Cirrhosis and Related Liver Disorders

The liver is the largest gland and second largest organ in the human body. It is also the only internal organ capable of regeneration following injury. Located in the abdominal cavity, this reddish brown organ is divided into lobes of different size and shape. The liver plays a critical role in metabolism, digestion, elimination, and detoxification, among other processes. This organ performs a surprisingly large number of functions that influence virtually all other body systems. This is why diseases of the liver can be so devastating. One class of chronic diseases affecting the liver is cirrhosis. (Kasper, 2008) Cirrhosis is a condition in which normal liver cells are damaged and replaced by scar tissue. As the scar tissue accumulates, blood flow through the organ is obstructed which prevents the liver from functioning normally. Cirrhosis can be difficult to notice early because the preliminary stages rarely demonstrate any signs or symptoms. As liver function deteriorates, the effects of cirrhosis become evident. Complications include swelling of the legs and abdomen, weight loss, jaundice, bleeding from the gastrointestinal tract and intense inching. (Kasper, 2008) The most common causes of cirrhosis are hepatitis C, fatty liver, and alcohol abuse. Other causes include repeated bouts of heart failure, cystic fibrosis, antitrypsin deficiency, and Wilson’s disease. Once diagnosed, treatment depends on the cause of the disease and what complications are present. The main goal is to slow the advance of scar tissue and reduce the impact of secondary health problems. Diagnosis can be made by assessing certain risk factors like alcohol use and obesity in conjunction with blood test and imaging. A liver biopsy provides absolute confirmation but is not always needed, as will be elaborated later. If deemed necessary, the biopsy is usually performed with a needle inserted between the ribs or into a vein in the neck. The prognosis for cirrhosis can be dim because cirrhotic liver damage is permanent and irreversible. In some cases further damage can be prevented and treatment is usually successful in prolonging life. Most treatments are centered on simply preventing complications. The Child-Pugh score is a medical reference that asses the prognosis of liver disease and helps determine which types of treatments are necessary, including transplantation. To understand how cirrhosis affects liver function, it is worthwhile to consider the structure and physiology of this vital organ. The liver is located in the right superior portion of the abdominal cavity, directly under the diaphragm. It weighs approximately 1.2-1.5 kilograms in a healthy adult. The liver is divided into four lobes. The falciform ligament divides the liver into left and right halves. The right lobe is substantially larger than the left. The ligamentum venosum and the ligamentum teres create the caudate lobe and the quadrate lobe. (Kasper, 2008) The liver is an extremely vascular organ. The hepatic artery and the portal vein deliver the liver’s blood supply. Twenty five percent of this blood comes from the hepatic artery and is rich in oxygen. The remainder is carried by the portal vein. This blood is saturated with nutrients absorbed through the digestive tract. Merging into capillaries, the blood makes its way to the hepatocytes, the functional cellular unit of the liver. Blood leaves the liver via hepatic veins which eventually flow into the inferior vena cava. Approximately 90 liters of blood flow through the liver per hour. (Kasper, 2008) The liver’s excretory products flow through the spaces between hepatocytes call bile canaliculi. These join to form intra hepatic ducts which coalesce into the left and right hepatic ducts. The hepatic ducts lead to the common bile duct of the gallbladder. The gall bladder secretions are then expelled into the duodenum of the small intestinal. Hepatocytes make up about eighty percent of the liver. These cells perform most of the functions in the liver including protein synthesis, detoxification, and synthesis of bile. These cells are also responsible for the regenerative capabilities of the liver. Specialized macrophages, called Kupffer cells, also inhabit the liver. These cells are capable of filtering bacteria and toxins from the blood. Kupffer cell activation is also responsible for early alcohol induced liver injury. In a cirrhotic liver these cells are replaced by scar tissue. Some of the damaged cells in the liver continue to divide and form nodules. This restricts blood supply and greatly reduces liver function. (Kasper, 2008) The liver is essential to digestion and subsequent metabolic processes. It is a plays a large part in the processing of carbohydrates and lipids. As carbohydrates are absorbed in the small intestine, they are first brought to the liver via the portal vein. Depending on the needs of the body, the liver will either store excess glucose as glycogen or breakdown glycogen to release glucose into the bloodstream. Lipids are not soluble in water and cannot be efficiently absorbed without bile produced by the liver. Bile emulsifies fats and allows lipase, an essential protease produced by the pancreas, to effectively break down complex lipids for absorption. The liver also detoxifies the body by trapping toxins that have entered through digestion, the skin, or the respiratory system. The first way that the liver detoxifies the body is through filtering the blood. It removes viruses, bacteria, and poisons before they can become harmful. Next, the liver detoxifies the body by producing bile. Bile helps eliminate toxins by flushing them out through the colon. Lastly, the liver neutralizes toxins by changing them into water soluble substances so they can be expelled in the bile or urine. (Kasper, 2008) The liver also destroys old red blood cells and recycles the iron released. The red blood cells are first broken up into components by the spleen. It is then released from the spleen as unconjugated bilirubin into the blood, where it circulates while bound to albumin. The liver efficiently takes up bilirubin and chemically modifies it to conjugated, or water soluble, bilirubin that can be excreted into bile.

