A rare case of macroamylasemia in a patient with SARS-CoV-2 infection

Abstract

Background

Macroamylasemia is a rare condition affecting 0.5–1.5% of the population. Macroamylasemia should be suspected in a patient with a high serum alpha-amylase level without an elevation in the urine alpha-amylase level. Serum amylase binds with other serum proteins like immunoglobulins A (92%), immunoglobulins G (< 30%), and others (< 5%), forming macromolecular complexes that weigh more than 400 KDa. Nephrones are unable to secrete these macromolecules into the urine due to their large size, which causes the accumulation of these macromolecules in the serum. Patients with COVID-19 during seroconversion develop higher concentrations of SARS-CoV-2-specific immunoglobulins and different plasma proteins, which can bind with the alpha amylase molecules and cause macroamylasemia.

Case presentation

In this case report, we report about a 70-year-old hypertensive and asthmatic patient who was under inward treatment for mild COVID-19. He complained ofburning epigastric pain for  one day and his elevated serum amylase level persisted months after the initial presentation.

He underwent extensive investigations to exclude acute pancreatitis and other causes of high amylase levels. His amylase creatinine clearance ratio was 0.2%, his pre- polyethylene glycol(PEG) amylase concentration was 644 U/L, and his post-PEG amylase concentration was 10 U/L with a very low post-PEG recovery (1.55%). He was diagnosed with macroamylasemia.

Introduction

Amylase is involved in the digestion of carbohydrates. It hydrolyzes alpha-1,4-glycoside bonds in polysaccharides and forms maltose and oligosaccharides. In a healthy adult, the pancreas (40–45%) and salivary glands (50–55%) account for almost all the alpha-amylase levels. It can be found in two isoenzymes. Pancreatic, or p-isoenzyme, and non-pancreatic, salivary, or s-isoenzyme forms. Fallopian tubes, testes, lungs, thyroid gland, tonsils, mammary glands, and sweat glands secrete a little amount of amylase, mainly s-isoenzyme type [1]. Alpha-amylase contains 496 amino acids with a molecular weight of 54 KDa. Amylase metabolism is not well understood, and the kidneys play a major role in the excretion of amylase [2].

Macroamylasemia is a rare, benign condition with a prevalence of 0.5–1.5% in the general population and 2–5% in the population with hyperamylasemia. It is more common in adult males, but the reason for this is unknown. Macroamylasemia was first described in 1964 by Wilding [3, 4].

Macroamylasemia should be suspected in a patient with a high serum alpha-amylase level without an elevation in the urine alpha-amylase level. Serum amylase proteins bind with other serum proteins like immunoglobulins A (92%), immunoglobulins G (< 30%), and others (< 5%), forming macromolecular complexes that weigh more than 400 KDa. Nephrones are unable to secrete these macromolecules into the urine due to their large size, which causes the accumulation of these macromolecules in the serum [5].

COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2, which manifests mainly as respiratory symptoms. Following entry into the cells, immunoglobulin A, immunoglobulin M, and immunoglobulin G against the S and N proteins of SARS-CoV-2 develop within 1–2 weeks after the onset of the symptoms. In the early phase, the antigen-specific immunoglobulin A level is higher than the immunoglobulin M level. Specific COVID-19 IgG antibodies rise months after the initial infection and remain elevated for more than a year [6]. The alpha amylase molecule can bind with these immunoglobulins, making a macromolecule that causes macroamylasemia.

Among COVID-19 patients, 1–2% of mild to moderate COVID-19 cases and 17% of severe COVID-19 cases had acutely elevated amylase levels. A USA study reported a prevalence of 0.27% of acute pancreatitis in COVID-19 patients, and 69% of them had idiopathic acute pancreatitis [7]. But macroamylasemia was not reported in a COVID-19 patient previously. In this article, we report the first case of macroamylasemia in a patient with COVID-19.

Case report

A 70-year-old hypertensive and asthmatic patient who is on losartan 50 mg twice daily and Fluticasone propionate/Salmeterol 250/25 microgram metered dose inhaler presented to a tertiary care hospital with a mild COVID-19. On day 1, he had normal basic investigations, including a normal serum amylase level (Table 1). He complained about burning epigastric pain on day 3. Even though the pain was not suggestive of pancreatic origin, he had a serum amylase level of 663 U/L. His renal functions and other basic investigations were normal (Table 1). We managed him for mild acute pancreatitis. He had normal triglyceride levels (135 mg/dL), calcium levels (8.7 mg/dL), and a tissue transglutaminase antibody (4 U/ml). His anti-nuclear antibody was negative. He was discharged once he recovered from COVID-19 and followed up in the gastroenterology clinic.

Table 1.

