Respiratory manifestations in hereditary angioneurotic edema

Hereditary angioneurotic oedema is an autosomal dominant state associated with a quantitative, and sometimes purely functional, deficiency of C1 esterase inhibitor (C1 INH). The clinical manifestations may begin during adulthood or childhood; they are periodical and of varying severity. Beside oedema of the skin and digestive disorders, respiratory disorders are bound to attract attention. They consist of laryngeal oedema, which may end in lethal asphyxia if tracheotomy is not performed, or, exceptionally, of pulmonary oedema requiring assisted ventilation, as in the case reported here. The diagnosis, suspected in the presence of a decrease in CH50 and C4, is confirmed by a quantitative assay of C1 INH, which is low, and/or by the Fong and Good's functional tests. The physiopathological mechanisms are complex. They involve complement activation through the classical route, and activation of the coagulation system contact phase. Patients with severe attacks now benefit from treatment with preparations of C1 INH in high concentrations. The best treatment, however, is prophylactic, using testosterone derivatives, danazol and stanozolol, which can be prescribed for long periods taking into account their usually moderate side-effects.     

Hereditary angioneurotic edema and familial Crohn's disease.

A 29-year-old man with Crohn's disease involving the ileum and cecum was seen. He had angioneurotic edema with C1' esterase inhibitor deficiency. Later, his 50-year-old mother was evaluated because of abdominal pain. She had recurrent urticaria, C1' esterase inhibitor deficiency and radiographic studies showed Crohn's disease of the ileum. A maternal family history revealed other members affected with either Crohn's disease or angioneurotic edema. The clinical observations in this family suggest that angioneurotic edema associated with C1' esterase inhibitor deficiency may be closely linked genetically with a familial form of Crohn's disease.     

Sex hormones in hereditary angioneurotic oedema

OBJECTIVE: The fluctuations in sex hormone levels at the beginning of adolescence, in the perimenopausal period, during pregnancy or during the use of oral contraceptives can precipitate oedematous attacks in hereditary angioneurotic oedema (HANO). Attacks usually disappear after the onset of menopause. This study was undertaken to establish any relationship between the serum levels of sex hormones and the incidence of HANO attacks. PATIENTS AND MEASUREMENTS: Serum levels of LH, FSH, progesterone, oestradiol, testosterone, PRL and SHBG were measured in 78 patients [mean age 30.3 years (range 4-70 years)] with HANO. A questionnaire was used to explore the medical history of adult patients to characterize the evolution and the characteristics of attacks. RESULTS: The number of attacks was significantly higher [odds ratio (OR) 6.36 (1.31-30.81); P = 0.022] in females with high progesterone levels (> or = 4 nmol/l), irrespective of age, menstrual cycle and danazol dose. The OR was even higher [13.4 (2.2-81.4); P = 0.005] when only subcutaneous attacks were considered. Multiple logistic regression analysis demonstrated a significantly lower attack frequency during 1-year follow-up in patients with a higher (40 nmol/l) SHBG level (OR 0.25 (0.07-0.90); P = 0.034). This difference existed independently of age and danazol dose. CONCLUSION: In view of these results, the monitoring of progesterone and SHBG levels can prove useful in the prediction of attacks in hereditary angioneurotic oedema.     

Hereditary angioneurotic edema: review of the literature

Congenital C1-inhibitor deficiency, or hereditary angioneurotic edema (HAE), is a rare autosomal dominant disease due to alterations in the C1 inhibitor gene that results in a deficiency of antigenic and/or functional C1-INH. Affected patients are heterozygous, and their deficiency is incomplete, many of them having up to 20% of the normal amount of the inhibitor. The disease is characterised by recurrent, circumscribed, non-pitting, and non-pruritic subepithelial swellings of sudden onset, which fade during the course of 48-72 hours, but can persist up to 1 week. Lesions can be solitary or multiple and primarily involve the extremities, larynx, face, and bowel wall. Bradykinin is believed to be the main, but certainly not the sole, mediator responsible for the bouts of edema in HAE. The diagnosis is suggested by family history, the lack of accompanying pruritus or urticaria, the presence of recurrent gastrointestinal attacks of colics, and episodes of laryngeal edema. Diminished C4 concentrations during symptomatic periods are highly suggestive for the diagnosis. Further laboratory diagnosis depends on demonstrating a deficiency of C1-INH antigen (type I) in most kindreds, but some kindreds have an antigenically intact but dysfunctional protein (type II) and require a functional assay to establish the diagnosis. Prophylactic administration of either attenuated androgens or protease inhibitors has proved useful in reducing frequency or severity of attacks. Infusions of a vapour-heated C1-INH concentrate are safe and effective means of both preventing and treating attacks. Nevertheless, this treatment is expensive and this extract is not readily available. It is emphasised that administration of angiotensin converting enzyme inhibitors is contraindicated in patients suffering from protease inhibitor deficiency states.     

