Gatot Sugiharto, MD, InternistInternal Medicine DepartmentFaculty of Medicine, Wijaya Kusuma University Surabaya

Enchepalophaty Hepaticum

Hepatic Failure (severe liver disease)

• > 80 to 90% of hepatic function is lost• Regeneration is rare (Hepatic transplantation -

only treatment)• Mortality - 70 to 95%• Patient dies in 2 to 3 weeks• Other causes :

– Drugs (Halothane, Tetracyclines, mushroom poisoning)

– Acute fatty liver of pregnancy

Clinical features

–Jaundice, hypoalbuminemia, hyperammonemia–Fetor hepaticus (a peculiar body odor related to

mercaptan formation) – Hyperestrogenemia : palmar erythema, spider

angiomas of the skin (one or two are normal esp. in pregnancy), hypogonadism, Gynecomastia

Complications • Coagulopathy ( ↓ hepatic synthesis of clotting factors) • Multi- organ failure• Hepatic encephalopathy ( ↑Ammonia)• Hepatorenal syndrome

Cirrhosis (1)

• Liver Cirrhosis is a histopathologic term (xirros = shrunken & hard)

• The eleventh leading cause of death by disease in the United States

• In the United States, chronic alcoholism and hepatitis C are the most common causes

Cirrhosis (2)

Three characteristics–Fibrosis : delicate bands or broad septa from portal

triad to central vein or c vein to c vein. • Fibrosis - irreversible and result in Portal HTN

–Nodules - regeneration of hepatocytes–Loss of architecture of the entire liver

Normal Liver

Inflammation (Hepatitis)

Fibrosis (Cirrhosis)

Patterns of Hepatic Injury

LIVER CIRRHOSIS

• Major causes :– Alcohol - (60-70%) called ASH (common in western)– Cryptogenic cirrhosis called NASH – Viral hepatitis B & C (tropical countries)

• For clinical practice, liver cirrhosis could be diagnosed if there are two clinical syndromes:– Hepatocellular failure, or– Portal Hypertension syndrome

Hepatocellular Failure Syndrome (HFS)

HFS consists of:• Loss of hair• Hyperpigmentation• Jaundice • Spidernaevi (neck, upper chest (front-back),

upper arm)• Gynaecomastia,testes atrophi,disturbance of

periodicity• Ascites • Liver palm• White nail

Spider angiomas

palmar erythema

Portal Hypertension Syndrome (PHS)

PHS consists of:• Varices of the esofagoes & rectum (haemorrhoid) It can be detected if the varix undergoes rupture as:– Hematemesis melena– Rectal bleeding (haematochezia/enterorrhagia)

• Vascular collateral in the abdominal wall It is important to define the direction of the passage

• Splenomegali • Ascites • Oedema of the lower extremeties

Complications of cirrhosis

• Portal hypertension–Varices, ascites, hypersplenism

• Synthetic dysfunction–Coagulopathy, encephalopathy hepaticum

• Immunodeficiency, infection spontaneus bacterial peritonitis

• Hypoalbumine, malnutrition• Hepato-cellular carcinoma• Hepato-renal syndrome

Hepatic Encephalopathy

• Disorder of CNS & neuromuscular transmission• Disturbances of consciousness & sleep, (behavioral

abnormalities, confusion, stupor, coma, death)• EEG changes, limb rigidity and Hyperreflexia, • Seizures & asterixis (a flapping tremor of

outstretched hands)• Pathogenesis : Severe loss of Hepatocellular function

& Exposure of the brain to excess ammonia levels

Etiology

• Fulminant hepatic failure due to acute hepatocellular necrosis• Acute severe viral hepatitis, drug/toxin, acute fatty

liver of pregnancy• Chronic liver disease due to one or more

potentially reversible precipitating factors• Cirrhosis of all types (70%),primary liver cancer,

surgically induced portal-cava shunts

Common precipitating factors

Nitrogenous

Encephalopathy

Uremia/azotemia

Gastrointestinal bleeding

Dehydration

Metabolic alkalosis

Hypokalemia

Constipation

Excessive dietary protein

Infection

Non-Nitrogenous

Encephalopathy

Sedative

Benzodiazepines

Hypoxia

Hypoglycemia

Hypothyroidism

Anemia

Pathogenesis (1)

