The early stages of cirrhosis often produce no symptoms. As scar tissue replaces healthy cells, the liver begins to fail and symptoms may become evident. The severity of symptoms depends on the extent of liver damage.

Because the liver is crucial for so many metabolic activities, cirrhosis impacts a wide range of the bodies functions, including nutrient and hormone metabolism, blood clotting, and processing of ammonia and other toxic wastes. Many of the symptoms of cirrhosis are directly related to disruption of these functions. However, most of these symptoms can also be caused by other conditions, so it is important to consult with your health care provider if you experience any of these symptoms, particularly if you have risk factors that increase your likelihood of developing cirrhosis.

Early symptoms of cirrhosis include:

Fatigue and weakness “ related to anemia and altered nutrient metabolism
Poor appetite
Nausea
Weight loss
In men:
- Impotence
- Reduced testicle size
- Enlarged, tender breasts
- Loss of interest in sex “ due to altered liver metabolism of sex hormones
Small, red spider-like blood vessels under the skin “ caused by increased pressure in the tiny blood vessels due to liver congestion
Increased sensitivity to drugs “ due to reduced ability of the liver to inactivate them

Symptoms become more pronounced as cirrhosis progresses. In addition, complications may develop that produce other, frequently life-threatening, symptoms of the disease.

Later symptoms, some of which are due to complications, include:

Reddened or blotchy palms
Loss of body hair
Sleep disturbances
Insulin resistance
Ulcers
Fever and other signs of infection “ due to altered immune function
Gallstones “ if cirrhosis prevents bile from reaching the gallbladder
Pale or clay-colored stools “ caused by a reduction in excreted bile pigments
Frequent nosebleeds, skin bruising or bleeding gums “ resulting from decreased liver synthesis of clotting factors
Ascites “ water retention and swelling in the legs and abdomen caused by obstructed blood flow through the liver and reduced synthesis of the protein albumin
Bacterial peritonitis “ infection of ascites causing abdominal pain and fever
Itching “ caused by deposition of bile products in the skin
Jaundice “ yellowing of the skin or eyes due to build-up of bile pigments (bilirubin)
Vomiting blood “ due to swollen veins in the esophagus that burst
Encephalopathy and coma “ mental changes, including forgetfulness, trouble concentrating, confusion, and agitation, caused by the build-up of ammonia in the blood
Decreased urine output and dark urine “ caused by kidney dysfunction or failure
Liver cancer

Etiology of Cirrhosis

Cirrhosis of the liver is a chronic, diffuse (widely spread throughout the organ), degenerative disease in which the parenchyma (the functional organ tissue) deteriorates; the lobules are infiltrated with fat and structurally altered; dense perilobular connective tissue forms; and often areas of regeneration develop. The surviving cells multiply in an attempt to regenerate and form "islands" of living cells that are separated by scar tissue. These islands of living cells have a reduced blood supply, resulting in impaired liver function. As the cirrhotic process continues, blood flow through the liver becomes blocked; portal hypertension may occur (high blood pressure in the veins connecting the liver with the intestines and spleen); glucose and vitamin absorption decrease; the manufacturing of hormones and stomach and bowel function are affected; and noticeable facial veins may appear. Most patients die from cirrhosis in the fifth or sixth decade of life (Wolf 2001).

Approximately one-third of cirrhosis cases are "compensated," meaning there are no clinical symptoms. Compensated cases are usually discovered during routine tests for other problems or during surgery or autopsy. Cirrhosis is irreversible. Unless the underlying cause of cirrhosis is removed and the person takes measures to treat the condition, the liver will continue to incur damage, eventually leading to liver failure, ammonia toxicity, gastrointestinal hemorrhage, kidney failure, hepatic coma, and death. For some people, the only chance for a long-term cure is a liver transplant.

According the Centers for Disease Control (CDC), in the year 2000, preliminary data compiled by the Division of Vital Statistics revealed that even though cause of death from cirrhosis and chronic liver disease had fallen a rank from 7th to 12th, the number of people who died from liver disease was 26,219, almost the same as when cirrhosis was ranked 7th (Minino et al. 2001).

