Correspondence

Carcinoid Heart Disease

N Engl J Med 2003; 348:2359-2361June 5, 2003

Article

To the Editor:

Møller et al. (March 13 issue)1 addressed the topic of the progression of carcinoid heart disease. Serial echocardiographic studies were available for 71 of the 273 referred patients. The median level of urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion at base line in patients with carcinoid heart disease was 209 mg per 24 hours, and in those without carcinoid heart disease it was 110 mg per 24 hours; the median duration of the syndrome was relatively short, at 1.0 and 1.8 years, respectively. Remarkably, data on 5-HIAA levels during the course of this disease are scarce. We therefore studied 73 patients with the carcinoid syndrome who were referred between 1985 and 2002, in whom the 5-HIAA level was measured at one-year intervals. The median urinary 5-HIAA level gradually increased, reaching 110 mg per 24 hours only after more than seven years had passed (Figure 1Figure 1Median Urinary 5-Hydroxyindoleacetic Acid (5-HIAA) Levels over Time.). The very high urinary 5-HIAA levels and the high incidence of carcinoid heart disease relative to that in another recent study2 suggest that Møller et al. studied a highly selected group. This underscores that although somatostatin analogues did not prevent carcinoid heart disease in their population, a beneficial effect is not precluded in less advanced disease.

Anouk N.A. van der Horst-Schrivers, M.D.
Anke N.M. Wymenga, M.D., Ph.D.
Elisabeth G.D. de Vries, M.D., Ph.D.
University Hospital Groningen, 9700 RB Groningen, the Netherlands
a.n.a.schrivers@int.azg.nl

2 References

1. 1

   Moller JE, Connolly HM, Rubin J, Seward JB, Modesto K, Pellikka PA. Factors associated with progression of carcinoid heart disease. N Engl J Med 2003;348:1005-1015
   Full Text | Web of Science | Medline

2. 2

   Zuetenhorst JM, Bonfrer JM, Korse CM, Bakker R, Van Tinteren H, Taal BG. Carcinoid heart disease: the role of urinary 5-hydroxyindoleacetic acid excretion and plasma levels of atrial natriuretic peptide, transforming growth factor-beta and fibroblast growth factor. Cancer 2003;97:1609-1615
   CrossRef | Web of Science | Medline

To the Editor:

Møller et al. reported that a high peak level of urinary 5-HIAA excretion is a predictor of carcinoid heart disease. However, the duration of exposure to elevated serotonin levels might be an even more important factor in the development of valvular fibrosis. The serotonin load can be assessed as the area under the curve for urinary 5-HIAA excretion. In our series of 37 consecutive patients (19 women and 18 men) with carcinoid heart disease,1 the median interval between the diagnosis and cardiac ultrasonography was 28 months (range, 2 to 121). There was a significant correlation between the presence of carcinoid heart disease and the median level of urinary 5-HIAA excretion during the interval between diagnosis and cardiac ultrasonography (5-HIAA level, 576 μmol per 24 hours in the patients with carcinoid heart disease, as compared with 233 μmol per 24 hours in those without it; P=0.02). However, there was an even stronger relation between carcinoid heart disease and the serotonin load over time (i.e., the area under the curve for urinary 5-HIAA excretion during this interval) (P<0.001). This finding supports the theory that total exposure to serotonin is even more important than the level of serotonin in the development of carcinoid heart disease.

Johanna M. Zuetenhorst, M.D.
Babs G. Taal, M.D., Ph.D.
Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
j.zuetenhorst@nki.nl

1 References

1. 1

   Zuetenhorst JM, Bonfrer JMG, Korse CM, Bakker R, van Tinteren H, Taal BG. Carcinoid heart disease: the role of urinary 5-hydroxyindoleacetic acid excretion and plasma levels of atrial natriuretic peptide, transforming growth factor-beta and fibroblast growth factor. Cancer 2003;97:1609-1615
   CrossRef | Web of Science | Medline

Author/Editor Response

Drs. Zuetenhorst and Taal raise a pertinent question regarding the relative importance of the duration of exposure to elevated serotonin levels as compared with the peak level of serotonin in the development and progression of carcinoid heart disease. If the area under the curve is going to be compared between groups, serotonin excretion should be assessed at fixed time points at similar stages in the development of the disease. Not infrequently, patients with the carcinoid syndrome have carcinoid heart disease at the time of diagnosis or a long history of symptoms of the carcinoid syndrome preceding the date of diagnosis. Meaningful assessment of the area under the curve would be impossible in these circumstances. Thus, we related the peak values of urinary 5-HIAA to changes in the cardiac score (a score based on valvular anatomy and function and right ventricular function) during follow-up.

Dr. van der Horst-Schrivers and colleagues raise a potential issue regarding selection bias. The population in our study was selected from 273 consecutive patients with carcinoid tumors who were referred for echocardiography because of suspected carcinoid heart disease. Thus, a high frequency of carcinoid heart disease and high 5-HIAA excretion would be expected. However, we did not find any difference in peak 5-HIAA levels between the patients who were included in the study (median, 222 mg per 24 hours; interquartile range, 148 to 345) and those who were excluded (median, 238 mg per 24 hours; interquartile range, 131 to 362) (P=0.79). In contrast to the data presented by van der Horst-Schrivers and colleagues, we found that 5-HIAA levels decreased during follow-up, probably as a result of an aggressive therapeutic strategy. The 5-HIAA levels in our study were similar to those measured in previous studies of similar populations.1,2 Thus, we believe that the population we studied is representative of patients with clinically significant carcinoid heart disease.

It is possible that somatostatin analogues may slow the progression of carcinoid heart disease. However, the available data indicate that current methods of treatment are inadequate to prevent the development and progression of carcinoid heart disease. Larger, prospective studies are needed to define the optimal treatment strategy.

Jacob E. Møller, M.D.
Heidi M. Connolly, M.D.
Patricia A. Pellikka, M.D.
Mayo Clinic, Rochester, MN 55905
pellikka.patricia@mayo.edu

2 References

1. 1

   Denney WD, Kemp WE Jr, Anthony LB, Oates JA, Byrd BF III. Echocardiographic and biochemical evaluation of the development and progression of carcinoid heart disease. J Am Coll Cardiol 1998;32:1017-1022
   CrossRef | Web of Science | Medline

2. 2

   Westberg G, Wangberg B, Ahlman H, Bergh CH, Beckman-Suurkula M, Caidahl K. Prediction of prognosis by echocardiography in patients with midgut carcinoid syndrome. Br J Surg 2001;88:865-872
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Anouk N.A. van der Horst-Schrivers, Wendy J. Post, Ido P. Kema, Thera P. Links, Pax H.B. Willemse, A.N. Machteld Wymenga, Elisabeth G.E. de Vries. (2007) Persistent low urinary excretion of 5-HIAA is a marker for favourable survival during follow-up in patients with disseminated midgut carcinoid tumours. European Journal of Cancer 43:18, 2651-2657
   CrossRef

2. 2

   Anouk N.A. van der Horst-Schrivers, A.N. Machteld Wymenga, Thera P. Links, Pax H.B. Willemse, Ido P. Kema, Elisabeth G.E. de Vries. (2004) Complications of Midgut Carcinoid Tumors and Carcinoid Syndrome. Neuroendocrinology 80:Suppl. 1, 28-32
   CrossRef