When cells are injured or damaged and die off, usually that dead tissue that was previously full of living cells becomes fibrotic, meaning it becomes thickened with heaps and heaps of protein and forms scar tissue. So when your liver is constantly forced to process alcohol like in alcoholic liver disease, or subject to a viral attack for a long time like in HBV, or anything else that causes a long-term or chronic state of liver cell or hepatocyte destruction and inflammation, your liver can become seriously scarred and damaged to the point where it’s no longer reversible, at which point it becomes fibrotic and in the liver we call this process cirrhosis. Because it’s usually irreversible, cirrhosis is often referred to as “end-stage” or “late-stage” liver damage. When liver cells are injured, they start to come together and form what are called regenerative nodules. You can think of these as colonies of living liver cells. These are one of the classic signs of cirrhosis and are why a cirrhotic liver is more bumpy as opposed to a smooth, healthy liver. Also with cirrhotic liver tissue, you’ll see that in between these clumps of cells or nodules, is fibrotic tissue and collagen. Here’s a classic histology image of cirrhotic tissue, this clump of cells in the middle is the regenerative nodule, and these blue stains surrounding it are the bands of protein from the process of fibrosis. If we zoom out a bit and look at it with the naked eye, we’ll again see these nodules, which have fibrotic protein bands in between. How do these bands of fibrotic tissue form though? Well fibrosis is a process mediated by special cells called stellate cells, that sit between the sinusoid and hepatocyte, known as the perisinusoidal space. Here’s a pretty basic layout of the basic functional unit of the liver, you’ve got the portal vein and hepatic artery that combine into a sinusoid, which then goes into the central vein, and these are all lined with hepatocytes. Along with these though you’ve also got a bile duct, and all three constitute a portal triad. So the perisinusoidal space, which literally means “around the sinusoidal space”, and stellate cells are about here. And usually in healthy tissue, these guys’ main function is to store vitamin A and are otherwise considered quiescent, or sort of dormant. When the hepatocytes are injured though, they secrete paracrine factors that “activates” and changes the stellate cells. When activated, the stellate cells lose vitamin A, proliferate, and start secreting secreting transforming growth factor beta1, or TGF-beta, which then causes them to produce collagen, which is the main ingredient in extracellular matrix, fibrosis, and scar tissue. As this fibrotic tissue builds up, it starts to compress the central veins and sinusoids. It’s thought that in a healthy, normal state, these cells play key roles in the natural wound-healing process, but when the liver cells are constantly injured, the stellate cells are constantly activated and so they constantly produce collagen and factors that lead to fibrosis. And this is when complications due to cirrhosis start to crop up. As the central veins and sinusoids become compressed and push on the fluid inside, their pressure starts to build up, leading to intrasinusoidal (or portal) hypertension, which is this higher pressure in the portal veins. Higher portal vein pressure means that fluid in blood vessels is more likely to get pushed into tissues and across tissues into large open spaces like the peritoneal cavity. That’s why cirrhosis leads to excess peritoneal fluid, a condition called ascites, and can result in other complications like congestive splenomegaly and hypersplenism, where the spleen becomes enlarged because all this fluid and blood can’t get into the liver, and backs up into the spleen. In the same way, your circulatory system starts diverting blood away from the liver because of the high liver pressures, this is known as a portosystemic shunt. Blood flow follows the path of least resistance and shunts away from the portal system and towards the systemic system of circulation. Though not fully understood, these changes in portal flow ultimately trigger renal vasoconstriction, so increased resistance in the renal circulation, which decreases blood flow through the kidneys, leading to decreased filtration hepatorenal failure, where kidney failure follows liver failure. The fibrotic tissue, pressure buildup, and diversion of blood from the hepatic circulation essentially reduces the number of functional sinusoidal veins, and the number of functional portal triads in general. As you have less and less of these basic liver functional units, your liver becomes less and less able to do its job of detoxification. When your liver isn’t detoxifying your blood, these toxins can get into the brain and start causing mental deficits, a condition known as hepatic encephalopathy. Although there are several neurotoxins that are thought to contribute to the development of these mental changes, the best understood factor is ammonia in the blood, which is produced mainly in the gastrointestinal tract; usually the liver plays a vital role in removing ammonia and stopping it from going into the systemic circulation. As more of these and other toxins get into the brain, patients might develop asterixis, where they have tremoring or jerky hands when outstretched, and as even more toxins build up, eventually patients can progress to a coma. Also, since the liver plays a big role in metabolizing estrogen into inactive metabolites that can be removedn from the blood and excreted, patients can also experience complications due to increased estrogen in the blood, like gynecomastia, spider angiomata, and palmar erythema. And, since the liver usually conjugates bilirubin, increased unconjugated bilirubin in the blood from a less-functional liver can lead to jaundice. Another important job of the liver is producing albumin, so again, if the liver’s not functioning right, you can have a decreased amount of albumin in the blood, or hypoalbuminemia. Finally, the liver helps in making clotting factors or proteins that help coagulate your blood, so when you aren’t producing these coagulation factors, you can develop issues related to your ability to coagulate blood, which you need in order to stop blood loss after an injury. To recap the general symptoms of cirrhosis, early on, with a small amount of scarring and fibrosis, we call it compensated cirrhosis, meaning the liver can still do a lot of its job. In this case, somebody with cirrhosis might not have any symptoms, or have nonspecific symptoms like weight loss, weakness, or fatigue. Later on, though, with extensive scarring, the liver progresses to decompensated cirrhosis, and can’t function properly. At this point many of the described symptoms start to develop, like jaundice and pruritus or itchy skin, ascites, hepatic encephalopathy leading to confusion, and easy bruising from low coagulation factors. For diagnosis, the “gold standard” is a liver biopsy, taking a tiny sample of the liver tissue examine under a microscope. Common lab findings include elevated serum bilirubin, as well as elevated liver enzymes like aspartate aminotransferase, (AST) and alanine aminotransferase (ALT), where AST is usually more elevated than ALT, alkaline phosphatase (ALP), and gamma glutamyl transpeptidase, and thrombocytopenia, or low platelet count. As to treatment, generally the scarring in cirrhosis is irreversible, so first of all it’s important to prevent continued liver damage by identifying the underlying cause and treating that, for example stopping alcohol consumption or antiviral treatment for those with hepatitis C. With advanced cirrhosis, though, where the liver stops functioning, a liver transplant might be needed. Alright, as a quick recap, cirrhosis is when inflammation and liver damage causes the liver to become fibrotic and develop scar tissue. Causes include things like excessive alcohol consumption or prolonged viral attack like from hepatitis B or hepatitis C virus. Over time as the liver becomes less functional, symptoms like jaundice, ascites, easy bruising, and hepatic encephalopathy develop. Diagnosis is often done with a biopsy or through lab tests, and treatment for advanced cirrhosis is to treat the underlying cause, but sometimes a liver transplant is required.