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Pathophysiology of Liver

Guo xiaosunShandong University

Liver anatomy:Four Lobes

AnatomyLungsHeartLiverOmentumDiaphragmGall bladder

Structure of Liver Lobule

Structure of Liver Lobule

Normal Liver Histology

Liver Functions:Metabolism Carbohydrate, Fat & ProteinSecretory bile, Bile acids, salts & pigmentsExcretory Bilirubin, drugs, toxinsSynthesis Albumin, coagulation factorsStorage Vitamins, carbohydrates etc.Detoxification toxins, ammonia, etc.

Causes and mechanisms of Liver DiseaseBiological Factors: virus(HBV)Physical and Chemic Factors(Alcohol Tetrachloride) Genetic FactorsHemochromatosisImmunity Factors: chronic hepatitis --activated T cell Nutritional Factors: (nutritional deficiency worsen the condition)

Alcoholic Fatty Liver

Jaundice A yellowing of the skin, sclerae, and other tissues caused by excess circulating bilirubin.

Jaundice

Jaundice

Bilirubin Metabolism Formation Plasma transport Liver uptake Conjugation Biliary excretion

CHOLESTASIS A clinical and biochemical syndrome that results when bile flow is impaired.

Etiology intrahepatic causes hepatitis, drug toxicity, and alcoholic liver disease. intrahepatic and extrahepatic causes duct stone and pancreatic cancer

Contributing factors interference with microsomal hydroxylating enzymes impaired activity of Na+,K+-ATPase altered membrane lipid composition and fluidityinterference with the function of microfilaments enhanced ductular reabsorption of bile constituents

The pathophysiologic effectsmixed hyperbilirubinemia pruritus steatorrhea and hypoprothrombinemia osteoporosis or osteomalacia hyperlipidemia

Portal Hypertension Increased pressure in the portal venous system.

Mechanism vascular compression and distortion by the fibrosis and regenerating nodules enhance resistance in the sinusoids and terminal portal venules. contractility of sinusoidal lining cells, production of vasoactive substances (eg, endothelins, nitric oxide), various systemic neurohumoral factors that affect splanchnic arterioles, and Swelling of hepatocytes.

Cirrhosis

CirrhosisFibrosis

Regenerating Nodule

Complicationsportal-systemic venous collaterals develop (caput medusae , rectal varices , esophageal varices )hepatic encephalopathy ascites hypersplenism

The principal consequences of portal hypertension are the result of reduced blood flow though the liver and the effects of elevated pressure in the hepatic portal system.

With less blood flowing through the cirrhotic liver,its remaining functional cells have reduced access to the blood, compromising their detoxification activities. It's as if the blood is by-passing the liver (shunting) . As a result,toxins are more concentrated in the blood and are more likely to produce damaging effects.

Massive ascites in an elderly woman.

Ascites Free fluid in the peritoneal cavity

Etiology cirrhosis chronic hepatitis, severe alcoholic hepatitis without cirrhosis, and hepatic vein obstruction

review:Pathogenesis of edema 1. imbalance of exchange between intra- and extra-vascular fluidincreased capillary blood presuredecreased plasma colloid osmotic presureincreased capillary permeabilityobstruction of lymphatic flow; 2. imbalance of exchange between intra- and extra- body fluid:decreased filtration rate of glomeruliincreased water and sodium reabsorption in renal.

Pathophysiology Low serum osmotic pressure Synthesized by the liver, albumin is the major contributor to oncotic pressure in the serum. Decreased levels usually develop only in severe hepatic dysfunction. osmotic pressure tends to retain fluid in capillaries (2) High portal venous pressure

(3) Hepatic lymphatic obstruction may also be involved. plasma proteins leaking into interstitial space rely on the lymphatics for movement back into the circulatory system with the interstitial fluid. If lymph flow is obstructed, not only is backflow of interstitial fluid blocked but also colloid pressure in interstitial fluid increases.

