liver Cirrhosis

and Hepatic Encephalop

athy

ByAshraf Okba

Prof. of Internal Medicine Ain Shams University

Overview

Enviromental causes

Hepatic InjuryHepatitis virusAlcoholDrugs and toxins

RecoveryFulminant hepatic failure

Chronic persistent hepatitis

Necrosis cirrhosis

Herritage/Genetic causes

Hepatic Failure hepatic insufficiency

Hepatorenal syndrome

Hepatic Encephalopathy

Triggers

Cirrhosis Cirrhosis is a liver disease characterized by

extensive fibrosis with regenerative nodule formation, and distortion of liver structure.

It is referred to as the end stage of many chronic liver diseases.

The progression of a specific chronic liver disease to cirrhosis can take many years and is dependent upon many factors such as the severity of the liver disease, lifestyle, and overall health of the individual.

Cirrhosis is an irreversible condition that also has serious complications

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Causes of Cirrohsis Chronic Viral Hepatitis

Hepatitis is the inflammation of the liver caused by hepatitis B or C virus

Chronic Alcoholism Excessive alcohol intake is the leading cause cirrhosis in the United

States. Chronic alcoholism is the most common cause of steatosis, a condition

characterized by fat build up in the liver. . Nonalcoholic steatohepatitis (NASH)

This condition exhibits the same characteristics of steatosis that inflames the liver. However, it is not caused by alcohol consumption. This condition often exists in conjunction with other health issues such as obesity, diabetes, and coronary artery disease.

Bile Duct Disease4

Cirrhosis stages:A) Compensated cirrhosisBody still functions fairly well despite

scarring of the liver. Few or no symptoms.

Symptoms of compensated cirrhosis1. Fatigue and loss of energy2. Loss of appetite and weight loss3. Nausea or abdominal pain

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B) Decompensated cirrhosissevere scarring of the liver disrupting

essential body functions , develop any serious symptoms and complications

Symptoms of decompensated cirrhosis:

1. LL. edema2. Ascites3. Portal hypertension4. jaundice

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HEPATIC FUNTION CLINICAL MANIFESTATIONS

Body’s metabolism1 ． Carbohydrate metabolism

2 ． Protein metabolism

3 ． Lipid metabolism

4. Water and Electrolyte

metabolism

5 ． Hormone metabolism

Blood coagulation Biotransformation

and detoxifcation Immunity Secretion and

excretory function

Metabolism dysfunction

1 ． Hypoglycemia

2 ． Hypoalbuminemia 、 high ammonia 、

3 ． Fatty liver 、 decreased plasma cholesteryl ester

4 ． Disorders Water and Electrolyte metabolism

5. High estrogen ， spider angioma 、 liver palms etc.

Bleeding tendency

Intoxication

Infection

Jaundice

Palmar erythema

Spider navei

Conditions in which the liver functions fall below the normal ranges. The symptom include jaundice, bleeding, secondary infection, renal dysfunction and hepatic encephalopathy .

Hepatic insufficiency

Hepatic failure

Hepatic failure is a terminal stage of hepatic insufficiency. Hepatic encephalopathy and hepatorenal syndrom are the primary clinical manifestations.

Severe hepatic insufficiency may cause liver failure or death.

HEPATORENAL SYNDROME

Hepatorenal syndrome is the development of a reversible and functional renal failure in patients with severe liver diseases in absence of any other identified cause of renal pathology.

It is characterized by a marked decrease in GFR and renal plasma flow.

Pathophysiology Of Hepatic Cirrhosis

Pathophysiology Normally, hepatocytes are capable of considerable

regeneration. However, chronic damage (from viral infection,

heavy alcohol consumption, trauma and other factors) can lead to scarring.

This scarring is referred to as fibrosis. Formation of scar tissue is a normal bodily response

to injury. The injury or death (necrosis) of hepatocytes stimulates inflammatory immune cells to release cytokines, growth factors, and other chemicals.

