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

1. By
Ashraf Okba
Prof. of Internal Medicine
Ain Shams University

2. Overview
Enviromental causes
Hepatic Injury
Hepatitis virus
Alcohol
Drugs and toxins
Recovery
Fulminant hepatic
failure
Chronic persistent
hepatitis
Necrosis cirrhosis
Herritage/Genetic causes
Hepatic Failure hepatic insufficiency
Hepatorenal
syndrome
Hepatic
Encephalopathy
Triggers

3.  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

4. 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 Disease
4

5. A) Compensated cirrhosis
Body still functions fairly well despite
scarring of the liver. Few or no symptoms.
Symptoms of compensated cirrhosis
1. Fatigue and loss of energy
2. Loss of appetite and weight loss
3. Nausea or abdominal pain
5

6. B) Decompensated cirrhosis
severe scarring of the liver disrupting
essential body functions , develop any
serious symptoms and complications
Symptoms of decompensated cirrhosis:
1. LL. edema
2. Ascites
3. Portal hypertension
4. jaundice
6

7. HEPATIC FUNTION CLINICAL MANIFESTATIONS
 Body’s metabolism
1．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

8. Palmar erythema
Spider navei

9. 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.

10. 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.

11. Pathophysiology Of
Hepatic Cirrhosis

12.  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. 13

13.  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.
14

14.  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 carcinoma
Most common liver cancer
15

16. 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.

17. 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 or
behavior. Asterixis absent.
Stage 1. Trivial lack of awareness. Shortened attention
span. Impaired addition or subtraction. Hypersomnia,
insomnia, or inversion of sleep pattern. Euphoria or
depression. Asterixis can be detected.
Stage 2. Lethargy or apathy. Disorientation. Inappropriate
behavior. Slurred speech. Obvious asterixis.
Stage 3. Gross disorientation. Bizarre behavior. Semistupor
to stupor. Asterixis generally absent.
Stage 4. Coma. THE AMERICAN JOURNAL OF GASTROENTEROLOGY
Vol. 96, No. 7, 2001
Staging

18. 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

19. 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:

20. 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

21. Ammonia intoxincation hypothesis
False neurotransmitters hypothesis
Amino acid imbalance hypothesis
The Gamma-aminobutyric acid hypothesis
Synergistic actions of multiple toxins
Pathogenesis

22.  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

23. 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

24. 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.

25. 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

26.  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

27. 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

28. 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.

29.  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

30. Glutamate L-glutamine
Glutatrate
GABA
Citric acid
Oxaloacetate
Succinate
NH3
ATP ADP
NAD
NADH
NH3
Pyruvic acid
Acetyl-CoA
Acetylcholine
Choline



NADH
NAD
Toxicaton effect of ammonia on brain tissue
 NH3

31.  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

32.  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

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

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

35. Ammonia-glutamate metabolism
in
Skeletal muscle and brain
BCAA
BCKA
 - Ketoglutarate
glutamate
NH4+
glutamine
37

36. 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

37. • 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

38. Essential & Non-essential Amino-Acids
EAA 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

39. Glutamic acid GABA
Metabolism  GABA
GABA 
Inhibit brain function

40.  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

41. Types of hepatic encephalopathy

42. Types of hepatic encephalopathy

43.  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)

45.  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

46. Clinical stages/ grades (MCNA 2008)

47.  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

48. 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 Test
Patient’s Name
Date
Completion Time
Testers Initials
Patient’s Signature

49. 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

51. 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)?

52. 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.

53. Normal Results
The normal range is 15 - 45 micrograms per deciliter (mcg/dL).
What Abnormal Results Mean
Abnormal results may mean you have increased ammonia
levels. This may be due to:
Congestive heart failure
Gastrointestinal (GI) bleeding - usually in the upper GI tract
Genetic diseases of the urea cycle
High body temperature (hyperthermia)
Leukemia
Liver failure
Low blood potassium level (hypokalemia)
Metabolic alkalosis
Severe muscle exertion

54. 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

55. 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

56. Hepatic
encephalopathy
Management

57.  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

58. 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.

60.  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

61. 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

62.  ↓ 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

63. 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.

64. 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)

65. 2- Lactulose or lactitol (cathartics)
 Lactulose (beta – galactosido fructose)
 Lactitol (beta – galactosido sorbitol)
 Lactulose & lactitol
Non 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

66. LACTULOSE
 Metabolized by colon bacterial flora to short chain fatty acids
altering luminal pH
Lactic Acid
-
NH3
NH4
+
Excreted in feces
Lactulose
Intestinal Flora

67.  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 .

68. 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

69.  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 ?

70.  ↑ammonia clearance
 L-ornithine – L-aspartate (LOLA)
 Stable salt of 2 amino acids:
 L-ornithine
 L-aspartate

71. MANAGEMENT
C) 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

72. 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)

75. 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

76.  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

77. Thank you