Wolf in the sheep’s clothing: intestinal angioedema mimicking infectious colitis

Abstract

Hereditary angioedema (HAE) is a relatively rare clinical entity that can potentially cause life-threatening airway or intestinal oedema, patients with the latter usually presents with symptoms of gastroenteritis like vomiting, diarrhoea and abdominal pain. Here, we present a unique case of a less recognised type of HAE that is type III in a patient who presented with signs and symptoms consistent with infectious colitis. She previously had similar episodes and was managed multiple times with antibiotics, with no satisfactory response. There, she underwent extensive diagnostic evaluation. On the basis of findings of further investigations on the current visit, she was eventually diagnosed with intestinal angioedema. To the best of our knowledge, the present paper represents the third reported case of type III HAE-induced intestinal angioedema. Additionally, we undertake a literature review of HAE.

Background

Hereditary angioedema (HAE) is classified into three main types based on the type of mutations and C1 inhibitor protein levels (C1-INH).¹ Types I and II both have mutation in the SERPING1 gene but the C1-INH protein levels are reduced in type I only while it is dysfunctional in type II.² In contrast to these two types, type III also called HAE with normal C1-INH, usually has two missense mutation of the factor XII gene, and has normal C1-INH levels.³ All three types usually have the similar initial clinical features and can only be differentiated at the molecular levels. However, type III is predominantly reported in the female population and has a special association with oestrogen, especially in cases with factor XII mutations.⁴ In patient with high oestrogen levels, such as who use oral contraceptives or with pregnancy, it may develop severe disease.⁴ We report here a case where HAE type III presenting with abdominal pain mimicked infectious colitis in the setting of irritable bowel syndrome and lead to delayed diagnosis, management and unnecessary antibiotic exposure. This patient is unique as she presented with the findings suggestive of infectious colitis with no evidence of high oestrogen state.

Case presentation

A 48-year-old Caucasian woman presented to our medical centre with nausea, vomiting, diarrhoea and abdominal pain of 1 day. Her pain was progressive, diffuse, cramping, non-radiating and severe in intensity. Vomitus was watery in consistency without any blood. She was unable to tolerate anything by mouth even water. She denied any fevers, chills, cough, urinary symptoms, recent travel or sick contacts. No history of ACE inhibitors, angiotensin-receptor blockers (ARBs) or oral contraceptive use. Previously, she had six hospitalisations for possible infectious colitis in a year and leucocytosis. However, infectious workup came out negative in all the episodes. She had a medical history significant for irritable bowel syndrome, factor V Leiden mutation and multiple admissions for suspected infectious colitis.

Physical and systemic examination

Physical examination showed that she was lethargic, with dry mucous membranes. On vital sign examination, she was found afebrile with blood pressure of 105/70 mm Hg, and heart rate of 108 beats per minute. Her abdomen was diffusely tender, non-distended without peritoneal signs with normal bowel sounds. Chest was clear bilaterally and the cardiovascular and neurovascular examinations were unremarkable for abnormalities.

Investigations

Laboratory results revealed her haemoglobin level of 14.1 g/dL and mean corpuscular haemoglobin of 91 fL/red cell, white cell count of 17x10⁹/L with a normal eosinophil count on differential and normal platelet counts. She had a serum protein level of 7.8 g/dL and serum albumin level of 4.5 g/dL. Her serum sodium level was 148 mEq/dL and serum potassium level was 3.2 mEq/dL. Urinalysis, renal and liver function tests were within the normal limits. Two-view chest X-ray was normal. Infectious work up including stool studies for ova, parasites, culture and Clostridium difficile came back negative. CT abdomen and pelvis revealed areas of mural thickening of the colon and distal ileum (figure 1). Her C4 level was normal and C1-esterase inhibitor protein and function levels were found to be low-normal. Testing for autoimmune and lymphoproliferative disorders was negative, which ruled out acquired angioedema.

Figure 1.

Abdominal contrast-enhanced CT scan showing edematous thickening of the intestinal wall (arrows).

Differential diagnosis

Initial suspicion of infectious colitis, acute pancreatitis, acute cholecystitis, gastritis and other classic causes of abdominal pain were ruled out by normal amylase, lipase, tryptase and negative porphyrins and urine pregnancy test. Furthermore, two endoscopies, two colonoscopies, gastrointestinal follow-ups and multiple emergency room visits failed to reveal a cause of her recurrent and redundant symptoms. She also had two family members who carried the diagnosis of angioedema.

