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Thyroid function, pulmonary arterial hypertension and scleroderma
322
The American Journal of Medicine, Vol 118, No 3, March 2005
ment can induce malabsorption or bleeding lesions,3–5 but can also be feebly symptomatic, as previously observed.5 We believe that this variant is probably underdiagnosed, as Congo red staining is not systematically performed. Previously studied families with lysozyme amyloidosis were of English,3,4 Scandinavian1 and French descent.2,5 Interestingly, our last reported family with digestive lysozyme amyloidosis was also of Piedmont origin without consanguinity.5 From a genetic point of view, only three mutations have been described in the lysozyme gene: Trp64Arg,2,5 Asp67His3,8 and Ile56Thr.1 The Trp64Arg mutation reported here has been associated with renal2 and digestive involvement.5 In the case of this patient, an incorrect diagnosis of systemic AL amyloidosis could have been made if complete analysis of the amyloid deposits had not been performed. In the study by Lachmann et al,8 a misdiagnosis of hereditary amyloidosis as AL amyloidosis was observed in 34 of 350 patients, with one case of misdiagnosis as lysozyme amyloidosis. Lysozyme amyloidosis belongs to the group of hereditary systemic autosomal dominant amyloidoses, but sporadic cases, such as those observed by Lachmann et al and in the present case, could occur due to low penetrance of the mutation.8,9 This observation reveals the need to precisely determine the nature of amyloid fibrils. Amyloidosis of different types (i.e., AA, AL, transthyretin, lysozyme, fibrinogen) can produce similar visceral involvement but prognosis and treatment are completely different.8,9
Brigitte Granel, MD Jacques Serratrice, MD Patrick Disdier, MD Pierre-Jean Weiller, MD Assistance Publique Hôpitaux de Marseille Centre Hospitalier Timone Marseille, France Sophie Valleix, MD Assistance Publique Hôpitaux de Paris Centre Hospitalier Cochin and Institut Cochin Paris, France Gilles Grateau, MD Assistance Publique Hôpitaux de Paris Centre Hospitalier de Tenon and Institut Cochin Paris, France Dominique Droz, MD Assistance Publique Hôpitaux de Paris Hôpital Saint Louis Paris, France doi:10.1016/j.amjmed.2004.10.022
References 1. Pepys MB, Hawkins PN, Booth DR, et al. Human lysozyme gene mutations cause hereditary systemic amyloidosis. Nature. 1993;362: 553–557. 2. Valleix S, Drunat S, Philip JB, et al. Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family. Kidney Int. 2002;61:907–912. 3. Gillmore JD, Booth DR, Madhoo S, et al. Hereditary renal amyloidosis associated with variant lysozyme in a large English family. Nephrol Dial Transplant. 1999;14:2639 –2644. 4. Harrison RF, Hawkins PN, Roche WR, et al. Fragile liver and massive hepatic haemorrhage due to hereditary amyloidosis. Gut. 1996;38:151–152. 5. Granel B, Serratrice J, Valleix S, et al. A family with gastrointestinal amyloidosis associated with variant lysozyme. Gastroenterol. 2002; 123:1346 –1349. 6. Friedman S, Janowitz HD. Systemic amyloidosis and the gastrointestinal tract. Gastroenterol Clin North Am. 1998;27:595– 614. 7. Zalin AM, Jones S, Fitch NJS, Ramsden DB. Familial nephropathic non-neuropathic amyloidosis: clinical features, immunohistochemistry and chemistry. Q J Med. 1991;81:945–956. 8. Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med. 2002;346: 1786 –1791. 9. Hachulla E, Grateau G. Diagnostic tools for amyloidosis. Joint Bone Spine. 2002;69:538 –545.