In cirrhosis, healthy, functioning liver cells are destroyed, and scarring and distortion of the liver eventually takes place. As fewer liver cells function, smaller amounts of albumin (a protein) are manufactured. Lower albumin levels facilitate water retention (edema) in the legs and abdomen (ascites). Excessive bile product deposits cause intense skin itching, often accompanied by jaundice (yellowed skin). Other symptoms are testicular atrophy (Swelling of Testicles) , gynecomastia (enlargement of the male breast), and loss of chest and armpit hair.

Psychotic mental changes such as extreme paranoia can also occur in cases of advanced cirrhosis.

Systemic Complications from Cirrhosis

In the cirrhotic liver, when blood flow is restricted, blood can back up in the spleen, causing an enlarged spleen and sequestered blood cells. In this situation, the platelet count typically falls and abnormal bleeding results. In extreme cases, blood actually flows backward from the portal circulation to systemic circulation. In addition to esophageal varices, varicose veins can develop in the stomach (gastric varices) and rectum (hemorrhoids). Ruptured varices cause massive bleeding and are often fatal. Bilirubin levels may also build up in the blood, causing jaundice and bright yellow to dark brown urine. Additionally, insulin resistance and diabetes mellitus, kidney dysfunction, and congestive heart failure, as well as osteomalacia (the adult form of rickets, resulting in bone softening that often leaves them brittle) and osteoporosis (reduction in bone mass) are associated with cirrhosis (NIDDK 2000).

If cirrhosis prevents bile, a green-brown fluid that is produced by the liver, from reaching the gallbladder, a person may develop gallstones (NIDDK 2000). It is then secreted through tiny channels within the liver into a duct to the gallbladder. Bile is stored in the gallbladder until it is needed for digestion of fats. Most gallstones are formed from cholesterol. If the liver is healthy, the bile contains the proper constituents to dissolve cholesterol excreted by the liver, but in a cirrhotic liver, the bile cannot adequately dissolve cholesterol. The cholesterol then forms crystals, which settle to the bottom of the gallbladder and eventually become stones (ALF 2002; MFMER 2002; WebMD 2002).

A cross-sectional study was conducted in 1010 patients with cirrhosis related to alcohol abuse, chronic viral infection, or miscellaneous causes (42%, 48%, and 10%, respectively). Gallstone development was monitored by ultrasound in 618 patients who were free of gallstones at enrollment. The overall prevalence of gallstones was 29.5% and increased significantly with age without differences according to sex or cause of cirrhosis. During a mean ± SD follow-up of 50 months ± 9 months, 141 (22.8%) of 618 patients developed gallstones, with an estimated cumulative probability of 6.5%, 18.6%, 28.2%, and 40.9% at 2, 4, 6, and 8 years, respectively. Multivariate analysis showed that degree of cirrhosis and high body mass index carried a significantly greater risk of gallstone formation, leading the researchers to conclude: "Cirrhosis per se represents a major risk factor for gallstones whose prevalence and incidence were far higher than those reported in a general population from the same area" (Conte et al. 1999).

Note: Cholesterol in the bile has no relation to the cholesterol in the blood. Therefore cholesterol-lowering drugs do not prevent gallstones.

Toxins that the liver normally removes build up in the blood, dulling mental function and leading to personality changes. The condition of the liver also affects how drugs are filtered from the body. Drugs the patient is taking that are normally filtered out by the liver and disposed of in the urine may remain in the bloodstream for a much longer period, acting longer than expected or even building up in body tissue. A cirrhotic liver is usually much larger than a healthy liver (Clayman 1989; Glanze 1996; NIDDK 2000; Wolf 2001).

Treating the Complications
In patients who have cirrhosis, complications from the disease must be treated. In particular, acute variceal bleeding is a very serious, life-threatening medical emergency. Infections such as spontaneous bacterial peritonitis must be promptly treated with appropriate antibiotics. Coagulation disorders will sometimes respond to vitamin K. However, drugs that are metabolized in the liver must be used with caution.

