Robert J Lock

C1 inhibitor deficiency: consensus document

We present a consensus document on the diagnosis and management of C1 inhibitor deficiency, a syndrome characterized clinically by recurrent episodes of angio‐oedema. In hereditary angio‐oedema, a rare autosomal dominant condition, C1 inhibitor function is reduced due to impaired transcription or production of non‐functional protein. The diagnosis is confirmed by the presence of a low serum C4 and absent or greatly reduced C1 inhibitor level or function. The condition can cause fatal laryngeal oedema and features indistinguishable from gastrointestinal tract obstruction. Attacks can be precipitated by trauma, infection and other stimulants. Treatment is graded according to response and the clinical site of swelling. Acute treatment for severe attack is by infusion of C1 inhibitor concentrate and for minor attack attenuated androgens and/or tranexamic acid. Prophylactic treatment is by attenuated androgens and/or tranexamic acid. There are a number of new products in trial, including genetically engineered C1 esterase inhibitor, kallikrein inhibitor and bradykinin B2 receptor antagonist. Individual sections provide special advice with respect to diagnosis, management (prophylaxis and emergency care), special situations (childhood, pregnancy, contraception, travel and dental care) and service specification.

Undiagnosed coeliac disease at age seven: population based prospective birth cohort study

Coeliac disease is uncommon in childhood and diagnosed in fewer than 1 in 2500 children in the United Kingdom.1 Subclinical disease is, however, common in adults, and can be detected by testing for serum IgA antiendomysial antibodies (IgA-EMA).2 We aimed to establish the prevalence of undiagnosed coeliac disease in the general population at age seven, and to look for associated clinical features. We studied children aged 7.5 years participating in the Avon Longitudinal Study of Parents and Children (ALSPAC), a population based birth cohort study established in 1990.3 Two stage screening included a sensitive initial radioimmunoassay for antibodies to tissue transglutaminase (endomysial antigen) with further testing of positive samples for IgA-EMA by indirect immunofluorescence.4 Children with tTG antibodies below the 97.5th centile were defined as antibody negative. Height, weight, and haemoglobin levels were measured at dedicated study clinics. Details of gastrointestinal symptoms and special diets were collected by routine questionnaire at age 6.75 years. Of …

Lymphoproliferative disease in antibody deficiency: a multi-centre study

We have undertaken a retrospective study of antibody deficient patients, with and without lymphoma, and assessed the ability of specific polymerase chain reaction (PCR) primers to determine if the detection of clonal lymphocyte populations correlates with clinical and immunohistochemical diagnosis of lymphoma. We identified 158 cases with antibody deficiency presenting during the past 20 years. Paraffin‐embedded biopsy specimens or slides were available for analysis in a cohort of 34 patients. Of these patients, 29 had common variable immunodeficiency, one X‐linked agammaglobulinaemia, one X‐linked immunoglobulin deficiency of uncertain cause and three isolated IgG subclass deficiency. We have confirmed that lymphoma in antibody deficiency is predominantly B cell in origin. Clonal lymphocyte populations were demonstrated in biopsies irrespective of histology (16/19 with lymphoma and 11/15 without). Isolated evidence of clonality in biopsy material is therefore an insufficient diagnostic criterion to determine malignancy. Furthermore, our data suggest that clonal expansions are rarely the result of Epstein–Barr virus‐driven disease.

Immunoglobulins and immunoglobulin subclasses in the elderly

Background: Published data imply that adult concentrations are achieved for all Ig isotypes and plateau by 15--18 years of age. Recent data, however, suggest that these results are not applicable in the elderly. There are no equivalent data for IgG subclasses. We present reference range data for an elderly UK patient population, for IgG, IgA, IgM and IgG subclasses. Methods: Serum immunoglobulins were reviewed on samples from 1146 patients > 60 years of age and 925 patients aged 18--60 years. Serum IgG subclasses were reviewed on samples from 498 patients >60 years and 484 patients aged 18--60 years. All Igs and subclasses were measured by nephelometry. Reference ranges were derived by probability plotting. Results: Serum median IgG and IgM concentrations are reduced in the elderly (IgG female P < 0·001, IgG male P < 0·03; IgM female P < 0·001, IgM male P < 0·001). Serum IgA concentrations are maintained. Indeed, men showed a slight increase in serum IgA with age (P = 0·03). Few differences dependent on gender were seen. Median IgM was lower in men in the younger age groups (18--60 years P < 0·001; 61--70 years P = 0·017). IgG2 is reduced in elderly men (P = 0·002) and IgG, reduced in elderly women (P = 0·009). Conclusions: We advocate that centres offering these investigations provide local, method-dependent reference ranges, and suggest an approach as to how this might be achieved.

