Drug-induced Liver Injury
Furthermore, acetaminophen is particularly toxic in heavy alcohol drinkers due to increased activation of the cytochrome p450 system, which leads to generation of the toxic metabolite acetaldehyde.24 It is also recognized that non-alcoholic fatty liver disease (NAFLD) can also increase susceptibility for DILI.25
augment the severity of inflammatory reactions to antituberculosis medication.22 drug toxicity.23
Thus, particular attention is needed when
medicating patients with liver disease (reviewed by Gupta and Lewis).26 However, the presence of pre-existing liver disease does not mean that potentially hepatotoxic medications cannot be used. For example, statins are commonly used in patients with NAFLD. Genetic factors predisposing patients to DILI have been attributed to polymorphisms of the cytochrome p450 enzymes that either slow the metabolism of toxic drugs or accelerate the generation of bioreactive drug metabolites.27–29
Human
leukocyte antigen (HLA) phenotype also plays a role in idiosyncratic, immune-mediated reactions to drugs.30–32
Clinical, Laboratory and Histopathological Features of Drug-induced Liver Injury The majority of cases of DILI are acute illnesses that resolve quickly after the offending medication is stopped. The clinical symptoms are similar to other forms of hepatitis or cholestasis where fatigue, nausea, malaise, pruritus, and jaundice predominate. In some circumstances, abdominal pain that is indistinguishable from acute cholecystitis may be present.33 Concurrent with the theory that immunologic mechanisms are responsible for certain forms of DILI, symptoms of systemic hypersensitivity may be occasionally seen (e.g. fever, rash and eosinophilia).
Certain medications may also cause chronic cholestasis, with clinical features remarkably similar to primary biliary cirrhosis (PBC). Prolonged jaundice, xanthomas, and pruritus have been described in patients taking a variety of different medications. Features that help to distinguish between PBC and drug-induced cholestasis are the lack of circulating anti-mitochondrial antibodies in the latter.34
While PBC may result in
end-stage liver disease (ESLD) and death, chronic cholestasis caused by medications is usually reversible and considered benign. Some forms of chronic medication-induced cholestasis are associated with destruction of the intra-hepatic bile ducts. Although the clinical features of this vanishing bile duct syndrome are similar to other forms of chronic cholestasis, the ductopenia is often irreversible and may lead to cirrhosis.
The diagnosis of DILI is typically made by establishing a temporal relationship between drug exposure and development of signs and symptoms of liver disease. Exclusion of infectious, autoimmune or other forms of liver disease is essential. A thorough medical history and a high clinical suspicion is the basis for a correct diagnosis. The astute clinician should actively investigate the chronological relationship between drug administration and onset of pathology. Drugs that have a dose-dependent toxicity usually elicit clinical features within hours to days, while immune-mediated reactions may manifest weeks after administering the drug. Another important feature that helps to confirm DILI is improvement after drug withdrawal. A rechallenge test may be confirmatory; however, re-administration of the drug is not practical in the clinical setting due to safety concerns, and is not recommended. The diagnosis of DILI is associated with increased levels of hepatic enzymes and bilirubin. The pattern of these abnormalities may be
US GASTROENTEROLOGY & HEPATOLOGY REVIEW Chronic alcohol consumption is also known to exacerbate
Table 1: Types of Drug-induced Liver Injury Type
Enzymatic profile Hepatocellular ALT > 2ULN
Serum ALT/Serum Alk. Phos ≥ 5*
Cholestatic Mixed Alk Phos ≥ 2ULN
Serum ALT/Serum Alk Phos ≤ 2*
ALT > 2 ULN
Serum ALT/Serum Alk Phos between 2 and 5*
* The values in the ratios are expressed as ULN multiples.
ALT = alanine aminotransferase; ULN = upper limit of normal; Alk Phos = alkaline phosphatase. Table 2: King’s College Criteria for Liver Transplantation Acetaminophen
Non-acetaminophen pH<7.3
Lactic acid>3.5mM at 8 hours Lactic acid>3.0mM at 12 hours Creatinine>3.4mg/dl INR>6.5 / PT>100sec
Encephalopathy grade 3 or 4
INR>6.5 / PT>100 seconds or any three of the following: • INR>3.4 / PT >50 seconds • Bilirubin >17.5mg/dl • Jaundice for >7 days • Age between 10 and 40
• Etiology: drug reaction or unknown
hepatocellular, cholestatic, or mixed (see Table 1). The hepatocellular pattern is characterized by increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which reflects hepatocyte destruction and is potentially associated with a worse prognosis. Toxic levels of acetaminophen can elevate liver enzymes above 20,000IU/L. Alkaline phosphatase elevation is the predominant laboratory feature of cholestatic DILI. Histopathological findings of DILI are not specific. The extent of hepatocyte necrosis may portend a worse outcome, while eosinophilia is potentially a marker of better prognosis.35
As the main challenge is to establish a causal relationship between a certain medication and liver injury, several clinical scales have been developed. The scoring criteria are based on the chronological relationship between drug intake/drug withdrawal and clinical effect, clinical course of reaction, exclusion of other potential causes, and rechallenge.
The Rousse Uclaf Causality Assessment Method of the Council of International Organization of Medical Science (RUCAM/CIOMS) is the most frequently used criteria set for the diagnosis of DILI.36
In addition to
the aforementioned criteria, the RUCAM/CIOMS scale scores several risk factors (age, alcohol consumption, and pregnancy) and separates DILI into the three patterns described above: hepatocellular, cholestatic, and mixed.37,38
The Maria and Victorino (M&V) Scoring system simplifies the approach by using only five of the seven criteria of the RUCAM/CIOMS scale, but also considers the presence of extra-hepatic manifestations such as fever, rash, arthralgia, eosinophilia, or cytopenia.39
A major critique of
the M&V scale is the omission of the liver injury pattern. In addition, the M&V scale is not sensitive to diagnosing chronic forms of DILI and fulminant drug-induced hepatitis.40,41
75 More prone to chronic disease More prone to chronic disease Prognosis More severe prognosis
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