Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, is a condition in which the liver does not function properly due to long-term damage.^[1] This damage is characterized by the replacement of normal liver tissue by scar tissue.^[1] Typically, the disease develops slowly over months or years.^[1] Early on, there are often no symptoms.^[1] As the disease worsens, a person may become tired, weak, itchy, have swelling in the lower legs, develop yellow skin, bruise easily, have fluid buildup in the abdomen, or develop spider-like blood vessels on the skin.^[1] The fluid build-up in the abdomen may become spontaneously infected.^[1] Other serious complications include hepatic encephalopathy, bleeding from dilated veins in the esophagus or dilated stomach veins, and liver cancer.^[1] Hepatic encephalopathy results in confusion and may lead to unconsciousness.^[1]

Cirrhosis is most commonly caused by alcohol, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease.^[1][2] Typically, more than two or three alcoholic drinks per day over a number of years is required for alcoholic cirrhosis to occur.^[1] Non-alcoholic fatty liver disease has a number of causes, including being overweight, diabetes, high blood fats, and high blood pressure.^[1] A number of less common causes of cirrhosis include autoimmune hepatitis, primary biliary cholangitis, hemochromatosis, certain medications, and gallstones.^[1] Diagnosis is based on blood testing, medical imaging, and liver biopsy.^[1]

Some causes of cirrhosis, such as hepatitis B, can be prevented by vaccination.^[1] Treatment partly depends on the underlying cause,^[1] but the goal is often to prevent worsening and complications.^[1] Avoiding alcohol is recommended in all cases of cirrhosis.^[1] Hepatitis B and C may be treatable with antiviral medications.^[1] Autoimmune hepatitis may be treated with steroid medications.^[1] Ursodiol may be useful if the disease is due to blockage of the bile ducts.^[1] Other medications may be useful for complications such as abdominal or leg swelling, hepatic encephalopathy, and dilated esophageal veins.^[1] In severe cirrhosis, a liver transplant may be an option.^[1]

Cirrhosis affected about 2.8 million people and resulted in 1.3 million deaths in 2015.^[3][4] Of these deaths, alcohol caused 348,000, hepatitis C caused 326,000, and hepatitis B caused 371,000.^[4] In the United States, more men die of cirrhosis than women.^[1] The first known description of the condition is by Hippocrates in the 5th century BCE.^[5] The term cirrhosis was invented in 1819, from a Greek word for the yellowish color of a diseased liver.^[6]

Signs and symptoms

Liver cirrhosis.

Cirrhosis has many possible manifestations. These signs and symptoms may be either a direct result of the failure of liver cells, or secondary to the resultant increased pressure in the blood vessels in the hepatic portal system (portal hypertension). Some manifestations of cirrhosis are nonspecific,

Cirrhosis is most commonly caused by alcohol, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease.^[1][2] Typically, more than two or three alcoholic drinks per day over a number of years is required for alcoholic cirrhosis to occur.^[1] Non-alcoholic fatty liver disease has a number of causes, including being overweight, diabetes, high blood fats, and high blood pressure.^[1] A number of less common causes of cirrhosis include autoimmune hepatitis, primary biliary cholangitis, hemochromatosis, certain medications, and gallstones.^[1] Diagnosis is based on blood testing, medical imaging, and liver biopsy.^[1]

Some causes of cirrhosis, such as hepatitis B, can be prevented by vaccination.^[1] Treatment partly depends on the underlying cause,^[1] but the goal is often to prevent worsening and complications.^[1] Avoiding alcohol is recommended in all cases of cirrhosis.^[1] Hepatitis B and C may be treatable with antiviral medications.^[1] Autoimmune hepatitis may be treated with steroid medications.^[1] Ursodiol may be useful if the disease is due to blockage of the bile ducts.^[1] Other medications may be useful for complications such as abdominal or leg swelling, hepatic encephalopathy, and dilated esophageal veins.^[1] In severe cirrhosis, a liver transplant may be an option.^[1]

Cirrhosis affected about 2.8 million people and resulted in 1.3 million deaths in 2015.^[3][4] Of these deaths, alcohol caused 348,000, hepatitis C caused 326,000, and hepatitis B caused 371,000.^[4] In the United States, more men die of cirrhosis than women.^[1] The first known description of the condition is by Hippocrates in the 5th century BCE.^[5] The term cirrhosis was invented in 1819, from a Greek word for the yellowish color of a diseased liver.^[6]

Cirrhosis has many possible manifestations. These signs and symptoms may be either a direct result of the failure of liver cells, or secondary to the resultant increased pressure in the blood vessels in the hepatic portal system (portal hypertension). Some manifestations of cirrhosis are nonspecific, and also occur in several unrelated conditions. Likewise, the absence of any signs does not rule out the possibility of cirrhosis.^[7] Cirrhosis of the liver is slow and gradual in its development. It is usually well advanced before its symptoms are noticeable enough to cause alarm. Weakness and weight loss may be early symptoms.

