Increased plasma histamine is not of value in making a diagnosis as an isolated finding. The short half-life of histamine limits the utility of measuring plasma histamine. Usually, urinary metabolites are utilized as confirming an increase in histamine release (see Ask the Expert question below). Histamine is produced by a variety of cells but primarily mast cells and basophils. The increase in eosinophil number, which I assume is 4400/uL, might suggest a hypereosinophilic syndrome if parasitic disease is excluded. You do not provide details as to why the plasma histamine was checked other than urticaria. I am not aware of any autoimmune syndrome associated with histamine, other than histamine release from mast cells or basophils with autoimmune urticaria. However, I would not expect eosinophilia with this form of urticaria.
Histamine blood levels are increased in polycythemia vera and chronic myelogenous leukemia, which could be related to a hematologic form of hypereosinophilia (1,2). A pruritic papule eruption, but not urticaria, has also been reported with chronic myelogenous leukemia and eosinophilia (3).
In summary, I would focus on the evaluation of the elevated eosinophil number. Since the total IgE is not increased, I doubt that the eosinophilia is related to parasitic disease. I agree with skin biopsy but would strongly consider consultation with a hematologist. Although you can obtain markers for hematologic eosinophilia in the peripheral blood, the expertise of the hematologist will likely be necessary. I do not think the histamine blood level is specifically related to the urticaria.
I hope this information is of help to you and your practice.
All my best.
Dennis K. Ledford, MD, FAAAAI, FACAAI
1. Westin, Jan, et al. "Histamine metabolism in polycythaemia vera." Scandinavian journal of haematology 15.1 (1975): 45-57.
2. Berg, Bertel, et al. "Urinary excretion of histamine and histamine metabolites in leukaemia." Scandinavian journal of haematology 8.1 (1971): 63-68.
3. Brydon, Jan, Paul A. Lucky, and Thomas Duffy. "Acne urticata associated with chronic myelogenous leukemia." Cancer 56.8 (1985): 2083-2086.
8/10/2018: Increased urinary histamine with urticaria and question of mast cell disorder
My question regards mast cell activation disorder and diagnosis. I have several patients who have problems with chronic idiopathic urticaria, multiple chemical sensitivity type of symptoms, reactions to multiple medications and only elevated 24 hour urine histamines (prostaglandin and leukotriene normal). Can I say they have a mast cell activation disorder, or am I missing something else?
Example:
37 YOF, mid-March 2017 she was in her usual state of health, getting her kid ready for school in the morning, before eating/drinking anything yet, she suddenly felt chest tightness, shortness of breath. Her husband took her to ER and she was treated for an asthma exacerbation. She had felt perfectly fine the day/evenings before and denies any h/o breathing problems prior to that morning.
Subsequently she was prescribed singular on April 6, 2017 and went into anaphylactic shock within 5 minutes, describing sensation of shortness of breath, wheezing, hives which led to her husband calling EMS. She recalls being treated with epinephrine and 5 albuterol nebs and steroids. Then on April 9 she had recurrence of her symptoms (after she ate a piece of lamb and potato) despite being on 50 mg of prednisone, leading her to give self epi injection and get back to the ER for further treatment.
She continues to have various symptoms, most of the time hives and episodes of chest tightness, heart palpitations.
Triggers include strong odors, some foods, and sometimes exposure to the sun. She reports hives/respiratory sx with multiple medications containing dyes first noticed around February time frame. (Strong odors resulting in rashes, respiratory symptoms.) She went on a very limited diet, high dose AH, bid Zantac, without any significant improvement in symptoms; frequent allergic type reactions.
Started Xolair 300 mg 4wks in September 2017, this initially resulted in decreased frequency of hives, diarrhea. as well as improve her tolerance to odors, ie she can now spend more time outdoors w/o any problems, and husband can now cook indoors. However over time Xolair seems to be losing efficacy with increased/worsening hives/allergic reactions again.
Also taking for sx (meds compounded so no fillers added)
cetirizine 30 mg/day
Ketotifen 1 mg Tid
ranitidine bid
She will add Benadryl, albuterol neb to control flares (up to several times a week); occasionally prednisone and epinephrine to control her flares (she has not required epinephrine since May 2017).