These chemical messengers direct support cells in the liver called hepatic stellate cells to activate and produce collagen, a fibrous connective tissue that gets deposited in the liver.

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In fibrosis, excessive scar tissue builds up faster than it can be broken down and removed from the liver.

 If the disease progresses, it can lead to cirrhosis, a condition in which the liver is severely scarred, its blood flow is restricted, and its ability to function is impaired.

The nodular regeneration of the liver tissue, permanently alters the structure of the liver.

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Complications of cirrhosis

The major complications of cirrhosis are similar in both alcoholic and nonalcoholic patients: Portal hypertensive bleeding

Increased blood pressure in the blood vessels supplying the liver due to increased in vessel resistance.

Portal hypertension leads to the development of new veins called collateral veins, at the end of esophagus and at the upper portion of the stomach. These collateral veins become varicose veins that are prone to bleeding.

Ascites Excess fluid in the peritoneal cavity

Hepatic encephalopathy Mental confusion , change in the level of consciousness

Hepatocellular carcinomaMost common liver cancer

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Hepatic Encepalopathy

2010 年 10 月 22 日

Definition of Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a complex, potentially reversible disturbance in CNS that occurs as a consequence of severe liver diseases.

It is characterized by neuropsychical manifestations ranging from a slightly altered mental status to coma.

The West Haven criteria of altered mental state in HE (In patients with cirrhosis and overt encephalopathy)

Stage 0. Lack of detectable changes in personality orbehavior. Asterixis absent.Stage 1. Trivial lack of awareness. Shortened attentionspan. Impaired addition or subtraction. Hypersomnia,insomnia, or inversion of sleep pattern. Euphoria ordepression. Asterixis can be detected.Stage 2. Lethargy or apathy. Disorientation. Inappropriatebehavior. Slurred speech. Obvious asterixis.Stage 3. Gross disorientation. Bizarre behavior. Semistuporto stupor. Asterixis generally absent.Stage 4. Coma. THE AMERICAN JOURNAL OF GASTROENTEROLOGY

Vol. 96, No. 7, 2001

Staging

A classification of hepatic encephalopathy was introduced at the World Congress of Gastroenterology 1998 in Vienna. According to this classification, hepatic encephalopathy is subdivided in type A, B and C depending on the underlying cause.

Types

Type A (=acute) describes hepatic encephalopathy associated with acute failure

Type B (=bypass) is caused by portal-systemic shunting without associated intrinsic liver disease

Type C (=cirrhosis) occurs in patients with cirrhosis this type is subdivided in episodic, persistent and minimal ncephalopathy

PATHOGENESIS OF HE

HE may be due to primarily to a failure of the liver to

remove adequately certain substances in plasma that

have the ability, directly or indirectly to modulate the

function of the central nervous system. Several

hypotheses have been proposed:

PATHOGENESIS

The pathogenesis of HE remains poorly understood

HE in liver cirrhosis is a clinical manifestation of a low-grade cerebral edema, which is exacerbated in response to ammonia and other neurotoxins

Ammonia intoxincation hypothesis

False neurotransmitters hypothesis

Amino acid imbalance hypothesis

The Gamma-aminobutyric acid hypothesis

Synergistic actions of multiple toxins

Pathogenesis

Causes of elevated ammonia in hepatic inssufficiency

1 ） Decreased clearance of ammonia 2 ） Increase production of ammonia in

gstrointestinal tract Intoxicaton of ammonia on the brain 1 ） Impairment of energy metabolism in

brain 2 ） Alteration of neurotransmitters 3 ） Inhibiting action of nerve cells

membrane

Ammonia intoxincation

Urea AANH3

NH3

NH3

Ornithine

CitrullineArgininosuccinate

Urea

NH3

Kidney

Brain

Systemic circulation

Liver

Intestine

Protal-systemic shunts

Other tissues to produce NH3

1 ） Impairment of energy metabolism in brain 2 ） Alteration of neurotransmitters 3 ） Inhibiting action of nerve cells membrane

False neurotransmisson hypothesis

In hepatic dysfunction or formation of portal-systemic shunt, some kind of amine elevated due to failure of hepatic deamination, and then filter into central nervous system interferes with physiologic functions by competitively inhibiting normal neurotransmitters (dopamine, norepinephrine) and favoring formation of false neurotransmitters (octopamine, phenylethanolamine) ,which have similar structure but much weaker activity than true neurotransmitters. The net physiologic result of such changes is reduced neural excitation an hence increased neural inhibition.

