conversion of androgens to estrogens in cirrhosis of the liver.docx
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Conversion of androgens to estrogens in cirrhosis of the liver.Gordon GG, Olivo J, Rafil F, Southren AL.AbstractThe contribution, by peripheral conversion, of androstenedione and testosterone to the circulating estrogens was determined in men with cirrhosis of the liver. The conversion ratio of androstenedione to estrone, estradiol and testosterone and the conversion ratio of testosterone to estrone (but not estradiol) and androstenedione were significantly increased. The plasma concentrations of androstenedione and testosterone were increased and decreased respectively; the mean plasma concentration of androstenedione being similar to that found in normal women. The metabolic clearance rate of androstenedione was not altered in cirrhosis although the metabolic clearance rate of testosterone was decreased. The production rate of androstenedione was elevated while that of testosterone was reduced. The instantaneous contribution of plasma androstenedione to estrone and estradiol was increased in cirrhosis as was the contribution of testosterone to estrone (but not to estradiol). Thus the increased estradiol levels in cirrhosis result, in large part, from increased peripheral conversion from the androgens. The percent contribution of plasma testosterone to plasma androstenedione was decreased although the absolute amount derived by conversion was normal. The percent contribution of plasma androstenedione to plasma testosterone was increased sevenfold in cirrhosis. The fraction of the daily androstenedione production derived from the plasma testosterone pool was not significantly altered. However, a significant fraction of the daily production rate of testosterone was derived from androstenedione. Thus, 15% of the circulating testosterone is not secreted but is derived by peripheral conversion from androstenedione. Normal levels of gonadotropins were found in cirrhosis.
Can Cirrhosis Cause Low Testosterone?
Numerous studies published since the 1970s have highlighted the link between hypogonadism and cirrhosis of the liver. The general consensus is that when the liver does not function optimally, being one of the body’s major organs, the person cannot manufacture enough low testosterone to stay healthy. Additionally, alcohol itself has a negative effect on testosterone production, and can also play a role in lowering levels, as well as cause cirrhosis, but it is not always possible to differentiate between the damage caused by each of the factors. Low testosterone as a result of cirrhosis is likely to manifest in a number of uncomfortable side effects, and in order to protect your quality of life, you need to find a professionalTestosterone Replacement Las Vegas clinic to find the best way to make life more comfortable.
In patients who have cirrhosis low testosterone impacts on the reproductive system in profound ways. Sufferers report a lower libido, reduced testicle size, erectile dysfunction and infertility. In men who suffer from cirrhosis and have had their testosterone levels monitored, higher levels of estrogen were also picked up. Numerous tests have also proven that the body does not respond to low levels by increasing its production of FSH (follicle stimulating hormone) and LH (luteinizing hormone), indicating the problem lies within the endocrine system.
Levels of low testosterone and the severity of its effects on the body have also been found to correspond directly with the severity of the cirrhosis the person has. In another study, cirrhosis sufferers showed a decreased level of testosterone in response to hCG hormone, leading medical experts to believe that hypogonadism is a primary effect of cirrhosis.
While the side effects of low testosterone as a result of cirrhosis seem to impact directly and markedly on the sexual function of the person in question, other symptoms of the hormone deficiency may also present. Men with low testosterone are likely to suffer from general fatigue and lethargy, a lower muscle mass and increased amount of body fat and mood disorders like depression, which could be further exacerbated after a history of excessive alcohol intake.
Alcohol lowers testosterone production and can affect the production of healthy sperm cells, especially over the long term, and alcohol abuse is one of the causes of infertility in men. If cirrhosis affects your life, there is a big chance that it will impact on your testosterone levels, and you need to get professional help from a Las Vegas Testosterone Therapy clinic to improve your quality of life.
What is cirrhosis?Cirrhosis is a complication of many liver diseases characterized by abnormal structure and function
of the liver. The diseases that lead to cirrhosis do so because they injure and kill liver cells, after
which the inflammation and repair that is associated with the dying liver cells causes scar tissue to
form. The liver cells that do not die multiply in an attempt to replace the cells that have died. This
results in clusters of newly-formed liver cells (regenerative nodules) within the scar tissue. There are
many causes of cirrhosis including chemicals (such as alcohol, fat, and certain medications),
viruses, toxic metals (such as iron and copper that accumulate in the liver as a result of genetic
diseases), and autoimmune liver disease in which the body's immune system attacks the liver.
