Cirrhosis: Risk of Liver Damage

Liver is one of the very important organs of body that participates in carrying out many important functions to sustain life of an individual. It can be affected with any disease or disorder and one of the commonest one includes cirrhosis. Cirrhosis is a type of chronic liver disease where the liver tissue is being replaced by fibrosis, scar tissue and regenerative nodules that result in loss of proper functioning of this vital organ. Alcoholism, fatty liver, hepatitis B and C are the major factors that are responsible for this chronic liver disease but other factors may also play minor role for example, viral infection, accumulation of toxic metals like iron and copper due to genetic disease and autoimmune disease. Some idiopathic factors also contribute to liver cirrhosis. Poor quality of life with increased risk of infection is basically responsible for the appearance of one of the most common complication of this disease identified as ascites. Hepatic encephalopathy and esophageal varices are other complications associated with cirrhosis. This chronic condition is generally irreversible and in advanced cases liver transplant is the only solution. The term cirrhosis actually originated from a Greek word meaning diseased liver. Ren矇 Laennec gave the term cirrhosis in 1819 while carrying out his work.

Liver is a very essential organ of human body as it carries out many critical functions out of which two are very important for example, it participates in the clotting of proteins in order to stop bleeding and it also aids in the removal of toxic materials like drugs that may be harmful for the human body. It also partakes in regulating the regular supply of body fuels namely glucose and lipids. In order to perform these essential functions the liver cells must work properly and must be able establish a close connection with blood so that substances can be easily transported as well as removed from blood via liver. The relationship of liver with blood is a unique one. Arteries supply a very small amount of blood to the liver. Major blood supply of liver actually comes from the intestinal veins as the blood returns to heart. The main vein that returns to heart from intestine is the portal vein. As this portal vein passes through liver it breaks up into smaller and smaller veins. The smallest veins are in close intimacy with the liver cells. This close relationship between the liver cells and the veins helps in addition as well as removal of materials from blood. The liver cells also line up along the whole length of the sinusoids and when the blood passes through these sinusoids blood is collected in larger veins that collectively combine and form a larger single vain known as the hepatic vein that in turn finally returns to the heart.

In liver cirrhosis this intimate relationship between liver cells and blood is destroyed. The liver cells that survive or are newly formed may be able to add or remove substances to blood but their normal functioning is hampered so they no longer are able to maintain the close relationship with blood. Formation of scars also hampers the regular blood flow from liver to the liver cells as result the pressure in the portal vein increases and the condition is known as portal hypertension. The second major problem caused by cirrhosis is disturbance in the relationship between the liver cells and the channels through which the bile flows. Bile is a fluid that is produced by the liver cells and it has two important functions for example, it helps in digestion as well as removal and elimination of toxic substances. The bile produced by the liver cells is secreted into very tiny channels that run between the liver cells and also line the sinusoids known as canaliculi. These canaliculi empty into smaller ducts that open into larger ducts. Finally all these ducts open into a single duct that opens in the intestine. So in this way the bile entering the intestine aids in digestion. At the same time the toxic substances present in the bile also enter intestine and are eliminated out from the body through feces. In cirrhosis, the canaliculi become abnormal and the relationship between the liver cells and these canaliculi is destroyed so the liver cells are not able to eliminate the toxic substance out from the body and they keep on accumulating inside the body. Digestion of food in the intestine is affected but on minor scale.

The symptoms of cirrhosis either develop due to the chronic liver disease or are the result of complications of cirrhosis. Many symptoms crop up which have no relation with cirrhosis. The chief symptoms include spider angiomata where vascular lesions develop that can be identified by a central arteriole surrounding many smaller vessels. This condition crops up because of higher secretion of estradiol. Palmer erythrema is another symptom where altered sex hormone metabolism results in speckled mottling of palm. Changes in the nail structure also appear for example, Muehrcke's lines identified by paired horizontal lines that are separated by normal color and this condition crops up due to hypoalbuminemia. Apart from this symptom the proximal two-thirds of the nail plates become white with one third portion red in color and this is also due to hypoalbuminemia. This condition is known as Terry's nails. Clubbing nails may also result where the angle between the nail plate and the proximal nail fold is greater than 180. Chronic proliferative periostitis of the long bones result in severe pain and the clinical condition is given the term hypertrophic osteoarthropathy. Dupuytren's contracture can be characterized by thickening and shortening of the palmar facia resulting in the deformities of fingers. This symptom is very common in 33% patients of liver cirrhosis. Benign proliferation of the tissue male of male breasts can also occur due to excessive secretion of estradiol known as gynecomastia and is common in 66% cases.