(4) Na retention In cirrhosis, arterial vasodilation leads to a decrease in splanchnic and systemic vascular resistance with pooling of blood in the splanchnic circulation, leading to a reduction in the effective arterial blood volume. This in turn leads to stimulation of the sympathetic nervous and renin-angiotensin-aldosterone systems, promoting renal sodium and water retention in an attempt to restore the effective arterial blood volume and maintain blood pressure.

patient with alcoholic cirrhosis and portal hypertension. Note the parotid hypertrophy, distended abdomen from ascites, and scrotal and pedal edema.

SYSTEMIC ABNORMALITIES Depression of the livers chemical and drug detoxification function Skin and endocrine changesSpider nevi, palmar erythema Complex derangements in the metabolism of sex hormonesOther endocrine derangements

Hematologic abnormalities Renal and electrolyte abnormalities Hypokalemia Hyponatremia Renal failure

Close-up view of a spider angioma of the skin in a patient with liver disease. Note the central, punctate filling vessel and the "spider-like" vessels emanating from it.

Liver palms: thenar and hypothenar erythema in a patient with chronic liver disease.

Hepatic Encephalopathy A neuropsychiatric syndrome caused by liver disease and usually associated with portal-systemic shunting of venous blood.

Etiology fulminant hepatitis ( viruses, drugs, or toxins)cirrhosis or other chronic disorders

Grade 0 - Clinically normal mental status but minimal changes in memory, concentration, intellectual function, and coordination , Asterixis absent Grade 1 - Mild confusion, euphoria, or depression; decreased attention; slowing of ability to perform mental tasks; irritability; and disordered sleep pattern, such as inverted sleep cycle, Asterixis can be detected

Grade 2 - Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behavior, and intermittent disorientation, usually regarding time, Obvious asterixis Grade 3 - Somnolent but can be aroused, unable to perform mental tasks, disorientation about time and place, marked confusion, amnesia, occasional fits of rage, present but incomprehensible speech, Asterixis generally absent Grade 4 - Coma with or without response to painful stimuli

1. The causative metabolic toxins (usually nitrogenous substances) most likely originate in the intestine. 2. Because of portal-systemic shunts, these toxic substances bypass the liver, where they normally are metabolized. 3. After bypassing the liver, these toxic substances cross the blood-brain barrier and exert direct or indirect neurotoxic effects on the central nervous system. Pathogenesis of HE

Ammonia intoxication hypothesisFalse neurotransmission hypothesisimbalance of plasma amino acid hypothesisGABA hypothesisPathogenesis of HE

Ammonia intoxication hypothesis The first experiment implicating a nitrogenous substance as a cause of hepatic encephalopathy was performed by Eck, a turn-of-the-century Russian physiologist who created portal-systemic shunts in healthy dogs and observed that these dogs promptly became comatose after eating meat. This important observation was ignored for more than 50 years until this condition was "rediscovered," and ammonia intoxication became a leading suspect.

The role of ammonia has been postulated on the basis of the following: a reproducible increase in blood ammonia levels of patients with cirrhosis; the development of hepatic coma in patients with advanced liver disease and in experimental animals after ingestion of ammonia;

source of ammonia1.Forty percent of ammonia is generated in the intestine from ingested nitrogenous substances that are broken down by bacterial ureases and amino acid oxidases.2. The remaining 60% is derived from the metabolism of glutamine and the deamination and transamination of other amino acids.

glutamine ammonia+glutaminic acid glutaminase

3. Additional sources of ammonia are skeletal muscle and the kidneys. ammonium ion is synthesized from glutamine, which is actively transported into the epithelial cells of the proxiamal tubules, thick ascending limb of the loop of the proximal tubules. in the collecting tubules, hydrogen ion is secreted by the tubular membrane into the lumen, where it combines with ammonia to form NH4+,which is then excreted. Ammonia is adenylic acids catabolism product. when the muscles shrink aggravatelly, Adenylic acids catabolism intensify.Thus, Ammonia increase.

