Hepatic encephalopathy is a brain dysfunction caused by liver failure or portal-systemic shunting. It ranges from mild subclinical alterations to coma. Type C hepatic encephalopathy, associated with chronic liver disease and portal hypertension, is the most common type. Management involves identifying and treating precipitating factors like infections, along with therapies to reduce ammonia like non-absorbable disaccharides (lactulose, lactitol), antibiotics (rifaximin), probiotics, and dietary changes. Resistant cases may require more invasive procedures like TIPS or liver transplantation.

1. Hepatology lectures for
5th Sem;MBBS
Pratap Sagar Tiwari
MBBS,MD (Medicine),DM (Hepatology)

2. HEPATIC ENCEPHALOPATHY
DEFINITION
1
2
3
PATHOPHYSIOLOGY
4 DIFFERENTIALS
MANAGEMENT

3. INTRODUCTION
• HE is a brain dysfunction caused by liver insufficiency and/or PSS; it manifests as a wide
spectrum of neurological or psychiatric abnormalities ranging from subclinical
alterations to coma. EASL
• The prevalence of OHE at the time of DX of LC is 15% in general, 20% in those with
decompensated LC, and 50% in pts with TIPS.
• Its occurrence is a poor prognostic indicator, with projected 1-year survival rates of
42%, without liver transplantation.
3
DEFINITION
PREVALENCE
PROGNOSIS

4. CLASSIFICATION: ACC TO UNDERLYING DISEASE
• There are 3 major types of HE:
1. Type A, a/with acute liver failure;
2. Type B, a/with portosystemic shunts in the absence of liver disease;
3. Type C, a/with CLD and portal hypertension.
4
GRADING
Type C HE is the MC type and has historically been graded from 0 to 4 based on the West
Haven criteria .

5. WEST HAVEN CRITERIA

6. POSSIBLE MECHANISMS IN DEVELOPMENT OF HE
A. NEUROTOXINS Ammonia
Oxidative stress
Oxindole
B. IMPAIRMENT OF NEUROTRANSMISSION GABA-benzodiazepine neurotransmitter system
Glutamine
Catecholamines
Serotonin
Histamine
Melatonin
C. ALTERATION OF THE BLOOD-BRAIN BARRIER
D. SYSTEMIC RESPONSE TO INFECTIONS AND NEUROINFLAMMATION
E. BACTERIAL OVERGROWTH
6

7. Ammonia: Ammonia Production
• Bacterial production of Ammonia
• Endogenous production of Ammonia
• Renal Ammonia flux
• Ammonia flux in muscles
7
Production Ammonia flux
endogenous
bacterial
muscles
renal

8. Creation of state of hyperammonia
Gut production of Ammonia
• The bacterial urease can break down urea derived from the bloodstream
into ammonia and CO2.
• Enterocytes within the small bowel (to a lesser extent, in the colon) also
generate a large amount of ammonia via intestinal glutaminase as they
metabolize their main energy source, glutamine into glutamate & ammonia.
h
y
p
e
r
a
m
m
o
n
i
a
8
Glutamine glutamate + ammonia

9. Creation of state of hyperammonia
Renal Ammonia Flux
• Kidney are involved in both production and excretion of ammonia, that is
largely driven by acid-base status.
• In terms of excretion, the kidneys can remove a significant amount of
ammonia in the urine, either as ammonium ion (NH4
+) or in the form of urea.
• Excretion is impaired in state of ↓ renal perfusion or AKI.
• Dehydration, overdiuresis, diarrhea, GI Bleeding can lead to prerenal
azotemia that further lead to reduced perfusion and a ↓ GFR.
Gut production of Ammonia
h
y
p
e
r
a
m
m
o
n
i
a
9

10. Creation of state of hyperammonia
Renal Ammonia Flux
• Generation of ammonia: Glutamine is metabolized to ammonia, bicarbonate,
and glutamate. This ammonia-genesis primarily serves a role in acid-base
homeostasis, since bicarbonate is also produced during the reaction; thus
serves to buffer systemic acidosis.
• However, during periods of acidosis, the kidneys can ↑ the amount of NH4
+
released into the urine several fold.
Gut production of Ammonia
h
y
p
e
r
a
m
m
o
n
i
a
10
Glutamine glutamate + ammonia +HCo3

11. Creation of state of hyperammonia
• Ammonia incorporated into glutamine via glutamine synthetase in
skeletal myocyte.
• In Sarcopenia: impaired incorporation of ammonia, so ammonia ↑.
• Catabolism state in LC: excessive glutamine (and other amino acids) from
muscle into the circulation.
Hypokalemia
Ammonia flux in muscle
• As less potassium reaches the collecting tubules, more hydrogen ions are
moved into the cells, leading to a state of relative intracellular acidosis.
The kidneys then generate more ammonia and bicarbonate from
glutamine in an effort to balance the acid-base status of the pt.
Renal Ammonia Flux
Gut production of Ammonia
h
y
p
e
r
a
m
m
o
n
i
a
11
Glutamate + Ammonia ----> Glutamine

12. Fate of hyperammonia in brain
Furthermore, glutamine enters the mitochondria and is cleaved by glutaminase to ammonia and glutamate, which
subsequently increases the intracellular ammonia concentration. This ↑ in intracellular ammonia concentration causes a
“feed forward loop,” also known as the Trojan horse hypothesis, whereby intracellular ammonia leads to production of
reactive oxygen and nitrogen species, causing further edema.
Glutamine is osmotically active, and thus an ↑ in glutamine leads to astrocyte swelling and edema.
12

