Correspondence

Sarcoidosis

N Engl J Med 1997; 337:789-791September 11, 1997

Article

To the Editor:

We were surprised that in their review of sarcoidosis, Newman et al. (April 24 issue)1 did not mention Crohn's disease as a cause of granulomatous disease in the classification shown in their Table 1. Indeed, granulomas in the gut mucosa are the most characteristic pathological findings in Crohn's disease.

From a clinical point of view, sarcoidosis may also involve the gut, and this may lead to difficulty in distinguishing between Crohn's disease and sarcoidosis.2 From a pathogenic point of view, the two diseases seem to share some features; examples include increased intestinal permeability in patients with active pulmonary sarcoidosis and abnormal pulmonary function in patients with Crohn's disease and pulmonary involvement.3,4

Alain Schmit, M.D.
André Van Gossum, M.D.
Erasme Hospital, B-1070 Brussels, Belgium

4 References

1
Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997;336:1224-1234
Full Text | Web of Science | Medline

2
Shapiro JL, Goldblum JR, Retras RE. A clinicopathologic study of 42 patients with granulomatous gastritis: is there really an “idiopathic“ granulomatous gastritis? Am J Surg Pathol 1996;20:462-470
CrossRef | Web of Science | Medline

3
Wallaert B, Colombel JF, Adenis A, et al. Increased intestinal permeability in active pulmonary sarcoidosis. Am Rev Respir Dis 1992;145:1440-1445
Web of Science | Medline

4
Levine JB, Lukawski-Trubish D. Extraintestinal considerations in inflammatory bowel disease. Gastroenterol Clin North Am 1995;24:633-646
Web of Science | Medline

To the Editor:

Newman et al. note that sarcoidosis remains a diagnosis of exclusion. But the liver is sometimes the only organ involved, and the clinical presentation, such as fever of unknown origin1 or abnormal liver-function tests, can be quite confusing. In this case, the discovery of noncaseating granulomas on liver biopsy presents a problem in the differential diagnosis. Indeed, the diagnosis of exclusion is idiopathic “granulomatous hepatitis.” 1-3 Hepatic granulomas are a common finding in up to 30 percent of liver biopsies; in 5 to 36 percent of cases, the exact cause remains obscure.1,3 Often, however, liver granulomas reflect an occult systemic disease. The most common causes of granulomatous hepatitis are sarcoidosis, tuberculosis, drug-related causes, and idiopathic causes.1-3

M. Piagnerelli, M.D.
M. Vanhaeverbeek, M.D.
Centre Hospitalier Universitaire André Vésale, 6110 Montigny-le-tilleul, Belgium

3 References

1
Zoutman DE, Ralph ED, Frei JV. Granulomatous hepatitis and fever of unknown origin: an 11-year experience of 23 cases with three years' follow-up. J Clin Gastroenterol 1991;13:69-75
CrossRef | Web of Science | Medline

2
Vial T, Descotes J. Hépatites granulomateuses médicamenteuses. Gastroenterol Clin Biol 1993;17:H44-H48
Web of Science | Medline

3
Sartin JS, Walker RC. Granulomatous hepatitis: a retrospective review of 88 cases at the Mayo Clinic. Mayo Clin Proc 1991;66:914-918
Web of Science | Medline

To the Editor:

Newman et al. do not mention the musculoskeletal findings associated with sarcoidosis.1 The incidence of joint lesions is 25 to 50 percent in established cases.2 Arthritis is often migratory, and the joints most often involved are the ankles, knees, wrists, and elbows.1 Frequently, erythema nodosum is associated with arthritis. Nevertheless, joint symptoms may precede the development of erythema nodosum.3 In addition, chronic sarcoid arthritis may occur, with deformities.2 Bone lesions are reported in 5 percent of patients, and lytic lesions are the most common findings.3 Therefore, joint and bone involvement should be included in the list of the manifestations of sarcoidosis, and sarcoidosis should be considered in the differential diagnosis of polyarthritis.

Fernando Díaz, M.D.
Hospital de Galdakao, 48960 Vizcaya, Spain

3 References

1
Mitchell DN. Sarcoidosis with skeletal involvement. In: Klippel SH, Dieppe PA, eds. Rheumatology. St. Louis: Mosby, 1994:3.37.1-3.37.8.

