Chapter 18 part 1--Liver failure, cirrhosis Flashcards
General features of Liver Disease–most common primary diseases
-viral hepatitis, alcohol related liver disease, nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC)
General features of Liver disease–most common secondary diseases
- secondarily affected by common disorders like congestive heart failure and metastatic cancer
- lab testing may show injury but an enormous functional hepatic reserve masks clinical impact of early damage
General features of Liver disease–symptoms
- Most liver disease is insidious with symptoms of decompensation developing over weeks to years
- but disrupted bile flow or progressive disease=life threatening
Tests that measure hepatocyte integrity
- Cytosolic hepatocellular enzymes:
- Serum aspartate aminostransferase (AST)
- Serum alanine aminotransferase (ALT)
- Serum lactate dehydrogenase (LDH)
Tests that measure Biliary excretory function
- substances normally secreted in bile:
- Serum bilirubin (Total=unconjugated + conjugated, direct=conjugated only, delta=covalently linked to albumin)
- urin bilirubin
- serum bile acids
- Plasma membrane enzymes (from damage to bile canaliculus)–serum alkaline phosphatase, serum GGT, serum 5’-nucleotidase
Tests that measure hepatocyte function
- Proteins secreted into blood:
- Serum albumin
- Prothrombin time (factors V, VII, X, prothrombin, fibrinogen)
- Hepatocyte metabolism:
- Serum ammonia
- Aminopyrine breath test (hepatic demethylation)
- Galactose elimination (IV injection)
Elevation vs. decrease in liver tests
- Elevation implicates disease
- Decrease also implicates liver disease
Mechanisms of injury and repair–hepatocyte and parenchymal responses—reversible degenerative changes include:
- fat accumulation (steatosis) and bilirubin buildup (cholestasis)
- when injury is not reversible, hepatocytes die by necrosis or apoptosis
Hepatocyte necrosis
-predominant mode of death in ischemic-hypoxic injury and responses to oxidative stress: defective osmotic regulation leads to cell swelling and rupture, also marked by local macrophage accumulation
Hepatocyte apoptosis
-typical of cell death associated with acute and chronic hepatitis and is marked by hepatocyte shrinkage, nuclear chromatin condensation (pyknosis), fragmentation (karyorrhexis), and cellular fragmentation into acidophilic bodies
Vascular insults and liver disease
-Even in diseases where hepatocytes are the principal targets of attack (e.g., hepatitis), vascular insults via inflammation or thrombosis–lead to confluent zones of parenchymal necrosis
Hepatocyte regeneration
- occurs primarily by proliferation of hepatocytes adjacent to those that have died
- stem cell replenishment is usually not a significant part of parenchymal repair
- In severe liver injury, the canal of Hering–the primary intrahepatic stem cell niche–can be activated but unclear how much they contribute to healing
- With chronic disease, hepatocytes can reach replicative senescence, at which point stem cell activation leads to formation of ductular reactions that can contribute to parenchymal restoration
scar formation and regression–hepatic stellate cell–what is it?
-lipid (vitamin A) storing cell is responsible for liver scar deposition
how are stellate cells activated?
- can be activated by:
- 1) inflammatory cytokines like TNF, lymphotoxin, and IL-1B and lipid per oxidation products
- 2) cytokine and chemokine production by Kupffer cells, endothelial cells, hepatocytes and bile duct epithelial cells
- 3)in response to disruption of ECM
- 4) direct stimulate of stellate cells by toxins
What happens after stellate cells are activated? how does further fibrogenesis occur?
- activation causes stellate cells to develop into highly fibrogenic and contractile myofibroblasts
- subsequent fibrogenesis is driven by cytokines released by Kupffer cells and lymphocytes (TGF-B)
- stellate cell contraction stimulated by endothelin1 (ET-1)
Portal fibroblasts
-Also contribute to scar deposition with ductular reactions leading to activation and recruitment of such fibrogenic cells
What happens if the chronic injury leading to scar formation is interrupted (clearance of hepatitis virus infection, cessation of alcohol use)?
