Autoimmune Hepatitis
Jeff Kiker and Amanda Daeges
What is autoimmune hepatitis?
• Autoimmune hepatitis is a disease in which the
body’s own immune system attacks the liver and
causes it to become inflamed. The disease is
chronic, meaning it lasts many years. If untreated, it
can lead to cirrhosis and liver failure.
• There are two forms of this disease. Type 1, or
classic, autoimmune hepatitis is the more common
form. This is the form that mostly affects young
women and is often associated with other
autoimmune diseases.
• Type 2 autoimmune hepatitis is less common and
generally affects girls between the ages of 2 and 14.
What causes autoimmune
hepatitis?
• Your immune system normally attacks bacteria, viruses
and other invading organisms. It is not supposed to
attack your own cells; if it does, the response is called
autoimmunity.
• In autoimmune hepatitis, your immune system attacks
your liver cells, causing long-term inflammation and liver
damage.
• Scientists don’t know why the body attacks itself in this
way, although heredity and prior infections may play a
role.
What are the symptoms and
complications of autoimmune
hepatitis?
Often, the symptoms of autoimmune hepatitis are minor.
When symptoms do occur, the most common are
fatigue
abdominal discomfort
aching joints
Itching
jaundice
enlarged liver
nausea
Other symptoms may include dark urine, loss of
appetite, pale stools and absence of menstruation.
More severe complications can include ascites (fluid
in the abdomen) and mental confusion.
 spider angiomas (blood vessels) on the skin.
In 10%-20% of cases, autoimmune hepatitis may
present with symptoms like an acute hepatitis.
How is autoimmune hepatitis
diagnosed?
• Autoimmune hepatitis often occurs suddenly. Initially, you may feel like
you have a mild case of the flu. As PE does not often offer the examiner
much information to confirm a diagnosis of autoimmune hepatitis, your
doctor will need to use…blood tests and a liver biopsy
–
–
–
–
antinuclear antibody (ANA),
smooth muscle antibody (SMA),
Liver/kidney microsomal antibody (LKM-1)
and anti-mitochondrial antibody (AMA)
• are all of use, as is finding an increased Immunoglobulin G level.
• However, the diagnosis of autoimmune hepatitis always
requires a liver biopsy.
•
In complex cases a scoring system can be used to help determine if a
patient has autoimmune hepatitis, which combines clinical and laboratory
features of a given case.
Liver biopsy histology at initial presentation showing peri-portal
lymphocytic infiltration and extensive peri-portal fibrosis.
Four subtypes
are recognized, but the clinical utility of distinguishing
subtypes is limited.
– Positive ANA and SMA, raised immunoglobulin G (classic
form, responds well to low dose steroids)
– Positive LKM-1 (typically female children and teenagers;
disease can be severe)
– All antibodies negative, positive antibodies against
soluble liver antigen (SLA)(now designated SLP/LP).
This group behaves like group 1.
– No autoantibodies detected (~13%)
Who is at risk for autoimmune
hepatitis?
• About 70 percent of people with autoimmune
hepatitis are women, usually between the
ages of 15 and 40.
• Many people with this disease also have
other autoimmune diseases, including type 1
diabetes, thyroiditis (inflammation of the
thyroid gland), ulcerative colitis (inflammation
of the colon), vitiligo (patchy loss of skin
pigmentation), or Sjogren’s syndrome (dry
eyes and dry mouth)
Case
Treatment Indications
How is autoimmune hepatitis
treated?
• The goal of treatment is to stop the body’s attack on itself by
suppressing the immune system.
– prednisone,,
– azathioprine (Imuran)
• Treatment starts with a high dose of prednisone. When symptoms
improve, the dosage is lowered and azathioprine may be added.In
most cases, autoimmune hepatitis can be controlled but not cured.
That is why most patients will need to stay on the medicine for
years, and sometimes for life.
•
long-term use of steroid can cause serious side effects including
diabetes, osteoporosis, high blood pressure, glaucoma, weight gain
and decreased resistance to infection.
Conventional Treatment Regimens
Black Cohosh causes AI Hep
•
The mechanism of action of black cohosh remains unclear, and the effects on
estrogen receptors or hormonal levels, if any, have not been fully elucidated.
