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Pyroglutamic acidosis is a rare and underdiagnosed high anion gap metabolic acidosis (HAGMA) caused by accumulation of 5-oxoproline associated with commonly used medications such as paracetamol and antibiotics. We report a case exhibiting the common risk factors of pyroglutamic acidosis and the clinical approach to diagnosis.

Case report

A 74-year-old female presented with abdominal pain, ascites, fever and reduced appetite. Her background included cholecystectomy and Caesarean section. She was initially treated with 13 days of cefuroxime and metronidazole (which was later changed to tazocin following clinical deterioration), paracentesis and analgesia. A CT scan showed paracolic abdominal masses later confirmed as liposarcomata.

After 13 days she developed worsening kidney impairment, malnutrition and HAGMA (Table 1). Various common causes of HAGMA were excluded in the setting of normal lactate and ketones. Medication review found regular paracetamol use calculated at a dose of 76 grams over 19 days, which raised the suspicion that 5-oxoproline had accumulated and was contributing to HAGMA. Paracetamol was stopped and intravenous bicarbonate was given, with brief clinical improvement.

Urine organic acid screen, performed using gas chromatography-mass spectrometry after liquid-liquid extraction, showed marked pyroglutamate excretion (>5,000µmol/mmol creatinine). Treatment with N-acetylcysteine (NAC) was considered. However, she continued to deteriorate and diagnostic laparoscopy found extensive carcinomatosis. Treatment was refocused towards palliation.

Table 1: Significant laboratory results. View Table 1.

Discussion

Pyroglutamic acidosis is an underdiagnosed form of HAGMA caused by excess pyroglutamate due to inhibition of negative feedback of the gamma-glutamyl cycle (Figure 1) via depletion of glutathione¹,² associated with chronic paracetamol use and certain antibiotics.[[3]]

Figure 1: The gamma-glutamyl cycle, displaying inhibition via negative feedback mechanism using glutathione. Image created on Biorender.com.

Our patient had risk factors. She was elderly with prolonged paracetamol use, sepsis, malnutrition, liver dysfunction (impairing synthesis and regeneration of glutathione) and kidney failure (preventing pyroglutamate clearance). Other risk factors for pyroglutamic acidosis include chronic alcohol excess, pregnancy and use of certain antibiotics, such as flucloxacillin, which inhibits breakdown of pyroglutamate by 5-oxoprolinase.[[2,3]]

Diagnosis requires clinical suspicion based on raised anion gap, exclusion of more common causes and the presence of relevant risk factors.[[3]] Formal diagnosis of pyroglutamic acidosis requires a urine organic acid screen.

After the appropriate respiratory compensation has been confirmed, the anion gap can be measured by subtracting measured cations from anions (AG=Na-Cl-HCO3 with reference interval of 10–14).[[4]] Serum proteins also contribute to the anion gap. Therefore, any significant change in serum albumin needs to be accounted for using the formula cAG=AG+0.25×(40-albumin in g/L).[[3]] Not doing so in a malnourished patient may underestimate the anion gap.[[3,4]] This is especially important in pyroglutamic acidosis, as malnutrition is common. This may have contributed to delayed recognition of our patient’s condition.

There can be co-existing acid base abnormalities, which are investigated using the delta gap (Δ-Δ=(ΔAG)-(ΔHCO3)). A delta gap between -5 and +5 indicates a pure HAGMA. Results outside this range suggests a concomitant acid-base disturbance.[[4]]

After confirming a pure HAGMA, other causes, such as high lactate or ketones, are excluded. The GOLDMARK mnemonic is helpful in recalling causes of a HAGMA (Table 2).[[5]]

Table 2: GOLDMARK mnemonic showing causes for a high anion gap metabolic acidosis.

Treatment involves stopping causative medications, bicarbonate administration, moderating acidosis and NAC that replenishes glutathione. Pyroglutamate is cleared renally, and dialysis has been used in severe cases.[[5,6]]

In conclusion, pyroglutamic acidosis is a rare and under-recognised cause of HAGMA that can be precipitated by prescription of simple analgesia or common antibiotics in individuals at risk. A high clinical suspicion is required to make the diagnosis and initiate targeted treatment.

