3. Metabolic functions of the
liver
It produces bile;
It metabolizes hormones and drugs;
In its capacity for metabolizing drugs and
hormones, the liver serves as an
excretory organ. In this respect, the bile,
which carries the end-products of
substances metabolized by the liver, is
much like the urine, which carries the
body wastes filtered by the kidneys.
It synthesizes proteins, glucose, and clotting
factors;
It stores vitamins and minerals;
It changes ammonia produced by
deamination of amino acids to urea;
It converts fatty acids to ketones
Ini menghasilkan empedu;
Ini memetabolisme hormon dan
obat-obatan;
Dalam kapasitasnya untuk
memetabolisme obat dan
hormon, hati berfungsi sebagai
organ ekskresi. Dalam hal ini,
empedu, yang membawa produk
akhir dari zat yang dimetabolisme
oleh hati, sangat mirip dengan
urin, yang membawa limbah
tubuh yang disaring oleh ginjal.
Ini mensintesis protein, glukosa, dan
faktor pembekuan;
Ini menyimpan vitamin dan mineral;
Ini mengubah amonia yang
dihasilkan oleh deaminasi asam
amino menjadi urea;
Ini mengubah asam lemak menjadi
keton
4. Carbohydrate metabolism
The liver is especially important
in maintaining glucose
homeostasis.
It stores excess glucose as
glycogen and releases it
into the circulation when
blood glucose levels fall.
The liver converts galactose
and fructose to glucose and
it synthesizes glucose from
amino acids, glycerol, and
lactic acid as a means of
maintaining blood glucose
during periods of fasting or
increased need.
The liver also converts excess
carbohydrates to triglycerides
for storage in adipose tissue.
Hati sangat penting dalam
mempertahankan homeostasis
glukosa.
Ini menyimpan kelebihan
glukosa sebagai glikogen dan
melepaskannya ke dalam
sirkulasi ketika kadar glukosa
darah turun.
Hati mengubah galaktosa dan
fruktosa menjadi glukosa dan
mensintesis glukosa dari asam
amino, gliserol, dan asam
laktat sebagai sarana untuk
mempertahankan glukosa
darah selama periode puasa
atau kebutuhan yang
meningkat.
Hati juga mengubah kelebihan
karbohidrat menjadi trigliserida
untuk disimpan di jaringan
adiposa.
5. Lipid metabolism
Certain aspects of lipid metabolism occur mainly in the liver. These
include:
The oxidation of fatty acids to supply energy for other body
functions;
To derive energy from neutral fats (triglycerides), the fat must
first be split into glycerol and fatty acids, and then the fatty
acids split into acetyl-coenzyme A (acetyl-CoA). Acetyl-CoA
can be used by the liver to produce adenosine triphosphate
(ATP) or it can be converted to acetoacetic acid and released
into the bloodstream and transported to other tissues, where it
is used for energy.
The acetyl-CoA units from fat metabolism also are used to
synthesize cholesterol and bile acids.
The synthesis of large quantities of cholesterol, phospholipids,
and most lipoproteins;
Cholesterol can be esterified and stored, it can be exported
bound to lipoproteins or it can be converted to bile acids.
The formation of triglycerides from carbohydrates and proteins.
6. Protein metabolism
The liver has the greatest rate of protein synthesis per gram of
tissue.
It produces the proteins for its own cellular needs and secretory
proteins that are released into the circulation. The most important of
these secretory proteins is albumin.
Albumin contributes significantly to the plasma colloidal osmotic
pressure and to the binding and transport of numerous
substances, including some hormones, fatty acids, bilirubin, and
other anions.
The liver also produces other important proteins, such as fibrinogen
and the blood clotting factors.
7. Bile production and cholestasis
The secretion of bile, approximately 600 to 1200 mL daily, is one of
the many functions of the liver.
Bile functions in the digestion and absorption of fats and fat-soluble
vitamins from the intestine, and it serves as a vehicle for excretion of
bilirubin, excess cholesterol, and metabolic end-products that cannot
be eliminated in the urine.
Bile contains water, electrolytes, bile salts, bilirubin, cholesterol, and
certain products of organic metabolism.
Approximately 94% of bile salts that enter the intestine are
reabsorbed into the portal circulation by an active transport process
that takes place in the distal ileum. From the portal circulation, the
bile salts pass into the liver, where they are recycled. Normally, bile
salts travel this entire circuit approximately 18 times before being
expelled in the feces.
This system for recirculation of bile is called the enterohepatic
circulation.
8. Bilirubin elimination
Bilirubin is formed during the breakdown of senescent red blood
cells.
