Carcinoid syndrome

A 37-year-old woman with a 10-year history of metastatic carcinoid presented to her oncologist with increased dyspnea. Further evaluation revealed hypoxemia and intrapulmonary vasodilatation. We describe a case of hepatopulmonary-like physiology associated with metastatic carcinoid in a patient with intact liver function. To our knowledge, this is the first documented case of intrapulmonary shunting and hepatopulmonary-like physiology associated with metastatic carcinoid.

(CHEST 1999; 115:1203-1207)

Key words: carcinoid syndrome; hepatopulmonary syndrome; hypoxemia

Abbreviations: DLCO = diffusing capacity of the lung for carbon monoxide; HPS = hepatopulmonary syndrome

The carcinoid syndrome is most often seen in patients with GI carcinoid tumors metastatic to the liver, and these tumors produce a variety of vasoactive substances. The release of these substances often results in flushing and diarrhea, characteristic of the carcinoid syndrome. High concentrations of mediators from the hepatic carcinoid traverse the tricuspid and pulmonic valves commonly causing right-sided valvular lesions. Subsequent metabolism of these mediators in the lung tends to protect the left-sided heart valves from carcinoid-related disease.

The hepatopulmonary syndrome (HPS) is defined as liver dysfunction, hypoxemia, and intrapulmonary vascular dilatations. The mechanism is believed to be an imbalance of vasodilators and vasoconstrictors resulting from metabolic liver insufficiency. Reduced diffusing capacity of the lung for carbon monoxide (DLCO) and orthodeoxia are also typical features of HPS.

We describe a case of severe intrapulmonary shunting with hepatopulmonary-like physiology associated with metastatic carcinoid. Despite the hepatic tumor involvement, this patient had otherwise normal liver function.

CASE REPORT

A 37-year-old woman with known metastatic carcinoid tumor (Fig 1) was admitted to the hospital with a complaint of increasing dyspnea. Her carcinoid was diagnosed 10 years earlier. At that time, she had known liver metastasis and symptoms of the carcinoid syndrome manifested by profound flushing, diarrhea, and bronchospasm. The primary site of her tumor has never been identified, but was presumed to have originated in the GI tract. Her carcinoid was treated with somatostatin for 4 years prior to hospital admission with good control of her symptoms. Three years prior to hospital admission, she was diagnosed as having carcinoid heart disease manifested by tricuspid stenosis and tricuspid insufficiency.

[Figure 1 ILLUSTRATION OMITTED]

Her symptom of dyspnea gradually increased over the past 5 years. At the time of hospital admission, she experienced dyspnea on exertion and intermittently at rest. She experienced increased dyspnea with rapid changes in position, both assuming a supine and upright posture. She quit smoking cigarettes 5 years prior to hospital admission but had a 20-pack-year history.

Initial physical examination showed a BP of 123/73 mm Hg, pulse rate of 98 beats/min, respirations of 19 breaths/min, temperature of 36.8 [degrees] C, and pulse oximetry on room air of 80%. Her physical examination was notable for large facial and upper chest telangiectasias with violacious nonblanching discoloration. A 2/6 systolic and 1/6 diastolic cardiac murmur was auscultated. She had no evidence of right heart failure or ascites. Results of hepatitis A, B, and C serologic tests were all normal. Initial liver-associated enzymes revealed an alkaline phosphatase level of 75 U/L, aspartate transaminase of 12 U/L, alanine transaminase of 9 U/L, lactate dehydrogenase of 141 U/L, and [Gamma]-glutamyl transferase of 17 U/L--all within normal limits. Hepatic functional capacity was normal, as manifested by an albumin of 3.5 g/dL, a total bilirubin of 0.3 mg/dL, a prothrombin time of 13.1 s, and a partial thromboplastin time of 25.2 s. Arterial blood gas on room air revealed a pH of 7.44, [Pco.sub.2] of 30 mm Hg, and [Po.sub.2] of 46 mm Hg. Arterial blood gas on 100% fraction of inspired oxygen showed a pH of 7.57, [Pco.sub.2] of 19 mm Hg, and [Pco.sub.2] of 71 mm Hg with an estimated shunt fraction of 31%. Pulmonary function testing showed FVC of 3.11 L (92% predicted), [FEV.sub.1] of 1.99 L (75% predicted), [FEV.sub.1]/FVC of 64%, and DLCO of 62% predicted. Echocardiogram revealed tricuspid stenosis with severe tricuspid regurgitation and mild aortic insufficiency. Bubble contrast echocardiogram showed delayed microbubble opacification of the left atrium consistent with intrapulmonary vasodilatation (Fig 2). Pulmonary angiogram revealed dilated pulmonary capillary beds (Fig 3).

[Figures 2 and 3 ILLUSTRATION OMITTED]

DISCUSSION

This patient, with long-standing carcinoid syndrome, presented with profound hypoxemia, positional dyspnea, and severe intrapulmonary shunting. Her evaluation revealed pulmonary vascular abnormalities remarkably similar to that of the hepatopulmonary syndrome. Despite the similarity with HPS, she had no evidence of synthetic or metabolic liver dysfunction and no ascites or evidence of portal hypertension. We believe the metastatic carcinoid caused her gas exchange abnormality by releasing a variety of humoral mediators into her central venous system. These mediators clearly exerted a vasodilatary effect as manifested by her symptom of profound flushing.

