CASE DESCRIPTION

A 39 year old African- American male was referred to our medical center in May 2017 for evaluation of metastatic midgut carcinoid and carcinoidheart disease (CHD).

Prior to presentation at Mount Sinai, the patient reported diaphoresis, appetite loss, worsening diarrhea, and fatigue with difficulty working, and wasadmitted to an outside hospital at the end of April with these symptoms. On physical exam, he was found to have a palpable abdominal mass. CT ofthe abdomen demonstrated liver metastases and a mesenteric mass. Liver biopsy demonstrated neuroendocrine tumor with Ki67<5%. He was foundto have an elevated 24h urine 5- HIAA. The patient was diagnosed with carcinoid syndrome and carcinoid heart disease and started on diuretics toassist with lower extremity edema. Somatostatin analogues were not started as the patient was scheduled to undergo somatostatin receptorscintigraphy.

At initial presentation to Mount Sinai, he noted increasing abdominal distension, flushing with diaphoresis, and wheezing in his sleep. He reportedincreased dyspnea on exertion with limited ability to ambulate, as well as increased diarrhea with 5 watery bowel movements daily and 15- 20 poundweight loss. He also noted increased edema in his legs. His blood pressure was 90/59 with a pulse of 120. On physical examination, he was noted tohave a harsh systolic IV/VI murmur, massive hepatomegaly with palpable masses, distended abdomen, and 4+ pitting edema extending to the back.

Given his right sided heart failure, he was referred for immediate cardiology consultation. Echocardiogram revealed carcinoid involvement oftricuspid valve with wide open tricuspid regurgitation, inability to see the pulmonic valve but with high velocities noted through PV, severe pulmonaryhypertension, mild pericardial effusion, without tamponade. The patient was admitted to our hospital the same day.

In the hospital, the patient was noted to have a leukocytosis with WBC 20.1, acute kidney injury with Na 134, K 5.8, and Cr 1.54. The patient wasgently diuresed with intravenous furosemide and started on subcutaneous octreotide 500 μg three times daily. The patient experienced substantialimprovement in diarrhea, flushing and diaphoresis, as well as improvement in kidney function. Patient was also able to ambulate and had improvedenergy and oral intake. NET markers were drawn, including serotonin 1612 and Chromogranin A 224.

Multiple cardiac tests were performed. Transesophageal echocardiography reported severe right ventricular dilation, moderately decreased rightventricular function, and tricuspid leaflets fibrosed and frozen in open position with severe tricuspid regurgitation, consistent with carcinoid heartdisease (FIGURE 1). Mean tricuspid valve gradient was 8 mmHg. Moderate valvular pulmonic stenosis with pulmonic valve leaflets thickened andfibrotic with restricted motion, and severe PR were noted. Moderate pulmonary hypertension and moderate pericardial effusion were also reported.Right heart catheterization revealed normal right pressures, decreased cardiac output, severe TR and moderate PS. Cardiac MRI demonstratedsevere TR, moderate PR, and moderate PS.

Authors Michelle Kang Kim, MD, PhD, Newsha Ghodsi, MD, David Adams, MD, Eric Wilck, MD, Myron Schwartz MD

E- mail Michelle.kim@mssm.edu

Institute Department of Gastroenterology, Mount Sinai School of Medicine

City/Nationality New York, New York, USA

Category Review

Case

Upper GI Lower GI Pancreatobiliary tract Others

Title of Case

Metastatic midgut carcinoid presenting with right sided heart failure and carcinoidheart disease

MRI of the abdomen with Eovist revealed enlarged liver with a pseudocirrhotic appearance (FIGURE 1). There were innumerable and diffuse hepaticmetastases. A mid- abdominal mesenteric mass was also present. There was also moderate volume abdominopelvic ascites.

The patient underwent tricuspid valve replacement, pulmonic valve replacement, and right ventricular outflow tract reconstruction. Perioperatively, hereceived octreotide 200 μg/hour in an intravenous drip. He was more aggressively diuresed with significant improvement in lower extremity edema.After a month- long hospitalization, the patient was discharged on subcutaneous octreotide with plans to receive long acting octreotide as anoutpatient. He was also started on telotristat, a tryptophan hydroxylase inhibitor.

