ACUT AND CHRONIC LIVER FAILURE

1. ACUT AND CHRONIC LIVER FAILURE

2. Acut liver failure Liver failure several hours or days after the damageing insult. The main problem is the death of the hepatocytes especially by necrosis. Types simple hepatitis: only liver is damaged (good recovery) fulminant and subfulminant liver failure: after and becuse of the liver damage the other organs are unfunctional: brain (= hepatic encephalopathy), cardiorespiratory, urinary and different infections. (recovery 40%, 20%)

3. Histological alterations • necrosis and apoptosis cell death • regenerative islands with new cells • inflammation (= hepatitis) by the infiltration of leucocytes, macrophages • steatosis = accumulation of TAG • fibrosis = connective tissue increase • Causes of acut liver failure • chemicals, medicines, organic solvents, ethanol, plant and fungi toxins (60%) • illness of other organs (18%): portal thrombosis, heart failure • viruses (12%): Hepatitis A,B,C,B+D, E,F,G, Cytomegalov., Varicella zoster, Adenov., Eppstein-Barr v., Q-fever, Yellow-fever • systemic: sepsis... • metabolic

4. Among all the acut liver failure phenacetin/paracetamol=acetaminophen causes 37 % (according to a study in USA) Signs of acut liver failure functional hepatocyte number ↓→ glycogen storage and gluconeogenetic capacity ↓→ hypoglycemia, lactacidosis bilirubin is not conjugated in liver, rather accumulated in sclera and skin → icterus blood clotting factors, inhibitors, fibrinolytics are not produced by liver → coagulopathy bleeding and hemorrhage at the same time urea cycle does not proceed → hyperammonemia → hepatic encephalopathy Treatment glucose + insulin fulminant failure: mannit, hemofiltration, help of the cardiovascular system

5. Chronic liver failure • Because of prolonged insult of liver it proceeds, worsens slowly. Liver normal structure is disrupted, something abnormal is accumulated and accompanied by inflammation. • inflammatory cells (leucocytes, lympocytes, macrophages) that produce cytokines, hepatocytes die (and regenerate): hepatitis • TAG = triglyceride accumulation: steatosis • connective tissue, collagen accumulates and appears where it was not normally:cirrhosis (= continuation of fibrosis) • immortalized tumor cells spred: carcinoma • bile acids hyperproduced but remain in liver, not secreted: cholostasis, cholangitis • Any of them can be combined. (E.g. hepatosteatitis, biliary cirrhosis, Hepatitis C infection leading to carcinoma)

6. Reasons of chronic liver failure • overfeeding, obesity, insulin resistance, diabetes mellitus • prolonged vitamin/trace element/amino acid deficiency (starvation, malnutrition) • medicines, alcohol, toxins (aflatoxin, Bacillus cereus toxin)), organic solvents • viruses (Hepatitis B,C, HIV), bacteria, parasites • cholostasis • tumor • Normal functions of liver • uptake and degradation of glucose, galactose, fructose to yield energy • formation and degradation of glycogen to maintain blood sugar level • synthesis and secretion of glucose from taken up lactate, glycerol, amino acids • synthesis of aminosugars, glycoproteins, secretion of some blood proteins

7. synthesis of glucuronic acid, conjugation of endogenious and exogenious molecules with it to be excreted • uptake and degradation of lipoprotein remnants • uptake of fatty acids, glycerol, cholesterol ester from lipoproteins • synthesis and degradation of fatty acids (any kind), TAG, phospholipids • storage of some TAG, and cholesterol ester • synthesis of cholesterol, its ester, bile acids, utake of bile acids • formation and secretion of VLDLand nascent HDL to blood • formation and secretion of bile to gall bladder (than to duodenum) • uptake and degradation of free fatty acids derived from adipocytes, formation and secretion of ketone bodies to blood • storage of some vitamins, metals, blood • synthesis of hemostasis proteins, IGF • uptake and degradation, detoxification of all kind of hormons • uptake and degradation of old proteins from blood

8. Alcoholic liver failure Alcohol can cause hepatitis, steatosis, steatohepatitis, cirrhosis, carcinoma. steatosis occures because the high amount of NADH (produced by alcohol dehydrogenase) shifts reactions toward formation of glycerol-3-P oxigen free radicals deteorate mitochondrial enzymes including respiratory chain and beta-oxidation, so FAs can not be broken down inflammation caused by ROS from respiratory chain and CYP (cytochrome P450), by TNFa, IL-8, TGF-beta from macrophages fibrosis and further cirrhosis is caused by TNFa, TGF-beta, IL-6, (leptin in obese) necrosis and apoptosis patomechanism contains: ROS, mutated DNA, aldehyde- protein adduct considered as foreign and immunogenic, enzymes’ inactivation by ROS, decrease of protecting antioxidant molecules: GSH, vitmin C and E, antioxidant enzymes

9. Signs of chronic liver failure and reasons of the signs • albumin synthesis ↓→ colloid osmotic pressure ↓→ edema • synthesis of hemostasis proteins ↓→ bleeding and thrombosis at the same time • biotransformation ↓→ bilirubin conjugation ↓→ icterus = jaundice transformation and excretion of androgens is faster than estrogens → feminization of men: testis atrophy, gynecomastia • abnormal amino acid degradation: fetor hepaticus = special smell • hyperammonemia → hepatic encephalopathy stages: • slowness of mentation, disturbed sleep drowsiness, inappropriate behavior confusion, dysorientation, agiteted coma (not respond to any stimuly)

10. Treatment • elimination of the injureous something • supply of antioxidant trace elements, amino acids, vitamins: selen, zink, manganeese, vitamin C,E • proper nutrition (cease of starvation or malnutrition) • withrawal or low dose of medicines • no immunsuppressants or steroids • Steatosis and fibrosis are reversible. Cirrhosis is uncurable. Carcinoma can be eliminated by surgery.

11. 6.) tumor, cirrhosis, thrombosis → portal hypertension → a.) portocaval shunts (blood vessel collaterals that bypass th liver from gut to systemic veins) b.) ascites (fluid in abdomen) c.) hepatorenal syndrome (anuria) d.) esophagus rupture and bleeding

12. How serious is the liver failure depends on • genetic polymorphism: effectiveness or susceptibility of proteins • additive and synergistic effect of environment: alcohol + medicine + viral infection+ fungi toxin is more serious than separately • food every overfeeding = oxidative stress starvation, malnutrion leads to amino acid, trace element, or vitamin deficiency that sensitizes the liver to next insult • male or female lipid protein ratio and localization is different sexual steroids effect on metabolism differently • increases with age radiation, chemical agents etc. cause mutations, their correction is detiorated • the illness of other organs can be a reason and consequence as well