The aromatic amino acids (AAA), tyrosine,phenylalanine and tryptophan are increased in liver disease whiletge branched amino acids (BCAA), valine,leucine and isoleucine are decreased. The AAA are the precursors of false neurotransmitters.

Amino acid imbalance hypothesis

Plasma level of GABA

In liver failure, a major resource of the increased plama GABA is considered to be the intestinal bacteria and the intestinal wall. The permeability of the blood-brain to GABA is increased in liver failure,if some of the GABAis not catabolized or taken up by neurons,it may reach GABA receptors and augment GABA-ergic neurotransmission. Activation of the GABA receptor increase neuronal membrane permeability to Cl- BY OPENING Cl- ionophore, and Cl- enters the neuron causing membrane hyperpolarization. Benzodizepines(BZ) recepter agonists increase the frequency of GABA-gate

Cl- channel openings.

GABA and/or BZ receptor density increased

Ammonia can augment the activity of GABA-ergic neurons.

Gamma-amino butyric acid hypothesis

SYNERGISTIC ACTIONS OF MULTIPLE TOXINS

Manganese: induce pathological changes of astrocyte

Mercaptans: inhibit the production of urea and Na+-k+-

ATPase on neuron membrane ， disturbe the

electron transport on mitochondria

Short-chain fatty acids: inhibit energy metabolism of

the brain, and disturbe the post neuron potential

Phenols: inhibite the activity of many enzymes

PATHOGENESIS

The accumulation of ammonia and other neurotoxins in the systemic circulation is the main pathogenic factor in HE.

Normally, these neurotoxins are produced (from gut bacteria) and absorbed from the gut and cleared by the liver.

When liver function is seriously impaired (Acute or Chronic LF), these neurotoxins bypass the liver and gain access to the systemic circulation, cross the blood-brain barrier, and accumulate in the CNS.

Pathogenesis Unchanged ammonia traverses the BBB,

and enter the parenchymal cells (especially astrocytes), where it is converted into glutamine.

Glutamine in turn has osmolar activity and increases the cell water content, contributing to cerebral edema.

Therefore, ammonia plays the key role in the pathogenesis of HE by inducing astrocyte swelling and/or sensitizing astrocytes to swelling by a heterogeneous panel of precipitating factors and conditions

Glutamate L-glutamine

Glutatrate

GABA

Citric acid

Oxaloacetate

Succinate

NH3

ATP ADPNAD

NADH

NH3

Pyruvic acid

Acetyl-CoA

Acetylcholine

Choline

NADH

NAD

Toxicaton effect of ammonia on brain tissue

NH3

Swelling of astrocytes produces reactive oxygen and nitrogen oxide species (ROS/RNOS), which again increases astrocyte swelling and subsequently induces RNA oxidation that may impair postsynaptic protein synthesis, which is required for memory formation and offers a novel explanation for multiple disturbances of

the neurotransmitter systems, gene expression, motor and cognitive deficits observed in HE

Pathogenesis

and the energy supply to other brain cells is decreased.

Other waste products implicated in hepatic encephalopathy include mercaptans , short-chain fatty acids and phenol

Benzodiazepine-like compounds have been detected at increased levels as well as abnormalities in the GABA neurotransmission system.

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An imbalance between aromatic amino acids (phenylalanine, tryptophan and tyrosine) AAA and branched-chain amino acids BCAA (leucine, isoleucine and valine) has been described; this would lead to the generation of false neurotransmitters (such octopamine and 2-hydroxyphenethylamine).

