Increased N-methyl histamine with eosinophilia
Question:
2/2/2020
My patient is a 25 year-old woman who is a mosaic for trisomy 14, and was sent to me by a hematologist for the evaluation of eosinophilia, from as low as 628 to as high as 1410, that had been present for at least a couple of years (we were unable to obtain CBC's for more than the last four years). Her hematology work up was negative (flow cytometry and staining for mast cells was negative for masocytosis), but was notable for moderate eosinophilia and a mild megakaryocytosis (normal morphology). She reported having a history of pollen allergy and mild asthma, none of which were active at the time of her visit. Skin testing to Northeastern aeroallergens was completely negative with good positive and negative controls, and her PFT’s were somewhat decreased, however, she was of very short stature and had scoliosis, at least some if which was related to her genetic abnormality. I sent her to pulmonary and her complete PFT’s were found to be unremarkable based on her body habitus. She has been diagnosed with sleep apnea, but no other abnormalities were noted by pulmonary with regard to her eosinophilia. Of note, she had no physical complaints at any time.
My work up included stools for O & P, C & S, and serologies for numerous parasites, serum tryptase, histamine (unlikely to be revealing). Her tryptase level was normal, 4.7 ug/L, (nl = < 11ug/L), but her serum histamine level was 13.8 ng/ml (nl = < 1.8 ng/ml). It is because of this that I ordered a 24 hour urine for 5-HIAA and n-methylhistamine, the 5-HIAA being normal but the n-methylhistamine being elevated to 1721 ug/g Cr (nl=30-200 ug/g Cr). A repeat tryptase level was also normal at 3.8 ug/ml. Chromogranin A was normal and ANCA’s were negative.
It is important to note that she has never suffered an episode of anaphylaxis and she has no complaints at this time. She has no cutaneous complaints and Dermatology was unable to find any suspicious skin lesions. Cardiology, GI, and pulmonary have found nothing abnormal in their work ups, and hematology could not explain her eosinophilia.
Of note, her mother, whose eosinophil count had always been normal, was found recently to have a eosinophil count > 4,000. She was sent to hematology but refused a bone marrow. She was evaluated by a second hematologist and it was noted that her eosinophil count had dropped to approximately 2,000, and that doctor told her that her psoriasis, which my patient does not have, was the cause of her eosinophilia, and as far as I am aware, no other work up was done.
My question is, what’s with the n-methylhistamine when there is no evidence of either cutaneous or systemic mastocytosis? I’m not really sure what to do with the information I have.
Answer:
The short answer is I would not recommend any additional evaluation of the increase in urinary histamine and no other evidence of mastocytosis or other mast cell disorder. The most common cause of eosinophilia in my experience is secondary to medication so would review medications, particularly NSAIDs, to determine if any may be related to eosinophilia. The medication would not explain the increased N-methyl histamine. There are reports of bacteria in the urogenital or gastrointestinal tract being associated with an increase in urinary histamine metabolites, but this has not been well confirmed (1). The role of histamine clearance in the development of systemic symptoms is also unclear (2). Diets with reduced histamine and supplementation with diamine oxidase to enhance histamine metabolism are completely unproven but of low risk.
Increased eosinophil blood counts above 1500/uL could be associated with hypereosinophilic syndrome. Evidence of tissue infiltration and adverse effects would be expected if this is the case. I would suggest cardiac ultrasound and troponin to be confident of the absence of eosinophilic carditis. I would consider measuring FIP1L1-PDGFR as this would indicate a greater risk of eosinophilic disease and possibly cardiac involvement (3). If these are negative and no medications can be associated with the increase in blood eosinophils, I would reassure the patient and repeat the CBC periodically to further reassure you and the patient that the eosinophil number is not a significant health risk. If any of these are positive, would attempt again to get a bone marrow.
In summary, I do not think the increase in urinary N-methylhistamine warrants additional studies with a negative bone marrow. I would consider discontinuing any medications, including NSAIDs, to be sure the eosinophil increase is not related to medication. I would obtain a cardiac troponin, cardiac ultrasound and possibly a FIP1L1-PDGFR. If all negative would follow for symptoms and repeat blood eosinophil counts but no additional testing unless symptoms develop.