Why does cirrhosis cause problems?The liver is an important organ in the body. It performs many critical functions, two of which are
producing substances required by the body, for example, clotting proteins that are necessary in
order for blood to clot, and removing toxic substances that can be harmful to the body, for example,
drugs. The liver also has an important role in regulating the supply of glucose (sugar) and lipids (fat)
that the body uses as fuel. In order to perform these critical functions, the liver cells must be working
normally, and they must have an intimate relationship with the blood since the substances that are
added or removed by the liver are transported to and from the liver by the blood.
The relationship of the liver to the blood is unique. Unlike most organs in the body, only a small
amount of blood is supplied to the liver by arteries. Most of the liver's supply of blood comes from the
intestinal veins as the blood returns to the heart. The main vein that returns blood from the intestines
is called the portal vein. As the portal vein passes through the liver, it breaks up into increasingly
smaller and smaller veins. The tiniest veins (called sinusoids because of their unique structure) are
in close contact with the liver cells. In fact, the liver cells line up along the length of the sinusoids.
This close relationship between the liver cells and blood from the portal vein allows the liver cells to
remove and add substances to the blood. Once the blood has passed through the sinusoids, it is
collected in increasingly larger and larger veins that ultimately form a single vein, the hepatic vein,
which returns the blood to the heart.
In cirrhosis, the relationship between blood and liver cells is destroyed. Even though the liver cells
that survive or are newly-formed may be able to produce and remove substances from the blood,
they do not have the normal, intimate relationship with the blood, and this interferes with the liver
cells' ability to add or remove substances from the blood. In addition, the scarring within the cirrhotic
liver obstructs the flow of blood through the liver and to the liver cells. As a result of the obstruction
to the flow of blood through the liver, blood "backs-up" in the portal vein, and the pressure in the
portal vein increases, a condition called portal hypertension. Because of the obstruction to flow and
high pressures in the portal vein, blood in the portal vein seeks other veins in which to return to the
heart, veins with lower pressures that bypass the liver. Unfortunately, the liver is unable to add or
remove substances from blood that bypasses it. It is a combination of reduced numbers of liver cells,
loss of the normal contact between blood passing through the liver and the liver cells, and blood
bypassing the liver that leads to many of the manifestations of cirrhosis.
A second reason for the problems caused by cirrhosis is the disturbed relationship between the liver
cells and the channels through which bile flows. Bile is a fluid produced by liver cells that has two
important functions: to aid in digestion and to remove and eliminate toxic substances from the body.
The bile that is produced by liver cells is secreted into very tiny channels that run between the liver
cells that line the sinusoids, called canaliculi. The canaliculi empty into small ducts which then join
together to form larger and larger ducts. Ultimately, all of the ducts combine into one duct that enters
the small intestine. In this way, bile gets to the intestine where it can help with the digestion of food.
At the same time, toxic substances contained in the bile enter the intestine and then are eliminated
in the stool. In cirrhosis, the canaliculi are abnormal and the relationship between liver cells and
canaliculi is destroyed, just like the relationship between the liver cells and blood in the sinusoids. As
a result, the liver is not able to eliminate toxic substances normally, and they can accumulate in the
body. To a minor extent, digestion in the intestine also is reduced.
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What are the complications of cirrhosis?Edema and ascitesAs cirrhosis of the liver becomes severe, signals are sent to the kidneys to retain salt and water in
the body. The excess salt and water first accumulates in the tissue beneath the skin of the ankles
and legs because of the effect of gravity when standing or sitting. This accumulation of fluid is called
edema or pitting edema. (Pitting edema refers to the fact that pressing a fingertip firmly against an
ankle or leg with edema causes an indentation in the skin that persists for some time after release of
the pressure. Actually, any type of pressure, such as from the elastic band of a sock, may be enough
to cause pitting.) The swelling often is worse at the end of a day after standing or sitting and may
lessen overnight as a result of the loss of the effects of gravity when lying down. As cirrhosis
worsens and more salt and water are retained, fluid also may accumulate in the abdominal cavity
between the abdominal wall and the abdominal organs. This accumulation of fluid (called ascites)
causes swelling of the abdomen, abdominal discomfort, and increased weight.