In the process of degradation, the heme portion of the hemoglobin
molecule is oxidized to form biliverdin, which is then converted to
free bilirubin.
Free bilirubin, which is insoluble in plasma, is transported in the
blood attached to plasma albumin. Even when it is bound to
albumin, this bilirubin is still called free bilirubin.
As it passes through the liver, free bilirubin is released from the
albumin carrier molecule and moved into the hepatocytes. Inside the
hepatocytes, free bilirubin is converted to conjugated bilirubin,
making it soluble in bile.
Conjugated bilirubin is secreted as a constituent of bile, and in this
form it passes through the bile ducts into the small intestine.
9. Bilirubin elimination
In the intestine, approximately one half of the bilirubin is converted
into a highly soluble substance called urobilinogen by the intestinal
flora.
Urobilinogen is either absorbed into the portal circulation or excreted
in the feces.
Most of the urobilinogen that is absorbed is returned to the liver to
be re-excreted into the bile.
A small amount of urobilinogen, approximately 5%, is absorbed into
the general circulation and then excreted by the kidneys.
Usually, only a small amount of bilirubin (0.1 to 1.2 mg/dL) is found
in the blood. Laboratory measurements of bilirubin usually measure
the free and the conjugated bilirubin as well as the total bilirubin.
These are reported as the direct (conjugated) bilirubin and the
indirect (unconjugated or free) bilirubin.
11. Jaundice (icterus)
Jaundice (i.e., icterus), which results from an abnormally high
accumulation of bilirubin in the blood, is a yellowish discoloration to
the skin and deep tissues.
Jaundice becomes evident when the serum bilirubin levels rise
above 2.0 to 2.5 mg/dL.
Bilirubin has a special affinity for elastic tissue. The sclera of the
eye, which contains considerable elastic fibers, usually is one of the
first structures in which jaundice can be detected.
12. Causes
The four major causes of jaundice are:
Excessive destruction of red blood cells
Impaired uptake of bilirubin by the liver cells
Decreased conjugation of bilirubin
Obstruction of bile flow in the canaliculi of the hepatic lobules or
in the intrahepatic or extrahepatic bile ducts.
From an anatomic standpoint, jaundice can be
categorized as:
Prehepatic
Intrahepatic
Posthepatic
13. Causes
Prehepatic (Excessive Red
Blood Cell Destruction)
Hemolytic blood transfusion
reaction
Hereditary disorders of the
red blood cell
Sickle cell anemia
Thalassemia
Spherocytosis
Acquired hemolytic
disorders
Hemolytic disease of the
newborn
Autoimmune hemolytic
anemias
Intrahepatic
Decreased bilirubin uptake by
the liver
Decreased conjugation of
bilirubin
Hepatocellular liver damage
Hepatitis
Cirrhosis
Cancer of the liver
Drug-induced cholestasis
Posthepatic (Obstruction of Bile
Flow)
Structural disorders of the bile
duct
Cholelithiasis
Congenital atresia of the
extrahepatic bile ducts
Bile duct obstruction caused by
tumors
14. Manifestations
In prehepatic jaundice there is:
Mild jaundice
The unconjugated bilirubin is elevated
The stools are of normal color
There is no bilirubin in the urine
Intrahepatic jaundice usually interferes with all phases of bilirubin
metabolism—uptake, conjugation, and excretion:
Both conjugated and unconjugated bilirubin are elevated
The urine often is dark because of the presence of bilirubin
Posthepatic or obstructive jaundice, also called cholestatic jaundice, occurs
when bile flow is obstructed between the liver and the intestine:
Conjugated bilirubin levels usually are elevated
The stools are clay colored because of the lack of bilirubin in the bile
The urine is dark
The levels of serum alkaline phosphatase are markedly elevated
The aminotransferase levels are slightly increased
Blood levels of bile acids often are elevated in obstructive jaundice. As
the bile acids accumulate in the blood, pruritus develops.
15. Tests of hepatobiliary function
The history and physical examination;
Elevated serum enzyme tests usually indicate liver injury earlier than
do other indicators of liver function.
The key enzymes are alanine aminotransferase (ALT) and aspartate
aminotransferase (AST), which are present in liver cells.
In most cases of liver damage, there are parallel increases in ALT
and AST. The most dramatic rise is seen in cases of acute
hepatocellular injury, such as occurs with viral hepatitis, hypoxic or
ischemic injury, and acute toxic injury.
The liver’s synthetic capacity is reflected in measures of serum
protein levels and prothrombin time (i.e., synthesis of coagulation
factors). Hypoalbuminemia caused by depressed synthesis may
complicate severe liver disease.
