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Carcinoid heart disease

Carcinoid heart disease
Literature review current through: Jan 2024.
This topic last updated: Jan 11, 2022.

INTRODUCTION — Carcinoid tumors are rare, arising in 1.2 to 2.1 per 100,000 people in the general population per year [1]. They can arise anywhere in the body, but are most commonly found in the gastrointestinal tract (midgut carcinoids) and bronchus (foregut carcinoids) (table 1). Primary midgut carcinoid tumors metastasize to the liver or regional lymph nodes and may present with bowel obstruction. In 20 to 30 percent of patients, the initial presentation occurs as a result of hormone production, called the carcinoid syndrome. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts".)

The most common manifestations of the carcinoid syndrome are vasomotor changes (flushing) (picture 1), gastrointestinal hypermotility (secretory diarrhea), bronchospasm, and hypotension (table 2). These symptoms are caused by the release of vasoactive substances, including serotonin (5-hydroxytryptamine), 5-hydroxytryptophan, histamine, bradykinin, tachykinins, and prostaglandins (table 3). The diagnosis of carcinoid syndrome is usually suspected by the clinical features and confirmed by identification of the primary tumor, localization of metastatic lesions, and detection of increased urinary excretion of the by-product of serotonin metabolism, 5-hydroxyindoleacetic acid (5-HIAA) (figure 1). (See "Clinical features of carcinoid syndrome" and "Diagnosis of carcinoid syndrome and tumor localization".)

Progress in the medical and surgical management of patients with carcinoid disease has resulted in improved symptoms and survival. (See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors".)

However, carcinoid heart disease, which eventually occurs in up to 50 percent of patients with carcinoid syndrome and may be the initial presentation of carcinoid disease in a minority of patients [2,3], remains a major cause of morbidity and mortality among patients with carcinoid syndrome [4,5].

PATHOPHYSIOLOGY

Pathologic findings — Carcinoid heart disease is characterized by pathognomonic plaque-like deposits of fibrous tissue. These deposits occur most commonly on the endocardium of valvular cusps, leaflets, papillary muscles and cords, cardiac chambers, and occasionally on the intima of the pulmonary arteries or aorta (figure 2) [6,7].

The affected cardiac valves in carcinoid heart disease have a white appearance with thickened leaflets and subvalvular apparatus with fused and shortened chordae and thickened papillary muscles [8]. Microscopic examination demonstrates deposits of fibrous tissue. The carcinoid plaque is composed of smooth muscle cells, myofibroblasts, and an overlying endothelial cell layer. Smooth muscle cells and myofibroblasts are surrounded by an extracellular matrix composed of microfibrils, acid mucopolysaccharides, basement membrane, and collagen fibers [7]. The morphology of the valve leaflet is not disrupted and the carcinoid plaque generally affects the ventricular aspect of the tricuspid valve leaflets and the arterial aspect of the pulmonic valve cusps [6,9].

The valves and endocardium of the right side of the heart are most often affected by carcinoid disease [2,3]; it is postulated that the left-sided valves are usually spared due to inactivation of humoral substances by the lung (picture 2). Carcinoid plaques are observed along either endocardial surface of the tricuspid leaflets with alterations ranging from mild disease (stiff thickened leaflets with trivial or mild tricuspid regurgitation) to severe disease (fixed, retracted leaflets with severe tricuspid regurgitation with or without accompanying mild or moderate tricuspid stenosis) [8]. Carcinoid plaques also commonly affect the pulmonic valve (particularly the arterial aspect) with consequent regurgitation, stenosis, or both. In patients with advanced disease, carcinoid plaque may also involve the endocardial lining of the right heart chambers.

Left-sided valvular pathology occurs in less than 10 percent of patients with cardiac involvement [2]. It is almost always associated with an atrial level right-to-left shunt (as with a patent foramen ovale) [2,8,10,11]. These conditions permit serotonin-rich blood to enter the left heart chambers without passing through the pulmonary capillaries. The degree of right-to-left shunting may correlate with the degree of valve involvement and associated valve regurgitation [8]. Infrequently, left-sided valve disease occurs in patients without a right-to-left shunt. This is usually related to severe, poorly controlled carcinoid syndrome with high levels of circulating serotonin. Carcinoid valve disease affecting the aortic or mitral valve generally manifests as valve thickening and pure regurgitation [7].

