Hereditary Angioedema (HAE) is a rare autosomal dominant (AD) disease characterized by deficient (type 1) or nonfunctional (type 2) C1 inhibitor protein. The disorder is associated with episodes of angioedema of the face, larynx, lips, abdomen, or extremities. The angioedema is caused by the activation of the kallikrein-kinin system that leads to the release of vasoactive peptides, followed by edema, which in severe cases can be life threatening. The disease is usually not diagnosed until late adolescence and patients tend to have frequent episodes that can be severely impairing and have a high incidence of morbidity. Gastrointestinal involvement represents up to 80% of clinical presentations that are commonly confused with other gastrointestinal disorders such as appendicitis, cholecystitis, pancreatitis, and ischemic bower. We present a case of an HAE attack presenting as colonic intussusception managed conservatively with a C1 esterase inhibitor. Very few cases have been reported in the literature of HAE presentation in this manner, and there are no reports of any nonsurgical management of these cases.
HAE is a condition presenting as recurrent attacks of angioedema usually without symptoms of pruritus or urticaria. It is an autosomal dominant condition typically presenting in childhood, characterized by nonpitting edema of subcutaneous and mucosal tissues and usually associated with the upper respiratory and gastrointestinal systems [
A 19-year-old female presented to the Emergency Department (ED) with complaints of abdominal pain. The patient was in her usual state of health when she experienced an acute onset of abdominal pain, localized to the right upper quadrant. The pain was described as cramp-like in character, accompanied by numerous bouts of vomiting and diarrhea, both of which were nonbloody. Her past medical history was significant for low complement C4 performed at the time of diagnosis. The patient’s father has a known history of type 1 HAE. Her medications include an intravenous (IV) C1 esterase inhibitor (Cinryze) taken every 3 days for HAE symptom prophylaxis and subcutaneous (SC) icatibant (Firazyr) to be used during an acute attack. The patient was on a clinical trial of Cinryze for prophylaxis as instructed by her allergy specialist. She had experienced similar episodes in the past which resolved with immediate treatment with Cinryze and Firazyr. The patient’s symptoms were well controlled on this regimen until 1 month ago when her symptoms increased in frequency to 1 episode a week. She denied any change in her daily activities but did admit increased stress due to college final exams. Within an hour of her current symptom onset the patient used one application of Cinryze and Firazyr, but the pain was unrelenting and she decided to go to the nearest ED. In the ED the patient was found to have an elevated blood pressure of 148/100 mmHg. Her physical exam revealed tenderness in the umbilical and right upper quadrant upon light palpation. There was no guarding, rigidity, or rebound tenderness, and Murphy’s sign was not elicited. Her head, neck, chest, extremities, and skin exam did not reveal any significant findings.
Laboratory work-up revealed a normal complete blood count and comprehensive metabolic panel. Serum amylase, lipase, and urinalysis were all within normal limits. Her C-reactive peptide was not obtained at the time of evaluation. Abdominal CT scan demonstrated a 2.4 cm segment of colocolic intussusception in the region of the hepatic flexure with a normal appearance of the appendix (Figure
CT abdomen demonstrating colocolic intussusception at the hepatic flexure (arrow).
The patient was admitted to the hospital and was given supportive care with IV fluids and pain medications and kept nothing per mouth (NPO) while the surgery team was consulted along with her outpatient allergy specialist. Additional diagnosis such as tumor or adhesions causing her abdominal pain was not contemplated given that she had no prior history of abdominal surgeries and the CT findings did not reveal a mass of concern. Her allergist recommended beginning treatment with three 1,000-unit doses of IV Cinryze delivered every 2 hours in an attempt to subside the edema causing the intussusception. The initiation of therapy with IV Cinryze was roughly 4 hours after arrival to the ED. If the treatment failed, then the patient would be scheduled to undergo air-contrast enema for decompression. Overnight the patient’s abdominal pain resolved, and repeat CT imaging demonstrated resolution of the intussusception and a normal appearance of the bowel wall with no evidence of obstruction (Figure
CT abdomen after C1 INH treatment, demonstrating resolution of intussusception (arrow).