Hypogonadism characterized by impotence, infertility, loss of sexual drive and testicular atrophy may also occur due to suppression of the pituitary function. Liver may be enlarged, normal or shrunken. Portal hypertension results in splenomegaly where the size of spleen is becomes very large than the normal. Accumulation of fluid in the peritoneal cavity results in the formation of ascites. In the portal hypertension the umbilical vein may be open and abnormality may result in a condition known as caput medusa. Fetor hepaticus may also appear where a musty odor is observed in the breath due to the increased concentration of dimethyl sulphide. Jaundice may also arise in later cases. Fatigue, weakness, loss of appetite, itching and bruising is other symptoms associated with cirrhosis. As the disease advances complications begin to appear and in some individuals they are the first signs of disease. As the disease advances signals are sent to the kidneys to retain salt and water in the body. The excess salt and water first begin to accumulate in the tissue just beneath the ankles and legs due to the effect of gravity. This fluid accumulation is known as edema or pitting edema. The condition of the patient worsens during the day time as intense swelling occurs while standing and sitting but swelling lessens during night while lying down. These changes are orientated by the effect of gravity. When cirrhosis worsens the fluid begins to accumulate in the abdominal cavity just beneath the abdominal wall and the abdominal organs. This results in abdominal swelling, abdominal discomfort and excessive weight gain.

Fluid present in the abdominal cavity provides a favorable condition for the bacteria to grow. In normal conditions very small amount of fluid is present in the abdominal cavity that is capable of resisting infection and the bacteria may be killed in the abdominal cavity or if they enter the portal vein or liver are ultimately killed by liver cells. In cirrhosis the fluid that collects n the abdominal cavity is unable to resist infection. The bacteria find their way from intestine into the ascites and therefore, this infection is known as spontaneous bacterial peritonitis or SBP and it may terminate fatally. Some patients with this complication may not symptoms but others suffer from fever, chills, abdominal pain, diarrhea and tenderness. The scar formed in the cirrhotic liver blocks the path of blood returning from the intestines to the heart and this result in increased pressure in the portal vein and the condition is known as portal hypertension. When the pressure becomes very high then the blood flows with lower pressure towards heart. The increased pressure in the veins of lower esophagus and upper stomach expand resulting in varices. The higher portal pressure results in intense bleeding from these varices in advanced stage. Bleeding in severe cases may terminate fatally if left untreated. The symptoms of bleeding varices may include vomiting blood, passage of black stools and orthostatic dizziness. Bleeding from varices may also occur through the intestines for example form the colon but this is very rare.

Some of the protein also escapes digestion and absorption and is utilized by the bacteria that normally inhabit the intestine. The proteins utilized by these bacteria for their own purpose results in the release of some of the substances in the intestine that can be absorbed in the body. Some of these substances namely, ammonia has an adverse effect over brain function. In general, these toxic substances are removed from the body the intimate relationship of the liver cells with blood. When these toxic substances accumulate in brain in sufficient amounts the brain function is impaired and the condition is known as hepatic encephalopathy. One of the earliest symptoms of hepatic encephalopathy is that the individual falls asleep during the day time rather than night. Other symptoms include irritability, inability to perform calculations, loss of memory, confusion, depressed levels of consciousness and in severe cases coma followed by death. Accumulation of toxic substances in brain also makes the patients sensitive to drugs that are normally removed from the body by the activity of the liver cells. Advanced cases of cirrhosis may also develop hepatorenal syndrome where the normal function of kidneys is altered. Kidneys are not damaged physically but there are changes in the blood flow within the kidneys. Hepatorenal syndrome is characterized by progressive failure of kidney function where they are unable to form adequate amount of urine although the salt and water retention function is normally maintained. If liver function is brought back to normal then this syndrome diminishes. This clearly indicates that loss in the activity of liver cells adversely affects kidney function.

