Acute Liver Failure/Injury Flashcards
Fulminant Hepatic Failure
- clinical syndrome
- massive necrosis of liver cells/dysfunction
- preceding liver disease absent
- duration <8 weeks
- 66% mortality
Etiology of Fulminant Hepatic Failure
- Viral (A,B,D,E, Herpes, CMV, EBV, Varicella, Adeno)
- Drug & Toxin (acetaminophen, halothane, NSAIDS, herbals)
- Ischemic (shock, Budd-Chiari)
- Metabolic (Wilson, Fatty liver of pregnancy, Reye’s Syndrome)
- Miscellaneous (Malignant Infiltration, Bacterial Infection)
Fulminant Hepatic Failure: Viral
- most common cause
- HAV rare usually > 40 years old
- HBV: 50% coinfection w/delta, reactivation after immunosuppression
- HEV: pregnant females
- Immunocompromised: HSV, CMV, EBV, Varicella, Adenovirus
Fulminant Hepatic Failure: Vascular
- Budd-Chiari: acute w/hepatic vein thrombosis
- Hypotension: surgical shock, cardiac failure, septic shock
- Hypoxia: hepatic artery occlusion, pulmonary failure
Fulminant Hepatic Failure: Metabolic
- Wilson’s Disease: ceruloplasmin low, Cu high, hemolysis w/Hepatic Failure
- Fatty Liver of Pregnancy: microvesicular fat with fatty acid metabolism abn.
- Reye’s Syndrome: same above mitochondrial dysfunction
Fulminant Hepatic Failure: Infiltrative
Malignant Infiltration -Lymphoma (Burkitt's) -Malignant histiocytosis -CML, acute monoblastic leukemia -massive infarction & necrosis -Metastic cancer-small cell carcinoma of lung Severe Bacterial Infection
FHF Investigations
Viral (HBsAg, HBcAb-IgM, HDV-Ab, HAV-IgM)
Metabolic-ceruloplasmin, anti-nuclear abs & smooth muscle abs
General-CMP, CBC, INR, AFP
Hepatotoxic Drugs
Mushroom poisoning
Herbal Remedies
Fulminant Hepatic Failure: Clinical
- Jaundice not related to neuropsych abn.
- Liver size large (small with collapse)
- vomiting
- inc. HR, BP, RR & fever are late signs
- focal neurological signs, high fever may indicate alternative source of PSE
R/O Chronic Liver Disease
- no liver history
- small hard liver
- splenomegally
- vascular collaterals
Portosystemic Encephalopathy
- Multifactoral: dec. glucose, perfusion, anoxia, change in electrolytes, edema
- Neurotoxins: ammonia, GABA mercaptins, benzos
- False Neurotransmitters: Aromatic Amino Acids (serotonin)
Encephalopathy & EEG
Stage 1: normal alert
2: inc. EEG amplitude with confusion
3: drowsy with dec. EEG wave frequency
4: coma w/triphasic EEG waves, diffuse slow waves
Neuropsychiatric: Fulminant Hepatic Failure
- reticular stimulation (brain stem depression)
- Early: personality change, anti-social, restless delerium (reticular stim)
- Late: decerebrate rigidity (spasticity, extention of limbs), disconjugate gaze, Pupillary reflux loss, CVS collapse
Cerebral Edema
-common cause of death w/cerebellar & brain stem coning
-PaCO2 rises & blood flow inc
-Inc in ICP
-Death w/brain stem vascular interruption
-Decerebrate rigidity, extention posture
-Pupillary reflexes lost
(arching neck, erratic breathing, pronation of hands, seizure like activity, hyperextended extremities)
Fulminant Liver Failure: Hypoglycemia
- seen in 40%
- high plasma insulin levels
- may lead to sudden death
- lactic acidosis develops in 50%
- due to inadequate tissue perfusion (+/- sepsis)
Fulminant Liver Failure: Good Indicator of Prognosis
INR
Fulminant Liver Failure: Other Effects
Acid-Base/Electrolytes
Renal Failure
Respiratory & CV failure
Infections
Fulminant Liver Failure: Prognostic Indicators
age: 40 y/o small liver ascites jaundice> 7 days before encephalopathy hypoglycemia hepatocyte necrosis >75% (biopsy) (Grade I or II encephalopathy 66%) (Grade III or IV encephalopathy 20%)
Fulminant Hepatic Failure: Treatment
- Vitals, Labs, LOC, I/O monitoring
- Encephalopathy (Lactulose, mannitol, hyperventilation)
- Coagulopathy
- Nutrition (glucose, MVI, Elemental feeds)
- Renal (ultrafiltration, dialysis)
- Infections - treat as indicated
Artificial Hepatic Support
- liver dialysis unit (don’t have)
- variations on charcoal hemoperfusion
Liver Transplantation
- Neuroaxis intact
- Survival 75%
- No comorbid contraindications: cardiac, renal, respiratory, psychosocial
Common Causes of Hepatic Injury?