An additional rare cardiac complication is metastasis to the heart, identified by echocardiography in 2 (4 percent) of 252 patients with carcinoid syndrome in one series [8]. In a review of 11 such patients, the small bowel was the source of the primary tumor in nine and all had the carcinoid syndrome and hepatic metastases [4]. Transthoracic echocardiography detected nine tumors ≥1 cm in size in 5 of 11 patients, revealing a well circumscribed, noninfiltrating, and homogeneous mass.

Role of serotonin — Evidence suggests a role for serotonin in the pathogenesis of carcinoid heart disease. Alterations in serotonin metabolism, its associated receptors, and transporter gene have been proposed as likely mechanisms for development of carcinoid related valvular heart disease [12,13]. It is thought that high circulating serotonin concentration is the major effector of carcinoid heart disease and of the similar valve lesions that may be induced by the ergot-alkaloid derivatives, the anorectic drugs fenfluramine (alone or in combination with phentermine) and dexfenfluramine and the dopamine receptor agonist pergolide and cabergoline used for Parkinson's disease. The data supporting the role of serotonin in the pathogenesis of valve disease are presented elsewhere. (See "Valvular heart disease induced by drugs", section on 'Pathogenesis'.)

In nearly all patients with carcinoid syndrome, tryptophan metabolism is altered so that 70 percent or more of dietary tryptophan is converted to serotonin, as compared with approximately 1 percent in normal subjects. Serotonin is metabolized to 5-hydroxyindoleacetic acid (HIAA) (figure 1). (See "Clinical features of carcinoid syndrome", section on 'Tryptophan metabolism'.)

Indirect evidence in support of the role of serotonin in the carcinoid syndrome in humans comes from a study that compared 19 patients with carcinoid heart disease (diagnosed by echocardiography or cardiac catheterization) with 585 carcinoid patients without heart disease [14]. The patients with heart disease had much higher (two- to fourfold) values for serum and plasma serotonin, platelet serotonin, and urinary 5-HIAA excretion. They were also three times as likely to have typical carcinoid symptoms. Similarly, in a report in 23 patients with carcinoid syndrome, urinary 5-HIAA values averaged 356 mg/day in those with heart disease compared with only 99 mg/day in those without cardiac involvement [15].

Urinary 5-HIAA excretion may also predict progression of carcinoid heart disease. In a report from Mayo Clinic, which included 71 patients in whom serial echocardiograms were performed more than one year apart, a "cardiac score" was developed to define the severity of cardiac involvement (including grading scales for tricuspid and pulmonic valve abnormalities as well as right ventricular size and function). Urinary 5-HIAA levels were significantly higher in those with a >25 percent increase in cardiac score than in those with lesser evidence of progression (265 versus 189 mg/day) [16].

Liver disease, usually due to hepatic metastases, is thought to play a permissive role by allowing large quantities of tumor products such as serotonin to reach the right heart without being inactivated [17,18]. Rarely, patients with a primary ovarian carcinoid develop carcinoid heart disease in the absence of hepatic metastases because the liver is bypassed by direct venous drainage of the ovary into the inferior vena cava [19,20].

Despite the likely pathogenic link between serotonin and carcinoid heart disease, it is not known if medical therapy to reduce serotonin secretion can prevent the development of cardiac lesions. In an uncontrolled observational series, patients treated with somatostatin analogs, which decrease serotonin secretion, did not demonstrate absent or delayed development of valve disease. (See 'Treatment of carcinoid syndrome' below.)

CLINICAL MANIFESTATIONS

Symptoms — The clinical manifestations of carcinoid heart disease are often subtle early in the course of the disease. In addition, moderate to severe tricuspid and pulmonary valve disease may be well tolerated for many months. Early symptoms of right-sided valvular heart disease include fatigue and dyspnea on exertion. Right-sided heart failure with worsening dyspnea, edema, ascites, and eventual cardiac cachexia occur with progressive disease.

