Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT05676346 |
| Other study ID # |
DAO-LUTS |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
October 11, 2022 |
| Est. completion date |
January 24, 2023 |
Study information
| Verified date |
February 2023 |
| Source |
Complexo Hospitalario Universitario de A Coruña |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The aim of this study is to determinate the prevalence os genetic DAO deficiency in patients
with lower urinary tract symptoms.
Description:
Lower urinary tract symptoms (LUTS) encompass different symptoms and different causes, but
their mechanism and etiology are not well defined. They have a high prevalence and cause
discomfort and alter the quality of life. It has usually been considered that they are
associated with advanced age and most scientific studies and clinical guidelines are aimed at
these patients. However, many young patients show symptoms that alter their voiding quality
of life. The etiology is multifactorial, the causes being attributed to bladder dysfunction
and its emptying; including the prostate, urethra, and sphincter; the neurological
innervation of the lower urinary tract, and medical co-morbidities. In the EPIC study, they
observed that the prevalence of LUTS increases with age, from 51% in the 18-39 age group, 62%
between 40-59 years, and up to 80% in patients older than 60 years. In young people, carrying
disorders were more common (37.5%) than voiding symptoms (19.9%)
The etiology of the symptoms in young patients has been related to overactive bladder (OAB),
benign hyperplasia (BPH), bladder neck dysfunction, urethral stenosis, drug abuse, and/or
neurological disorders. Because the underlying causes are not fully known and cannot be
reversed, most prevention advice is scarce. The clinical guidelines provide recommendations
for lifestyle changes: fluid restriction in the hours before sleep, avoiding stimulating
drinks, distraction techniques, bladder training, and pelvic floor exercises, chronic
medication review and schedule readjustment, reduction weight (in case of overweight),
treatment of constipation and adequate fluid intake during the day. Despite this, very few
patients can improve their symptoms with these recommendations. The next step of treatment
already becomes pharmacological; where alpha-blockers, anticholinergics, antimuscarinics,
betamimetics, and 5 alpha-reductase inhibitors come into action. These treatments may be
useful in certain patients, but in young people, failure is the norm, and surgery is often
required. Both therapies imply morbidity associated with the patient, who has to deal with
adverse effects, dependence on a drug for their quality of life, and the consequent economic
expense. At the health level, the cost is high; It supposes a significant consumption of
human, temporal, and economic resources, in progression due to the increasing prevalence and
aging of the population.
The enzyme diamine oxidase (DAO) is an enzyme encoded by the AOC1 gene (OMIM#104610), located
on chromosome 7 (7q-34-36). It is a secretory protein stored in vesicular structures of the
plasma membrane. It is responsible for the degradation of extracellular histamine (Novotny et
al., 1994, Chassande et al., 1994). In mammals, DAO is mainly expressed in the small
intestine and localized to intestinal villi. Reduced histamine degradation as a consequence
of low concentration or impaired activity of DAO may lead to its accumulation in plasma and
the occurrence of a wide range of adverse effects due to the ubiquitous distribution of
histamine receptors in different organs and tissues.
It is estimated that DAO deficiency affects 15% of the general population, according to
clinical practice. It may have a genetic background. In this sense, the polymorphisms of the
gene that encodes DAO have been analyzed in-depth, and more than 50 non-synonymous single
nucleotide polymorphisms (SNPs) have been identified that can alter its activity. The three
most relevant SNPs affecting Caucasian individuals and leading to a reduction in their
enzymatic activity are c.47C>T (rs10156191), c.995C>T (rs1049742), c.1990C>G (rs1049793). The
following frequencies have been described for these AOC1 variants (95% confidence interval)
among Spanish Caucasian individuals: rs10156191, 25.4% (20.16-30.58), rs1049742, 6.3% (3.42
-9.26) and rs1049793, 30.6% (25.1 -36.1).
In addition, another SNP present in the promoter region of the AOC1 gene has also been
identified, with a frequency of 41.7%, which has been associated with a decrease in DAO
transcriptional activity: c.-691G>T (rs2052129).
Austrian researchers recently analyzed the clinical manifestations expressed by patients
diagnosed with DAO deficiency. They described a wide range of symptoms involving the
gastrointestinal tract, nervous and cardiovascular systems, in addition to respiratory and
dermatological symptoms. Regarding the nervous system, in patients with a confirmed diagnosis
of migraine, DAO deficiency has a prevalence of 87%. At the same time, preliminary data have
shown a prevalence of around 77% in a pediatric cohort of Attention Deficit Hyperactivity
Disorder (ADHD) and 75% in patients with clinically diagnosed fibromyalgia. Histamine is
involved in the urinary tract, affecting not only the detrusor but also the lamina propria
and the urothelium. It causes an increase in muscle tension and the frequency and amplitude
of spontaneous contractions. Histamine has recently also been shown to affect bladder
sensation, affecting spinal sensory afferents and causing sensory urgency.
The objective of this study is to estimate the prevalence of DAO deficiency in patients with
LUTS and to explore the potential role of histamine accumulation in the pathophysiology of
these symptoms.