Some patients with very advances cirrhosis may develop hepatopulmonary syndrome but its incidence is very rare. The patients with this syndrome generally experience difficulty in breathing due to the excessive secretion of hormones that cause impairment of lung function. The major problem associated with lung function is decrease in the blood flow in the small vessels that pass through the alveoli of the lungs. Due to the decreased blood supply the alveoli are unable to pick up sufficient amounts of oxygen that result in breathing problem. Spleen normally acts as a filter for the removal of older red blood cells, white blood cells and the platelets. The blood that drains from spleen joins the blood in the portal vein from the intestine. As the pressure in the portal vein is very the blood supply to the spleen is blocked. Due to this the size of spleen increases and this condition is known as splenomegaly. Sometimes the spleen swells so intensely that it causes severe abdominal pain. As the size of the spleen enlarges it draws out more and more blood cells and platelets that their number reduces in the blood. The total count of red blood cells, white blood cells and the platelets is reduced and the condition is known as hypersplenism. Anemia causes weakness, leucopenia leads to infections and thrombocytopenia results in loss of blood clotting and causes prolonged bleeding. Cirrhosis also increases the risk of primary liver cancer. Primary indicates that a tumor arises in liver that becomes cancerous later on and secondary condition is that the cancerous growth occurs somewhere else in the body that later spreads in liver also. Most common symptoms of primary liver cancer are abdominal pain, swelling, enlarged liver, weight loss and fever. Liver cancer can also cause increased red blood cell count, low blood sugar and high blood calcium levels.

A number of factors are responsible for this chronic liver disease and more than one cause is present in the same patient. In the western world alcoholism and Hepatitis C are the chief factors which are generally responsible for cirrhosis of liver. The amount and regularity of alcohol intake are responsible for cirrhosis development. Very high consumption of alcohol generally damages the liver cells. Individuals who drink daily with an amount ranging between 8-16 ounces per day are generally at a higher risk of liver damage. Alcoholism is also responsible for the development of fatty liver. Nonalcoholic fatty liver disease (NAFLD) is a group of liver diseases like alcoholic liver disease, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) to cirrhosis. All these diseases are identified by heavy accumulation of fat in the liver cells. The term nonalcoholic is used because this condition crops up in those individuals who do not consume alcohol but if the liver cells are examined microscopically then the symptoms resemble with those present in the liver of those individuals who consume alcohol. NAFLD is associated with insulin resistance, metabolic syndrome and diabetes type 2 and obesity can be considered as a prime factor associated with these clinical symptoms. In the United States about 24% cases with liver cirrhosis undergo liver transplants and NAFLD is responsible for cirrhosis. Cryptogenic cirrhosis is another symptom which is responsible for liver transplant. This issue was earlier debatable among the doctors but now the debate has been solved and nonalcoholic steatohepatitis (NASH) is the major cause. Chronic viral hepatitis is a condition where hepatitis B and hepatitis C virus affect the functioning of liver for many years. Most of the patients with viral hepatitis generally do not develop chronic hepatitis and cirrhosis. Patients suffering from hepatitis generally recover within weeks without the development of cirrhosis but in case of hepatitis B and C in severe cases chronic liver infection and sometimes liver cancer may develop.