- then stellate cell activation ceases and fibrosis can be fragmented by metalloproteinases produced by hepatocytes
- so in this way, scar formation can be reversed!!
Inflammation and Immunity
- Innate and adaptive immune systems involved in liver injury and repair
- TLRs detect molecules derived from foreign invaders like bacteria and viruses
- lead to pro inflammatory cytokines
- adaptive immunity plays critical role in viral hepatitis by destroying infected hepatocytes
Liver failure
- occurs when greater than 80-90% of hepatic function lost
- without liver transplantation, mortality rate is 80%
- Although occasionally caused by massive acute destruction (fulminant hepatic failure), more commonly bc of successive waves of injury or progressive chronic damage
- Pts with marginal function can also go into failure when intercurrent dz places a greater demand on hepatic fnx
Stellate cell activation and liver fibrosis
- Kupffer cell activation leads to secretion of multiple cytokines
- PDGF and TNF activate stellate cells and contraction of activated stellate cells is stimulated by ET-1
- Fibrosis is simulated by TGF-B
- Chemotaxis of activated stellate cells to areas of injury is promoted by PDGF and monocyte chemotactic protein-1 (MCP-1)
Acute liver failure
- liver illness associated with encephalopathy within 6 months of initial diagnosis
- fulminant hepatic failure is designated when encephalopathy develops within 2 weeks of jaundice onset
Most acute liver failure is caused by?
- massive hepatic necrosis attributable to drugs or toxins, often compounded by immune mediated hepatocyte destruction
- acetaminophen overdose accounts for almost half of cases in US whereas in Asia, hep B and E predominate
Mnemonic for acute liver failure causes:
A: Acetaminophen, hep A, autoimmune hep (AIH)
B: Hep B
C: Hep C, cryptogenic
D: Drugs or toxins, hep D
E: Hep E, esoteric causes (Wilson disease, Budd Chiari dz)
F: Fatty change of the microvesicular type (fatty liver of pregnancy, valproate, tetracycline, Reye syndrome
Clinical course of acute liver failure–symptoms
- loss of normal hepatocyte function; same manifestations regardless of etiology:
- nausea, vomiting, jaundice, progressing to encephalopathy (due to inadequate hepatic synthesis of coagulation factors)
Clinical course of acute liver failure–changes in the liver
- liver initially swells due to edema and inflammation
- liver transaminases are elevated reflecting hepatocyte destruction
- liver dramatically shrinks and transaminase levels decline because few viable hepatocytes remain
Consequences of acute liver failure
- Portal HTN–>ascites exacerbated by reduced albumin synthesis
- Hepatic encephalopathy
- Hepatorenal syndrome
- multiorgan failure and death
Hepatic encephalopathy
- Life threatening disorder of CNS and neuromuscular transmission caused by portosystemic shunting and loss of hepatocellular function
- Resulting excess ammonia in blood impairs neuronal function and causes brain edema, leading to disturbances in consciousness (confusion to coma), limb rigidity, hyperreflexia and asterixis
Hepatorenal syndrome
- causes renal failure
- etiology=decreased renal perfusion pressure followed by renal vasoconstriction with sodium retention and impaired free-water excretion
Chronic liver failure
-often but not uniformly associated with cirrhosis=12th leading cause of death in US
Most common causes of cirrhosis leading to chronic liver failure
- alcohol abuse
- viral hepatitis
- non-alcoholic steatohepatitis (NASH)
- Biliary disease and hemochromatosis (less frequent)
- 20% of cases=unknown cause
Three morphologic characteristics of cirrhosis
- Bridging fibrosis
- Parenchymal nodules
- Disruption of hepatic parenchymal architecture
Bridging fibrosis
-links portal tracts to each other and to central veins
Parenchymal nodules
-results from hepatocyte regeneration when encircled by fibrosis
Clinical features of cirrhosis
- clinically silent until far advanced (40% of cases)
- presents w/ anorexia, weight loss, weakness and debilitation, hypererestrogenemia due to impaired estrogen metabolism with palmar erythema, spider angiomata, hypogonadism, and gynecomastia
Overt hepatic failure can be precipitated by
-intercurrent infection or GI hemorrhage
Death in cirrhosis can be due to what causes?