Ammonia liberated in the intestine normally is metabolized in the liver through the cycle of urea synthesis into urea, which is excreted through the kidneys and into the colon. Formation of glutamine from glutamate by glutamine synthetase in the liver and brain is another means of detoxifying ammonia.ammonia+glutaminic acid glutamine

The net reaction for one turn of the urea cycle isCO2 + NH4+ + 3 ATP + Aspartate + 2H2O -> Urea + 2 ADP + 2 Pi +AMP + PPi + Fumaratesynthesis of urea is energetically expensive.

Ammonia intoxication hypothesis the patient with hepatic cirrhosis has hyperammonemia and encephalopathy occuring is due to entering of ammonia into the brain. All of the neuropsychiatric symptoms are due to the poisonous action of ammonia to central nervous system.

causes of hyperammonemia excess of the ammonia formationinsufficiency of the ammonia elimination

excess of the ammonia formation1)Varices can rupture, causing sudden GI (gastrointestinal) hemorrhage. so nitrogenous substances in the intestine increase. And Forty percent of ammonia is generated in the intestine from ingested nitrogenous substances that are broken down by bacterial ureases and amino acid oxidases. So plasma ammonia increase.

2)portal hypertensionincreased capillary blood presurecongestion and edema of gastrointestinal tractdisorders of the function(motion, secretion, absorption, degestion) inadequate digestion of protein and excess reproduction of intestinal bacteria(remainder protein is decomposed by bacteria enzyme) increased plasma ammonia

3) severe liver diseaserenal failureazotemia(an abnormally high level of nitrogen-type wastes in the bloodstream.)the urea in blood defuses into intestine it is decomposed(by urease of bacteria) increased ammonia

4) tic of the muscles(before HE, pateints often are restlessness)adenylic acids catabolism intensify increased ammonia

5) increased pH of renal tubular fluiddecreased ammonia secretion of renal tubules increased ammonia diffusion to bloodincreased pH of gastrointestinal tractdecreased ammonia excretion of gastrointestinal tract increased ammonia diffusion to bloodNH3+H+NH4 NH4 + OH- NH3 + H2O

insufficiency of the ammonia eliminationdysfunction of the liverdecreased urea syntheses due to lack of ATP, reaction substrate and enzyme damage.

ammonia in intestine enter the bloodPortal-systmic shuntsDisorder of detoxication

the mechanism of that ammonia leads to encephalopothy (1)Ammonia leads to the disorder of energy metabolism in the brain In normal conditions: Brain needs much of energy steming from oxidation of glucose and glycogen reserves are less in the brain. Excess ammonia ultimately may cause cerebral energy failure due to inhibition of key rate-limiting tricarboxylic-acid-cycle enzymes.

(2)The changes of the neurotransmitters in the brain: decreased glutamic acid, acetylcholine(excitatory transmitter), increased GABA, glutamine(inhibitory transmitter). The correct balance of neurotransmitters is critical to the brain.so increased GABA, glutamine lead to disorder of CNS. ammonia+glutaminic acid glutamineGABA so glutaminic acid glutamine GABA ammonia inhibite the activation of pyruvate decarboxylase, so Acetyl-CoA; Acetyl-CoA+ bilineurine acetylcholine,SO acetylcholine

(3) Ammonia disturbs the ions transfer of the nervous cells membrane.Na+-K+-ATPaseNa+K+NH3

Na+-K+-ATPase which is located in the surface membrane of cells is responsible for the active transport of sodium and potassium ions between extracellular fluid and cytoplasm. Ammonia may contribute to changes in the activity of Na+-K+-ATPase that are found in the brain in models of HE.so the active transport of sodium and potassium ions between extracellular fluid and cytoplasm is damaged.thus Ammonia inhibits excitatory postsynaptic potentials, thereby depressing overall central nervous system function.

However, not all data are consistent with the ammonia toxicity theory. Poor correlation of ammonia with hepatic encephalopathy, the presence of this condition in the absence of elevated ammonia levels, and the neuroexcitatory effects of low ammonia concentrations all cast doubt on the theory.

