What Goes Wrong in the Liver with Cirrhosis?

What is Cirrhosis?
Cirrhosis is scarring of the liver.

Widespread nodules in the liver combined with fibrosis characterize cirrhosis anatomically. The fibrosis and nodule formation causes distortion of the normal liver architecture, which interferes with blood flow through the liver. Cirrhosis can also lead to an inability of the liver to perform its biochemical functions. To understand the pathophysiology of cirrhosis, the normal anatomy and physiology of the liver must first be briefly reviewed.

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Liver Blood Flow

Oxygenated blood that has returned from the lungs to the left ventricle of the heart is pumped to all of the tissues of the body. This is called the systemic circulation.

After reaching the tissues, blood is returned to the right side of the heart, from where it is pumped to the lungs and then returned to the left side of the heart after taking up oxygen and giving off carbon dioxide. This is called the pulmonary circulation.

Blood from the large and small intestines and spleen flow to and through the liver before returning to the right side of the heart. This is called the portal circulation and the large vein through which blood is brought to the liver is called the portal vein.

After passing through the liver, blood flows into the hepatic vein, which leads into the inferior vena cava to the right side of the heart. The liver also receives some blood directly from the heart via the hepatic artery. In the esophagus, stomach, small intestine and rectum, the portal circulation and veins of the systemic circulation are connected. Under normal conditions, there is little to no back flow from the portal circulation into the systemic circulation.

Bilirubin Secretion

The liver is the site of bile formation. Bile contains bile salts, fatty acids, cholesterol, bilirubin and other compounds. The components of bile are synthesized and modified in hepatocytes (the predominant cell type in the liver) and secreted into small bile ducts within the liver itself. These small bile ducts form a branching network of progressively larger ducts that ultimately become the common bile duct that takes bile to the small intestine. Bilirubin is a yellow pigment that derives primarily from old red blood cells. Bilirubin is taken up by hepatocytes from the blood, modified in the hepatocytes to a water-soluble form and secreted into the bile.

Biochemical Functions

The liver performs many biochemical functions-over 200 in all. Blood clotting factors are synthesized in the liver. Albumin, the major protein in the blood, is also synthesized in and secreted from the liver. The modification and/or synthesis of bile components also take place in the liver. Many of the body’s metabolic functions occur primarily in the liver including the metabolism of cholesterol and the conversion of proteins and fats into glucose. The liver is also where most drugs and toxins, including alcohol, are metabolized.

What Goes Wrong in the Liver with Cirrhosis?

Cirrhosis results from damage to liver cells from toxins, inflammation, metabolic derangements and other causes. Damaged and dead liver cells are replaced by fibrous tissue, which leads to fibrosis (scarring). Liver cells regenerate in an abnormal pattern primarily forming nodules that are surrounded by fibrous tissue. Grossly abnormal liver architecture eventually ensues that can lead to decreased blood flow to and through the liver. Decreased blood flow to the liver and blood back up in the portal vein and portal circulation leads to someof the serious complications of cirrhosis. Blood can back up in the spleen causing it to enlarge and sequester blood cells. Most often, the platelet count falls because of splenic sequestration. The low platelet count seen in cirrhosis is due to trapping in the spleen, not due to a primary problem with production in the bone marrow. If the pressure in the portal circulation increases because of cirrhosis and blood back up (note: this can also sometimes occur in severe cases of acute hepatitis and liver damage), blood can flow backwards from the portal circulation to the systemic circulation where they are connected. This can lead to varicose veins in the stomach and esophagus (gastric and esophageal varices) and rectum hemorrhoids or rectal varicies). Gastric and esophageal varices can rupture, bleed massively and even cause death. Hypertension in the portal circulation, along with other hormonal, metabolic and kidney abnormalities in cirrhosis, can also lead to fluid accumulation the abdomen (ascites) and the peripheral tissue (peripheral edema).

