Lecture 21.2 Hepatic Failure PDF

Hepatic failure portal vein: blood enters one organ goes into vein goes into other organ back into circulatory circulation all bring blood to liver blocking, slowed blood flow splenomegaly hemorrhoids : liver failure Lecture 21...

Hepatic failure portal vein: blood enters one organ goes into vein goes into other organ back into circulatory circulation all bring blood to liver blocking, slowed blood flow splenomegaly hemorrhoids : liver failure Lecture 21 Unit 3 Table of content 1. Assessing liver function (covered in the introduction) 2. Cirrhosis 3. Alcoholic liver disease 4. Hepatitis-induced cirrhosis 2. Cirrhosis lumps on liver surface d/t nodule Overview - injury causes cells to lay down fibrotic scar tissue, while hepatocytes regeneration is constricted. once scarred: hepatocytes regenerate into noduel and constrict blood flow in liver - constriction by the growing nodules impedes transport by the vasculature (portal hypertension ) and biliary ducts (bile stasis ). - main causes of fibrotic scarring and nodular growth are 1) parenchymal damage, 2) vascular disease, and 3) biliary tract disease. 3 2. Cirrhosis hep B: chronic liver dysfunction Etiologies of liver damage damage direct to liver cells - parenchymal damage : alcohol (most common), autoimmune hepatitis (presence of autoantibodies), viral-induced (hepB and hepC), and nonalcoholic fatty liver disease (obesity, hypertension, hyperlipidemia). before - vascular disease : right heart failure (causes hepatic congestion) and clots in hepatic veins. - biliary tract disease (least common): inflammation of intrahepatic and/or extrahepatic bile passageways (cholangitis) causing backflow of bile. 4 post renal injury: backing up of urine into kidney: causing icreased pressure and damage 2. Cirrhosis Clinical manifestations when you have symptoms: pateitn is decompensating - compensated cirrhosis is largely asymptomatic, while manifestations become apparent when patient is decomp. - signs and symptoms attributed to three main complications: 1) portal hypertension, 2) decreased liver function, and 3) hepatocellular carcinoma. huge promoter chronic inflammation: precursor fro cancer - portal hypertension : hepatic encephalopathy, liver converts ammonia into urea: water build up in brain esophageal varices, ascites, splenomegaly, and acute kidney injury* (among others) AKI: not known really why but very high correlation AKI body wants to increase blood pressure: RAS activation -> renal artery liver: releases vasodilators: arteries and veins: decreases hypertension yes but blood also pools into GI organs vascular volumes start to drop - dec. liver function : hypoalbuminemia, coagulopathies, ammonia buildup, hyperestrogenism, hyperbilirubinemia (jaundice). 5 2. Cirrhosis 1) Portal hypertension shunting: avoid blockage: natural channels : anastemoses 6 2. Cirrhosis Portal hypertension - characterized by inc. resistance to blood flow in the portal venous system backflow into inf. and sup. mesenteric veins and gastric vein. and greater portal vein pressures. we can create new shunts as an adaptive mesure - portosystemic shunts can cause esophageal varices and buildup of ammonia. - backflow of blood in the mesenteric veins can cause ascites and splenomegaly. 7  varices: weakens the wall: easier to rupture 2. Cirrhosis distension of vessel walls Portal hypertension: Portosystemic shunts - high pressure in the hepatic portal vein causes existing collateral channels to carry blood backwards towards other tissues. along the gastric vein - when new channels are made between the gastric vein and esophagus, this can cause esophageal varices. blood that has not been through liver goes directly into heart - when they’re made to circumvent the liver altogether, ammonia is not processed into urea, causing hepatic encephalopathy. 8 2. Cirrhosis Portosystemic shunts: complications - pressure building in the 1) internal iliac veins causes hemorrhoids , while in the remnant umbilical veins, it causes caput medusae. - esophageal varices may rupture and cause hematemesis or melena; may also cause major blood loss. melena: blood in stool: very dark: time to oxidize very dark red color - elevated levels of ammonia cause hepatic toxins affect brain encephalopathy, characterized by loss of alertness, confusion, anxiety, personality changes, and speech impairment. 9 2. Cirrhosis Portal hypertension: Portosystemic shunts - treatment is directed towards 1) preventing varices , 2) managing acute hemorrhages , and 3) preventing recurrent hemorrhaging. 1) β-adrenergic blockers (propranolol) lower portal pressures to prevent initial hemorrhages. 