Case 18

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 18

Doris is a 25-year-old married black woman. Over the past 6 months she has noticed increasing swelling in her legs with “frothy” dark urine and she has had intermittent severe headaches, unrelated to menses. Despite her and her husband’s wishes, she has been unable to conceive for 5 years and now has had three spontaneous abortions, all in the first 8 to 12 weeks of pregnancy. Query into the family history indicated that she was an adopted child. A detailed analysis of Doris’s serum immunoglobulin, a complete blood cell count, and blood chemistry was ordered. Laboratory results indicated a mild increase in leukocytes, elevated IgG and serum creatinine levels, but a mild thrombocytopenia. Additionally, urinalysis indicated that she was spilling protein in her urine, along with some red cells.

QUESTIONS FOR GROUP DISCUSSION

1. What is the significance of leg swelling and urinary problems in an otherwise healthy 25-year-old? List the three facts that indicate that Doris has urinary problems.

2. Explain why a kidney infection or kidney stone is not high on your list of considerations. In the absence of these conditions, what would the spilling of protein and red blood cells into the urine suggest?

3. Noninfectious inflammation in the kidneys as a consequence of autoantibodies could trigger an inflammatory response. In some conditions, autoantibodies bind directly to cells forming immune complexes. In other conditions, autoantibodies form complexes with soluble antigens. These complexes may lodge in small vessels and trigger inflammatory processes. Explain how the inflammatory response would be triggered, irrespective of which of these two scenarios was occurring (see Case 23).

4. Despite the similarities with respect to urinalysis and elevated serum creatinine, there are differences with respect to clinical presentation in this patient and the one described in Case 17. Discuss these differences.

5. Doris has had severe intermittent headaches. Although this could be a forerunner of a central nervous system (CNS) malignancy, we should consider immunologic causes of headaches, given the apparent noninfectious inflammation in the kidney. What immunologic conditions can cause headaches?

6. Doris has had three spontaneous abortions. Are there any immunologic causes that can lead to spontaneous abortions? Explain how this would occur.

7. Given the diverse spectrum of symptoms, we could consider multiple causes or focus on a systemic autoimmune disorder. Explain how immune complex deposition could account for both the renal problems and the headaches.

8. What might you expect to see if we measured the serum C3 levels? Why? How could you use this “marker” to monitor active disease or therapy?

9. What would you expect to see if you performed a biopsy with immunofluorescence staining? Compare/contrast with what was reported in Case 17.

10. This patient has a mild thrombocytopenia. Explain the role that the indirect and the direct Coombs’ tests have in determining the cause of thrombocytopenia.

RECOMMENDED APPROACH

Implications/Analysis of Family History

At 25 years of age, congenital defects are unlikely to make their first appearance. Unfortunately, because Doris is adopted we cannot trace any potential genetic susceptibility for her disease. However, we need to consider those disorders in which data indicate a significant ethnic susceptibility in black females.

Implications/Analysis of Clinical History

Peripheral Edema

Leg swelling in an otherwise healthy individual should make you wonder about renal problems (see Case 17). In the absence of infection or an obstruction (kidney stone, which generally presents with pain as severe as childbirth labor!), the peripheral edema suggests noninfectious inflammation “higher up” the urinary tract (in the kidney). Immune complex deposition in the glomeruli, with subsequent complement and neutrophil activation, triggers an inflammatory response that leads to a condition known as glomerulonephritis.

Headaches

In the absence of other causes (both non–life threatening [e.g., migraine] and otherwise [tumor]), headaches are often caused by inflammation within blood vessel walls in the central nervous system (CNS). This vasculitis (cerebritis) is again a result of immune complex deposition on basement membranes/endothelia, with complement and neutrophil activation, resulting in subsequent changes in vessel permeability with edema/release of inflammatory mediators.

Spontaneous Abortion

The spontaneous abortions could be an indication of an autoimmune disease, in which autoantibodies formed cross the placenta and interfere with fetal well-being. Antiphospholipid antibody, the so-called lupus anticoagulant (a misnomer, since it is a cause of thrombosis!) that is detected in about 15% of patients with systemic lupus erythematosus [SLE], has been shown to induce spontaneous abortion. This is presumed to reflect an increased susceptibility to thrombosis in the fetal:maternal circulation with subsequent fetal demise. Several other autoantibodies (antiplatelet, anti-leukocyte, and anti-DNA antibodies) are also formed in SLE patients. These autoantibodies lead to the formation of immune complexes, deposition in the glomeruli, and renal failure (glomerulonephritis).

Implications/Analysis of Laboratory Investigation

Urinalysis revealed that she was spilling protein in her urine, along with some red cells. The presence of protein and red blood cells in her urine would explain the “frothy,” dark description.

