Spectrum, Time Course, Stages, and a Proposal for the Diagnosis of Histamine Intolerance in General Practice: A Nonrandomized, Quasi-Experimental Study

Abstract

Background/Objectives: Limited research has explored histamine intolerance from the perspective of primary caregivers. Our objective was to develop a practical symptom profile from the standpoint of general practice. We also aimed to gather data on the frequency and timing of disease progression and to establish a staging system. Methods: This study utilized a nonrandomized, quasi-experimental design. An in-depth interview was conducted with 217 patients involving 120 questions. To evaluate associations between food intake and symptoms, we recommended either an exclusion diet or a low-histamine diet. A follow-up questionnaire was subsequently administered. We also analyzed 3831 doctor-patient meetings involving upper respiratory symptoms. Results: Symptoms in 77 patients were associated with histamine-rich meals. The most characteristic symptoms included respiratory symptoms (95%), bloating (94%), headache (91%), fatigue (83%), postprandial drowsiness (81%), skin symptoms (81%), diarrhea/loose stool (77%), psychological symptoms (77%), dyspepsia (69%), and muscle/eyelid twitching (61%). Patients with suspected histamine intolerance visited primary care three times more often with upper respiratory symptoms than those without suspected histamine intolerance. The symptom spectrum of histamine intolerance involves multiple organ systems and occurs in distinct, repeating patterns. Symptoms can be described by their duration, sequence, and severity level, which is the key focus of this research, including visual representations. In its most severe stages, histamine intolerance may potentially involve mast cell activation. A personalized diet is associated with a gradual reduction in both the intensity and frequency of symptoms. Conclusions: The spectrum of histamine intolerance can be characterized by specific symptom patterns with defined frequencies, timelines, and symptom stages.

Keywords: histamine; histamine intolerance; mast cell activation syndrome (MCAS).

Figure 1

Symptom spectrum of histamine intolerance. The chart was constructed on the basis of various symptom combinations patients encountered, where frequency and severity scores aid in the description and identification of recurring events. Symptoms can be categorized into stages along the severity axis and chronological occurrences along the time axis. In some of these cases, symptoms worsen with the consumption of offending food until they reach an individual breaking point.

Figure 2

Stages of the most common immediate symptoms of histamine intolerance, organized by severity. The symptoms gradually unfold in a stepwise manner. Each succeeding stage may also include the previous stages. Stages 3B and 4 suggest a tendency toward generalization, with the associated symptoms persisting for a more extended period. An individual may experience various levels of severity after different meals. When a low-histamine diet is applied, patients become symptom-free or symptoms significantly diminish to lower levels.

Figure 3

Timeline of immediate symptom development in patients with histamine intolerance following a single meal. Symptoms after a single meal likely correspond to the progression of food through the digestive system, beginning with upper respiratory issues, followed by gastrointestinal symptoms, and concluding with general and neurological complaints. The average time elapsed until the onset of symptoms in patients with histamine intolerance was 1.1 h (SD = 0.9, n = 63). The timeline is influenced by both the specific food matrix and the quantities consumed. It complicates recognition that a specific symptom does not always occur at the same time; nonetheless, a characteristic sequence can be observed.

Figure 4

Timelines of potential manifestations associated with histamine intolerance over the course of several days. The timelines were created via personal symptom descriptions gathered from patient interviews as well as from food and symptom diaries. The symptom severity score, frequency score, and duration reports contributed to the development of the charts. Symptoms either appear or worsen after meals. Eighty percent (n = 36) of confirmed patients experienced at least three different types of timelines. Isolated episodes with differing intensities (Timeline 1), episodes marked by moderately extended symptoms (Timeline 2), persistent symptoms with intermittent flares (Timeline 3), and severe, prolonged attacks with full-scale symptoms and possible mast cell activation (Timeline 4) are included. As patients begin to implement a low-histamine diet, they gradually move from the more severe end of the spectrum (Timeline 3–4) toward the milder end (Timeline 1) or experience no symptoms.