Ascites
Mild cases of ascites are treated with a salt-restricted diet (2000 mg of sodium daily or less in some cases). Cirrhosis patients often need guidance in planning a diet that has low sodium content without compromising caloric and nutritional requirements (NIDDK 2000). If salt restriction is not effective, diuretic drugs are the next treatment consideration (e.g., Aldactone or Lasix). In patients who continue to be resistant to drug therapy, peritoneovenous and portosystemic shunts (plastic tubing) are inserted subcutaneously to connect the peritoneal cavity or the portal system to an internal jugular or subclavian vein (Wolf 2001).

Hepatic Encephalopathy
Blood ammonia will be checked because an elevated serum ammonia level is a classic laboratory finding in hepatic encephalopathy. Lactulose is helpful in some patients to assist in removal of ammonia (Wolf 2001). Lactulose is a synthetic sugar that is not absorbed by the body and is used a laxative. Neomycin and other antibiotics are also used to decrease bacteria in the intestine that produce ammonia. Depending on nutritional status, dietary protein may be restricted in patients who are having an acute flare-up of hepatic encephalopathy (Wolf 2001).

Esophageal Varices
Restricted blood flow in the portal vein causes blood from the intestines and spleen to back up into stomach and esophagus blood vessels. These vessels are not intended to carry large amounts of blood and become enlarged. As these veins enlarge (varicose veins or varices), the walls become thin and are likely to burst as pressure increases. Variceal hemorrhaging is very serious and requires immediate medical attention. As part of routine monitoring, a diagnostic endoscopy will be done to determine if a patient has asymptomatic esophageal varices. If varices are present, treatment can include reducing salt intake; taking diuretics to eliminate excess salts and fluids from the body; taking a beta-blocker (propranolol, nadolol); injection of a clotting agent; injection of a scarring chemical (sclerotherapy); or rubber-band ligation (a surgical procedure using a device to compress the varices and stop bleeding) (Pugh et al. 1973; NIDDK 2000; Wolf 2001). In addition, there is a radiological procedure called transjugular intrahepatic protosystemic shunt (TIPS) that shows some promise.

Hepatoma
In the United States, hepatocellular carcinoma is observed in 10-20% of patients who have cirrhosis (Wolf 2001). The liver cells develop a malignant change leading to a type of cancer called hepatocellular carcinoma (HCC). As with other cancers, early detection and number and size of tumors influence survival. Treatment for HCC ranges from surgical removal of the HCC if the patient has good liver function to transplantation (NIDDK 2000; Columbo 2001; Wolf 2001). If the patient cannot have surgery (advanced age, other health conditions, poor liver function, large tumors, or tumors in strategic locations), possible treatment includes ultrasound-guided injection of solutions that cause necrosis of tumor cells in the cancerous area; using a catheter to eliminate blood supply to the tumor; injecting antitumor agents directly into the tumor; systemic chemotherapy; and radiation (Columbo 2001).

Portal Hypertension
A healthy liver can accommodate a wide range of changes in portal blood flow without alteration of portal blood pressure. However, when the portal vein is obstructed, portal hypertension (very high blood pressure) occurs (Clayman 1989; Wolf 2001). Factors causing increased resistance to blood flow are fibrotic changes in the liver caused by cirrhosis, compression of the nodules that are regenerating liver tissue, and increased collagen deposition and levels of chemicals that act to constrict the blood vessels in the liver. Other causes are a blood clot in the portal vein or congenital narrowing (Clayman 1989). Treatment can consist of controlling ascites with salt restriction and diuretics; treating varices; or surgically implanting a shunt to divert blood from the portal vein to another blood vessel to relieve some of the pressure on the portal vein (Clayman 1989).

Cirrhosis and the Hepatitis C Factor

Until recently, the most common cause of cirrhosis of the liver in the United States was attributed to alcohol abuse. Because of the rapid increase of hepatitis C virus infection, hepatitis C has now taken over first place (26%), with alcohol abuse falling to second place, but only slightly behind at 21% (NIDDK 2000). There are vaccines for some of the hepatitis viruses, but at this time, there is no vaccine to prevent transmission of the hepatitis C virus. Preventive and deterrent practices are the only means to avoid it (Alter et al. 1998; Buggs 2002; NIDA 2002). The most common routes of infection with the hepatitis C virus are via needles, sexual contact, and blood transfusions, and from an infected pregnant female to her newborn (NIDA 2002) (see the protocol on Hepatitis C for a complete discussion of the hepatitis C virus).

