Module 2 Chapter 9: Autoimmune and Drug Induced Hepatitis Flashcards
what gender is AIH more prevalent in
women
pathophysiology of AIF and DIh
Complex interaction of a dysregulated immune response in response to an environmental trigger (e.g. drug or virus) in a genetically susceptible host which leads to autoantibody production and injury to hepatocytes o Some drugs can induce an AIH-like picture [see Chapter 9.2] o Drugs associated with AIH include: Minocycline Propylthiouracil Nitrofurantoin Isoniazid Phenytoin Sulfonamides Trazodone -methyldopa
clinical presentation of AIH and DIH
o Asymptomatic rise in liver tests (mild, moderate, or severe ALT elevation) Often have other autoimmune diseases, frequently have subclinical cirrhosis at time of diagnosis o Symptomatic Fatigue, arthralgias, jaundice are common, Severe acute hepatitis (40%) with ALT > 1000, jaundice, coagulopathy and acute liver failure (ALF) presentation [see Chapter 10] but may have established cirrhosis
Autoantibodies seen AIH
ANA, ASMA, anti-liverkidney microsomal (Anti-LKM) They are not specific for AIH, and are not pathogenic or predictive of the natural history, but rather are an epiphenomena of liver damage & immune activation F-actin, soluble liver antigen (SLA) / liver pancreas (LP), liver cytosol 1 (LC1)/ liver kidney microsomal 3 (LKM3), and peripheral antinuclear cytoplasmic antibody (pANCA) which is also often elevated in PSC [see Chapter 5.3] Antibodies to pyruvate dehydrogenase complex – E2 subunit (PDC-E2) are more specific than the anti-mitochondrial antibody (AMA) for PBC [see Chapter 5.2]
How is AIH classified
Type 1 = young/ middle age, more common, ANA and ASMA positive, no viral trigger Type 2= rare, usually children, anti-LKM positive, HCV association.
diagnosing AIH
need to rule out drugs and alcohol and viral hepatitis. patients will usually have an elevated gig or gamma globulin levels. -
autoantibodies are non=specific and can be elevated in other autoimmune conditions or other liver diseases (HCV, PBC, PSC)
therefore, LIVER BIOPSY IS NEEDED TO ESATLISH THE DIAGNOSIS. - must look for lymphocyte infiltration with an abundance of plasma cells which make immunoglobulins, and interface hepatitis with inflammatory cells spilling across the limiting plate into the lobule.
what notable histological findings would you see with someone with AIH
LIVER BIOPSY IS NEEDED TO ESATLISH THE DIAGNOSIS. - must look for lymphocyte infiltration with an abundance of plasma cells which make immunoglobulins, and interface hepatitis with inflammatory cells spilling across the limiting plate into the lobule.
ABSOLUTE indications of AIH
o ALT or AST>10 ULN
o ALT or AST >5 ULN with igG >2 ULN
o Interface hepatitis (bridging necrosis) on biopsy
o Severe symptoms
two initial treatment options for AIH
Prednisone alone
Prednisone with azathioprine (AZA): preffered to reduce the prednisone side effecgts
o Remission rates
90% some response within 2 weeks, 65% remit within 18 months, 80% within 3 years
Median duration therapy before remission is approximately 2 years o Histologic improvement typically lags behind biochemical remission by 3-6 months
Management upon remission
o Withdraw prednisone over 4-8 weeks
o Later attempt withdrawal of AZA
o Regular monitoring for relapse
If a person with AIH is not responding to steroids, what may they hav? and waht should you do?
REFRACTORY AIH: Worsening clinical, biochemical & histological features despite compliance
need to continue prednisone and add sceond line therapies like mycophenolate mofetil
biggest drug that causes DILI
acetaminophen. leading cause of actue liver failure.
Toxic dose is >10 grams and is usually safe if <4 grams ingested per day, However, 2 – 4 grams is sufficient for injury in alcoholics
how are acetominophen overdoses treated
Overdoses are treated with N-acetylcysteine (NAC) which donates cysteine to replenish
glutathione (anti-oxidant)
Why are alcoholics more susceptible to acetaminophen toxicity?
NOTE: Acetaminophen is much safer than NSAIDs in cirrhosis, which can cause bleeding from ulcers
and hepatorenal syndrome
THEREFORE, TYLENOL IS SAFE IN PATIENTS WITH LIVER DISEASE (with the exception of those
actively abusing alcohol)
Acetaminophen has two metabolism pathways
- sulfation and glucuronidation (similar to bilirubin) metabolize it to non-toxic metabolites
CYP2E1 metabolizes it to NAPQI (TOXIC metabolite = direct hepatic injury)
- glutathione helps change NA{QI to mercapturic acid which is non-toxic.
Alcohol is metabolized by two pathways [see Chapter 7.1] and with chronic ingestion more
is metabolized by MEOS (specifically CYP2E1)
If alcoholics ingest acetaminophen,
more NAPQI is produced because of the upregulation of CYP2E1
Also, they often are glutathione
depleted because of poor nutrition This leads to increased risk of liver
injury
how cna vitamin A toxicity cause fibrosis
Vitamin A causes toxicity by activating Ito cells to become hepatic stellate cells and
typically at doses of 25,000 IU/d for 6 years or 50,000 IU/d for 2 years ( toxicity if alcohol abuse)