• Toxic materials derived from nitrogeneous substrate in the gut and bypass the liver

• Postulated factors/mechanisms:• Ammonnia neurotoxicity• Synergistic neurotoxins• Excitatory inhibitory neurotransmitters and plasma

amino acid imbalance hypothesis• γ-Aminobutyric acid hypothesis

• Ammonia production : resulting from the degradation of urea or protein

• Primary site : gut (generating ammonia: 4g/day)• Other site :kidney and skeletal muscles• Equilibrium of ammonia and ammonium:

Ammonia neurotoxicity (1)

Ammonia neurotoxicity (2)

• Elevation of ammonia : detected in 60%~80%• Ammonia intoxication interfere cerebral

metabolism:• Depletion of glutamic acid, aspartic acid and

ATP• Depression cerebral blood flow and oxigen

consumption

Synergistic neurotoxins

Ammonia

Mercaptans fetor hepaticus

Short-chain fatty acids

Phenols

Excitatory inhibitory neurotransmitter

• Increased aromatic amino acids (AAAs) : • Tyrosine, Phenylalanine, Tryptophan• Due to the failure of hepatic deamination

• Decreased branched-chain amino acids (BCAAs) :• Valine, Leucine, Isoleucine • Due to increased metabolism by skeletal muscle and

kidneys or increased insulin• Decreased synthesis of normal neurotransmitters :

• L-Dopa, Dopamine, Noradrenoline• Enhanced synthesis of false neurotransmitters :

• Octopamine, Tryptophan, Serotonin

γ- Aminobutyric acid hypothesis

γ- Aminobutyric acid (GABA):

• Principle inhibitory neurotransmitters

• Generated in the gut by bacteria

• Bypasses the diseased or shunted liver

Pathohistology

• Brain may be normal or cerebral edema (particularly in fulminant heptic failure)

• In patients with chronic liver disease : increase in number and enlargement of Astrocytes

• In a very long-standing case : Thin cortex, loss of neurons fibers, laminar, necrosis , pyramidal tracts demyelination

Clinical manifestation(1)

In acute liver failure : • Spontaneously appearing• High fever, tachycardia, tachypnea,

hyperventilation• Severe fatal hepatic dysfunction + abrupt mental

deterioration coma/death

In chronic liver disease• Insidious onset• Characterized by subtle and/or intermittent changes in

consciousness, personality, intelligence speech• Disturbed consciousness: slowness, somnolence,

Disorientation, confusion, deep coma• Personality changes: Childishness, irritability• Intellectual deterioration : inability to produce simple

designs with blocks or matches, Reitan trail-making test, Daily writing chart

• Speech: slow, slurred, monotonous voice • Flapping tremor (asterixis)• Fetor hepaticus

Clinical manifestation(2)

Clinical stages of HE(1)

Clinical stages of HE(2)

Laboratory and other tests

• Serum ammonia : Elevation of serum ammonia: 60%~80%• Particularly in chronic HE with portosystemic

shunting• Electroencephalogram (EEG)

• Severe slowing with frequencies in the theta and delta

• Evoked potentials• Variation, lack of specificity and sensitivity

Differential diagnosis

• Hypoglycemia • Uremia• Diabetic ketoacidosis• Nonketotic hyperosmolar syndrome• Subdural hematoma• Cerebrospinal infection

Treatment

Strategy for the management of HE• Identify and correct the precipitating cause(s)

• Initiate ammonia-lowering therapy

• Minimize the potential medical complications of cirrhosis and depressed consciousness

Identification and treatment of precipitating factors

Essential management• Bleeeding : it must be controlled• Azotemia : rehydration, attention to other prerenal

factors• Eliminate sedative/tranquilizers/similar drugs

Initiate ammonia-lowing therapy

Decreasing nitrogen load

Decreasing ammonia

production

Decreasing absorption of

enteric toxins

Management

• Supportive care• Correction of fluid, electrolyte, glucose, acid-alkaline

abnormalities• Management of cerebral edema, bacteremia• Initiate ammonia-lowing therapy• Bowel cleaning• Antibiotics : Neomycin: 2~4g/D (4~6g/D), Metronidazol:

0.2g qid as effective as neomycin• Dietary protein restriction: 40-60 g/day• Lactulosa• Administration of BCAAs: oral or parenteral administration• Livert ransplantation