In mid- July 2017, the patient was seen in follow- up at the cardiology office. While he reported some tightness around the incision, his exercisetolerance and appetite were much improved. The patient reported improved oral intake and stable weight. He has recently received his first dose oflong- acting octreotide.

The patient will continue to undergo cardiac rehabilitation and undergo gallium PET CT. His case is being reviewed with our NET tumor board. He isunder consideration for surveillance with somatostatin analogues alone, while simultaneously being evaluated for liver transplantation.

DISCUSSION

Carcinoid heart disease is a relatively rare manifestation of metastatic carcinoid and carcinoid syndrome. It is most frequently a result of midgutcarcinoid, but may occur with primary tumors of the lung, colon, and ovary. Although CHD has been described in more than 50% of patients withcarcinoid syndrome, the incidence may actually be lower.1

While the precise pathophysiology of CHD remains unknown, it is likely due to the many substances released by the tumor, including serotonin,prostaglandins, bradykinin, and others. These mediators lead to the deposition of plaques on the leaflets of the valves (predominantly right- sided).13

Tricuspid regurgitation occurs most frequently across the tricuspid valves, while pulmonic disease may present with valvular stenosis andregurgitation. Left- sided valves are rarely affected due to pulmonary deactivation of the hormonal mediators.1

A high index of suspicion is needed to establish an early diagnosis. Echocardiography is the diagnostic modality of choice. Biomarkers such as N-terminal brain natriuretic peptide may be helpful to screen patients for carcinoid heart disease.4,5 A multidisciplinary team of NET experts, cardiology,and cardiothoracic surgeons are needed to develop the best treatment plan. For those patients who are suitable for surgery, valve replacement is thetreatment of choice. Patients often experience substantial symptomatic improvement. Median survival after valve replacement has been reported tobe between 6 and 11 years .6

Medical treatment should also be considered. Patients with carcinoid syndrome benefit from somatostatin analogues (SSA).6 For this reason,patients with carcinoid heart disease are frequently already on SSAs. The new agent telotristat, a tryptophan hydroxylase inhibitor, has recently beenshown to reduce diarrhea in patients with carcinoid syndrome. As a significant proportion of patients treated with this agent have been found to havelowered levels of serotonin metabolites, it may be a promising adjunctive agent in the management of carcinoid heart disease.

FIGURES

FIGURE 1 MRI Imaging of the abdomen.

A. T1 post contrast axial through the mid abdomen shows perihepatic ascites, pseudocirrhotic liver, and mesenteric mass. B. T1 post contrastcoronal images shows hepatomegaly, liver metastases and mesenteric mass. C, D. Diffusion images show multiple hepatic metastases andmesenteric mass with diffusion restriction. E. Delayed T1 post contrast hepato- biliary phase shows numerous large liver masses.

REFERENCES

01 Pellikka PA, Tajik AJ, Khandheria BK, et al.   Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients.Circulation. 1993;87(4):1188.

02 Bernheim AM, Connolly HM, Hobday TJ, et al. Carcinoid heart disease. Prog Cardiovasc Dis 2007;49(6):439- 451.

03 Patel C, Mathur M, Escarcega RO, et al. Carcinoid heart disease: current understanding and future directions. Am Heart J2014;167(6):789- 795.

04 Dobson R, Burgess MI, Banks M, et al. The association of a panel of biomarkers with the presence and severity of carcinoid heartdisease: a cross- sectional study. PLoS One. 2013;8(9):e73679.

05 Bhattacharyya S, Toumpanakis C, Caplin ME, Davar J. Usefulness of N- terminal pro- brain natriuretic peptide as a biomarker of thepresence of carcinoid heart disease. Am J Cardiol. 2008;102(7):938- 942

06 MØller JE, Pellikka PA, Bernheim AM, Schaff HV, Rubin J, Connolly HM: Prognosis of carcinoid heart disease: analysis of 200 cases overtwo decades. Circulation 2005;112:3320- 3327.

07Rinke A, Muller HH, Schade- Brittinger C, et al. Placebo- controlled, double- blind, prospective, randomized study on the effect ofoctreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMIDStudy Group. J Clin Oncol 2009;27(28):4656- 4663.