13. CEREBRAL OEDEMA
• Cerebral oedema may occur due to increased intracranial pressure, causing
➢unequal or abnormally reacting pupils, fixed pupils,
➢hypertensive episodes, bradycardia,
➢hyperventilation, profuse sweating,
➢local or general myoclonus, focal fits or decerebrate posturing.
• Papilloedema occurs rarely and is a late sign.
• More general symptoms include weakness, nausea and vomiting

14. FACTORS
Controlling precipitating factors in the MX of overt HE is of paramount importance, as
nearly 90% of pts can be treated with just correction of the precipitating factor .

15. DIFFERENTIAL DIAGNOSIS
15

16. Diagnosis
• No specific laboratory findings indicate the presence of HE definitively.
• Blood ammonia levels are commonly measured in pts with cirrhosis and
PHTN but are not sensitive or specific for the presence of HE.
Blood ammonia levels may be a useful indicator of HE in the absence of cirrhosis and PHTN, as in pts with metabolic
disorders that influence ammonia generation or metabolism, such as urea cycle disorders
16

17. MANAGEMENT OF OHE:
• OHE therapy follows a four-pronged approach
(i) Excluding other causes of altered mental status
(ii) Caring for the unconscious patient
(iii) Determining and treating precipitating factors
(iv) Initiating empiric therapy.
17

18. THERAPIES
18
LUMINAL THERAPY
EXTRA LUMINAL THERAPY
• LACTULOSE
• RIFAXIMIN
• L-ORNITHINE L-ASPARTATE
• ALBUMIN
• PROBIOTICS / PREBIOTICS
• BCAA
• ZINC
• NUTRITION
• OTHERS:FMT, SHUNT EMBOLIZATION

19. NONABSORBABLE DISACCHARIDES
• Lactulose (β-galactosidofructose) and lactitol (β-galactosidosorbitol) are two very
common nonabsorbable synthetic disaccharides .
• The MOA of these agents are multifactorial.
➢When administered, these agents are degraded by the natural flora in the large
intestine to short-chain organic acids, creating both an acidic environment and an
osmotic gradient in the intestinal lumen.
➢The acidic environment created causes destruction of urease-producing bacteria and
also facilitates the conversion of ammonia to nonabsorbable ammonium.
➢In addition, the increased osmolality also causes intestinal cleansing via removal of
excess fecal nitrogen through a laxative effect.
➢All of these effects decrease ammonia levels in the colon and portal circulation.
19

20. NONABSORBABLE DISACCHARIDES
• It is usually administered as an oral syrup with dosages being based on
clinical response for a goal of 2-3 soft bowel movements a day.
• Lactulose can also be given rectally, which is preferred in those in whom
oral administration is CI.
• Common side effects : flatulence, abdominal discomfort, and diarrhea.
• Lactitol : better tolerated than and as efficacious as lactulose.
20

21. RIFAXIMIN
• Rifaximin is a nonabsorbable antibiotic belonging to the rifamycin class.
• Its antibiotic action is due to the inhibition of chain formation in RNA
synthesis. It has a broad spectrum of action against several aerobic and
anaerobic gram-positive and gram-negative bacteria and does not have
any interactions with the cytochrome P450 substrates.
• The most common side effects reported include flatulence, abdominal
pain, headaches, and constipation.
• Dosing : 550 mg twice per day
21

22. PROBIOTICS AND PREBIOTICS
• Probiotics are live microbiologic dietary supplements that are intended to
have health benefits when consumed.
• Prebiotics are nondigestable food ingredients that selectively stimulate
the growth of bacteria in the colon.
• The combination of prebiotics and probiotics is called synbiotics.
22

23. ALBUMIN
• Albumin infusion has been used for the treatment of OHE, specifically
diuretic-induced OHE.
• In addition to volume expansion, albumin has antiinflammatory,
detoxifying, and immune modulating properties.
23

24. NUTRITION
• The current recommendations per the International Society for Hepatic
Encephalopathy and Nitrogen Metabolism -to have protein intake of 1.2
g/kg to 1.5 g/kg ideal body weight.
• In addition, it is also recommended for HE pts to consume 35-40 kcal/kg by
eating smalls meals that are evenly distributed throughout the day as well
as to have a late-night snack of complex carbohydrate to help minimize
protein utilization.
24

25. REASONS FOR HE RESISTANT TO RX
1. End-stage liver disease .
2. Excessive purgation leading to dehydration/free water loss
3. Failure to identify and treat sepsis
4. Ileus, especially in association with azotemia
5. Long-acting sedative drug intake
6. Undiagnosed concomitant CNS problem
7. Too-effective portosystemic shunt procedure
8. Profound zinc deficiency
25

26. LIVER TRANSPLANTATION
• Although it is not commonly the primary indication for LT, HE is generally
relieved by a successful graft.
• At present, recurrent or persistent HE does not give pts priority for liver
transplantation.
26
ISSUES OF LIVER TRANSPLANTATION AND HE
• HE is not included in the MELD score
• No priority is given to pts with severe recurrent or resistant HE
• How much HE is too much HE before transplant?

27. END OF SLIDES