Two patients diagnosed with hereditary angioedema in Pinar del Río

INTRODUCTION

HAE is a rare disease with autosomal dominant inheritance that can be fatal if not treated in time.(1,2,3,4) It is clinically characterized by recurrent episodes of inflammation affecting the subcutaneous tissues, the gastrointestinal tract, and the oropharyngeal area.(5,6) Genetic mutations are the most common genetic cause of HAE and are observed in more than 90 % of patients. To date, more than 700 mutation variants have been described.(2,3,4)

Three types are recognized: HAE types I and II, which involve mutations in the C1NH (SERPING1) gene,(7) which encodes the C1 inhibitor protein, while in HAE type III, several mutations have been described, the best known of which involves mutations in the F12 gene, which encodes coagulation factor XII (Hageman factor). The three types of HAE share a common final pathway that leads to increased bradykinin formation.(6,8,9) It is estimated that one in every 10,000 to 50 000 individuals is affected, although the number of unknown cases is probably much higher. In Europe, it is estimated that there were around 75 000 people affected in 2009, of whom only 45 % were correctly diagnosed.

When episodes are not diagnosed, they lead to suspected diagnoses such as acute abdomen, and patients undergo unnecessary surgical procedures. Upper airway edema, which frequently affects the pharynx, uvula, and larynx, is less common but is the most dramatic event for these patients.

It was initially called Quincke's edema, after Heinrich I. Quincke, who published the first detailed description in 1882, after observing the condition in two generations of the same family. Three years later, Strubing first used the term angioedema to refer to this disorder, and by 1888, Osler demonstrated its hereditary nature.(11)

It has also traditionally been called angioneurotic edema, because one of the manifestations of the disease, unexplained abdominal pain, led to the assumption that it was caused by a nervous disorder.(11,12)

More than 125 years after Osler recognized the hereditary nature of HAE, the heterogeneity of its clinical manifestations, the genetics of this disorder, and the genotype-phenotype relationships still represent a challenge for the attending physician.(9)

With the aim of reviewing the clinical presentation, diagnosis, and treatment of two patients with hereditary angioedema in Pinar del Río, we intend to provide essential tools that contribute to improving clinical diagnosis and knowledge of the disease, and allow for improved prognosis and evolution of these patients, as well as a reduction in the risk of death, in an approach to personalized medicine and evidence-based medicine.

CASE REPORT

Patient 1

A 31-year-old male patient with a history of recurrent edema beginning at the age of 4, presenting with abdominal colic attacks accompanied by vomiting lasting approximately 4 days, as well as edema in the upper and lower limbs treated with steroids and antihistamines with clinical improvement after 72 hours. He had two episodes of glottis edema. He was treated by several specialists, including gastroenterologists and allergists, and almost underwent surgery due to signs of acute abdomen.

There was no family history of angioedema symptoms.

Diagnostic tests showed decreased plasma C4 levels (0,063 g/L) and low C1-INH antigen, confirming the diagnosis of type 1 HAE.

He was treated with danazol and tranexamic acid.

Patient 2

28-year-old male patient with a history of recurrent edema on the soles of the feet and toes, beginning in childhood, accompanied by episodes of pain. At age 18, he began to develop edema in his knees, testicles, upper and lower limbs, for which he was treated by several specialists, including gastroenterology, orthopedics, rheumatology, and urology, without obtaining a definitive diagnosis.

He has a family history of angioedema symptoms.

Diagnostic tests showed decreased plasma C4 levels, confirming the diagnosis of HAE.

He received treatment with danazol.