A multicentre study comparing two methods for serum free light chain analysis

Background Serum free light chain analysis is now well established in the investigation of monoclonal gammopathies. In the UK there has, until recently, been a single supplier of kits for such analysis. Recently, a second method using monoclonal antisera was introduced. We have compared the performance of these two kits in four routine laboratories. Method Samples submitted for routine analysis (327 samples, 258 [79%] from patients with B-cell lymphoproliferative disease) for serum free light chains were tested by both technologies (Freelite, Binding Site and N Latex FLC, Siemens), according to the manufacturers’ instructions. Results Qualitative data were available by both methods on 313 samples for serum free kappa chains and 324 samples for lambda free light chains. We found poor correspondence of 81% for kappa and 74% for lambda. Five percent of samples were significantly discordant in these assays. Conclusions These assays perform very differently in clinical practice. They cannot be used interchangeably, especially if monitoring patient responses to therapy.

Subclinical hypothyroidism: a comparison of strategies to achieve adherence to treatment guidelines

Background: Subclinical hypothyroidism is an entity based on the laboratory findings of a raised serum thyrotrophin (TSH) concentration and a normal free thyroxine (FT4) concentration. Patients with subclinical hypothyroidism who also have anti-thyroid peroxidase (TPO) antibodies have a higher conversion to overt hypothyroidism than those without, and treatment with thyroxine is recommended. Method: We audited anti-TPO assay requests within two NHS Trust hospitals, against consensus standards, to ascertain whether a cascade approach to anti-TPO testing and direct advice leads to more appropriate prescribing of thyroxine in general practice. Results: Our data show that where anti-TPO status was automatically tested for and clear advice for treatment given, >85% of patients were treated according to the standard required by the consensus document, with >90% of those recommended to be commenced on thyroxine actually doing so. In contrast, where anti-TPO was not routinely assessed, treatment was started in 46% of patients, without clear evidence that this was appropriate. Conclusion: In order to better advise clinicians and in accordance with the agreed protocol, laboratory-generated cascade testing for anti-TPO antibodies should be an integral part of the investigation of subclinical hypothyroidism, and reports should contain appropriate interpretation and advice.

Laboratory testing for C1 inhibitor deficiency: a comparison of two approaches to C1 inhibitor function

Background: C1 inhibitor deficiency may be hereditary or acquired. It is characterized by absent or poorly functioning C1 inhibitor. The disorder is rare, with prevalence estimated at 1/50,000. The very low incidence of the condition makes the sensitivity and specificity of assays used particularly important. Two different methods are commercially available to measure C1 inhibitor function. There are few data comparing these assays. Methods: Two assays of C1 inhibitor function (C1 inhibitor-C1s complex formation or inhibition of C1 esterase cleavage of artificial substrate [colorimetric]) were compared in 71 patients (28 hereditary angioedema, 2 acquired angioedema and 41 controls). Results: Qualitatively, the two assays showed good correspondence (92%). Six of 71 results were discordant. Correlation in quantitative terms was moderate (R = 0.81). Conclusions: Both assays show high sensitivity for hereditary/acquired angioedema. The colorimetric assay is more prone to false-positive results. However, clinical interpretation is not adversely affected.

Cinryze™ (C1-inhibitor) for the treatment of hereditary angioedema

Cinryze™ is a pasteurized, nanofiltered plasma derived concentrate of C1-inhibitor (pdC1-INH) licensed for the prophylactic treatment of hereditary angioedema. In a double-blind placebo-controlled crossover trial to evaluate Cinryze as prophylaxis, the frequency of attacks was halved (6.26 per 12 weeks on Cinryze versus 12.73 per 12 weeks on placebo). Furthermore, attacks were generally milder and of shorter duration. For treatment of acute attacks in patients receiving Cinryze, 1000 units, within 4 h of the start of an attack, the estimated time to the onset of unequivocal relief was reduced to 2 h, compared with more than 4 h in those treated with placebo. Cinryze and other similar products are going to change the future management of hereditary angioedema and have potential in other areas of medicine.

Immunoglobulin E deficiency: a forgotten clue pointing to possible immunodeficiency?

Background Patients with primary antibody deficiency often have delayed diagnosis. Very low IgE, found during investigations for allergy, may be a marker for other immunodeficiency. Methods We introduced a new laboratory policy of testing cases with very low IgE levels for possible linked antibody deficiency. The data represent an audit of routine results collected over two years. Results Very low IgE (≤2 IU/mL) was identified in 85/2622 (3.2%) routine patient samples. Two children and four adult patients were found to have one or more classes of immunoglobulin below the reference range for age. In 2/6, the initiative of the laboratory led to a new unsuspected diagnosis of antibody immunodeficiency. Conclusions Common variable immunodeficiency continues to be overlooked as a primary cause of lung disease in adults. Very low serum IgE should trigger appropriate investigation (immunoglobulin quantification and serum electrophoresis).

Laboratory clues to immunodeficiency; missed chances for early diagnosis?

Primary immunodeficiency is seen in an estimated one in 1200 people, and secondary immunodeficiency is increasingly common, particularly with the use of immunosuppresion, cancer therapies and the newer biological therapies such as rituximab. Delays in the diagnosis of immunodeficiency predictably lead to preventable organ damage. Examples of abnormal pathology tests that suggest immunodeficiency from all laboratory specialities are given, where vigilant interpretation of abnormal results may prompt earlier diagnosis. If immunodeficiency is suspected, suggested directed testing could include measuring immunoglobulins, a lymphocyte count and T-cell and B-cell subsets.