Guide Drug-Induced Liver Disease

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These patients also have higher amiodarone-to- N -desethyl-amiodarone ratios, indicating a greater accumulation of the parent compound. Amiodarone and its major metabolite N -desethyl-amiodarone remain in the liver of all patients for several months after therapy is stopped.

Usually the phospholipidosis develops in patients treated for more than 1 year. The patient can present with either elevated aminotransferases or hepatomegaly; jaundice is rare. Generalized hepatocellular necrosis mimics the changes associated with the more common viral hepatitis. The onset of symptoms is usually delayed as much as a week or more after exposure to toxin. Bioactivation is often important for toxic hepatitis to develop. Many drugs that are associated with toxic hepatitis produce metabolites that are not inherently toxic to the liver. Instead, they bind with proteins to create haptens, which serve as neoantigens and induce the innate immune response see eFig.

The rate of bioactivation can vary between males and females and between individuals of the same sex. The receptor is found in the liver, and to a lesser extent in the cells lining the intestinal tract, and is responsible for cholesterol catabolism and bile acid homeostasis. The activity of this receptor is subject to genetic polymorphism. This results in a wide variation in the sensitivity of the population to hepatic damage. A study of patients who developed elevated liver enzymes defined as at least 2.

It is acetylated to acetylisoniazid, which, in turn, is hydrolyzed to acetylhydrazine. Therefore, it is the rate and efficiency of this reaction sequence that ultimately determines if hepatocellular damage will ensue. Isoniazid simultaneously is an example of the potential predictability of drug-induced liver disease based on single nucleotide polymorphism and a lesson in the limitations of our current understanding.

DRUG INDUCED LIVER INJURY (Hepatotoxicity) causative agents, mechanisms and pathology 🏥

There are definite links to NAT2 genotype and toxicity. In fact, age may be more important than genotype.

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The onset is usually early in therapy. In immunocompromised patients in whom ketoconazole is used, special care should be taken to watch for changes in liver function. The scarring effect of hepatitis in the liver leads to the development of cirrhosis. Some drugs tend to cause such a mild case of hepatitis that it may not be detected.

Mild hepatitis can be easily mistaken for a more routine generalized viral infection.


If the offending drug or agent is not discontinued, this damage will continue to progress. The patient eventually presents not with hepatitis, but with cirrhosis. Methotrexate causes periportal fibrosis in most patients who experience hepatotoxicity. The lesion results from the action of a bioactivated metabolite produced by CYP Periodic liver biopsies have a low yield in patients without other risk factors for liver disease, and should be reserved for select high-risk patients.

Hepatomegaly is a common finding, along with ascites and portal hypertension. In patients with vitamin A toxicity, gingivitis and dry skin are also very common. This is accelerated by ethanol, which competes with retinol for aldehyde dehydrogenase. A second pattern of hepatic damage is an injury that primarily involves the bile canalicular system and is known as cholestatic injury. Cholestatic disease is more often seen in patients over the age of 60 compared with under age 60 and is slightly more common in males. Drug-induced cholestasis can occur as an acute disorder e.

Most patients with this acute disorder present with nausea, malaise, jaundice, and pruritus. Cholestatic injury, also known as cholestatic jaundice or cholestasis, can be classified by the area of the bile canalicular or ductal system that is impaired. Canalicular cholestasis is often associated with long-term, high-dose estrogen therapy. These patients are often asymptomatic and present with mild-to-moderate elevations of serum bilirubin. The administration of total parenteral nutrition for periods greater than 1 week induces cholestatic changes and nonspecific enzyme elevations in some patients.

Patients with low serum albumin concentrations may be at greater risk than patients with normal serum albumin concentrations. The final pattern of hepatic damage is a combining of the previous two patterns. This presentation can be the result of three different processes.

In some patients, an injury may begin as hepatocellular or cholestatic and simply spread so rapidly that by the time the patient presents for diagnosis and treatment, all areas of the liver are affected. In other patients, the underlying mechanism of damage is such that cells are injured regardless of their anatomical location or primary metabolic role.


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Focal lesions in hepatic venules, sinusoids, and portal veins occur with various drugs. The most commonly associated drugs are the cytotoxic agents used to treat cancer, the pyrrolizidine alkaloids, and the sex hormones. A centralized necrosis often follows and can result in cirrhosis. Azathioprine and herbal teas that contain comfrey a source of pyrrolizidine alkaloids are associated with the development of venoocclusive disease. The exact incidence is rare and may be dose related.

