causing a drop in plasma
    circulat ion (1).
      Vitamins and minerals: Hepatic injury results in decreased absorption, transport, and storage and may
       alter the metabolis m of vitamins and minerals. Cirrhotic livers have been reported to store decreased
       levels of thiamine; folate; riboflav in; niacin; pantothenic acid; vitamins B6 , B12 , and A; zinc; and cobalt
       (1,4). In chronic liver d isease, the hydroxylation of dietary and endogenous vitamin D to the active
       form (25-hydroxy derivative) is impaired and may lead to a deficiency state with concomitant
       osteomalacia. A lthough there are possibilit ies of vitamin and mineral deficiencies, supplementation
       should be administered only when a specific nutrient deficiency is identified. Supplementation should
       be monitored. Vitamin K deficiency may be induced from malabsorption with steatorrhea, d ietary
       deficiency, impaired hepatic storage, and/or decreased production of gut flora due to intake of
       antibiotics. If v itamin K deficiency occurs, the rate at which prothrombin is converted to thrombin is
       affected, thus hampering the coagulation process and producing inadequate clotting factors (1).
       Intravenous or intramuscular vitamin K often is given for 3 days to rule out hypopothrombinemia due
       to deficiency (4).

Nutri tional Adequacy
Diets containing less than 50 g of protein may be inadequate in thiamin, riboflav in, calciu m, niacin,
phosphorus, and iron based on the Statement on Nutritional Adequacy in Section IA. Supplementation may
be indicated but should be assessed on an individual basis. This diet should be considered a transitional
diet. Normal p rotein intake should be resumed soon after the cause of encephalopathy has been identified
and treated. Long-term protein restriction should only be considered in patients with refractory
encephalopathy (3).



                                   How to Order the Diet
                                      The diet order should specify the grams of protein required fro m food.
                                   Base the grams of protein ordered on the patient’s estimated desirable dry
                                   weight or ad justed weight. To calcu late weight, see Section II (Estimat ing
                                   Energy Needs for Obese Patients , or Weight for Height Calculat ion – 5’
                                   Rule). If a special formu la is requested, the amount should be specified.
                                   Specify any restriction such as sodium, flu id, or other nutrients.



                                   Planning the Diet
The table below outlines the recommended nutrient prescription according to type of hepatic disease (3,5,6).


    Type of Hepatic Disease                               Nutrient Prescription
    Fatty liver/steatosis                                 Abstinence from ethanol
                                                          Weight reduction, if attributable to obesity
                                                        Reduced energy and dextrose intake, especially if
                                                          patient is receiving total parenteral nutrition (PN)

    Hepatitis                                                      Energy: 30 – 35 kcal/ kg
                      (acute/chronic/alcoholic)            Protein: 1 – 1.2 g/kg

            Cirrhosis                                      Energy: 30 – 35 kcal/ kg
      (uncomplicated)                                      Protein: 1 – 1.2 g/kg

    Cirrhosis                                             Energy: 30 – 35 kcal/ kg
                      (comp licated)                      Protein: 1 – 1.2 g/kg (with malnutrition)

    Esophageal varices                                    Liberal diet consistency, normal consistency is
                                                          encouraged as tolerated
    Ascites                                               Sodiu m restrict ion: 2 g/day with diuret ics
                                                          Flu id restriction: use clinical judgment
                                                        Fat-soluble vitamin supplement up to 100% RDA may
                                                          be necessary in cholestatic cirrhosis (see steatorrhea)
 Hepatic encephalopathy                                                             Energy: 35 kcal/ kg
                                                             Protein:    0.6 – 1.2 g/kg. Start at 0.6 g/kg per day and
                                                               progress to 1 – 1.2 g/kg as tolerated. Do not give
                                                               products enriched with glutamine.
                                                               Consider high soluble fiber diet
 Hepatic co ma                                                 Use tube-feeding
                                                               Protein: Start at 0.6g/kg per day and progress to 1 –
                                                               1.2 g/kg day as tolerated. Do not give products
                                                               enriched with glutamine.
 Steatorrhea >10 g/day                                         Fat: 40 g/day (long-chain trig lycerides)
 Or cholistatic liver disease with weight loss                                       Supplement with med iu m-chain
                                                                                         triglycerides to provide
                                                                                         additional energy.
                                                                                     Oral supplement with calciu m,
                                                                                         1,25 hydroxy -vitamin D, and
                                                                                         calcitonin may be required.
                                                                                          May require
                                                                                     supplementation of fat-soluble
                                                                                     vitamins.