Summary

Abstract

Aim

Method

Results

Conclusion

Author Information

Tom Crisp: Emergency Department Registrar, Southern District Health Board, Dunedin. Peter Sizeland: Renal Physician, Waikato District Health Board, Hamilton. Stephen Du Toit: Chemical Pathologist, Waikato District Health Board, Hamilton. Lai Wan Chan: Renal Physician, Waikato District Health Board, Hamilton.

Acknowledgements

Correspondence

Dr Lai Wan Chan, Renal Physician, Waikato District Health Board, Hamilton

Correspondence Email

Laiwan.chan@waikatodhb.health.nz

Competing Interests

Nil.

1) Fenves AZ, Kirkpatrick HM 3rd, Patel VV, et al. Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): a role for acetaminophen. Clin J Am Soc Nephrol. 2006;1(3):441-7.

2) O'Brien LM, Hooper M, Flemmer M, Marik PE. Chronic acetaminophen ingestion resulting in severe anion gap metabolic acidosis secondary to 5-oxoproline accumulation: an under diagnosed phenomenon. BMJ Case Rep. 2012 Jul 3;2012:bcrbcr0320126020. doi: 10.1136/bcr.03.2012.6020. PMID: 22761219; PMCID: PMC3391392.

3) Hunter RW, Lawson C, Galitsiou E, et al. Pyroglutamic acidosis in association with therapeutic paracetamol use. Clin Med (Lond). 2016;16(6):524-9.

4) Berend K, de Vries AP, Gans RO. Physiological approach to assessment of acid-base disturbances. N Engl J Med. 2014 Oct 9;371(15):1434-45. doi: 10.1056/NEJMra1003327. Erratum in: N Engl J Med. 2014 Nov 13;371(20):1948. PMID: 25295502.

5) Serpa MJ, Falcão L, Franco S, Repolho D, Ferreira NR. Metabolic Acidosis Due To Pyroglutamic Acid. Eur J Case Rep Intern Med. 2018 Oct 24;5(10):000949. doi: 10.12890/2018_000949. PMID: 30755980; PMCID: PMC6346886.

6) Raibman Spector S, Mayan H, Loebstein R, Markovits N, Priel E, Massalha E, Shafir Y, Gueta I. Pyroglutamic acidosis as a cause for high anion gap metabolic acidosis: a prospective study. Sci Rep. 2019 Mar 5;9(1):3554. doi: 10.1038/s41598-019-39257-4. Erratum in: Sci Rep. 2020 Aug 4;10(1):13397. PMID: 30837497; PMCID: PMC6400893.

For the PDF of this article,
contact nzmj@nzma.org.nz

View Article PDF

Pyroglutamic acidosis is a rare and underdiagnosed high anion gap metabolic acidosis (HAGMA) caused by accumulation of 5-oxoproline associated with commonly used medications such as paracetamol and antibiotics. We report a case exhibiting the common risk factors of pyroglutamic acidosis and the clinical approach to diagnosis.

Case report

A 74-year-old female presented with abdominal pain, ascites, fever and reduced appetite. Her background included cholecystectomy and Caesarean section. She was initially treated with 13 days of cefuroxime and metronidazole (which was later changed to tazocin following clinical deterioration), paracentesis and analgesia. A CT scan showed paracolic abdominal masses later confirmed as liposarcomata.

After 13 days she developed worsening kidney impairment, malnutrition and HAGMA (Table 1). Various common causes of HAGMA were excluded in the setting of normal lactate and ketones. Medication review found regular paracetamol use calculated at a dose of 76 grams over 19 days, which raised the suspicion that 5-oxoproline had accumulated and was contributing to HAGMA. Paracetamol was stopped and intravenous bicarbonate was given, with brief clinical improvement.

Urine organic acid screen, performed using gas chromatography-mass spectrometry after liquid-liquid extraction, showed marked pyroglutamate excretion (>5,000µmol/mmol creatinine). Treatment with N-acetylcysteine (NAC) was considered. However, she continued to deteriorate and diagnostic laparoscopy found extensive carcinomatosis. Treatment was refocused towards palliation.

