Liver Failure Flashcards
What are 5 major criteria for ALF? What is fulminant hepatic failure? Subfulminant?
- Major criteria for Acute Liver Failure (also known as Fulminant Hepatic Failure)
a. Absence of underlying liver disease (exception: Wilson’s)
b. Coagulopathy (elevated prothrombin time internationalized ratio [INR] (>1.5)
c. Altered mental status
d. Hyperbilirubinemia (jaundice)
e. Alanine aminotransferase (ALT) & aspartate aminotransferase (AST) usually quite high (>1000-15,000 IU/L) - Acute liver failure includes onset within 26 weeks
a. Fulminant hepatic failure
i. All of the criteria above with….
ii. Altered mental status (encephalopathy) within 8 weeks of jaundice onset
b. Subfulminant hepatic failure
i. All of the criteria above with….
ii. Altered mental status (encephalopathy) more than 8 weeks of jaundice.
c. A and B are popular but not particularly helpful as they lack prognostic significance
List various etiologies of ALF in order of incidence.
Tylenol Unknown Drug Autoimmune Hep B Ischemic Hep A Other Wilson's Budd-Chiari Pregnancy
Describe various mechanisms of ALF including which etiologies cause the mechanism? What do they have in common?
- All have massive loss of liver function as common endpoint
a. Several pathways lead to this necrosis.
i. Direct toxin
1. Acetaminophen
2. Amanita phalloides (mushroom poisoning)
ii. Hypoxia
1. Heart failure
2. Trauma/shock
3. Sepsis/hypotension
iii. Immune mediated (3 examples follow)
1. Hepatitis B
2. Autoimmune
3. Idiosyncratic/hypersensitivity
iv. Vascular compromise
1. Budd-Chiari
v. Infiltrative diseases
1. Cancer (melanoma, breast)
2. Amyloidosis
vi. Mitochondrial damage or shutdown (relatively rare)
1. Massive necrosis NOT present
2. Microvesicular fat droplets seen in intake hepatocytes
3. Examples:
a. Fatty liver of pregnancy
b. Certain drugs like tetracycline and nucleoside analogues.
What are 5 consequences of massive necrosis and loss of liver function? Describe each of them in detail.
Pathophysiology II: Consequences of massive necrosis and loss of liver function
- Loss of biotransformation (detoxification) capabilities: Encephalopathy/cerebral edema
a. Exact mechanism of insult unclear
b. May be linked to ammonia accumulation
i. Ammonia accumulation may lead to more CNS glutamine, leading to cerebral edema (swelling) and increased seizure risk.
c. Cerebral edema is a leading cause of death - Loss of protein synthesis: Coagulopathy
a. Both consumption (DIC) and loss of synthesis leads to factor deficiencies
i. Predominantly II, V, VII, IX deficient
b. Complement deficiencies lead to increase infection risk.
i. Opsonin function disturbed - Loss of secretory function:
a. Hyperbilirubinemia: icterus, jaundice
b. Loss of vitamin A, D, E, K absorption (less important in ALF, but vitamin K often given). - Disturbed storage function:
a. Depleted or poorly available glycogen stores may lead to profound hypoglycemia.
b. Serum iron levels often high
c. Serum copper levels may be high particularly in acute Wilson’s disease. - Loss of immune and inflammatory regulation, function:
a. Impaired Kupffer cell function (loss of toxin clearance)
i. Increased bacterial translocation (leak) from intestines
b. Massive hepatocyte debris and inability to clear leads to
i. Cytokine release with diffuse inflammatory response
ii. Clotting cascade initiation/Disseminated Intravascular Coagulation (DIC)
iii. Increased vascular mediators causing vasodilation - Acute renal failure due to hepatorenal syndrome (from
vasodilation) and/or acute tubular necrosis (ischemia from
vascular collapse)
iv. Acute respiratory distress syndrome and multi-organ failure.
List 5 reasons why people with cirrhosis die? List 4 complications of cirrhosis including subcomplications.
Why do people with cirrhosis die?
Bleeding
Infections
Renal failure
Encephalopathy
Hepatocellular carcinoma
Complications of Cirrhosis
- Portal hypertension
- Ascites
- Hepatorenal syndrome
- Varices
- Hepatic encephalopathy
- Hepatocellular carcinoma
- Hepatopulmonary syndrome & Portal pulmonary hypertension
What is portal hypertension? Describe its pathogenesis? What are 3 consequences?
