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Cirrhosis is a condition that is a consequence of chronic liver disease in which the healthy liver cells become replaced by fibrotic tissue or scarring, giving only small islands of regenerated hepatic tissue. As a result, the liver is no longer able to carry out its functions properly. The causes include chronic viral hepatitis, alcohol use, and the damage is exponentially increased in people who have viral hepatitis at the same time. There are metabolic causes such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, hemochromatosis, Wilson's disease, and alpha 1-antitrypsin deficiency. You can also have drug-induced cirrhosis from compounds such as methotrexate, not only directly from itself but also because it enhances damage from other drugs and from viral causes. Chronic autoimmune hepatitis is another cause, such as primary biliary cirrhosis, which is almost only seen in middle-aged women, or secondary biliary cirrhosis associated with primary sclerosing cholangitis. So, what actually happens in cirrhosis? This is a normal sinusoid in the liver, which is a specialized form of capillary, and you'll see why that's important in a minute. The hepatocytes of the liver are separated from these sinusoids by a space known as the space of Disse, where hepatic stellate cells are found. These cells are crucial in cirrhosis pathophysiology because they are involved in scar formation in response to liver damage. Kupffer cells are a type of specialized macrophage that have phagocytic and scavenger activity, and these are found in the sinusoid. Venous blood from the portal system mixes with arterial blood from the hepatic artery in the same sinusoid and then flows through into a central vein. These central veins collect together in the hepatic veins, which take blood into the inferior vena cava. Just for completeness, the green you see on the top is bile produced by hepatocytes flowing into the biliary system. So regardless of what causes the damage, the end result is very similar, with only the pattern of fibrosis changing. Initially, there is an insult that leads to inflammation and formation of scars, as we mentioned, coming from the hepatic stellate cells. The fibrosis pushes against the sinusoid and leads to an increase in the resistance to the flow of blood. The remaining healthy hepatocytes then proliferate and end up taking the shape of nodules, which end up squeezing the portal vein branches within the liver, leading to portal hypertension. The second change is what's known as capillarization of the liver sinusoids, which, as we said, are specialized capillaries. The liver sinusoidal endothelial cells are different from vascular capillary endothelial cells because under normal circumstances they feature fenestrations and do not have a basement membrane. Capillarization means that they undergo differentiation and become the vascular type of endothelium with a basement membrane as well as losing their fenestrations. This makes it harder to have the bi-directional exchange with the hepatocytes that normally occurs, and overall this leads to a lower compliance of the sinusoid, meaning an increased resistance to blood flow and so contributes to portal hypertension. Portal hypertension is when the blood pressure in the portal vein is higher than normal. Its usual values are between 5 and 10 millimeters of mercury. The portal system refers to the portal vein, which drains into the liver, and the main vessels that link to the portal vein are the superior mesenteric vein, which comes from the small intestines, the splenic vein, which of course carries blood from the spleen, also the gastric veins that connect onto the portal vein. The inferior mesenteric vein connects onto the splenic vein and carries blood from the large intestine. So if the pressure is higher than usual, blood essentially backlogs into these veins and ends up forming varices in some cases, opening up previously closed connections such as the round ligament, which is the obliterated umbilical vein. The hepatic veins bring blood into the inferior vena cava. The clinical features can vary. Initially, liver damage is reversible, but cirrhosis itself is irreversible and may be initially asymptomatic. Then, with disease progression, patients may have fatigue or pruritus, which is itching due to the build-up of bile acid and release of endogenous opioids. They may have jaundice or edema, which may be peripheral, but we may also of course see ascites. Gynecomastia may be seen in males as the liver plays a role in balancing testosterone and estrogen levels by sex hormone-binding globulin production. Palmar erythema occurs for a similar reason, as well as nitric oxide release. You may also see spider nevi, a type of telangiectasia meaning swollen capillaries, and caput medusae, which are distended superficial epigastric veins that radiate from the umbilicus. Hepatosplenomegaly may also be seen. Patients can also present directly with complications either of portal hypertension, such as rupture of the varices, which can lead to catastrophic bleeding, or due to a decrease in liver function. They may present with hepatic encephalopathy. The complications of ascites include conditions like spontaneous bacterial peritonitis and hepatorenal syndrome. Another potential complication of cirrhosis is hepatocellular carcinoma. Liver biopsy is the gold standard for diagnosing cirrhosis but is not needed if the clinical manifestations, lab findings, and imaging suggest cirrhosis. The lab tests include platelet count, aminotransferases, alkaline phosphatase, gamma-glutamyl transferase, bilirubin, albumin, bleeding times, as well as looking for viral hepatitis serology. Ferritin and copper levels may also be checked for hemochromatosis or Wilson disease suspicions, and of course alpha 1-antitrypsin levels may also be taken. Ultrasound is useful in the evaluation of cirrhosis because it can evaluate the portal system, but also FibroScan is a device based on ultrasound that evaluates liver stiffness by sending a pulse through the liver. The Bonacini score is a predictive tool that uses platelet count, aminotransferase ratio, and INR to give a cirrhosis probability. Liver cirrhosis itself is irreversible, but there are some options, some treatments aimed to prevent further progression. So in patients with hepatitis B, an entecavir or tenofovir may be given. Hepatitis C can now be treated with drugs like DAAs. Severe patients with cirrhosis due to alcohol should abstain from alcohol, while non-alcoholic steatohepatitis-related cirrhosis need patients to control weight, and hemochromatosis needs iron chelation. Transplantation is an option for some patients, but given the strict criteria, a lot of patients with cirrhosis will not be eligible. The complications need specific treatments. To prevent bleeding, patients may be given medication such as beta blockers, nitrates, and vasopressin analogues, literally pressors, as well as surgical treatments like variceal ligation if they do bleed. Hepatic encephalopathy is reduced by giving lactulose, rifaximin, and antibiotics such as rifaximin and vancomycin in an attempt to reduce the urea produced by microbes, but the efficacy is debatable. Ascites will also need to be treated both to prevent complications as well as symptomatic relief for the patient. This includes salt restriction in the diet and the use of diuretics as well as paracentesis. You. [Music]