Inherited disorders can also result in accumulation of the toxic substances within the liver cells which in turn cause chronic liver disease the common example is abnormal accumulation of copper and iron inside the liver cells. In hemochromatosis patients develop an abnormal tendency of absorbing higher levels of iron from food. Excessive accumulation in the body cells is responsible for cirrhosis, arthritis, heart muscle damage leading to heart failure and testicular dysfunction that causes loss of sexual drive. Treatment is basically focused on removal of excess iron amounts from body by bloodletting. In Wilson disease there is abnormal accumulation of copper in eyes, liver and brain. Cirrhosis, neurological disturbances and tremors make their appearance if this condition is not treated. Generally oral medication is given which aims at removal of copper from the body through urine. Primary biliary cirrhosis (PBC) is a liver disease caused by abnormality of the immune system and is chiefly found in females. In this disease inflammation and destruction of small bile ducts take place within the liver. Bile ducts are the passages through which the bile travels from liver to the intestines. Bile is a fluid produced by the liver which contains substances responsible for the digestion and absorption of fats in the intestine and also contains some waste products like bilirubin. In PBC destruction of the small bile ducts causes blockage of flow of bile from liver to the intestine. As the hepatocytes or liver cells are damaged fibrosis makes its appearance and finally cirrhosis occurs.

Primary sclerosing cholangitis (PSC) is a rare disease found in patients with ulcerative colitis. In this condition the bile ducts present outside liver become inflamed, narrowed and obstructed. Obstruction is responsible for the infection of bile ducts, jaundice and finally cirrhosis occurs. In some patients damage to the bile ducts can directly lead to liver cirrhosis. Autoimmune hepatitis is another liver disease where the immune system becomes abnormal and cirrhosis occurs but this disease is very common among women. Progressive inflammation and destruction of hepatocytes are the primary symptoms that ultimately result in cirrhosis. Biliary atresia is a condition where the infants are born without bile ducts so cirrhosis occurs. Other infanst may be lacking vital enzymes responsible for the cleavage of sugars so abnormal sugar accumulation takes place so cirrhosis develops. In rare cases, the loss of a specific enzyme can cause alpha 1 antitrypsin deficiency. Liver plays a vital role in synthesis of proteins, detoxification and storage. It also participates in the metabolism of lipids and carbohydrates. Cirrhosis is often preceded by hepatitis and fatty liver. The hallmark of cirrhosis is the development of a scar tissue that replaces the normal parenchyma, blocks the portal flow of blood through liver and finally disturbs its normal functioning. According to the recent research, stellate cell that normally stores vitamin A plays a pivotal role in the development of liver cirrhosis. Damage of the liver parenchyma results in the activation of this stellate cell and finally the portal supply of blood is obstructed. Stellate cell also secretes the TGF-?1 which is responsible for the fibrotic response causing proliferation of the connective tissue. It also secretes TIMP 1 and 2 which prevents the matrix metalloproteinases from breaking within the matrix. Spleen becomes enlarged causing hypersplenism and increased sequestration of platelets. Portal hypertension is highly responsible for the appearance of symptoms of cirrhosis.

Liver biopsy carried out through percutaneous, transjuglar and laparoscopic approaches are considered very effective which searching for cirrhosis. If clinical, laboratory and radiologic data predict about cirrhosis then biopsy is not needed. A number of clinical trials in the laboratory can be carried out which assure about the presence of cirrhosis for example, the levels of aminotransferases, alkaline phosphatase, gamma-glutamyl transferase are elevated. The levels of bilirubin are also elevated. Albumin levels fall and prothrombin time also increases. Globulin, serum sodium levels are increased. Ultrasound is chiefly used for the diagnosis of the cirrhosis as it shows a small nodular liver but in advanced stages echogenicity becomes prominent. Ultrasound also screens for hepatocellular carcinoma, portal hypertension and Budd-Chiari syndrome. Fibrscan is a newly invented device that uses elastic waves to check out the stiffness of liver which can be read with the help of METAVIR scale. This device generates the image of liver along with pressure reading. This test is very fast than biopsy and is painless. It shows reasonable relation with severity of cirrhosis. Other tests include abdominal CT and liver or bile duct MRI. Gastroscopy is performed in patients with established cirrhosis in order to exclude the possibilities of esophageal varices. If they are found then prophylactic local therapy and beta blocker treatment is suggested.

