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Conversion of androgens to estrogens in cirrhosis of the liver.

Gordon GG, Olivo J, Rafil F, Southren AL. Abstract


The 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 bodys 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 ascites


As 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 varices


In 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 encephalopathy
Some 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 syndrome
Patients 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 syndrome
Rarely, 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.

Hypersplenism
The 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.