Liver dysfunction

The following features are as a direct consequence of liver cells not functioning.

• Spider angiomata or spider nevi are vascular lesions consisting of a central arteriole surrounded by many smaller vessels (hence the name "spider") and occur due to an increase in estradiol. One study found that spider angiomata occur in about 1/3 of cases.^[8]
• Palmar erythema is a reddening of palms at the thenar and hypothenar eminences also as a result of increased estrogen.^[9]
• Gynecomastia, or increase in breast gland size in men that is not cancerous, is caused by increased estradiol and can occur in up to 2/3 of patients.^[10] This is different from increase in breast fat in overweight people.^[11]
• Hypogonadism, a decrease in male sex hormones may manifest as impotence, infertility, loss of sexual drive, and testicular atrophy, and can result from primary gonadal injury or suppression of hypothalamic/pituitary function. Hypogonadism is associated with cirrhosis due to alcoholism or hemochromatosis.^[12]
• Liver size can be enlarged, normal, or shrunken in people with cirrhosis.
• Ascites, accumulation of fluid in the peritoneal cavity (space in the abdomen), gives rise to "flank dullness". This may be visible as an increase in abdominal girth.^[13]
• Fetor hepaticus is a musty breath odor resulting from increased dimethyl sulfide.^[14]
• Jaundice, or icterus, is yellow discoloration of the skin and mucous membranes (with the white of the eye being especially noticeable) due to increased bilirubin (at least 2–3 mg/dl or 30 µmol/l). The urine may also appear dark.^[13]

Portal hypertension

Liver cirrhosis increases resistance to blood flow and leads to higher pressure in the portal venous system, resulting in portal hypertension. Effects of portal hypertension include:

• Splenomegaly (increase in size of the spleen) is found in 35% to 50% of patients.^[7]
• Esophageal varices result from collateral portal blood flow through vessels in the stomach and esophagus (a process called portacaval anastomosis). When these blood vessels become enlarged, they are called varices and are more likely to rupture.^[13] Variceal rupture often leads to severe bleeding, which can prove fatal.
• Caput medusae are dilated periumbilical collateral veins due to portal hypertension. Blood from the portal venous system may be shunted through the periumbilical veins and ultimately to the abdominal wall veins, manifesting as a pattern that may resemble the head of Medusa.^[13]
• Cruveilhier-Baumgarten bruit is a venous hum heard in the epigastric regio

  The following features are as a direct consequence of liver cells not functioning.

  • Spider angiomata or spider nevi are vascular lesions consisting of a central arteriole surrounded by many smaller vessels (hence the name "spider") and occur due to an increase in portal hypertension. Effects of portal hypertension include:
    • Splenomegaly (increase in size of the spleen) is found in 35% to 50% of patients.^[7]
    • Esophageal varices result from collateral portal blood flow through vessels in the stomach and esophagus (a process called portacaval anastomosis). When these blood vessels become enlarged, they are called varices and are more likely to rupture.^[13] Variceal rupture often leads to severe bleeding, which can prove fatal.
    • Caput medusae are dilated periumbilical collateral veins due to portal hypertension. Blood from the portal venous system may be shunted through the periumbilical veins and ultimately to the abdominal wall veins, manifesting as a pattern that may resemble the head of Medusa.^[13]
    • Cruveilhier-Baumgarten bruit is a venous hum heard in the epigastric region (on examination by stethoscope) due to collateral connections forming between the portal system and the periumbilical veins as a result of portal hypertension.

    Unestablished cause

    There are some changes seen in cirrhosis whose causes are not clearly known. They may also be a sign of other non-liver related causes.