Safety and efficacy data beyond six months are not available," she added.
•
Dr. Cohen and colleagues came to the conclusion that their patient, a 57-year
old woman, likely suffered from black cohosh–induced autoimmune hepatitis
after exhaustive examination.
•
The woman, who presented with history of increasing fatigue and lethargy for
two weeks, was receiving treatment for diabetes mellitus and hypertension, he
said.
•
For at least two years, she had been taking labetolol, fosinopril, verapamil,
metformin, aspirin, and insulin.
•
At the advice of her primary physician, she had recently stopped HRT. She had
started taking black cohosh three weeks prior to the onset of symptoms.
Black Cohosh causes AI Hep
•
The patient said she did not drink, smoke, or use intravenous drugs, and
had had no transfusions, tattoos, or recent travel to areas in which hepatitis
is endemic.
•
Physical examination was unrevealing, Dr. Cohen said. Hepatitis A, B, and
C serologies and smooth muscle antibodies were negative, but alkaline
phosphatase was mildly elevated and antinuclear antibodies were positive
at 1:640.
•
A liver biopsy revealed piecemeal necrosis and lobular infiltrates with
extensive plasma cells and eosinophils, both features of autoimmune and
drug-induced hepatitis, Dr. Cohen said.
•
Black cohosh was discontinued, and the woman's symptoms resolved
completely after two weeks. A tapering course of prednisone was started,
Dr. Cohen said, and liver function tests were back to normal about nine
weeks later.
Did Black Cohosh cause an CYP
enzyme shift?
Or was it secondary to d/c HRT
• Reports of liver injury have been cited for
– Labetolol ~ metabolized in liver (MetLv) CYP 450 S/fx:
hepatotoxicity, SLE, Raynaud’s phenomenon, hepatic necrosis
(rare)
– Fosinopril ~ MetLv CYP450/GI S/fx: Hepatotoxicity (rare),
elevated BUN,Cr, renal dysfxn/failure
– V erapamil ~ MetLv CYP450:3A4 substrate/inhib. S/fx:
Hepatotoxicity (rare)
– aspirin ~ MetLv Salicylate CYP 450 S/fx: hepatotoxicity high
dose ASA
Black Cohosh & hepatotoxic drugs
•
Black Cohosh has been use in German studies since the mid 1950’s for menopausal
and menstrual disturbances
•
Eclectics have been using it in the last trimester to prepare for birth
•
Pharmacokinetics largely unknown
•
Black Cohosh has been shown to be immuno suppressive towards B-cell Fxn and at
larger doses T-cell suppression has been observed
•
toxic doses often describe neurologic symptoms
–
–
•
vertigo, visual disturbance, seizures
over dose produces N/V
BLACK COHOSH <<interacts with>> CYTOCHROME P450 2D6 (CYP2D6)
SUBSTRATES
Black Cohosh
P450 2D6 (CYP2D6)
• Some clinical research suggests that black cohosh might
modestly inhibit cytochrome P450 2D6 (CYP2D6) (13536).
• Some drugs metabolized by CYP2D6 include amitriptyline
(Elavil), codeine, desipramine (Norpramin), flecainide
(Tambocor), haloperidol (Haldol), imipramine (Tofranil),
metoprolol (Lopressor, Toprol XL), ondansetron (Zofran),
paroxetine (Paxil), risperidone (Risperdal), tramadol
(Ultram), venlafaxine (Effexor), and others.
• Use black cohosh cautiously or avoid in patients taking
these drugs.
Black Cohosh & hepatotoxic drugs
• There is concern that black cohosh might be linked to
cases of liver failure and autoimmune hepatitis
(4383,10692,11906,11909,12006,13144,14469,15160).
Theoretically, taking black cohosh with hepatotoxic drugs
might increase the risk of liver damage.
• Advise patients against combining black cohosh with
potentially hepatotoxic drugs. Some drugs that can
adversely affect the liver include acetaminophen
(Tylenol), amiodarone (Cordarone), carbamazepine
(Tegretol), isoniazid (INH), methotrexate (Rheumatrex),
methyldopa (Aldomet), and many others.
