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 caudate lobe hypertrophy on ultrasound due to cirrhosis hepatofugal (non-forward) flow in portal vein the diagnosis of cirrhosis in an individual is based on multiple factors. cirrhosis may be suspected from laboratory findings, physical exam, and patient 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, widening of the fissures and enlargement of the spleen. an enlarged spleen, which normally measures less than 11–12 cm 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). pulsatility indices (pi) indexcalculationcutoff average-based(max – min) / average0.5 max-relative(max – min) / max0.5–0.54 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. liver cirrhosis on ct imaging of the abdomen in transverse view 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). bonacini score scoreplatelet count x109alt/ast ratioinr 0>340>1.7<1.1 1280-3401.2-1.71.1-1.4 2220-2790.6-1.19>1.4 3160–219<0.6... 4100-159...... 540-99...... 6<40...... 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. however, this rarely results in a platelet count < 50 000/ml. aminotransferases ast and alt are moderately elevated, with ast > alt. however, normal aminotransferase levels do not preclude cirrhosis. alkaline phosphatase – slightly elevated but less than 2–3 times the upper limit of normal. gamma-glutamyl transferase – correlates with ap levels. typically much higher in chronic liver disease from alcohol. bilirubin levels are normal when compensated, but may elevate as cirrhosis progresses. albumin levels fall as the synthetic function of the liver declines with worsening cirrhosis since albumin is exclusively synthesized in the liver. prothrombin time increases, since the liver synthesizes clotting factors. globulins increase due to shunting of bacterial antigens away from the liver to lymphoid tissue. serum sodium levels fall(hyponatremia) due to inability to excrete free water resulting from high levels of adh and aldosterone. leukopenia and neutropenia are due to splenomegaly with splenic margination. coagulation defects occur, as the liver produces most of the coagulation factors, thus coagulopathy correlates with worsening liver disease. glucagon is increased in cirrhosis. vasoactive intestinal peptide is increased as blood is shunted into the intestinal system because of portal hypertension. vasodilators are increased (such as nitric oxide and carbon monoxide) reducing afterload with compensatory increase in cardiac output, mixed venous oxygen saturation. 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, antismooth 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 immunoglobins are nonspecific, but may help in distinguishing various causes. 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) presepsin soluble cd14 soluble cd163 soluble cd206 (mannose receptor) soluble trem-1 a recent study identified15 microbial biomarkers from the gut microbiota. these could potentially be used to discriminate patients with liver cirrhosis from healthy individuals. pathology micrograph 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. 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. no fibrosis, but mild zone 3 steatosis, in which collagen fibres (pink–red, arrow) are confined to portal tracts (p) (van gieson's stain) histopathology of steatohepatitis with mild fibrosis in the form of fibrous expansion (van gieson's stain) histopathology of steatohepatitis with moderate fibrosis, with thin fibrous bridges (van gieson's stain) histopathology of steatohepatitis with established cirrhosis, with thick bands of fibrosis (van gieson's stain) trichrome stain, showing cirrhosis as a nodular texture surrounded by fibrosis (wherein collagen is stained blue). 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, 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. 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 if associated with steatosis the color is yellow. 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. micronodular cirrhosis, with diffuse areas of pallor. pale macronodules of cirrhosis. 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. this scoring system uses multiple lab values including bilirubin, albumin, and inr. the presence of ascites and severity of encephalopathy is also included in the scoring. patients are classified into class a, b, or c. class a has a favorable prognosis while class c is at high risk of death. child-pugh score in relation to liver function, prognosis and post-op mortality child-pugh class points liver function prognosis abdominal surgery post-operative mortality child-pugh class a 5–6 points good liver function 15–20 years 10% child-pugh class b 7–9 points moderately impaired liver function 30% child-pugh class c 10–15 points advanced liver dysfunction 1–3 years 82% the child-pugh score is a validated predictor of mortality after a major surgery. for example, child class a patients have a 10% mortality rate and child class b patients have a 30% mortality rate while child class c patients have a 70 to 80% mortality rate after abdominal surgery. elective surgery is usually reserved for those in child class a patients. there is an increased risk for child class b individuals and they may require medical optimization. overall, it is not recommended for child class c patients to undergo elective surgery. in the past, the child-pugh classification was used to determine patients who were candidates for a liver transplant. child-pugh class b is usually an indication for evaluation for transplant. however, there were many issues when applying this score to liver transplant eligibility. thus, the meld score was created. the model for end-stage liver disease (meld) score was later developed and approved in 2002. 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. in 2016, sodium was added to the variables and the score is often referred to as meld-na. meld-plus is a further risk score to assess 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. the variables include all model for end-stage liver disease (meld)'s components, as well as sodium, albumin, total cholesterol, white blood cell count, age, and length of stay. the hepatic venous pressure gradient (difference in venous pressure between incoming and outgoing blood to the liver) also determines the severity of cirrhosis, although it is hard to measure. a value of 16 mm or more means a greatly increased risk of death. 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