Decreased bilirubin secretion from hepatocytes in cirrhosis leads to the back up of bilirubin in the blood. This leads to jaundice, the yellow discoloration of the skin and eyes. As the water-soluble form of bilirubin also backs up in the blood, bilirubin can also spill into the urine giving it a bright yellow to dark brown color.

Abnormal biochemical function of the liver in cirrhosis can lead to several complications.
The serum albumin concentration falls, which can lead to aggravation of ascites and edema. The metabolism of drugs can change requiring dose adjustments. In men, breast enlargement (gynecomastia) sometimes occurs because metabolism of estrogen in the liver is decreased. Sexual function in men will also become abnormal. Decreased production of blood clotting factors can lead to bleeding complications. Derangements in the metabolism of triglycerides, cholesterol and sugar can occur. In earlier stages, cirrhosis frequently can cause insulin resistance and diabetes mellitus. In later stages or in severe liver failure, blood glucose may be low because it cannot be synthesized from fats or proteins. Cirrhosis, especially in advanced cases, can cause profound abnormalities in the brain.

In cirrhosis, some blood leaving the gut bypasses the liver as blood flow through the liver is decreased. Metabolism of components absorbed in the gut can also be decreased as liver cell function deteriorates. Both of these derangements can lead to hepatic encephalopathy as toxic metabolites, normally removed from the blood by the liver, can reach the brain. In its early stages, subtle mental changes such as poor concentration or the inability to construct simple objects occurs. In severe cases, hepatic encephalopathy can lead to stupor, coma, brain swelling and death.

Cirrhosis of the liver can also cause abnormalities in other organ systems. Cirrhosis can lead to immune system dysfunction causing an increased risk of infection. Ascites fluid in the abdomen often becomes infected with bacteria normally present in the gut (spontaneous bacterial peritonitis). Cirrhosis can also lead to kidney dysfunction and failure. In end-stage cirrhosis, a type of kidney dysfunction called hepatorenal syndrome can occur. Hepatorenal syndrome is almost always fatal unless liver transplantation is performed.

Clinical Symptoms and Diagnosis of Cirrhosis

Cirrhosis is usually an easy diagnosis to make when any or all of the above abnormalities and complications are present. This is especially true when the underlying liver disease can be identified. The underlying liver disease is identified in most patients, however, sometimes it will not be discovered. Such cases are called “cryptogenic” cirrhosis. Sometimes, other conditions such as metastatic cancer, hepatic or portal vein thrombosis, severe acute hepatitis or acute bile duct obstruction can cause some of the abnormalities seen in cirrhosis. A careful history combined with special diagnostic tests will usually identify these conditions. I rare cases, despite having cirrhosis of the liver, patients may still have very few, vague complaints. Some patients, especially early in the course of the disease, will have no overt clinical signs or symptoms. Some may have only subtle physical changes such as red palms, red spots that blanch on their upper body (spider angiomata), enlargement of the parotid glands in the face, gynecomastia, or fibrosis of tendons in the palms. Some patients may only have subtle abnormalities on blood tests, and in some cases, all blood tests may be normal. Radiological tests may give clues as to the presence of cirrhosis, but the diagnosis of cirrhosis must often be made by liver biopsy.

Causes of Cirrhosis

There is a general misunderstanding that alcohol is the sole cause of cirrhosis. Alcohol accounts for approximately 50% of the cases of cirrhosis. Almost any chronic liver disease can lead to cirrhosis.

