is a consequence of chronic liver
disease characterized by replacement of liver tissue by fibrosis , scar tissue and regenerative nodules (lumps that occur as a result of a process in which damaged tissue is regenerated), leading to loss of liver function.
After heart disease
, cirrhosis is the third most common cause of death in people aged 45-65 years.
This peculiar transformation of the liver was identified by the first anatomic pathologist, Gianbattista Morgagni
in his 500 autopsies published in 1761 but the name of "cirrhosis" (greek=orange color) was given by Laennec
in 1826 because of the yellowish-tan color of the cirrhotic liver. Only in 1930, one hundred years later, however, the first theory as to the pathogenesis of this disorder was advanced by Roessle
: parenchymal degeneration, regeneration and scarring which is now understood according to the following sequence:
- FORMATION OF FIBRO-VASCULAR MEMBRANES
- DISSECTION INTO NODULES
- REARRANGEMENT OF BLOOD CIRCULATION
which is considered by most experts as a self-perpetuating irreversible process
The definition of cirrhosis remains morphological, described by a working party for the World Health Organization (WHO) in 1978 as: “ a diffuse process characterized by fibrosis and the conversion of normal liver architectures into structurally abnormal nodules ”.
Cirrhosis is scarring of the liver and poor liver function. It is the final phase of chronic liver disease, October 2011
Classification of cirrhosis
According to World Health Organization
1) MORPHOLOGIC: Macronodular Micronodular Mixed
MICRONDULAR CIRRHOSIS: Small rather uniform 2cm nodules seperated by thin fibroussepta usually due to a chemicalagent as alcohol which diffuseuniformly throught the liver.
MACRONODULAR CIRRHOSIS: Larger nodules separated by wider scars and irregularly distributed throughout the liver usually due to an infectious agent such as viral hepatitis which does not diffuse uniformly throughout the liver.
Nodular regenerative hyperplasia: Evolving concepts on underdiagnosed cause of portal hypertension,World J Gastroenterol. 2011 March 21
- these occur in micro and macro nodular cirrhosis.
- they arise in the midst of scars favored by the rich arterial blood of scar tissue.
- they are round nodules with a fibrous pseudocapsule with bile ductules due to
obstruction of bile flow.
- they have embryonal type of cell plates, two cells thick, "twinning of cell plates".
- nuclei are aligned at the sinusoidal pole of the plates.
- they often show focal cholestasis.
- they may undergo dysplastic and malignant changes.
- they compress the vessels of the capsule contributing to the perpetuation of the
2) ETIOLOGIC AGENTS :
Chronic alcoholism particularly endangers the liver by causing alcoholic liver disease (also called alcohol-induced liver disease). Alcoholic liver disease includes fatty liver (build-up of fat cells in the liver), alcoholic hepatitis (inflammation of the liver caused by chronic drinking), and alcoholic cirrhosis. Alcoholic cirrhosis is the primary type of cirrhosis in the U.S. It develops in 10 - 20% of heavy drinkers, usually after 10 - 15 years of heavy alcohol consumption. People who drink heavily and who also have hepatitis C are at particular risk of developing cirrhosis. In the liver, alcohol converts to toxic chemicals that trigger inflammation and tissue injury, which lead to cirrhosis.
Chronic Hepatitis Chronic hepatitis, both hepatitis B and hepatitis C, is another primary cause of cirrhosis. Chronic hepatitis C is a more common cause of cirrhosis in developed countries, while hepatitis B is a more common cause of cirrhosis worldwide, especially in sub-Saharan Africa and parts of Asia. People with chronic hepatitis B who are co-infected with hepatitis D are especially at risk for cirrhosis. The longer a patient has had chronic hepatitis, the greater the risk for eventually developing cirrhosis. The hepatitis virus can produce inflammation in liver cells, causing injury or destruction. If the condition is severe enough, the cell damage becomes progressive, building a layer of scar tissue over the liver. In advanced cases, as with alcoholic cirrhosis, the liver shrivels in size, a condition called postnecrotic or posthepatic cirrhosis.
Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets,Gastroenterology. 2011 November
Bile Ducts Disorders
Autoimmune hepatitis, like other autoimmune disorders, develops when a misdirected immune system attacks the body's own cells and organs. People who have autoimmune hepatitis also often have other autoimmune conditions, including systemic lupus erythematosus, rheumatoid arthritis, Sjgren syndrome, scleroderma, inflammatory bowel disease, glomerulonephritis, and hemolytic anemia. Autoimmune hepatitis typically occurs in women ages 15 - 40.