Hepatitis C is one of six viruses known to cause liver disease (Buggs 2001; NIDA 2002, Strickland 2002). Hepatitis C is very difficult for the immune system to overcome and often becomes chronic, leading to serious and permanent liver damage. Typically hepatitis C infection is mild in the early stages and rarely recognized until it has caused significant damage to the liver. From infection to noticeable or significant liver damage can take 20 years or more. The symptoms of hepatitis C are also very mild in the early stages. Fatigue, the most common symptom, may not appear for many years. Other symptoms are mild fever, muscle and joint aches, nausea and vomiting, poor appetite, and vague abdominal pains. Hepatitis C often goes undiagnosed because the symptoms come and go and are so suggestive of a flu-like illness. Its presence is usually identified during a routine blood test or because the hepatitis C antibody is positive at the time of a blood donation.

A low level of infection with practically no symptoms can continue for years. The hepatitis C infection causes inflammation of the liver, with chronic infection resulting in cirrhotic-like scarring. Unfortunately, more than 80% of infected individuals eventually progress to the chronic stage of hepatitis C which results in cirrhosis (severe scarring of liver tissue). Persons with the late stages of hepatitis C can also develop liver cancer. When the hepatitis C virus is a cofactor, there is an increased risk of cirrhosis in those who also consume alcohol in excess (NIDA 2002).

“How will I know if I get cirrhosis?

Kara Wright, PA-C

One of the most common questions from a patient with hepatitis C is: “How will I know if I get cirrhosis?” People always want to know what to look for. In reality, many patients with cirrhosis may not even know they have significant liver disease until further evaluated by a medical provider. Many patients may have cirrhosis and have no signs or symptoms at all. In this article, we will discuss the physical and laboratory signs of cirrhosis.

Cirrhosis is late stage liver disease. It is characterized by actual distortion of the liver architecture due to scarring of the liver and is generally considered irreversible. Once the liver cells become scarred, liver function declines which produces a number of physical as well as laboratory findings. Although these findings often indicate cirrhosis, they are not specific only to liver disease.

Physical signs
Ascites is the accumulation of fluid in the abdominal cavity. In many cases, several liters of fluid can build up and cause severe abdominal distention. This is the most common complication of cirrhosis. Nearly 60% of all patients with compensated cirrhosis will develop ascites in 10 years.

Spontaneous bacterial peritonitis (SBP) is an infection of ascitic fluid. Manifestations of SBP include fever, abdominal pain, abdominal tenderness, and altered mental status. In the event of SBP, a provider must do a diagnostic paracentesis (draining of the fluid from the abdomen).

Hepatomegaly is enlargement of the liver. The cirrhotic liver may be large, normal sized, or small. When it can be felt, it will have a firm and nodular consistency.

Splenomegaly is enlargement of the spleen and is common in patients with cirrhosis.

Caput medusa is noted when the veins in the abdomen are very prominent. This appearance has been said to resemble the head (caput) of the mythical Gorgon Medusa.

Hepatic encephalopathy is a potentially reversible disturbance in consciousness and behavior. Disturbance of sleep pattern is a common early feature that typically precedes overt neurologic features. Patients often feel very confused. Physical findings include asterixis. Asterixis is the bilateral but non-uniform flapping motions of outstretched hands.

Fetor hepaticus is a sweet, pungent smell to the breath of cirrhotic patients. It is caused by increased concentrations of a chemical, which is not being detoxified by the liver.

Variceal hemorrhage is a devastating complication that occurs in 25-40 percent of patients with cirrhosis. This occurs when a blood vessel has very high-pressure blood flow, which causes it to break and bleed.

Jaundice is the yellow coloring of the skin and mucus membranes that results from increased serum bilirubin.

Spider angiomata, also known as spider telangiectasias, are markings on the body, which, as indicated in the name, look like spiders. They have a central circular artery with smaller vessels radiating from the center like spokes, or legs of a spider. The lesion is typically red or purple in color and the central part of the lesion may pulsate when compressed with a glass slide. Spider angiomata are most frequently found on the trunk, face and arms. As a general rule, the number and size of the spider angiomata correlate with the severity of liver disease.

