Case 20

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 20

A 38-year-old female, MM, is seen in your office complaining of malaise for the past several months, a chronic cough, and pain in the left flank with hematuria (red blood cells in the urine). There is no medical history of note. There is no recent travel; she is afebrile, a nonsmoker, and not on any medication (either over-the-counter or prescribed). There is a family history of kidney stones, but her diet is not particularly rich in proteins, oxalates, or dairy products.

You order a routine chest radiograph and blood work/urinalysis. The report from the laboratory shows increased serum/urinary calcium concentrations and urinary red blood cells, and bilateral hilar lymphadenopathy (enlargement of the lymph nodes where the blood vessels and nerves enter the lung) is evident on the radiograph. Otherwise the blood work is normal, including serum/urinary urate levels. Urate elevation is a common cause of stone formation with genetically linked altered purine metabolism.

QUESTIONS FOR GROUP DISCUSSION

1. Hematuria and pain in the left flank, combined with the family history, is suggestive of renal colic. Explain why this does not account for all of this patient’s symptoms.
2. What diseases might affect both the lungs and kidney, as well as contributing to this patient’s feeling unwell? Review Case 17.
3. The laboratory studies showed normal serum/urinary urate levels. Explain why this would rule out kidney stones as an explanation for this patient’s symptoms described in question 1. Why might drug-induced allergies cause a similar presentation?
4. The laboratory report also indicated that this patient had an increase in serum calcium concentration. Discuss some of the causes of this finding.
5. Explain how you would rule out (a) lytic bone disease (e.g., myeloma with osteolytic lesions) and (b) parathyroid adenoma (tumor of the parathyroid gland).
6. The chest radiograph indicated bilateral adenopathy (enlargement of glandular tissue, particularly of the lymph glands). Given the results of the chest radiograph, it is likely that infection with Mycobacterium tuberculosis would be high on the list of probabilities. What test could you administer to your patient to indicate whether this patient had been exposed to this infectious agent? What antigen would you use as a positive control? Explain why a positive control would be necessary.
7. Having ruled out tuberculosis as a consideration to explain this patient’s symptoms, a computed tomographic (CT) scan was performed for more definition of the lungs. Results suggest granulomatous lesions in the peripheral lung fields with confirmation of hilar adenopathy, which is suggestive of sarcoidosis. What would you expect a biopsy of the lung tissue to show?
8. Compare/contrast the granulomas in tuberculosis with those in sarcoidosis.
9. Patients with sarcoidosis have elevated levels of angiotensin-converting enzyme (ACE). Although a positive result supports a diagnosis of sarcoidosis, it is not confirmatory. Explain.
10. Describe the Kviem test. Discuss the limitations of the test and provide a rationale for the fact that it is not approved by the U.S. Food and Drug Administration (FDA).

RECOMMENDED APPROACH

Implications/Analysis of Family History

A familial history of kidney stones in a female directs us away from any X-linked disorders.

Implications/Analysis of Clinical History

The hematuria, combined with MM’s family history, is suggestive of renal colic (intense pain in the lower back on one side as a result of passing a small stone down the ureter). But, if this is the problem, what is causing the kidney stone formation? Of note is the fact that both the lungs and kidneys are affected. We have already encountered two autoimmune diseases, Goodpasture’s syndrome (see Case 17) and systemic lupus erythematosus (see Case 18), that cause a similar type of presentation owing to immune complex deposition in these tissues. Some drug-induced allergies can also manifest like this.

Implications/Analysis of Laboratory Investigation

We need to consider the implications of the increased serum/urinary calcium concentrations. MM’s blood work indicated hypercalcemia, which is significant because kidney stones may develop in the presence of high serum calcium or urate. In this case, the serum urate value was normal. There are multiple causes of elevated serum calcium, including high doses of dietary supplements, altered bone metabolism (increased osteolysis [bone breakdown] vs. osteoblastogenesis [bone formation]), altered renal excretion, and parathyroid gland problems (this gland produces parathyroid hormone [PTH], which with vitamin D is an essential regulator of calcium/bone metabolism). None of these, however, clearly links the radiographic findings with calcium metabolism changes. Nevertheless you need to ensure that this patient does not have a lytic bone disease that could be causing this problem (e.g., myeloma with osteolytic lesions). A skeletal survey and/or bone scan will answer this.

Additional Laboratory Tests

Tests to investigate the possibility of a parathyroid adenoma (tumor of the parathyroid gland) were negative, but the levels of parathyroid hormone were elevated, suggesting that this may be contributing to (or the cause of) the increased calcium levels. A CT scan performed for more definition of the lung lesions revealed granulomatous-like lesions in the peripheral lung fields and confirmed the hilar lymphadenopathy.