Physical examination — The major findings on physical examination include an elevated jugular venous pressure with a prominent "v" wave; this is often the earliest clinical finding (see "Examination of the jugular venous pulse"). Additional clinical features include a palpable right ventricular impulse, and murmurs of tricuspid and pulmonic valve regurgitation [21]. Less frequently, a systolic murmur of pulmonary stenosis or a diastolic murmur of tricuspid stenosis is audible. Right-sided cardiac murmurs are accentuated by inspiration. (See "Auscultation of cardiac murmurs in adults".)

The auscultatory findings may be subtle, as the murmurs of tricuspid and pulmonary valve disease may be difficult to detect due to the low pressure in the pulmonary circulation. As an example, the murmur of pulmonic regurgitation in the absence of pulmonary hypertension does not have the high-pitched, blowing quality heard with higher pulmonary pressures.

As the valve disease progresses, the physical features generally become readily apparent with progressive peripheral edema, ascites, and pulsatile hepatomegaly. (See "Etiology, clinical features, and evaluation of tricuspid regurgitation".)

Aggressive metastatic carcinoid disease with active carcinoid syndrome may cause relatively acute severe tricuspid regurgitation.

Initial test findings

Electrocardiogram — An electrocardiogram is not required for the diagnosis of carcinoid heart disease but is commonly included as a component of the cardiac evaluation. Electrocardiographic findings are nonspecific, with many cases lacking any electrocardiographic abnormalities (eg, 32 percent normal in one series [2]). Nonspecific electrocardiographic findings may include ST-T wave abnormalities, sinus tachycardia, and prolonged PR interval [2]. The electrocardiogram in advanced carcinoid heart disease demonstrates low QRS voltage [2]. The cause of the low voltage is not clear but may be related to decreased conduction of the electrical signal to the body surface.

Chest radiograph — A chest radiograph is not required for diagnosis of carcinoid heart disease but is commonly included as a component of evaluation of this condition. The chest radiograph is often normal (46 percent in one series) [2]. A common radiographic finding is cardiomegaly with prominence of the right-sided cardiac chambers. Pulmonary congestion, if present, is mild. Pleural effusions and metastatic pleural plaque formation occur late in the course of the disease.

DIAGNOSIS AND EVALUATION — Diagnosis of carcinoid syndrome, including biochemical testing, is discussed separately. (See "Diagnosis of carcinoid syndrome and tumor localization" and "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Serotonin and 5-hydroxyindoleacetic acid (5-HIAA)'.)

When and how to initially test for carcinoid heart disease

Patients with carcinoid syndrome — We recommend that all patients with carcinoid syndrome undergo 6 to 12 monthly clinical evaluations for symptoms and signs of valve disease or heart failure and have a serum N-terminal brain natriuretic peptide (NT-proBNP) level measured. It is particularly important to screen for carcinoid heart disease in patients with carcinoid syndrome scheduled to undergo liver or abdominal surgery given the risk of hemorrhage related to liver or abdominal surgery in patients with carcinoid syndrome with elevated right atrial pressures [22]. Guidelines for screening and diagnosis of carcinoid heart disease are evolving, with differing recommendations in various major society guidelines [23,24].

After this initial evaluation, echocardiography should be performed in patients with signs and/or symptoms of valvular heart disease or heart failure, in patients with NT-proBNP level greater than 260 ng/mL (or 31 pmol/l) [24], as well as in patients who are scheduled to undergo liver or abdominal intervention. Some experts use a urinary 5-hydroxyindoleacetic acid (5-HIAA) level >300 micromol/24 hours to help identify individuals at risk for carcinoid heart disease. However, we do not use 5-HIAA levels to help identify candidates for echocardiographic screening, since there is evidence that NT-proBNP levels correlate better with carcinoid heart disease severity. (See 'Role of biomarkers' below.)

In addition, a follow-up echocardiogram is recommended in patients who later develop new or worsening signs and symptoms of valve disease or heart failure or elevation of NT-proBNP above 260 ng/mL [25].

