Chronic disease of the liver, characterized by fibrosis
Medical condition
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is an acute condition of the liver in which the normal functioning tissue, or parenchyma, is replaced with scar tissue (fibrosis) and regenerative nodules as a result of chronic liver disease. Damage to the liver leads to repair of liver tissue and subsequent formation of scar tissue. Over time, scar tissue and nodules of regenerating hepatocytes can replace the parenchyma, causing increased resistance to blood flow in the liver's capillaries—the hepatic sinusoids—and consequently portal hypertension, as well as impairment in other aspects of liver function. The disease typically develops slowly over months or years.
Stages of cirrhosis include compensated cirrhosis and decompensated cirrhosis. Early symptoms may include tiredness, weakness, loss of appetite, unexplained weight loss, nausea and vomiting, and discomfort in the right upper quadrant of the abdomen. As the disease worsens, symptoms may include itchiness, swelling in the lower legs, fluid build-up in the abdomen, jaundice, bruising easily, and the development of spider-like blood vessels in the skin. The fluid build-up in the abdomen may develop into spontaneous infections. More serious complications include hepatic encephalopathy, bleeding from dilated veins in the esophagus, stomach, or intestines, and liver cancer.
Cirrhosis is most commonly caused by medical conditions including alcohol-related liver disease, metabolic dysfunction–associated steatohepatitis (MASH – the progressive form of metabolic dysfunction–associated steatotic liver disease, previously called non-alcoholic fatty liver disease or NAFLD), heroin abuse, chronic hepatitis B, and chronic hepatitis C. Chronic heavy drinking can cause alcoholic liver disease. Liver damage has also been attributed to heroin usage over an extended period of time as well. MASH has several causes, including obesity, high blood pressure, abnormal levels of cholesterol, type 2 diabetes, and metabolic syndrome. Less common causes of cirrhosis include autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis that disrupts bile duct function, genetic disorders such as Wilson's disease and hereditary hemochromatosis, and chronic heart failure with liver congestion.
Diagnosis is based on blood tests, medical imaging, and liver biopsy.
Hepatitis B vaccine can prevent hepatitis B and the development of cirrhosis from it, but no vaccination against hepatitis C is available. No specific treatment for cirrhosis is known, but many of the underlying causes may be treated by medications that may slow or prevent worsening of the condition. Hepatitis B and C may be treatable with antiviral medications. Avoiding alcohol is recommended in all cases. Autoimmune hepatitis may be treated with steroid medications. Ursodiol may be useful if the disease is due to blockage of the bile duct. Other medications may be useful for complications such as abdominal or leg swelling, hepatic encephalopathy, and dilated esophageal veins. If cirrhosis leads to liver failure, a liver transplant may be an option. Biannual screening for liver cancer using abdominal ultrasound, possibly with additional blood tests, is recommended due to the high risk of hepatocellular carcinoma arising from dysplastic nodules.
Cirrhosis affected about 2.8 million people and resulted in 1.3 million deaths in 2015. Of these deaths, alcohol caused 348,000 (27%), hepatitis C caused 326,000 (25%), and hepatitis B caused 371,000 (28%). In the United States, more men die of cirrhosis than women. The first known description of the condition is by Hippocrates in the fifth century BCE. The term "cirrhosis" was derived in 1819 from the Greek word "kirrhos", which describes the yellowish color of a diseased liver.
Signs and symptoms.
Cirrhosis can take quite a long time to develop, and symptoms may be slow to emerge. Some early symptoms include tiredness, weakness, loss of appetite, weight loss, and nausea. Early signs may also include redness on the palms known as palmar erythema. People may also feel discomfort in the right upper abdomen around the liver.
As cirrhosis progresses, symptoms may include neurological changes affecting both the peripheral and central nervous systems, disrupting the neurotransmission within the brain and causing neuromuscular fatigue. This can consist of cognitive impairments, confusion, memory loss, sleep disorders, and personality changes.Steatorrhea or presence of undigested fats in stool is also a symptom of cirrhosis.
Worsening cirrhosis can cause a build-up of fluid in different parts of the body such as the legs (edema) and abdomen (ascites). Other signs of advancing disease include itchy skin, bruising easily, dark urine, and yellowing of the skin.
Liver dysfunction.
These features are a direct consequence of liver cells not functioning:
Portal hypertension.
Liver cirrhosis makes it hard for blood to flow in the portal venous system. This resistance creates a backup of blood and increases pressure. This results in portal hypertension. Effects of portal hypertension include:
Other nonspecific signs.
Some signs that may be present include changes in the nails (such as Muehrcke's lines, Terry's nails, and nail clubbing). Additional changes may be seen in the hands (Dupuytren's contracture) as well as the skin/bones (hypertrophic osteoarthropathy).
Advanced disease.
As the disease progresses, complications may develop. In some people, these may be the first signs of the disease.
Causes.
Cirrhosis has many possible causes, and more than one cause may be present. History taking is of importance in trying to determine the most likely cause. Globally, 57% of cirrhosis is attributable to either hepatitis B (30%) or hepatitis C (27%). Alcohol use disorder is another major cause, accounting for about 20–40% of the cases.
Pathophysiology.
The liver plays a vital role in many metabolic processes in the body including protein synthesis, detoxification, nutrient storage (such as glycogen), platelet production and clearance of bilirubin. With progressive liver damage; hepatocyte death and replacement of functional liver tissue with fibrosis in cirrhosis, these processes are disrupted. This leads to many of the metabolic derangements and symptoms seen in cirrhosis.