2
Crystal RG. Sarcoidosis. In: Isselbacher KJ, Martin JB, Braunwald E, Fauci AS, Wilson JD, Kasper DL, eds. Harrison's principles of internal medicine. 13th ed. Vol. 2. New York: McGraw-Hill, 1994:1679-84.

3
Arnold WJ. Sarcoidosis. In: Kelley WN, Harris ED Jr, Ruddy S, Sledge CB, eds. Textbook of rheumatology. 4th ed. Vol. 2. Philadelphia: W.B. Saunders, 1993:1429-34.

To the Editor:

I enjoyed the excellent review of sarcoidosis by Newman et al. I was surprised, however, not to find hypothalamic and pituitary invasion in the list of possible types of organ involvement. Hypothalamic and pituitary diseases have been reported in patients with systemic sarcoidosis.1,2 The clinical manifestations include diabetes insipidus,2 polyphagia with morbid obesity,3 abnormalities in the regulation of temperature and vessel-tone control,4 and hypopituitarism.5 The diagnosis is usually confirmed by nuclear magnetic resonance imaging. Occasionally, sarcoidosis may cause a mass that can be mistaken for a nonsecreting pituitary adenoma.1 The physician caring for patients with sarcoidosis should be aware of these possible clinical manifestations in order to detect early manifestations of neuroendocrine dysfunction.

Roberto Salvatori, M.D.
Johns Hopkins University, Baltimore, MD 21287

5 References

1
Lara Capellan JI, Cuellar Olmedo L, Martinez Martin J, et al. Intrasellar mass with hypopituitarism as a manifestation of sarcoidosis: case report. J Neurosurg 1990;73:283-286
CrossRef | Web of Science | Medline

2
Baylis P, Thompson CJ. Diabetes insipidus and hyperosmolar syndromes. In: Beckett KL, ed. Principles and practice of endocrinology and metabolism. Philadelphia: J.B. Lippincott, 1995:257-65.

3
Vesely DL. Hypothalamic sarcoidosis: a new cause of morbid obesity. South Med J 1989;82:758-761
CrossRef | Web of Science | Medline

4
Wathen CG, Campbell I, Douglas AC. Hypothalamic malfunction in cerebral sarcoidosis with abnormalities in temperature regulation and vascular control. Sarcoidosis 1988;5:74-76
Medline

5
Stuart CA, Neelon FA, Lebovitz HE. Hypothalamic insufficiency: the cause of hypopituitarism in sarcoidosis. Ann Intern Med 1978;88:589-594
Web of Science | Medline

To the Editor:

We commend Newman and colleagues for an outstanding review of sarcoidosis. However, the issue of lung transplantation for end-stage sarcoidosis warrants additional consideration. Newman et al. acknowledge the increased rate of acute rejection and the possibility of recurrent sarcoidosis after transplantation but argue that these problems should not preclude transplantation.

The authors state that most recurrences are mild. However, follow-up data in patients undergoing lung transplantation for sarcoidosis are limited, and the long-term effect of recurrent sarcoidosis is unknown. In addition, for patients with sarcoidosis and fungal colonization or mycetomas, the optimal prophylactic therapy before transplantation is unclear. In our limited experience, patients with sarcoidosis have a high rate of invasive fungal infection after lung transplantation despite pretransplantation prophylaxis with itraconazole, inhaled amphotericin B, or both. Furthermore, the optimal transplantation procedure (single or bilateral) in such patients is unclear. Finally, recent data suggest an increased rate of obliterative bronchiolitis in patients with sarcoidosis after lung transplantation.1 Obliterative bronchiolitis is a form of chronic allograft rejection and contributes substantially to post-transplantation morbidity and mortality.2

Scott M. Palmer, M.D.
Ara P. Miralles, R.N.
Victor F. Tapson, M.D.
Duke University Medical Center, Durham, NC 27710

2 References

1
Muller C, Briegel J, Haller M, et al. Sarcoidosis recurrence following lung transplantation. Transplantation 1996;61:1117-1119
CrossRef | Web of Science | Medline