Role of biomarkers — As noted above, we suggest annual measurement of serum NT-proBNP levels in all patients with carcinoid syndrome without known carcinoid heart disease to screen for carcinoid heart disease. This recommendation is based upon studies suggesting that NT-proBNP is a sensitive and specific marker for carcinoid heart disease [25,26]. Based on two studies, an NT-proBNP level >260 pg/mL has a sensitivity of 69 to 92 percent and specificity of 80 to 91 percent for detection of carcinoid heart disease [25,26]. NT-proBNP and plasma 5-HIAA levels are both sensitive and specific markers for the presence of carcinoid heart disease, but NT-proBNP correlated moderately with severity of carcinoid heart disease while plasma 5-HIAA correlated only weakly [25].

Biochemical testing for carcinoid syndrome is discussed separately. Urinary levels of 5-HIAA are significantly elevated in patients with carcinoid heart disease, and higher levels are associated with greater risk of progression of carcinoid heart disease [27]. A study identified an association between plasma 5-HIAA and carcinoid heart disease progression and death [28]. (See "Diagnosis of carcinoid syndrome and tumor localization" and "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Serotonin and 5-hydroxyindoleacetic acid (5-HIAA)'.)

Chromogranin A (CgA) is another potential nonhormonal marker for carcinoid heart disease, but its specificity for detection of severe carcinoid heart disease is low (eg, 30 percent [29]); we do not recommend its use to screen for carcinoid heart disease. In a study of 102 patients with neuroendocrine tumors, levels of CgA and NT-proBNP were independently associated with carcinoid heart disease and with overall mortality [29]. Survival at five years was 81 percent in patients with normal CgA levels, 44 percent in those with elevated CgA but normal NT-proBNP levels, and 16 percent in those with elevations in both CgA and NT-proBNP. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Chromogranin A (CgA)'.)

Patients with tricuspid and/or pulmonic valve disease — Acquired valvular heart disease involving the tricuspid and/or pulmonary valves, in the absence of left-sided valve disease, is uncommon and when detected clinically or echocardiographically should prompt consideration of carcinoid heart disease with clinical cardiovascular evaluation (as described above), evaluation for carcinoid syndrome, and echocardiography. (See "Diagnosis of carcinoid syndrome and tumor localization" and "Clinical features of carcinoid syndrome".)

Approach to diagnosis and evaluation — Transthoracic echocardiography (TTE) is the main modality for diagnosis and evaluation of carcinoid heart disease as it enables identification and assessment of valve disease and right heart chamber size and function. If the TTE evaluation is inadequate to assess valve structure and function and right heart size and function, transesophageal echocardiogram (TEE), cardiovascular magnetic resonance (CMR), or computed tomography (CT) (image 1) may be helpful, particularly for assessing the right heart.

Echocardiography — Characteristic echocardiographic features of advanced carcinoid heart disease include thickening and retraction of immobile tricuspid valve leaflets with associated tricuspid regurgitation, which is severe at the time of identification in 90 percent of patients (movie 1A-B) [2]. Less commonly, tricuspid valve stenosis is noted. (See "Echocardiographic evaluation of the tricuspid valve".)

Pulmonary valve involvement usually coexists with tricuspid valve disease. The major finding on echocardiography is immobility of the pulmonary valve cusps. However, the pulmonary valve cusps may be difficult to visualize by echocardiography due to cusp retraction. Pulmonary annular constriction may also occur, resulting in predominant pulmonary outflow tract obstruction.

Left-sided valve involvement (characterized by diffuse thickening of valve leaflets) is much less common and usually less severe than right-sided valve disease due to vasoactive peptide inactivation within the pulmonary circulation [5,30]. Left-sided valve disease may be caused by right-to-left shunting (eg, through a patent foramen ovale), or high levels of circulating vasoactive substances. An agitated saline contrast injection (bubble study) is recommended at the time of initial echocardiogram to assess for a patent foramen ovale. This does not generally need to be repeated in follow-up studies. (See "Patent foramen ovale", section on 'Diagnosis and evaluation'.)

