Block 1: Drug induced Liver Injury/Cirrhosis Flashcards
What is the liver function?
- Bile production
- Fat-soluble vitamin storage and metabolism (ADEK)
- Drug metabolism
- Billirubin metabolism
- Produces proteins for blood clotting and osmotic pressure
- Metabolizes nutrients from food to produce energy prn
Most common DILI medications?
- Alcohol
- Antibiotics
- Antiseizure
- APA
Most common cause of drug withdrawal, difficult to detect
Fisk facotors of DILI?
- Older age
- Females with severe hepatotoxicity
- Males with azathioprine, anabolic steroids, amox-clav
- Genetic polymorphisms
- DDI
- Livertox score
How do you diagnose DILI?
Patient with one of the following:
1. AST or ALT >5x ULN or ALP >2x (or fromt baseline) on 2 separate occasions
2. Total serum bilirubin >2.5 mg/dL with elevated AST, ALT or ALP
3. INR >1.5 with elevated AST, ALT, ALP
What are the elemetns that a drug might cause liver injury?
- Drug exposure preceded injury
- Causes of liver disease are excluded
- Drug discontinuation leads to improvement in the liver injury
- Rapid and severe recurrence occurs if there is repeated exposure to the drug (rechallenge)
Types of hepatotoxic medications classes?
- Antibiotics/Antimicrobial
- Immunosuppressive
- Birth control
- NSAIDs
- Antineoplastic
- Antiepiletic
MOA of APA toxicity?
What is the tx of APAP toxicity?
- NAC: most effective within 8hr of ingestion
N-acetylcysteine?
MOA, Forms, Monitoring
MOA: repletes glutathione reserves by providing cysteine, an essential precursor to glutathione production (binds to toxic metabolites and scavenges free radicals)
Forms: IV or Oral (rotten eggs)
Tx continues untils APAP levels are undetectable, PT/INR near normal, Encepalopathy resolved, transaminase levels trending down
What are liver chemistries?
Markers of injury not function
What is on a liver comprehensive metabolic panel?
- ALT
- AST
- ALP
- Bilirubin
- Albumin
What is cirrhosis?
- Caused by chronic liver injury
- Regenerative nodules surrounding dense fibrotic material
- Impacts portal BF, hepatocyte perfusion, hepatic synthetic functions
- Leads to portal HTN. varices, variceal bleeding, ascites, infection, encephalopathy, and hepatocellular carcinoma
What is varices?
Enlarged esophagus and stomach veins
Common causes of cirrhosis?
- Alcoholism
- Chronic Hep C
- NAFLD
Sx of cirrhosis?
- Asymptomatic
- SPLENOMEGALY
- Jaundice
- Gynecomastia
- Ascites, edema
- Malaise, anorexia, weight loss
- Encephalopathy
What are the labs of cirrhosis?
- Hypoalbuminemia
- PT elevation
- Thrombocytopenia
- Elevated ALP, AST, ALT, GGT
How do you diagnose to severity of liver disease?
Child-Pugh Classification
A patient has the following information: albumin 4.1 g/dL (41 g/L), serum bilirubin 3.3 mg/dL (56.4 µmol/L), prothrombin time that is 5 seconds prolonged, no ascites, and no encephalopathy. In terms of Child-Pugh score, what is the patient’s severity?
Grade B
What is the geneal approaches of cirrhosis tx?
- Identify and eliminate causes
- Assess risk for variceal bleeding
- Evaluate for signs of ascites
- Monitor for HE (lower ammonia)
- Monitor for signs of hepatorenal syndrome, pulmonary insufficiency, and endocrine dysfunction
What is protal HTN from mechanism to diagnosis?
- Resistance to portal blood flow = increased resistance and structural changes
- Asymptomatic utill complicatins (ascites, variceal, SBP)
Diagnosis: Known RF and clinical manifestations, if doubt, HVPG
What are the strageties to treat variceal bleeding?
- Primary prophylaxis (prevention of first episode)
- Tx of acute variceal hemorrhage
- Secondary prophylaxis (prevention of rebleeding)
Tx of primary variceal bleeding prophylaxis?
