Hepatic encephalopathy
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Transcript of Hepatic encephalopathy
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
3
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
5
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
6
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.
33
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
34
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
36
Ammonia-glutamate metabolism in
Skeletal muscle and brain
BCAA
BCKA
α- Ketoglutarate
glutamate
NH4+
glutamine
37
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.
38
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
40
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