1. Influence of decontamination of the digestive tract on the urinary excretion of histamine and some of its metabolites. Keyzer JJ, van Saene HK, van den Berg GA, Wolthers BG
Agents Actions. 1984;15(3-4):238.
Urinary excretions of histamine, N tau-methylhistamine and N tau-methylimidazoleacetic acid have been determined for 8 healthy volunteers during 14 consecutive days. Selective decontamination of the digestive tract was performed from day 3 to day 6, followed by total decontamination from day 7 to day 10. Urinary excretions of N tau-methylhistamine and N tau-methylimidazoleacetic acid decreased to a small though significant degree (about 15-20%) after total decontamination, suggesting a histamine production by anaerobic bacteria. Cadaverine decreased for about 70% under both selective and total decontamination, suggesting that this amine in human urine mainly originates from aerobic bacteria in the intestinal tract.
2. Constitutive hyperhistaminaemia: a possible mechanism for recurrent anaphylaxis.
Hershko AY, Dranitzki Z, Ulmanski R, Levi-Schaffer F, Naparstek Y
Scand J Clin Lab Invest. 2001;61(6):449.
The process underlying anaphylaxis involves an uncontrolled elevation in blood levels of mediators, including histamine. Usually, these abnormal levels are attributed to the degranulation of basophils and mast cells. Few reports have assessed the contribution of defects in histamine pharmacodynamics to allergic responses. In this report we describe a patient with recurrent anaphylaxis who was initially suspected to have enhanced histamine intolerance. We evaluated urine and blood samples collected from this patient and from control individuals using an ELISA test. Our data clearly show constitutive hyperhistaminaemia and a markedly impaired urinary histamine clearance ratio in the index patient. It is suggested that this defect facilitates
anaphylaxis.
3. The Spectrum of FIP1L1-PDGFRA-Associated Chronic Eosinophilic Leukemia: New Insights Based on a Survey of 44 Cases.
Legrand F, Renneville A, Macintyre E, Mastrilli S, Ackermann F, Cayuela JM, Rousselot P, Schmidt-Tanguy A, Fain O, Michel M, de Jaureguiberry JP, Hatron PY, Cony-Makhoul P, Lefranc D, Sène D, Cottin V, Hamidou M, Lidove O, Baruchel A, Dubucquoi S, Bletry O, Preudhomme C, Capron M, Prin L, Kahn JE, on behalf of the French Eosinophil Network
Medicine (Baltimore). 2013;
Imatinib is the treatment of choice for FIP1L1/PDGFRA (F/P)-associated chronic eosinophilic leukemia (F/P CEL), but its optimal dosing, duration, and possibility of discontinuation are still a matter of debate. A retrospective multicenter study was conducted with 44 F/P CEL patients identified in the French Eosinophil Network and treated with imatinib. The most frequently involved systems were skin (57%), spleen (52%), and lung (45%), and eosinophilic heart disease was observed in 15 patients (34%). Complete hematologic response (CHR) was obtained in all patients, and complete molecular response (CMR) in 95% of patients (average initial imatinib dose, 165 mg/d). For 29 patients the imatinib dose was tapered with a maintenance dose of 58 mg/d (±34 mg/d), allowing sustained CHR and CMR. None of the patients developed resistance during a median follow-up of 52.3 months (range, 1.4-97.4 mo). Imatinib was stopped in 11 patients; 6 of the patients subsequently relapsed, but 5 remained in persistent CHR or CMR (range, 9-88 mo). These results confirm that an initial low-dose regimen of imatinib (100 mg/d) followed by a lower maintenance dose can be efficient for obtaining long-term CHR and CMR. Our data also suggest that imatinib can be stopped in some patients without molecular relapse.
I hope this information is of help to you and your practice.
All my best.
Dennis K. Ledford, MD, FAAAAI