Table 1: Significant laboratory results. View Table 1.

Discussion

Pyroglutamic acidosis is an underdiagnosed form of HAGMA caused by excess pyroglutamate due to inhibition of negative feedback of the gamma-glutamyl cycle (Figure 1) via depletion of glutathione¹,² associated with chronic paracetamol use and certain antibiotics.[[3]]

Figure 1: The gamma-glutamyl cycle, displaying inhibition via negative feedback mechanism using glutathione. Image created on Biorender.com.

Our patient had risk factors. She was elderly with prolonged paracetamol use, sepsis, malnutrition, liver dysfunction (impairing synthesis and regeneration of glutathione) and kidney failure (preventing pyroglutamate clearance). Other risk factors for pyroglutamic acidosis include chronic alcohol excess, pregnancy and use of certain antibiotics, such as flucloxacillin, which inhibits breakdown of pyroglutamate by 5-oxoprolinase.[[2,3]]

Diagnosis requires clinical suspicion based on raised anion gap, exclusion of more common causes and the presence of relevant risk factors.[[3]] Formal diagnosis of pyroglutamic acidosis requires a urine organic acid screen.

After the appropriate respiratory compensation has been confirmed, the anion gap can be measured by subtracting measured cations from anions (AG=Na-Cl-HCO3 with reference interval of 10–14).[[4]] Serum proteins also contribute to the anion gap. Therefore, any significant change in serum albumin needs to be accounted for using the formula cAG=AG+0.25×(40-albumin in g/L).[[3]] Not doing so in a malnourished patient may underestimate the anion gap.[[3,4]] This is especially important in pyroglutamic acidosis, as malnutrition is common. This may have contributed to delayed recognition of our patient’s condition.

There can be co-existing acid base abnormalities, which are investigated using the delta gap (Δ-Δ=(ΔAG)-(ΔHCO3)). A delta gap between -5 and +5 indicates a pure HAGMA. Results outside this range suggests a concomitant acid-base disturbance.[[4]]

After confirming a pure HAGMA, other causes, such as high lactate or ketones, are excluded. The GOLDMARK mnemonic is helpful in recalling causes of a HAGMA (Table 2).[[5]]

Table 2: GOLDMARK mnemonic showing causes for a high anion gap metabolic acidosis.

Treatment involves stopping causative medications, bicarbonate administration, moderating acidosis and NAC that replenishes glutathione. Pyroglutamate is cleared renally, and dialysis has been used in severe cases.[[5,6]]

In conclusion, pyroglutamic acidosis is a rare and under-recognised cause of HAGMA that can be precipitated by prescription of simple analgesia or common antibiotics in individuals at risk. A high clinical suspicion is required to make the diagnosis and initiate targeted treatment.

Summary

Abstract

Aim

Method

Results

Conclusion

Author Information

Tom Crisp: Emergency Department Registrar, Southern District Health Board, Dunedin. Peter Sizeland: Renal Physician, Waikato District Health Board, Hamilton. Stephen Du Toit: Chemical Pathologist, Waikato District Health Board, Hamilton. Lai Wan Chan: Renal Physician, Waikato District Health Board, Hamilton.

Acknowledgements

Correspondence

Dr Lai Wan Chan, Renal Physician, Waikato District Health Board, Hamilton

Correspondence Email

Laiwan.chan@waikatodhb.health.nz

Competing Interests

Nil.

1) Fenves AZ, Kirkpatrick HM 3rd, Patel VV, et al. Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): a role for acetaminophen. Clin J Am Soc Nephrol. 2006;1(3):441-7.

2) O'Brien LM, Hooper M, Flemmer M, Marik PE. Chronic acetaminophen ingestion resulting in severe anion gap metabolic acidosis secondary to 5-oxoproline accumulation: an under diagnosed phenomenon. BMJ Case Rep. 2012 Jul 3;2012:bcrbcr0320126020. doi: 10.1136/bcr.03.2012.6020. PMID: 22761219; PMCID: PMC3391392.