Meal size and frequency: Some patients require small portions and frequent feedings because ascites limits
the capacity for gastric expansion. Studies have shown that the metabolic profile after an overnight fast in
patients with cirrhosis is similar to normal indiv iduals undergoing prolonged starvation without any
associated stress. Cirrhosis can be considered a disease of accelerated starvation with early recruit ment of
alternative fuels. A s mall-scale study showed patients with cirrhosis who received an evening snack to
supply energy during sleeping hours were able to maintain a greater positive nitrogen balance than did other
patients who were fed less frequently (2). Co mmercial supplements: Supplementation with enteral formu las
is often necessary to increase the patient’s intake. Modular products of carbohydrates and fat can increase
energy intake without increasing protein intake. The usefulness of special products containing BCAAs is
controversial, and these products generally have a higher cost. The guidelines for nutrition therapy in liver
disease developed by the American Society for Enteral and Parenteral Nutrit ion (ASPEN) restrict the use of
BCAA enriched formu las to patients with refractory encephalopathy not responding to medical therapy (7).

                                                     SAMPLE MEN U
                                                      (50 g of protein)
Breakfast                              Noon                                            Evening
Orange Juice (½ c)                    Garden Green Salad (1 o z)                       Cranberry Juice Cocktail (½ cup)
Oat meal (½ c)                             with Dressing (1 Tbsp)                      Oven Fried Chicken (2 o z)
Toast (2 slices)                       Roast Beef Sandwich                             Buttered Rice (½ c)
Margarine (2 tsp)                      Roast Beef, Shaved (1 oz)                       Seasoned Green Beans (½ c)
Jelly (1 Tbsp)                                  Bread (2 slices)                       Dinner Ro ll (1)
Milk (½ c)                             Mayonnaise (2 Tbsp)                             Margarine (2 tsp)
Sugar                                  Sliced To mato (1 o z)                          Sliced Peaches (½ c)
Coffee; Tea                            Fresh Fruit Salad (½ c)                         Lemonade
Nondairy Creamer                       Fruit Punch

Snack                                    Snack                                         Snack
Hard Candy (6 pieces)                    Fruit Ice (3 o z)                             Banana (1)
Jelly Beans (1 o z)                                                                    Dry Cereal (¾ o z)
                                                                                       Milk (½ c)


Re ferences
      1. Wong K, Klein B, Fish J. Nutrition Management of the Adult with Liver Disease. In: Skipper A, ed. Dietitian’s Handbook
          of Enteral and Parenteral Nutrition. 2nd ed. Gaithersburg, Md: Aspen Publishers; 1998.
      2. Levinson M. A practical approach to nutritional support in liver disease. Gastroenterologist. 1995;3:234-240.
      3. Teran TC, McCullough AJ. Nutrition In Liver Disease. In: Gottschlich M, ed. The Science and Practice of Nutrition
          Support A Core Based Curriculum. Dubuque, Ia: Kendall/Hunt Publishing Company; 2001.
      4. Hasse JM, Matarese LE. Medical nutrition therapy for liver, biliary system, and exocrine pancreas disorders. In: Mahan K,
          Escott-Stump E, eds. Krause’s Food, Nutrition and Diet Therapy. 10th ed. Philadelphia, Pa: WB Saunders; 2000:710.
      5. Corish C. Nutrition and liver disease. Nutr Rev. 1997;55:17-19.
      6. Shronts EP, Fish J. Hepatic failure. In: Merrit RJ, ed. The A.S.P.E.N. Nutrition Support Practice Manual. Silver Spring,
          Md: Aspen Publishers;1998.
      7. ASPEN Board of Directors. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J

				
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