1 Reticular activating systemReticular activating system is a structure in the brain stem that is responsible for arousal and sleep. The reticular activation system is responsible for getting you up in the morning and putting you asleep at night .if the Reticular Activating System failed to activate the cortex at all one would see a lack of consciousness or even coma. Neurotransmitters (such as noradrenaline, dopamine) is nessesary to fullfil the Reticular Activating Systems function.

False neurotransmitter hepothesis

In 1970, Parkes first reported bendopa treat HE succesfully. Then Fischer et al proposed false neurotransmitter hepothesis: In the pateint with hepatic failure FNT(phenylethanolamine and octopamine) is accumulated in the synapse of the reticular structure(RS) in the brain stem. The FNT can compete with true Neurotransmitter (TN, noradrenaline(NE) and dopamine;DA) because their chemical structure is similar to the TN. The RS has a specific action to keep waking and excitability of the pallium. When FNT replaces TN in RS of brain stem, disorders of CNS occur.

Interstinal bacteriadecarboxylaseTyrominephenylethylaminetheir concentration in bloodphenylethanolamine

octopamineInto the brainhydroxylaseproduceliver metabolismPotal-systemic shuntPhenylala-ninetyrosine(food)

Note(1)congestion and edema of gastrointestinal tractdisorders of the function(motion, secretion, absorption, degestion) inadequate digestion of proteinproduceTyromine phenylethylamine(2) Tyromine and phenylethylamine can be cleared from the blood by the process of enzymatic degradation in liver.

FNT competes with TN but their physiological effects are very weak.Dysfunction of RSlethargy, coma

Plasma amino acid imbalance hypothesisPatients with cirrhosis have a decreased ratio of branched-chain amino acids (BCAA) to aromatic amino acids (AAA), from 3.5:1 to 1:1. BCAA include valine, leucine, and isoleucine. AAA include phenylalanine, tyrosine, and tryptophan.

The decrease in BCAA is caused predominantly by their excessive use by skeletal muscle. The increase in AAA is caused predominantly by failure of hepatic deamination. It has been postulated that the increase in AAA in the central nervous system may interfere with physiologic neurotransmission by competitively inhibiting "normal" neurotransmitters (ie, dopamine, norepinephrine) and favoring formation of weak, false neurotransmitters (ie, octopamine, phenylethanolamine)

Causes(BCAA): undernutrition, starvationdecomposition of BCAA(for energy supply); stressglucocorticosteroiddecomp-osition of intra-musculi BCAA; hyperinsulinemiauptake and utilization of BCAA in muscular and fatty tissueCauses(AAA): insufficiency of elimination of AAA in the liver.

Both BCAA and AAA are neutral amino acid. They are through blood-brain barrier by the aid of the same carrier. So, there is competition between AAA and BCAA, finally, AAA enters in to the brain more and formation of FNT is more too. Thus, decreased ratio of BCAA/AAA relates to encephalopathy due to FNT formation in CNS. So, this hypothesis is an extension of FNH.

(1)As increased phenylalanine enter into the brain and phenylalanine can inhibite the activation of tyroxine hydroxylase, physiologic neurotransmission decrease. (2)in the brain,increased FNT

decarboxylaseTyrominephenylethylaminehydroxylasephenylethanolamine octopaminePhenylala-ninetyrosine(food)

AAA/BCAA AAA enter intobrain :

true neurotran- smitters

false neurotran- smitters

inhibitory neuro-transmitters

This attractive hypothesis raises the possibility that correction of the AAA:BCAA ratio may lead to amelioration of hepatic encephalopathy. However, a multitude of clinical trials have failed to prove that changes in the ratio through intravenous or oral administration of BCAA result in significant improvement of clinical signs or symptoms of this condition.