Spontaneous bacterial peritonitis (SBP)Fluid in the abdominal cavity (ascites) is the perfect place for bacteria to grow. Normally, the
abdominal cavity contains a very small amount of fluid that is able to resist infection well, and
bacteria that enter the abdomen (usually from the intestine) are killed or find their way into the portal
vein and to the liver where they are killed. In cirrhosis, the fluid that collects in the abdomen is
unable to resist infection normally. In addition, more bacteria find their way from the intestine into the
ascites. Therefore, infection within the abdomen and the ascites, referred to as spontaneous
bacterial peritonitis or SBP, is likely to occur. SBP is a life- threatening complication. Some patients
with SBP have no symptoms, while others have fever, chills,abdominal pain and
tenderness, diarrhea, and worsening ascites.
Bleeding from esophageal varicesIn the cirrhotic liver, the scar tissue blocks the flow of blood returning to the heart from the intestines
and raises the pressure in the portal vein (portal hypertension). When pressure in the portal vein
becomes high enough, it causes blood to flow around the liver through veins with lower pressure to
reach the heart. The most common veins through which blood bypasses the liver are the veins lining
the lower part of the esophagus and the upper part of the stomach.
As a result of the increased flow of blood and the resulting increase in pressure, the veins in the
lower esophagus and upper stomach expand and then are referred to as esophageal and gastric
varices; the higher the portal pressure, the larger the varices and the more likely a patient is to bleed
from the varices into the esophagus or stomach.
Bleeding from varices usually is severe and, without immediate treatment, can be fatal. Symptoms of
bleeding from varices include vomiting blood (the vomitus can be red blood mixed with clots or
"coffee grounds" in appearance, the latter due to the effect of acid on the blood), passing stool that is
black and tarry due to changes in the blood as it passes through the intestine (melena), and
orthostatic dizziness or fainting (caused by a drop in blood pressure especially when standing up
from a lying position).
Bleeding also may occur from varices that form elsewhere in the intestines, for example, the colon,
but this is rare. For reasons yet unknown, patients hospitalized because of actively bleeding
esophageal varices have a high risk of developing spontaneous bacterial peritonitis.
Hepatic encephalopathySome of the protein in food that escapes digestion and absorption is used by bacteria that are
normally present in the intestine. While using the protein for their own purposes, the bacteria make
substances that they release into the intestine. These substances then can be absorbed into the
body. Some of these substances, for example, ammonia, can have toxic effects on the brain.
Ordinarily, these toxic substances are carried from the intestine in the portal vein to the liver where
they are removed from the blood and detoxified.
As previously discussed, when cirrhosis is present, liver cells cannot function normally either
because they are damaged or because they have lost their normal relationship with the blood. In
addition, some of the blood in the portal vein bypasses the liver through other veins. The result of
these abnormalities is that toxic substances cannot be removed by the liver cells, and, instead, the
toxic substances accumulate in the blood.
When the toxic substances accumulate sufficiently in the blood, the function of the brain is impaired,
a condition called hepatic encephalopathy. Sleeping during the day rather than at night (reversal of
the normal sleep pattern) is among the earliest symptoms of hepatic encephalopathy. Other
symptoms include irritability, inability to concentrate or perform calculations, loss of
memory, confusion, or depressed levels of consciousness. Ultimately, severe hepatic
encephalopathy causes coma and death.
The toxic substances also make the brains of patients with cirrhosis very sensitive to drugs that are
normally filtered and detoxified by the liver. Doses of many drugs that normally are detoxified by the
liver have to be reduced to avoid a toxic buildup in cirrhosis, particularly sedatives and drugs that are
used to promote sleep. Alternatively, drugs may be used that do not need to be detoxified or
eliminated from the body by the liver, for example, drugs that are eliminated by the kidneys.
Hepatorenal syndromePatients with worsening cirrhosis can develop hepatorenal syndrome. This syndrome is a serious
complication in which the function of the kidneys is reduced. It is a functional problem in the kidneys,
meaning there is no physical damage to the kidneys. Instead, the reduced function is due to
changes in the way the blood flows through the kidneys themselves. The hepatorenal syndrome is
defined as progressive failure of the kidneys to clear substances from the blood and produce
adequate amounts of urine while other important functions of the kidney, such as retention of salt,
are maintained. If liver function improves or a healthy liver is transplanted into a patient with
hepatorenal syndrome, the kidneys usually begin to work normally again. This suggests that the
reduced function of the kidneys is the result of the accumulation of toxic substances in the blood
when the liver fails. There are two types of hepatorenal syndrome. One type occurs gradually over
months. The other occurs rapidly over a week or two.