Laboratory results also indicated an elevated serum creatinine level, which suggests that the kidneys are not clearing creatinine efficiently, and this should be followed with a 24-hour urine collection to measure the rate of clearance (see Case 17). Ineffective clearance of creatinine is consistent with immune complex–mediated damage to the kidneys.

The elevated IgG value indicates that there is an ongoing antibody response. In the absence of an infection, this is highly suggestive of an autoimmune (or malignant) disease. The mild lymphopenia and thrombocytopenia are both consistent with the presence of autoantibodies causing lysis of both normal white blood cells and platelets. There is no evidence of anemia (autoantibodies to red cells) and so a Coombs’ test is not necessary (see Case 15).

Additional Laboratory Tests

Antinuclear Antibody Immunofluorescence Test

Based on the clinical presentation and laboratory investigations, a presumptive diagnosis of SLE would be reasonable. To further investigate this possibility, a request should be made for an antinuclear antibody (ANA) immunofluorescence assay. In this assay the patient’s serum is incubated with human epithelioid cells, followed by the addition of antihuman Fcγ fluorescent-labeled (e.g., fluorescein isothiocyanate [FITC]) antibodies for detection. Although a negative result rules out a diagnosis of SLE, a positive result is not confirmatory in that normal patients and those with chronic inflammatory disorders may test positive for ANA (highly sensitive, moderate specificity). In this case, Doris’s ANA test was positive, suggesting that she could have SLE.

Anti-DNA test

To support a positive ANA result, the anti-DNA antibody titer, which is commonly measured using an enzyme-linked immunosorbent assay (ELISA), should be determined. This test has moderate sensitivity and high specificity, and so a negative anti-DNA antibody test does not eliminate SLE as a possible diagnosis because not all SLE patients have anti-DNA antibodies. A positive anti-DNA antibody test, combined with a positive ANA, makes a diagnosis of SLE very likely. Doris’s anti-DNA antibody titer was significantly high, supporting a diagnosis of SLE.

Complement C3 and C4

In active disease the levels of C3 and C4 are decreased. C3 and C4 are proteolytically cleaved when immune complexes activate the classical pathway of complement. Because C3 and C4 complement protein levels are “concordant” with disease activity, this can be used to monitor disease and its response to therapy.

Kidney Biopsy

The prognosis regarding kidney function is assessed using a renal (glomeruli) biopsy with immunofluorescence staining (Fig. 18-1). This assay detects immune complexes that have been deposited in the basement membrane and endothelia. You would expect to see bright staining that appears “lumpy and bumpy,” indicating that the detected autoantibodies are part of a preformed immune complex and not simply bound to the basement membrane.

FIGURE 18-1 Lupus nephritis with immune complex deposition. Type III hypersensitivity occurs along the basement membrane of glomerular capillary loops. (Immunofluorescent staining for IgG, ×400.)

DIAGNOSIS

Doris has systemic lupus erythematosus.

THERAPY

Therapy for SLE consists of high doses of corticosteroid (intermittent cyclophosphamide for kidney disease).

ETIOLOGY: SYSTEMIC LUPUS ERYTHEMATOSUS

SLE is a multisystem/systemic disorder with manifestations in multiple organs/tissues (see Cases 22 and 31). There is a known genetic association with human leukocyte antigens (HLA) DR2/DR3. Further evidence for genetic susceptibility in SLE is the greater concordance in monozygotic (MZ) rather than dizygotic (DZ) twins (30% vs. <10%). There is also a correlation with the complement C2 and C4 genes and tumor necrosis factor (TNF) receptor genes. Presumably (in a multisystem/multigenic disorder) these genes are all implicated at different stages in either the ontogeny of immune development to antigens that are important in the etiology of the disease or in the subsequent inflammatory responses that follow.

The CNS inflammation can often cause very significant CNS pathology. Seizures have been described in this scenario. Neuropsychiatric testing often reveals significant deficits (e.g., in memory, intellectual ability). These are generally not permanent if aggressive treatment of the underlying cause (i.e., SLE) is used. Presumably, the deficits reflect transient neurologic “stunning” from inflammatory processes.

Note that another autoantibody (Anti-Ro antibody), which can be passed from mother to fetus, has been described to cause transient neonatal heart block (potentially fatal fetal arrhythmia). Because the source of this autoantibody is the mother, the condition in the newborn is of a limited duration after birth. The maternal anti-Ro antibodies can be detected in the newborn, but the half life of IgG is 21 days and so the antibodies generally have disappeared by the time the infant is 6 months of age.

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