Case 17

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 17

Edward is 35 years old and has noted some general malaise over the past few months with some weight gain and bloating. He notices his feet, in particular, are quite swollen. When he urinates he has seen some darker tinges to the urine, even when he is clearly not passing concentrated urine (as in the morning). What has finally brought him to the doctor’s office is some bright red sputum he coughed up this morning. He is not, and never has been, a smoker. He has had no recent symptoms suggestive of a respiratory disease and he is currently afebrile. His physician ordered routine blood chemistry, a complete blood cell count with differential, a Mantoux test, and a chest radiograph. Explain the rationale for requesting each of these laboratory tests.

QUESTIONS FOR GROUP DISCUSSION

1. Edward’s primary concern is the red sputum, which he believes is blood. Although you would certainly want to investigate the possibility of a malignancy, you would not have this as the most likely cause. Explain.
2. Infection may be an issue, but if so it must be of a chronic nature such as cytomegalovirus or Mycobacterium tuberculosis. About which risk factors would you want to ask your patient to help rule out tuberculosis? What tests would you request?
3. In addition to the red-tinged sputum, you need to consider the weight gain (as per description), some peripheral edema, and blood in the urine. Which of these issues could be caused by a (a) liver-related problem? (b) kidney-related problem? Explain. How would you proceed to investigate this?
4. Blood chemistry revealed elevated potassium and creatinine levels. What potential problem is indicated by these results?
5. A 24-hour urine collection revealed that Edward is spilling a considerable amount of red blood cells and protein into the urine. What does this result indicate?
6. You have a patient with evidence for both lung and renal involvement. While the possibility exists that this unfortunate man has multiple problems, Occam’s razor suggests that we try to explain both with one diagnosis. What feature(s) are common to both lungs and kidney?
7. Direct binding of autoantibodies to antigens of the basement membrane could trigger an inflammatory response that would present in the manner described in this case. Review the immunologic processes that would lead to the pathologic process observed.
8. What autoimmune disorders would you now suspect?
9. Explain how a biopsy with immunofluorescent staining could help you in your diagnosis of Goodpasture’s syndrome, an autoimmune disorder in which antibody binding to the basement membrane leads to kidney problems, versus an autoimmune disorder in which antigen-antibody complexes lodge in the glomeruli and trigger an inflammatory response.
10. An enzyme-linked immunosorbent assay (ELISA) could be used to support the results of your biopsy. For what specific autoantibodies would you be testing?

RECOMMENDED APPROACH

Implications/Analysis of Family History

No information is provided regarding family history.

Implications/Analysis of Clinical History

Edward’s primary concern is the red (blood-tinged?) sputum, and you certainly need to consider this along with other clinical presentations. Obviously there will be some concern over malignancy, but there are no obvious risk factors, and so other causes should be pursued first. Infection remains a possibility, but it must be of a chronic nature if this is causative. Certainly, tuberculosis might present this way, but one would expect a weight loss not a weight gain. Despite this, it is still important to ask about travel and exposure, both of which are risk factors for this disease. A chest radiograph and a Mantoux test were ordered to rule out exposure to Mycobacterium tuberculosis, the causative agent of tuberculosis.

The other issues that need explanation are the weight gain, bloating, some peripheral edema (swollen feet), and dark urine. The dark urine may be an indication of blood or bilirubin (a pigment derived from a breakdown of heme from red blood cells). Because bilirubin is metabolized in the liver, this may reflect a liver-related problem. However, this may also indicate a disorder of the renal filtration system because the renal glomerulus normally filters out red blood cells. Disorders of the renal filtration system, therefore, can lead to leakage of protein (causing osmotic shifts and edema) as well as to blood-tinged urine.

Implications/Analysis of Laboratory Investigation

The Mantoux test was negative and the chest radiograph was uninformative, although a sputum sample showed red blood cells and neutrophils, indicating an inflammatory response in the respiratory system. However, sputum culture to establish whether an infection was the stimulus for the inflammatory response indicated only normal lung/buccal flora.