Hepatopulmonary syndromeRarely, some patients with advanced cirrhosis can develop hepatopulmonary syndrome. These
patients can experience difficulty breathing because certain hormones released in advanced
cirrhosis cause the lungs to function abnormally. The basic problem in the lung is that not enough
blood flows through the small blood vessels in the lungs that are in contact with the alveoli (air sacs)
of the lungs. Blood flowing through the lungs is shunted around the alveoli and cannot pick up
enough oxygen from the air in the alveoli. As a result the patient experiences shortness of breath,
particularly with exertion.
HypersplenismThe spleen normally acts as a filter to remove older red blood cells, white blood cells, and platelets
(small particles that are important for the clotting of blood.). The blood that drains from the spleen
joins the blood in the portal vein from the intestines. As the pressure in the portal vein rises in
cirrhosis, it increasingly blocks the flow of blood from the spleen. The blood "backs-up,"
accumulating in the spleen, and the spleen swells in size, a condition referred to as splenomegaly.
Sometimes, the spleen is so enlarged that it causes abdominal pain.
As the spleen enlarges, it filters out more and more of the blood cells and platelets until their
numbers in the blood are reduced. Hypersplenism is the term used to describe this condition, and it
is associated with a low red blood cell count (anemia), low white blood cell count (leucopenia),
and/or a low platelet count (thrombocytopenia). The anemia can cause weakness, the leucopenia
can lead to infections, and the thrombocytopenia can impair the clotting of blood and result in
prolonged bleeding.
Liver cancer (hepatocellular carcinoma)Cirrhosis due to any cause increases the risk of primary liver cancer (hepatocellular carcinoma).
Primary refers to the fact that the tumororiginates in the liver. A secondary liver cancer is one that
originates elsewhere in the body and spreads (metastasizes) to the liver.
The most common symptoms and signs of primary liver cancer are abdominal pain and swelling, an
enlarged liver, weight loss, and fever. In addition, liver cancers can produce and release a number of
substances, including ones that cause an increased in red blood cell count (erythrocytosis), low
blood sugar (hypoglycemia), and high blood calcium (hypercalcemia ).
What are the common causes of cirrhosis? Alcohol is a very common cause of cirrhosis, particularly in the Western world. The
development of cirrhosis depends upon the amount and regularity of alcohol intake. Chronic,
high levels of alcohol consumption injure liver cells. Thirty percent of individuals who drink daily
at least eight to sixteen ounces of hard liquor or the equivalent for fifteen or more years will
develop cirrhosis. Alcohol causes a range of liver diseases; from simple and
uncomplicated fatty liver(steatosis), to the more serious fatty liver with inflammation
(steatohepatitis or alcoholic hepatitis), to cirrhosis.
Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver diseases that, like
alcoholic liver disease, ranges from simple steatosis, to nonalcoholic steatohepatitis (NASH), to
cirrhosis. All stages of NAFLD have in common the accumulation of fat in liver cells. The term
nonalcoholic is used because NAFLD occurs in individuals who do not consume excessive
amounts of alcohol, yet, in many respects, the microscopic picture of NAFLD is similar to what
can be seen in liver disease that is due to excessive alcohol. NAFLD is associated with a
condition called insulin resistance, which, in turn, is associated with metabolic
syndrome and diabetes mellitus type 2.Obesity is the most important cause of insulin
resistance, metabolic syndrome, and type 2 diabetes. NAFLD is the most common liver disease
in the United States and is responsible for 24% of all liver disease. In fact, the number of livers
that are transplanted for NAFLD-related cirrhosis is on the rise. Public health officials are
worried that the current epidemic of obesity will dramatically increase the development of
NAFLD and cirrhosis in the population.
