Four times between 2022 and 2025, a young man in China went to the hospital with cramping pain around his navel and watery diarrhea. Each time the episode settled on its own within two or three days, and each time the working diagnosis was some version of acute gastroenteritis.
The actual answer was a genetic disorder, and the test that pointed to it is cheap and available almost everywhere.
The case was published August 26 in Frontiers in Immunology by clinicians at Sanmenxia Central Hospital, Beijing Friendship Hospital, and Yellow River Hospital. The diagnosis was hereditary angioedema with C1-inhibitor deficiency, a condition most people associate with swollen lips rather than the gut.
The Details That Did Not Fit an Infection
By July 2025, the man was 26 and having more than eight episodes of watery diarrhea a day. His white cell count was elevated at 11.4 x 10⁹/L with 83 percent neutrophils, and his C-reactive protein was mildly raised. A CT scan showed the wall of his duodenum and upper small intestine thickened circumferentially, with nearby inflammation and free fluid in the abdomen, measuring 41 millimeters at its maximum depth.
That combination normally triggers a hunt for infection. The hunt came up empty. A tap of the abdominal fluid returned sterile, clear fluid. Stool cultures were negative, as were tests for Clostridioides difficile toxin and fecal calprotectin, a marker of intestinal inflammation. Antibiotics before admission had not helped, and neither did the antibiotic started after it.
Then, on hospital day four, the pain stopped abruptly and repeat ultrasound showed the abdominal fluid had vanished.
Fluid that appears and disappears within days is not typical of bacterial peritonitis. The team reconsidered, and a piece of history that had been sitting in plain view suddenly mattered: he also got recurrent swelling of his hands and feet, which he thought had started around the time of his first abdominal episode.
A Complement Test, Then a Second Opinion
The screening test is serum C4, a complement protein. His level came back at 0.05 g/L against a reference of 0.10 to 0.40. Functional C1-inhibitor activity was 22 percent of normal, while the antigen level sat at the bottom of the normal range.
Repeat testing at an external reference laboratory two days later confirmed this, showing low C1-inhibitor antigen and function below 7 percent, compared with a reference of 58.9 percent or higher. The pattern fit type 1 hereditary angioedema with C1-inhibitor deficiency.
The mechanism explains the confusing presentation. C1-inhibitor normally restrains the plasma contact system. Without enough working protein, the body overproduces bradykinin, blood vessels leak, and tissue swells. When that happens in the bowel wall rather than the skin, the result is severe abdominal pain, watery diarrhea, and sterile fluid in the abdomen, which is easy to mistake for gastroenteritis, inflammatory bowel disease, or appendicitis.
Genetic testing during follow-up identified a heterozygous nonsense variant in SERPING1, classified as likely pathogenic. The same variant has previously been reported in Chinese patients with the condition.
He received a single subcutaneous 30 mg dose of icatibant, a bradykinin receptor blocker, and was counseled on recognizing throat symptoms. Through follow-up, he reported no further attacks. Of the diagnosis itself, he said simply: "I am grateful to understand what has been causing my symptoms all these years."
Fifty Relatives and Three Deaths
The family investigation is the part that changes the stakes. With written consent, the team collected history on 50 traceable relatives across three generations. Thirteen were classified as clinically suspected cases based on recurrent self-limited swelling of the limbs, genitals or upper airway, or fatal throat attacks described by family members. Three of them reportedly died of laryngeal swelling between the ages of 20 and 40.
The authors are careful about what that number means. Laboratory confirmation was available for only three people: the patient, his father, and an 8-year-old paternal second cousin whose main symptom was recurrent abdominal pain. Everyone else was identified through interviews and family recollection, and cascade genetic testing was recommended but never completed.
They list that explicitly as a limitation, noting that retrospective family recall can overstate or understate who is actually affected, particularly for relatives who have died. It is an unusually candid framing for a pedigree that looks dramatic on paper.
Why C4 Keeps Getting Skipped
The practical argument the authors make is aimed at gastroenterologists. C4 is inexpensive and widely available, and a low result during a compatible attack is a meaningful screening clue. It is not a standalone diagnosis. Confirmation requires C1-inhibitor antigen testing and functional testing, with genetic analysis providing supporting evidence.
The cost of missing it is not just discomfort. Abdominal attacks send patients cycling through emergency departments, taking antibiotics that do nothing, and in some reported cases into abdominal surgery they did not need. Meanwhile, the same disorder can swell the airway.
US guidelines for managing the condition cover on-demand treatment and long-term prevention, and international recommendations were updated in 2025. Effective drugs exist. None of that helps someone who has not been diagnosed.
Two caveats belong on this story. It is a single case and cannot establish how often abdominal attacks get misread. And anyone with recurrent unexplained episodes should raise the question with a clinician rather than self-diagnosing.
Key Questions Answered
What is hereditary angioedema?
It is a rare inherited disorder in which a deficiency of functional C1-inhibitor protein leads to excessive bradykinin production, causing episodes of swelling in the skin, gut, or airway. It is not an allergic reaction.
Why did it look like gastroenteritis?
Swelling in the bowel wall produces severe abdominal pain, watery diarrhea, and sterile abdominal fluid. Attacks resolve on their own, which makes antibiotics look effective when they are not.
What test finally pointed to it?
Serum C4, a complement protein, was markedly low. That prompted C1-inhibitor antigen and functional testing, which confirmed the diagnosis.
Was genetic testing necessary?
It added support rather than making the diagnosis. Testing found a likely pathogenic nonsense variant in SERPING1 that has been reported before in Chinese patients.
How many relatives were affected?
Thirteen of 50 traceable relatives were classified as clinically suspected, including three who reportedly died of throat swelling. Only three people in total had laboratory confirmation.
What should someone with recurring unexplained abdominal attacks do?
Bring the pattern to a clinician, particularly if episodes are self-limited, cultures are negative, and antibiotics do not help. Diagnosis requires specific testing rather than assumption.
