Cirrhosis

Cirrhosis can take quite a long time to develop, and symptoms may be slow to emerge. People may also feel discomfort in the right upper abdomen around the liver. This can consist of cognitive impairments, confusion, memory loss, sleep disorders, and personality changes. Worsening cirrhosis can cause a build-up of fluid in different parts of the body, such as the legs (edema) and abdomen (ascites). There is a central, red spot with reddish extensions that radiate outward. This creates a visual effect that resembles a spider. It occurs in about one-third of cases. • Palmar erythema, a reddening of the palm below the thumb and little finger, is seen in about 23% of cirrhosis cases, and results from increased circulating estrogen levels. • Gynecomastia, or the increase of breast size in men, is caused by increased estradiol (a potent type of estrogen). This can occur in up to two-thirds of cases. • Hypogonadism signifies a decreased functionality of the gonads. This can result in impotence, infertility, loss of sexual drive, and testicular atrophy. A swollen scrotum may also be evident. • Liver size can be enlarged, normal, or shrunken in people with cirrhosis. As the disease progresses, the liver will typically shrink due to the result of scarring. • Jaundice is the yellowing of the skin. It can additionally cause yellowing of mucous membranes notably of the white of the eyes. This phenomenon is due to increased levels of bilirubin, which may also cause the urine to be dark-colored. 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. When the blood vessels in this circulation become enlarged, they are called varices. Varices are more likely to rupture at this point. It is due to extra connections forming between the portal system and the paraumbilical veins. Additional changes may be seen in the hands (Dupuytren's contracture) as well as the skin/bones (hypertrophic osteoarthropathy). • Hepatic encephalopathy (HE) occurs when ammonia and related substances build up in the blood. • Increased sensitivity to medication can be caused by decreased metabolism of the active compounds. • Acute kidney injury (particularly hepatorenal syndrome). • Cachexia associated with muscle wasting and weakness. ==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. Alcohol use disorder is another major cause, accounting for about 20–40% of the cases. Alcohol seems to injure the liver by blocking the normal metabolism of protein, fats, and carbohydrates. 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. In the United States, 40% of cirrhosis-related deaths are due to alcohol. This type of disorder can be caused by obesity, diabetes, malnutrition, coronary artery disease, and steroids. Though similar in signs to alcoholic liver disease, no history of notable alcohol use is found. Blood tests and medical imaging are used to diagnose NAFLD and NASH, and sometimes a liver biopsy is needed. • Chronic hepatitis C, an infection with the hepatitis C virus, causes inflammation of the liver and a variable grade of damage to the organ. Rises in alkaline phosphatase, cholesterol, and bilirubin levels occur. Patients are usually positive for anti-mitochondrial antibodies. • Alpha-1 antitrypsin deficiency is an autosomal co-dominant disorder of low levels of the enzyme alpha-1 antitrypsin • Glycogen storage disease type IV • Cystic fibrosis • Hepatotoxic drugs or toxins, such as acetaminophen (paracetamol), methotrexate, or amiodarone ==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. In addition, stellate cells secrete TGF beta 1, which leads to a fibrotic response and proliferation of connective tissue. TGF-β1 has been implicated in the process of activating hepatic stellate cells (HSCs), with the magnitude of fibrosis being in proportion to the increase in TGF-β levels. ACTA2 is associated with the 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==