The angioedema in HAE develops secondary to excess bradykinin production due to low levels of functionally active C1 inhibitor (C1 INH). This leads to the activation of the kallikrein-kinin system causing the release of vasoactive peptides and ultimately angioedema formation [
Characteristic locations for HAE attacks involve the skin, upper respiratory tract, and gastrointestinal system [
Common prodromal symptoms include nausea abdominal pain, rash, fatigue, muscle aches, numbness, and tingling [
Gastrointestinal tract involvement is an important feature and one of the most common in HAE. The difficulty in recognizing gastrointestinal symptoms as being related to HAE often leads to a delay in diagnosis and to unnecessary surgical procedures [
Gastrointestinal manifestations of Hereditary Angioedema.
Site | Clinical manifestation | Frequency (%) |
---|---|---|
Skin | Swelling and edema | 97% [ |
|
||
Oropharynx | Laryngeal edema | 0.9% [ |
Tongue swelling | 0.3% [ | |
Dysphagia | 16% [ | |
|
||
Abdomen | Nausea and vomiting | 88% [ |
Crampy and colicky abdominal pain | 43–93% [ | |
Abdominal distention | 72.8% [ | |
Ascites | 30% [ | |
Diarrhea | 15% [ | |
|
||
Circulatory system | Hypovolemic shock | 4.4% [ |
|
||
Less frequent presentation | Pancreatitis | Rare [ |
Intussusception | Rare [ | |
Tetany | Rare [ | |
Dysuria | Rare [ |
The nonspecific character of HAE symptoms can lead to an extensive work-up and unless there is a high index of clinical suspicion, the diagnosis can be delayed leading to inappropriate surgical interventions. Nationwide surveys in Denmark and Spain found mean delays in diagnosis of 13–16 years, with an international Internet based survey finding of 8.3-year delay in diagnosis [
Key findings of an international Internet based survey of HAE patients in relation to surgical interventions.
Population group | Number of patients who underwent unnecessary surgery due to misdiagnosis ( |
---|---|
Patients in the United States with HAE | 24 out of 125 (19%) |
Patients in the United Kingdom with HAE | 12 out of 52 (24%) |
Obtaining a detailed patient history and performing a thorough physical exam are crucial to help direct the medical team to appropriate diagnostic testing. Questions pertaining to time of onset, duration, age at first attack, intervals between attacks, triggering medication and events, family history of similar symptoms, and a thorough review of systems are areas of interest that should be investigated [
To confirm the diagnosis of HAE it is important to correlate the history and physical exam findings with laboratory and radiographic evidence. The recommended initial screening laboratory testing for HAE includes serum C4 level, C1 INH antigenic protein, C1 INH function/activity, and serum C1q levels which is the result from C1 INH breakdown [
Clinical presentation of HAE abdominal attacks in comparison to other gastrointestinal disorders.
Disorder | Sign/symptom | Laboratory data | Distinguishing features |
---|---|---|---|
HAE abdominal attacks | Nausea, vomiting, diarrhea, crampy abdominal pain | Type 1 HAE: low C4 and C1 inhibitor level/activity, normal C1q level [ |
History of HAE, colonoscopy: massive segmental mucosal edema [ |
|
|||
Acute diverticulitis | Acute LLQ abdominal pain and tenderness, fever, anorexia, nausea, vomiting, constipation or loose stools | Mild to moderate leukocytosis | LLQ palpable abdominal mass |
|
|||
Acute appendicitis | Periumbilical abdominal pain that migrates to RLQ with noted rebound tenderness, anorexia, nausea, vomiting, fever | Leukocytosis with neutrophils >70%, elevated levels of CRP, SAA, ProCT [ |
Peak incidence occurs at age 10–19 years [ |
|
|||
Small bowel obstruction (SBO) | Diffuse abdominal pain, colicky with waxing/waning characteristic, nausea, vomiting, abdominal distention and tenderness, hyperactive or hypoactive bowel sounds, feculent emesis |
Leukocytosis, hemoconcentration, electrolyte imbalance | Most common in adults with history of abdominal surgery raising suspicion for peritoneal adhesions (75% cases); the second most common cause is hernias |
|
|||
Pancreatitis | Acute onset of abdominal pain, located in epigastrium with radiation to back, nausea and vomiting, low grade fever, tachypnea, epigastric tenderness to palpation | Leukocytosis, hemoconcentration with elevated hematocrit, elevated serum amylase and lipase | Most common occurrence in childhood between ages of 15 and 19 years |
|
|||
Inflammatory bowel disease-ulcerative colitis (UC) and Crohn’s disease (CD) | UC: bloody diarrhea, with symptoms of urgency and tenesmus [ |
Elevated acute phase reactants CRP, ESR |
Both: most frequently diagnosed in the second decade of life. Stool examination to rule out infectious etiology |
|
|||
Intussusception | Abdominal pain, nausea, vomiting, diarrhea, hematochezia [ |
