Drug induced liver injury is an important adverse drug reaction, which has been proven to be caused by over 1000 drugs, herbs, or dietary additives[8]. DILI can manifest as acute or chronic liver disease, which can be divided into liver cell injury type, cholestasis type, and mixed type according to the type of liver injury. Most cases are self limiting after discontinuation of medication, but it may also lead to serious consequences such as chronic liver injury, liver transplantation, or death[9–15]. The diagnostic criteria for acute DILI are (1) ALT ≥ 5ULN; (2) ALP ≥ 2ULN; (3) ALT ≥ 3ULN and TBil ≥ 2ULN. The histological manifestations of DILI are diverse, covering almost all types of liver pathological changes. The gold standard for DILI diagnosis is that taking the same medication again causes the same liver damage, but attempting again poses a fatal risk to the patient. Due to the lack of specific diagnostic markers, the commonly used method for determining the causal relationship between drugs and liver injury is the Roussel Uclaf causality assessment (RUCAM), which includes two assessment forms: liver cell injury type and cholestasis type/mixed type. Diagnosis relies on a comprehensive assessment of medical history, clinical symptoms, serum biochemistry, immunology, and histology, and is an exclusive diagnosis.[16]
Fenofibrate is a fibrous acid derivative used to treat hypertriglyceridemia and dyslipidemia. Among patients receiving fenofibrate treatment, up to 20% of patients experience mild and transient elevation of serum transaminases, only 3% -5% of patients experience an elevation three times higher than normal. These abnormalities are usually asymptomatic and transient, and can be resolved even with continued use of fenofibrate [17]. However, occasional significant discomfort symptoms and elevated serum transaminases require discontinuation of medication[18].But there are also literature reports on cases of liver injury that occur immediately after 48 hours of taking fenofibrate[19], as well as cases of severe liver injury caused by fenofibrate[3]. Autoimmune mediated liver injury has not yet been found. The patient we reported first used fenofibrate and developed obvious liver injury, consistent with drug-induced liver injury. After discontinuation for a period of time, liver function returned to normal. Therefore, we believe that there is a causal relationship between liver dysfunction and the use of fenofibrate.
The patient subsequently experienced liver dysfunction again after using atorvastatin during normal liver function. Atorvastatin is the main rate limiting enzyme in cholesterol synthesis. 1% -3% of patients may experience mild, asymptomatic transient elevation of serum transaminases, but in less than 1% of patients, serum transaminase levels are three times higher than ULN, and most of the increases are self limiting and do not require dose adjustment. Atorvastatin hepatotoxicity can also manifest as a clear pattern of liver cell damage, but at least one-third of liver cell cases have autoimmune features, characterized by high levels of immunoglobulin, positive ANA, and liver biopsy results of autoimmune hepatitis, indicating that it may be immune mediated[20]. DI-AIH has been reported to occur in monotherapy with statin drugs such as simvastatin, rosuvastatin, and atorvastatin, or in combination with other lipid-lowering drugs. [21–23]. Either a positive ANA or a smooth muscle antibody is found in approximately two out of three patients with statin-associated DI-AIH[23]. Yehia Saleh, Khader Herzallah reported a case of atorvastatin induced autoimmune myopathy, and glucocorticoid therapy is effective, further suggesting the possibility of atorvastatin inducing autoimmune diseases[24.] Related studies have found that in some patients with atorvastatin induced DI-AIH, more patients relapse after glucocorticoid discontinuation, indicating that atorvastatin is more likely to induce classical AIH[25]. The patient we reported experienced liver injury again after using atorvastatin during normal liver function, and exhibited autoimmune features such as high immunoglobulin levels and positive ANA. After treatment with glucocorticoid, the liver function has been restored. We believe that atorvastatin caused liver injury and exhibited autoimmune mediated characteristics.
After two liver injuries, the patient voluntarily chose different mechanisms of action of ezetimibe to lower blood lipids, which also resulted in liver injury and exhibited autoimmune characteristics again. Ezetimibe is a type of intestinal cholesterol absorption inhibitor with a unique mechanism of action and chemical structure. There is no reason to doubt the cross sensitivity of ezetimibe to liver injury with other cholesterol lowering drugs. Compared with statin therapy, severe side effects are very rare, particularly when the drug is used as monotherapy in patients with statin intolerance[26].In fact,a lot of previous published cases of ezetimibe-induced liver injury have been reported in combination with a statin [27–29]. Reports of severe acute liver injury caused by the sole use of Ezetimibe are very rare. However, cases of autoimmune hepatitis like syndrome suggest that immune mediated damage may be the cause of some clinically significant liver damage caused by ezetimibe[29].
Autoimmune hepatitis (AIH) is a severe liver disease The diagnosis of AIH depends on increased serum transaminase and immunoglobulin G levels, presence of autoimmune and interface diseases on liver history. The International Autoimmune Hepatitis Group published revised diagnostic criteria (RDC) for AIH in 1999 and simplified diagnostic criteria (SDC) in 2008. A pretreatment RDC score of 15 is considered defined for the diagnosis of AIH, A pretreatment RDC score of 10 notes a possible diagnosis of AIH[7]. Our patient scores 12.
Autoimmune like drug induced liver injury (DI-AIH) is a subtype of DILI, which has been increasingly recognized and reported in recent years. Drugs that cause immunity related DILI can trigger immune response against hepatic proteins which can lead to a clinical course similar to autoimmune diseases (AIH) DI-AIH and DILI are both exclusive diagnoses. Similar to DILI, the incubation period of most DI-AIH is greater than 2 months[31], the pattern of life injury with DI-AIH is typically heterocellular with 'R' ratio > 5, (ALT) compared to (ALP)[9]. The appearance of higher levels of immunoglobulin G (IgG) tends to favor DI-AIH[29], A positive antibody antibody (ANA), although non-specific, is found in anywhere from 50–83% of patients with DI-AIH [30–32]. Anti smooth drug antibiotics are less frequently positive in about 55% of cases [20]. Due to the high levels of immunoglobulin and positive ANA in the patient's serum biochemistry results, in order to further distinguish whether the patient is DI-AIH or AIH, our case improved liver biopsy histology, which showed acute liver injury. No typical histological manifestations of AIH were observed.
DI-AIH is a challenging diagnosis. Although autoantibodies are common, they are neither specific nor diagnostic for DI-AIH and may appear in other non immune mediated liver diseases, including NASH. Histology may help describe the subtle differences between DI-AIH and newly developed iAIH, but the two are often indistinguishable histologically. Although RUCAM is a useful tool, any drug should consider DI-AIH if there are features that suggest autoimmunity. The complete recovery of liver injury is most common in DI-AIH, Long term injury may also occur and immunosuppressive therapy may be needed. If there is a suspected recurrence of DI-AIH after discontinuing corticosteroids, the possibility of iAIH should be considered[33, 34].
Based on the above, Continuing to observe whether the disease has recurred, or conducting another liver biopsy, will be helpful in making a clear diagnosis of DI-AIH or AIH.