hypertrophy on ultrasound due to cirrhosis The diagnosis of cirrhosis in an individual is based on multiple factors. 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. Portal vein pulsatility is usually measured by a pulsatility index (PI). When a liver becomes cirrhotic, it will generally become stiffer. Determining the stiffness through imaging can determine the location and severity of the 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. These findings are typical in cirrhosis: • Thrombocytopenia, typically multifactorial, is due to alcoholic marrow suppression, sepsis, lack of folate, platelet sequestering in the spleen, and decreased thrombopoietin. • Aminotransferases AST and ALT are moderately elevated, with AST > ALT. However, normal aminotransferase levels do not preclude cirrhosis. • Renin is increased (as well as sodium retention in kidneys) secondary to a fall in systemic vascular resistance. FibroTest is a biomarker for fibrosis that may be used instead of a biopsy. Other laboratory studies performed in newly diagnosed cirrhosis may include: • Serology for hepatitis viruses, autoantibodies (ANA, anti-smooth muscle, antimitochondria, anti-LKM) • Ferritin and transferrin saturation: markers of iron overload as in hemochromatosis, copper and ceruloplasmin: markers of copper overload as in Wilson's disease • Immunoglobulin levels (IgG, IgM, IgA) – these immunoglobulins are nonspecific, but may help in distinguishing various causes. • IgG level is elevated in chronic hepatitis, alcoholic hepatitis, and autoimmune hepatitis. It is a slow and sustained increase is seen in viral hepatitis. • IgM significantly increased in primary biliary cirrhosis and moderately increased in viral hepatitis and cirrhosis. • IgA is increased in alcoholic cirrhosis and primary biliary cirrhosis. • Cholesterol and glucose • Alpha 1-antitrypsin Markers of inflammation and immune cell activation are typically elevated in cirrhotic patients, especially in the decompensated disease stage: • C-reactive protein (CRP) • Procalcitonin (PCT) • soluble CD14 • soluble CD206 (mannose receptor) • soluble TREM-1 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 showing cirrhosis, trichrome stain 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. and can deliver bi-lobar biopsies. 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. File:Histopathology of mild zone 3 steatosis without fibrosis (van Gieson).jpg|No fibrosis, but mild zone 3 steatosis, in which collagen fibres (pink–red, arrow) are confined to portal tracts (P) (Van Gieson's stain) File:Histopathology of steatohepatitis with mild fibrosis in the form of fibrous expansion (van Gieson).jpg|Histopathology of steatohepatitis with mild fibrosis in the form of fibrous expansion (Van Gieson's stain) In primary biliary cholangitis, there is fibrosis around the bile duct, the presence of granulomas and pooling of bile. Lastly in alcoholic cirrhosis, there is infiltration of the liver with neutrophils. File:Gross pathology of alcoholic liver cirrhosis.jpg|Micronodular cirrhosis, with diffuse areas of pallor File:Wątroba marska (Ultima Thule).jpg|Pale macronodules of cirrhosis File:Hepatocellular carcinoma 1.jpg|Cirrhosis leading to hepatocellular carcinoma == Grading ==

The severity of cirrhosis is commonly classified with the Child–Pugh score (also known as the Child–Pugh–Turcotte score). This system was devised in 1964 by Child and Turcotte, and modified in 1973 by Pugh and others. It was first established to determine who would benefit from elective surgery for portal decompression. Class A has a favorable prognosis while class C is at high risk of death. The Child-Pugh score is a validated predictor of mortality after a major surgery. It was approved by the United Network for Organ Sharing (UNOS) as a way to determine the allocation of liver transplants to awaiting people in the United States. It is also used as a validated survival predictor of cirrhosis, alcoholic hepatitis, acute liver failure, and acute hepatitis. The variables included bilirubin, INR, creatinine, and dialysis frequency. MELD-Plus is a further risk score to assess the severity of chronic liver disease. It was developed in 2017 as a result of a collaboration between Massachusetts General Hospital and IBM. Nine variables were identified as effective predictors for 90-day mortality after a discharge from a cirrhosis-related hospital admission. ==Prevention==

Key prevention strategies for cirrhosis are population-wide interventions to reduce alcohol intake (through pricing strategies, public health campaigns, and personal counseling), programs to reduce the transmission of viral hepatitis, and screening of relatives of people with hereditary liver diseases. Little is known about factors affecting cirrhosis risk and progression. However, many studies have provided increasing evidence for the protective effects of coffee consumption against the progression of liver disease. These effects are more noticeable in liver disease that is associated with alcohol use disorder. Coffee has antioxidant and antifibrotic effects. Caffeine may not be the important component; polyphenols may be more important. Drinking two or more cups of coffee a day is associated with improvements in the liver enzymes ALT, AST, and GGT. Even in those with liver disease, coffee consumption can lower fibrosis and cirrhosis. ==Treatment==

