Drugs and chemicals can cause a wide
spectrum of liver injury. These include:
· Mild
elevations in blood levels of liver enzymes without symptoms or signs of liver disease
· Hepatitis (inflammation of liver cells)
· Necrosis (death of liver cells) that often is caused
by more severe hepatitis
· Cholestasis (decreased secretion and/or flow of bile)
· Steatosis (accumulation of fat in the liver)
· Cirrhosis (advanced scarring of the liver) as a result
of chronic hepatitis, cholestasis, or fatty liver
· Mixed
disease, for example both hepatitis and necrosis of liver cells, hepatitis and
fat accumulation, or cholestasis and hepatitis.
·
Fulminant
hepatitis with severe, life threatening liver failure
·
Blood
clots in the
veins of the liver
Elevated blood levels of liver enzymes
Many drugs cause mild elevations in
blood levels of liver enzymes without symptoms or signs of hepatitis. AST, ALT,
and alkaline phosphatase are enzymes that normally reside within the cells of
the liver and bile ducts. Some drugs can cause these enzymes to leak from the
cells and into the blood, thus elevating the blood levels of the enzymes.
Examples of drugs that more commonly cause elevations of liver enzymes in the
blood include the statins (used in treating high blood
cholesterol levels) some antibiotics, some antidepressants (used in treating depression),
and some medications used for treating diabetes, tacrine,
aspirin, and quinidine.
Since these patients typically
experience no symptoms or signs, the elevations of liver enzymes usually are
discovered when blood tests are performed as a part of an annual physical
examination, as pre-operative screening, or as a part of periodic monitoring
for drug toxicity. Typically, these abnormal levels will become normal shortly
after stopping the drug, and there usually is no long-term liver damage. With
some drugs, low levels of abnormal liver enzymes are common and don't appear to
be associated with important (severe or progressive) liver disease, and the
patient may continue taking the drug.
Acute and chronic hepatitis
Certain drugs can cause acute and chronic hepatitis (inflammation of
liver cells) that can lead to necrosis (death) of the cells. Acute drug-induced
hepatitis is defined as hepatitis that lasts less than 3 months, while chronic
hepatitis lasts longer than 3 months. Acute drug-induced hepatitis is much more
common than chronic drug-induced hepatitis by a ratio of 9:1.
Typical symptoms of drug-induced
hepatitis include:
·
loss of
appetite,
·
nausea,
·
vomiting,
·
fever,
·
weakness,
·
tiredness,
and
·
abdominal
pain.
In more serious cases, patients can
develop dark urine, fever, light-colored stool, and jaundice (a yellow
appearance to the skin and white portion of the eyes). Patients with hepatitis
usually have high blood levels of AST, ALT, and bilirubin. Both acute and
chronic hepatitis typically resolve after stopping the drug, but sometimes
acute hepatitis can be severe enough to cause acute liver failure, and chronic
hepatitis can on rare occasions, lead to permanent liver damage and cirrhosis.
Examples of drugs that can cause acute hepatitis include acetaminophen, phenytoin, aspirin, isoniazid, diclofenac, and amoxicillin/clavulanic acid .
Examples of drugs that can cause chronic hepatitis include minocycline, nitrofurantoin, phenytoin, propylthiouracil, fenofibrate, and methamphetamine.
Acute liver failure
Rarely, drugs cause acute liver failure (fulminant hepatitis). These
patients are extremely ill with the symptoms of acute hepatitis and the
additional problems of confusion or coma (encephalopathy) and bruising or
bleeding (coagulopathy). In fact, up to 80% of people with fulminant hepatitis
die within days to weeks. In the U. S., acetaminophen is the most common cause
of acute liver failure.
Cholestasis
Cholestasis is a condition in which
the secretion and/or flow of bile is reduced. Bilirubin and bile acids normally
secreted by the liver into bile and eliminated from the body via the intestine,
collect in the body leading to jaundice and itching, respectively. Drugs
causing cholestasis typically interfere with the liver cell's secretion of bile
without causing hepatitis or liver cell necrosis (death). Patients with
drug-induced cholestasis typically have elevated blood levels of bilirubin but
have normal or mildly elevated AST and ALT levels. Blood levels of alkaline
phosphate (an enzyme made by bile ducts) increase because the cells of the bile
ducts also are dysfunctional and leak the enzyme. Aside from itching and
jaundice, patients usually are not as sick as patients with acute hepatitis.
Examples of drugs that have been
reported to cause cholestasis include erythromycin,chlorpromazine, sulfamethoxazole and trimethoprim, amitriptyline, carbamazepine, ampicillin, ampicillin/clavulanic acid, rifampin, estradiol, captopril, birth control pills(oralcontraceptives),anabolic,steroids, naproxen, amiodarone, haloperidol,imipramine, tetracycline , and phenytoin.
Most patients with drug-induced
cholestasis will recover fully within weeks after stopping the drug, but in
some patients, jaundice, itching, and abnormal liver tests can last months
after stopping the drug. An occasional patient can develop chronic liver
disease and liver failure. Drug-induced jaundice and cholestasis lasting longer
than 3 months is called chronic cholestasis.
Steatosis (fatty liver)
The most common causes of
accumulation of fat in the liver are alcoholism and non-alcoholic fatty liver disease
(NAFLD)associated
with obesity and diabetes. Drugs may cause fatty liver with or
without associated hepatitis. Patients with drug-induced fatty liver may have
only a few symptoms, or none. They typically have mild to moderate elevations
in blood levels of ALT and AST, and also may develop enlarged livers. In severe
cases, drug-induced fatty liver can lead to cirrhosis and liver failure.
Drugs reported to cause fatty liver
includetotal parenteral nutrition, methotrexate, griseofulvin, tamoxifen, steroids, valproate, and amiodarone.
In certain situations, fatty liver
alone can be life threatening. For example, Reye's syndrome is a rare liver disease that can cause
fatty liver, liver failure, and coma. It is believed to occur in children and
teenagers with influenza when they are given aspirin. Another example of
serious fatty liver is caused by high doses of intravenous tetracycline or
amiodarone. Certain herbs (for example, the Chinese herb Jin Bu Huan, used as a
sedative and pain reliever) also can cause serious fatty liver.
Cirrhosis
Chronic liver diseases such as
hepatitis, fatty liver, or cholestasis can lead to the necrosis (death) of
liver cells. Scar tissue forms as part of the healing process that is associated
with the dying liver cells, and severe scarring of the liver can lead to
cirrhosis.
The most common example of
drug-induced cirrhosis is alcoholic cirrhosis . Examples of drugs that can cause
chronic liver diseases and cirrhosis include methotrexate, amiodarone, and
methyldopa. Please read the article on Cirrhosis for more information.
Hepatic vein thrombosis
Normally, blood from the intestines is delivered to the liver via the
portal vein, and the blood leaving the liver for the heart is carried via the
hepatic veins into the inferior vena cava (the large vein that drains into the
heart). Certain drugs can cause blood clots to form (thrombosis) in the hepatic
veins and in the inferior vena cava. Thrombosis of the hepatic vein and
inferior vena cava can lead to an enlarged liver, abdominal pain, fluid
collection in the abdomen (ascites), and liver failure. This syndrome is called
the Budd Chiari syndrome. The most important drugs that cause Budd-Chiari
syndrome are birth control pills (oral contraceptives). Birth control pills
also can cause a related disease called veno-occlusive disease in which blood
clots only in the smallest hepatic veins. Pyrrolizidine alkaloids found in certain
herbs (e.g., borage, comfrey) also can cause veno-occlusive
disease.
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