Although bronchopulmonary carcinoid has been postulated as an additional potential cause of left-sided valve involvement [5,30], a series of patients with bronchopulmonary carcinoid identified no cases of left-sided valve involvement attributable solely to this tumor location [31]. In a series of 186 patients with bronchopulmonary carcinoid, only two patients (1 percent) had echocardiographic features of carcinoid heart disease: one patient had clinical features more consistent with diet-drug related valve disease and the other had tricuspid, pulmonary and aortic valve disease, liver metastases, and a patent foramen ovale [31]. Thus, no carcinoid heart disease was identified in patients with bronchopulmonary carcinoid without liver metastases, and no left-sided valve involvement was found in the absence of a patent foramen ovale.

The frequency with which these and other findings occur was illustrated in a report in which comprehensive echocardiography was performed in 74 patients with carcinoid heart disease [2]. The following distribution of lesions was noted:

All patients had tricuspid regurgitation, which was moderate to severe in 90 percent.

Pulmonic stenosis was present in 53 percent, and some degree of pulmonic regurgitation was present in 81 percent.

Left-sided valvular involvement was noted in five patients (7 percent).

A small pericardial effusion was seen in 14 percent; these effusions are rarely hemodynamically significant.

Long-standing tricuspid and pulmonary valve regurgitation result in progressive right ventricular volume overload and right ventricular diastolic pressure elevation [2].

Metastatic carcinoid tumors in the myocardium are uncommonly detected, but larger tumors (eg, 1.0 cm or greater) may be identified by echocardiography in the left ventricle, right ventricle, or interventricular septum and may protrude into the ventricular cavity as sessile masses [6].

Three-dimensional echocardiography may play an incremental role for the preoperative assessment of the pulmonary valve in patients with carcinoid heart disease [32]. The impact of 3D echocardiography on assessment of the tricuspid valve has not been assessed.

Transesophageal echocardiography — TEE is primarily used intraoperatively to image the patient with carcinoid heart disease during valve replacement surgery. In addition, for patients with features of carcinoid heart disease in whom incomplete data are obtained by TTE, TEE is used as a complementary imaging test. TEE may provide incremental assessment of the degree of cardiac valve involvement and the atrial septal anatomy in patients with carcinoid heart disease. Since the right-sided valves are in the far field, assessment by TEE is less reliable than assessment of left-sided valves, but an experienced examiner is usually able to obtain diagnostic images of the right-sided valves.

CMR and CT — CMR or CT are used as complementary imaging tests for patients with features of carcinoid heart disease where incomplete data are obtained by echocardiography. Features of carcinoid valve disease, including valve dysfunction and right ventricular size and function, can be evaluated by CMR or CT (image 1) [33,34]. CT is helpful to assess coronary anatomy prior to planned intervention. These modalities are also helpful for quantification of right ventricular volumes and ejection fraction. There is no specific right heart size and function threshold that is used as an indication for valve intervention, so we do not perform routine serial CT or CMR.

MANAGEMENT

Approach to management — Valve surgery is the only current effective therapy for carcinoid heart disease. Early diagnosis of carcinoid heart disease and regular cardiac follow-up are recommended for timely identification of patients likely to benefit from surgery. Diuretics are generally only temporarily effective in reducing edema, and they may reduce cardiac output. Therapies that reduce circulating serotonin levels (such as somatostatin analogs and antitumor therapy) have not been demonstrated to reverse valve disease.

Diuretic therapy — Diuretics temporarily improve symptoms related to edema but may result in a further reduction in cardiac output, which in turn worsens fatigue.

Telotristat ethyl — Telotristat ethyl is an oral tryptophan hydroxylase inhibitor that has been approved in the United States for use in combination with somatostatin analog for control of diarrhea associated with the carcinoid syndrome. There is no evidence that this agent prevents development of carcinoid heart disease. However, given that carcinoid heart disease is thought to be related to high levels of circulating serotonin, it may be reasonable to consider telotristat therapy in select patients with active metastatic carcinoid disease, high levels of circulating serotonin, and no or early carcinoid heart disease to try to prevent carcinoid heart disease progression. (See "Treatment of the carcinoid syndrome", section on 'Telotristat'.)