Cryptogenic cirrhosis (cirrhosis due to unidentified causes) is a common reason for liver
transplantation. It is termed cryptogenic cirrhosis because for many years doctors have been
unable to explain why a proportion of patients developed cirrhosis. Doctors now believe that
cryptogenic cirrhosis is due to NASH (nonalcoholic steatohepatitis) caused by long standing
obesity, type 2 diabetes, and insulin resistance. The fat in the liver of patients with NASH is
believed to disappear with the onset of cirrhosis, and this has made it difficult for doctors to
make the connection between NASH and cryptogenic cirrhosis for a long time. One important
clue that NASH leads to cryptogenic cirrhosis is the finding of a high occurrence of NASH in the
new livers of patients undergoing liver transplant for cryptogenic cirrhosis. Finally, a study from
France suggests that patients with NASH have a similar risk of developing cirrhosis as patients
with long standing infection with hepatitis C virus. (See discussion that follows.) However, the
progression to cirrhosis from NASH is thought to be slow and the diagnosis of cirrhosis typically
is made in patients in their sixties.
Chronic viral hepatitis is a condition where hepatitis B or hepatitis C virus infects the liver for
years. Most patients with viral hepatitis will not develop chronic hepatitis and cirrhosis. For
example, the majority of patients infected with hepatitis A recover completely within weeks,
without developing chronic infection. In contrast, some patients infected with hepatitis B virus
and most patients infected with hepatitis C virus develop chronic hepatitis, which, in turn,
causes progressive liver damage and leads to cirrhosis, and, sometimes, liver cancers.
Inherited (genetic) disorders that result in the accumulation of toxic substances in the liver,
which leads to tissue damage and cirrhosis. Examples include the abnormal accumulation of
iron (hemochromatosis) or copper (Wilson's disease). In hemochromatosis, patients inherit a
tendency to absorb an excessive amount of iron from food. Over time, iron accumulation in
different organs throughout the body causes cirrhosis, arthritis, heart muscle damage leading
to heart failure, and testicular dysfunction causing loss of sexual drive. Treatment is aimed at
preventing damage to organs by removing iron from the body through bloodletting (removing
blood). In Wilson disease, there is an inherited abnormality in one of the proteins that controls
copper in the body. Over time, copper accumulates in the liver, eyes, and brain. Cirrhosis,
tremor, psychiatric disturbances and other neurological difficulties occur if the condition is not
treated early. Treatment is with oral medication, which increases the amount of copper that is
eliminated from the body in the urine.
Primary biliary cirrhosis (PBC) is a liver disease caused by an abnormality of the immune
system that is found predominantly in women. The abnormal immunity in PBC causes chronic
inflammation and destruction of the small bile ducts within the liver. The bile ducts are passages
within the liver through which bile travels to the intestine. Bile is a fluid produced by the liver that
contains substances required for digestion and absorption of fat in the intestine, as well as other
compounds that are waste products, such as the pigment bilirubin. (Bilirubin is produced by the
breakdown of hemoglobin from old red blood cells.). Along with the gallbladder, the bile ducts
make up the biliary tract. In PBC, the destruction of the small bile ducts blocks the normal flow
of bile into the intestine. As the inflammation continues to destroy more of the bile ducts, it also
spreads to destroy nearby liver cells. As the destruction of the hepatocytes proceeds, scar
tissue (fibrosis) forms and spreads throughout the areas of destruction. The combined effects of
progressive inflammation, scarring, and the toxic effects of accumulating waste products
culminates in cirrhosis.
Primary sclerosing cholangitis (PSC) is an uncommon disease frequently found in patients
with Crohn's disease and ulcerative colitis. In PSC, the large bile ducts outside of the liver
become inflamed, narrowed, and obstructed. Obstruction to the flow of bile leads to infections of
the bile ducts and jaundice, eventually causing cirrhosis. In some patients, injury to the bile
ducts (usually as a result of surgery) also can cause obstruction and cirrhosis of the liver.
Autoimmune hepatitis is a liver diseasefound more commonly in women that is caused by an
abnormality of the immune system. The abnormal immune activity in autoimmune hepatitis
causes progressive inflammation and destruction of liver cells (hepatocytes), leading ultimately
to cirrhosis.
Infants can be born without bile ducts (biliary atresia) and ultimately develop cirrhosis.
Other infants are born lacking vital enzymes for controlling sugars that leads to the
accumulation of sugars and cirrhosis. On rare occasions, the absence of a specific enzyme can
cause cirrhosis and scarring of the lung (alpha-1 antitrypsin deficiency).