High blood flow into the liver:
• Portal vein blood flow = 1.5 liters/min
• Hepatic artery = 0.5 liters/min
• Total: about 2 liters/min
+
Obstruction
• Fibrosis
• Clots
• Schistosomiasis
=
Increased portal pressure
• Normal: 4-10 mm Hg
• Portal hypertension: 12-30 mm Hg
Portal hypertension
- Consequences
- Ascites
- Hepatorenal syndrome
- Varices
Describe the pathogenesis of cirrhotic ascites.
- Pathogenesis
- Portal hypertension
- Splanchnic vasodilation by nitric oxide release
- Renin angiotensin system turned on
- Increased renal sodium retention
- Fluid retention and portal hypertension overwhelms lymphatics of abdomen
(hepatic lymph formation > thoracic duct drainage and peritoneal reabsorption)
• Accumulation of hepatic lymph in abdominal cavity
What are some reasons to treat cirrhotic ascites? What are 4 forms of treatment?
Cirrhotic ascites
- Why treat?
- Discomfort: abdomen, back
- Appearance
- Spontaneous bacterial peritonitis
- Hernias
- Early satiety
- Hepatic hydrothorax
- Spontaneous rupture and drainage
- Treatment
- Dietary sodium restriction
- Diuretics
- Paracentesis
- Withdraw 5-10 liters of fluid through a needle
- TIPS (transjugular intrahepatic portosystemic shunt)
- Shunt portal blood directly into the inferior vena cava
Describe how dietary sodium restriction is used to treat cirrhotic ascites? Diuretics?
Dietary sodium restriction
• 2 grams sodium/day = 88 mmol/day
• Daily sodium excretion may be < 10 mmol/day
• Most patients will not respond to sodium restriction alone
Diuretics for cirrhotic ascites
• Mechanism of sodium retention
• Aldosterone binds the mineralocorticoid receptor and induces expression of the gene for the renal sodium pump
• Spironolactone (50-400 mg/day)
• Competitively inhibits the receptor binding of aldosterone
• The effect on gene expression takes time: days to have effect, days to wear off (patience with dose changes!)
• Associated with gynecomastia
- Loop diuretic (furosemide)
- Balances potassium level
Describe the pathophys of varices. What are some complications?
Varices
- Pathophysiology
- Enlargement of veins to allow increased blood flow around the liver
- Portal pressure > 16 mm Hg can cause varices
- Most common in esophagus
- Also:
- Gastric varices
- Rectal varices
- Umbilical varices
Varices
- Major complication of varices:
- Massive bleeding
- Bleeding risk occurs with pressure gradient across liver (portal pressure gradient) >10-12 mm Hg
How are varices treated? What is the natural history?
- Treatment
- Band ligation
- Non-selective beta-blockers
- Propranolol
- Nadolol
- Mechanism: decreased flow into mesenteric circulation
- Combined blockade-Carvedilol, Hepatology 2009
- Transjugular intrahepatic (TIPS) or surgical shunt
- Transplant
• Natural history
- Depends on cause of liver disease
- Irreversible: death or transplant over months
- Reversible: possible stabilization
Describe the pathophys of hepatic encephalopathy.
- Pathophysiology
- Accumulation of “toxins” normally cleared by liver
- Ammonia may be one toxin
- GABA-nergic substances
- Endogenous benzodiazepines
- Other?
- Toxins probably derive largely from gut flora
- Altered mentation
- Irritability to coma
How do you diagnose hepatic encephalopathy?
• Diagnosis
- Asterixis
- 100 msec delays in motor neurotransmission
- Commonly detected by “flapping” tremor
- History
- Altered sleep pattern
- Irritability
- No good lab test
- Serum ammonia is useless (except in ER patient with MS changes)
- CSF glutamine may be best but rarely obtained
How do you treat hepatic enceph? What shouldn’t you do?
- Treatment
- Lactulose
- It may “feed” enteric flora, promote retention of nitrogen in bacteria
- Old idea: lowers pH of colon—probably not accurate
- Antibiotics
- Neomycin, bacitracin
• Zinc: mechanism unclear
- Abandoned idea: protein restriction
- Dietary protein restriction increases muscle catabolism
- Typically aim for 1 g protein/kg weight
- Do not order “low protein diet” for cirrhotics with encephalopathy
What is the pathophys of hepatorenal syndrome?
• Pathophysiology
- Intense renal vasoconstriction overcomes protective effect of prostaglandins
- (Non-steroidal anti-inflammatory agents may inhibit prostaglandin protection; therefore NSAIDs should be avoided in cirrhotics particularly if ascites is present)
- Mediators
- Nitric oxide
- Renin-angiotensin system
- Common cause of death (median survival can be as short as 10-14 days!)
- Kidneys are relatively normal (ischemic injury over time)