This list gives some of the many causes:

Alcoholic liver disease – most common cause in the U. S. A.Chronic viral hepatitis B, C and D Chronic autoimmune hepatitis Inherited metabolic diseases (e. g. hemochromatosis, Wilson disease)Chronic bile duct diseases (e. g. primary biliary cirrhosis)Chronic congestive heart failureParasitic infections (e. g. schistosomiasis) Nonalcoholic steatohepatitis (liver inflammation that can be caused by fatty liver) Long term exposure to toxins or drugs

Treatment

Cirrhosis of the liver is irreversible but treatment of the underlying liver disease may slow or stop the progression. Such treatment depends upon the underlying etiology. Termination of alcohol intake will stop the progression in alcoholic cirrhosis and for this reason, it is important to make the diagnosis early in a chronic alcohol abuser. Similarly, discontinuation of a hepatotoxic drug or removal of an environmental toxin will stop progression. Treatments of metabolic diseases, such as treatment of iron overload in hemochromatosis or copper overload in Wilson disease, are also effective therapies. Chronic viral hepatitis B and C may respond to treatment with interferon and autoimmune hepatitis may improve with prednisone and azathioprine (Imuran). Drugs such as ursodiol (Actigall) may slow the progression of primary biliary cirrhosis and possibly sclerosing cholangitis.

In patients with cirrhosis of the liver, treatment must also be directed at the complications. Bleeding esophageal varices can be treated with endoscopic sclerotherapy or rubber band ligation (banding). Ascites and edema are often responsive to a low sodium diet and such a diet must be emphasized in patients with these symptoms. More advanced ascites and edema can respond to diuretic therapy. A low protein diet and agents such as lactulose may help hepatic encephalopathy. Infections such as spontaneous bacterial peritonitis must be rapidly treated with appropriate antibiotics. Drugs metabolized in the liver must be given with caution. Coagulation/clotting disorders will sometimes respond to vitamin K.

Liver transplantation is an effective for the treatment of end-stage cirrhosis in the proper setting. Transplantation is usually needed when complications such as encephalopathy, ascites or bleeding varices are uncontrollable or when biochemical function is severely depressed. In patients with primary biliary cirrhosis, a rising bilirubin indicates a poor prognosis and such patients should be considered for transplantation as the serum bilirubin concentration begins to rise. Active drug or alcohol abuses are contraindications to liver transplantation. However, alcoholics who have abstained from drinking for an extended period of time (usually more than six months), and have participated in rehabilitation programs and support groups such as Alcoholics Anonymous, can be considered as candidates and will often have a good prognosis. Liver cancer needs to be evaluated on a case-by-case basis. In many cases, it is a contraindication to transplantation. Liver transplantation is usually not performed in patients more than 70 years old.

How are complications of cirrhosis treated?

The abnormal accumulation of fluid may cause swelling of the ankles (edema) and abdomen (ascites). Therefore, patients should reduce the amount of fluid and salt in their diet or use drugs call diuretics that mobilize and excrete the excess fluid through the kidneys. Usually, you’ll be instructed to limit you daily sodium (salt) intake to 2,000 mg of sodium/day or less.

Occasionally, the ascites may become infected, a condition known as Spontaneous Bacterial Peritonitis, and require treatment with antibiotics. This complication is associated with increased complications, and an increased risk of premature death. Liver transplantation needs to be considered at this time should peritonitis develop.

When the liver does not efficiently function to cleanse the body of toxins and drugs, the mental state of patients may change dramatically and lead to coma, called Hepatic Encephalopathy. Treatment is directed at reducing the protein in the diet, avoiding sedatives and pain medications, and using laxatives and/or antibiotics to decrease absorption of toxins from the intestines. Sometimes, bleeding from the esophagus or stomach caused by abnormal veins (varices) may occur and is a life-threatening emergency requiring hospitalization. Variceal bleeding can usually be controlled with the use of a flexible tube (endoscope) that is inserted through the mouth into the esophagus and stomach and used to inject clotting agents into the veins or to rubber band ligate the varices.

Liver failure refers to end stage of liver disease and cirrhosis when the liver stops working and cannot support life. Liver failure is difficult to treat and survival is limited. Therefore, patients with any complication of cirrhosis are considered to be at risk of developing liver failure.When complications develop, it may be possible to manage them, though more complications are likely to develop. At this time, liver transplantation should be considered

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