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Drug-induced injury: liver pathology’s big imitator

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Karen Lusky

Dr. Najarian

Dr. Najarian

April 2017—In a presentation at CAP16 on common patterns of liver injury, Robert M. Najarian, MD, called drug-induced liver injury the great mimicker in liver pathology. “When in doubt, rule drugs out,” he said, including herbal agents, supplements, and over-the-counter agents.

The effect of drugs on the liver can imitate many different patterns of liver injury, including hepatitic, vascular, and cholestatic, among others, said Dr. Najarian, a consultant in gastrointestinal, hepatobiliary, and pancreatic pathology at Beth Israel Deaconess Medical Center and Harvard Medical School. He described the image of an amoxicillin-clavulanic acid (Augmentin)-induced liver injury as essentially simulating a cholestatic pattern with bile ductular proliferation, portal tract edema, and neutrophils. “You could easily call this duct obstruction, if you didn’t know better that a patient had started a new drug recently,” he said (Fig. 1).

Fig. 1. Amoxicillin-clavulanic acid (Augmentin)-induced liver injury

Fig. 1. Amoxicillin-clavulanic acid (Augmentin)-induced liver injury

“So when in doubt, I say rule out drugs, including over-the-counter drugs [and herbal supplements] that patients may be taking but not telling their physicians about,” Dr. Najarian advised. “We have certainly seen several cases of acute liver failure from herbal supplements, oftentimes muscle-building supplements, causing a lot of damage and acute liver damage that is persistent.”

Dr. Najarian displayed a biopsy image of an acute toxic liver injury caused by over-the-counter weight-loss supplements (Fig. 2). “Zone 1 hepatocytes around the portal tract itself are preserved because these hepatocytes are the best perfused and least susceptible to oxidative stress, while centrilobular hepatocytes have become damaged,” he said in an interview with CAP TODAY. An acute toxic injury can mimic the pattern of an acute vascular ischemic injury to the liver.

Fig. 2. Acute toxic liver injury caused by over-the-counter weight-loss supplements

Fig. 2. Acute toxic liver injury caused by over-the-counter weight-loss supplements

Cytotoxic chemotherapeutic agents, among others, can damage the specialized sinusoidal endothelial cells, which causes a vascular pattern of liver injury with congestion and hemorrhage around the terminal hepatic or central vein, Dr. Najarian says. “With chronic damage, complete occlusion of the central vein can occur, resulting in what’s clinically known as sinusoidal obstruction syndrome or veno-occlusive disease.”

Dr. Najarian shared an image of what he called “a relatively bland-looking liver injury,” except for a centrally located bile plug. The patient was on chemotherapy for multiple myeloma. “The question that we often are asked: Is it the drug or is it the disease that’s causing the liver injury? Sometimes we can tell, but sometimes we can’t.” When patients are started on cytotoxic chemotherapeutic agents, he noted, some respond with liver injury from the drug, while infection and the neoplastic processes can cause the injury in other instances.

People often want to know what sort of pattern of injury he would expect if the patient were taking a certain drug. “Sometimes we have an answer because of what has been reported in the literature,” he said. Allopurinol use presents with fibrin ring granulomas, while amiodarone mirrors the histologic features of alcoholic steatohepatitis.

“But what we have certainly found, and it’s probably your experience too,” Dr. Najarian told CAP16 attendees, “is that many drugs have a multitude of injury patterns.” For additional information, he recommended a review article on drug-induced liver injury in the July 2015 Archives of Pathology & Laboratory Medicine, coauthored by Romil Saxena, MBBS, a professor of pathology and laboratory medicine and a professor of medicine in the Division of Gastroenterology and Hepatology, Indiana University School of Medicine (Fisher K, et al. Arch Pathol Lab Med. 2015;139[7]:876–887).

Courtesy of Robert Najarian, MD

Courtesy of Robert Najarian, MD

It can take weeks to many months for a drug-induced liver injury to resolve, Dr. Najarian says. “Often these medications are only taken for a week or so, but they can still cause a prolonged period of injury. Thus, it’s important for pathologists to ask those who send their patients for liver biopsy about a patient’s drug/medication use history for up to a year prior to the procedure,” including dosage adjustments.

Some drugs, such as those that cause autoimmune hepatitis, may create “irreversible, self-perpetuating damage,” Dr. Saxena tells CAP TODAY. “The autoimmunity might be self-perpetuating. It won’t go away in some patients. What probably happens is the drug unmasks a hidden epitope or it combines with molecules within a cell to create a ‘novel epitope’ that the body recognizes as foreign.”

In many but not all cases of drugs mimicking autoimmune hepatitis, or AIH, elevated antinuclear antibody titers and significantly elevated anti-smooth muscle titers will be seen, Dr. Najarian said. “So do not use merely these as confirmation of a primary autoimmune hepatitis. You really need help from your clinician to exclude a drug as the cause of this acute pattern of immune-mediated injury.”

Pathologists can also use LiverTox (livertox.nlm.nih.gov). LiverTox is “a very unbiased source of a compound’s potential to cause drug toxicity,” says Naga Chalasani, MD, an investigator for the Drug-Induced Liver Injury Network, known as DILIN, which the National Institutes of Health established in 2004. “The network’s purpose is to better characterize this disease,” Dr. Chalasani explains. LiverTox “isn’t part of DILIN but has been involved in its development.”

DILIN is conducting a prospective study of nearly 1,900 patients enrolled at several centers in the U.S. who are followed from six months to two years so the condition can be studied, says Dr. Chalasani, who is the David W. Crabb professor and director of the Division of Gastroenterology and Hepatology, Indiana University School of Medicine. (DILIN also has an ongoing retrospective study but the network’s primary objective is the prospective study.)

Dr. Chalasani

Dr. Chalasani

The DILIN study protocol requires eliminating all competing etiologies of the patient’s liver disease. “In clinical practice, you want to exclude competing etiologies,” Dr. Chalasani says. “Sometimes what seems very much like a drug-induced liver injury is not.” Even some of the cases enrolled in the DILIN study that appeared to be due to anesthetics and other things turned out to be hepatitis C or E. And some cases that appeared to be caused by Augmentin turned out to be pancreatic cancer. “So it goes both ways,” Dr. Chalasani says. Sometimes practitioners don’t suspect drug-induced liver injury, and sometimes they over-diagnose it just because the patient was put on a medication.

“There are instances where drugs may exacerbate underlying autoimmune hepatitis or other types of underlying liver disease,” Dr. Chalasani says. Drugs—tamoxifen, for example—can worsen fatty liver disease. Although it’s not directly a drug-induced injury, immunosuppressants or chemotherapy can activate hepatitis B or C.

“Twenty percent of drug-induced liver injury cases we see are from dietary supplements, which are poorly regulated and poorly labeled,” Dr. Chalasani says. “What’s on the label is not necessarily what you sometimes find when you actually test those supplements chemically.” Weight-loss and body-building supplements make up the two large groups of herbal and dietary products to cause drug-induced liver injury.

Herbal extracts can have thousands of chemical compounds to which some people will react badly, says George K. Michalopoulos, MD, PhD, a professor in and chair of the Department of Pathology at the University of Pittsburgh. He points out that drugs and xenobiotic compounds are largely metabolized by the cytochrome P450 (CYP) family of liver enzymes. “Typically, hydrophobic compounds are converted to water-soluble metabolites to facilitate excretion. In some situations, the CYP-dependent metabolism generates intermediate products that act as free radicals and can cause widespread [liver] damage.”

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