Hepatocellular carcinoma in patients with autoimmune hepatitis,World J Gastroenterol. 2009 February 7
Disorders that block or damage the bile ducts can cause bile to back up in the liver, leading to inflammation and cirrhosis. These diseases include primary biliary cirrhosis and primary sclerosing chlorangitis.
- Primary Biliary Cirrhosis. Up to 95% of primary biliary cirrhosis (PBC) cases occur in women, usually around age 50. In people with PBC, the immune system attacks and destroys cells in the livers bile ducts. Like many autoimmune disorders, the causes of PBC are unknown.
- Primary sclerosing cholangitis (PSC) is a chronic disease that mostly affects men, usually around age 40. The cause is unknown, but immune system defects, genetics, and infections may play a role.
Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)
Nonalcoholic fatty liver disease (NAFLD) resembles alcoholic liver disease, but it occurs in people who do not drink a lot of alcohol. Obesity and type 2 diabetes are the two main causes of a fatty liver. Some evidence suggests that insulin resistance (the primary problem in type 2 diabetes) is a major factor in development of a fatty liver. A diet high in fatty foods may also be a risk factor, as dietary fat accumulates in the liver. Due to the recent rise in childhood obesity, NAFLD is increasingly occurring in children. In fact, NAFLD is now the most common liver disease in American children. Nonalcoholic fatty liver disease is usually benign and very slowly progressive. But, in certain patients, it can lead to cirrhosis, liver failure, or liver cancer. About 8 - 20% of people with nonalcoholic steatohepatitis go on to develop cirrhosis.
Nonalcoholic fatty liver disease and the metabolic syndrome: clinical implications and treatment,Nutr Clin Pract. 2013 Feb
- Hemochromatosis is a disorder of iron metabolism. This disease interferes with the way the body normally handles iron. People with hemochromatosis absorb too much iron from the food that they eat. The iron overload accumulates in organs in the body. When excess iron deposits accumulate in the liver, they can cause cirrhosis.
- Wilsons disease (which causes an accumulation of copper in the body), alpha-1 antitrypsin deficiency (a genetic disorder caused by defective production of a particular enzyme).
- Glycogen storage diseases (a group of disorders that cause abnormal amounts of glycogen to be stored in the liver).
- Alpha 1-antitrypsin deficiency (A1AD). Autosomal recessive disorder. Patients may also have COPD, especially if they have a history of tobacco smoking . Serum AAT levels are low. Recombinant AAT is used to prevent lung disease due to AAT deficiency.
- Lysosomal acid lipase deficiency (LAL Deficiency) is a rare autosomal recessive genetic condition and is characterized by hepatomegaly, persistently abnormal LFTs and type II hyperlipidemia. Splenomegaly and evidence of mild hypersplenism may affect some patients. Untreated, LAL Deficiency may lead to fibrosis, cirrhosis, liver failure and death.
Cardiac cirrhosis Due to chronic right sided heart failure which leads to liver congestion.
Glycogen storage disease type IV
Hepatotoxic drugs or toxins
The liver plays a vital role in synthesis of proteins (e.g., albumin, clotting factors and complement), detoxification and storage (e.g., vitamin A). In addition, it participates in the metabolism of lipids and carbohydrates.
Cirrhosis is often preceded by hepatitis and fatty liver (**steatosis**), independent of the cause. If the cause is removed at this stage, the changes are still fully reversible.
The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, blocking the portal flow of blood through the organ and disturbing normal function. Recent research shows the pivotal role of the stellate cell, a cell type that normally stores vitamin A, in the development of cirrhosis. Damage to the hepatic parenchyma leads to activation of the stellate cell, which becomes contractile (called myofibroblast) and obstructs blood flow in the circulation. In addition, it secretes TGF-β, which leads to a fibrotic response and proliferation of connective tissue. Furthermore, it secretes TIMP 1 and 2, naturally occurring inhibitors of matrix metalloproteinases, which prevents them from breaking down fibrotic material in the extracellular matrix.
The fibrous tissue bands (septa) separate hepatocyte nodules, which eventually replace the entire liver architecture, leading to decreased blood flow throughout. The spleen becomes congested, which leads to hypersplenism and increased sequestration of platelets. Portal hypertension is responsible for most severe complications of cirrhosis.
The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma
Cirrhosis can cause many serious complications including:
Portal hypertention is a state in which the pressure within the hepatic portal vein is increased, causing enlargement of the spleen, enlargement of the veins in the oesophagus (gullet) (which may rupture to cause severe bleeding), and accumulation of fluid in the peritoneal cavity (ascites). The commonest cause is cirrhosis, but other diseases of the liver or thrombosis of the portal vein can also produce it.