alcohol shock tylenol sepsis antibiotics pregnancy viral hepatitis
What does portal vein do?
-brings blood from intestines and spleen to liver
Hepatic Blood Supply
Duel
- Portal Vein (70%)
- Hepatic Artery (30%)
- less vulnerable to ischemia, but shock can cause ischemic hepatitis (especially from long term heart failure)
- portal vein thrombosis can cause ischemia limited to liver
Hepatic Vein Thrombosis
- Ischemic hepatitis (Budd-Chiari syndrome)
- tender hepatomegaly
- abdominal pain, ascites
- hypercoagulable state (myeloproliferative disorder)
Shock Liver Causes?
- rapid rise in transaminases to a peak 25-250x normal
- steady decline to normal in 7-10 days
- Bilirubin rises only as transaminases are falling & rarely goes above 4x upper limit normal
- Alkaline phosphatase rarely goes above 2xULN
Endothelium of Hepatic Sinusoids
-have fenestrations (windows) very in size, some let platelets pass
Hepatic Sinusoids: Open Circulation
- lined by fenestrated cells (no tight junctions or basement membranes)
- no continuous diffusion barrier b/w plasma and hepatocytes’ cell surface
Hepatic Sinusoids: Kupffer Cells
- intercalated b/w endothelial cells and forming part of sinusoidal lining
- have phagocytic capacities & defend us by nabbing intestinal bacterial and products
- stimulates them to release IL-1, TNF, IL-6, IL-8, IL-12, TGF-beta, interferon, PGD2, PGE2, thromboxane & complement (mediating sepsis)
Sepsis & Liver
- acute liver injury with inc. bilirubin & transaminases & alkaline phosphatase
- measures of liver injury*
Hepatic Sinusoids: Ito Cells
“perisinusoidal; fat storing or stellate cells”
- underneath sinusoidal lining cells, with apparently random distribution
- multipotential mesenchymal cells with the ability to differentiate into fibroblasts or myofibroblasts with chronic liver injury
Hepatic Sinusoids: Space of Disse
- b/w sinusoidal lining cells & hepatocyte cell membranes there is a tiny space (
- has some extracellular matrix glycoproteins & occasional collagen fibrils
Bile
- flows in reverse direction to afferent blood supply (central to portal)
- hepatocytes secrete it into bile canaliculus, a structure formed by apposing lateral surfaces of 2 hepatocytes
- canaluculi are sealed by tight junctions & actin filaments around the canaliculus provide some peristaltic action
Hepatocytes as Metabolic Detoxification sites
- vulnerable to injury
- hepatocellular is most common form of drug-induced liver injury (inc. transaminases & moderately elevated alkaline phosphatase & bilirubin)
- abx are most common type of drug for injury
Canaliculi drain into?