    • Nail changes.
      • Muehrcke's lines – paired horizontal bands separated by normal color resulting from hypoalbuminemia (inadequate production of albumin). It is not specific for cirrhosis.^[15]
      • Terry's nails – proximal two-thirds of the nail plate appears white with distal one-third red, also due to hypoalbuminemia.^[16]
      • Clubbing – angle between the nail plate and proximal nail fold > 180 degrees. It is not specific for cirrhosis and can therefore be due to a number of conditions.^[16]
    • Hypertrophic osteoarthropathy. Chronic proliferative periostitis of the long bones that can cause considerable pain. It is not specific for cirrhosis.^[16]
    • Nail changes.
      • Muehrcke's lines – paired horizontal bands separated by normal color resulting from hypoalbuminemia (inadequate production of albumin). It is not specific for cirrhosis.^[15]
      • Terry's nails – proximal two-thirds of the nail plate appears white with distal one-third red, also due to hypoalbuminemia.^[16]
      • Clubbing – angle between the nail plate and proximal nail fold > 180 degrees. It is not specific for cirrhosis and can therefore be due to a number of conditions.^[16]
    • Hypertrophic osteoarthropathy. Chronic proliferative periostitis of the long bones that can cause considerable pain. It is not specific for cirrhosis.^[16]
    • Dupuytren's contracture. Thickening and shortening of palmar fascia (tissue on the palm of the hands) that leads to flexion deformities of the fingers. Caused by fibroblastic proliferation (increased growth) and disorderly collagen deposition. It is relatively common (33% of patients).^[16]
    • Other. Weakne

      As the disease progresses, complications may develop. In some people, these may be the first signs of the disease.

      • Bruising and bleeding resulting from decreased production of coagulation factors.
      • Hepatic encephalopathy – occurs when ammonia and related substances build up in the blood and affect brain function when they are not cleared from the blood by the liver. This may result in neglect of personal appearance, unresponsiveness, forgetfulness, trouble concentrating, changes in sleep habits or psychosis. One classic physical exam findings is asterixis, bilateral asynchronous flapping of outstretched, dorsiflexed hands.^[13]
      • Sensitivity to medication caused by decreased metabolism of the active compounds.
      • Acute kidney injury (particularly hepatorenal syndrome)^[17]
      • Cachexia associated with muscle wasting and weakness^[18]

      Causes

      Liver cirrhosis has many possible causes; sometimes more than one cause is present in the same person. Globally, 57% of cirrhosis is attributable to either hepatitis B (30%) or hepatitis C (27%).^[19] Alcohol consumption is another major cause, accounting for about 20% of the cases.^[19]

      • Alcoholic liver disease (ALD). Alcoholic cirrhosis develops for 10–20% of individuals who drink heavily for a deca

        Liver cirrhosis has many possible causes; sometimes more than one cause is present in the same person. Globally, 57% of cirrhosis is attributable to either hepatitis B (30%) or hepatitis C (27%).^[19] Alcohol consumption is another major cause, accounting for about 20% of the cases.^[19]

        • Alcoholic liver disease (ALD). Alcoholic cirrhosis develops for 10–20% of individuals who drink heavily for a decade or more.^[20] Alcohol seems to injure the liver by blocking the normal metabolism of protein, fats, and carbohydrates. This injury happens through the formation of acetaldehyde from alcohol which itself is reactive, but which also leads to the accumulation of other reactive products in the liver.^[13] Patients may also have concurrent alcoholic hepatitis with fever, hepatomegaly, jaundice, and anorexia. AST and ALT blood levels are both elevated, but at less than 300 IU/liter, with an AST:ALT ratio > 2.0, a value rarely seen in other liver diseases.^[7] In the United States, 40% of cirrhosis-related deaths are due to alcohol.^[13]
        • Non-alcoholic steatohepatitis (NASH). In NASH, fat builds up in the liver and eventually causes scar tissue. This type of hepatitis appears to be associated with obesity (40% of NASH patients) diabetes, protein malnutrition, coronary artery disease, and treatment with steroid medications. This disorder is similar in it signs to alcoholic liver disease, but the patient does not have an alcohol history. A biopsy is needed for diagnosis.albumin, clotting factors and complement), detoxification, and storage (for example, 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 fully reversible.

          The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma. This scar tissue blocks the portal flow of blood through the organ, raising the blood pressure 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 (due to inflammation) leads to activation of stellate cells, which increases fibrosis (through production of myofibroblasts) and obstructs hepatic blood flow.^[25] In addition, stellate cells secrete TGF-β₁, 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 the fibrotic material in the extracellular matrix.^[26][27]

          As this cascade of processes continues, 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 the spleen's retention of platelets, which are needed for normal blood clotting. Portal hypertension is responsible for the most severe complications of cirrhosis.

          Diagnosis

          

          Micrograph showing cirrhosis. Trichrome stain.

