Background
Glucocorticoids (GCs) exert antiinflammatory and immunosuppressive effects by interfering with genome transcription and through transactivation of inflammatory cytokines [
1]. In addition, GCs mediate physiological activities such as activation of gluconeogenesis, insulin resistance, skin atrophy, and inhibition of bone formation, resulting in corresponding complications and adverse reactions [
2]. Methylprednisolone (mPSL) is a synthetic GC and is currently the first-line drug for inflammatory and autoimmune diseases. Common mPSL adverse reactions include Cushing’s syndrome, induction and exacerbation of infections, gastrointestinal reactions, osteoporosis, and obesity [
3]. High-dose intravenous administration of GCs may induce other rare adverse reactions.
This study reviewed the clinical features and treatment of four patients with hyperamylasemia who received high-dose intravenous mPSL in our hospital from 2019 to 2021. The findings of this study provide information to improve understanding of clinicians on the application of high-dose GCs. The reporting of this study conforms to CARE guidelines [
4].
Discussion
Hyperamylasemia can be divided into four types: pancreatic hyperamylasemia, salivary gland hyperamylasemia, megaamylasemia, and mixed hyperamylasemia [
7], being mainly due to pathological changes in the organs that secrete AMY and impaired metabolic clearance. Common causes such as acute pancreatitis, pancreatic or salivary gland trauma, ERCP, etc., lead to gland storage AMY secretion to the blood, resulting in hyperamylasemia. AMY is cleared through the kidney and reticuloendothelial system in the human body, and hyperstarchemia occurs in renal insufficiency and liver disease (hepatitis or cirrhosis) [
5]. Studies have shown that AMY is increased in patients with chronic renal insufficiency when eGFR < 60 ml/min/1.73 m
2, and AMY increased level was negatively correlated with eGFR [
8]. Cases 1 and 2 had normal renal function throughout the disease, while cases 3 and 4 had renal insufficiency, especially case 4, which could have been diagnosed as uremia, relying on hemodialysis for a long period of time to maintain renal function. On outpatient follow-up, we observed a normalization of amylase in the latter two, but there has been no significant recovery of renal function. Therefore, the possibility of increased amylase due to renal insufficiency was temporarily ruled out. The renal function results of the four cases are presented in Table
2.
Table 2
Renal function results of the four cases
Case 1 | | | | |
2 | 61.9 | 45.5 | 142.1 | 113 |
8 | 78.4 | 40.2 | 164 | 117.7 |
18 | 233.6 | 39 | 120 | 118.9 |
27 | 167.6 | 36.2 | 142.7 | 121.8 |
Case 2 | | | | |
2 | 79.9 | 61.3 | 153 | 120.4 |
5 | 68.7 | 44.8 | 125.7 | 133.5 |
9 | 211.2 | 46.1 | 107.9 | 132.2 |
32 | 109.9 | 39.7 | 258.6 | 138.9 |
Case3 | | | | |
1 | 150.8 | 98.1 | 486.4 | 57.8 |
4 | 162.6 | 85.9 | 456.5 | 67.9 |
9 | 112.5 | 129.5 | 571 | 41.3 |
14 | 163 | 105.4 | 474.1 | 53 |
18 | 193.1 | 105.2 | 372.8 | 53.1 |
Case 4 | | | | |
1 | 60.1 | 466.3 | 297.2 | 7.6 |
8 | 58.7 | 260.2 | 206.1 | 15.4 |
13 | 186 | 343.6 | 272 | 11 |
21 | 196.4 | 385.6 | 319.6 | 9.8 |
34 | 257.9 | 345.4 | 404.1 | 11 |
Moreover, previous studies have reported that systemic lupus erythematosus is associated with elevated AMY, which can be attributed to the production of autoantibodies, immune process activation, and vasculitis-induced lupus pancreatitis [
9]. Case 3, in which amylase was above normal on admission, was considered to be related to SLE. The amylase then decreased to normal with low doses of mPSL and cyclophosphamide. SLE was effectively treated with high-dose mPSL from day 8, after which amylase increased again, which was considered to be related to the high-dose mPSL. Interestingly, when case 3 was admitted for the second time, 60 mg of mPSL was administered for 13 consecutive days and a slight increase in amylase was noted.