Figure 1. Healthy liver vs. liver undergoing cirrhosis

The buildup of scar tissue and subsequent damage to the liver is evident in Figure 1. The progression of this disorder can be divided into three main stages. In mild cirrhosis the liver cells are still capable of regenerating themselves and the liver can still function normally, while in end-stage cirrhosis the liver is covered in scar tissue and is no longer able to replace liver cells and can no longer function (Mayo Clinic, 2009). The scar tissue that cirrhosis causes blocks “the flow of blood through the liver and slows the processing of nutrients, hormones, drugs, and naturally produced toxins. It also slows the production of proteins and other substances made by the liver” (Mohan, 2008). Signs and symptoms of cirrhosis do not manifest themselves until there is extensive damage to the liver. Symptoms vary at different stages of the disease, symptoms include: fatigue, bleeding easily, easy bruising, fluid accumulation in your abdomen, loss of appetite, nausea, swelling of the lower extremities, yellowing of the skin and yellowing of the whites of the eyes, pruritis (an irritating skin rash), brownish or orange tint to the urine, light colored stool, confusion, disorientation, personality changes, blood in stool, fever, spiderlike blood vessels on the skin and weight loss (Mohan, 2008). There are a variety of causes that could lead to cirrhosis of the liver. The two most common causes in the United States are the virus hepatitis C and alcohol abuse. Non-alcoholic fatty liver disease is an “increasingly common liver disease is associated with obesity, diabetes, protein malnutrition, coronary artery disease, and corticosteroid medications” (Runyon, 2008). Cirrhosis can be caused by anything that damages the liver. Other than hepatitis C, hepatitis B and D can cause cirrhosis of the liver. Any blockage of the bile ducts causes a buildup of bile in the liver and leads to cirrhosis (Mohan, 2008). There are a number of inherited diseases that can cause cirrhosis; some diseases include “hemochromatosis, Wilson disease, galactosemia, and glycogen storage diseases are inherited diseases that interfere with how the liver produces, processes, and stores enzymes, proteins, metals, and other substances the body needs to function properly. Cirrhosis can result from these conditions” (Runyon, 2008). Complications in the liver continue to grow as the liver deteriorates and cirrhosis progresses. The complications of the liver caused by cirrhosis could cause the signs and symptoms to appear. Ascites, the swelling of the abdomen, and edema, the swelling of the legs, can occur due to the fluid buildup and collection. The easy bruising and bleeding is due to the fact the liver is no longer able to make the proteins necessary for blood clotting (Runyon, 2008). Cirrhosis causes scar tissue to build on the liver which can obstruct and slow the flow of blood causing portal hypertension. The hypertension can cause esophageal varices, enlarged blood vessels; gastropathy; splenomegaly, the enlargement of the spleen (Mohan, 2008). Since the liver functions such as removal of toxins is interrupted by the scar tissue, jaundice can occur because the liver is not filtering out bilirubin or hepatic encephalopathy can occur because the failing liver cannot remove the toxins from the blood which could eventually lead to a buildup of toxins in the brain. “Cirrhosis slows the liver’s ability to filter medications from the blood. When this occurs, medications act longer than expected and build up in the body. This causes a person to be more sensitive to medications and their side effects” (Runyon, 2008). Cirrhosis could also lead to increased risk for liver cancer, hepatocellular carcinoma. This form of liver cancer has a high mortality rate but there are treatments available for hepatocellular carcinoma (Mayo Clinic, 2009). Physicians are able to make a diagnosis of cirrhosis when distinct signs and symptoms are apparent during a physical examination, such as the enlargement of the spleen, specific skins changes (spidery veins with presence of rash, for example), and enlargement of the breast tissue in men. When cirrhosis is suspected, doctors will typically order a battery of blood tests to assess liver function and help determine possible causes of the damage. The first of these laboratory tests analyzes bilirubin levels. When performing this analysis in the lab, it is important that bilirubin samples be protected from hemolysis by avoiding light and heat and storing them in the dark at low temperatures. Increased levels of total bilirubin indicate possible cirrhosis, viral hepatitis, or infectious mononucleosis. In contrast, increased levels of conjugated bilirubin indicates impairment of excretory functions of the liver, such as blockage, which occurs in non-cirrhosis type liver disorders such as hepatobiliary disease, biliary tract obstruction, choledo-cholithiasis, cancer of the head of the pancreas, and Dubin-Johnson syndrome (Lee, 2009). Other initial tests include the measurement of albumin, whose levels fall as cirrhosis progresses since it is produced exclusively in the liver, and serum globulin levels, which increase due to bacterial