TESTING
6/ 2017
normal 24 hour urine prostaglandin F2 (1529, with nl <5205) and D2 at <20 nl/l
HIGH 24 urine histamine at 1.528 (normal range 0.006-0.131)
Normal serum tryptase (3)
Normal alpha gal IgE ab
neg immunocap pork, chicken, beef, lamb
8/2017
negative immunocap to environmental allergens as well as rice, wheat, soybean, peanut, milk, egg
1-2/2018
normal AM cortisol
normal Vitamin B12 and folate
Vitamin D low at 22.5 (since repleted)
Normal tsh
Normal total serum protein
negative lyme IgG and IgM ab titers
CBC: normal wbc, hct, plts. 74% segs (high), 19% lymph (low)
tryptase 3
Normal SPEP
7/2018
Normal 2,3 dinor 11b prostaglandin
normal leukotriene E4
24 hour urine histamine elevated at 2.871 (nl 0.06-0.131)
The simple answer is no, your patients do not have mast cell activation disorder or other described mast cell disorder. It might help to know if the urinary histamine metabolites increase during acute symptoms but even with that information I do not think you could conclude this is a mast cell disorder.
There are multiple publications related to the diagnosis of mast cell disorders, mast cell activation and anaphylaxis (1,2). Urinary histamine assays may be used to support other clinical and laboratory information in the diagnosis of a mast cell activation event or disorder, but this assay generally is not accepted as independent evidence of mast cell activation or disorder. Urinary levels of prostaglandins and histamine metabolites correlate with bone marrow findings in mastocytosis (3). However, histamine assays are fraught with pitfalls, making the information of limited value in most situations (4). Urinary histamine metabolites are reported as an isolated finding in idiopathic histamine intolerance (5). This condition is controversial, generally associated with gastrointestinal symptoms, is attributed to a decrease in diamine oxidase and improves with a reduced-histamine diet (6).
In summary, in my opinion an isolated finding of increased urinary histamine metabolites does not independently diagnose a mast cell disorder. Histamine intolerance or decreased capacity to metabolize histamine as a cause of symptoms is controversial. You may want to try high dose daily antihistamine therapy to evaluate clinical response in light of the increase in histamine metabolites. This would be dosed as the chronic urticaria guidelines suggest, up to four times the approved dose of a second or third generation antihistamine. I would not recommend bone marrow biopsy with this information unless new symptoms or findings develop.
1. Valent, Peter, et al. "Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: consensus statements and report from a working conference." Leukemia research 31.6 (2007): 727-736.
2. Valent, Peter, et al. "Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal." International archives of allergy and immunology 157.3 (2012): 215-225.
3. Divekar, R., and J. Butterfield. "Urinary 11β-PGF 2α and N-methyl histamine correlate with bone marrow biopsy findings in mast cell disorders." Allergy 70.10 (2015): 1230-1238.
4. Early biological markers of anaphylactoid reactions occurring during anesthesia
Laroche D, Dubois F, Lefrançois C, Vergnaud MC, Gérard JL, Soufarapis H, Sillard B, Bricard H Ann Fr Anesth Reanim. 1992;11(6):613.
Three markers of in vivo histamine release, i.e. plasma histamine and tryptase, and urinary methylhistaminewere assessed using sensitive radioimmunoassays in 18 patients who had experienced an adverse reaction to an anaesthetic agent. Controls were obtained from 35 patients following a general anaesthetic, which included a muscle relaxant, and who remained free from any adverse reaction. A first blood sample was obtained from all 18 patients a mean 25 +/- 26 min after the reaction, and a second one in thirteen a mean 120 +/- 65 min after the reaction. Ten patients had had a life-threatening reaction. Plasma histamine levels were increased in all these cases, and tryptase concentrations in 9 out of 10. Urinary methylhistamine rarely reached pathological levels (4 out of 10). Skin tests were positive in the four tested patients. Plasma histamine concentration was still high in 8 cases thirty minutes after the reaction, and remained increased for more than 2 h in two patients. Among the other eight patients with a moderate reaction, 3 had high histamine levels, with normal or weakly increased tryptase concentrations, and normal urinary methylhistamine. Two of these patients had positive skin tests. There were no abnormal findings in any of the investigations carried out in the other five patients, except for a slightly positive skin test to atracurium in one patient. Plasma histamine had a higher sensitivity than tryptase levels. Methylhistamine concentrations were only rarely of interest. There were no false positives with the three investigated markers.
5. Comas-Basté, Oriol, et al. "New approach for the diagnosis of histamine intolerance based on the determination of histamine and methylhistamine in urine." Journal of pharmaceutical and biomedical analysis 145 (2017): 379-385.
6. Lackner, Sonja, et al. "Histamine-reduced diet and increase of serum diamine oxidase correlating to diet compliance in histamine intolerance." European journal of clinical nutrition (2018): 1.
I hope this information is of help to you and your patient.
All my best.
Dennis K. Ledford, MD, FAAAAI