Mantoux Test

Granulomatous-like lesions are present in the lungs of patients with tuberculosis; however, the classic presentation is a bilateral posterior apical lesion. Still, given the chronic cough and malaise, a Mantoux test, with an appropriate positive control, should be administered to rule out tuberculosis. In the Mantoux test tuberculin protein (purified protein derivative) isolated from cultures of Mycobacterium tuberculosis is injected intradermally and the effect examined 48 hours later. In this case, both the Mantoux test and the positive control were negative, and so one cannot definitively rule out tuberculosis. Anergic skin testing, along with the bilateral hilar adenopathy, are consistent with sarcoidosis, a multisystemic disease of unknown etiology. It is thought that the low ratio of circulating CD4+ T cells to CD8+ suppressor and cytotoxic T cells explains this nonresponsiveness. Additionally, it is thought that the low CD4+ T helper cell count is the result of these cells migrating to the granulomas.

Biopsy

Fiberoptic bronchoscopy with transbronchial lung biopsy revealed noncaseating granulomas, consistent with sarcoidosis. In caseating granulomas the degraded tissue is converted to a dry cheesy mass, whereas in noncaseating granulomas this change does not occur. Although noncaseating granulomas are present in conditions other than sarcoidosis, the granulomas in tuberculosis are caseating, which would also rule out tuberculosis.

Angiotensin-Converting Enzyme

Diagnosis of sarcoidosis is mainly one of “exclusion” in that there is no test that functions as a “gold standard.” To support this presumptive diagnosis, the serum level of ACE should be determined. In its active form, ACE plays a role in the regulation of blood pressure by stimulating the production of a hormone (aldosterone) and by inducing vasoconstriction, both of which lead to an increase in blood pressure. MM’s serum indicated an elevated level of ACE, which is consistent with sarcoidosis but is not diagnostic in that patients with miliary tuberculosis will have elevated levels of ACE as will patients with inflammatory reactions occurring after inhalation of metal dust (e.g., beryllium dust), mold, and so on.

Pulmonary Function Tests

A spirometer is used to measure how rapidly a person can blow air out of the lungs following deep inhalation. Another lung test measures how much air the lung can hold (lung volume). (See Case 19.) Both of these were lower than normal when MM was tested, which is consistent with a diagnosis of sarcoidosis.

Kviem Test

This is a skin test, similar to the Mantoux test, in that it involves the subcutaneous injection of a substance and examination 48 hours later. In the Kviem test, which was developed in the late 1930s, a spleen homogenate from a person with sarcoidosis is injected intradermally into the person suspected of having sarcoidosis. Although a positive result can be seen after 48 hours, the area is not sampled for 4 to 6 weeks to allow time for granuloma formation. Formation of a noncaseating granuloma supports a diagnosis of sarcoidosis. A positive result is obtained in about 80% of all patients with active sarcoidosis (50% nonactive disease) but less than 1% of the normal population. This test is not FDA approved, nor has it been standardized.

DIAGNOSIS

Although there is no definitive test for sarcoidosis, the number of test results consistent with this disease strongly suggests that this is the correct diagnosis.

THERAPY

Not all patients with sarcoidosis require corticosteroid therapy. In some patients the disease follows a benign course. When required, long-term treatment with corticosteroids (to arrest granulomatous inflammation) is suggested. Other immunosuppressive therapies include cyclosporine and methotrexate. Electrocardiograms should be performed on all patients with sarcoidosis to ensure that there is no nonspecific granulomatous involvement of cardiac tissue and no evidence of cardiac ischemia (secondary to impaired lung function). In rare cases renal involvement can also occur. (See also amyloidosis, a condition characterized by the deposition of amyloid in tissues or organs.)

ETIOLOGY: SARCOIDOSIS

Sarcoidosis is a multisystemic disease of unknown etiology that may affect any organ in the body. However, most patients have some degree of lung involvement. The highest incidence of the disease occurs in young African American males. Sarcoidosis is a type IV hypersensitivity reaction, precipitated by chronic Th1 sensitization/activation in response to ill-defined antigens, leading (as in tuberculosis) to chronic granuloma formation. A granuloma consists of an aggregate of cells arranged in almost concentric layers focused about macrophage-derived epithelioid cells (so named because histologically they resemble epithelial cells). Giant cells resulting from the fusion of macrophages may be present. Lymphocytes surround this region (Fig. 20-1). Older granulomas develop a circle of fibroblasts that define the outer region along with fibrous connective tissue.

image

FIGURE 20-1 Sarcoid granulomas in the lung. The center of the lesion contains endothelioid cells, some of which fuse to form giant cells but (unlike the lesions of M. tuberculosis) without caseation and a peripheral ring of leukocytes. (Hematoxylin & eosin, ×200.)

Macrophages and epithelioid cells in these granulomas often produce an excess of ACE, an enzyme normally produced locally within the renal architecture that regulates filtration pressures and calcium absorption in the glomerulus. In those patients with active disease, the levels of ACE increase and can be used to monitor response to medication and disease progression. Granulomas may also produce 1,25-dihydroxyvitamin D, a hormone that increases intestinal absorption of calcium and increases the likelihood of kidney stone formation.

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