DISCUSSION

Hereditary angioedema is commonly subclassified into three types, all of which are virtually indistinguishable clinically and largely driven by bradykinin.(13)

Type I HAE presents with a C1-INH deficiency and accounts for 85 % of cases, type II presents with a dysfunctional C1-INH and accounts for 15 %, and type III is generally estrogen-dependent or hereditary angioedema with normal C1-INH activity and accounts for a very small percentage of cases. The three types of HAE behave similarly and present with similar symptoms.(14)

HAE is largely mediated by the proinflammatory mediator bradykinin and results from a deficiency in the acute phase reactive C1 inhibitor protein produced in the liver.(13) The C1 inhibitor protein minimizes the activation of C1r, C1s, MASP 1, and MASP 2, thereby inhibiting the complement system. Low or non-functional levels of C1 inhibitor protein allow unrestricted complement activity, facilitating vascular permeability and edema.(3,13,16)

In addition, C1 inhibitor protein inhibits plasma kallikrein, the enzyme involved in the conversion of high molecular weight kininogen (HMWK) to bradykinin. Low levels of C1 inhibitor allow plasma kallikrein levels to rise, subsequently increasing bradykinin levels.(15) Plasma kallikrein increases the active form of factor XII, factor XIIa, which feeds back positively to facilitate the conversion of prekallikrein to kallikrein, facilitating the production of bradykinin, which is responsible for many of the symptoms in patients with HAE, as it acts on endothelial contraction, nociceptor activation, and bronchoconstriction, explaining the edema, pain, and dry cough typical of HAE presentation.(3,13,16)

The third type of angioedema is an extremely rare subclass that was only described at the beginning of the second millennium. Although the pathophysiological mechanism has not been fully elucidated, it is strongly associated with increases in estrogen levels and, consequently, is called estrogen-dependent HAE. It occurs more frequently in women and has been shown to initiate the onset and/or exacerbate symptoms in pregnant patients or users of hormonal contraceptives.(1)

The clinical manifestations of HAE include sudden onset of swelling around the eyes, face, and extremities; abdominal pain (as a result of intestinal edema); and laryngeal edema causing hoarseness, difficulty breathing, and occasionally death.(16,17)

In addition to clinical symptoms, the age of onset of symptoms is also taken into account when diagnosing the disease. Most patients with HAE present symptomatic cases before the age of 20. However, it is rare for the disease to present in young children, as they are often asymptomatic.(18)

In 50 % of cases, clinical manifestations generally begin before the age of 10, with symptoms increasing during puberty and then again in the third decade of life. In 20-25 % of patients with HAE, there is no family history.(6)

In most cases, episodes of acute angioedema last between 2 and 5 days and resolve spontaneously without medical intervention.(18)

Cutaneous edema is characterized by recurrent inflammation without urticaria, i.e., it does not cause hives, is not itchy or painful, and does not cause a rise in temperature.(19)

An increase in the incidence of autoimmune diseases (12 %) has been reported in patients with HAE, the most common being arthritis, glomerulonephritis, and inflammatory bone diseases.(6,20)

Some attacks may have a previous trigger, but often many attacks have no trigger.(9)

While triggers vary for each patient, the most common may include trauma, medical procedures, stress, oral contraceptives (estrogens), infectious processes, and ACE inhibitors. In addition, patients have different levels of disease response to the same triggers.(21)

Several disorders can manifest with subcutaneous or submucosal swelling. The presence of severe swelling can be confused with an allergic reaction or an acute abdominal condition. Misdiagnosis can lead to ineffective therapies and unnecessary surgery.(22,23)

Since the symptoms of acute episodes are similar to those of more common diseases, such as allergic angioedema or, in the case of abdominal attacks, appendicitis, an important clue is the lack of response of edema to antihistamines or cortisone preparations, which allows for a differential diagnosis from allergic reactions. The diagnosis is most difficult in patients who experience episodes exclusively in the digestive tract.(20)

It would also be important to differentiate the diagnosis from other causes of acquired angioedema, such as immune complex diseases.(6)

To diagnose HAE, a thorough interview and physical examination must be performed. The necessary complementary tests will be carried out for a definitive diagnosis, including quantification of C1-INH, C2, and C4, as well as determination of the functional activity of C1-INH proteins in cases excluded from the diagnosis of type I HAE. To diagnose type II, if the possibility of acquired angioedema (AEA) is reconsidered, it is necessary to quantify C1q, as this is only altered in these cases.(20)

