Drug-induced liver injury from high-dose intravenous methylprednisolone: A rare but known adverse effect

Abstract

In general, the use of steroids is associated with three forms of liver injury that include hepatitis B reactivation, drug-induced liver injury, and steatosis/steatohepatitis. Drug-induced liver injury is a known but rare adverse effect of high-dose steroids. While corticosteroids, including methylprednisolone, are generally considered safe, high doses have been linked to hepatic injury. This form of insult is often idiosyncratic and unpredictable. We present the case of a 60-year-old female who was admitted due to a 6-week history of paresthesia and weakness involving her bilateral hands and feet. Magnetic resonance imaging of the brain, cervical, and thoracic regions revealed several enhancing lesions, highly concerning for multiple sclerosis. One day following high-dose intravenous methylprednisolone, liver enzymes were found to be significantly elevated on her complete metabolic panel. Steroid therapy was discontinued, and liver enzymes returned to normal values within 4 days. Symptoms ultimately resolved following a 7-day course of plasmapheresis. This article brings attention to providers about this rare adverse effect, especially to clinical specialists who often use high-dose steroids. Suggestions regarding monitoring and treatment are also provided.

Key Words: Methylprednisolone; Drug-induced liver injury; Corticosteroids; Hepatotoxicity; Transaminitis; Glucocorticoids; Multiple sclerosis; Inflammation

Core Tip: Corticosteroids are widely used in the treatment of various diseases. In general, these medications are considered safe. However, several recent cases have reported severe liver injury with high-dose methylprednisolone (Methyl-PNL). This article reports a case of asymptomatic hepatitis from high-dose Methyl-PNL that resolved with medication discontinuation. This known adverse effect should not preclude providers from treating various clinical conditions with high-dose Methyl-PNL. However, it should not be surprising if acute hepatitis or severe liver injury occurs as an adverse reaction, especially with high doses. We call for more providers to be aware of this idiosyncratic and rare drug side effect.

TO THE EDITOR

We wanted to comment on a rare but known adverse effect of high-dose methylprednisolone (Methyl-PNL) and bring this to providers’ awareness globally. High-dose intravenous glucocorticoid treatment is one of the most effective options for managing various autoimmune and inflammatory conditions[1-3]. A review of the literature shows that corticosteroids are not entirely safe for the liver and, in some instances, have been associated with severe liver injury[4-6]. In our case, a 60-year-old female with a past medical history of type 2 diabetes mellitus, hypothyroidism, asthma, and alopecia presented to the emergency department, endorsing a 6-week history of paresthesia and weakness involving her bilateral hands and feet. Home medications included metformin, levothyroxine, and albuterol. Neurology was consulted, who subsequently recommended admission and further work-up. She underwent a lumbar puncture, which revealed elevated white blood cells, and a subsequent magnetic resonance imaging of the brain, cervical, thoracic, and lumbar areas. Findings revealed multiple enhancing lesions within the brainstem, cerebellum, and cervical and thoracic cords. At this moment, the treatment team was concerned about multiple sclerosis. As such, she started treatment with 1 gm of intravenous Methyl-PNL. The following day, her metabolic panel (Table 1) showed elevated transaminases compared to normal values (aspartate aminotransferase 39 U/L and alanine aminotransferase 41 U/L) from the previous day, before steroid treatment. Methyl-PNL was discontinued, and her liver enzymes trended back to normal over the span of 4 days. She subsequently received a 7-day course of plasmapheresis, which resulted in complete symptom resolution. No alternative immunosuppression therapy for this acute flare was considered.

Table 1 Complete metabolic panel showing elevated liver enzymes the following day after high-dose methylprednisolone.

Variable	Patient values	Normal range
AST	224	15-41 U/L
Alkaline phosphatase	111	32-91 U/L
Total bilirubin	0.8	0.3-1.0 mg/dL
Calcium	9.1	8.6-10.4 mg/dL
Total protein	6.4	5.8-8.2 g/dL
Albumin	4.0	3.5-5.1 g/dL
Glucose, blood	211	70-139 mg/dL
BUN	16	6-20 mg/dL
Creatinine	0.60	0.44-1.03 mg/dL
BUN/creatinine ratio	24.2	10.0-20.0 mgUN/mgCR
Sodium, blood	141	136-145 mmol/L
Potassium, blood	4.4	3.5-5.1 mmol/L
Chloride, blood	107	98-107 mmol/L
Osmolality, calculated	298	275-295 mOsm/kg
CO2	25	22-32 mmol/L
Anion gap	9	4-15 mmol/L
ALT	233	7-52 U/L
CKD-EPI eGFR	100	> 59 mL/minute/1.73 m2

AST: Aspartate aminotransferase; BUN: Blood urea nitrogen; UN: Urea nitrogen; CR: Creatinine; ALT: Alanine aminotransferase; CKD-EPI eGFR: Chronic kidney disease epidemiology collaboration equation for estimating glomerular filtration rate.

