Drug Induced Liver Injury

Question 1

What does the hepatic triad consist of?

Answer 1

Portal vein, Hepatic artery, Bile duct

Question 1

What does the liver do?

Answer 1

Cleans the blood
Makes transport proteins (albumin)
Metabolizes stuff
Makes coagulation factors

Question 2

What are the Transaminases and what do they tell you?

Answer 2

AST and ALT
May become elevated in the event of hepatocyte death

Question 3

Tell me about Alkaline Phosphatase.

Answer 3

It is found in a lot of tissues including the liver
Serum alkaline phosphatase levels maybe elevated in cholestatic diseases (bilirubin tract slows down)

Question 4

Hyperbilirubinemia

Answer 4

high bilirubin in blood
signs and sx: Jaundice develops at >2mg/dL
Scleral icterus (yellow eyes)
Pruritus
Clay colored stool
increased heart rate

Question 5

What can cause liver injury?

Answer 5

Non-alcoholic fatty liver disease
Alcohol associated hepatitis
Viral Hepatits
Ischemic hepatitis
Autoimmune hepatitis
Hepatotoxic medications/DILI

Question 6

What are the types of DILI

Answer 6

Direct hepatotoxins
Idiosyncratic Rxns
other stuff

Question 7

Describe Direct hepatotoxins

Answer 7

Direct hepatotoxic effect induces a dose-dependent liver injury
May be induced by metabolism of parent drug to toxic metabolites (occurs rapidly after med administration)
Drugs include: Acetaminophen, methotrexate

Question 8

Idiosyncratic

Answer 8

Not dose or duration dependent
Variable presentation such as aberrant immune rxns
May occur months after med inxn
Eg: Antibiotics (Augmentin, cephalosporins, nitrofurantoin)

Question 9

What are some other stuff that can cause DILI

Answer 9

Indirect Hepatotoxicity
Aberrations in calcium homeostasis
Carcinogens
Mitochondrial injury
Alteration in liver transport proteins

Question 10

How does DILI present itself?

Answer 10

Asymptomatic
S/s of hepatitis: ab pain, Nausea, alcoholic stool, Jaundice
S/S of cholestasis: Pruritis, jaundice, feeling foggy
S/s Acute liver failure: Coagulopathy, Encephalopathy

Question 11

How do you diagnose DILI

Answer 11

1) Other Causes must be excluded
2) One of the following lab profiles:
-AST or ALT >/= 5 x ULN
-Alk Phos >/= 2 x ULN
-Tbili >/= 2.5 mg/dL AND either ALT, AST or Alk phos elevated
-INR >/= AND either ALT, AST, or alk phos elevated

Question 12

What are the labs for DILI?

Answer 12

Hep A/B/C negative
Anti-mitochondrial antibody </= 1:5
Ceruloplasmin within normal range
Antinuclear antibody </= 1:40
Anti smooth muscle antibody </= 1:40
(the last two are exceptions when it comes to drug induced autoimmune hepatitis)

Question 13

DILI Assessment when a patient comes in

Answer 13

“Have u taken any new herbals/supplements in the last 6 months? Any new meds? When did u start, whats the dose, when did u start and stop?”

Question 14

What is the R factor formula?

Answer 14

Question 15

What are some DILI signatures I should remember? And where do I go if I am unsure?

Answer 15

Question 16

What is the pathway towards DILI management?

Answer 16

Question 17

How do I mange Pruritus caused by DILI?

Answer 17

Thought to be due to increases in serum bile salts.
Treated with cholestyramine 4 g daily or BID
ADRs: Constipation, fat-soluble vitamin deficiency, Increase Triglycerides
Separate from other meds by ~4 hours.

Question 18

Drug induced Auto Immune Hepatitis

Answer 18

Prednisone ~40 mg QD can be considered
Watch for glucocorticoid ADRs

Question 19

Describe APAP metabolism

Answer 19

Question 20

What happens during APAP overdose?

Answer 20

During APAP overdose -> glutathione depletion -> NAPQI buildup -> hepatotoxicity

Question 21

How do I treat APAP overdose?

Answer 21

Activated Charcoal: Adsorbs APAP, Indicated if presenting within 4 hours of overdose, 1g/kg (max 50g)
ADRs: Non protected airway, GI Perforation

N-acetyl cysteine (NAC): Refills hepatic cysteine stores increasing glutathione which rescues the liver from NAPQI
ADRs: Hypersensitivity, pruritus, urticaria, hypotension, N/V (PO only)

Hypersensitivity ADR less frequent with 2 bag method

Question 22

When do I give NAC and what is the dosing?

Answer 22

Indicated:
-Time/Concentration matrix above Rumack-Matthew nomogram line
-Any evidence of liver injury present
-Detectable acetaminophen in serum >24 hrs after ingestion
Acute APAP ingestion of 150mg/kg or 7.5g (whichever is less) & serum levels cannot be obtained within 8 hrs of ingestion

Question 23

Tell me about Isoniazid and how it can be a hepatotoxin

Answer 23

It is used to treat TB.

Baseline and monthly monitoring recommended: Symptom check (Anorexia, Nausea, fatigue, Jaundice, Abdominal Pain)
Physical exam
Liver function tests (LFTs)

Question 24

Tell me about Statins and how they can be a hepatotoxin

Answer 24

Used for ASCVD risk reduction
Known to cause transaminitis in patients, but true dysfunction is rare
Test: LFTs:
1) At baseline
2) As clinically indicated (for ab. pain, dark urine, jaundice, fever)

Question 25

Whats the overview of DILI treatment?

Answer 25

-Get rid of offending drug
-Treat N/V, Itchiness, and AIH if you need to
-APAP overdose? check treatment nomogram
-Check LFTs with use of some medications