Serum bilirubin, γ-glutamyltransferase (GGT), and alkaline
phosphatase measure hepatic excretory function.
Ultrasonography and computed tomography (CT) scanning;
Selective angiography;
Liver biopsy.
16. Hepatitis
Hepatitis refers to inflammation of the liver.
It can be caused by:
Hepatotropic viruses that primarily affect liver cells or
hepatocytes;
Reactions to chemical agents, drugs, and toxins;
Autoimmune diseases;
Infectious mononucleosis that cause secondary hepatitis.
17. Acute viral hepatitis
The known hepatotropic viruses include hepatitis A virus (HAV),
hepatitis B virus (HBV), the hepatitis B-associated delta virus (HDV),
hepatitis C virus (HCV), and hepatitis E virus (HEV).
Although all of these viruses cause acute hepatitis, they differ in the
mode of transmission and incubation period, mechanism, degree,
and chronicity of liver damage, and ability to evolve to a carrier
state.
There are two mechanisms of liver injury in viral hepatitis:
Direct cellular injury;
Immune responses against viral antigens in infected hepatocytes;
It is thought that the extent of inflammation and necrosis
depends on the person’s immune response.
18. Acute viral hepatitis
A prompt immune response during the acute phase of the infection
would be expected to cause cell injury but at the same time
eliminate the virus.
People who respond with fewer symptoms and a marginal immune
response are less likely to eliminate the virus, and hepatocytes
expressing the viral antigens persist, leading to the chronic or carrier
state.
Fulminant hepatitis would be explained in terms of an accelerated
immune response with severe liver necrosis.
19. Manifestations
The manifestations of acute hepatitis can be divided into three
phases:
1. The prodromal period - preicterus phase
Is marked by nonspecific symptoms, which vary from abrupt to
insidious. There are usually complaints of malaise, easy
fatigability, nausea, and loss of appetite. Weight loss, low-
grade fever, headaches, muscle aches and pains, vomiting,
and diarrhea are less constant symptoms. In some persons,
the nonspecific symptoms are more severe sometimes
accompanied by right upper quadrant abdominal pain and liver
enlargement and tenderness.
Serum levels of AST and ALT show variable increases and
precede a rise in serum bilirubin that accompanies the onset of
the icterus or jaundice phase of infection.
2. The icterus or jaundice phase
If it occurs, usually follows the prodromal phase by 5 to 10
days. Jaundice is less likely to occur with HCV infection.
The symptoms may become worse with the onset of jaundice,
followed by progressive clinical improvement.
Severe pruritus and liver tenderness are common duringthe
icterus period.
20. Manifestations
The manifestations of acute hepatitis can be divided into three
phases:
3. The convalescent phase
It is characterized by an increased sense of well-being, return
of appetite, and disappearance of jaundice.
The acute illness usually subsides gradually during a 2- to 3-
week period, with complete clinical recovery by approximately
9 weeks in hepatitis A and 16 weeks in uncomplicated hepatitis
B.
Infection with HBV and HCV can produce a carrier state, in
which the person does not have symptoms but harbors the
virus and can transmit the disease. Evidence also indicates a
carrier state for HDV infection.
21. Carrier state
There are two types of carriers:
Healthy carriers who have few or no ill effects
Those with chronic disease who may or may not have symptoms
Factors that increase the risk of becoming a carrier are age at time
of infection and immune status.
Persons at high risk for becoming carriers are:
Infants of HBV-infected mothers
Persons with impaired immunity
Those who have received multiple transfusions or blood products
Those who are on hemodialysis
Drug addicts
22. Chronic viral hepatitis
Chronic viral hepatitis is the principal cause of chronic liver disease,
cirrhosis, and hepatocellular cancer in the world and now ranks as
the chief reason for liver transplantation in adults.
Chronic hepatitis B accounts for 5% to 10% of chronic liver disease
and cirrhosis in the United States. Hepatitis B is less likely than
hepatitis C to progress to chronic infection.
Chronic hepatitis C accounts for most cases of chronic viral
hepatitis. HCV infection becomes chronic in 75% to 80% of cases.
Chronic HCV infection often smolders during a period of years,
silently destroying liver cells. Most persons with chronic hepatitis C
are asymptomatic. Because the course of acute hepatitis C often is
mild, many persons do not recall the events of the acute infection.
23. Autoimmune hepatitis
Chronic autoimmune hepatitis is a chronic inflammatory liver
disease of unknown origin, but it is associated with circulating
autoantibodies and high serum gamma globulin levels.
Autoimmune hepatitis accounts for only approximately 10% of
chronic hepatitis cases in the United States.