Similar to bowel obstruction: leukocytosis, hemoconcentration, electrolyte imbalance | Peak age at presentation is 4–8 months |
|
|||
Celiac disease | Abdominal discomfort, weight loss, diarrhea, increased flatus | Iron and folate deficiency, steatorrhea, hypoalbuminemia, hypocalcemia, elevated serum transaminases | May manifest as early as childhood after introduction of gluten in diet |
HAE: Hereditary Angioedema, LLQ: left lower quadrant, RLQ: right lower quadrant, CRP: C-reactive protein, ESR: Erythrocyte Sedimentation Rate, SAA: Serum Amyloid A, ProCT: serum procalcitonin, p-ANCA: perinuclear antineutrophil cytoplasmic antibodies, and ASCA: anti-
Radiologic tests may be helpful during initial investigations of abdominal pain episodes but not necessary to confirm a diagnosis of HAE. Abdominal X-ray during an acute attack may show dilated small bowel loops, thickened mucosal folds, air fluid levels, and a “thumbprint” sign representing an area of mucosal edema [
The literature on endoscopic procedures in HAE episodes is minimal, and it is generally not a recommended step during diagnosis. Upper endoscopy reports described the mucosa to appear erythematous and edematous with findings of small nodules and raised erosions [
The treatment options for HAE patients involve supportive care, individualized action plans, pharmacological treatment, and prophylactic measures. This combination can prevent or minimize future attacks and save the patient from unnecessary exploratory laparotomies, appendectomies, or other invasive procedures. These treatment guidelines are based on the World Allergy Organization (WAO) 2012 and practice parameters developed by a Joint Task Force of American College of Allergy, Asthma and Immunology and American Academy of Allergy, Asthma and Immunology in 2013 [
Icatibant marketed as Firazyr is a bradykinin receptor antagonist that has been approved for on-demand use by the FDA in acute attacks. Bradykinin can cause angioedema by activation of B2 bradykinin receptors. This pathway is blocked by icatibant because the medication competitively binds to these B2 receptors. Efficacy studies have shown that when compared to placebo and tranexamic acid significantly more patients had symptom relief at the 4-hour follow-up period with icatibant [
Epinephrine, antihistamines, and corticosteroids have been proven to be ineffective and are not recommended as part of the HAE treatment regimen. This is because the swelling caused in HAE is due to bradykinin, and the medications mentioned above do not antagonize the generation of effects of bradykinin. Prior to the research and development of the present approved interventions, fresh frozen plasma FFP had been used to abate acute HAE attacks because it contains high circulating levels of C1 INH protein, but it also contains prekallikrein, kininogen, and coagulation factor XII which may lead to worsening of attacks in some patients. Caution is advised if this treatment option is considered [
Novel to our case is the fact that after being treated with Cinryze the patient’s intussusception resolved completely, as confirmed by CT scan. This management strategy prevented further invasive interventions, including air-contrast enema. There are only a few reports of intussusception in the literature regarding HAE patients, all of which relied on surgical management as the ultimate treatment of this complication, given the lack of evidence on alternative management, along with the pressing factor of worsening complications if surgery is delayed [
A necessary part of the treatment regimen is to prevent future attacks. One method can be achieved through an individualized patient action plan. The action plan can be established between the patient and a healthcare professional in order to educate patients on recognizing an attack, recognizing triggers, learning how to self-administer treatment, and planning routes to facilitate access to healthcare. Patients should be advised to carry an identification card to assist healthcare professionals in delivering care [
The prognosis for patients with HAE before current treatment modalities reached as high as 25–50% in some families with the cause of death almost always secondary to laryngeal edema and fatal asphyxiation [
Gastrointestinal symptoms are a common feature of HAE attacks and can present in a wide array of clinical manifestations. Symptoms can be nonspecific and may overlap with other abdominal conditions leading to delay in diagnosis and treatment. Physicians should consider HAE as a differential diagnosis when presented with a cause of unexplained abdominal pain. A combination of an individualized action plan, pharmacologic therapy, and prophylactic measures can help prevent years of patient distress and unnecessary surgeries and decrease mortality.
The authors declare that they have no conflict of interests.