Correspondence Address: Dr. Ramya Iyyadurai Department of Medicine, Christian Medical College, Vellore - 632 004 India
Source of Support: None, Conflict of Interest: None
Hereditary angioedema is a rare life-threatening disease. Undiagnosed angioedema is associated with high mortality. Diagnosis is often delayed due to lack of clinical suspicion. We report two cases of patients (mother and son) with angioedema who had been wrongly diagnosed as nephrotic syndrome and hypothyroidism. These case reports highlight the need for a high index of suspicion to diagnose a potentially life-threatening disease which can lead to timely treatment, preventing morbidity and mortality.
How to cite this article: Iyyadurai R, Teja HP, Satyendra S. Hereditary angioedema in mother and son: Challenges in diagnosis for the primary physician. Curr Med Issues 2018;16:13-5
How to cite this URL: Iyyadurai R, Teja HP, Satyendra S. Hereditary angioedema in mother and son: Challenges in diagnosis for the primary physician. Curr Med Issues [serial online] 2018 [cited 2022 Aug 15];16:13-5. Available from: https://www.cmijournal.org/text.asp?2018/16/1/13/231371
Hereditary angioedema (HAE) is an autosomal dominant inherited disorder. It does not have any gender or race predilection. The estimated incidence is 1 in 150,000 persons. It is a life-threatening disorder depending on the organ system that is involved, and recurrent attacks of HAE can be debilitating. It is characterized by brawny nonpitting edema. Mainly, the respiratory tract, skin soft tissue, and the gastrointestinal system are involved.
The index case was the son who presented to us with a history of swelling of the face and the upper limbs for the past 2 years. He was a 20-year-old-male who was studying in college. The swelling was intermittent and localized. The swelling would involve the face and upper limbs. It was associated with minimal redness, but there was no itching over the area. The patient had sought health-care advice and he had been diagnosed with hypothyroidism though his thyroid-stimulating hormone (TSH) was 6.15 (range: 0.3–4.5μIU/ml). The patient had been started on levothyroxin 25 μg early morning on empty stomach which the patient took for 3 months; though the TSH values improved, he did not have any relief of symptoms.
The patient stopped his medications and consulted another physician and the physician had considered a diagnosis of nephrotic syndrome and tests were done. The urine protein at this time was negative, and 24-h urine analysis showed protein of 28 mg/1800 ml over 24 h. Other investigations such as serum creatinine and complete blood count, liver functions tests, and repeat TSH were normal [Table 1]. The patient was started on steroids for nephrotic syndrome. The patient took 1 mg/kg prednisolone for 3 months. The patient developed swelling of the face consistent with cushingoid features, and so, he stopped his medications, and also, since the episodes continued to occur, he came to our hospital for further evaluation. Sometimes, the patient had feeling of breathlessness associated with the episodes, especially when he had facial swelling.
On examination, the patient had cushingoid features. His vitals pulse, blood pressure, and respiratory rate were stable. He had no pedal edema or anemia or any other significant systemic findings on physical examination.
During this consultation, he developed a swelling in the hand associated with erythema [Figure 1] and [Video 1] which gave a clue to the diagnosis. The swelling was nonpitting with ill-defined margins, with erythema but not warm or pruritic [Figure 1]. This patient had intermittent swelling in the hands/feet sometimes of the face along with noisy breathing (stridor). All these features fitted into a diagnosis of angioedema.
Differential diagnosis and evaluation: Differential diagnosis considered at this point was acquired angioedema, hypothyroidism, and nephrotic syndrome. The patient had been evaluated, and these diseases had been ruled out with a urine routine and TSH levels. Acquired angioedema was not considered since the lesions were not pruritic.
Mrs. S, a 40-year-old female, presented to us along with her son with a history of swelling of the face, palpitations, and intermittent episodes of breathlessness. The patient had intermittent episodes of face swelling with noisy breathing. She had been diagnosed to have juvenile asthma and was on intermittent inhalers. The patient did not have any relief of symptoms and hence had come to our hospital for further evaluation.
Since the patient had clinical presentation similar to her son, we considered HAE. Investigations revealed low levels of C4 which was a clue to the diagnosis of HAE.
The diagnosis was confirmed by estimation of C1 esterase levels.