Treatment

No antibiotics were given in this admission and diagnosis of HAE presenting primarily with gastrointestinal symptoms was made. She kept having multiple attacks on a daily basis during the hospital stay. Antihistamine and steroids were futile and her episode subsided on day 5 with no subsequent recurrence of abdominal pain with supportive therapies such as intravenous normal saline and pain killers.

Outcome and follow-up

The patient recovered well with conservative treatment. On 6 months follow-up, she did not report any signs and symptoms suggestive of recurrence of her HAE and she continues to do well to date.

Discussion

HAE is a condition characterised by recurrent, but self-limited episodes of subcutaneous and submucosal angioedema that may last up to 3–5 days without treatment. Skin involvement is the most common feature, followed by upper respiratory and gastrointestinal involvement.² The skin involved is usually non-pruritic and cutaneous oedema is non-pitting. It can be broadly divided into two categories. The first group, which includes HAE, types I and II, is characterised by a deficiency in the level or function of the C1-INH.² This group is also collectively referred to as C1INH-HAE. Historically, this was the only group recognised, until the past decade when cases were reported with normal C1-INH. This led to the identification of the second group, which includes our patient.^{5 6} These patients have some other associated mutation, but in an increasing number of cases no mutation has been identified. This group was initially called HAE type III and was thought to occur only in women in association with a defect in factor XII gene. There was also postulated to be some association with oestrogen levels. Since then, cases with normal factor XII gene have been reported and similar cases have been reported in men too.^{7 8} This group is now further categorised into two sub-categories. The first one is HAE with normal C1-INH and a mutation in factor XII (FXII-HAE) and the second is HAE with normal C1-INH of unknown cause (U-HAE). In our discussion we will use ‘C1INH-HAE’ for types I and II and will use ‘HAE type III’ for all different subgroups of HAE with normal C1-INH.

HAE type III usually presents in adulthood with a mean age of 26.8 years. However, C1INH-HAE presents at an earlier age, with a mean age of onset at 11.7 years. The frequency of tongue, uvula and face involvement is more common in HAE type III; however, abdominal symptoms are much less frequent (50% vs 90%).⁹ HAE type III is more common in women, and they are usually more symptomatic as compared with men. It is further notable that episodes are also much less frequent with HAE type III; some patient have disease free intervals lasting years, and recurrent attacks are more likely to involve a single location.⁹ In our patient, the initial clinical presentation was unusual as she developed symptoms suggestive of infectious colitis. She was not using any medication and was not having any medical medication which could have put her in high oestrogen state triggering her HAE; furthermore, she presented with abdominal pain which was only rarely reported in the past.

Our extensive literature search for HAE in association with abdominal pain showed a total of 27 cases but only 17 cases (19 patients) had enough data to be discussed (table 1). HAE in association with abdominal symptoms was attributed to intestinal angioedema and diagnosis was made on CT scan in almost all cases including ours, except in one patient where the ultrasound was used as a diagnostic tool. The mean age of all the patients was about 42 years (range 9–52 years) and it was most commonly reported among women. Most commonly observed type of HAE was type I in 16/19 patients and only 3 patients had HAE type III associated intestinal angioedema. Almost all patients presented with abdominal pain and associated nausea and vomiting, since the presentation of HAE with normal C1-INH was very similar HAE with abnormal C1-INH and it is not possible to identify the type of HAE solely on signs and symptoms. HAE differentiation in all cases was made by looking at the C1-INH and C4 levels and by measuring C1-INH function capacity. This classification was the key to management of HAE, patients with HAE type III were treated with icatibant, while those with C1INH-HAE required danazol along with cessation of oral contraceptive pills (OCP) and delivery, in cases where OCP and pregnancy were the triggering factors.

Table 1.