antigens being directed away from the liver and to the lymphoid tissues. High levels of serum sodium, or hyponatremia, is also a common finding due to high levels of antidiuretic hormone (ADH) and aldosterone which inhibit the body’s ability to excrete water (Bishop, 2008). One other important test to assess the functioning of the liver is the prothrombin time, which tests for defects in the myriad of coagulation factors that are produced by the liver. In this test, a protein, thromboplastin, which converts prothrombin to thrombin, is added to a patient’s plasma along with other factors such as calcium chloride, and the time for clotting to take place is measured and compared to reference times (Lee, 2009) Other laboratory tests involving key enzymes are used to detect any inflammation in the liver. These tests include the following: The blood tests include: aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase, and gamma-glutamyl transpeptidase (GGT). Anytime the hepatocyte cell membrane becomes compromised, enzymes such as AST and ALT will find their way into the blood stream. Increased levels of AST, however, are also found in myocardial infarction, diseases affecting skeletal muscle, and renal infarction, among other diseases, since other forms of AST are found in the heart, muscle, and brain. Hence, a more important indicator is the ratio of AST to ALT, which is typically above two when the liver is in a damaged state. It is important to note, however, that ratios can greatly exceed two in acute conditions such as viral hepatitis, drug and toxin induced liver necrosis, and hepatic ischemia, and that sometimes cirrhosis patients will exhibit normal levels of these enzymes. LDH is another enzyme which is moderately elevated in cirrhosis, but is relatively non-specific—although some liver disorders such as biliary tract disease only produce slight elevations, which may help in making a differential diagnosis (Bishop, 2008). Increased ALP levels also are non-specific but can often indicate blockage of bile ducts. GGT correlates with ALP levels and is typically much higher in chronic liver disease caused by alchohol, but may also increase due to certain medications, such as dilantin and phenobarbital. Hence, although no individual enzyme test is an absolute indicator of cirrhosis, taken as a whole, these battery of tests can confirm liver inflammation, a hallmark of cirrhosis that is progressing. Once cirrhosis has been diagnosed, additional laboratory tests may be performed to help determine its cause. Ferritin and transferrin saturation tests are performed to determine iron overload, along with serum ceruloplasmin, to determine copper overload (such as in Wilson’s disease). Serology tests are performed to test for antibodies present against hepatitis B and hepatitis C to rule out viral causes, in conjunction with an antimitochondrial antibody test (AMA) which would indicate a primary biliary cirrhosis. Alpha 1-antitrypsin levels are also tested since deficiency in this enzyme by itself (usually, an inherited disorder) is sufficient to cause cirrhosis. Finally, a routine BAL (blood alcohol level) test, which often provides a first clue to alcohol abuse, can also be used as confirming evidence (Lee, 2009) Although the most confirmatory test for the presence of cirrhosis is a liver biopsy, as described earlier, one of the primary goals of these laboratory tests is to eliminate the invasiveness involved with a biopsy procedure, which also poses moderate risk to patients if, in fact, cirrhosis is present. To this end, a powerful, new diagnostic and prognostic biomarker test called FibroTest (marketed as FibroSure in the United States), was developed by BioPredictive just a few years ago. The test is comprised of six specific blood serum tests and generates a score that is related to the degree of fibrosis—the formation of fibrous, scar tissue which leads to cirrhosis—that is present. (Biopredictive) In addition to the types of tests already discussed, there are a number of other highly-effective, albeit more costly, tests available to detect and diagnose cirrhosis. First, in order to confirm and examine the extent of damage from cirrhosis, an endoscopy is sometimes performed. This procedure involves the insertion of an illuminated, flexible optical tube called an endoscope through the body, with the goal of examining the gastrointestinal tract for signs of varices which cause bleeding. An endoscopy could also reveal diseases of the bile ducts, which may be the root cause of the cirrhosis. A second type of test is ultrasound imaging, a non-invasive test which uses high-frequency sound waves to create precise images of structures within the body. Ultrasound can be used to screen for various causes of cirrhosis, such as hepatocellular carcinoma and portal hypertension (obstruction of blood flow through the portal vein). One of the latest incarnations of this technology is the FibroScan, which uses elastic waves to measure the stiffness of the liver.
In addition to ultrasound imaging, other tests may include CT (computed tomography) scans of the abdomen and MRI (magnetic resonance imaging) of both the liver and bile duct to evaluate such things as the presence (or absence) of tumors and blood flow through the liver.