Less common causes of cirrhosis include unusual reactions to some drugs and
prolonged exposure to toxins, as well as chronic heart failure (cardiac cirrhosis). In
certain parts of the world (particularly Northern Africa), infection of the liver with a parasite
(schistosomiasis) is the most common cause of liver disease and cirrhosis.
How is cirrhosis diagnosed and evaluated?The single best test for diagnosing cirrhosis is biopsy of the liver. Liver biopsies, however, carry a
small risk for serious complications, and, therefore, biopsy often is reserved for those patients in
whom the diagnosis of the type of liver disease or the presence of cirrhosis is not clear. The
possibility of cirrhosis may be suggested by the history, physical examination, or routine testing. If
cirrhosis is present, other tests can be used to determine the severity of the cirrhosis and the
presence of complications. Tests also may be used to diagnose the underlying disease that is
causing the cirrhosis. The following are some examples of how doctors discover, diagnose and
evaluate cirrhosis:
In taking a patient's history, the physician may uncover a history of excessive and prolonged
intake of alcohol, a history of intravenous drug abuse, or a history of hepatitis. These pieces of
information suggest the possibility of liver disease and cirrhosis.
Patients who are known to have chronic viral hepatitis B or C have a higher probability of having
cirrhosis.
Some patients with cirrhosis have enlarged livers and/or spleens. A doctor can often feel
(palpate) the lower edge of an enlarged liver below the right rib cage and feel the tip of the
enlarged spleen below the left rib cage. A cirrhotic liver also feels firmer and more irregular than
a normal liver.
Some patients with cirrhosis, particularly alcoholic cirrhosis, have small red spider-like markings
(telangiectasias) on the skin, particularly on the chest, that are made up of enlarged, radiating
blood vessels. However, these spider telangiectasias also can be seen in individuals without
liver disease.
Jaundice (yellowness of the skin and of the whites of the eyes due to elevated bilirubin in the
blood) is common among patients with cirrhosis, but jaundice can occur in patients with liver
diseases without cirrhosis and other conditions such as hemolysis (excessive break down of red
blood cells).
Swelling of the abdomen (ascites) and/or the lower extremities (edema) due to retention of fluid
is common among patients with cirrhosis, although other diseases can cause them commonly,
for example, congestive heart failure.
Patients with abnormal copper deposits in their eyes or certain types of neurologic disease may
have Wilson's disease, a genetic disease in which there is abnormal handling and accumulation
of copper throughout the body, including the liver, which can lead to cirrhosis.
Esophageal varices may be found unexpectedly during upper endoscopy (EGD), strongly
suggests cirrhosis.
Computerized tomography (CT or CAT) or magnetic resonance imaging (MRI) scans
and ultrasound examinations of the abdomen done for reasons other than evaluating the
possibility of liver disease may unexpectedly detect enlarged livers, abnormally nodular livers,
enlarged spleens, and fluid in the abdomen, which suggest cirrhosis.
Advanced cirrhosis leads to a reduced level of albumin in the blood and reduced blood clotting
factors due to the loss of the liver's ability to produce these proteins. Thus, reduced levels of
albumin in the blood or abnormal bleeding suggest cirrhosis.
Abnormal elevation of liver enzymes in the blood (such as ALT and AST) that are obtained
routinely as part of yearly health examinations suggests inflammation or injury to the liver from
many causes as well as cirrhosis.
Patients with elevated levels of iron in their blood may have hemochromatosis, a genetic
disease of the liver in which iron is handled abnormally and which leads to cirrhosis.
Auto-antibodies (antinuclear antibody, anti-smooth muscle antibody and anti-mitochondrial
antibody) sometimes are detected in the blood and may be a clue to the presence of
autoimmune hepatitis or primary biliary cirrhosis, both of which can lead to cirrhosis.
Liver cancer (hepatocellular carcinoma) may be detected by CT and MRI scans or ultrasound of
the abdomen. Liver cancer most commonly develops in individuals with underlying cirrhosis.
If there is an accumulation of fluid in the abdomen, a sample of the fluid can be removed using
a long needle. The fluid then can be examined and tested. The results of testing may suggest
the presence of cirrhosis as the cause of the fluid.