3) Hunter RW, Lawson C, Galitsiou E, et al. Pyroglutamic acidosis in association with therapeutic paracetamol use. Clin Med (Lond). 2016;16(6):524-9.

4) Berend K, de Vries AP, Gans RO. Physiological approach to assessment of acid-base disturbances. N Engl J Med. 2014 Oct 9;371(15):1434-45. doi: 10.1056/NEJMra1003327. Erratum in: N Engl J Med. 2014 Nov 13;371(20):1948. PMID: 25295502.

5) Serpa MJ, Falcão L, Franco S, Repolho D, Ferreira NR. Metabolic Acidosis Due To Pyroglutamic Acid. Eur J Case Rep Intern Med. 2018 Oct 24;5(10):000949. doi: 10.12890/2018_000949. PMID: 30755980; PMCID: PMC6346886.

6) Raibman Spector S, Mayan H, Loebstein R, Markovits N, Priel E, Massalha E, Shafir Y, Gueta I. Pyroglutamic acidosis as a cause for high anion gap metabolic acidosis: a prospective study. Sci Rep. 2019 Mar 5;9(1):3554. doi: 10.1038/s41598-019-39257-4. Erratum in: Sci Rep. 2020 Aug 4;10(1):13397. PMID: 30837497; PMCID: PMC6400893.

For the PDF of this article,
contact nzmj@nzma.org.nz

View Article PDF

Pyroglutamic acidosis is a rare and underdiagnosed high anion gap metabolic acidosis (HAGMA) caused by accumulation of 5-oxoproline associated with commonly used medications such as paracetamol and antibiotics. We report a case exhibiting the common risk factors of pyroglutamic acidosis and the clinical approach to diagnosis.

Case report

A 74-year-old female presented with abdominal pain, ascites, fever and reduced appetite. Her background included cholecystectomy and Caesarean section. She was initially treated with 13 days of cefuroxime and metronidazole (which was later changed to tazocin following clinical deterioration), paracentesis and analgesia. A CT scan showed paracolic abdominal masses later confirmed as liposarcomata.

After 13 days she developed worsening kidney impairment, malnutrition and HAGMA (Table 1). Various common causes of HAGMA were excluded in the setting of normal lactate and ketones. Medication review found regular paracetamol use calculated at a dose of 76 grams over 19 days, which raised the suspicion that 5-oxoproline had accumulated and was contributing to HAGMA. Paracetamol was stopped and intravenous bicarbonate was given, with brief clinical improvement.

Urine organic acid screen, performed using gas chromatography-mass spectrometry after liquid-liquid extraction, showed marked pyroglutamate excretion (>5,000µmol/mmol creatinine). Treatment with N-acetylcysteine (NAC) was considered. However, she continued to deteriorate and diagnostic laparoscopy found extensive carcinomatosis. Treatment was refocused towards palliation.

Table 1: Significant laboratory results. View Table 1.

Discussion

Pyroglutamic acidosis is an underdiagnosed form of HAGMA caused by excess pyroglutamate due to inhibition of negative feedback of the gamma-glutamyl cycle (Figure 1) via depletion of glutathione¹,² associated with chronic paracetamol use and certain antibiotics.[[3]]

Figure 1: The gamma-glutamyl cycle, displaying inhibition via negative feedback mechanism using glutathione. Image created on Biorender.com.

Our patient had risk factors. She was elderly with prolonged paracetamol use, sepsis, malnutrition, liver dysfunction (impairing synthesis and regeneration of glutathione) and kidney failure (preventing pyroglutamate clearance). Other risk factors for pyroglutamic acidosis include chronic alcohol excess, pregnancy and use of certain antibiotics, such as flucloxacillin, which inhibits breakdown of pyroglutamate by 5-oxoprolinase.[[2,3]]

Diagnosis requires clinical suspicion based on raised anion gap, exclusion of more common causes and the presence of relevant risk factors.[[3]] Formal diagnosis of pyroglutamic acidosis requires a urine organic acid screen.