2
Hosenpud JD, Novick RJ, Bennett LE, Keck BM, Fiol B, Daily OP. The Registry of the International Society for Heart and Lung Transplantation: thirteenth official report -- 1996. J Heart Lung Transplant 1996;15:655-674
Web of Science | Medline

To the Editor:

We think Newman et al. understate the value of antimalarial agents in the treatment of sarcoidosis. Chloroquine and hydroxychloroquine have been used successfully to treat sarcoidosis since the first published report on such treatment in 1953.1 Many studies have shown that these agents are effective in the treatment of hypercalcemia.2-5 Current guidelines suggest that a safe daily dose is 250 mg (maximal cumulative dose, 600 g), with funduscopic and visual examinations every six months. If the frequent side effects of long-term corticosteroid therapy are weighed against the relatively rare retinal toxic effects of chloroquine (in 0.45 to 2 percent of patients) and given that patients receiving chloroquine are closely monitored with sensitive ophthalmologic techniques, there is a strong case for the use of chloroquine as a second-line therapy and a corticosteroid-sparing drug in the treatment of chronic sarcoidosis.

Nilar Than, M.B., Ch.B.
John H. Turney, M.D.
General Infirmary at Leeds, Leeds LS1 3EX, United Kingdom

5 References

1
Shaffer B, Cahn MM, Levy EJ. Sarcoidosis apparently cured by quinacrine (Atabrine) hydrochloride. Arch Dermatol 1953;67:640-641
Web of Science

2
Hunt BJ, Yendt ER. The response of hypercalcemia in sarcoidosis to chloroquine. Ann Intern Med 1963;59:554-564
Web of Science | Medline

3
O'Leary TJ, Jones G, Yip A, Lohnes D, Cohanim M, Yendt ER. The effects of chloroquine on serum 1,25-dihydroxyvitamin D and calcium metabolism in sarcoidosis. N Engl J Med 1986;315:727-730
Full Text | Web of Science | Medline

4
Barre PE, Gascon-Barre M, Meakins JL, Goltzman D. Hydroxychloroquine treatment of hypercalcemia in a patient with sarcoidosis undergoing hemodialysis. Am J Med 1987;82:1259-1262
CrossRef | Web of Science | Medline

5
Adams JS, Diz MM, Sharma OP. Effective reduction in the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia with short-course chloroquine therapy. Ann Intern Med 1989;111:437-438
Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Drs. Schmit and Van Gossum and Drs. Piagnerelli and Vanhaeverbeek raise important points concerning the clinical overlap between sarcoidosis and various disorders of the gut and liver. Because of its protean manifestations and the absence of a known etiologic agent or diagnostic test, sarcoidosis can mimic many other inflammatory diseases. Practitioners should maintain a high index of suspicion with regard to the possibility of systemic disease and should be willing to look for other organ involvement whenever they find granulomas. We must listen carefully to patients who report a variety of seemingly diverse symptoms.

The observations of Dr. Díaz and Dr. Salvatori help emphasize the point that sarcoidosis can affect virtually any organ and should be considered in the differential diagnosis of bone and joint disorders1 and of endocrinopathies.2 In addition to the pituitary and hypothalamus, sarcoidosis can affect the thyroid, parathyroid, and adrenal glands, as well as nearly every part of the male and female reproductive systems.

The possible involvement of diverse organs and the lack of well-designed clinical trials make treatment decisions difficult, especially for complicated cases of sarcoidosis. We agree with Palmer et al. that further research is needed to examine the role of lung transplantation in sarcoidosis. We agree with Drs. Than and Turney that quinolines may be beneficial in treating sarcoidosis-related hypercalcemia and skin disease. With appropriate daily doses and monitoring of side effects, hydroxychloroquine is a safe treatment option.3 Given the limited treatment armamentarium for sarcoidosis, clinical investigation of novel immunomodulatory agents is warranted.

Lee S. Newman, M.D.
Cecile S. Rose, M.D., M.P.H.
Lisa A. Maier, M.D.
National Jewish Medical and Research Center, Denver, CO 80206

3 References