MOA, Dosing, CI
Nonselective B-blocker: Propranolol, nadalol, carvedilol
MOA: Reduce portal pressure by decreasing cardiac output by blocking beta-1 receptors and decrease in splanchnic blood by blocking beta-2 receptors
Dosing: propranolol 20-40 mg PO BID or nadalol 20-40 mg daily
(Titrate dose to resting HR of 55-60 beats/min, SBP > 90 mmHg)
CI: Given with present varices not to prevent the formation of
Tx of acute variceal hemorrhage?
Medical emergency
1. Adequate fluid resuscitation
2. Protection of airway for aspirating blood
3. prophylaxis against SBP/other infections
4. control bleeding, prevention re-bleeding
5. prevent AK, preserve liver function
6. Abx to prevent SBP: IV ceftriaxone 1g/day
7. 6. Stop/slow bleeding:
* Octreotide IV bolus 50 mcg followed by continuous IV infusion of 50 mcg/hr (up to 2-5 days)
ADR: bradycardia, HTN, arrhythmia, abdominal pain
Tx of secondary variceal bleeding?
- TIPS procedure
- Nadolol or propranolol only w/ EVL (endoscopic variceal ligation)
Which of the following represents an appropriate goal for a patient started on propranolol for variceal bleeding prophylaxis?
Heart rate of 55 to 60 beats/min; systolic blood pressure > 90 mm Hg
Describe the patho of ascites?
What is ascites?
Accumulation of an excessive amount of fluid within the abdomen
Major complication of cirrhosis
Tx of ascites?
- Paracentesis for new-onset
- Sodium restriction of 2000 mg/day
- Aldosterone antagonist or aldosterone antagonist + loop diuretic (Spironolactone 100 mg PO QD + furosemide 40 mg PO QD)
- Abstain from alcohol
What is Spontaneous Bacterial Peritonitis?
Infection of ascitic fluid from altered intestinal permeability and resultant bacterial translocation
Spontaneous Bacterial Peritonitis
Causes, sx, diagnosis
Causes: E. coli, Kleb pneumonia, pneumococci
Sx: Abdominal pain, diarrhea, vomiting
Diagnosis: (+) ascitic fluid bacterial culture and elevated ascitic fluid cell count of leukocytes
Tx of Spontaneous Bacterial Peritonitis?
Broad spectrum Abx: 3rd gen cephalosporin (cefataxime-Claforan or - ceftriaxome-Rocephin)
MDRO: piperacillin/tazobactam (zosyn)
Add vancomycin if MRSA
Which of the following symptoms is most consistent with Spontaneous Bacterial Peritonitis?
Increased leukocytes in ascites fluid
What is hepatic encephalopathy?
Functional disturbance of the brain caused by liver insufficiency:
1. Neurotoxic accumulation
2. Ammonia is most common, but also glutamine, benzodiazepine receptor agonists, and aromatic amino acids
3. Increased levels of ammonia in acute and chronic liver disease
Sx of hepatic encephalopathy?
- Confusion
- Personality changes
- Disorientation
- Depressed level of consciousness
- Lethargy
Can cause coma and death
Non pharm of hepatic encephalopathy tx?
- Protein Restriction: 1 to 1.5g/kg/day
- High fiber diet (favor plant-based proteins- beans, etc)
Pharm of hepatic encephalopathy?
- Non-absorbable disaccharide -Lactulose: Dose 15-45mL PO Q8-12 hours targeting 2-3 soft stools/day, Rectal enema, and can consider PEG 3350
- Abx: Neomycin, Metronidazole (don’t use) - high risk for neurotox and lower effectiveness
- Rifaximin ($$$) - Low systemic absorption
Your patient has a history of chronic alcohol use and cirrhosis and now presents with altered mental status with alternating delirium and loss of consciousness. He has no evidence of ascites or hematemesis. Which of the following is your immediate next step?
Assessing ammonia levels and screening for hepatic encephalopathy.
ADME changes of heptaic encephalopathy treatment?
- Increased sensitivity of NSAIDs, benzos, opiates
- Reduced liver blood flow, loss of CYP enzyme activity, decreased first pass extraction, hypoalbuminemia, ascites, impaired biliary excretion, etc
- Requires closer monitoring