Having discussed what cirrhosis is and how it is diagnosed, it would be appropriate to consider how it can be treated. Unfortunately, cirrhosis is generally irreversible; however, treatment for the disease consists of several goals. Management of cirrhosis involves treating the underlying causes of liver disease and also preventing further liver damage and complications (NLM).
Proper diagnosis of the underlying cause of cirrhosis is crucial to the treatment of the disease. For alcohol related cirrhosis the patient is strongly advised to stop drinking as it may cause further damage to the liver. A treatment plan for alcohol addiction is also usually provided for the patient. Management of hepatitis related cirrhosis depends on the type of hepatitis the patient has contracted. Viral hepatitis is treated through administration of interferons and anti-viral drugs. Auto-immune hepatitis treatment consists of corticosteroids and other drugs that suppress the immune system. In some extreme cases patients may not be able to tolerate treatments for the underlying causes because the cirrhosis is too advanced (Lee, 2009).
Management of the many complications that may arise with cirrhosis is also important in treatment for the disease. Build-up of fluid, as in ascites, is one of the most common complications of cirrhosis. There are several routes of treatment depending on the severity of the fluid build-up. In mild cases antibiotics and a diuretic medication, also known as “water pills”, can be prescribed. Also dietary salt restrictions may be implemented for the patient. Salt causes the further retention of fluids and therefore a low sodium diet may help to alleviate that concern. In major cases of ascites, fluid may be drained by insertion of a needle into the abdominal cavity, a procedure known as paracentesis. Surgery may also be performed to help relieve pressure from severe build-up (Lee, 2009).
Another complication with cirrhosis is esophageal varices, as mentioned earlier. These particular varices are extremely dilated sub-mucosal veins in the esophagus. If endoscopy reveals their presence, medication may be prescribed to reduce the patient’s blood pressure. Banding therapy may also be done in which elastic bands are inserted to tie off the blood vessel and constrict them. The varices can become problematic if they begin to rupture and bleed and therefore immediate hospitalization and emergency treatment would be needed (MFMER).
Another abnormality seen with cirrhosis is hepatic encephalopathy. It develops as a result of toxic substances accumulating in the liver which can no longer be removed by the organ because of the cirrhosis. These toxins affect brain cells and can result in a change in cognitive function, a flapping tremor known as asterixis, and even a loss of consciousness and death. There are several modes of treatment for hepatic encephalopathy. Excess protein intake leads to increased ammonia production which can adversely affect an individual with liver disease and hepatic encephalopathy. Therefore the patient may be advised to reduce their dietary protein intake. This is observed very carefully because it may lead to malnutrition which is very common in patients with cirrhosis. Lactulose may also be prescribed. It causes diarrhea, which lessens the chance intestinal bacteria can metabolize protein into ammonia. Antibiotics may also be prescribed which can kill bacteria in the bowel also stopping them from turning protein into ammonia (Lee, 2009). Infections are also a prominent cause of illness in individuals with cirrhosis. In these circumstances the physician may advise the patient to update their vaccinations for influenza and pneumonia. They may also recommend the individual gets tested and vaccinated for hepatitis A and B. Oral or intravenous antibiotics may also be administered (MFMER). Since hepatocellular carcinoma, a potential consequence of cirrhosis, has a very high mortality rate, treatment depends on early detection. This presents a problem to patients of liver cancer because there are very few symptoms early on. When it is diagnosed early an aggressive approach to surgery or liver transplantation may be performed to treat the cancer. Liver transplantation is only considered for individuals in which there is severe liver damage or when complications can no longer be controlled. This procedure consists of surgery in which the diseased liver is replaced with a healthy liver from an organ donor. This is accompanied by life-long anti-rejection medication for the patient (NIDDK).
Prevention techniques are important for individuals with cirrhosis and those at risk. Alcohol consumption is a major contributing factor to cirrhosis and therefore prevention involves drinking in moderation. Individuals with cirrhosis should eliminate alcohol consumption altogether as it can cause further damage. Certain drugs should also be avoided such as aspirin and also other non-steroidal anti-inflammatory medications. A healthy diet and exercise are also helpful as obesity may also be a contributing factor to cirrhosis. These important methods of prevention may help individuals from developing cirrhosis (NIDDK).