Studies of four Japanese families with hereditary angioneurotic edema: Simultaneous activation of plasma protease systems and exogenous triggering stimuli

Summary Forty-five relatives of 4 families with hereditary angioneurotic edema (HANE) were studied. Twenty-five, including 11 asymptomatic kindreds with the disposition, showed typical changes in complement system compatible with HANE. Follow-up study of HANE patients showed that, even in remission period, complement, coagulation and fibrinolytic systems can be activated. During edema attacks, moderate haemoconcentration and neutrophilia were encountered and kallikrein-kinin system was found to be also activated. Replacement therapy with C -inhibitor preparation for an edema attack revealed that clinical improvement paralleled the increase in blood levels of high molecular weight kininogen. Thus, HANE attack is considered to be elicited in kindreds with the hereditary disposition by activation of plasma protease systems, particularly by that of kallikrein-kinin system. On the other hand, exogenous triggers that can initiate activation of the protease systems can be classified into 2, neuro-humoral (sympathetic nerve response) and physico-chemical, categories. Hence, the edema attack of kindreds with the hereditary disposition can at least be modified by the biosynthesis of plasma factors and the individual susceptibility to the liberated catecholamines. These two different reaction processes are considered to be linked by the release of plasminogen activator and/or Hageman factor activating enzyme.Dedicated to Prof. emer. Dr. med. Tsuneo Yoshida on his 83^rd birthday and to the late Prof. emer. Dr. med. Ernst Wollheim on his 80^th birthday     

A practical approach to familial and hereditary colorectal cancer.

Recent genetic research has isolated the primary genetic defect underlying many of the hereditary colorectal cancer syndromes. Obtaining a detailed family history is the first step in identifying individuals at increased risk of developing colorectal cancer. Once identified, individuals and their families may benefit from earlier, more intensified surveillance, prophylactic surgery, cancer risk assessment and education, and genetic testing. Clinicians, especially those with many patients with colorectal cancer in their practice, must be able to address the complex issues associated with the familial and hereditary colorectal cancer syndromes. A well-integrated partnership among colorectal surgeons, gastroenterologists, oncologists, and medical geneticists is necessary to address these complex issues and provide comprehensive medical care.     

Treatment of hereditary angioneurotic oedema (HANE) with tibolone

OBJECTIVE: Eight women, aged 25-58 years, with hereditary angioneurotic oedema (HANE) were treated with tibolone, a synthetic steroid exhibiting oestrogenic, androgenic and progestational activity. DESIGN: Pilot study. RESULTS: Tibolone at a dose of 2.5-7.5 mg/day significantly reduced the number and severity of attacks and the number of ampoules of C1-esterase inhibitor (C1-INH) needed for symptomatic therapy. The efficacy of tibolone was comparable to that of danazol, while the androgenic side-effects were considerably reduced. CONCLUSIONS: Tibolone may represent an alternative to danazol administration for the prophylaxis of HANE in women.     

Type II hereditary angioneurotic edema that may result from a single nucleotide change in the codon for alanine-436 in the C1 inhibitor gene.

Identical single-base changes in the C1 inhibitor gene that may result in dysfunctional inhibitor proteins are described in two different families with type II hereditary angioneurotic edema. Initially, a restriction fragment length polymorphism was defined that resulted from loss of a Pst I site within exon VIII, which encodes the region containing the reactive center. Exon VIII from the normal and abnormal allelles was amplified by the polymerase chain reaction. Amplified DNA product was cloned into plasmid pUC18; clones representing normal and mutant allelles were distinguished by the presence and absence, respectively, of the Pst I restriction site. DNA sequence analysis revealed a G----A mutation in the codon for alanine-436, which would result in replacement with a threonine residue. This position is nine amino acid residues amino-terminal to the reactive-center arginylthreonine peptide bond. In contrast, previously defined mutations in type II hereditary angioneurotic edema result in replacement of the reactive-center arginine.     

Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology.

OBJECTIVE: To review available information on cough and angioneurotic edema associated with angiotensin-converting enzyme (ACE) inhibitors. DATA SOURCES: All relevant articles from 1966 through 1991 were identified mainly through MEDLINE search and article bibliographies. STUDY SELECTION: More than 400 articles were identified; 200 reporting incidence or possible mechanisms for the side effects or both were selected. DATA EXTRACTION AND SYNTHESIS: All pertinent information, including incidence and mechanisms of ACE inhibitor-induced cough and angioedema, was reviewed and collated. CONCLUSIONS: Cough occurs in 5% to 20% of patients treated with ACE inhibitors, recurring with reintroduction of the same or another ACE inhibitor. It is more common in women. The mechanism may involve accumulation of prostaglandins, kinins (such as bradykinin), or substance P (neurotransmitter present in respiratory tract C-fibers); both bradykinin and substance P are degraded by ACE. A 4-day trial of withdrawal of the ACE inhibitor or temporary substitution of another class of antihypertensive agent inexpensively and easily ascertains if the ACE inhibitor caused the cough. Change to another ACE inhibitor or additive therapy with nonsteroidal anti-inflammatory drugs is not recommended. Prompt recognition of ACE inhibitor-related cough can prevent unnecessary diagnostic testing and treatment. Angioedema occurs in 0.1% to 0.2% of patients receiving ACE inhibitors. The onset usually occurs within hours or, at most, 1 week after starting therapy. The mechanism may involve autoantibodies, bradykinin, or complement-system components. Treatment involves first protecting the airway, followed by epinephrine, antihistamines, and corticosteroids if needed. Therapy is then resumed with an alternate class of antihypertensive agent.     

