C ~ prime esterase inhibitor deficiency presenting as intestinal pseudo ~ obstruction and angioedema

A 17-year-old man presented with episodic abdominal pain, distension 
and vomiting. Esophageal manometry showed a reduced lower esophageal pressure 
with massive reflux, gastric emptying of liquids was normal and migrating 
myoelectric complexes were present on small bowel motility tracing. Full thickness 
surgical biopsies from the upper jejunum, mid-small bowel and ileum showed a 
normal villus pattern bur a reduction in the number of neurons in the myenteric 
plexus, degeneration and shrinkage of some of the persisting neurons in the myenteric 
plexus and swelling of the accompanying nerve fibres and Schwann cells. This 
was interpreted to be compatible with intestinal neurogenic pseudo-obstruction. He 
initially responded to glucocorticosteroids with reduction in the frequency and severity 
of these symptoms, accompanied by weight gain and a 14 cm growth in height. 
The steroids were stopped after two years, but within weeks his pain and distension 
returned. He then developed symptoms of angioedema, with markedly reduced C1 
esterase inhibitor activity and reduced C4 Both the symptoms of ,mgioedema and 
pseudo-obstruction were well controlled with stanozolol. His younger brother later 
developed similar symptoms. also had C1 esterase inhibitor deficiency, and also responded 
to stanozolol; an older brother had previously had similar symptoms which 
were lost over time. This suggests that C1 esterase inhibitor deficiency may produce 
symptoms indicative of intestinal obstruction.

C -PRIM!: ESTERA'iE INIIIBITOR Dl:.FI• cie ncy is th e most co mmon genetically in herited disorder of com plement inhibition, producing a syndrome of recurren t angioedema characterized b y swelling of face, larynx, bowel wall, genitalia and exrremiries.The inheritance is of autosoma l dominant m oc.le , although a rarer acquired form may occur.In one study of l04 cases, attacks of swelling affected the subcutaneous tissue, the upper airway and the bowel mucosa in 86'\, .76''., and 7 5"o of parient~.respectively (I).More than hal( of the patients had onset of the sympto ms of the disease before 12 years of age; l2 to IH<l~ of pa tients underwent unnecessary surgery because of an erroneous di agnosis ( 1,2 ).About th ree-q u:i rte rs of patients may present with symptoms of abdominal pain or vomiti ng (1)(2)(3)(4).The diagnosis may be obscured by the absence of cutaneous, oropharyngeal and respiratory invo lvement (5).Abc.lomin;il films may show evidence of thumb-printing and mucosa!edema (2, "l ).Respirntory obstruction Jue to laryngeal ede ma can CAN J GASTROL~TI:ROI be fatal without appropriate treatment.Prodromes of attacks are Je~cribcd by one-half of the patients as a feeling of 'discomfort' or anxiety.starti ng 24 h before the attack ( l,2).Alsn.one-half of the patients can iden tify triggering factors such a!> foods, local trauma (ie.dental procedures), anxiety and psychological stress ( I. 2).
The biochemical d efect is deficiency ofC' csterase inhibitor or prod uction of an inactive inhibitor.T his will cause uncontrolled activation of the complement ~vstem; activation of the plasma billikrein system lcaJs ro formation of vasoactive substances (6).The diagnosis can be confirmed by the reduced level ofC• c~tcrasc inhibitor or the presence of funcuonal inacti ve inhibitor.c! and c4 are both reduced duri ng acute attacks.
Antihistamines, corticosteroids a n d adrenaline are usua lly not effective for the treatment of hereditary angioedema.Treatment of acute attacks wou ld include infusion ofC• esterase in h ibitor concentrate or fresh , frozen plasma wh ich contains the inhibitor ( 1,7,8 ).The re is a theoretical danger that fresh frozen plasma may supply su bstrate fo r c• and rhereforc perpet ua te the attack.Antifibrinolytic agents such as aminocaproic acid or transexamic acid are pmcnt inhibitors of plasma which may activate C 1 and can be used in preventative therapy.These agents can.however, ca use serious adverse effects (8,9); both can induce rhabdomyolysis and thrombosis.ln addition, transexamic acid h as tumourogenic poten tial.
Androgen derivatives such as oxymetholone, stanozolol and danazol are efiective in preventing attacks of angioedema (8-10).The poten tia l ad verse effects include masculinization and mensrrual disorders in women, diminished spermatogenesis in men, peliosis h epatitis, benign hepatomas and hepatic carcinoma.Androgen derivatives shou ld be avoided in pregnant women or children .Patients with infrequen t or m ild attacks of hereditary angioedema may not need 1 0 be trea ted with drugs.Before Jental proced ures, these patien ts should receive cirhcr C' esterase inh ibitor concentrate or a short course of androgen derivatives.