Other — The role of peptide receptor radionuclide therapy (PRRT), a radioisotope therapy used to treat neuroendocrine tumors, in preventing or delaying development of carcinoid heart disease has not been determined. This treatment is approved by the US Food and Drug Administration for management of patients with metastatic neuroendocrine tumors. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Somatostatin receptor-expressing tumors'.)

Monitoring — Early diagnosis of carcinoid heart disease and regular clinical follow-up are recommended to enable identification of the most appropriate timing of surgical intervention for each patient. Cardiac follow-up should include clinical assessment, echocardiography, and exercise testing. Additional imaging may be suggested in select patients. (See 'CMR and CT' above.)

Valve intervention — Surgical valve replacement is the current standard of care when intervention is indicated for carcinoid heart disease and should be considered for symptomatic patients with severe native valve involvement whose metastatic carcinoid disease and symptoms of carcinoid syndrome are well controlled [35]. Transcatheter valve replacement to treat carcinoid native pulmonic valve disease has been reported [36,37]. Catheter-based valve interventions have also been reported in the setting of carcinoid prosthetic valve disease [38].

Indications for valve intervention include symptomatic valve dysfunction (with symptoms such as impaired exercise capacity, progressive fatigue, or symptoms and signs of right heart failure such as edema, pleural effusions, or ascites) or progressive decline in right ventricular function with valve dysfunction. Valve surgery should be considered only for patients whose metastatic carcinoid disease and symptoms of carcinoid syndrome are well controlled. For patients with symptomatic tricuspid or pulmonic valve disease, valve replacement is the procedure of choice. Determining the best approach to the individual patient requires a multidisciplinary approach, with the neuroendocrine specialist, cardiologist, and surgical team optimizing carcinoid disease activity and recognizing the best selection and order of advanced treatment options. (See "Management and prognosis of tricuspid regurgitation", section on 'Indications' and "Pulmonic valve stenosis in adults: Management", section on 'Indications for intervention' and "Pulmonic regurgitation", section on 'Intervention'.)

When pulmonary valve disease is present, valve replacement is preferable to valve resection [39]; double (tricuspid and pulmonic) or multiple valve replacement can be undertaken simultaneously [35,40,41]. Balloon valvuloplasty is not recommended for pulmonic stenosis given the presence of concurrent tricuspid and pulmonary valve regurgitation. Transcatheter valve replacement has been reported for carcinoid-related pulmonic valve disease, but experience is lacking for transcatheter tricuspid valve replacement.

Surgical resection of cardiac metastases is not routinely indicated since these do not generally cause complications, but surgical resection can be performed at the time of valve surgery if only one or two such lesions are present [6]. Patients with severe unoperated carcinoid cardiac disease are not candidates for hepatic surgery due to the risk of hepatic hemorrhage, induced by the elevated right-sided cardiac pressures, at the time of surgery. In occasional patients, cardiac surgical intervention is carried out despite minimal cardiac symptoms, in anticipation of hepatic surgical resection of metastatic disease [42]. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)

Choice of surgical valve prosthesis — The choice of surgical valve prosthesis requires meticulous discussion and individual selection in patients with carcinoid heart disease. In a series of 195 patients with carcinoid heart disease referred for valve replacement, no difference in survival or reoperation rate was noted related to prosthesis valve type [35].

With the use of bioprosthetic valves, premature degeneration may be induced by the carcinoid process [43-45]. The risk of valve degeneration may be offset by aggressive carcinoid tumor intervention and somatostatin therapy [40,46,47].

Bioprosthetic valve dysfunction may be related to thrombosis [35,48], carcinoid plaque deposition, or degeneration. If bioprosthetic valve dysfunction is identified, a comprehensive review of the potential causes and treatment options is needed [47]. For patients with bioprosthetic valve dysfunction that might be caused by valve thrombosis, a trial of anticoagulation with warfarin should generally be attempted (unless the potential risks outweigh the potential benefits) prior to considering surgical or percutaneous valve replacement. (See "Bioprosthetic valve thrombosis, thromboembolism, and obstruction: Management".)