Follow up investigations of the patient

	On Day 1	Day 3	On discharge	2 weeks after the discharge	1 month after the discharge	2 months after the discharge	3 months after the discharge	6 months after the discharge
Serum Amylase (U/L)	55	663	540	584	573	579	601	588
Serum Lipase (25–125 U/L)				37			40
Aspartate aminotransferase (U/L	29	33			25			22
Alanine aminotransferase (U/L)	32	38			27			24
Total Bilirubin(mg/dl)	0.5	0.5			0.6			0.5
Alkaline phosphatase (U/L)	68	69			67
Gamma-glutamyl transferase (U/L)	28	29			27
Serum creatinine(mg/dl)	0.8	0.8			0.8			0.8
CECT Abdomen						Normal
Magnetic resonance cholangiopancreatography							Normal
USS andomen and Neck		Normal
Upper GI Endoscopy			Mild antral gastritis
Lower GI Endoscopy						Normal
Amylase creatinine clearance ratio							0.2%
Pre-polyethylene glycol (PEG) amylase concentration							644U/L
Post-PEG amylase concentration							10U/L
Post-PEG recovery							1.55%

On follow-up, he had a persistently high amylase level with a normal serum lipase level without pancreatic pain. He was extensively evaluated for hyperamylasemia because clinical and radiological features were not suggestive of acute pancreatitis, and serum amylase levels were persistently elevated (Table 1). The CECT abdomen, thorax, and pelvis were done, and the pancreas appears normal without other solid organ malignancies. Upper and lower gastrointestinal endoscopies were done and found to have non-significant findings, including mild antral gastritis. His amylase creatinine clearance ratio was 0.2%, his pre-polyethylene glycol (PEG) amylase concentration was 644 U/L, and his post-PEG amylase concentration was 10 U/L with a very low post-PEG recovery (1.55%), which was suggestive of macroamylasemia.

Discussion

Among COVID-19 patients, 1–2% of mild to moderate COVID-19 cases and 17% of severe COVID-19 cases had acutely elevated amylase levels [7]. 2–5% of the population without COVID-19 with hyperamylasemia had macroamylasemia [3, 4].

Our patient with mild COVID-19 had an elevated amylase level and abdominal pain. It is important to exclude causes of abdominal pain in a COVID-19 patient, especially diseases with high mortality like acute pancreatitis, acute appendicitis, and bowel ischaemia, which in turn can worsen COVID-19 outcomes. So it is important to exclude other causes of an elevated serum amylase level (Table 2).

Table 2.

Important causes of hyperamylasemia

Cause	Possible mechanism
Kidney failure Liver disease	Reduce amylase metabolism
Pancreatitis/Pancreatic trauma Mumps/ salivary gland trauma or radiation	Reduce amylase metabolism Increase amylase release from damaged organ
Intestinal disease(Inflammatory bowel disease, Bowel ischaemia, peritonitis, Perforated peptic ulcer disease, Celiac disease)	Unknown
Ruptured ectopic pregnancy Ovarian cyst Pelvic inflammatory disease	Increase amylase release from damaged organ
Carcinoma of lungs, ovaries, breast, pancreas, and colon; pheochromocytoma; multiple myeloma.	Ectopic amylase production
Pneumonia	Unknown
Anorexia nervosa	Unknown
Ciprofloxacin Organophosphate poisoning	Unknown
Chronic nonpathological hyperamylasemia of pancreatic origin Ethnic hyperamylasemia Familial hyperamylasemia Chronic asymptomatic pancreatic hyperenzymemia,	Unknown

Amylase-creatinine clearance ratio is an investigation that can be used to screen for macroamylasemia. The normal value is between 3 and 5%. Less than 1% is suggestive of macroamylasemia, and more than 5% is suggestive of acute pancreatitis. The confirmatory tests are electrophoresis or polyethylene glycol precipitation tests and chromatography [2].

Macromolecules are precipitated in concentrated solutions of polyethylene glycol. The polyethylene glycol precipitation test is the method of choice for detecting macroamylase complexes. It is a quick (about 10 min) and very cost-effective method. After the precipitation of macroamylase, serum amylase levels can be determined by subtracting macroamylase concentration from total amylase [8].

We proposed that dysregulation of immune tolerance plays a major role in macroamylasemia development in SARS-CoV infection. Following entry into the cells, immunoglobulin A, immunoglobulin M, and immunoglobulin G against the S and N proteins of SARS-CoV-2 develop within 1–2 weeks after the onset of the symptoms. In the early phase, the antigen-specific immunoglobulin A level is higher than the immunoglobulin M level. Specific COVID-19 IgG antibodies rise months after the initial infection and remain elevated for more than a year. These immunoglobulins can cross-react with alpha amylase molecules, making a macromolecule, which in turn can cause macroamylasemia due to the increased half-life of the amylase due to reduced renal clearance. Dysregulation of immune tolerance also occurs in autoimmune disorders like systemic lupus erythematosus, rheumatoid arthritis, and celiac disease [9].

Patients with high amylase levels repeatedly undergo extensive investigations. A study reported that, after extensive investigations, 13.7% had no specific diagnosis for high amylase levels [10]. A macroamylasemia diagnosis in a patient with hyperamylasemia has great value for the health care system and for the patient because high amylase levels can warrant repeated, unnecessary, and extensive investigations.

Conclusion

Macroamylasemia is a rare but benign disease that clinicians should keep in mind when managing patients with high amylase levels. Amylase-creatinine clearance ratio is a simple and cost-effective test that can be used to screen for macroamylasemia. A macroamylasemia diagnosis in a patient with hyperamylasemia has great value for the health care system and for the patient because high amylase levels can warrant repeated hospital admissions and unnecessary and extensive investigations.

Author contributions

Dr Tilan Aponso and Dr.W.M.D.A.S.Wanninayake did the literature review and writing of the initial manuscript was done by Dr Tilan Aponso. Dr N.M.M.Nawarathne finalized the manuscript and gave expert opinion. All the authors reviewed the final manuscript.

Funding

None.

Data availability

The data is available from the corresponding author on reasonable request.

Declarations

Ethical approval

Not applicable.

Consent for publication

Informed written consent for publication of details was taken from the patient. Consent form can be made available to the editor on request.

Competing interests

The authors declare no competing interests.