In general, macroscopically the liver becomes enlarged but with advancement of disease the size of the liver shrinks to small. The surface of liver becomes irregular and it acquires yellowish colouration. Three types of macroscopic nodules namely, macronodular, micronodular and mixed cirrhosis are identified. In micronodular form the nodules are less than 3 mm in size while in macronodular form nodules are larger than 3 mm in size. The mixed cirrhosis consists of mixed nodules of different sizes. A number of microscopical pathological features are identified for cirrhosis for example, presence of regenerating nodules in hepatocytes, presence of fibrosis. Fibrosis is responsible for the destruction of other normal structures like sinusoids, space of Disse, portal hypertension, damage of other vascular structures. A number of other entities may also be responsible for the development of cirrhosis. In chronic hepatitis B there is infiltration of liver parenchyma along with the lymphocytes however, in cardiac cirrhosis, the amount of erythrocytes increase and fibrosis occurs in the hepatic veins. In primary biliary cirrhosis, fibrosis occurs around the bile duct, granulomas and pooling of bile can be identified, in alcoholic cirrhosis there is infiltration of liver along with neutrophils. The severity of cirrhosis is classified on the basis of Child-Pugh Score. The score makes use of bilirubin, albumin, INR, presence and severity of ascites and encephalopathy and the patients are then kept in A, B and C classes. Class A individuals have a favorable prognosis while those belonging to class C are at the risk of death. The score was first given by Child and Turcotte in 1964 and was modified by Pugh et al., in 1973.

According to a study carried out in the United States in 2001, about 27,000 people die every year due to cirrhosis and chronic liver disease. Treatment of cirrhosis can be accomplished in four ways namely, prevention of further damage to liver, treatment of complications of cirrhosis, prevention of liver cancer and its early detection and finally liver transplantation. Consumption of a balanced diet with daily intake of a multivitamin can prevent further damage to liver. Patients with primary biliary cirrhosis require additional doses of vitamin D and K. avoidance of drugs that damage liver cells and well as alcohol quitting can protect liver from damage. Avoidance of non-steroidal anti-inflammatory drugs, eradication of virus of hepatitis B and C, removal of blood from the patients with hemochromatosis to get rid of excessive iron, oral medication for removal of excessive copper through urine can also prevent further damage of liver cells. Retention of salt and water can cause swelling of legs and ankles (edema) or abdomen (ascites) especially in the patients with cirrhosis. Doctors advise these patients to restrict the dietary use of sodium. The amount of salt intake is restricted to 2 grams per day and fluid intake must not exceed 1.2 liters in a day. Diuretic medications are often suggested by the health experts so that excessive salt and water may leave the body through urine. The blood urea and creatinine levels of kidneys must be monitored regularly while using diuretics.

If large varices develop in esophagus and upper part of stomach then the patient may experience excessive bleeding that may terminate fatally. Propranolol is an effective beta blocker commonly used for stopping the bleeding. Patients with abnormal sleep cycle, impaired thinking, odd behavior or other signs of hepatic encephalopathy should be treated with a low protein diet and oral lactulose. Dietary protein is restricted as it can be responsible for the formation of toxic substances responsible for hepatic encephalopathy. Lactulose is a liquid that traps toxic compounds in colon and therefore these cannot be absorbed back in the blood stream to cause encephalopathy. The filtration of blood by an enlarged spleen normally results in mild reduction of red blood cells, white blood cells and platelets that in general do not require treatment. Severe anemia requires transfusions or hormone therapy to stimulate red blood cell production. If the number of white blood cells declines then a hormone identified as granulocyte-colony stimulating factor is used. No approved medication is yet available to increase the number of platelets. Patients suffering from spontaneous bacterial peritonitis usually undergo paracentesis. Several types of liver diseases are associated with increased risk of cancer especially hepatitis B and C and early liver transplant only can save the life of the patient. Cirrhosis is irreversible and in patients where all other possible ways fail to give the desired result, liver transplantation is the only hope. On an average about 80% of the patients who have undergone liver transplantation live for about five years after transplantation.

Research is going on to trace out the exact mechanism underlying scar formation and how it can be stopped and reversed. Better treatments are being searched for the viral liver diseases so the progression of liver cirrhosis may be stopped.