2) vasoconstrictive drugs (octreotide) can control variceal bleeding. balloon tamponade can compress esophageal veins and prevent bleeding; sclerotherapy is used to close the lumen of variceal veins. cutorize veins 10 2. Cirrhosis Portal hypertension: Portosystemic shunts 3) surgery can further prevent hemorrhaging by creating portosystemic shunts. a metallic stent can be inserted to connect the portal vein and hepatic vein; this presumably decreases portal hypertension. stenosis and thrombosis of the stent occurs over time. 11 2. Cirrhosis excessive amount of fluid Portal hypertension: Ascites - occurs as the peritoneal cavity fills with fluid. - as blood backs up into the inf. and sup. mesenteric veins, capillary hydrostatic pressure inc. - this causes fluid buildup in the tissues which begins to accumulate in the peritoneal cavity, causing abdominal distension. - danger of bacterial translocation , whereby microbes travel into the peritoneum to cause peritonitis 12 2. Cirrhosis Ascites: treatment - focuses on dietary restrictions and diuretics. - diuretics used are those that inhibit aldosterone-sensitive portions of nephron and loop diuretics (furosemide). - bed rest prevents activating the renin system. - paracentesis may be needed to remove large volumes, while volume expanders (albumin) may be required to maintain an effective circulating volume. 13 2. Cirrhosis Portal hypertension: Splenomegaly - as blood is shunted back along the splenic vein , the spleen enlarges. - the sequestration of formed elements is called hypersplenism. - increased transit time through the spleen causes more formed elements to be removed from the blood. loss of RBC: anemia loss of platelets: thrombocytopenia - this causes anemia, thrombocytopenia, and leukopenia. loss of leukocytes: 14 2. Cirrhosis 2) Decreased liver function - the following occurs as 80-90% of the liver’s functional capacity is lost. - manifestations result from the loss of the liver’s synthesis, storage, metabolic, and elimination functions. 2, 7, 10 specifically - main complications include: 1) dec. clotting factors, 2) dec. thrombopoietin prod., 3) hypoalbuminemia, 4) dec. ammonia clearance, hormone that starts prod of RBC 5) hyperestrogenism, 6) dec. bilirubin processing. 15 2. Cirrhosis Liver failure 16 2. Cirrhosis Liver function - coagulopathies appear as clotting factors are not produced; results in GI bleeds, intracranial hemorrhages, and/or nosebleeds. - blood loss exacerbated by fewer platelets (↓ thrombopoietin and hypersplenism) and esophageal varices rupture. - hypoalbuminemia exacerbates ascites and edema, as colloid pressures are severely disrupted. - fewer hepatocytes available to convert ammonia into urea, resulting in hyperammonemia , exacerbated by portosystemic shunts. 17 2. Cirrhosis Liver failure: Endocrine disorders - the liver metabolizes estrogens, causing it to remain in circulation much longer; i.e. hyperestrogenism. - in males, this causes testicular atrophy, gynecomastia, and impotence; in females, we see menstrual irregularities and sterility; and in both sexes, this is linked to loss of libido, palmar erythema and spider angioma. - impaired bilirubin conjugation impairs bile acid A’ D’ E’ K production, causing malabsorption of fats and fat-soluble vitamins. specifically vitamin K: clotting factor - bilirubin remains unconjugated and accumulates in the blood (cholestasis) , building up in the sclera and skin, i.e. jaundice. 18 2. Cirrhosis Liver failure: Treatment - this is directed toward eliminating alcohol if - alcohol-related. providing sufficient carbohydrates to prevent protein breakdown. - managing ammonia production in the GI tract by controlling protein intake. - preventing infections. - liver transplantations can help treat end-stage liver disease. 19 3. Alcoholic liver disease Alcohol metabolism production of ROS - the majority of alcohol (i.e. ethanol) is metabolized by the liver via alcohol dehydrogenase (alDH) in the cytoplasm of hepatocytes. - alDH catalyzes the conversion of ethanol into acetaldehyde and NADH (reduced from NAD+ by the addition of an H+ ion). - acetaldehyde is further metabolized into acetate. pyruvate will be turned into lactic acid to get back our NAD with new NAD and acetyl coa: were making fats: fatty liver: ketones - acetate is converted to acetyl-CoA. NAD+ -> NADH : electron transport chain - excess NADH production is we don’t have a lot of NAD left problematic. 2 ATP + 2 NAD -> NADH glucose -> pyruvate NADH -> NAD+ 20 Pyruvate -> lactic acid 3. Alcoholic liver disease Alcohol metabolism - NAD + is required for other metabolic processes to generate NADH, and alcohol metabolism competes for the use of NAD+. - as a result, lactic acid production rises, β-oxidation and gluconeogenesis are inhibited, and lipogenesis and ketogenesis are stimulated. hepatic cell injury - acetaldehyde can also breakdown and form free oxygen species, which are ROS!!! primarily responsible for liver injury. - biological sex, age, and genetic factors may confer some protection against alcohol-induced liver damage. 