12 PORTOSYSTEMIC ENCEPHALOPATHY
Definition, Etiology, Precipitating factors, Manifestations,
Complications, Treatment
● Definition
○ Portosystemic encephalopathy is
neuropsychiatric syndrome that can develop in
patients with liver failure and/or portosystemic
shunt.
● Etiology
○ It is caused by an underlying liver dysfunction in
the presence of precipitating factors
○ In most cases, it occurs on the background of
chronic liver failure like cirrhosis
● Diagnosis
○ However, it can also be caused by acute liver
failure such as in the setting of viral hepatitis,
drug-induced hepatitis, and autoimmune hepatitis
● Precipitating factors
○ Increased ammonia production (GI bleeding,
infections)
■ GI bleeding – globin from hemoglobin can be broken down
into amino acids and eventually, ammonia
■ Infections – trigger immune response leading to release of
cytokines and alter BBB permeability, allowing toxins to
enter the brain easily)
○ Decreased ammonia secretion (hypokalemia,
metabolic alkalosis, constipation)
■ Hypokalemia – ↓ serum/urine K, ↓ H+/K+ exchanger
activity, ↓H+ in lumen favoring NH3 reabsorption
■ Metabolic alkalosis – reabsorbs ammonia in kidney tubules
■ Constipation – slower GI transit favors ammonia
reabsorption
○ Portosystemic shunting (Transjugular
Intrahepatic Portosystemic Shunt (TIPS)
■ TIPS – Redirect blood flow from the portal vein directly into
the hepatic vein or vena cava, bypassing the liver.
Redirection can also lead to the bypass of the liver's
detoxification processes, allowing toxins, including
ammonia, to reach systemic circulation.
○ Progressive hepatic parenchymal damage
(fatty liver disease, chronic hepatitis,
hepatocellular carcinoma)
● Pathogenesis
○ The most important causative factor of hepatic
encephalopathy is increased ammonia level in
the blood
○ Ammonia is produced primarily in the colon. In
the colon, bacteria metabolize proteins and other
nitrogen-based products into ammonia.
○ The colonic ammonia is then transported to the
liver via the portal circulation where it is
normally converted into a nontoxic water
soluble metabolite urea, which is excreted in
the kidneys.
○ However, in patients with liver cirrhosis, there is
reduced hepatocyte function which impairs the
ability to metabolize ammonia into urea.
○ The primary site of ammonia toxicity appears to
be the CNS
○ Because the CNS is not equipped for urea cycle,
excess ammonia is converted to glutamine within
the astrocytes via glutamine synthetase
○ Consequently, glutamine being an osmotic agent,
astrocyte swells leading to cerebral edema
accounting for the different neuropsychiatric
symptoms seen in hepatic encephalopathy.
● Manifestations
○ Hepatic encephalopathy is characterized by
cognitive deficits and impaired
neuromuscular function
■ Cognitive findings: forgetfulness,
personality changes, attention deficits,
changes in sleep-wake cycle, behavioral
changes, somnolence, confusion,
disorientation, coma
■ Neuromuscular impairments, include
bradykinesia, hyperreflexia, rigidity,
myoclonus, and asterixis
○ In addition, patients frequently have clinical
manifestations of chronic liver disease (spider
angioma, palmar erythema, jaundice, asterixis,
ascites)
■ Chronic liver disease: spider angiomas,
palmar erythema, gynecomastia, testicular
atrophy, jaundice, Dupuytren contractures
■ Portal hypertension: caput medusae,
ascites, splenomegaly, esophageal varices
○ CBC – rule out infection, GI bleed
○ CBG – rule out hypoglycemia
○ Serum ammonia – elevated
○ Serum Na, K – check for electrolyte imbalance
○ ABG – check for acid base disturbances
○ Urinalysis – rule out UTI
○ Liver enzymes (AST, ALT) and synthetic function
tests (TPAG, PT, INR) – for underlying liver
disease
○ Cranial CT scan or MRI – to rule out intrinsic
brain pathology
○ Severity of hepatic encephalopathy is graded
according to West Haven Criteria which is based
on clinical manifestations:
■ Minimal: Abnormal results on psychometric
or neurophysiological testing without clinical
manifestations
■ Grade I: Changes in behavior, mild
confusion, slurred speech, disordered sleep
■ Grade II: Lethargy, moderate confusion
■ Grade III: Marked confusion (stupor),
incoherent speech, sleeping but arousable
■ Grade IV: Coma, unresponsive to pain
○ Management
■ When to admit patients?
● Grade I encephalopathy – managed as
outpatients
● Grade II encephalopathy – depends on
the degree of lethargy and confusion
● Grades III-IV hepatic encephalopathy –
require hospital admission for treatment
■ General resuscitative measures for patients
with hepatic encephalopathy include
insertion of IV line and hydration of the
patient, oxygen supplementation, airway
assessment and management.
■ Correction or treatment of precipitating
causes combined with standard therapy to
lower ammonia levels
■ Lower ammonia concentration with oral
lactulose or lactitol (titrate amount to
achieve 2-3 stools per day) is the mainstay
of treatment to lower blood ammonia
concentration
MOA: Synthetic disaccharide which is
catabolized by the colonic bacterial flora into
short-chain fatty acids (SCFA) such as lactic
acid and acetic acid which lower the colonic pH
to approximately 5, thereby favoring formation of
non-absorbable NH4+ from NH3, trapping it in
the colon for excretion
Lactulose 30 mL BID-QID PO
Lactitol 100g diluted in 100ml water BID-QID
PO titrated to achieve 2-3 soft stools per day
■ For patients who do not improve within 48
hours of lactulose, treatment with
Rifaximin is indicated and is added to
lactulose.

MOA: reduce ammonia production by

eliminating ammonia-producing colonic bacteria

Rifaximin 550 mg/tab BID orally