References

Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. (2008). Harrison's principles of internal medicine (17th ed.). New York: McGraw-Hill Medical Publishing Division

Bishop, M. L., Fody, E.P., Schoeff, L. E., (2009) Clinical Chemistry: techniques, principles, correlations . Wolters Kluwer-Lippincott Williams & Wilkins, Baltimore, MD.Mohan,

Venkat. (2008). Cirrhosis of the liver. Digestive Disorders Health Center, Retrieved from http://www.webmd.com/digestive-disorders/cirrhosis-liver

Runyon, Bruce A. (2008). Cirrhosis. National Digestive Diseases Information Clearinghouse,
Retrieved from http://digestive.niddk.nih.gov/ddiseases/pubs/cirrhosis/

Mayo Clinic Staff, Initials. (2009, January 23). Cirrhosis. Retrieved from http://www.mayoclinic.com/health/cirrhosis/DS00373 “Cirrhosis.” National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 2008. National Institutes of Health (NIH). 5 Dec. 2009. http://digestive.niddk.nih.gov/ddiseases/pubs/cirrhosis/.

Lee, Dennis. “Cirrhosis of the Liver.” 2009. MedicineNet.com. 5 Dec. 2009. http://www.medicinenet.com/cirrhosis/article.htm.

“Cirrhosis.” Mayo Clinic. 2009 Mayo Foundation for Medical Education and Research (MFMER).5 Dec. 2009. http://www.mayoclinic.com/health/cirrhosis/DS00373.

“Cirrhosis.” Medline Plus. 2009. National Library of Medicine (NLM). 5 Dec. 2009. http://www.nlm.nih.gov/medlineplus/cirrhosis.html. “Biopredictive”. http://www.biopredictive.com/us?set_language=en&cl=en