The causal relationship between high-dose Methyl-PNL and drug-induced liver injury (DILI) was assessed using the Naranjo adverse drug reaction probability scale[7,8]. This imputability scale includes several criteria, such as the temporal relationship between drug exposure and the development of liver injury, previous case reports of DILI, the evolution of liver enzymes following drug withdrawal, concomitant medication, and alternative causes that could have induced the reaction. In our case, the Naranjo score (Table 2) was 7 on a scale from 0 to 12, where a score of ≥ 9 constitutes definitive evidence that the drug was the likely cause of the reaction. The score of 7 correlated with the probable category. Some questions on the probability scale, such as “Was the drug detected in any body fluid in toxic concentrations?” were not feasible to answer, which most likely accounted for the score outcome. Alternative causes of liver injury, including viral illness, autoimmune disease, other medication use, and ischemia, were ruled out, giving more credence to an adverse drug reaction. There have been previously documented cases of acute hepatotoxicity following high-dose Methyl-PNL therapy, including Loraschi et al[9] who reported on a similar scenario in which liver enzymes normalized within a few days.

Table 2 Naranjo adverse drug reaction probability scale for the patient.

Question	Yes	No	Do not know	Score
Are there previous conclusive reports on this reaction?	+ 1	0	0	+ 1
Did the adverse event appear after the suspected drug was administered?	+ 2	- 1	0	+ 2
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	+ 1	0	0	+ 1
Did the adverse reaction reappear when the drug was readministered?	+ 2	- 1	0	0
Are there alternative causes (other than the drug) that could on their own have caused the reaction?	- 1	+ 2	0	+ 2
Did the reaction reappear when a placebo was given?	- 1	+ 1	0	0
Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?	+ 1	0	0	0
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+ 1	0	0	0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+ 1	0	0	0
Was the adverse event confirmed by any objective evidence?	+ 1	0	0	+ 1
Total score				7

The mechanism of steroid-induced liver injury remains unknown. Low-dose corticosteroids are generally considered safe for liver function, but long-term use may result in steatohepatitis[10]. High-dose steroids such as intravenous Methyl-PNL may rarely cause intrinsic hepatotoxicity[4-6,11]. Corticosteroids are metabolized by the cytochrome P450 system[12]. Aberrant hepatic metabolism resulting in metabolic idiosyncrasy should be considered the mechanism of steroid-induced liver toxicity[11-14]. Predisposing risk factors for this condition include older age, female sex, alcohol consumption, underlying comorbidities (i.e., pre-existing liver disease, human immunodeficiency virus infection, diabetes), drug interactions, and genetic variations (i.e., human leukocyte antigen polymorphisms and variations in phase 1 and 2 drug metabolizing enzymes)[15-17]. In this case, older age, sex, and diabetes were present that may have played a role in the observed drug reaction. Providers should obtain baseline liver function tests before the initiation of high-dose steroids and monitor daily. If DILI (elevated alanine aminotransferase or aspartate aminotransferase ≥ 3 times the upper limit of normal or elevated bilirubin ≥ 2 times the upper limit of normal) is suspected, there should be prompt cessation of the agent and continued monitoring of liver enzymes daily for improvement.

CONCLUSION

In summary, our case illustrates a rare but true hepatotoxicity associated with high-dose Methyl-PNL therapy. Steroid discontinuation is the best-recommended treatment as liver enzymes typically normalize over days to weeks, depending on the severity. In this scenario, severity was mild, which allowed for improvement back to baseline in just 4 days. This type of DILI is likely related to a transient immune rebound[14,18], and physicians should be cognizant to avoid misdiagnosis and provide the appropriate follow-up in patients treated with high-dose Methyl-PNL pulse therapy. Prompt recognition of the adverse event and early drug withdrawal could prevent hepatic failure. A better understanding of risk factors and the mechanism through which Methyl-PNL induces liver injury could prevent future events.