The HPS is defined as liver dysfunction, hypoxemia, and intrapulmonary vascular dilatations. Reduced DLCO and orthodeoxia are also common findings in HPS.[1] All reported cases of HPS are associated with gross evidence of hepatic dysfunction.[1-4] The pathophysiology of HPS is believed to result from metabolic liver insufficiency causing an imbalance of vasodilators and vasoconstrictors. This imbalance is thought to cause dilation of the pulmonary vasculature, resulting in ventilation/perfusion mismatch and shunting.[5] The pulmonary vascular abnormalities can be imaged by contrast-enhanced two-dimensional transthoracic echocardiography[4,6] or by pulmonary angiograms that show diffuse, small "spider-like" branches.[5] This patient's contrast-enhanced echocardiogram, pulmonary angiogram, and pulmonary hemodynamic profile are all consistent with those seen in the HPS.

Careinoid is found anywhere in the body, but [is greater than] 95% of these tumors arise in the appendix, rectum, or small bowel. The carcinoid syndrome is a common manifestation of GI carcinoid that has metastasized to the liver and is less frequently seen when the carcinoid tumor arises from other organs.[7] The carcinoid syndrome includes flushing, diarrhea, valvular heart disease, bronchospasm, telangiectasias, and paroxysmal hypotension.[1] The median survival with malignant carcinoid syndrome is 38 months from the time of the first flush. This decreases to 14 months if the 5-hydroxyindoleacetic acid is [is greater than] 150 mg/24 h, and to only 11 months with clinical evidence of carcinoid heart disease.[7] This woman has survived 10 years with known carcinoid syndrome and 3 years with known carcinoid heart disease. The fact that she outlived the typical life expectancy given the extent and duration of her disease may contribute to her unusual pulmonary pathophysiology.

Two case reports of carcinoid syndrome with hypoxemia were described in the literature.[8,9] One had indications of liver dysfunction, and no angiographic proof of intrapulmonary dilation. The other patient showed liver dysfunction and pulmonary hypertension. In both of these patients, documented liver dysfunction potentially produced mediators contributing to their hypoxemia. Our case describes a patient without any evidence to impugn metabolic liver dysfunction in the etiology of her hypoxemia. In addition, all other causes of hypoxemia were excluded. The only remaining possibility is that the carcinoid-related mediators resulted in pulmonary vascular dilation. This certainly seems plausible given the marked systemic vascular dilation caused by these vasoactive mediators.

In summary, we postulate that the excess vasoactive mediators produced by the carcinoid tumor resulted in pulmonary vascular dilation. Once the pulmonary vasculature is dilated, the subsequent hypoxemia, reduced DLCO, and orthodeoxia occur by pathophysiology similar to HPS. Unlike the proposed mechanism of HPS, our patient did not demonstrate clinical or biochemical liver insufficiency. The similarity of this patient's physiology to HPS lends credence to the hypothesis of an imbalance of vasoactive substances in the pathogenesis of HPS. To our knowledge, this is the first case that dearly documents HPS pathophysiology in a patient with metastatic carcinoid.

REFERENCES

[1] Edell ES, Cortese DA, Krowka MJ, et al. Severe hypoxemia and liver disease. Am Bev Bespir Dis 1990; 140:1631-1635

[2] Krowka, MJ, Cortese DA. Hepatopulmonary syndrome: current concepts in diagnostic and therapeutic considerations. Chest 1994; 105:1528-1537

[3] Hourani JM, Bellamy PE, Tashkin DP, et al. Pulmonary dysfunction in advanced liver disease: frequent occurrence of an abnormal diffusing capacity. Am J Med 1991; 90:693-700

[4] Agusti A, Boca J, Rodriquez-Boisin B, et al. Mechanism of gas exchange impairment in patients with liver cirrhosis. Clin Chest Med 1996; 17:49-67

[5] Castro M, Krowka MJ. Hepatopulmonary syndrome: a pulmonary vascular complication of liver disease. Clin Chest Med 1996; 17:33-44

[6] Hind CBK, Wong CM. Detection of pulmonary arteriovenous fistulae in patients with cirrhosis by contrast two-dimensional echocardiography. Gut 1981; 22:1042-1045

[7] Kvols LK. The carcinoid syndrome, a treatable malignant disease. Oncology 1988; 2:33-41

[8] Robert R, Matuchansky C, Picker F, et al. Severe hypoxemia in a case of midgut carcinoid tumor. Intensive Care Med 1989; 15:536-537

[9] Hussain A, Young ET, Greaves JD, et al. Intrapulmonary shunting causing hypoxaemia in a case of carcinoid syndrome. Clin Endocrinol 1994; 41:535-537

(*) From the Dwight David Eisenhower Army Medical Center, Fort Gordon, GA.

Manuscript received March 10, 1998; revision accepted October 1, 1998.

Correspondence to: Daniel F. Lee, DO, Pulmonary Fellow, Walter Reed Army Medical Center, Washington, DC 20307

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