Dysregulation of the serotonin system, too, has been reported. Depletion of zinc and accumulation of manganese may play a role

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Normal Liver diseases

BCAA/AAA=about 3.5(Fischer’s ratio)

BCAA/AAA=about 1 (in a severe condition)

Increased amount of ammonia disposed of in the skeletal muscles Increased amount of BCAA used as an energy source

BCAA

AAA AAA

BCAA

Metabolisms of BCAA and AAA in Liver Disease

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Ammonia-glutamate metabolism in

Skeletal muscle and brain

BCAA

BCKA

α- Ketoglutarate

glutamate

NH4+

glutamine

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PHYSIOLOGICAL FUNCTIONS OF BCAA

• Energy source for the peripheral organ (e.g.

skeletal muscle)

• Ammonia detoxification by glutamate and

glutamine pathway.

• Improve nitrogen balance and elevate plasma

protein level including albumin.

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Essential & Non-essential Amino-Acids

• EAAs can't be produced by the body and can therefore

only be obtained via the diet.

• Foods containing complete range of EAAs, approximately

40%, and termed as HBV (High Biological Value), as Milk,

cheese, yoghourt, beef, lamb, poultry, fish, and eggs.

• NEAAs produced by the body through "Amino Acid Pool",

and containing foods are foods with LBV "Low Biological

value". As beans, peas, and nuts.

• Patient with trauma, or surgery, or recovering from burns

or open wounds should be supplied with protein and

energy. 39

Essential & Non-essential Amino-AcidsEAA NEAA

Lysine Proline

Phenylalanine Glycine

Valine (BCAA) Arginine (may become essentialduring specific disease states and is therefore termed "semi-essential")

Leucine (BCAA) Cystine

Isoleucine (BCAA) Cysteine

Threonine Tyrosine

Tryptophane Serine

Methionine Aspartic acid

Glutamic acid

Alanine

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Glutamic acid GABA

Metabolism GABA

GABA

GABA

Inhibit brain function

Clinical significant and magnitude of the Hepatic encephalopathy About 1/3 to ½ of hospitalizations for

cirrhosis are related to HE Patients with HE often have other

manifestations of end-stage liver disease ESLD, however HE can also develop as an isolated manifestation of decompensate cirrhosis.

Hepatic encephalopathy may disable the patient from employment, driving and self care.

HE usually signals advanced liver disease and consequently is often considered a clinical indication for liver transplantation

Types of hepatic encephalopathy

Types of hepatic encephalopathy

Precipitating factor GI bleeding Infections: (UTI, chest, skin, SBP(Spontaneous

Bacterial Peritonitis)) Constipation Excessive dietary proteins Electrolyte disturbance: (Hypokalemia,

Hyponatremia) Superimposed liver injury: (acute viral hepatitis,

drugs Surgery CNS depressant drugs HCC (Hepatocellular carcinoma) Dehydration Renal failure TIPS (Transjugular intrahepatic portosystemic

shunt)

portosystemic shunts Transjugular intrahepatic

portosystemic shunts (TIPS) are an established treatment in the management of variceal bleeding and in a limited number of patients with refractory ascites.

The incidence of hepatic encephalopathy increases in the presence of portosystemic shunts

Clinical stages/ grades (MCNA 2008)

Diagnosis and differential diagnosis

Suspect in any liver disease patient presenting with mental changes

HE is usually preceded by ppt factor Asterexis = flapping tremors

Stage II Weakens in stage III Disappears in coma

NUMBER CONNECTION TEST Used for > 50 years to assess

mental performance

Simple, readily available

Results influenced by age and level of education

Source: Weissenborn et al. J Hepatology May 2011

Time required HE Grade

≤30 seconds None-Minimal

31-50 seconds Minimal - I

51 to 80 seconds I - II

81 – 120 seconds II - III

Forced termination III

Number Connection TestPatient’s Name

Date

Completion Time

Testers Initials

Patient’s Signature

MAJOR DIFFERENTIAL DIAGNOSIS

Seizures and focal neurological signs are uncommon manifestation of HE warrants appropriate brain imaging

Structural brain damage : Subdural hematoma !