Gallstone is the common cause of acute pancreatitis. In these four cases, we could almost observe gallbladder sediment-like stones, but before the application of high-dose glucocorticoid, amylase was normal, and there were no relevant imaging manifestations of acute pancreatitis, so we can reject the influence of gallbladder stones.
In this study, the relationship between mPSL and hyperamylasemia was evaluated by the Naranjo scoring method [
10], as shown in Table
3, and the following is a detailed description of the contents of the rating scale. (1) According to literature, Logsdon
et al. reported that GC induced synthesis of AMY by AR42J pancreatic acinar cells in 1985 [
11], indicating that GC could cause an increase of amylase. (2) In addition, except for case 3, the other cases had normal AMY levels at admission, and hyperamylasemia occurred only after high dose of mPSL. (3) In cases 1 and 2, AMY secretion was inhibited by somatostatin, and hyperamylasemia was relieved. (4) The fluctuation of amylase can be used as objective evidence, and other possible causes of hyperamylasemia are excluded in the discussion above, indicating that effective diagnosis of hyperamylasemia was performed.
Table 3
Naranjo scale questionnaire
a | Are there previous conclusive reports on this reaction? | 1 | 0 | 0 |
b | Did the adverse event occur after the suspected drug was administered? | 2 | −1 | 0 |
c | Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? | 1 | 0 | 0 |
d | Did the adverse reaction reappear when the drug was readministered? | 2 | −1 | 0 |
e | Are there alternative causes (other than the drug) that could have on their own cause the reaction? | −1 | 2 | 0 |
f | Did the reaction reappear when a placebo was given? | −1 | 1 | 0 |
g | Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? | 1 | 0 | 0 |
h | Was the reaction more severe when the dose was increased or less severe when the dose was decreased? | 1 | 0 | 0 |
i | Did the patient have a similar reaction to the same or similar drugs in any previous exposure? | 1 | 0 | 0 |
j | Was the adverse event confirmed by any objective evidence? | 1 | 0 | 0 |
However, our research also has some limitations. For example, there was no mention of similar adverse drug reactions in patients’ previous medical history nor high dose of GC rechallenge. In this study, we did not carry out placebo-controlled trials or monitor blood concentrations after addition and subtraction doses to compare the severity of hyperamylasemia. Due to the failure of follow-up, we only know that the AMY of the four patients returned to normal after the first outpatient review, so it is impossible to predict whether hyperamylasemia will recur.
In summary, the total score for the above evaluation criteria was 7 points, indicating that the causal relationship of hyperamylasemia caused by high-dose mPSL is “very likely.”
Previous studies have reported that GCs can lead to acute pancreatitis [
12‐
14]. China’s latest guidelines [
15] suggest that the diagnosis of acute pancreatitis should meet at least two of the following three criteria: (1) acute, sudden, persistent, severe upper abdominal pain, which may radiate to the back; (2) serum amylase and/or lipase activities at least three times higher than the upper limit of normal levels; (3) enhanced CT/MRI showing typical AP imaging changes (pancreatic edema or peripancreatic effusion). These four cases did not meet the diagnostic criteria for pancreatitis, so the diagnosis was a simple increase in AMY caused by drugs, which might be a direct toxicity of mPSL.
Conclusion
Elevated amylase levels may be a result of pancreatitis or a reflection of nonpancreatic disease. Simple hyperamylasemia is clinically insignificant and does not require treatment. However, etiological differentiation of hyperamylasemia should be emphasized in clinical practice, especially when the diagnosis of acute pancreatitis is not clear. The hyperamylasemia in this study was most likely caused by acute pancreatitis, as the diagnosis has not yet been reached. It is recommended to increase tests of serum lipase, giant amylase, and pancreatic amylase isoenzyme as well as imaging examinations of pancreas when necessary, and to follow up outpatients with high amylase.
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