          The gold standard for diagnosis of cirrhosis is a liver biopsy, through a percutaneous, transjugular, laparoscopic, or fine-needle approach. A biopsy is not necessary if the clinical, laboratory, and radiologic data suggests cirrhosis. Furthermore, there is a small but significant risk of complications from liver biopsy, and cirrhosis itself predisposes for complications caused by liver biopsy.^[28]

          Cirrhosis is diagnosed with a variety of elastography techniques. Because a cirrhotic liver is generally stiffer than a healthy one, imaging the liver's stiffness can give diagnostic information about the location and severity of cirrhosis. Techniques used include transient elastography, acoustic radiation force impulse imaging, supersonic shear imaging and magnetic resonance elastography. Compared to a biopsy, elastography can sample a much larger area and is painless. It shows a reasonable correlation with the severity of cirrhosis.^[36]

          Other tests performed in particular circumstances include abdominal CT and liver/bile duct MRI (MRCP).

          • elastography techniques. Because a cirrhotic liver is generally stiffer than a healthy one, imaging the liver's stiffness can give diagnostic information about the location and severity of cirrhosis. Techniques used include transient elastography, acoustic radiation force impulse imaging, supersonic shear imaging and magnetic resonance elastography. Compared to a biopsy, elastography can sample a much larger area and is painless. It shows a reasonable correlation with the severity of cirrhosis.^[36]

            Other tests performed in particular circumstances include abdominal CT and liver/bile duct MRI (MRCP).

            • CT and liver/bile duct MRI (MRCP).

              Liver cirrhosis with ascites

            • <

              Liver cirrhosis as seen on a CT of the abdomen in transverse orientation

            • 

              caudate lobe hypertrophy

              caudate lobe hypertrophy in ultrasound due to cirrhosis

            • 

              Hepatofugal flow in portal vein in ultrasound

            Endoscopy

            Gastroscopy (endoscopic examination of the esophagus, stomach, and duodenum) is performed in patients with established cirrhosis to exclude the possibility of esophageal varices. If these are found, prophylactic local therapy may be applied (sclerotherapy or banding) and Gastroscopy (endoscopic examination of the esophagus, stomach, and duodenum) is performed in patients with established cirrhosis to exclude the possibility of esophageal varices. If these are found, prophylactic local therapy may be applied (sclerotherapy or banding) and beta blocker treatment may be commenced.

            Rarely are diseases of the bile ducts, such as primary sclerosing cholangitis, causes of cirrhosis. Imaging of the bile ducts, such as primary sclerosing cholangitis, causes of cirrhosis. Imaging of the bile ducts, such as ERCP or MRCP (MRI of biliary tract and pancreas) may aid in the diagnosis.

            Macroscopically, the liver is initially enlarged, but with the progression of the disease, it becomes smaller. Its surface is irregular, the consistency is firm, and the color is often yellow (if associated with steatosis). Depending on the size of the nodules, there are three macroscopic types: micronodular, macronodular, and mixed cirrhosis. In the micronodular form (Laennec's cirrhosis or portal cirrhosis), regenerating nodules are under 3 mm. In macronodular cirrhosis (post-necrotic cirrhosis), the nodules are larger than 3 mm. Mixed cirrhosis consists of nodules of different sizes.^[37]

            • 

              

              Pale macronodules of cirrhosis.

            <

            Pale macronodules of cirrhosis.

          • 

            Cirrhosis leading to hepatocellular carcinoma (autopsy specimen)

            Cirrhosis leading to hepatocellular carcinoma (autopsy specimen)

          However, cirrhosis is defined by its pathological features on microscopy: (1) the presence of regenerating nodules of hepatocytes and (2) the presence of fibrosis, or the deposition of connective tissue between these nodules. The pattern of fibrosis seen can depend on the underlying insult that led to cirrhosis. Fibrosis can also proliferate even if the underlying process that caused it has resolved or ceased. The fibrosis in cirrhosis can lead to destruction of other normal tissues in the liver: including the sinusoids, the fibrosis, or the deposition of connective tissue between these nodules. The pattern of fibrosis seen can depend on the underlying insult that led to cirrhosis. Fibrosis can also proliferate even if the underlying process that caused it has resolved or ceased. The fibrosis in cirrhosis can lead to destruction of other normal tissues in the liver: including the sinusoids, the space of Disse, and other vascular structures, which leads to altered resistance to blood flow in the liver, and portal hypertension.^[38]

          Van Gieson's stain)^[39]