Treatment must be defined according to the patient's clinical condition. In the chronic phase of the disease, i.e., between attacks, it is necessary to know whether or not the patient is using prophylactic medication to prevent attacks.(6)

In the prophylaxis phase, the basic treatment is mainly the use of attenuated androgens such as Danazol or Stazonolol and antifibrinolytics such as tranexamic acid and epsilon aminocaproic acid, all taken orally. In the case of acute attacks, it is necessary to individualize and personalize each case, as well as to define the use of one or another medication according to the intensity and location of the angioedema; in severe cases, the use of plasma C1 inhibitor, marketed under the name Berinert-500, is required. Subcutaneous epinephrine in divided doses may be used, but its effect is limited.(24)

The age of onset for both patients was in childhood with characteristic clinical manifestations; however, the most severe case was patient 1, who developed laryngeal edema on two occasions.

The course of the disease tends to be more severe in patients with early onset of symptoms.(16) The literature suggests that in a subset of HAE, which is more dependent on the patient's clinical presentation, there are identifiable clinical symptoms, normal laboratory values (including C1-INH), a positive family history, and a known failure of treatment with chronic high-dose antihistamines; clinical findings are more predictive and diagnostic for the disease, and the combination of these different factors may help establish a diagnosis of HAE with normal C1-INH levels.(25) However, despite the typology of the disease, the clinical manifestations are practically identical in all of its variants, and no correlation has been found between the different genetic and clinical forms of the disease, as it is characterized by great allelic heterogeneity, demonstrating that each carrier family has its own genetic defect, as well as poor genotype-phenotype correlation,(26) There are more than 500 different alterations of SERPING 1, distributed throughout all the exons of the gene.(18)

The diagnosis was based on the determination of C4 and C1 INH antigenic and functional levels.

C4 (Patient 1 (0,063 g/L), Patient 2 (0,053 g/L))

C1-INH was low in patient 1 and not tested in patient 2.

C4 levels correlate with quantitative and qualitative values of C1-INH, so they are a good diagnostic test for HAE on their own, but not for the type of angioedema where it is essential to determine antigenic and functional C1-INH levels. Therefore, patient 1 was diagnosed with type 1 hereditary angioedema, and it was not possible to classify the type of angioedema in patient 2.(20,21,27)

The diagnosis is commonly confused with allergies, appendicitis, stress disorders, reactions to insect bites, gastroenteritis, and gastric ulcers. In certain cases, the presentation of the disease with exclusive abdominal involvement, together with limited knowledge of the disease, means that this deficiency is underdiagnosed, with an average delay in diagnosis of 13 years.(12,28) In both patients, there was a delay in diagnosis of approximately 20 years, and the long time between the onset of symptoms and diagnosis, as well as access to therapy, increases the morbidity related to the disease, affecting the quality of life of patients and their families. Patients who are not treated properly have an estimated mortality rate of 25% to 40% due to laryngeal angioedema, resulting in asphyxia.(10)

This disease has a major impact on patients' quality of life, both due to the recurrence of symptoms and the risk to life. The importance of a correct diagnosis can never be underestimated and is essential to avoid potentially fatal consequences such as airway obstruction or unnecessary abdominal surgery.(29)

A family tree is a chart that represents the inheritance of a trait or condition through generations of a family. It shows the relationships between family members and, when the information is available, indicates which individuals have a trait of interest. Although it has traditionally been used to recognize the pattern of inheritance of hereditary diseases with a specific genetic trait, its clinical use goes beyond this. Following the sequencing of the human genome, it has gained greater interest, partly because of the possibility of identifying the hereditary component of many diseases and, on the other hand, because of the proliferation of preventive clinical practice guidelines where the evaluation of heritable factors and personalization are of interest, contributing to the diagnosis and prevention of risks in family members,(30) This was evidenced in patient 2, where C1-INH antigen and function testing was not performed, but the information provided by this tool, together with clinical manifestations and laboratory results, allowed the diagnosis of the disease.