21 3. Alcoholic liver disease Alcohol consumption - the amount of alcohol needed to produce liver disease depends on body size, age, sex, and ethnicity. are you binge drinking 8-9 shots, or 2 bottles per day, 6-8 beers - conservative estimates are around 80 g/day for 10 to 12 years. on average - fat accumulation can disappear and inflammation and cholestasis can subside if alcohol consumption is curbed, but fibrotic scarring remains. - progressive changes in alcoholic liver disease occur across three stages: 1) fatty liver , 2) alcoholic hepatitis , and 3) cirrhosis. 3 stages of injury 22 3. Alcoholic liver disease 1) Fatty liver - increased lipogenesis results in the deposition of fat in hepatocytes; called steatosis. accumulation of fat in liver - the liver enlarges and becomes yellow , while its progression is not fully understood; depends on amount alcohol consumed, diet, hormone status, etc. - fatty liver progression does not usually produce symptoms and is reversible. no permanent damage yet - nodules not present in this stage. when you have nodules: irreversible damage 23 3. Alcoholic liver disease 2) Alcoholic hepatitis pain r/t hepatomegaly: enlargement of nodules - characterized by inflammation, necrosis of liver cells, and the presence of fibrotic tissue (not extensive yet). - may develop acutely if alcohol intake or binge drinking is increased. - signs and symptoms include hepatic tenderness, pain, anorexia, nausea, fever, jaundice, ascites, hepatic encephalopathy, and liver - failure. acute phase has a mortality rate of 10%; if person continues to drink, persistent alcoholic hepatitis can progress to cirrhosis in 1 to 2 years. - fibrotic tissue infiltration is not reversible (damage is permanent). 24 3. Alcoholic liver disease 3) Alcoholic cirrhosis very bumpy liver - designates the onset of end-stage alcoholic liver disease characterized by extensive uniform nodules on the surface of the liver; the regenerative capacity of the liver causes the nodules to grow. - the growing nodules can compress the hepatic veins and bile ducts producing: cholestasis : accumulation of bile components in the blood; portal hypertension (causing portosystemic shunts ). 25 4. Hepatitis-induced cirrhosis Hepatotropic viruses - hepatitis refers to inflammation of the liver. - many viruses can cause systemic diseases that involve the liver, including Epstein-Barr virus, herpesviruses, and enteroviruses. - hepatotropic viruses are those that trigger acute liver inflammation, and include the non-related hepatitis A, B, C, D, and E viruses. - hepatitis occurs due to direct hepatocellular injury and the body’s response to the viral antigens. - an inability to remove the virus early may lead to chronic hepatitis and the ability to transmit the virus (carrier state). 26 4. Hepatitis-induced cirrhosis Disease progression acute affects hep b and c - viral hepatitis can present with different syndromes : asymptomatic infection; acute hepatitis with or without progression to liver failure; carrier state with or without chronic hepatitis; chronic hepatitis with or without progression to cirrhosis; or - hepatitis A, D, and E infections do not progress to chronic liver disease (i.e. cirrhosis); hepB and hep C are associated with cirrhosis. 27 4. Hepatitis-induced cirrhosis hep c: very unstable virus: harder to create vaccine Hepatitis B twinrix - caused by a double-stranded DNA virus and is transmitted via infected blood or serum , i.e. drug use and sexual contact. - clinical course includes acute and chronic forms of hepatitis, cirrhosis, fulminant hepatitis, and the carrier state; may also present as asymptomatic. - immunization provides long-term - protection. treatment in the absence of immunization includes the use of interferons and antiviral agents and liver transplantation. 28 4. Hepatitis-induced cirrhosis Hepatitis C RNA much less stable than DNA viruses remain dormant lin liver - caused by a single-stranded RNA virus and is transmitted via infected blood or serum , i.e. drug use and sexual contact. - it is the most common cause of chronic hepatitis, cirrhosis, and hepatocellular cancer in the world. - genetic instability prevents the development of a vaccine. - treatment includes interferons and nucleoside agents, while transplantations are more successful than for hepB; graft often becomes reinfected but the disease progresses more slowly. 29 4. Review Questions - What is particular about the blood circulation in the liver compared to other organs? - How is a lobule organised? - What are the main categories of liver function? Give examples of each. What would be the manifestation of your examples' altered function. - What are the functions of the hepatocytes? - What is a nodule is cirrhosis? How are they formed and how to they affect liver function? - What is portal hypertension? How does it occur and what are some of the manifestations? - What are some manifestations of cirrhosis? - Why are individuals with cirrhosis more likely to have edema or ascites? - What are the stages of alcoholic liver disease? What are their manifestations? - Which hepatitis viruses can cause cirrhosis? 30