The liver develops large, blood-filled lacunae space or cavity within the parenchyma. Rupture of the lacunae can lead to severe peritoneal hemorrhage. Peliosis hepatitis is associated with exposure of the liver to androgens, estrogens , tamoxifen , azathioprine, and danazol. Androgens with a methyl alkylation at the carbon position of the testosterone structure are the most frequently reported agents that cause peliosis hepatitis, usually after at least 6 months of therapy.

Liver Injury Caused by Drugs

Autoimmune injuries involve antibody-mediated cytotoxicity or direct cellular toxicity. The liver plays host to all of the cells that make up the innate immune response system in the body along with Kupffer cells, which are a type of macrophage. These cells sit in anticipation around the hepatocytes, in the space of Disse and elsewhere waiting for antigens or neoantigens to present themselves. The neoantigens serve as targets for cytolytic attack by killer T-cells, and others. Dantrolene , isoniazid , phenytoin , nitrofurantoin , and trazodone are associated with a type of autoimmune-mediated disease in the liver called chronic active hepatitis.

It is a progressive disease with a high mortality rate and is more common in females than males. Antinuclear antibodies appear in most patients. These drugs appear to form antiorganelle antibodies. Idiosyncratic drug-related hepatotoxicity is rare and usually occurs in a small proportion of individuals. These adverse reactions are often categorized into allergic and nonallergic reactions.

The allergic reactions are characterized by fever, rash, and eosinophilia. They are usually dose-related and have a short latency period minocycline , nitrofurantoin , and phenytoin can cause allergic reactions. Unlike the allergic reactions, the nonallergic idiosyncratic reactions are devoid of the hypersensitivity features and usually have a long latency period several months. These patients often have normal liver function tests for 6 months or longer and then suddenly develop hepatotoxicity.

Dependent on the medication, the incident can be independent of dose or dose related. Amiodarone, isoniazid , and ketoconazole are associated with nonallergic drug-related hepatotoxicity. Drug-induced damage to the cellular proteins that are involved with calcium homeostasis can lead to an influx of intracellular calcium that causes a decline in adenosine triphosphate levels and disruption of the actin fibril assembly.

The resulting impact on the cell is blebbing of the cell membrane, rupture, and cell lysis. Most hepatocellular injuries involve the production of high-energy reactive metabolites by the CYP system. These reactive metabolites are capable of forming covalent bonds with cellular proteins enzymes and nucleic acids that lead to adduct formation. In the case of acute toxicity, the enzyme—drug adduct can cause cell injury or cell lysis. Adducts that form with DNA can cause long-term consequences such as neoplasia. Acetaminophen, furosemide, and diclofenac are examples of this mechanism of liver injury.

Patients with a single nucleotide polymorphism SNP that codes for slow-reacting variants of CYP will react differently from those with a SNP that codes for very fast-reacting variants.

Apoptosis represents a distinct pattern of cell lysis that is characterized by cell shrinkage and fragmentation of nuclear chromatin. Apoptotic pathways are triggered by interactions between death ligands tumor necrosis factor and Fas ligand and death receptors tumor necrosis factor receptor 1 and Fas. These interactions activate caspases, which cleave cellular proteins and eventually lead to cell death.

A large body of the current literature on adverse reactions and the liver addresses the development of neoplasms following drug therapy. Both carcinoma- and sarcoma-like lesions have been identified. Fortunately, hepatic tumors associated with drug therapy are usually benign and remit when drug therapy is discontinued.

Drug-Induced Liver Injury: An Overview

Except in rare instances, these lesions are associated with long-term exposure to the offending agent. The model for drug-induced hepatic cancer is polyvinyl chloride exposure. Used in the production of many types of plastic products, polyvinyl chloride induces angiosarcoma in exposed workers after as few as 3 years of exposure. Cocaine has been directly linked to liver disease. Many of these adulterants are either directly toxic or serve to enhance the toxicity of the drug eTable An approach to determining a drug monitoring plan for patients prescribed potentially hepatotoxic drugs.

Notes: a Serious reactions would include those that occur rarely but have a very high morbidity or mortality rate.

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A total score As the score approaches 14; the possibility that this is a hepatotoxic reaction increases toward certainty.