Thyroid function, pulmonary arterial hypertension and scleroderma To the Editor: Pulmonary arterial hypertension, a serious disease of unknown cause, has been found to be associated with scleroderma1 and thyroid disorders.2 We studied 40 scleroderma patients (9 with diffuse scleroderma, 31 with limited scleroderma; 38 women, 2 men; age 62 ⫾ 12 years). Pulmonary arterial systolic pressure was determined by Doppler echocardiography: a value ⱖ35 mm Hg defined pulmonary hypertension. Thyroid involvement was assessed by measurements of thyrotropin (reference range, 0.4 to 5.5 IU/mL [3]), free triiodothyronine, free thyroxin, and antithyroid antibodies (i.e., antithyroid peroxidase, antithyroglobulin). Seventeen patients (42.5%) had pulmonary systolic pressure ⱖ35 mm Hg. Elevated pulmonary pressures were not related to age or type of sclerodema. Five female patients (12.5%) had thyroid dysfunction (2 had hypothyroidism, 3 had hyperthyroidism). Pulmonary pressure was significantly higher in patients with thyroid dysfunction (40.40 ⫾ 11.33 mm Hg vs. 31.43 ⫾ 5.84 mm Hg; P ⬍ 0.01) and tended to be higher in hypothyroidism versus hyperthyroidism (46.00 ⫾ 19.80 mm Hg vs. 36.67 ⫾ 2.86 mm Hg). In contrast with previous studies,4 antithyroid antibodies were less frequent in patients with pulmonary hypertension than in those without (6% vs. 33%; P ⫽ 0.05). In particular, 7 patients without pulmonary hypertension but none with pulmonary hypertension had antiperoxidase (P ⫽ 0.01), and only 1 of the 3 patients with antithyroglobulin had pulmonary hypertension.
Letters
323
Pulmonary systolic pressure was higher in sclerodermic patients who had abnormal thyroid function than in those who were euthyroid. The lack of differences between hyperthyroid and hypothyroid patients, as well as the low frequency of antithyroid antibodies in scleroderma-associated pulmonary hypertension, suggest a vasomotor role of hormones, rather than the previously suggested autoimmune mechanism.5,6 Markers of autoimmunity have not been found in scleroderma-associated thyroid dysfunction,7 and pulmonary hypertension can resolve after normalization of thyroid function.8 Hypothyroidism might be due to gland fibrosis, a feature of scleroderma, rather than be part of an autoimmune thyroid disease. The thyroid gland expresses a number of genes that encode for vasoactive substances, including endothelin-1,9 where the role in pulmonary hypertension is well known.10 Bianca Marasini, MD Marco Massarotti, MD Roberta Cossutta, MD Rheumatology Unit Istituto Clinico Humanitas Department of Medicine Surgery and Dentistry University of Milan Milan, Italy doi:10.1016/j.amjmed.2004.09.020
References 1. Steen V. Systemic sclerosis and related syndromes: clinical features. In: Primer on Rheumatic Diseases. Klippel JHCL, Stone JH, Weyand CM, eds. Atlanta: Atlanta Arthritis Foundation: 1997;267–272. 2. Curnoch AL, Dweik RA, Higgins BH, et al. High prevalence of hypothyroidism in patients with primary pulmonary hypertension. Am J Med Sci 1999;318:289 –292. 3. Ghamra ZW, Dweik RA, Arroliga AC. Hypothyroidism and pulmonary arterial hypertension. Am J Med 2004;116:354 –355. 4. Yanai-Landau H, Amital H, Bar-Dayan Y, et al. Autoimmune aspects of primary pulmonary hypertension. Pathobiology 1995;63:71–75. 5. Badesch DB, Wynne KM, Bovallet S, et al. Hypothyroidism and primary pulmonary hypertension: an autoimmune pathogenetic link? Ann Intern Med 1993;119:44 – 46. 6. Chu JW, Kao PN, Faul JL, Doyle RL. High prevalence of autoimmune thyroid disease in pulmonary arterial hypertension. Chest 2002;122: 1668 –1673. 7. Kahl LE, Medsger TA Jr, Klein I. Prospective evaluation of thyroid function in patients with systemic sclerosis. J Rheumatol 1986;13: 103–107. 8. Mercé J, Ferrás S, Oltra C, et al. Cardiovascular abnormalities in hyperthyroidism: a prospective Doppler echocardiographic study. Am J Med. 2005;118:126 –131. 9. Colin IM, Nava E, Toussaint D, Maiter DM, et al. Expression of nitric oxide synthase isoform in the thyroid gland: evidence for a role of nitric oxide in vascular control during goiter formation. Endocrinology, 1995;136:5283–5290. 10. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732–1739.