Other metabolic encephalopathies: Uremic Hypoglycemia Ketoacidosis Hypoxia Thyroid dysfunction

CNS infections (meningitis, encephalitis) Ischemic brain disease (TIAs, Ischemic strokes) CNS tumors

INVESTIGATION

Overt HE from history and clinical examination

Diagnosis not clear or in question Blood ammonia level Brain imaging (CT, MRI) EEG Psychometric tests (MHE)?

CLINICAL EVALUATION

NH3 elevated in 90% of all HE but also at least marginally elevated in 90% of all patients with cirrhosis

NH3 levels correlate (poorly) with HE Grade

EEG not used routinely- Normal for stage 0 or MHE- Triphasic waves over frontal lobes that oscillate at 5 Hz for stage I,II,III- Slow delta wave activity in stage IV

MRI/CT typically only show findings in Type A (fulminate liver failure) and Grade 4 HE

Source: Ong JP, et al. Am J Med. 2003;114:188-93.

Blood ammonia normal level

Normal ResultsThe normal range is 15 - 45 micrograms per deciliter

(mcg/dL).What Abnormal Results MeanAbnormal results may mean you have increased

ammonia levels. This may be due to:Congestive heart failureGastrointestinal (GI) bleeding - usually in the upper GI

tractGenetic diseases of the urea cycleHigh body temperature (hyperthermia)LeukemiaLiver failureLow blood potassium level (hypokalemia)Metabolic alkalosisSevere muscle exertion

Problem in bioassay of ammonia

• Labile spontaneous determination + evaporation at room temp

Venous blood ammonia correlates well with arterial ammonia when properly assessed

Samples must be withdrawn in heparinized container, placed in ice and assayed within 30 min

CONCERNS

Normal blood ammonia level doesn’t support the diagnosis of HE

Conversely, an elevated ammonia level in a comatosed patient doesn’t exclude a coexistent condition.

However, markedly elevated blood ammonia

(> 150 – 200 umol/l) strongly suspicious of HE

Blood ammonia is moderately elevated in cirrhotic without HE

Hepatic encephalopathy

Management

European Society for Parenteral and Enteral

Nutrition concluded the following:

Cirrhotic patients tend to be hypermetabolic,

and need higher than normal supply of protein

to achieve nitrogen balance.

Most patients tolerate a normal or even

increased dietary protein intake without risk of

hepatic encephalopathy.

ESPEN Consensus Review

ESPEN Consensus Review A modified eating pattern based on several

meals and a late evening snack, is useful.

In severe cases, AA should be supplied to

meet protein requirements.

Intolerant patients to the required protein

intake, BCAA may be considered to provide

necessary nitrogen intake without

detrimental effect on the mental state, or

even improving it.

Patient care guideline

MANAGEMENT

Precipitating factors:

Dehydration GI bleeding Infection Electrolyte

disturbance Hypokalemia Hyponatremia

Artificial liver support

Ammonia ↓ production +

absorption Diet Lactulose + lactitol Oral antibiotics

↑ ammonia clearance L ornithine – L –

Aspartate

Liver transplantation

MANAGEMENT A) Precipitating factor

Dehydration: Stop diuretics IV physiologic saline

GI bleeding: Infection

SBP UT Chest

Electrolyte disturbance

Hypokalemia → IV k

Hyponatremia → hypertonic saline

(150 ml of 3% NaCl IV)(S. sodium < 125

mEq/L) Any episode of HE is considered due to

end-stage liver disease ESLD only after exclusion of any ppt factor

MANAGEMENTB) ammonia

↓ Production of gut ammonia

1- Diet Excessive dietary protein can ppt

HE Patients with compensated

cirrhosis: No restriction Diet containing 1.2 gm

protein/kg/ day is Recommended

Diet HE episode → Protein restriction to 40 gm/ day is advocated

not more than 48 hours and then minimized Prolonged protein restriction in HE → can

exacerbate the catabolic state of cirrhosis →release of AA and other nitrogenated byproducts from the muscles.