Mechanical prostheses are not ideal for patients with carcinoid heart disease since subsequent surgical procedures for tumor control are often required and are complicated by anticoagulation management. In addition, the risk of mechanical tricuspid prosthesis thrombosis is approximately 4 percent per year [49]. (See "Mechanical prosthetic valve thrombosis or obstruction: Clinical manifestations and diagnosis".)

Anesthesia management — Anesthesia can precipitate carcinoid crisis in patients with carcinoid syndrome [50,51]. This syndrome, which is characterized by profound flushing, extreme changes in blood pressure related to vasodilatation, bronchoconstriction, arrhythmias, and confusion or stupor, can be fatal. Prevention and management of carcinoid crisis is discussed separately. (See "Treatment of the carcinoid syndrome", section on 'Carcinoid crisis: prevention and management'.)

Treatment of carcinoid syndrome — Management of carcinoid syndrome with somatostatin-analogs, antitumor therapies, and other therapies is discussed separately. (See "Treatment of the carcinoid syndrome".)

Given evidence of a pathogenic role for serotonin or its metabolites in the development of carcinoid heart disease, it is likely that somatostatin analogs and other therapies that reduce circulating serotonin levels can reduce the risk of developing carcinoid heart disease, and they may inhibit progression of existing disease. However, there is no evidence that such therapy can reverse valvular damage.

Treatment of the tumor itself does not typically result in regression of valvular disease, as illustrated by the following observations [2,15,17]:

In a study of 23 patients, serial echocardiography was used to examine the association of urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion with the appearance or worsening of valvular lesions after treatment with a somatostatin analog, presumably octreotide [15]. Despite major declines in 5-HIAA excretion in most patients, existing valvular lesions did not regress. However, the post-treatment levels of 5-HIAA independently predicted the development or progression of valvular abnormalities, with a threshold of approximately 100 mg/day.

In the report of 71 patients from Mayo Clinic cited above, all patients received treatment with a somatostatin analogue, hepatic dearterialization, and/or chemotherapy [17]. None of these therapies, which had a variable effect on urinary 5-HIAA excretion, were associated with a reduction in the risk of progressive valvular disease; to the contrary, chemotherapy was statistically correlated with a higher rate of progression, possibly because this form of therapy is typically reserved for patients with more aggressive carcinoid tumors.

Rarely, an ovarian carcinoid tumor can cause carcinoid heart disease without liver metastases. Because the ovarian veins bypass the portal circulation and enter the systemic venous circulation directly, cardiac involvement can occur without liver metastases. Tumor resection in such patients can be curative [20]. Even in such cases, however, the cardiac manifestations do not typically regress after curative surgery [52].

PROGNOSIS — Without treatment, the median duration of survival with malignant carcinoid syndrome ranges from 12 to 38 months from the onset of systemic symptoms [53,54]. Carcinoid heart disease with advanced symptoms (New York Heart Association class III or IV) portends a particularly poor prognosis and the median survival is only 11 months; most die within one year because of progressive heart failure [46].

Cardiac surgery, chiefly tricuspid valve replacement and pulmonic valve replacement, has been successful in reducing or relieving the cardiac symptoms of many patients with carcinoid heart disease. However, surgical series from the Mayo Clinic noted an overall surgical mortality of 10 percent, which is higher than expected for other valve disease patients, but lower than in prior series; the operative mortality rate after 2000 was 6 percent [35,46,55]. Cardiac surgery was primarily performed on patients with advanced right heart failure manifested by edema and ascites. Despite the high surgical mortality, the survival among surgically treated patients was better than that in medically treated patients with similar symptoms. By multivariate analysis, the operative mortality was related to era of operation (higher mortality rate before 2000) and need for intravenous loop diuretic therapy [35]. Overall mortality was associated with older age, preoperative cytotoxic chemotherapy, and preoperative tobacco use. Incomplete symptom resolution was noted among surgical survivors; 75 percent of survivors had symptomatic improvement at follow-up [35].