Routine blood chemistry and a complete blood cell count will help to develop understanding of this problem. In this case, chemistry revealed elevated serum creatinine and potassium levels, both reflective of a potential problem in renal filtration. Creatinine, a protein released by muscles, is released into the blood and the rate at which it is removed is an indication of kidney function. An increase in serum creatinine and potassium values indicates that neither is being removed as efficiently as it should be (a normal process in the healthy functioning kidney), but verification requires a creatinine clearance test. The white blood cell count indicated an increase in both neutrophils and lymphocytes. In the absence of infection, an increase in both neutrophils and lymphocytes suggests that there is an ongoing immune response, as would occur in autoimmune disorders.

Additional Laboratory Tests

To examine kidney function in more detail, a 24-hour urine collection was ordered to measure creatinine clearance (which is not affected by muscle mass). In effect, this test measures the decrease in serum/blood creatinine over a period of time. When serum creatinine concentration is elevated, one would expect a low clearance rate for creatinine, as this test indicated.

Additionally, an assay of the urine collected indicated that Edward is spilling red blood cells and a considerable amount of protein into the urine (both normally filtered out at the glomerulus and returned to the circulation).

Occam’s Razor

At this stage you have a patient with evidence for both lung and renal involvement. Occam’s razor suggests we try to explain both with one diagnosis, rather than presume this unfortunate man has multiple problems (but remember…this can happen!). Because both the lung and kidney have a basement membrane that looks (immunologically speaking) the same, an inflammation at this membrane could produce the very pathologic process we are observing.

Biopsy and Staining

An antibody-mediated inflammatory reaction at this site will cause the pathophysiology described previously. You should request a biopsy of the relevant affected organs (lung-transbronchial biopsy; renal biopsy) and also staining of tissues (immunofluorescence assay [IFA]) to look for evidence of immunoglobulin deposition. For the IFA, the patient’s serum is deposited on a normal kidney tissue section. To detect autoantibodies that have bound to the tissue, fluorescein-labeled anti-human IgG (or IgA) antibodies are added. Not only is the presence of fluorescein-labeled antibodies diagnostic, but so is the pattern of fluorescence that is observed. If the autoantibodies are bound directly to the tissue (e.g., Goodpasture’s syndrome), a ribbon-like pattern is observed. In contrast, if preformed immune complexes have been deposited in the tissues (e.g., systemic lupus erythematosus [SLE], rheumatoid arthritis [RA]), the pattern will appear to be “lumpy bumpy.”

Staining of Edward’s tissue indicated a ribbon-like (smooth linear) deposit of antibody along the glomerular capillaries (basement membrane), which is consistent with a diagnosis of Goodpasture’s disease. It is important to determine the cause of the pathology, not only because the treatment will be different but also because the longer-term prognosis and course of disease will be very different. The IFA test does not detect specific antibodies, rather it detects any IgG and IgA antibodies that are bound directly to the basement membrane.

Confirmatory Test

An ELISA can be performed to confirm that the patient’s serum contains antibodies specific for the globular domain of collagen IV polypeptides, which is present in the glomerular basement membrane.

DIAGNOSIS

A diagnosis of Goodpasture’s syndrome, an autoimmune disorder, was confirmed. This is another excellent example of a type II antibody-mediated hypersensitivity reaction (mediated by antibody binding direct to antigen on a cell surface, with subsequent induction of inflammation and pathology, via complement- and/or Fc-mediated events).

THERAPY

Plasmapheresis to remove the circulating anti–basement membrane antibodies, along with potent immunosuppression is the recommended therapy.

ETIOLOGY: GOODPASTURE’S SYNDROME

Goodpasture’s syndrome is a rare autoimmune disorder in which autoantibodies bind to antigenic determinants in the basement membrane of the lungs (alveoli) and kidneys (glomeruli). These antigen/antibody complexes activate the classical pathway of complement and phagocytes, which results in inflammation in the glomeruli (glomerulonephritis) and bleeding in the lungs (pulmonary hemorrhage). Normally, the alveolar endothelium prevents antibody contact with the basement membrane; therefore, an increase in alveolar-capillary permeability, as occurs in a nonspecific inflammation, must occur to allow the anti–basement membranes access to the basement membrane epitopes.

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