The pathogenesis of the disorder is one of a genetically predisposed
person exposed to an environmental agent that triggers an
autoimmune response directed at liver cell antigens.
The factors surrounding the genetic predisposition and the
triggering events that lead to the autoimmune response are
unclear.
The resulting immune response produces a necrotizing inflammatory
response that eventually leads to destruction of liver cells and
development of cirrhosis.
Autoimmune hepatitis is mainly a disease of young women,
although it can occur at any age and in men or women.
24. Alcohol-induced liver disease
The spectrum of alcoholic liver disease includes fatty liver disease,
alcoholic hepatitis, and cirrhosis.
Because only approximately 10% to 15% of alcoholics have
cirrhosis, it was suggested that other conditions such as genetic and
environmental factors contribute to its occurrence.
Fatty liver
It is characterized by the accumulation of fat in hepatocytes, a
condition called steatosis.
The pathogenesis of fatty liver is not completely understood and
can depend on the amount of alcohol consumed, dietary fat
content, body stores of fat, hormonal status, and other factors.
There is evidence that ingestion of large amounts of alcohol can
cause fatty liver changes even with an adequate diet.
The fatty changes that occur with ingestion of alcohol usually do
not produce symptoms and are reversible after the alcohol intake
has been discontinued.
25. Alcohol-induced liver disease
Alcoholic hepatitis is the intermediate stage between fatty changes
and cirrhosis.
It often is seen after an abrupt increase in alcohol intake.
Alcoholic hepatitis is characterized by inflammation and necrosis of
liver cells.
This stage usually is characterized by hepatic tenderness, pain,
anorexia, nausea, fever, jaundice, ascites, and liver failure, but some
individuals may be asymptomatic.
The condition is always serious and sometimes fatal.
In persons who survive and continue to drink, the acute phase often
is followed by persistent alcoholic hepatitis, with progression to
cirrhosis in a matter of 1 to 2 years.
26. Cirrhosis
Cirrhosis represents the end stage of chronic liver disease in which
the normal architecture of the liver is replaced by fibrous septa that
encompass regenerative nodules of hepatic tissue.
Although cirrhosis usually is associated with:
Alcoholism
Viral hepatitis
Toxic reactions to drugs and chemicals
Biliary obstruction
Metabolic disorders that cause the deposition of minerals in the
liver:
Hemochromatosis (i.e., iron deposition)
Wilson’s disease (i.e., copper deposition)
27. Cirrhosis
The manifestations of cirrhosis are variable, ranging from
asymptomatic hepatomegaly to hepatic failure. Often there are no
symptoms until the disease is far advanced.
The most common signs and symptoms of cirrhosis are:
Weight loss (sometimes masked by ascites)
Weakness
Anorexia
Diarrhea frequently is present, although some persons may
report constipation
Hepatomegaly
Splenomegaly and thrombocytopenia
Bleeding caused by decreased clotting factors; Jaundice
Abdominal pain because of liver enlargement or stretching of
Glisson’s capsule
The late manifestations of cirrhosis are related to portal
hypertension and liver failure
28. Portal hypertension
Portal hypertension is characterized by increased resistance to flow
in the portal venous system and sustained portal vein pressure
above 12 mm Hg (normal, 5–10 mm Hg).
Venous blood returning to the heart from the abdominal organs
collects in the portal vein and travels through the liver before
entering the vena cava.
Portal hypertension can be caused by a variety of conditions that
increase resistance to hepatic blood flow, including prehepatic,
posthepatic, and intrahepatic obstructions.
Complications of portal hypertension arise from the increased
pressure and dilatation of the venous channels behind the
obstruction.
Collateral channels open that connect the portal circulation with the
systemic circulation.
The major complications of the increased portal vein pressure and
the opening of collateral channels are:
Ascites
Splenomegaly
Formation of portosystemic shunts (i.e., esophageal varices,
anorectal varices, and caput medusae).
29. Pathogenesis
Prehepatic obstruction
Portal vein thrombosis and external compression caused by
cancer or enlarged lymph nodes that produce obstruction of the
portal vein before it enters the liver.
Posthepatic
Any obstruction to blood flow through the hepatic veins beyond
the liver lobules, either within or distal to the liver.
It is caused by conditions such as:
Thrombosis of the hepatic veins
Venoocclusive disease
Severe right-sided heart failure that impede the outflow of
venous blood from the liver
Intrahepatic obstructions (with hepatic referring to the liver lobules,
rather than the entire liver)
Conditions that cause obstruction of blood flow within the liver
Alcoholic cirrhosis is the major cause of portal hypertension