The American Journal of Medicine, Vol 118, No 3, March 2005
ment can induce malabsorption or bleeding lesions,3–5 but can also be feebly symptomatic, as previously observed.5 We believe that this variant is probably underdiagnosed, as Congo red staining is not systematically performed. Previously studied families with lysozyme amyloidosis were of English,3,4 Scandinavian1 and French descent.2,5 Interestingly, our last reported family with digestive lysozyme amyloidosis was also of Piedmont origin without consanguinity.5 From a genetic point of view, only three mutations have been described in the lysozyme gene: Trp64Arg,2,5 Asp67His3,8 and Ile56Thr.1 The Trp64Arg mutation reported here has been associated with renal2 and digestive involvement.5 In the case of this patient, an incorrect diagnosis of systemic AL amyloidosis could have been made if complete analysis of the amyloid deposits had not been performed. In the study by Lachmann et al,8 a misdiagnosis of hereditary amyloidosis as AL amyloidosis was observed in 34 of 350 patients, with one case of misdiagnosis as lysozyme amyloidosis. Lysozyme amyloidosis belongs to the group of hereditary systemic autosomal dominant amyloidoses, but sporadic cases, such as those observed by Lachmann et al and in the present case, could occur due to low penetrance of the mutation.8,9 This observation reveals the need to precisely determine the nature of amyloid fibrils. Amyloidosis of different types (i.e., AA, AL, transthyretin, lysozyme, fibrinogen) can produce similar visceral involvement but prognosis and treatment are completely different.8,9
Brigitte Granel, MD Jacques Serratrice, MD Patrick Disdier, MD Pierre-Jean Weiller, MD Assistance Publique Hôpitaux de Marseille Centre Hospitalier Timone Marseille, France Sophie Valleix, MD Assistance Publique Hôpitaux de Paris Centre Hospitalier Cochin and Institut Cochin Paris, France Gilles Grateau, MD Assistance Publique Hôpitaux de Paris Centre Hospitalier de Tenon and Institut Cochin Paris, France Dominique Droz, MD Assistance Publique Hôpitaux de Paris Hôpital Saint Louis Paris, France doi:10.1016/j.amjmed.2004.10.022
References 1. Pepys MB, Hawkins PN, Booth DR, et al. Human lysozyme gene mutations cause hereditary systemic amyloidosis. Nature. 1993;362: 553–557. 2. Valleix S, Drunat S, Philip JB, et al. Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family. Kidney Int. 2002;61:907–912. 3. Gillmore JD, Booth DR, Madhoo S, et al. Hereditary renal amyloidosis associated with variant lysozyme in a large English family. Nephrol Dial Transplant. 1999;14:2639 –2644. 4. Harrison RF, Hawkins PN, Roche WR, et al. Fragile liver and massive hepatic haemorrhage due to hereditary amyloidosis. Gut. 1996;38:151–152. 5. Granel B, Serratrice J, Valleix S, et al. A family with gastrointestinal amyloidosis associated with variant lysozyme. Gastroenterol. 2002; 123:1346 –1349. 6. Friedman S, Janowitz HD. Systemic amyloidosis and the gastrointestinal tract. Gastroenterol Clin North Am. 1998;27:595– 614. 7. Zalin AM, Jones S, Fitch NJS, Ramsden DB. Familial nephropathic non-neuropathic amyloidosis: clinical features, immunohistochemistry and chemistry. Q J Med. 1991;81:945–956. 8. Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med. 2002;346: 1786 –1791. 9. Hachulla E, Grateau G. Diagnostic tools for amyloidosis. Joint Bone Spine. 2002;69:538 –545.
