Cirrhosis - Pathogenesis & Clinical Manifestations

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Cirrhosis signifies the terminal stage of various liver diseases, hallmarked by irreversible fibrosis and the functional decline of liver tissue. The predominant etiologies are chronic alcohol use and chronic viral hepatitis (Hep B and C), though autoimmune diseases and genetic disorders like alpha-1 antitrypsin deficiency (AAT), Wilson disease, and hemochromatosis can also cause cirrhosis.

Structural alterations in the liver's microscopic architecture have far-reaching implications. The perisinusoidal space (space of Disse) harbors stellate cells that transform into myofibroblasts under pathological conditions. These ‘activated stellate cells’ produce excess collagen that deposits in the perisinusoidal space, leading to bands of fibrosis encircling regenerative nodules of proliferating hepatocytes. These changes prompt a cascade of detrimental effects, such as compression of sinusoids and portal hypertension, disrupting the liver's capacity for detoxification and solute exchange.

Clinically, cirrhosis manifests in various forms affecting multiple organ systems, and can increase the risk of developing hepatocellular carcinoma (HCC). Portal hypertension is key complication, and is associated with esophageal and gastric varices hemorrhoids and the engorgement of paraumbilical veins known as ‘caput medusae’. Splenomegaly occurs due to increased splenic blood flow, leading to splenic dysfunction and thrombocytopenia. Additionally, portal hypertension exacerbates ascites by increasing pressure in the perisinusoidal space, overwhelming the lymphatic system and leading to leakage of fluid into the peritoneal cavity. This protein-rich fluid is susceptible to infection by enteric bacteria that can result in spontaneous bacterial peritonitis (SBP).

Cirrhosis can also lead to decreased clotting factors, causing coagulopathy with a prolonged PT & elevated INR, indicating impaired synthesis in hepatic coagulation factors II, VII, IX, & X. Cirrhosis can also cause hypoalbuminemia, leading to peripheral edema and a decrease in total serum calcium (normal ionized). In the liver's diseased state, various metabolic pathways are compromised: impaired synthesis of 25-hydroxylase can cause Vitamin D deficiency, and a decrease in glycogenolysis and gluconeogenesis can result in fasting hypoglycemia. Elevated levels of conjugated and unconjugated bilirubin result in jaundice, and the decreased metabolism of ammonia can result in hepatic encephalopathy, characterized by altered mental status, seizures, and asterixis.

Cirrhosis also causes hormonal imbalances, notably impaired estrogen & androstenedione metabolism. The increased estrogen leads to symptoms like palmar erythema and vascular telangiectasis, as well as gynecomastia & ED in men. Increased androstenedione (as well as low intravascular volume) contribute to RAAS activation, resulting in hypokalemia and hyponatremia, as well as pre-renal AKI in severe cases. Involvement of the kidney in cirrhosis is known as hepatorenal syndrome, occurs due decreased Kupffer macrophages in the liver and a consequent increase in bacterial DNA, triggering the release of nitric oxide. Excessive NO can cause vasodilation in the splanchnic (GI) arteries in hepatorenal syndrome, as well as vasodilation in the pulmonary capillaries and V/Q mismatch, known as hepatopulmonary syndrome.

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What is the pathogenesis of cirrhosis?

Cirrhosis is the result of long-term liver damage, where normal liver tissue is replaced by scar tissue (fibrosis). This scarring is mainly caused by activation of liver stellate cells in the perisinusoidal space. Upon injury, these cells transform into myofibroblasts, which produce excess collagen, leading to a greater fibrous extracellular matrix in place of normal liver tissue. In response to injury, new hepatocytes are created by liver stem cells that form regenerative nodules surrounded by bands of fibrosis. As fibrosis becomes widespread, the sinusoids are compressed, leading to increased intrasinusoidal pressure and complications such as portal hypertension.

What are the clinical manifestations of cirrhosis?

Cirrhosis can cause a range of clinical manifestations due to its impacts on numerous body systems. These include coagulopathy (easy bruising, prolonged bleeding after injury, due to decreased synthesis of clotting factors), hypoalbuminemia (decreased total serum calcium levels with normal ionized calcium, peripheral edema), Vitamin D deficiency, fasting hypoglycemia, conjugated and unconjugated hyperbilirubinemia (leading to jaundice), increased serum ammonia leading to hepatic encephalopathy, and altered sex hormone levels leading to symptoms such as gynecomastia in men and palmar erythema.

How does cirrhosis contribute to portal hypertension and its complications?

Portal hypertension is a common complication of cirrhosis, resulting from increased intrasinusoidal pressure due to widespread fibrosis and compression of sinusoids. This elevated pressure in the portal venous system can lead to various complications such as esophageal and gastric varices, hemorrhoids, and engorged paraumbilical veins known as ‘caput medusae.’ Portal hypertension also causes splenomegaly and splenic dysfunction, which can result in thrombocytopenia due to sequestration of platelets in the spleen.

How does cirrhosis affect the detoxification function of the liver?

In cirrhosis, fibrosis disrupts the liver's ability to detoxify the blood. The thickened extracellular matrix and narrowed openings in the liver's blood vessels, or sinusoids, limit the exchange of substances between the blood and liver cells. One consequence is that the liver becomes less efficient at converting ammonia into less toxic forms through the urea cycle, leading to elevated levels of ammonia in the blood. High ammonia levels can penetrate the blood-brain barrier and result in hepatic encephalopathy, which may manifest as cognitive changes, seizures, or even death.

What complications and secondary conditions can develop due to cirrhosis?

The development and progression cirrhosis can cause various complications. These include portal hypertension, which can lead to esophageal and gastric varices, hemorrhoids, splenomegaly, thrombocytopenia, ascites, and spontaneous bacterial peritonitis (SBP). Cirrhosis can also lead to the activation of the renin-angiotensin-aldosterone system, which leads to hypoalbuminemia, hypokalemia, and hyponatremia. Advanced cases can result in hepatorenal syndrome, a deterioration of kidney function in severe cases of liver disease.