MANAGEMENTB) ammonia

Diet Chronic HE Vegetable proteins are better tolerated than

animal proteins: ↑ content of dietary fibers → natural cathartic ↓ levels of AA acids→ false transmitters

Supplementation with oral branched chain AAs → improves survival and QOL (expensive)

MANAGEMENTB) ammonia

2- Lactulose or lactitol (cathartics) Lactulose (beta – galactosido fructose) Lactitol (beta – galactosido sorbitol)

Lactulose & lactitolNon absorbable disaccharides

Cathartic ↓ colonic bacterial load ↓ Gut ammonia production

Degradation by gut bacteria Lactic acid + other organic A Acidification of gut lumen Inhibit ammoniagenic coliform bacteria

MANAGEMENTB) ammonia

LACTULOSE

Metabolized by colon bacterial flora to short chain fatty acids altering luminal pH

Lactic Acid

-

NH3

NH4 +

Excreted in feces

Lactulose

Intestinal Flora

MANAGEMENTB) ammonia

Lactulose Orally 30 ml/2-4 times/day (stage I, II) 3 – 5

loose motions Lactulose Enema

300 ml + 700 ml tap water / 4h (stage III, IV = coma)

(massive ascites) Many clinical trials demonstrated the

efficacy of lacutlose in the treatment of HE However, one recent metanalysis

contradicts these trials and forces the use of antibiotics particularly rifaximin .

3- Oral antibiotics They ↓ the concentration of ammoniagenic

bacteria → ↓ production of ammonia and other gut derived neurotoxins

Neomycin →250 mg/ 2-4 times/ day Its efficacy is ambigous . Long term therapy → toxicity due to some

systemic absorption Metronidazole + oral Vancomycin are little

studied

MANAGEMENTB) ammonia

Rifaximin

non absorbable derivative of rifampin

550 mg orally TWICE DAILY

Studies have demonstrated that rifaximin showed superior efficacy compared with lacutlose and neomycin in HE as well as better tolerability than both drugs due to minimal absorption

Concerns → cost ?

MANAGEMENTB) ammonia

↑ammonia clearance

L-ornithine – L-aspartate (LOLA) Stable salt of 2 amino

acids: L-ornithine L-aspartate

MANAGEMENTB) ammonia

MANAGEMENTC) LIVER

DIALYSIS 2 systems: MARS:

molecular adsorbent recirculating system Albumin dialysis .

Prometheus: Fractionated plasma separation (FDPS) Introduced 2003

Both systems are capable of removing both water solved and albumin bound toxins without providing synthetic functions.

Several clinical trials have shown that artificial liver support, is able to improve HE in acute and acute on chronic liver fialure

MOLECULAR ADSORBENT RECIRCULATING SYSTEM(MARS)

MARS is a device used to perform albumin liver dialysis.

The basic technical concept is based on conventional HD

It is a liver support system developed to support excretory liver function

It uses an albumin enriched dialysate to facilitate the removal albumin bound toxin(ABT)

USES OF MARS Acute fulminant liver failure Acute on chronic liver failure (acute

hepatorenal synd) ALF with extensive liver resection for

tumour As temporary support in spontaneous

recovery following abalative liver surgery

Liver transplant pt with primary graft dysfunction

MANAGEMENTD) liver

transplantation Cirrhotic patients who develop severe

HE have poor survival even with a fairly low MEID score, therefore, this constitutes a clinical indication for liver transplant evaluation is the only mode of therapy that tackles

the real cause of chronic HE which is the lack of functioning hepatocytes

Thank you