A case series of diamine oxidase deficiency misdiagnosed as anxiety or panic attacks in patients with tachycardia

Abstract

Background:

Diamine oxidase (DAO) deficiency, a key marker of histamine intolerance (HIT), often mimics anxiety or panic disorders, leading to a misdiagnoses and delayed treatment.

Cases:

We present five female patients (aged 25–54) with chronic, non-specific symptoms, including palpitations, nasal congestion, and gastrointestinal disturbances, initially attributed to the anxiety. Serum DAO levels below 10 IU/mL confirmed HIT in all cases. Treatment with a low-histamine diet and DAO supplementation significantly improved symptoms, highlighting the importance of considering HIT in such cases. One patient experienced recurrence after discontinuing treatment, emphasizing the need for long-term management. Genetic testing in one case revealed variants linked to reduced DAO activity, suggesting a potential genetic predisposition.

Conclusion:

These findings underscore the importance of DAO level assessment in patients with unexplained symptoms and the role of multidisciplinary care in accurate diagnosis and management. Further studies are needed to refine diagnostic criteria and explore long-term strategies for HIT.

INTRODUCTION

Histamine, involved in allergic disease pathogenesis, is both endogenously produced and exogenously ingested. Diamine oxidase (DAO) is the key enzyme responsible for degrading exogenous histamine in the intestine. DAO deficiency leads to histamine accumulation and histamine intolerance (HIT), which manifests as skin itching and redness, nasal congestion, postnasal drip, nausea, vomiting, hypotension, palpitations, diarrhea, headache, and ocular symptoms.[1,2] Histamine, through H2 receptor binding, has positive inotropic and chronotropic effects on the heart.[3] DAO deficiency is estimated to affect 1%–3% of the general population, with higher prevalence among women.[4] Nevertheless, HIT often goes undiagnosed and is frequently misattributed to psychiatric disorders such as panic attacks or anxiety. A pilot cross-sectional study showed that patients with anxiety disorders had a higher incidence of histamine intolerance, suggesting a link between the low DAO activity and psychiatric symptoms.[5]

CASE PRESENTATİONS

Case 1

A 40-year-old woman presented with sneezing, postnasal drip, chest tightness, pruritus, fatigue, and palpitations. Alcohol triggered vomiting and hypotension. She also experienced bloating after eating shrimp and had softer stools. Her only relevant history was thalassemia minor. Cardiac evaluation revealed no abnormalities, and she was diagnosed with anxiety.

Her frequent air travel and fear of flying reinforced this diagnosis. Propranolol was prescribed, but she developed widespread urticaria after the first dose and required emergency treatment. DAO level was 8.9 IU/mL. A low-histamine diet and DAO supplementation significantly improved symptoms. Her fear of flying persisted, likely representing a separate phobia rather than HIT.

Case 2

A 25-year-old woman presented with persistent postnasal drip, throat irritation, sneezing (triggered by sunlight), nasal discharge and congestion, occasional dyspnea, and frequent palpitations. She also reported gastrointestinal symptoms, including diarrhea after consuming fast food and chocolate.

She had gallbladder polyps, PCOS, and rosacea. During palpitations, her heart rate reached 140 beats per minute (bpm), and blood pressure was typically low (90/60 mmHg). A full cardiac evaluation was normal. Anxiety was suspected. DAO level was 10.3 IU/mL. Upon starting a low-histamine diet and DAO supplementation, she experienced increased energy and decreased fatigue, sneezing, and palpitations. However, inconsistent adherence to the regimen corresponded with declining energy levels.

Case 3

A 54-year-old woman presented with nasal congestion, nausea, and palpitations that occasionally awoke her at night. Her heart rate sometimes reached 180 bpm, and blood pressure was consistently low. Panic attacks were previously diagnosed. Her history included ovarian dermoid cyst removal and Ménière’s disease.

DAO level was 9.9 IU/mL. Genetic testing showed heterozygosity for rs2052129 and rs10156191. A low-histamine diet and DAO supplementation led to improved allergic symptoms and near-resolution of palpitations.

Case 4

A 45-year-old woman presented with postnasal drip, a sensation of head heaviness, and palpitations. She had low blood pressure and a history of panic attack diagnoses in 2018 and 2021. Multiple evaluations by neurologists, cardiologists, and psychiatrists revealed no significant pathology.

Her medical history included subacute thyroiditis, gastroesophageal reflux disease (GERD), vocal cord cyst surgery, breast implants, chondromalacia patella, and vitamin B12 deficiency. DAO level was 7.4 IU/mL. Following a low-histamine diet and DAO supplementation, she experienced significant symptom relief.

Case 5

A 26-year-old woman presented with clear nasal discharge, sneezing, mild cough, sputum, skin rashes on her arms, pruritus, and palpitations. Her heart rate occasionally reached 140 bpm at rest.

Cardiology work-up, including echocardiography and Holter monitoring, was unremarkable. She was diagnosed with anxiety. DAO level was 5.6 IU/mL. A 2-month course of low-histamine diet and DAO supplementation led to complete symptom resolution. Symptoms recurred 3 weeks after discontinuation, prompting renewed dietary intervention and supplementation. DAO levels were not re-tested.