bile ducts
- at interface b/w lobule and portal tirad, the ductules are lined by flattened epithelial cells; the oval cells that communicate with the bile ducts that eventually drain into the main bile duct
- extracellular matrix in portal tirad stroma contains collagen (I, III, IV), glycoproteins, & proteoglycans
Oval Cell
-become ductal cell or hepatocyte
Canalicular Cholestasis
-preferentially affect bile canaluculi, interfering with their motility & resulting in canalucular bile “plugs”
hepatocellular Cholestasis
-impede secretion of bile into the canaliculi, resulting in the accumulation of bile in hepatocytes
Color of Bile
- Green: most common, can be any shade
- Yellow: common (gold/brown)
- White Bile = mucus
Pregnancy induces Liver Disease
-1 in 1,000 pregnancies
3 forms
1) HEELP syndrome (hemolysis, elevated liver enzymes, low platelets)
2) Acute Fatty Liver in Pregnancy
3) Intrahepatic cholestasis of pregnancy (most common)
Intrahepatic Cholestasis of Pregnancy
- due to epiallopregnanolone sulfate inhibition of farnesoid X receptor mediated bile acid efflux
- mild inc. bilirubin, inc. alk phos, maternal pruritis, modest fetal distress,premature birth & stillbirth, responds to ursodeoxycholic acid treatment
Cholestatic Liver Injury
- second most common drug-induced liver injury
- inc. bilirubin & alkaline phosphatase, & moderately elevated transaminases
- Psychoactive drugs (cause injury in hepatocellular or cholestatic pattern
3 Zones in Liver Lobule
- Periportal
- Midzonal
- Central
Centrolobular Hepatocytes
- “downstream”
- receive blood with lower content of oxygen & metabolites than peri-portal hepatocytes
- often first cells affected in many forms of hepatic injury
Midlobular Hepatocytes
-Intermediate with blood supply
Periprotal Hepatocytes
- best blood supply (rich in oxygen, nutrients)
- in severe injury they are only ones that survive
Tylenol Toxicity
- metabolized to toxic N-acetyl-p-benzoquinoneimine (NAPQI)
- conjugated with glutathione to non-toxic compound (when run out it builds up)
- centrolobular run out first
- likely if >12g in day
Tylenol Toxicity Symptoms
- nausea, vomiting, sweating, pallor, lethargy, malaise
- fine b/w 24-72 hrs then 72-96 re-appear with:
- jaundice, confusion, bleeding
Location of necrosis: Acetaminophen
central
Location of necrosis: Yellow fever, mushrooms
midzone
Location of Necrosis: Phosphorus Compounds
periportal
Focal Necrosis
only few cells affected and with random distribution
Confluent Necrosis
affects large cell groups
Acute Viral Hepatitis also causes?
-swollen pale hepatocytes
-portal & lobular infiltration by lymphocytes, macrophages (plasma cells)
-Kupffer cell hypertrophy & hyperplasia
+/- cholestasis
Symptoms of Viral hepatitis? (acute liver injury & necrosis)
- malaise, anorexia, nausea, fatigue
- jaundice, transaminases are elevated
- alkaline phosphatase usually do not rise as markedly
Autoimmune Hepatitis (liver injury)
not common
- clinical similar to viral hepatitis but diagnostic abs
- plasma cells more prominent
Microscopic: Alcohol cause of Acute Liver Injury
- ballooning degeneration
- steatosis
- Mallory bodies
- feathery degeneration
- apoptosis
- acute inflammation
Chronic Liver Injury is Usually Associated with?
- chronic inflammation & simultaneous ongoing
- repair response
- scarring (fibrosis)
Key players in Hepatic repair response?
- stellate cells (Ito)
- differentiate into myofirboblasts & secrete collagen and other extracellular matrix substances into the space of Disse
The end-stage of liver disease?
Cirrhosis
Spider Angiomas
- vascular lesions consisting of a central arteriole surrounded by many smaller vessels, most frequent on the trunk, face, arms
- central arteriole can be seen pulsating when compressed with a glass slide
Most common causes of cirrhosis are?
- alcohol
- hepatitis C
- non-alcoholic steatohepatitis
- hemochromatosis