Generally, liver damage from cirrhosis cannot be reversed, but treatment can stop or delay further progression and reduce complications. A healthy diet is encouraged, as cirrhosis may be an energy-consuming process. A recommended diet consists of a high-protein, high-fiber diet plus supplementation with branched-chain amino acids. Close follow-up is often necessary. Antibiotics are prescribed for infections, and various medications can help with itching. Laxatives, such as lactulose, decrease the risk of constipation. Carvedilol increases survival benefit for people with cirrhosis and portal hypertension. Diuretics in combination with a low-salt diet reduce fluid in the body, which helps reduce oedema. Alcoholic cirrhosis caused by alcohol use disorder is treated by abstaining from alcohol. Treatment for hepatitis-related cirrhosis involves medications used to treat the different types of hepatitis, such as interferon for viral hepatitis and corticosteroids for autoimmune hepatitis. Cirrhosis caused by Wilson's disease is treated by removing the copper which builds up in organs. A combination of cilofexor/firsocostat was studied in people with bridging fibrosis and cirrhosis. It was observed to have led to improvements in NASH activity with a potential antifibrotic effect. Lanifibranor is also shown to prevent worsening fibrosis. Preventing further liver damage Regardless of the underlying cause of cirrhosis, consumption of alcohol and other potentially damaging substances is discouraged. There is no evidence that supports the avoidance or dose reduction of paracetamol in people with compensated cirrhosis; it is thus considered a safe analgesic for said individuals. Vaccination against hepatitis A and hepatitis B is recommended early in the course of illness due to a decline in effectiveness of the vaccines with decompensation. Treating the cause of cirrhosis prevents further damage; for example, giving oral antivirals such as entecavir and tenofovir where cirrhosis is due to hepatitis B prevents progression of cirrhosis. Similarly, control of weight and diabetes prevents deterioration in cirrhosis due to non-alcoholic fatty liver disease. These agents are hepatotoxic as they are metabolized by the liver. If a medication that harms the liver is still recommended by a doctor, the dosage can be adjusted to aim for minimal stress on the liver. Lifestyle According to a 2018 systematic review based on studies that implemented 8 to 14 week-long exercise programs, there is currently insufficient scientific evidence regarding either the beneficial or harmful effects of physical exercise in people with cirrhosis on all-cause mortality, morbidity (including both serious and non-serious adverse events), health-related quality of life, exercise capacity and anthropomorphic measures. These conclusions were based on low to very low quality research, which imposes the need to develop further research with higher quality, especially to evaluate its effects on clinical outcomes. Transplantation If complications cannot be controlled or when the liver ceases functioning, liver transplantation is necessary. Survival from liver transplantation has been improving over the 1990s, and the five-year survival rate is now around 80%. The survival rate depends largely on the severity of the disease and other medical risk factors in the recipient. In the United States, the MELD score is used to prioritize patients for transplantation. Transplantation necessitates the use of immune suppressants (ciclosporin or tacrolimus). Decompensated cirrhosis Manifestations of decompensation in cirrhosis include gastrointestinal bleeding, hepatic encephalopathy, jaundice or ascites. In patients with previously stable cirrhosis, decompensation may occur due to various causes, such as constipation, infection (of any source), increased alcohol intake, medication, bleeding from esophageal varices or dehydration. It may take the form of any of the complications of cirrhosis listed below. People with decompensated cirrhosis generally require admission to a hospital, with close monitoring of the fluid balance, mental status, and emphasis on adequate nutrition and medical treatment – often with diuretics, antibiotics, laxatives or enemas, thiamine and occasionally steroids, acetylcysteine and pentoxifylline. Administration of saline is avoided, as it would add to the already high total body sodium content that typically occurs in cirrhosis. Life expectancy without a liver transplant is low, at most three years. Palliative care Palliative care is specialized medical care that focuses on providing patients with relief from the symptoms, pain, and stress of a serious illness, such as cirrhosis. The goal of palliative care is to improve quality of life for both the patient and the patient's family, and it is appropriate at any stage and for any type of cirrhosis. Especially in the later stages, people with cirrhosis experience significant symptoms such as abdominal swelling, itching, leg edema, and chronic abdominal pain, which would be amenable to treatment through palliative care. Because the disease is not curable without a transplant, palliative care can also help with discussions regarding the person's wishes concerning health care power of attorney, do not resuscitate decisions and life support, and potentially hospice. Immune system Cirrhosis is known to cause immune dysfunction in numerous ways. It impedes the immune system from working normally. This will ultimately increase bleeding as clotting factors are diminished. Clotting function is estimated by lab values, mainly platelet count, prothrombin time (PT), and international normalized ratio (INR). The American Gastroenterological Association (AGA) provided recommendations in 2021 in regards to coagulopathy management of cirrhotic patients in certain scenarios. • The AGA does not recommend extensive pre-procedural testing, including repeated measurements of PT/INR or platelet count, before patients with stable cirrhosis undergo common gastrointestinal procedures. Nor do they suggest the routine use of blood products, such as platelets, for bleeding prevention. Cirrhosis is stable when there are no changes in baseline abnormalities of coagulation lab values. • For patients with stable cirrhosis and low platelet count undergoing common low-risk procedures, the AGA does not recommend the routine use of thrombopoietin receptor agonists for bleeding prevention. • In hospitalized patients who meet standard guidelines for clot prevention, the AGA suggests standard prevention. • The AGA does not recommend routine screening for portal vein thrombosis. If there is a portal vein thrombosis, the AGA suggests treatment by anticoagulation. • In the case of cirrhosis with atrial fibrillation, the AGA recommends using anticoagulation over no anticoagulation. ==Complications==