Treatment is :
-by diuretic drugs
-by surgery to join the portal vein to the inferior vena cava (bypassing the liver)
-implanting a stent within the liver to join portal tract veins to a hepatic vein tributary ( TIPS – transjugular intrahepatic porto-systemic shunt)
Treatment of portal hypertension,World J Gastroenterol. 2012 March 21
Transjugular Intrahepatic Portosystemic Shunt (TIPS),ACR(American College of Radiology
Ascites is fluid buildup in the abdominal cavity. It is uncomfortable and can impair breathing and other functions. Ascites is caused by a combination of portal hypertension (high pressure in the blood vessels of the liver) and low albumin levels. Albumin is a protein produced by the liver. Although ascites itself is not fatal, it is a marker for severe progression.
Guidelines on the management of ascites in cirrhosis
Hepatorenal syndrome occurs if the kidneys drastically reduce their own blood flow in response to the altered blood flow in the liver. It is a life-threatening complication of late-stage liver disease that occurs in patients with ascites. Symptoms include dark colored urine and a reduction in volume, yellowish skin, abdominal swelling, mental changes (such as delirium and confusion), jerking or coarse muscle movement, nausea, and vomiting.
Clinical Guidelines for the management of Hepatorenal syndrome
Variceal Bleeding one of the most serious consequences of portal hypertension is the development of varices, veins that enlarge to provide an alternative pathway for blood diverted from the liver. In most patients, they form in the esophagus. They can also form in the upper stomach. Varices pose a high risk for rupture and bleeding because they are thin-walled, twisted, and subject to high pressure. Variceal intestinal bleeding is a life-threatening event. Symptoms include vomiting blood or black and tarry stools.
UK guidelines on the management of variceal haemorrhage in cirrhotic patients,Gut 2000
Spontaneous bacterial peritonitis is a life-threatening bacterial infection of the ascitic fluid.The main symptoms include confusion and altered mental status, fever, chills, and abdominal pain.
Hepatic Encephalopathy. Mental impairment is a common event in advanced cirrhosis. In severe cases, the disease causes encephalopathy (impaired brain function), with mental symptoms that range from confusion to coma and death. Hepatic encephalopathy is caused by a buildup in the blood of harmful intestinal toxins, particularly ammonia, which then accumulate in the brain. Encephalopathy can be triggered by many different conditions including internal bleeding, infection, constipation, and dehydration.Early symptoms of hepatic encephalopathy include forgetfulness, unresponsiveness, and trouble concentrating. Sudden changes in the patient's mental state, including agitation or confusion, may indicate an emergency condition. Other symptoms include bad fruity-smelling breath and tremor. Late-stage symptoms of encephalopathy are stupor and eventually coma.
PRACTICE GUIDELINES Hepatic Encephalopathy,THE AMERICAN JOURNAL OF GASTROENTEROLOGY
Liver Cancer. People with cirrhosis have an increased risk for hepatocellular carcinoma, a type of liver cancer. Hepatitis B and C, alcoholism, hemochromatosis, and primary biliary cirrhosis -- all causes of cirrhosis -- are some of the major risk factors for liver cancer. Cirrhosis due to hepatitis C is the leading cause of hepatocellular carcinoma, while cirrhosis due to hepatitis B is the leading cause of deaths related to liver cancer
Kidney Failure. Portal hypertension can cause several secondary complications, including kidney failure (severe cirrhosis )
Chronic Ingestion of Ethanol Induces Hepatocellular Carcinoma in Mice Without Additional Hepatic Insult,Nutr Clin Pract. 2013 Feb
Osteoporosis. Many patients with cirrhosis develop osteoporosis, a bone-thinning disease.
THE CHILD-PUGH CLASSIFICATION SYSTEM
The Child-Pugh classification is a scoring system used to determine the prognosis with cirrhosis.
Scoring is based upon several factors: albumin, ascites, total bilirubin, prothrombin time, and encephalopathy, as follows:
>3 means higher than 3
<3 means lower than 3
The three classes and their scores are:
**Class A** is score 5 - 6
**Class B** is score 7 - 9
**Class C** is score >9
Patients with a score of 10 or more (in the Class C category) have a prognosis with 1-year survival being about 50%. Patients with Class A or B have a better prognosis of 5-years, with a survival rate of 70%- 80%.
Additional poor prognistic indices include refractory ascites, albumin < 3.2 gm/l, and a recent episode of SBP (spontaneous bacterial peritonitis). All individually are associated with a one-year survival of 50% or less.
Improvement of prognostic power of the Child-Pugh classification of liver cirrhosis by hyaluronan,J Hepatol. 2003 Dec.