Course in hospital management: The patient was started on tablet danazol on an outpatient department basis. This had led to a reduction in the frequency of attacks to less than 1 attack per month. The drug was tapered to least effective dose on follow-up, and the patient did not develop any drug-related toxicity on follow-up.
HAE is caused by a deficiency of C1 esterase. This is a rare inherited disease. There is no race or gender predilection. Attacks are characterized by localized edema without pruritus; often, attacks are initiated by several known triggers.
Angioneurotic edema was first described by Milton and Quincke, but the hereditary nature was recognized by William Osler who described the disease in a family over five generations. The name angioneurotic was coined by Quincke who added the term “neurotic” to emphasize on the effect of mental stress on the development of attacks.
HAE is of three types: Type 1 – where there is decreased production of C1 esterase, this is the most common type of HAE (85% of the patients). The second type: Type 2 – C1 esterase levels are normal or high, but the enzyme is functionally abnormal. Type 3 HAE – the C1 esterase and C4 levels are normal and they probably have a congenital deficiency of enzymes such as ACE, carboxypeptidase N, and α2-macroglobulin or a phenotypic decrease in the function of these enzymes.
C1 esterase is a serine protease produced mainly in the liver  whose main function is to prevent C1-mediated autoactivation of the complement cascade.
The patients usually present with this disease during their second decade of life and attacks are quite rare in childhood in the first decade of life.
The attacks are precipitated by trauma, invasive medical procedures, emotional stress, menstruation, oral contraceptive use, infections, or the use of medications such as ACE inhibitors.
The attacks usually last for 2–3 days, and spontaneous remission occurs due to the rapid consumption of the substrates, which outpaces the body's ability to produce them.
Patients who have angioedema which is nonhereditary present with urticaria as the attacks are medicated by histamine, while in HAE, the attacks are mediated by bradykinnin, and hence, the patients have no urticaria. This also means that unlike acquired angioedema, HAE is resistant to treatment with antihistamines, corticosteroids, and epinephrine.
The skin, respiratory, and the gastrointestinal tract are the most commonly affected organs.
Acute attacks must be managed by C1 esterase concentrate; if this is not available, the patient must be started on attenuated androgens immediately.
Other options are to treat the patient with fresh frozen plasma (FFP) which has high levels of C1 esterase inhibitors. This increases the level of C1 esterase inhibitors and reduces the intensity of the attack. The effect will last up to 12 days.
Who to give prophylaxis to? Earlier recommendation was that prophylaxis must be initiated in patients who have more than 1 attack a month. But then, later studies showed that among those people who asphyxiated due to HAE, most of the patients had experienced <3 attacks in a year. Hence, prophylaxis must be initiated in any patient with a history of even a single attack of HAE.
Attenuated androgens are the drugs of choice for long-term prophylaxis for HAE; they can be used in both male and female patients. Our patients were also initiated on danazol and they reported a reduction in the frequency of attacks. The dose of danazol was reduced to 50 mg per day. Side effects of danazol include hypertension, lipoprotein abnormalities, deepening of voice, acne, hair growth, and weight gain; unusual side effects include hepatic neoplasms. Our patients were monitored for hypertension and lipid profile abnormalities, but they did not develop any of these side effects.
In case surgery or any invasive procedure like dental extraction is planned, the patient must be started on tablet danazol 200 mg daily for 10 days before the surgery to prevent attacks. These drugs are contraindicated in childhood, pregnancy, and lactation.
In case the procedure is planned emergently or the patent is a child, pregnant, or lactating, then FFP can be used instead of danazol. The usual dose is 2 units of FFP at least 12–24 h before the procedure.
Angiotensin-converting enzyme inhibitors (ACEIs) and angioedema: ACEI causes angioedema in 0.1%–0.5% of the patients initiated on ACEI. Treatment includes withdrawal of the drug. The patients who develop angioedema due to ACEI do not have any C1 esterase abnormalities.
Recognition of HAE by primary-care providers and distinguishing it from allergic histamine-mediated angioedema is essential in preventing recurrent attacks and inappropriate therapy. Early recognition of HAE is life-saving.
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.
We would like to thank Dr. Satish for arranging for the C1 esterase levels to be done which allowed us to make a confirmatory diagnosis for these patients.