Ascites Salt restriction is often necessary, as cirrhosis leads to the accumulation of salt (sodium retention). Diuretics may be necessary to suppress ascites. Diuretic options for inpatient treatment include aldosterone antagonists (spironolactone) and loop diuretics. Aldosterone antagonists are preferred for people who can take oral medications and do not need an urgent volume reduction. Loop diuretics can be added as additional therapy. Where salt restriction and the use of diuretics are ineffective, then paracentesis may be the preferred option. This procedure requires the insertion of a plastic tube into the peritoneal cavity. Human serum albumin solution is usually given to prevent complications from the rapid volume reduction. In addition to being more rapid than diuretics, 4–5 liters of paracentesis is more successful in comparison to diuretic therapy. or as a palliative measure. Balloon-occluded retrograde transvenous obliteration can be used to treat gastric variceal bleeding. Gastroscopy (endoscopic examination of the esophagus, stomach, and duodenum) is performed in cases of established cirrhosis. If esophageal varices are found, prophylactic local therapy may be applied, such as sclerotherapy or banding, and beta blockers may be used. Hepatic encephalopathy Hepatic encephalopathy is a potential complication of cirrhosis. Most pharmaceutical approaches to treating hepatic encephalopathy focus on reducing ammonia levels. Per 2014 guidelines, the first-line treatment involves the use of lactulose, a non-absorbable disaccharide which decreases the pH level of the colon when it is metabolized by intestinal bacteria. The lower colonic pH causes increased conversion of ammonia into ammonium, which is then excreted from the body. Rifaximin, an antibiotic that inhibits the function of ammonia-producing bacteria in the gastrointestinal tract, is recommended for use in combination with lactulose as prophylaxis against recurrent episodes of hepatic encephalopathy. In addition to pharmacotherapy, providing proper hydration and nutritional support is also essential. Several factors may precipitate hepatic encephalopathy, which include alcohol use, excess protein, gastrointestinal bleeding, infection, constipation, and vomiting/diarrhea. The annual risk of developing hepatorenal syndrome in those with cirrhosis is 8% and once the syndrome develops the median survival is 2 weeks. Infection Cirrhosis can cause immune system dysfunction, leading to infection. Signs and symptoms of infection may be nonspecific and are more difficult to recognize (for example, worsening encephalopathy but no fever). Moreover, infections in cirrhosis are major triggers for other complications (ascites, variceal bleeding, hepatic encephalopathy, organ failures, death). Cirrhosis associated immune dysfunction is caused by reduced complement component synthesis in the liver including C3, C4 and reduced total complement activity (CH50). It is estimated that 3.5% of people with cirrhosis and ascites may have asymptomatic spontaneous bacterial peritonitis. The mortality rate for infections in those with cirrhosis is higher than that of the general population. In those with cirrhosis and severe infections with sepsis, the mortality rate is greater than 50%, and in those with septic shock, the mortality rate is 65%. Screening using an ultrasound with or without cancer markers such as alpha-fetoprotein can detect this cancer and is often carried out for early signs which has been shown to improve outcomes. ==Epidemiology==

for cirrhosis of the liver per 100,000 inhabitants in 2004: Each year, approximately one million deaths are due to complications of cirrhosis, making cirrhosis the 11th most common cause of death globally. Cirrhosis and chronic liver disease were the tenth leading cause of death for men and the twelfth for women in the United States in 2001, killing about 27,000 people each year. The cause of cirrhosis can vary; alcohol and non-alcoholic fatty liver disease are main causes in western and industrialized countries, whereas viral hepatitis is the predominant cause in low and middle-income countries. The cost of cirrhosis in terms of human suffering, hospital costs, and lost productivity is high. Globally, age-standardized disability-adjusted life year (DALY) rates have decreased from 1990 to 2017, with the values going from 656.4 years per 100,000 people to 510.7 years per 100,000 people. In males DALY rates have decreased from 903.1 years per 100,000 population in 1990, to 719.3 years per 100,000 population in 2017; in females the DALY rates have decreased from 415.5 years per 100,000 population in 1990, to 307.6 years per 100,000 population in 2017. However, globally the total number of DALYs has increased by 10.9 million from 1990 to 2017, reaching the value of 41.4 million DALYs. ==Etymology==

The word "cirrhosis" is a neologism derived from ; kirrhos , meaning "yellowish, tawny" (the orange yellow colour of the diseased liver) and the suffix -osis, i.e., "condition" in medical terminology. While the clinical entity was known before, René Laennec gave it this name in an 1819 paper. == See also ==