In a series of 200 patients with carcinoid heart disease treated medically and surgically at the Mayo Clinic (partially overlapping with the cohorts in the studies above), cardiac surgery was associated with significant risk reduction (hazard ratio 0.44; 95% CI 0.29-0.61) in a multivariate analysis [56]. An increasing number of mildly symptomatic patients with severe valve dysfunction were offered surgery over time. In an updated series of 240 patients treated with surgical valve replacement for carcinoid heart disease at the Mayo Clinic between 1985 and 2018, lower 30-day mortality was observed during the most recent era (2005 to 2018, 5 percent) compared to earlier experience (1995 to 2004, 7 percent and 1985 to 1994, 29 percent) [47].

Other modalities such as somatostatin analogs for carcinoid syndrome, hepatic artery embolization, or chemoembolization for hepatic metastases improve symptoms but not survival. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac valve disease".)

SUMMARY AND RECOMMENDATIONS

Carcinoid heart disease eventually occurs in up to 50 percent of patients with carcinoid syndrome and may be the initial presentation in up to 20 percent of patients. (See 'Introduction' above.)

Carcinoid heart disease is characterized by plaque-like deposits of fibrous tissue, most frequently affecting the right heart valves (most commonly tricuspid regurgitation and commonly pulmonic stenosis or regurgitation) and endocardium. Left-sided valve disease occurs in less than 10 percent of patients with cardiac involvement and is almost always associated with an atrial right-to-left shunt (as with a patent foramen ovale). (See 'Pathophysiology' above and 'Echocardiography' above.)

Evidence suggests a role for serotonin in the pathogenesis of carcinoid heart disease. (See 'Role of serotonin' above.)

The clinical manifestations of carcinoid heart disease are often subtle early in the course of the disease. Symptoms range from fatigue and dyspnea on exertion to right heart failure with edema, ascites, and eventual cardiac cachexia with progressive disease. (See 'Symptoms' above.)

The major findings of carcinoid heart disease on physical examination include an elevated jugular venous pressure, palpable right ventricular impulse, and murmurs of tricuspid and pulmonary valve regurgitation. (See 'Physical examination' above.)

We recommend that all patients with carcinoid syndrome undergo annual clinical evaluation for symptoms and signs of valve disease or heart failure and have an annual serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level measurement. (See 'When and how to initially test for carcinoid heart disease' above.)

An echocardiogram is recommended for all patients with carcinoid syndrome who have symptoms or signs of carcinoid heart disease, an NT-proBNP level greater than 260 ng/mL, or are undergoing liver or abdominal surgical intervention. (See 'When and how to initially test for carcinoid heart disease' above.)

Carcinoid heart disease with advanced symptoms (New York Heart Association class III or IV) portends a poor prognosis and the median survival without intervention is only 11 months. (See 'Prognosis' above.)

Early diagnosis of carcinoid heart disease and regular cardiac follow-up are recommended for timely identification of patients likely to benefit from valve replacement surgery. Diuretics are generally only temporarily effective in reducing edema, and they may reduce cardiac output. Therapies that reduce circulating serotonin levels (such as somatostatin analogs and antitumor therapy) have not been demonstrated to reverse valve disease. (See 'Management' above.)

Valve replacement (tricuspid valve replacement with addition of pulmonary valve replacement in patients with pulmonary valve disease) is the only effective intervention for carcinoid heart disease. Standard indications for valve replacement apply, including symptomatic valve disease (impaired exercise capacity, progressive fatigue) or progressive decline in ventricular function. Valve replacement should be reserved for patients whose metastatic carcinoid disease and symptoms of carcinoid syndrome are well controlled, emphasizing the importance of a multidisciplinary approach to these patients. Catheter-based interventions have been reported in the setting of native and carcinoid prosthetic valve disease. (See 'Valve intervention' above and "Management and prognosis of tricuspid regurgitation", section on 'Indications' and "Pulmonic valve stenosis in adults: Management", section on 'Indications for intervention' and "Pulmonic regurgitation", section on 'Intervention'.)

In carcinoid patients with cardiac symptoms and controlled systemic disease, cardiac valve replacement surgery alleviates otherwise intractable symptoms and appears to improve survival. (See 'Valve intervention' above.)

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Topic 8135 Version 24.0

References

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