CASE PRESENTAT ION
The case of a young man with 5ymp-Vol 2 No.2,June 1988 toms and parhological changes compatib le with familial n eurogenic psuedoobstruction.associated with C• esterase inhibitor deficiency is described.
The patient was a ca ucasian male who was 17 years o ld w hen he was in itiall y referred to the Gastroenrerology Teaching C linic, University of Alberta in 1980 for investigation of episodic abdom inal pain and vomiting, though t to be due to irritable bowel synJrome.
Because of crampy peri u mbilical abdominal pain associated with vomiting.he had hnd a laparo tomy in 1974 fo r suspected appendicitis.The append ix was normnl but the terminal ileum was noted to be questionably inflammed.He subsequently had several upper gastrointesti n al series with foll ow-th rough examinations.w h ich demonstrated a possibly abnormal terminal ileum, but no definitive diagnosis wa5 made.
A duodenal ulcer wns su~pected o n barium meal examinations performed in 197 5 and 1977.He had no pain to suggest active peptic disease and the radiological abnormalities were not treated.He had intermittent abdominal pain and vomiting.The pain was described as severe dull epigastric discomfort, associated with d istension, b u rping and flatulence.He developed vomiting of partially digested food anywhere from 12 to 36 h after the onset of the pain.Once the episodes of vomit1ng stopped.his abdominal pai n improved.The frequency of these attacks varied from once every fo ur weeks, to once weekly.T here was no histor y of d iarrhea of dysphagia.
The p hysical examination in 1980 was unremarkable, apart from the presence of a prominen t gastric succussion splash which was aud ible 3 h after ingestion of a small meal.T here were no featu res of scleroderma, palpable thyroid or neurologica l abnormalities, in clud ing no clinical evidence of autonomic dysfunction.
A gastroscopy in 1980 revealed a dilatcJ stomach and the ACM [ panendoscope could be introduced I to 2 cm past the pylorus.There was no evidence of ulcer in e ither th e stomach or the duodenum.Small bowel enteroclysis showed mucosa!th ickening of the descending duoden um.A small bowel mucosa!b iop~y was subsequently found to be u nremarkable.He was initia lly treat• C 1 esterase Inhibitor deficiency and the intestine ed with mcroclopramiJe (Maxernn; Nordic) 10 mg qid before meab ,ind at bedtime.T h e metoclopram ide made him nauseated and it was discontinued.
The patient continued to experience the symptoms of pain, vomiting, distension and excess gas, therefore, he was fu rther investiga ted in 1981.The upper gastrointestinal and fo ll ow-through examination demonstrated a Jilared stomach wi th th icken ing of the mucosa!fo ld~ of the duodenum and jeiu num.The barium enema was unremarkable, with reflux of barium into a normal appearing terminal ileum.A technetium-sulphur colloid gastric emptying scan performed w h en the patient was symptomatic showed a normal gastric h alf-emptyi ng time for liq u ids of92 mins.Esophageal motil ity study (i ncluding a pH probe) showed massive gastroesophagcal reflux , hut the motility of the body of the esophagus was normal.
Because of the concern that the abnormal radiological appearance of the small inte~tine represented lymphomatous infiltration , explorat0ry laparotomy was performed.There was approximately 700 ml of clear fluid within rhe peritoneal cavity and th is flu id was sent for culture and cy tology, which were negative The entire upper half to two-thirds of small hmvel was rhickcnecl and edem-Mous.Sections of full thickness surgical biopsies (Figures I and 2) from the upper jejunum, mithma ll bowel and ileum showed: swollen myenreric plexus at all levels of small howcl examined ( ie, upper jejunum, mid-anJ small intestine and ileum); moderate subm ucosal edema from the upper jejunum a nd midsmall in testine, but not from the ileum; in testinal villi well preserved at all levels; swnllen ganglia in thl' myenteric plexus at all levels.an apparen t reduction in the n umber of neurons and enlarge ment and fine vacuolation of Sch wann cells (also present were dark.shrunken neurons with misshapen perikarya and irregular processes, and neurons with swollen perikarya and intra-n uclear vacuoles); Sch wann cells were not increased in numbers (Schwannosis); identical but much less severe changes were observed in ganglia of the submucous nerve plexus.
Because of the failure of the metoclopramide, the severity of symptoms and the minim:11 congestion and edema in the   The known second ar y causes of pseudo-obstruction arc shown in Ta hlc I. and newer causes arc being rernncd (24).With idi opathic intestinal pseudo-obstruction, a bnorma Ii l it's may be found m either the smooth muscle or myentcric plexus 12 5-34) Rarely, no hisl(llogical abnormality of the smooth musde or myenteric plexus is detected (27.29).
In  oral an tihioucs such as IL'tracycline or metronidazole (26).Dietary manipulations arc of little value ( 26).Total parenteral nutri tion is useful for treatment of the symptoms and for improvement of the nutritional status 126.27.31.41,42).
Use o f steroid h as been infrequent in rhl' management of th is syndrome ( 31 ).
G lucocnrucosteroids wcrL' used in this patient because of the albeit modest con• gestion and edema in the small bowel.ln n:trospect, thl'Se h istological changes may have been due in pare to the angio-11l'tirnut edema whid1 certainly must h,t\'l' been prl•sent at that time.