The treatment of hereditary angioedema consists of several pillars: treatment of acute attacks or on demand, short-term prophylaxis, and long-term prophylaxis.(23)

The first group includes human C1-INH plasma concentrate (pdC1-INH) or Berinert, recombinant human C1-INH concentrate (rhC1-INH, Ruconest®), fresh frozen plasma, and plasma with solvent or detergent. The second group includes therapies such as icatibant (Firazyr®) and ecalantide (Kalbitor®). Long-term prophylaxis includes intravenous phC1INH, subcutaneous phC1INH, lanadelumab (Takhzyro®) or berotralstat (Orladeyo®), attenuated androgens, or antifibrinolytics such as tranexamic acid (Anchafibrin®).(15)

Both patients were treated with danazol (attenuated androgen). Berinert was used in severe crises in the patient with type I hereditary angioedema, and tranexamic acid was used for prophylaxis, with good subsequent evolution in both cases.

Treating patients with different phenotypes in a personalized, evidence-based manner is an art.

Evidence-based medicine and personalized medicine are crucial in the study of hereditary angioedema. Evidence-based medicine ensures that clinical decisions are based on the results of rigorous research, allowing for the evaluation of the efficacy and safety of existing and emerging treatments for HAE, which is characterized by its clinical variability.

At the same time, personalized medicine is essential for understanding the genetic and phenotypic heterogeneity of HAE, adapting management to the particularities of each patient, optimizing crisis prevention and therapeutic choice, considering factors such as age, gender, medical history, and individual response to medications, thus maximizing effectiveness and minimizing risks.

CONCLUSIONS

There is a delay in the diagnosis of this disease due to its rarity.

The family tree contributes to early diagnosis in cases with a family history of angioedema.

Although the clinical picture was similar in both cases, the greater severity and complications are related to the quantitative deficiency of C1 inhibitor (type I) in one of the patients. However, the lack of correlation between the different genetic and clinical forms of the disease and the high allelic heterogeneity do not allow patient 2 to be classified as having any of the specific types of the disease.

HAE is a potentially fatal disease, so it is very important to be aware of it for early diagnosis to ensure improved quality of life for patients and the prevention of complications, based on personalized, evidence-based medicine.

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31. 31 AUTHORS' CONTRIBUTIONS
32. 32 Conceptualization: Mayelín García García, Lidia Morejón Gamboa, Luis Alexis Peláez Yáñez, Odalys Orraca Castillo.
33. 33 Data curation: Mayelín García García, Lidia Morejón Gamboa, Luis Alexis Peláez Yáñez, Odalys Orraca Castillo.
34. 34 Formal analysis: Mayelín García García, Lidia Morejón Gamboa, Luis Alexis Peláez Yáñez, Odalys Orraca Castillo.
35. 35 Research: Mayelín García García, Lidia Morejón Gamboa, Luis Alexis Peláez Yáñez, Odalys Orraca Castillo.
36. 36 Methodology: Mayelín García García, Lidia Morejón Gamboa, Luis Alexis Peláez Yáñez, Odalys Orraca Castillo.
37. 37 Project management: Mayelín García García, Lidia Morejón Gamboa, Luis Alexis Peláez Yáñez, Odalys Orraca Castillo.
38. 39 Software: Mayelín García García, Lidia Morejón Gamboa, Luis Alexis Peláez Yáñez, Odalys Orraca Castillo.
39. 40 Supervision: Mayelín García García, Lidia Morejón Gamboa, Luis Alexis Peláez Yáñez, Odalys Orraca Castillo.
40. 41 Validation: Mayelín García García, Lidia Morejón Gamboa, Luis Alexis Peláez Yáñez, Odalys Orraca Castillo.
41. 42 Presentation: Mayelín García García, Lidia Morejón Gamboa, Luis Alexis Peláez Yáñez, Odalys Orraca Castillo.
42. 43 Original draft: Mayelín García García, Lidia Morejón Gamboa, Luis Alexis Peláez Yáñez, Odalys Orraca Castillo.
43. 44 Writing, correction, and editing: Mayelín García García, Lidia Morejón Gamboa, Luis Alexis Peláez Yáñez, Odalys Orraca Castillo.