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 tissue, which is normally organized into lobules. This scar tissue blocks the portal flow of blood through the organ, raising the blood pressure. This manifests as portal hypertension in which the pressure gradient between the portal circulation as compared to the systemic circulation is elevated. This portal hypertension leads to decreased sinusoidal flow from liver cells to nearby sinusoids in the liver, and increased lymph production with extravasation of lymph to the extracellular space, causing ascites. This also causes reduced cardiac return and central blood volume, which activates the renin-angiotensin system (RAAS) which causes kidneys to reabsorb sodium and water, causing water retention and further ascites. Activation of the RAAS also causes kidney vasoconstriction and may cause kidney injury.
Research has shown the pivotal role of the stellate cell, that normally stores vitamin A, in the development of cirrhosis. Damage to the liver tissue from inflammation leads to the activation of stellate cells, which increases fibrosis through the production of myofibroblasts, and obstructs hepatic blood flow. In addition, stellate cells secrete TGF beta 1, which leads to a fibrotic response and proliferation of connective tissue. TGF-β1 have been implicated in the process of activating hepatic stellate cells (HSCs) with the magnitude of fibrosis being in proportion to increase in TGF β levels. ACTA2 is associated with TGF β pathway that enhances contractile properties of HSCs leading to fibrosis. Furthermore, HSCs secrete TIMP1 and TIMP2, naturally occurring inhibitors of matrix metalloproteinases (MMPs), which prevent MMPs from breaking down the fibrotic material in the extracellular matrix.
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, and enlarged, resulting in its retention of platelets, which are needed for normal blood clotting. Portal hypertension is responsible for the most severe complications of cirrhosis.
Diagnosis.
The diagnosis of cirrhosis in an individual is based on multiple factors. Cirrhosis may be suspected from laboratory findings, physical exam, and the person's medical history. Imaging is generally obtained to evaluate the liver. A liver biopsy will confirm the diagnosis; however, is generally not required.
Imaging.
Ultrasound is routinely used in the evaluation of cirrhosis. It may show a small and shrunken liver in advanced disease. On ultrasound, there is increased echogenicity with irregular appearing areas. Other suggestive findings are an enlarged caudate lobe, liver surface nodularity widening of the fissures and enlargement of the spleen. An enlarged spleen, which normally measures less than in adults, may suggest underlying portal hypertension. Ultrasound may also screen for hepatocellular carcinoma and portal hypertension. This is done by assessing flow in the hepatic vein. An increased portal vein pulsatility may be seen. However, this may be a sign of elevated right atrial pressure. Portal vein pulsatility are usually measured by a pulsatility indices (PI). A number above a certain values indicates cirrhosis (see table below).
Other scans include CT of the abdomen and MRI. A CT scan is non-invasive and may be helpful in the diagnosis. Compared to the ultrasound, CT scans tend to be more expensive. MRI provides excellent evaluation; however, is a high expense.
Portable ultrasound is a low cost tool to identify the sign of liver surface nodularity with a good diagnostic accuracy. 
Cirrhosis is also diagnosable through a variety of new elastography techniques. When a liver becomes cirrhotic it will generally become stiffer. Determining the stiffness through imaging can determine the location and severity of disease. Techniques include transient elastography, acoustic radiation force impulse imaging, supersonic shear imaging and magnetic resonance elastography. Transient elastography and magnetic resonance elastography can help identify the stage of fibrosis. Compared to a biopsy, elastography can sample a much larger area and is painless. It shows a reasonable correlation with the severity of cirrhosis. Other modalities have been introduced which are incorporated into ultrasonagraphy systems. These include "2-dimensional shear wave elastography" and "point shear wave elastography" which uses acoustic radiation force impulse imaging.
Rarely are diseases 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.
Lab findings.
The best predictors of cirrhosis are ascites, platelet count ; 160,000/mm3, spider angiomata, and a Bonacini cirrhosis discriminant score greater than 7 (as the sum of scores for platelet count, ALT/AST ratio and INR as per table).
These findings are typical in cirrhosis:
FibroTest is a biomarker for fibrosis that may be used instead of a biopsy.
Other laboratory studies performed in newly diagnosed cirrhosis may include:
Markers of inflammation and immune cell activation are typically elevated in cirrhotic patients, especially in the decompensated disease stage:
The link between gut microbiota constitution and liver health (Particularly in Cirrhosis) has been well described, however specific biomarkers for prediction of Cirrhosis still requires further research. A 2014 study identified 15 microbial biomarkers from the gut microbiota. These could potentially be used to discriminate patients with liver cirrhosis from healthy individuals. 
Pathology.
The gold standard for diagnosis of cirrhosis is a liver biopsy. This is usually carried out as a fine-needle approach, through the skin (percutaneous), or internal jugular vein (transjugular). Endoscopic ultrasound-guided liver biopsy (EUS), using the percutaneous or transjugular route, has become a good alternative to use. EUS can target liver areas that are widely separated, and can deliver bi-lobar biopsies. A biopsy is not necessary if the clinical, laboratory, and radiologic data suggest cirrhosis. Furthermore, a small but significant risk of complications is associated with liver biopsy, and cirrhosis itself predisposes for complications caused by liver biopsy.
Once the biopsy is obtained, a pathologist will study the sample. Cirrhosis is defined by its 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 space of Disse, and other vascular structures, which leads to altered resistance to blood flow in the liver, and portal hypertension.
As cirrhosis can be caused by many different entities which injure the liver in different ways, cause-specific abnormalities may be seen. For example, in chronic hepatitis B, there is infiltration of the liver parenchyma with lymphocytes. In congestive hepatopathy there are erythrocytes and a greater amount of fibrosis in the tissue surrounding the hepatic veins. In primary biliary cholangitis,