HRT
• Case: AutoImmune Hepatitis in a Male-to-Female
Transsexual Treated with Conjugated Estrogens. IJT
5,3, http://www.symposion.com/ijt/ijtvo05no03_03.htm
• Abstract
• Estrogen hormone in male-to-female transsexuals is a
major component of therapy in the treatment of gender
dysphoria. There are many adverse reactions to
estrogen therapy that require close monitoring.
We describe a case of autoimmune hepatitis that
may have been exacerbated by estrogens: this is
an additional adverse effect of estrogens on liver
function that has not previously been reported. We
recommend routine liver function tests to screen for
such adverse reactions.
case of type I autoimmune hepatitis
• Presented is a case of type I autoimmune hepatitis occurring in a male-tofemale transsexual taking oral estrogens. The etiology of this rare liver
disease is unknown. This condition occurs predominantly in young females
of reproductive age (Czaja, 1996). A major clinical finding is the presence of
serum autoantibodies (Czaja, 1996). Several antibodies define the type of
autoimmune hepatitis. Type I is associated with positive anti-nuclear
antibodies (ANA). A liver biopsy is required to confirm the diagnosis
and exclude other etiologies (Czaja, 1996). Other criteria that are
needed for the diagnosis include the absence of viral antibodies and
other liver toxins (Johnson and MacFarlane, 1993). Treatment consists
of corticosteroids alone or in combination with azothioprine (Czaja,
1996). However, treatment failure occurs in 9% of all cases and may
require liver transplantation (Czaja, 1996).
• Estrogens may play a role in triggering this autoimmune process: a
higher prevalence of autoimmune hepatitis in pre-menopausal women
has been noted by some authors (Herzog et al., 1997). This case
indicates that there may be a potential adverse effect of estrogens on liver
function in male-to-female transsexuals. We stress the need for careful
surveillance of liver function during treatment of male-to-female transsexuals
with estrogens, especially in the initial months of therapy. Liver function
should be monitored every two months initially until the estrogen dose is
stable; thereafter, every six months may be sufficient.
Minocycline-Related
Autoimmune Hepatitis
•
Background Minocycline is an antibiotic commonly used in the treatment of
adolescent acne.
•
Results Three adolescents (age, 15-16 years), while being treated with therapeutic
doses of minocycline for periods of 12 to 20 months, met the 1993 International
Autoimmune Hepatitis Group criteria for autoimmune hepatitis. All had a positive
antinuclear antibody titer. Other features included hypergammaglobulinemia
and a positive anti–smooth muscle antibody titer. Two patients underwent liver
biopsy that revealed severe chronic lymphoplasmacytic inflammation,
necrosis, and fibrosis.
•
All other causes of liver disease were excluded. One patient had resolution of
symptoms with withdrawal of the drug, while 2 required immunosuppression
therapy. A review of the literature yielded only 18 similar cases, none in the pediatric
literature, the majority of which contained incomplete pertinent data.
•
Conclusions Minocycline is related to the development of autoimmune hepatitis in
some adolescents. Pediatricians who use this drug for treatment of acne should be
aware of this serious potential relation and stop the drug immediately when suspicion
is raised.
•
Arch Pediatr Adolesc Med. 1998;152:1132-1136
Citation
•
Handbook of Liver Disease 2nd ed. Friedman,L Keeffe, E. Elsevier inc. 2004
•
Principles and Practice of Phytotherapy Mills,S Bone,K 2005 Simon Mills and Kerry Bone
•
http://www.naturaldatabase.com/(S(mgges145e12a1o55b45q1z45))/nd/Search.aspx?cs=&s=
ND&pt=100&id=857&ds=interdrug&name=Cimicifuga+(BLACK+COHOSH)
•
Case Report: Autoimmune HCase AutoImmune Hepatitis in a Male-to-Female Transsexual
Treated with Conjugated Estrogens. IJT 5,3,
http://www.symposion.com/ijt/ijtvo05no03_03.htm
•
Minocycline-Related Autoimmune Hepatitis
Case Series and Literature Review
Jonathan E. Teitelbaum, MD; Antonio R. Perez-Atayde, MD; Mark Cohen, MD; Athos
Bousvaros, MD; Maureen M. Jonas, MD
Arch Pediatr Adolesc Med. 1998;152:1132-1136.