Palmar erythema is an exaggeration of the normal spotty redness on the palms of the hands. It is characterized by a deep redness on the fleshy part of the palm.

Nail changes are sometimes found. Muehrcke’s nails are characterized by paired horizontal white bands separated by normal color in the nail. Another nail disorder, Terry’s nails, is seen in patients with cirrhosis. In this case, the two-thirds of nail plate closest to the hand appears white whereas the furthest one-third is red.

Gynecomastia is benign growth of the tissue of the male breast. The tissue typically feels firm and rubbery. Up to two-thirds of patients with cirrhosis have gynecomastia. Men may also develop other features such as loss of chest or underarm hair and inversion of the normal male pubic hair pattern.

Constitutional symptoms such as weakness, fatigue, anorexia, and weight loss also occur. The fever of cirrhosis is typically low grade and continuous.

Laboratory findings
Liver enzymes may provide the first clue to liver dysfunction. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are usually moderately elevated in cirrhotic patients. AST is often more elevated than ALT, but levels can be normal in cirrhotics.

Alkaline phosphatase is usually elevated but less than 2-3 times the upper normal limit.

Bilirubin is often normal in well-compensated cirrhosis, but will rise as cirrhosis progresses.

Albumin is synthesized exclusively in the liver. Albumin levels fall as the synthetic function of the liver declines due to worsening cirrhosis. Serum albumin levels can help to grade the severity of cirrhosis.
The liver synthesizes many proteins required for normal clotting. The prothrombin time (PT) reflects the degree of liver dysfunction. The PT increases as the ability of a cirrhotic liver to synthesize clotting factors diminishes.

Anemia may occur in cirrhotic patients due to a number of causes.

Thrombocytopenia (low platelets) is very common in cirrhotic patients and is often caused by an enlarged spleen, which can sequester up to 90% of circulating platelets.

If a patient has any of these signs, he or she should discuss them with a medical provider. These signs do not always indicate cirrhosis, but can help establish that diagnosis.

http://www.hcvadvocate.org/news/newsLetter/advocate1103.html#3

Risk Factors for Developing Cirrhosis from Hepatitis C.

Between 20% and 30% of people with hepatitis C develop cirrhosis after twenty years. (It should be noted that even in patients with cirrhosis, survival rates in one study were nearly 80% at 10 years in these patients.) The following conditions put people with hepatitis C at higher risk for liver damage:

Having a specific genetic type of hepatitis C (genotype 1). This is the strongest risk factor for severity and risk for cirrhosis.
Being male may pose a higher risk for severity than being female.
Developing hepatitis C at an older age.
Heavy alcohol use.
Co-infection with HIV or hepatitis B.
A history of transfusions. (One study reported that they are twice as likely as intravenous drug users to develop cirrhosis.)
Being overweight, particularly if fat is distributed in the abdomen (an apple-shape). This condition may pose a higher risk for a fatty liver, which in turn is more apt to become scarred and cirrhotic.
Having large iron stores in the liver.

Risk Factors for Developing Cirrhosis from Hepatitis B. The great majority of people with chronic persistent hepatitis B have a good long-term outlook, but between 5% and 10% become carriers of the virus and 5% to 10% of these individuals eventually develop cirrhosis. The addition of hepatitis D is a particular danger and increases the risk for cirrhosis. [ See also Well-Connected, Report #59, Hepatitis.]

To read full article on Cirrhosis : http://www.reutershealth.com/wellconnected/doc75.html

Natural History of Cirrhosis

Two recent studies examined the natural history of liver cirrhosis in individuals with viral hepatitis. In the May issue of Gut, L. Benvegnu and colleagues investigated the progression and outcome of initially compensated cirrhosis in a cohort of 312 Italian patients with hepatitis B (43 patients), C (254 patients), or both (15 patients), followed for an average of about eight years. Tests were performed every six months to assess liver disease progression and identify major complications. During the follow-up period, 102 patients (about 33%) developed at least one complication. The most common were hepatocellular carcinoma (HCC, a type of liver cancer; about 21%), ascites (about 20%), gastrointestinal bleeding (about 5%), and encephalopathy (about 2%). About 20% experienced liver disease progression as evidenced by an increased Child-Pugh cirrhosis score. About 19% died from liver disease during follow-up, most (70%) due to HCC. The authors concluded that HCC was “the most frequent and life-threatening complication, particularly in HCV positive cases.”