A case of red-cell adenosine deaminase overproduction associated with hereditary hemolytic anemia found in Japan

A case of red cell adenosine deaminase (ADA) overproduction associated with hereditary hemolytic anemia is reported here. This appears to be the second report. Proband is a 38-year-old Japanese male who had hemoglobin, 15.8 g/100 ml; reticulocyte count, 4.5%; serum indirect bilirubin, 4.9 mg/100 ml; ⁵¹ Cr-labeled red cell half-life, 12 days; red cells showed moderate stomatocytosis. His red cell ADA activity showed 40-fold increase while that of the mother showed 4-fold increase. The mother was hematologically normal. The father had a normal enzyme activity. The proband and the mother showed slightly high serum uric acid levels. The proband's red cell showed: ATP, 628 nmoles/ml (normal, 1,010-1,550); adenine nucleotide pool, 46% of the normal mean; 2,3-diphosphoglycerate content, 3,782 nmoles/ml (normal 4,170-5,300); increased oxygen affinity of hemoglobin, P₅₀ of intact crythrocytes being 21.8 mmHg (normal, 24.1-26.1). Red cell glycolytic intermediates in the proband were low in general, and the rate of lactate production was low. Kinetic studies using crude hemolysate revealed a normal Km for adenosine, normal electrophoretic mobility but slightly abnormal pH curve and slightly low utilization of 2-deoxyadenosine. The ADA activity of lymphocytes was nearly normal.     

Ultrasonography in the diagnosis and monitoring of ascites in acute abdominal attacks of hereditary angioneurotic oedema.

BACKGROUND: Hereditary angioneurotic oedema (HAE) is a rare cause of ascites. As acute abdominal attacks of the disease can mimic surgical emergencies, prompt and accurate diagnosis is essential. This study was undertaken to evaluate the usefulness of serial abdominal ultrasound (US) examinations. PATIENTS AND METHODS: Seventy patients with HAE were followed up for almost a decade. All patients presenting with an acute oedematous attack underwent abdominal US, which was then repeated 24 and 48 h after appropriate therapy. RESULTS: Twenty-two acute oedematous attacks with abdominal complaints severe enough to justify hospital admission occurred in the study population. Abdominal US performed during the attack showed oedematous thickening of the intestinal wall in 80% of cases and invariably demonstrated the presence of free peritoneal fluid in all patients. Rapid symptomatic relief achieved by treatment was accompanied by the significant regression of US abnormalities. CONCLUSIONS: Transitory ascites demonstrated by abdominal US is a clue to the diagnosis of an acute abdominal attack of HAE. The possibility of HAE should always be considered whenever unexplained abdominal pain recurs with or without ascites.     

Unilateral neurogenic pulmonary edema. A case report

A vascular lesion was identified in the posterior cerebral fossa in a 65-Year-old stroke victim. The patient suddenly developed unilateral pulmonary edema. Bilateral alveolar opacities is the usual radiological aspect of neurogenic pulmonary edema but a unilateral presentation is extremely rare. The differential diagnosis includes excessive vascular filling, infectious pneumonia, gastric fluid aspiration edema, and cardiogenic pulmonary edema. The mechanisms underlying neurogenic pulmonary edema are discussed.     

Type I familial amyloidotic polyneuropathy in Japan.

We studied 107 cases and 64 carriers of type I familial amyloidotic polyneuropathy (FAP) residing in 16 districts in Japan. The age of onset of illness ranged from 20 to 71 years old, with a mean of 40.1 +/- 12.8 years (SD). One quarter of the cases were late-onset patients who developed the disorder after age 50. Asymptomatic carriers older than age 50 accounted for 20% of total carriers, with the oldest carrier being a 94-year-old woman. All the patients had a variant transthyretin with a methionine-for-valine substitution at position 30 with a mean serum level of 9.78 +/- 3.27 (SD) mg/dl. The serum level did not significantly differ by gender in either patients or carriers, nor between patients and carriers. Incomplete penetrance of clinical expression was shown in eight cases. This study indicates that there is a considerable variety in age of onset, progression and geographic distribution of type I FAP in Japan.