DILD Flashcards
What are Hy’s laws?
ALT > 3x ULN and T Bili > 2x ULN
ALT > 3x ULN x symptoms
ALT > 5x ULN for > 2 weeks
ALT > 8x ULN anytime
What are the symptoms for Hy’s law?
Fatigue N/V RUQ pain or TN Fever Rash/eosinophilia (>5%)
What must be ruled out before determining fatal risk of DIL injury?
Viral and Environmental causes
What are drug RFs for DILD?
Cumulative dose
Duration of treatment
Concurrent hepatotoxic agents (alcohol/APAP)
What are the disease RFs for DILD?
Chronic liver disease
Chronic renal disease
HIV
Obesity
What are the patient RFs for DILD?
Age (very young/old)
Occupation: agriculture, dyes (textile), plastic (fabrication)
What would we look for in a patient’s history as RFs for DILD?
Medical
Concurrent medication
Alcohol use
What are the RFs for medications in DILD?
Dose (acute/cumulative)
Duration
Which phase in drug metabolism creates reactive metabolites?
Phase I
Potentially hepatotoxic
Which phase in drug metabolism creates inactive metabolies?
Phase II
Lack of which metabolite causes hepatotoxic metabolites in APAP and bactrim?
Glutathione
Which phase is glutathione a part of?
Phase II
What are the three mechanisms of hepatic injury?
Intrinsic hepatotoxicity
Hypersensitivity
Idiosyncratic hepatotoxicity
What is intrinsic hepatotoxicity?
Usually dose and/or duration dependent = time of onset (predictable)
What are examples of intrinsic hepatotoxins?
Methotrexate (cumulative dose > 1.5g; duration > 2 yrs)
Ceftriaxone (dose > 1g/d; duration > 7 days)
How long is the sensitization period in hypersensitivity?
1-5 weeks
What are the systemic manifestations of hypersensitivity?
Eosinophilia
Rash
Fever
What medications re common for hypersensitivity?
Amox
NSAIDs
Convulsants
Allopurinol
What causes idiosyncratic hepatotoxicity?
Toxic metabolites that result from abnormal metabolic pathways in a susceptible patient
Both genetic factor (enzyme deficiency) + acquired factor (age)
What are drugs that cause idiosyncratic hepatotoxicity?
Valproic acid = results from enzyme deficiency (involving oxidation) greatest frequency in children < 2 yo
Isoniazid = slow acytelators (NAT2) = increase predisposition (increased in adults > 35 yo)
What are the classifications of DILD?
Hepatocellular
Cholestatic
Vascular
Neoplasia (hepatic)
How do hepatocellular changes cause DILD?
Interferes with metabolic processes
How do cholestatic changes cause DILD?
Interferes with secretory processes
What is a mixed presentation of DILD?
Has both hepatocellular and cholestatic causes for DILD
What is hepatocellular DILD?
Selective hepatocyte injury
What is the pathology hepatocellular DILD?
Local or diffuse necrosis
Steatosis = fat droplet deposition in the hepatocytes
What is the presentation of hepatocellular DILD?
Anicteric or icteric
Resemble viral hepatitis = fever, arthralgias, hepatomegaly
Labs = R >/= 5
How do we calculate R?
ALT/ULN ÷ AP/ULN
What can hepatocellular DILD lead to?
Fulminant hepatitis
What is fulminant hepatitis?
Encephalopathy
Increased INR
Death
What are the mortality rates for hepatocellular DILD?
> /= 10% if bili > 3x ULN
What is cholestatic DILD?
Selective disturbances in bile secretion
What is the pathology of cholestatic DILD?
Mild to severe canalicular cell damage
Disabled bile salt transport proteins
What is the presentation of cholestatic DILD?
Jaundice and pruritis Acholic stools (no bile = gray); dark urine (bilirubinuria) Severe form = fevere, RUQ pain Lab: R = 2; bile stasis with canalicular injury/inflammation
What drugs can cause cholestatic DILD?
Ceftriaxone
What is the mortality for cholestatic DILD?
< 1% - not fatal
What are the labs seen in mixed hepatocholestatic DILD?
R between 2 and 5
What drugs can cause mixed DILD?
Anticonvulsants
Abx
NSAIDs
How does vascular injury cause DILD?
Involves partial or full thrombosis of hepatic vein
What is Budd-Chiari syndrome?
Acute onset of ascites, rapid weight gain and jaundice \+ ab pain (severe upper quadrant) \+ Hepatomegaly Increased D-dimer LFTs variable but all elevated
What drugs can cause vascular injury?
BC (+ additional RFs)
What is hepatic neoplasia
Benign tumors filled with blood found w/in the liver that can rupture
What can hepatic neoplasia lead to?
Clinically dramatic hemoperitoneum upon rupture
-May occur in as many as one third of cases
-Rare, but seen with anabolic steroids (avg 6 yrs from initiation)
Regression often occurs when the medication is withdrawn
What are the presentations of hepatic neoplasia?
Ab pain
Wt loss
Fatigue
LFTs: mild increase
What are examples of drugs that cause hepatic neoplasia?
Anabolic steroids Oral contraceptives (HD estrogen)
What are the preventions for DILD?
Baseline LFTs
Patient counseling (at the very least)
Take precautionary measures
What sx do we tell a patient to contact their doctor if they develop?
N/V and/or ab pain of unexplainable origin lasting several days
OR
Mental status changes/bleeding episodes/jaundice
How often should LFT follow ups be preformed?
1-3 months
How do we take precautionary measures with intrinsic hepatotoxins?
Limit/watch dose
Duration of therapy
How do we take precautionary measures with hypersensivity reactions?
Watch for h/o allergies
How do we take precautionary measures with idiosyncratic hepatotoxins?
Watch for age/concurrent medications
How fast does a 50% reduction in LFTs occur upon discontinuation of hepatotoxin?
If injury is mild to moderate
2 weeks - hepatocellular
4 weeks - cholestatic
When do we not rechallenge?
Fulminant hepatitis
Hypersensitivity reaction
When do we rechallenge?
Diagnosis of DILD is questionable (only after s/sx resolved)
AND
Imperative medication only
How do we manage DILD?
Supportive care Symptomatic pruritis - cholestyramine Encephalopathy - lactulose Coagulopathy - vit K Spontaneous bacterial peritonitis - abx