The same month in the Journal of Hepatology, Ramon Planas and colleagues from Spain reported on the natural history of decompensated cirrhosis in patients with hepatitis C. Two hundred patients were followed from their first hospitalization for hepatic decompensation; average follow-up was about three years. The most common initial complications related to decompensation were ascites (48%), gastrointestinal bleeding (about 33%), severe bacterial infection (about 15%), and encephalopathy (5%). During follow-up, about 17% developed HCC and about 43% died. “Once decompensated HCV-related cirrhosis was established,” the researchers concluded, “patients showed not only a very high frequency of readmissions, but also developed decompensations different from the initial one.”
http://www.hcvadvocate.org/news/newsRev/2004/HJR-1.11.html#3

NATURAL HISTORY OF COMPENSATED CIRRHOSIS


The natural history of compensated cirrhosis due to hepatitis C virus 06 June 2006
Hepatitis C-related cirrhosis is a slowly progressive disease and may be accelerated by other potential causes of liver disease, find scientists in the June issue of Hepatology.

It is necessary to follow large groups of patients for long periods to establish the rates, chronology, and hierarchy of complications of cirrhosis, and other potential causes of liver disease. In this study, scientists followed a cohort of 214 patients with compensated cirrhosis due to hepatitis C virus (HCV) for 17 years. Study subjects were HCV RNA-seropositive with Child-Pugh class A cirrhosis. They had no previous clinical decompensation. The team found that hepatocellular carcinoma (HCC) developed in 32%of patients during follow-up. Ascites developed in 23%, jaundice in 17%, upper gastrointestinal bleeding in 6%, and encephalopathy in 1%.

They found that clinical status remained unchanged in 72%, progressed to Child-Pugh class B in 21% and class C in 7%.

The scientists determined that HCC was the cause of death in 44% of patients and also the first complication to develop in 27%.

Overall, the annual mortality rate was 4% per year.

Dr Angelo Sangiovanni's team concluded, "Hepatitis C-related cirrhosis is a slowly progressive disease that may be accelerated by other potential causes of liver disease".

"HCC was the first complication to develop and the dominant cause for increased mortality".

Hepatology 2006; 43(6): 1303-10
06 June 2006

http://www.gastrohep.com/

NATURAL HISTORY OF COMPENSATED CIRRHOSIS

This study was presented at the EASL liver meeting in Madrid by a Greek research group from the University of Crete. The aim of this study was to define the natural history of compensated cirrhosis and analyze age, sex and cirrhosis etiology at diagnosis to identify prognostic factors available at diagnosis which might influence the time or decompensation or survival.

The authors retrospectively analyzed data of 306 compensated cirrhotic patients from diagnosis to decompensation and, death, using the log rank test and univariate Cox PH models.

RESULTS: 54.9% of the patients were males, 47.06% were <64 years old. 56 had alcoholic cirrhosis, 17 had alcoholic cirrhosis with a viral infection, 45 had HBV cirrhosis, 145 had HCV cirrhosis and 43 had cryptogenic cirrhosis. 150 patients (49.02%) became decompensated within the study period. Median time to decompensation was 58 months (95% CI 51 and 65 months). Patients with HCV cirrhosis had longer times to decompensation than the other groups (81 months).

65% of all patients remain compensated 3 years after diagnosis, reduced to 34% after 7 years. 70 patients (22.88%) died within the study period. The median survival time was 126 months (95% CI 103 to 149 months). The prognostic factors available at diagnosis that were found to have a significant effect on decompensation and survival time were sex (p = 0.0024 and p = 0.0007) and etiology of cirrhosis (p < 0.0001 and p = 0.0024). The authors found that females with HCV cirrhosis have the longest time until decompensation and the longest survival times.

http://www.natap.org/2002/easl/day9.htm

Hepatology. 1987 Jan-Feb;7(1):122-8.

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The natural history of compensated cirrhosis due to hepatitis C virus