Characteristics of previously reported cases with intestinal angioedema due to HAE

S. no	Author, year, reference	Age/sex	Presentation	HAE type	C1-INH	C4	C1-INH function	Diagnosis mode	Associations/co-morbids	Management	Outcome	Follow-up
1	Vogetseder, 201140	26/F	NVD, abdominal pain	HAE 1	NA	NA	NA	CT	NA	NA	Repeat episode	6 m
2	Yakushiji, 201641	38/F	Abdominal pain and NV, oedema	HAE 1	Decreased	Decreased	NA	NA	NA	NA	NA	NA
3	Miranda, 201342	26/F	Face swellings, abdominal pain	HAE 1	Normal	Normal	NA	CT	OCP	Suspension of OCP	No relapse	21 m
4	Prieto, 200943	35/F	Swelling of face, airway, abdominal pain, VD	HAE 1	Normal	Normal	NA	NA	Pregnancy	Delivery of the baby	No relapse	8 m
5	Zingale, 200844	65/F	Swelling at cutaneous, laryngeal sites, abdominal pain	HAE 1	Decreased	Decreased	Decreased	NA	NA	Endotracheal cannula, danazol	No relapse	7 d
6	Bouillet, 200929	32, 37, 43	Oedema of the face, abdominal pain	HAE 3	Normal	Normal	NA	CT	OCPs and pregnancy	Icatibant	No relapse	NA
7	Patel, 200845	51/M	Abdominal pain, periorbital swelling	HAE 3	Normal	Normal	Normal	CT	NA	NA	NA	NA
8	Kasamatsu, 201146	44/F	Extremities swelling, abdominal pain, NV	HAE 1	Decreased	Decreased	Decreased	CT	Pregnancy	C1-INH concentrate	Repeat episode	3 y
9	Talavera, 199547	NA	Abdominal pain, ascites	HAE 1	NA	NA	NA	CT	NA	Danazol	NA	NA
10	Bork, 199748	35/M	Cutaneous swellings, abdominal pain, NV	HAE 1	Decreased	Decreased	NA	CT	NA	Danazol	No relapse	15 m
11	Goti, 199849	25/F	Abdominal pain	HAE 1	Decreased	NA	NA	CT		Supportive care	Resolved	2 d
12	Hara, 199950	31/M	Extremities swelling, abdominal pain, NV	HAE 1	Decreased	Decreased	NA	CT	Positive family history	NA	No relapse	55 d
13	Kjaer, 201351	9/M	Airway swelling, skin swellings, abdominal pain	HAE 1	NA	NA	NA	CT	NA	NA	NA	NA
14	Grivcheva-Panovska, 201252	21/M	Abdominal pain, NV	HAE 1	Decreased	Decreased	Decreased	CT	NA	NA	No relapse	NA
15	Bergmann, 201353	10/M	Eyelids swelling, extremities swelling, penis swelling, dysphagia, abdominal pain	HAE 3	Normal	Normal	Normal	HAE 3	Positive family history	Icatibant	Repeat episode	6 m
16	Belkhouribchia, 201654	25/F	Acute abdominal pain, ND	HAE 1	NA	NA	NA	US	NA	C1-inhibitor	No relapse	NA
17	Soni, Kumar, 201655	44/F	Abdominal pain, D	HAE 1	Decreased	Decreased	NA	CT	Positive family history	NA	NA	NA
18	The present report	48/F	Abdominal pain, NV	HAE 3	Normal	Normal	Normal	CT	Positive family history	Supportive care	Resolved	6 m

N, Nausea; V, Vomiting; D, Diarrhea; HAE, hereditary angioedema; OCP, oral contraceptive pill: NA, Not available.

It is thought that the activation of the kinin system and excess bradykinin has a major etiological role in the pathogenesis of C1INH-HAE, whereas this is not the case in HAE type III.¹⁰ The exact underlying molecular mechanism for HAE type III has not been identified. Studies of families do show that the inheritance pattern is consistent with an autosomal dominant mode of inheritance.^{6 7 11} Mutations in factor XII is one of the most common identified defects.^{7 12 13} These patients are known to be having HAE-factor XII or F12-HAE as opposed to those with an unknown mutation labelled as Un-HAE. Further evidence of FXII involvement in pathogenesis of HAE type III can be derived from the fact that FXII expression is enhanced by oestrogen via oestrogen responsive elements in the promoter gene area.¹⁴ The exact mechanism by which factor XII is associated with HAE is not known; however, patients with some factor XII mutations like defect in mucin type Thr309Lys-linked glycosylation have higher factor XII activity that results in increased activation of the kallikrein–kinin pathway.¹⁵ However, this effect has not been reproducible in subsequent studies.^{15 16} An interesting character of these patients is that most of them are women and they have some association of attacks with high oestrogen states and women taking OCPs having more frequent attacks.^{6 17–19} The exact role of oestrogens is not known, and the effect is variable too. Some women with HAE with normal C1-INH have been known to tolerate high levels of oestrogen without a worsening of angioedema attacks.^{17 20} It is postulated that oestrogen has its effect on the expression of factors important in the metabolism of bradykinin. High oestrogen levels are known to increase the transcription of factor XII, increase plasma prekallikrein levels and reduce the plasma C1-INH levels. Furthermore, patients with HAE with normal C1-INH who had factor XII mutations were also found to be more sensitive to the effects of oestrogen, as compared with those with unknown mutations, also labelled Un-HAE.^{8 21} Other mechanisms include possible reduced expression of ACE, which allows bradykinin to accumulate. Oestrogen exposure may also result in an increased expression of the bradykinin receptor type II.²² Other mutations associated with HAE with normal C1-INH include patients with the gene encoding angiopoietin-1.²³ This protein in known to reduce bradykinin-induced plasma leakage.²⁴ Recently, a missense mutation within the plasminogen kringle 3 domain of the plasminogen gene, in HAE with normal C1 inhibitor has been reported, but mainly associated with tongue swelling.²⁵ Finally, patients with no known mutation are categorised into U-HAE, and not much is known about the mechanism of pathogenesis in these patients. They however are less sensitive to the effects of oestrogen.