Thyroid function, pulmonary arterial hypertension and scleroderma To the Editor: Pulmonary arterial hypertension, a serious disease of unknown cause, has been found to be associated with scleroderma1 and thyroid disorders.2 We studied 40 scleroderma patients (9 with diffuse scleroderma, 31 with limited scleroderma; 38 women, 2 men; age 62 ⫾ 12 years). Pulmonary arterial systolic pressure was determined by Doppler echocardiography: a value ⱖ35 mm Hg defined pulmonary hypertension. Thyroid involvement was assessed by measurements of thyrotropin (reference range, 0.4 to 5.5 IU/mL [3]), free triiodothyronine, free thyroxin, and antithyroid antibodies (i.e., antithyroid peroxidase, antithyroglobulin). Seventeen patients (42.5%) had pulmonary systolic pressure ⱖ35 mm Hg. Elevated pulmonary pressures were not related to age or type of sclerodema. Five female patients (12.5%) had thyroid dysfunction (2 had hypothyroidism, 3 had hyperthyroidism). Pulmonary pressure was significantly higher in patients with thyroid dysfunction (40.40 ⫾ 11.33 mm Hg vs. 31.43 ⫾ 5.84 mm Hg; P ⬍ 0.01) and tended to be higher in hypothyroidism versus hyperthyroidism (46.00 ⫾ 19.80 mm Hg vs. 36.67 ⫾ 2.86 mm Hg). In contrast with previous studies,4 antithyroid antibodies were less frequent in patients with pulmonary hypertension than in those without (6% vs. 33%; P ⫽ 0.05). In particular, 7 patients without pulmonary hypertension but none with pulmonary hypertension had antiperoxidase (P ⫽ 0.01), and only 1 of the 3 patients with antithyroglobulin had pulmonary hypertension.
Letters
323
Pulmonary systolic pressure was higher in sclerodermic patients who had abnormal thyroid function than in those who were euthyroid. The lack of differences between hyperthyroid and hypothyroid patients, as well as the low frequency of antithyroid antibodies in scleroderma-associated pulmonary hypertension, suggest a vasomotor role of hormones, rather than the previously suggested autoimmune mechanism.5,6 Markers of autoimmunity have not been found in scleroderma-associated thyroid dysfunction,7 and pulmonary hypertension can resolve after normalization of thyroid function.8 Hypothyroidism might be due to gland fibrosis, a feature of scleroderma, rather than be part of an autoimmune thyroid disease. The thyroid gland expresses a number of genes that encode for vasoactive substances, including endothelin-1,9 where the role in pulmonary hypertension is well known.10 Bianca Marasini, MD Marco Massarotti, MD Roberta Cossutta, MD Rheumatology Unit Istituto Clinico Humanitas Department of Medicine Surgery and Dentistry University of Milan Milan, Italy doi:10.1016/j.amjmed.2004.09.020
References 1. Steen V. Systemic sclerosis and related syndromes: clinical features. In: Primer on Rheumatic Diseases. Klippel JHCL, Stone JH, Weyand CM, eds. Atlanta: Atlanta Arthritis Foundation: 1997;267–272. 2. Curnoch AL, Dweik RA, Higgins BH, et al. High prevalence of hypothyroidism in patients with primary pulmonary hypertension. Am J Med Sci 1999;318:289 –292. 3. Ghamra ZW, Dweik RA, Arroliga AC. Hypothyroidism and pulmonary arterial hypertension. Am J Med 2004;116:354 –355. 4. Yanai-Landau H, Amital H, Bar-Dayan Y, et al. Autoimmune aspects of primary pulmonary hypertension. Pathobiology 1995;63:71–75. 5. Badesch DB, Wynne KM, Bovallet S, et al. Hypothyroidism and primary pulmonary hypertension: an autoimmune pathogenetic link? Ann Intern Med 1993;119:44 – 46. 6. Chu JW, Kao PN, Faul JL, Doyle RL. High prevalence of autoimmune thyroid disease in pulmonary arterial hypertension. Chest 2002;122: 1668 –1673. 7. Kahl LE, Medsger TA Jr, Klein I. Prospective evaluation of thyroid function in patients with systemic sclerosis. J Rheumatol 1986;13: 103–107. 8. Mercé J, Ferrás S, Oltra C, et al. Cardiovascular abnormalities in hyperthyroidism: a prospective Doppler echocardiographic study. Am J Med. 2005;118:126 –131. 9. Colin IM, Nava E, Toussaint D, Maiter DM, et al. Expression of nitric oxide synthase isoform in the thyroid gland: evidence for a role of nitric oxide in vascular control during goiter formation. Endocrinology, 1995;136:5283–5290. 10. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732–1739.