After the appropriate respiratory compensation has been confirmed, the anion gap can be measured by subtracting measured cations from anions (AG=Na-Cl-HCO3 with reference interval of 10–14).[[4]] Serum proteins also contribute to the anion gap. Therefore, any significant change in serum albumin needs to be accounted for using the formula cAG=AG+0.25×(40-albumin in g/L).[[3]] Not doing so in a malnourished patient may underestimate the anion gap.[[3,4]] This is especially important in pyroglutamic acidosis, as malnutrition is common. This may have contributed to delayed recognition of our patient’s condition.

There can be co-existing acid base abnormalities, which are investigated using the delta gap (Δ-Δ=(ΔAG)-(ΔHCO3)). A delta gap between -5 and +5 indicates a pure HAGMA. Results outside this range suggests a concomitant acid-base disturbance.[[4]]

After confirming a pure HAGMA, other causes, such as high lactate or ketones, are excluded. The GOLDMARK mnemonic is helpful in recalling causes of a HAGMA (Table 2).[[5]]

Table 2: GOLDMARK mnemonic showing causes for a high anion gap metabolic acidosis.

Treatment involves stopping causative medications, bicarbonate administration, moderating acidosis and NAC that replenishes glutathione. Pyroglutamate is cleared renally, and dialysis has been used in severe cases.[[5,6]]

In conclusion, pyroglutamic acidosis is a rare and under-recognised cause of HAGMA that can be precipitated by prescription of simple analgesia or common antibiotics in individuals at risk. A high clinical suspicion is required to make the diagnosis and initiate targeted treatment.

Summary

Abstract

Aim

Method

Results

Conclusion

Author Information

Tom Crisp: Emergency Department Registrar, Southern District Health Board, Dunedin. Peter Sizeland: Renal Physician, Waikato District Health Board, Hamilton. Stephen Du Toit: Chemical Pathologist, Waikato District Health Board, Hamilton. Lai Wan Chan: Renal Physician, Waikato District Health Board, Hamilton.

Acknowledgements

Correspondence

Dr Lai Wan Chan, Renal Physician, Waikato District Health Board, Hamilton

Correspondence Email

Laiwan.chan@waikatodhb.health.nz

Competing Interests

Nil.

1) Fenves AZ, Kirkpatrick HM 3rd, Patel VV, et al. Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): a role for acetaminophen. Clin J Am Soc Nephrol. 2006;1(3):441-7.

2) O'Brien LM, Hooper M, Flemmer M, Marik PE. Chronic acetaminophen ingestion resulting in severe anion gap metabolic acidosis secondary to 5-oxoproline accumulation: an under diagnosed phenomenon. BMJ Case Rep. 2012 Jul 3;2012:bcrbcr0320126020. doi: 10.1136/bcr.03.2012.6020. PMID: 22761219; PMCID: PMC3391392.

3) Hunter RW, Lawson C, Galitsiou E, et al. Pyroglutamic acidosis in association with therapeutic paracetamol use. Clin Med (Lond). 2016;16(6):524-9.

4) Berend K, de Vries AP, Gans RO. Physiological approach to assessment of acid-base disturbances. N Engl J Med. 2014 Oct 9;371(15):1434-45. doi: 10.1056/NEJMra1003327. Erratum in: N Engl J Med. 2014 Nov 13;371(20):1948. PMID: 25295502.

5) Serpa MJ, Falcão L, Franco S, Repolho D, Ferreira NR. Metabolic Acidosis Due To Pyroglutamic Acid. Eur J Case Rep Intern Med. 2018 Oct 24;5(10):000949. doi: 10.12890/2018_000949. PMID: 30755980; PMCID: PMC6346886.

6) Raibman Spector S, Mayan H, Loebstein R, Markovits N, Priel E, Massalha E, Shafir Y, Gueta I. Pyroglutamic acidosis as a cause for high anion gap metabolic acidosis: a prospective study. Sci Rep. 2019 Mar 5;9(1):3554. doi: 10.1038/s41598-019-39257-4. Erratum in: Sci Rep. 2020 Aug 4;10(1):13397. PMID: 30837497; PMCID: PMC6400893.

Contact diana@nzma.org.nz
for the PDF of this article

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