- Progressive liver failure with encephalopathy and coagulopathy
- Complications of portal HTN like variceal bleeding
- Bacterial infections due to gut mucosal damage and Kupffer cell dysfunction
- HCC
Portal HTN results from:
- combination of increased flow into portal circulation and/or increased resistance to portal blood flow
- Prehepatic, intrahepatic or post hepatic!!
Specific causes of portal HTN: Prehepatic
- Obstructive thrombosis of portal vein
- structural abnormalities like portal vein narrowing before it ramifies in the liver
- increased splanchnic arterial circulation, or massive splenomegaly with increased splenic vein blood flow
Specific causes of portal HTN: Intrahepatic
- Cirrhosis (most common)
- PBC (even in absence of cirrhosis)
- Schistosomiasis
- Massive fatty change
- Diffuse, fibrosing granulomatous disease (ex:sarcoidosis)
- Nodular regenerative hyperplasia
- Infiltrative malignancy, primary or metastatic
- Focal malignancy with invasion into portal vein (esp HCC)
- Amyloidosis
Specific causes of portal HTN: Posthepatic
- Right sided heart failure
- constrictive pericarditis
- hepatic vein outflow obstruction
Major clinical consequences of portal hypertension
- Ascites: collection of excess serous fluid in peritoneal cavity–most often a consequence of cirrhosis
- Portosystemic shunts
- Splenomegaly
- Hepatopulmonary syndrome
- portopulmonary HTN
Pathogenesis of ascites
- Hepatic sinusoidal HTN (exacerbated by hypoalbunemia)
- Percolation of hepatic lymph into peritoneal cavity
- Splanchnic vasodilation causes systemic hypotension that triggers vasoconstrictor responses (ex: renin-angiotensin) with renal retention of sodium and water and subsequent intestinal capillary transudation
Figure 18-2: Major clinical consequences of portal HTN in the setting of cirrhosis in males
- Hepatic encephalopathy!!!
- Malnutrition
- Skin spider angiomata
- Esophageal varices!!!
- Ascites!!!
- Periumbilical caput medusae
- Hemorrhoids
- Testicular atrophy
Figure 18-2: Major clinical consequences of portal HTN in the setting of cirrhosis in females
- oligomenorrhea
- amenorrhea
- sterility as a result of hypogonadism
Portosystemic shunts in portal HTN
- arise as portal pressures rise
- flow is reversed from portal into systemic circulation where there are shared capillary beds
- Esophagogastric varices, rectal hemorrhoids, falciform ligament and umbilicus (caput medusae)
Esophagogastric varices
- most significant
- occur in 40% of patients with advanced cirrhosis
- rupture and cause massive hematemesis
- each bleed has a 30% mortality
Splenomegaly from portal HTN
-caused by long-standing congestion and can cause thrombocytopenia (or even pancytopenia) due to hypersplenism
Hepatopulmonary syndrome from portal HTN
- occurs in 1/3 of patients with cirrhosis and portal HTN
- pts develop intrapulmonary vascular dilation (due to increased nitric oxide production) with accelerated flow that reduces time for O2 diffusion and leads to ventilation-perfusion mismatch and hypoxia
Portopulmonary HTN results from
-excessive pulmonary vasoconstriction and vascular remodeling due to inadequate liver clearance of circulating ET-1
Acute on chronic liver failure
- Adv chronic liver disease can be well compensated despite cirrhosis with extensive vascular shunting
- but large volumes of liver have borderline vascular supply and sepsis or cardiac failure may lead to hypotension that tips balance into acute liver failure
- drug or toxic injury can also precipitate failure
- short term mortality=50%
Other causes of acute on chronic liver failure
- Patients with chronic hep B infection who become infected with hep D can undergo sudden decompensation
- Also its with medically suppressed hep B who develop resistant viral mutants
- Malignancy in compensated patient either from hepatic metastases of a secondary unrelated tumor or secondary to liver dz itself esp HCC or cholangiocarcinoma (CCA)