GABA hypothesis In the 1980s, Basile and Jones at the National Institutes of Health promoted gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, as a cause of hepatic encephalopathy. GABA is a neuroinhibitory substance produced in the gastrointestinal tract. Of all brain nerve endings, 24-45% may be GABAergic. Increased GABAergic tone is observed in patients with cirrhosis, perhaps because of decreased hepatic metabolism of GABA.

A major sources of the increased plasma GABA levels observed in liver failure is considered to be the gut (that is,intestinal bacteria and the interstinal wall ).If the permeablity of the blood-brain barrier to plasma GABA is increased in liver failure, and if some of this GABA is not catabolized or taken up by neurons, it may reach GABA receptors , augment GABA-ergic neurotransmission and lead to disorder of CNS.

Cl-Cl-Post-synapse inhibition

When GABA crosses the extrapermeable blood-brain barrier of patients with cirrhosis and is released by Vesicle of excited presynaptic neuron cell, it interacts with supersensitive postsynaptic GABA receptors. The GABA receptor, in conjunction with receptors for benzodiazepines and barbiturates, results in the opening of a Cl- ion channel. As [Cl-]out is more than [Cl-]in, binding of GABA to its receptor permits an influx of chloride ions into the postsynaptic neuron causing membrane hyperpolarization and leading to the generation of an inhibitory postsynaptic potential.

Cl-Cl-cellBRBZGABARGABACl-Cl-Pre-synapse inhibition

GABA also causes an inhibitory presynaptic potential. The same point is Binding of GABA to GABA receptors results in the opening of a Cl- ion channel located in neurite membrane. But theres different between postsynaptic and presynapse. As [Cl-]in is more than [Cl-]out, binding of GABA to its receptor permits an outflux of chloride ions out of the presynaptic neuron causing membrane depolarization.so it results in releasing less neurotransmitters when pulses come and also causes an inhibitory presynaptic potential.

Precipitating factors in hepatic encephalopathy

1.Renal failure: Renal failure leads to decreased clearance of urea, ammonia, and other nitrogenous compounds 2. Gastrointestinal bleeding: The presence of blood in the upper gastrointestinal tract results in increased ammonia and nitrogen absorption from the gut. Bleeding may predispose to kidney hypoperfusion and impaired renal function.

3. Infection: Infection may predispose to impaired renal function and to increased tissue catabolism, both of which increase blood ammonia levels. 4. Constipation: Constipation increases intestinal production and absorption of ammonia. 5.Medications: Drugs that act upon the central nervous system, such as opiates, benzodiazepines, antidepressants, and antipsychotic agents, may worsen hepatic encephalopathy.

6.Diuretic therapy: Decreased serum potassium levels and alkalosis may facilitate the conversion of NH4+ to NH3. 7.Dietary protein overload: This is an infrequent cause of hepatic encephalopathy.

Treatment 1. Provision of Supportive Care Prevention of falls in disoriented patients at earlier stages of HE may require special measures. In deeper stages of HE, the need for prophylactic tracheal intubations needs to be considered. Adequate nutrition should be provided during the period of altered mental state

2. Identification and Removal of Precipitating Factors (1)Dietary protein should be eliminated and oral or IV carbohydrate should be given to supply lost calories. (2)Oral lactulose should be given Lactulose is degraded by colonic bacteria and converted to lactic acid and other acids, with resulting acidification of the gut lumen. This favors conversion of NH4+ to NH3 and the passage of NH3 from tissues into the lumen.

(3) Gastrointestinal bleeding must be stopped. The intestines must be emptied of blood. Blood breaks down into protein components that are converted to ammonia. (4)Treatment of infections, renal failure, and electrolyte abnormalities (especially potassium) is important. 3. Sedation deepens encephalopathy and should be avoided, even if the patient is agitated.

4. Other potential therapies include levodopa, a precursor of normal neurotransmitters; bromocriptine, a dopamine agonist; infusions of branched chain amino acids or of keto-analogs of essential amino acids; flumazenil, a benzodiazepine antagonist; and sodium benzoate, for enhanced urinary nitrogen excretion. However, none of these therapies has proved effective. 5. Liver transplantation

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