ACUT AND CHRONIC LIVER FAILURE

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%)

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

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

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)

Reasons of chronic liver failure

1) overfeeding, obesity, insulin resistance, diabetes mellitus

2) prolonged vitamin/trace element/amino acid deficiency (starvation, malnutrition)

3) medicines, alcohol, toxins (aflatoxin, Bacillus cereus toxin)), organic solvents

4) viruses (Hepatitis B,C, HIV), bacteria, parasites

5) cholostasis

6) tumor

Normal functions of liver

a) uptake and degradation of glucose, galactose, fructose to yield energy

b) formation and degradation of glycogen to maintain blood sugar level

c) synthesis and secretion of glucose from taken up lactate, glycerol, amino acids

d) synthesis of aminosugars, glycoproteins, secretion of some blood proteins

e) synthesis of glucuronic acid, conjugation of endogenious and exogenious

molecules with it to be excreted

f) uptake and degradation of lipoprotein remnants

g) uptake of fatty acids, glycerol, cholesterol ester from lipoproteins

h) synthesis and degradation of fatty acids (any kind), TAG, phospholipids

i) storage of some TAG, and cholesterol ester

j) synthesis of cholesterol, its ester, bile acids, utake of bile acids

k) formation and secretion of VLDLand nascent HDL to blood

l) formation and secretion of bile to gall bladder (than to duodenum)

m) uptake and degradation of free fatty acids derived from adipocytes, formation and

secretion of ketone bodies to blood

n) storage of some vitamins, metals, blood

o) synthesis of hemostasis proteins, IGF

p) uptake and degradation, detoxification of all kind of hormons

q) uptake and degradation of old proteins from blood

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

Signs of chronic liver failure and reasons of the signs

1) albumin synthesis ↓→ colloid osmotic pressure ↓→ edema

2) synthesis of hemostasis proteins ↓→ bleeding and thrombosis at the same time

3) biotransformation ↓→

bilirubin conjugation ↓→ icterus = jaundice

transformation and excretion of androgens is faster than estrogens →

feminization of men: testis atrophy, gynecomastia

4) abnormal amino acid degradation: fetor hepaticus = special smell

5) hyperammonemia → hepatic encephalopathy stages:

slowness of mentation, disturbed sleep

drowsiness, inappropriate behavior

confusion, dysorientation, agiteted

coma (not respond to any stimuly)

Treatment

a) elimination of the injureous something

b) supply of antioxidant trace elements, amino acids, vitamins: selen, zink,

manganeese, vitamin C,E

c) proper nutrition (cease of starvation or malnutrition)

d) withrawal or low dose of medicines

e) no immunsuppressants or steroids

Steatosis and fibrosis are reversible. Cirrhosis is uncurable. Carcinoma can be

eliminated by surgery.

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

How serious is the liver failure depends on

a) genetic polymorphism: effectiveness or susceptibility of proteins

b) additive and synergistic effect of environment: alcohol + medicine + viral infection+

fungi toxin is more serious than separately

c) food

every overfeeding = oxidative stress

starvation, malnutrion leads to amino acid, trace element, or vitamin

deficiency that sensitizes the liver to next insult

d) male or female

lipid protein ratio and localization is different

sexual steroids effect on metabolism differently

e) increases with age

radiation, chemical agents etc. cause mutations, their correction is

detiorated

f) the illness of other organs can be a reason and consequence as well