The diagnosis of HAE requires appropriate clinical features and evidence of normal C1-INH levels. An expert panel developed diagnostic criteria. They suggest that a diagnosis can be made if the patient has characteristic episodes of angioedema affecting any of the organs, along with normal C1-INH and C4 levels. This should also be associated with either a mutation in factor XII or a known family history.¹² One of the important differentials is idiopathic angioedema. The important difference is there would be no family history. It is important to make this distinction as this form of angioedema usually responds to antihistamines and glucocorticoids. It is also essential to exclude other secondary causes, including drug reactions.²⁶ For the intestinal angioedema, CT scan was inevitable, most common findings observed were oedematous thickening of the small or large bowel walls.²⁷

The management for type III HAE can broadly be divided into treatment of acute attacks, treatment of complications and prophylactic therapy to prevent further attacks.²⁸ No medications for acute therapy have been found to be universally effective. The most important aspect is to maintain a patent airway. Patients can develop severe upper respiratory obstruction and they should be promptly intubated and moved to the ICU at the earliest sign of respiratory compromise. Specific agents used to treat HAE type III are icatibant, which is an injectable bradykinin type II receptor antagonist. However, it has been effective in treating acute symptoms in a small number of patients and no large-scale studies have been done so far.^{29 30} Ecallantide is another agent used to treat acute attacks. It is a plasma-kallikrein inhibitor which has been used to treat acute attacks of HAE with normal C1-INH with some success.^{31 32} C1-INH concentrate is another agent that has been used; however, its efficacy is debatable. It is also associated with a higher risk of thrombosis.^{5 33} HAE type III patients do not tend to respond to antihistamine, epinephrine and glucocorticoids. However, in cases of emergency when the diagnosis is not clear, these agents should not be withheld.^{28 33}Patients should also be counselled how to avoid triggers that may include trauma, physical pressure, emotional stress and some medications.³³ ACE inhibitors and ARBs have also been implicated in cases, and these should be avoided.^{34 35}

Long-term prophylactic treatment should be considered in patients who have at least one or more severe episodes a month, who are unable to perform their usual activities more than 5 days a month, and those with a history of a laryngeal attack. Some patient who are predisposed to frequent attacks can also receive short-term prophylaxis, especially prior to surgical and dental procedures. Two agents that have been used for long-term prophylaxis with some success include danazol, an androgen and tranexamic acid. Danazol has been found to be more effective in HAE with C1-INH and its efficacy in type III yet needs to be established. The presumed mechanism of action is it causes an increase in C1-INH and factor XII levels in animals.5 11 18 36 Tranexamic acid, however, was used with success in many studies.5 14 21 33 37–39 The efficacy of injected C1-INH and progesterone contraceptives has not been proven and should be avoided.³²

Learning points.

• Intestinal angioedema should be considered as a possible cause of abdominal pain especially in cases of recurrent intractable symptoms and in patients with positive history of hereditary angioedema (HAE).

• HAE type III does not have decreased C1-INH levels or functions, and it should not rule out the possibility of intestinal angioedema.

• HAE type III does not require glucocorticoids and antihistamine as compared with acquired HAE. It was successfully managed with icatibant in previous cases but can also be managed supportively with analgesics and intravenous fluids as in our case.

• Prophylaxis can be tried with danazol but tranexamic acid has been proven beneficial in many studies.