DISCUSSION

These five cases illustrate the multisystemic presentation of HIT, including dermatological (pruritus, rashes), gastrointestinal (nausea, bloating), cardiovascular (palpitations), and respiratory symptoms (postnasal drip, nasal congestion). Symptoms were frequently misattributed to anxiety or panic disorders. One patient underwent multiple evaluations (cardiology, neurology, psychiatry) without a clear diagnosis. This diagnostic uncertainty emphasizes the importance of considering HIT in patients with persistent, unexplained symptoms and low DAO levels.[6]

DAO testing was not arbitrary but triggered by recurring symptoms unresponsive to conventional psychiatric or cardiac management. All patients experienced persistent symptoms, including postprandial palpitations, flushing, nasal congestion, and GI upset. Notably, many symptoms were temporally associated with food intake, suggesting dietary histamine as a trigger. These clinical features, along with previous clinical experience, prompted DAO testing.

DAO is produced in the small intestine and degrades dietary histamine. Reduced DAO activity can result in histamine accumulation, leading to systemic symptoms. Levels under 10 IU/mL are often associated with significant HIT symptoms.[7]

HIT is more prevalent in women, potentially due to hormonal effects on DAO. Estrogen, which fluctuates during menstruation, pregnancy, or with hormonal contraceptives, may potentially suppress DAO activity.[8] All patients in this series were women, supporting this proposed hormonal influence.

Although DAO testing is not standard in clinical protocols, it should be considered in patients—especially women—with unexplained, recurrent somatic symptoms, such as palpitations, flushing, or GI issues, particularly when temporally associated with meals and unresponsive to conventional treatments.[9]

Psychiatric assessments were not dismissed. All patients were previously evaluated for anxiety. In some cases, SSRIs or benzodiazepines were recommended. These were either refused due to side effect concerns or discontinued having no significant benefit. In one case, propranolol induced a hypersensitivity reaction, prompting further diagnostic exploration. The combination of food-triggered symptoms, treatment resistance, and the lack of clear psychiatric pathology strengthened the rationale for DAO testing.

The patients all improved with a low-histamine diet and DAO supplementation, consistent with evidence suggesting dietary intervention is central to HIT management.[10] One patient experienced symptom recurrence after discontinuing the diet and supplements, highlighting HIT’s chronic nature and the necessity for long-term management.

One case showed heterozygosity for rs2052129 and rs10156191 genetic variants, which are associated with reduced DAO activity. This supports the idea of a genetic predisposition in HIT. Comorbidities such as rosacea, GERD, and Ménière’s disease—also observed in our cases—are frequently linked to histamine dysregulation and may warrant further study.[11]

A multidisciplinary approach is vital in patients with chronic, non-specific symptoms. HIT should be considered, particularly when standard psychiatric or cardiologic workups fail to explain palpitations, dizziness, or GI issues. Assessing DAO activity, along with dietary and pharmacologic interventions, can lead to improved outcomes.

A stepwise clinical pathway [Figure 1] is suggested for suspected HIT related to DAO deficiency—starting from symptom assessment and diagnostic work-up to therapeutic interventions. Table 1 outlines the clinical distinctions between HIT and primary anxiety disorders, including symptom triggers, response to therapy, and laboratory markers.

Figure 1.

Clinical decision-making algorithm for suspected histamine intolerance related to diamine oxidase (DAO) deficiency. The flowchart outlines the stepwise evaluation process, including the assessment of unexplained symptoms, exclusion of organic pathology, consideration of dietary and medication history, and measurement of serum DAO levels. Management recommendations are provided based on test results

Table 1.

Comparison between histamine-related organic symptoms and primary anxiety disorders

Feature	Histamine Intolerance (Organic Etiology)	Primary Psychiatric Etiology
Symptom Triggers	Frequently meal-related (fermented foods, alcohol, aged cheese, etc.)	Unrelated to food intake; often situational or stress-induced
Onset of Symptoms	Typically, within 30–90 min after food ingestion	Often spontaneous or gradual onset
Symptom Profile	Palpitations, flushing, bloating, vomiting, diarrhea, skin rashes, nasal congestion, postnasal drip, hypotension, headache	Palpitations, restlessness, hypervigilance, fear-based thoughts
Psychiatric History	Usually, absent	Often present (e.g., generalized anxiety disorder, panic disorder, trauma history)
Response to Psychotropic Medication	Poor or none; sometimes adverse reactions (e.g., beta-blocker intolerance)	Typically responsive to SSRIs, benzodiazepines
Response to DAO-targeted Intervention	Frequently shows improvement with dietary changes and/or DAO support	No effect
Laboratory/Clinical Indicators	Low DAO levels, symptom correlation with histamine-rich food	No specific biomarker

DAO=Diamine oxidase

To enhance diagnostic accuracy and patient care, future research should focus on refining HIT diagnostic criteria, validating DAO testing, and evaluating long-term treatment strategies.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.