Differential diagnosis
The
histological features can be indistinguishable from other causes of acute
hepatitis such as acute viral hepatitis, initial presentation of autoimmune
hepatitis and Wilson disease. The presence of bile duct injury, prominent
eosinophilic infiltrate, granulomas, sharply defined perivenular necrosis, or
cholestasis out of proportion to hepatocellular injury, favours adverse drug
reaction, but none of these features is specific.
Acute liver failure
(fulminant hepatitis)
Acute liver failure (ALF) is defined as the onset of hepatic
encephalopathy within 8 weeks of onset of symptoms.
Based on morphological features, ALF can be
subdivided into three categories.
·
Extensive microvesicular steatosis. This pattern is rare and has
been observed with tetracycline and nucleoside analogues such as zidovudine.
·
Necrosis with marked inflammatory activity. It is similar to the
acute hepatitis pattern discussed above except that the confluent necrosis
involves most of the liver parenchyma (massive/submassive hepatic necrosis).
The most commonly implicated drugs are isoniazid, other antimicrobial
agents (sulfonamides, cotrimoxazole, ketoconazole), monoamine oxidase
inhibitors, and anticonvulsants (phenytoin, valproate). Any drug that
causes acute hepatitis can potentially cause ALF.
·
Necrosis with little or no inflammation. This pattern is seen
with acetaminophen (fig
4), recreational drugs such as cocaine and
3,4-methylenedioxymethylamphetamine (MDMA; ecstasy), industrial organic
compounds such as carbon tetrachloride, and some herbal preparations. Necrosis
can be accompanied by steatosis.
Acetaminophen
Acetaminophen toxicity is the leading
drug-related cause, implicated in nearly 40% of ALF, the remaining being
attributed to idiosyncratic drug reactions.
Chronic hepatitis
Chronic liver disease typically refers to
persistent biochemical abnormalities beyond 6 months. In some series, the
cut-off of 3 months has been used for hepatocellular injury and 6 months for
cholestatic or mixed injury. Progression to chronicity has been reported
in 5–10% of adverse drug reactions and is higher for the cholestatic/mixed
injury pattern. Histologically proven drug-induced chronic hepatitis with
fibrosis is a rare phenomenon. Some specific patterns and clinicopathological situations
are discussed below.
Chronic hepatitis with negative autoimmune
markers
The histological features are
indistinguishable from chronic viral hepatitis, and progression to fibrosis and
even cirrhosis can occur. The features of acute hepatitis may be seen to a
variable degree. Drugs associated with this pattern include lisinopril (antihypertensive),
sulfonamide (antibiotic), trazodone (antidepressant), and
chemotherapeutic agents such as uracil,
5-fluorouracil prodrug tegafur and tamoxifen.
Isolated
case reports implicate numerous other drugs including phenytoin and the Chinese herb
Jin bu huan.
Autoimmune hepatitis
Several drugs can
cause chronic hepatitis that is serologically and morphologically
indistinguishable from de novo autoimmune hepatitis (AIH). The hepatic disease
may be accompanied by features of hypersensitivity such as rash, arthralgia and
peripheral eosinophilia.
Minocycline
Long-term use of minocycline, a synthetic
tetracycline for treatment of acne, can lead to hepatitis that can mimic
lupus-related hepatitis, AIH or overlap syndrome. Autoimmune disease can
develop within days of starting the drug or may be delayed for many years. High
titres of antinuclear antibodies (ANAs) are common, but smooth muscle (SMA) and
other autoantibodies often are negative. Autoimmune markers may be elevated in
chronic hepatitis due to drugs (drug-induced autoimmune hepatitis).
Inflammatory activity can be minimal to mild, and eosinophils are typically
inconspicuous (fig
5). Marked fibrosis and cirrhosis are rare, and
patients often improve after drug withdrawal.
Nitrofurantoin
Nitrofurantoin is used to treat urinary tract
infections. The hepatic injury can manifest as self-limited acute hepatitis,
chronic hepatitis, and rarely as hepatic failure. Chronic hepatitis can be
indistinguishable from de novo AIH and is often associated with ANA and SMA.
Others
Other drugs implicated in AIH include
methyldopa (antihypertensive) and clometacin non-steroidal
anti-inflammatory drug (NSAID). Antibodies to liver-kidney-microsomal
antibodies, akin to type 2 AIH, have been described in hepatitis related to
hydralazine (antihypertensive) and tienilic acid (ticrynafen, a diuretic
withdrawn from the American market), but this association is not clearly defined.
Methotrexate
Methotrexate is a folate antagonist that is
used for long-term treatment of rheumatoid arthritis, psoriasis and
inflammatory bowel disease. The histological features of methotrexate-related
toxicity range from minor fatty change, hepatocyte anisonucleosis, mild
portal-based inflammation, and focal necrosis to more severe hepatocellular
necrosis, fibrosis and cirrhosis (fig 6).
Acute cholestatic
injury
Drug-induced
cholestatic injury can manifest clinically with jaundice, pruritus, dark urine
and pale stools. Liver enzyme studies typically reveal elevation of alkaline
phosphatase and γ-glutamyl transferase. Transaminases can be variably elevated.
A Danish study of 1100 cases of drug-associated injury reported 16% with the
acute cholestatic pattern.
The histological patterns of injury can be
divided into two forms. Pure (bland) cholestasis in which bile plugs are seen
in hepatocytes or canaliculi and are most prominent in zone 3. Inflammation and
hepatocellular injury are not observed. This pattern is typically observed with
anabolic steroids (fig
7) and oral contraceptives. Other drugs that have
been incriminated include prochlorperazine, thiabendazole and warfarin. Cholestatic
hepatitis can result from a wide variety of drugs; it is the classic pattern
seen with toxicity due to macrolide antibiotics such as erythromycin (fig
8) and the
antipsychotic agent chlorpromazine.
No comments:
Post a Comment